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CAMEROON ACADEMY OF SCIENCES

ACADEMIE DES SCIENCES DU CAMEROUN

CAMEROON ACADEMY OF SCIENCES

RECENT ADVANCES IN ONCHOCERCIASIS RESEARCH AND IMPLICATIONS FOR CONTROL

PRODUCED BY AN EXPERT COMMITTEE OF THE CAMEROON ACADEMY OF SCIENCES

Committee Members (Authors) Vincent N. TANYA, DVM, M.Sc., PhD, FCAS, FTWAS (Chair); Chief Research Officer, Institute of Agricultural Research for Development; Technical Adviser No1, Ministry of Scientific Research and Innovation, Yaoundé, Cameroon Samuel WANJI, Dr Habl; Associate Professor of Molecular Parasitology and Entomology, Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Cameroon Joseph KAMGNO, MD, MPH, PhD, Senior Lecturer, Department of Public Health, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Cameroon and Director of the Centre for Research on Filariasis and other Tropical Diseases, Yaoundé, Cameroon Daniel M. ACHUKWI, DVM, PhD, Chief Research Officer, Director of Scientific Research, Institute of Agricultural Research for Development, Yaoundé, Cameroon Peter Ayuk Ivo ENYONG, DEA, Doct. es Sc, Senior Research Fellow, Research Foundation in Tropical Diseases and Environment, Buea, Cameroon Study Staff of the CameroonAcademy of Sciences David Akuro Mbah, PhD, Executive Secretary

Vincent N. Tanya, PhD, Programme Officer

Thaddeus A. Ego, Administrative Assistant

December 2012

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Recent advances in onchocerciasis research and implications for control

Published by The Cameroon Academy of Sciences P.O. Box 1457 Yaoundé, Cameroon

Tel: (237)2223 9741; Fax: (237) 2222 9741 E-mail: [email protected]

Website: www.casciences.com

NOTICE

The project that is the subject of this study was supported by grant agreement n°IOM-5855-05-002 between the United States National Academy of Sciences and the Cameroon Academy of Sciences. International Standard Book Number 9956-26-38-x

Additional copies of this publication are available from the Cameroon Academy of Sciences, P.O. Box 1457 Yaoundé, Cameroon or http:www.casciences.com Cover pictures provided by Drs Achukwi and Kamgno Citation: CAS (2012). Recent Advances in Onchocerciasis Research and Implications for Control. Cameroon Academy of Sciences, Yaoundé, Cameroon.

All rights reserved © The Cameroon Academy of Sciences

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Table of Contents

Table of Contents ......................................................................................................................................................... iii

List of Figures ................................................................................................................................................................ v

Acronyms...................................................................................................................................................................... vi

Cameroon Academy of Sciences ................................................................................................................................ viii

Acknowledgements ..................................................................................................................................................... ix

Preface ........................................................................................................................................................................... x

Executive Summary ...................................................................................................................................................... xi

Resumé ....................................................................................................................................................................... xiv

Background information on onchocerciasis ................................................................................................................. 1

Introduction .............................................................................................................................................................. 1

Global magnitude...................................................................................................................................................... 1

Onchocerciasis in Cameroon ..................................................................................................................................... 2

Bio‐ecology of S. damnosum .................................................................................................................................... 3

Life cycle of Onchocerca volvulus ............................................................................................................................. 4

Pathology of onchocerciasis ..................................................................................................................................... 6

Socio‐economic implications of onchocerciasis ........................................................................................................ 8

Treatment and control of onchocerciasis................................................................................................................... 11

Introduction ................................................................................................................................................................ 11

Surgical treatment .................................................................................................................................................. 11

Vector control ......................................................................................................................................................... 11

Historical Background ........................................................................................................................................ 11

The phases of vector control in Africa ................................................................................................................ 12

Problems of vector control ................................................................................................................................. 15

Drug treatment ....................................................................................................................................................... 16

Ivermectin in the control of onchocerciasis ............................................................................................................ 16

Ivermectin family and chemical structure .............................................................................................................. 16

Effect of ivermectin on O. volvulus ......................................................................................................................... 17

Clinical trials with Ivermectin .................................................................................................................................. 17

African Programme for Onchocerciasis Control ..................................................................................................... 18

Effect of the drug on the transmission of onchocerciasis ....................................................................................... 19

Problems associated with the use of ivermectin for onchocerciasis control ......................................................... 20

APOC achievements ................................................................................................................................................ 24

APOC challenges ..................................................................................................................................................... 24

Onchocerciasis control strategies in Cameroon ......................................................................................................... 25

Introduction ............................................................................................................................................................ 25

Identification of priority populations to be treated in Cameroon .......................................................................... 25

Evolution of onchocerciasis control strategies in Cameroon .................................................................................. 26

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Early large scale distributions ............................................................................................................................ 26

Community‐based strategies ............................................................................................................................. 26

The advent of the African Programme for Onchocerciasis Control in Cameroon .................................................. 26

Difficulties related to onchocerciasis control in Cameroon .................................................................................... 27

Chemotherapy and immunology of onchocerciasis: insights from the bovine model ............................................. 29

Introduction ............................................................................................................................................................ 29

O. ochengi/cattle model for onchocerciasis research ............................................................................................ 29

O. ochengi and chemotherapeutic studies ............................................................................................................. 29

Chemotherapeutic studies with anthelmintics .................................................................................................. 29

Antibiotic therapy for onchocerciasis ................................................................................................................ 30

O. ochengi and immunological studies ................................................................................................................... 32

Putative immunity .............................................................................................................................................. 32

Zooprophylaxis ................................................................................................................................................... 33

Vaccination trials ................................................................................................................................................ 33

Antibiotic therapy for the control of onchocerciasis: current status and perspectives ........................................... 35

Introduction ............................................................................................................................................................ 35

A new opportunity for the treatment of onchocerciasis: the endosymbiont Wolbachia ....................................... 35

Anti‐Wolbachia treatment: current status ............................................................................................................. 36

Lessons from animal models .............................................................................................................................. 36

Anti‐Wolbachia therapy: from animal models to humans ................................................................................. 26

Anti‐Wolbachia as alternative treatment for onchocerciasis in areas of co‐endemicity with loiasis ................ 37

Scaling up the anti‐Wolbachia treatment: the community‐directed delivery approach ................................... 37

The way forward for the elimination of onchocerciasis ............................................................................................ 41

Vector Control ......................................................................................................................................................... 41

The improvement of Community Directed Treatment with Ivermectin ................................................................. 42

Anti‐Wolbachia treatment ...................................................................................................................................... 44

Vaccination ............................................................................................................................................................. 46

Sustainability and ownership of control programmes ............................................................................................ 46

References ................................................................................................................................................................... 49

Appendices.................................................................................................................................................................69

Statement of task .................................................................................................................................................... 70

Biographical sketch of committee members .......................................................................................................... 72

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List of Figures

Figure 1. Distribution of onchocerciasis showing current status of global onchocerciasis control............................... 2

Figure 2. Rapid epidemiological mapping of onchocerciasis in Cameroon .................................................................. 3

Figure 3. Transmission cycle of Onchocerca volvulus, O.ochengi and O. ramachandrini .............................................. 5

Figure 4. Life cycle of O.volvulus ................................................................................................................................... 5

Figure 5. Chemical structure of ivermectin ................................................................................................................. 17

Figure 6. Sub‐conjunctival haemorrhage in a post ivermectin SAE case ..................................................................... 23

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Acronyms

ABRs Annual biting rates

APOC African Programme for Onchocerciais Control

ATPs Annual transmission potentials

CAS Cameroon Academy of Sciences

CDDs Community‐directed distributors

CDTI Community‐Directed Treatment with Ivermectin

CHC Chlorinated hydrocarbon

CRFilMT

DALYs

Centre for Research on Filariasis and other Tropical Diseases

Disability‐Adjusted Life‐Years

DDT Dichlorodiphenyltrichloroethane

DEC Diethylcarbamazine

EAC Expert Advisory Committee

FAO Food and Agriculture Organisation of the United Nations

GABA ϒ‐aminobutyric acid

GTZ Gesellshaft fur Technische Zusammenarbeit (German Technical Cooperation)

HKI Helen Keller International

IAMP Inter Academy Medical Panel

IAP Inter Academy Panel on International Issues

IEF International Eye Foundation

IMPM Institut de Recherches Médicales et d’Etudes de Plantes Médicinales

IRAD Institute de Recherche Agricole pour le Développement

IRD Institut de Recherche pour le Développement

IVM Ivermectin

JPC Joint Programme Committee

LCIF Lions Club International Foundation

MDD Mass Drug Distribution

MDP Mectizan Donation Programme

MEC Mectizan®Expert Committee

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NASAC Network of African Science Academies

NGDOs Non Governmental Development Organizations

NGOs Non Governmental Organizations

NOCP National Onchocerciasis Control Programme

NOTF National Onchocerciasis Task Force

OCCGE

OCP

Organisation de Coordination et de Coopération pour la Lutte contre les Grandes Endémies

Onchocerciasis Control Programme

ORSTOM Office de la Recherche Scientifique et Technique Outre‐Mer

PLERI Probable L. loa encephalopathies related to the treatment with Ivermectin

RAPLOA Rapid Epidemiological Assessment of Loiasis

RBF River Blindness Foundation

REA Rapid Epidemiological Assessment of Onchocerciasis

REMO Rapid Epidemiological Mapping of Onchocerciasis

ROD Reactive onchodermatitis

SAEs Severe Adverse Events

SSI Sight Savers International

TCC Technical Consultative Committee

TDR Special Programme for Research and Training in Tropical Diseases (TDR) of the WHO

TWAS Third World Academy of Sciences (the Academy of Sciences for the Developing World)

UNDP United Nations Development Programme

USAID United States Agency for International Development

USNAS United States National Academy of Sciences

WHO World Health Organisation

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Cameroon Academy of Sciences

The Cameroon Academy of Sciences (CAS) was formally recognized by declaration N° Reg. 00701/RDA/J06/BAPP of 29 May 1991 by the Cameroon Government in accordance with law N° 90/053 of 19 December 1990, regulating freedom of association. It is a non‐profit society of distinguished scholars engaged in promoting excellence and relevance in science and technology and providing advice to the government of Cameroon and other partners.

The vision of the Cameroon Academy of Sciences is to be the prime mover of science and technology, making scientific knowledge available to decision and policy makers with a view to influence investment priorities in science and technology, and promoting the use of science and innovation in the economic, social and cultural development of Cameroon. Consequently, the Academy produces robust forum and committee advisory documents as well as reports on priority problems that are delivered to policy and decision makers and the public. The independence, highly qualified membership, multidisciplinary composition and rigorous procedures for objective and unbiased analysis enable the Academy to effectively deliver credible advice.

In carrying out its work, the Academy collaborates with the various ministries of the Government of Cameroon, the United States National Academy of Sciences (USNAS), the Academy of Sciences for the Developing World (TWAS), Royal Society (UK), the Network of African Science Academies (NASAC), Inter Academy Panel on International Issues (IAP), Inter Academy Medical Panel (IAMP) and other international and national organizations. EXECUTIVE COMMITTEE OF CAS

President Prof. Samuel Domngang 1st Vice President Prof. Sammy Beban Chumbow 2nd Vice President Prof. Peter M. Ndumbe Executive Secretary Dr. David Akuro Mbah Assistant Executive Secretary Prof. Manguelle‐Dicom E. Treasurer/Programme Officer Dr. Vincent N. Tanya

DEANS OF CAS COLLEGES

College of Biological Sciences Prof. Daniel N. Lantum College of Mathematics and Physical Sciences Prof. Samuel Domngang College of Social Sciences Prof. Sammy Beban Chumbow

JOURNAL OF THE CAMEROON ACADEMY OF SCIENCES (JCAS)

Editor‐in‐Chief Prof. Vincent P. K. Titanji KEY ADMINISTRATIVE STAFF OF CAS

David Akuro Mbah, PhD, Executive Secretary E. Manguelle‐Dicom, PhD, Assistant Executive Secretary Vincent N. Tanya, PhD, Treasurer/Programme Officer Thaddeus A. Ego, Administrative Assistant

CONTACT INFORMATION

Cameroon Academy of Sciences P.O. BOX 1457 Yaoundé, Cameroon Telephone: +237 2223 9741 Fax: +237 2223 9741 Email: [email protected] Website: www.casciences.com

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Acknowledgements

The Cameroon Academy of Sciences (CAS) Expert Committee is appreciative of the contributions and efforts of all

those who helped in the realisation of this project. The Committee thanks the Members of the CAS Forum on

Public Health for choosing this subject and for their guidance and support through out the period of the study.

The Committee gratefully acknowledges the United States National Academy of Sciences (USNAS) for facilitating

financial support from Bill and Melinda Gates Foundation and for providing technical support for this work within

the framework of its African Science Academy Development Initiative (ASADI). Gratitude is conveyed to Dr. Patrick

Kelley, Ms Patricia Cuff, Mr. Jim Banihashemi and Ms Angela Mensah for making possible the collaboration

between the Cameroon Academy of Sciences and the USNAS. Dr. Kelly and Ms Cuff also provided guidance on

carrying out consensus studies.

We would like to thank Drs Marcelline Ntep and Benjamin Biholong of the National Onchocerciasis Control

Programme, Yaounde, Cameroon for providing information, input and assistance that facilitated the writing of this

report.

The review process for the study was overseen by Dr. David A. Mbah, Executive Secretary of the Cameroon

Academy of Sciences.

This report was reviewed independently by experts who were selected for their technical competence. They

provided candid and critical comments that greatly improved the quality of this report. The Committee would like

to thank the following for the review :

Bridget B. Kelly, MD, PhD, Senior Programme Officer, Board on Global Health, Institute of Medicine of the

National Academies, Washington, DC, USA;

Ben L. Makepeace, PhD, Senior Research Fellow, Department of Infection Biology, Institute of Infection

and Global health, University of Liverpool, Liverpool, England, UK;

Vincent P.K. Titanji, PhD, Professor of Biochemistry, Former Vice‐Chancellor of the University of Buea,

Cameroon;

Roger Moyo‐Somo, MD, PhD, Professor of Parasitology, Faculty of Medicine and Biomedical Sciences,

University of Yaoundé I, Cameroon.

Responsibility for the final content and quality of this report is totally that of the Expert Committee and CAS.

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Preface

As part of its present strategic plan, the Cameroon Academy of Sciences (CAS) organises workshops and seminars

and carries out research and consensus studies in order to provide information for evidence‐based actions by

various stakeholders. It has so far organised several seminars and workshops either alone or in collaboration with

other partners.

In its meeting of 21 April 2011, the Academy’s Forum on Public Health decided to carry out its first consensus

study. From among several themes that were short‐listed during the meeting, it was decided that a consensus

study should be carried out on recent advances in onchocerciasis research and implications for control. The

members of the Forum felt that Cameroonian scientists, their partners (British, German, Ghanaian and French)

and others had done significant scientific research in recent years on onchocerciasis which could even be

described as ground breaking. They also believed that the studies had important implications for the control of the

disease in Cameroon. Unfortunately, this crucial scientific information is buried in different scientific journals and

is not readily available to stakeholders involved in treatment and control efforts in developing countries in general

and Cameroon in particular. Consequently, the Forum members asked the Academy to carry out a consensus

study. Accordingly, CAS in recognition of its advocacy role in giving visibility to Cameroonian research efforts and

that of its partners and other scientists, convened an expert panel to bring together the data on recent research

on onchocerciasis, analyse it and present sound advice and reasoning for reorientation of the current

onchocerciasis control strategies in Africa in general and in Cameroon in particular.

In view of all of the above, it is hoped that the report herein presented will provoke dialogue among stakeholders

and draw public attention.

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Executive Summary

The Cameroon Academy of Sciences convened an expert panel to bring together the data on recent research on

onchocerciasis, analyse it and present sound advice and reasoning for reorientation of the current onchocerciasis

control and research strategies in Cameroon in particular and the world in general.

Onchocerciasis is a parasitic disease caused by Onchocerca volvulus and transmitted via the bites of a black fly of

the genus Simulium. It is a debilitating dermal filariasis which is endemic mainly in tropical Africa and to a lesser

extent in Central and South America and the Arabian Peninsula particularly in Yemen. The clinical and socio‐

economic effects are most severe in sub‐Saharan Africa where it causes blindness and severe skin diseases.

Presently, onchocerciasis is recognised as the world’s second leading infectious cause of blindness. Figures on its

global magnitude cited in the literature are quite varied. The World Health Organization estimates that about 37

million people are currently infected with the parasite with about 99% of them living in sub‐Saharan Africa. Almost

1.5 million are visually impaired and about 500,000 are blind. A total of 90 million people are at risk of becoming

infected with the parasite.

Over the years, attempts to control the disease have been based on vector control and drugs. Despite more than

forty years of control in Africa, the disease is still a public health concern in many African countries, where the

prevalence in some foci is still very high. It is therefore important to seek for complementary strategies so that the

current control strategies can be improved.

Vector control

Early efforts to control onchocerciasis were based on treatment of water courses with insecticides to kill the larvae

of the Simulium vectors. This approach, used by the Onchocerciasis Control Programme (OCP) in West Africa

successfully reduced the burden of disease in the areas covered by the programme. This strategy can still be used

in combination with other approaches today. The two recent cases of vector elimination in Itwara (Uganda) and

Bioko Island (Equatorial Guinea) applied the OCP methodology with the help of the African Programme for

Onchocerciasis Control (APOC).

In view of the on‐going construction of new hydroelectric dams in Cameroon, the authorities of the projects should

already build into their operational activities, some black fly vector control components so as to be prepared to

handle any unforeseen S. damnosum population explosion after the construction. The main rivers of Cameroon

should also be the target of focal black fly control activities as they all contribute to the breeding of S. damnosum.

Furthermore, operational research is needed to improve monitoring and establish thresholds that determine when

and where vector control is needed. It is also necessary to evaluate the adverse environmental effects of the

insecticides used in any control operations.

Community‐Directed Treatment with Ivermectin

Ivermectin (Mectizan) donated by Merck & Co was introduced in 1987 for mass treatment of onchocerciasis.

APOC launched in 1996 the Community‐Directed Treatment with Ivermectin (CDTI) strategy. Ivermectin is

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microfilaricidal and its use successfully reduced the morbidity of onchocerciasis in various communities. It had

been hoped that CDTI would eliminate the disease by breaking transmission but this has not happened, probably

as a result of specific epidemiological, sociological and logistical factors that make elimination using ivermectin

alone unlikely in some areas.

The main limitation of ivermectin is that it has little effect on the adult worms that continue to produce

microfilariae and hence re‐treatment is required at intervals that experts in many on‐going programmes have not

definitely determined or agreed upon. A major obstacle for onchocerciasis control using ivermectin has been the

occurrence of post ivermectin severe adverse events in areas co‐endemic with loiasis.

In view of the above, we suggest that CDTI should be improved by the following:

• There is need for the research organisations in charge of medical research in Cameroon to investigate the

epidemiological, sociological and logistical factors that contribute to the maintenance of high levels of the

prevalence of onchocerciasis after more than 17 years of treatment with ivermectin using the CDTI

approach in areas where loaisis is absent.

• The National Onchocerciasis Control Programme should intensify communication to inform the population

on the benefits of treatment with ivermectin. Efforts should also be made to seek for permanent non

compliers in order to inform, educate and properly treat them.

• The strategy of the control programme in the Americas which is based on at least twice yearly treatment

and which has resulted in the near elimination of onchocerciasis in that area should be adopted in all

endemic foci in general and Cameroon in particular where the results of the epidemiological evaluation

are not as good as was expected. This should be accompanied by epidemiological surveillance to detect

and control disease resurgence. Therapeutic approaches to reduce the load of L. loa infections are also

necessary to increase ivermectin coverage. Hypoendemic areas should also be covered under the new

strategy of “Test and Treat” that is being developed.

To date, there is a lot of controversy regarding the emergence of resistance of O. volvulus to ivermectin. In

addition to the phenotypic suspicions of resistance, many studies have revealed that selection occurs in some

genes of the parasite. Despite these phenotypic and genotypic studies, the unequivocal proof of resistance is yet

to be established. Further studies are therefore needed to clarify this situation in order to preserve the benefits of

past and current onchocerciasis control programmes.

Antibiotic therapy of human onchocerciasis

The symbiosis of filarial nematodes and intracellular Wolbachia bacteria has been studied as a target for antibiotic

therapy of filariasis in cattle using O. ochengi. The results showed that doxycycline is macrofilaricidal. As a result of

the close phylogenetic relationship between O. volvulus and O. ochengi, antibiotic treatment may also be

macrofilaricidal in humans. Trials in humans have demonstrated that:

• antibiotic treatment of O. volvulus results in sterility and inhibits larval development and adult worm

viability;

• depletion of bacteria following treatment with doxycycline resulted in a complete and long‐term blockage

of embryogenesis;

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• doxycycline also had macrofilaricidal effect on O. volvulus;

• the endosymbiont Wolbachia is absent from L. loa and this fact can be exploited for the administration of

antibiotherapy for the treatment of onchocerciasis in areas where L. loa is co‐endemic;

• the large scale administration of doxycycline for six weeks is feasible in co‐endemic villages of loiasis and

onchocerciasis using community directed approach with high therapeutic coverage and very high

compliance rates.

In view of the above results, we recommend as follows:

• The recently completed community‐directed intervention (CDI) trials using a 6‐week course of doxycycline

at 100 mg/day demonstrated that prolonged courses of treatment can be effectively delivered either

through individual or mass treatment using doxycycline. Consequently, doxycycline at this regimen could

be used for individual treatment and should be a reserve in cases of ivermectin resistance.

• Given that the cost of purchase and delivery of doxycycline for the six week treatment per patient is

relatively high for most onchocerciasis patients living in endemic communities, research efforts should be

maintained to develop shorter regimens of this drug. Lobbying should be made by governments and Non

Governmental Development Organisations for the reduction of the prices of this drug.

Vaccination

Vaccination can be a complementary tool for the present onchocerciasis control efforts as it can protect

vulnerable groups particularly children living in endemic areas against infection and reduce adult worm burden

and fecundity, thus reducing the pathological effects caused by the microfilariae. Many research groups have

identified a number of O. volvulus larval vaccine candidates. Trials with some of them have obtained proof‐of‐

principle of vaccination against L3 infection as it was shown that microfilarial loads reduced significantly in animal

models. Consequently, we recommend that donors should provide funding for research groups which have

identified promising vaccine candidates for the purpose of vaccine design, formulation and delivery.

Sustainability and ownership of control programmes

APOC’s mandate is expected to end in 2015. At that time, it will transfer full responsibility for onchocerciasis

control to national control programmes. Governments would be expected to provide adequate technological and

financial support for national control programmes to enable them take on the responsibilities that would be

transferred from APOC. The inability of national control programmes to sustain disease control efforts can have

important ramifications as disease resurgence can reverse the gains in public health produced by both OCP and

APOC over the years.

To create sustainable disease control efforts beyond APOC’s mandate, we urge National Programmes to develop

technical and technological competence that would enable them to function properly after the withdrawal of

APOC. We appeal to National Governments and donors not to abdicate their financial responsibility which is

needed to ensure that the substantial investments and progress made towards eliminating onchocerciasis in Africa

are sustained for the future.

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Resumé

L’Académie des Sciences du Cameroun a réuni un panel d’experts afin de rassembler les données relatives aux

recherches récentes sur l'onchocercose, les analyser et prodiguer des conseils pratiques et judicieux aux fins de

donner une nouvelle orientation aux stratégies de lutte contre l’onchocercose au Cameroun en particulier et dans

le monde en général.

L’onchocercose est une maladie parasitaire causée par Onchocerca volvulus. Elle est transmise par les piqures

d’une mouche du genre Simulium. Il s’agit d’une filariose dermique débilitante, endémique surtout en Afrique

tropicale et dans une moindre mesure en Amérique Centrale et du Sud, ainsi que dans la Péninsule arabique et au

Yémen en particulier. Les effets cliniques et socio‐économiques sont plus néfastes en Afrique subsaharienne car

elle y entraîne la cécité et des dermatoses sévères. De nos jours, l’onchocercose est connue comme la deuxième

cause de cécité d’origine infectieuse dans le monde. Les statistiques relatives à son impact sont très variées. Les

estimations de l’Organisation Mondiale de la Santé font état de près de 37 millions de personnes infectées par le

parasite avec approximativement 99% vivant en Afrique subsaharienne. Près de 1,5 millions de personnes

souffrent de déficience visuelle et près de 500 000 sont aveugles. Un total de 90 millions de personnes est à risque

d’infection par le parasite.

Au cours des années écoulées, les tentatives relatives à la lutte contre la maladie ont été basées sur la lutte

antivectorielle et la chimiothérapie. Malgré plus de quarante années de lutte en Afrique, la maladie représente

toujours un problème de santé publique dans plusieurs pays, et la prévalence dans certains foyers reste très

élevée. Il est donc très important de rechercher des stratégies complémentaires afin d’améliorer la lutte contre

l’onchocercose.

Lutte antivectorielle

Les efforts de lutte contre l'onchocercose portaient plus sur le traitement des cours d’eaux à l’aide d’insecticides

afin d’éliminer la lave de la simulie. Cette approche utilisée par le Programme de Lutte contre l'Onchocercose en

Afrique de l’Ouest ou encore Onchocerciasis Control Program in West Africa (OCP) a considérablement réduit

l’endémicité de la maladie dans les zones couvertes par ce Programme. Cette lutte antivectorielle peut encore être

utilisée de nos jours en association avec d’autres approches. Les deux derniers cas d'éradication de l’agent vecteur

à Itwara (Ouganda) et sur l’Ile de Bioko (Guinée Equatoriale) ont appliqué la méthode du programme OCP avec

l’aide du Programme Africain de Lutte contre l'Onchocercose (APOC).

Compte tenu de la construction en cours de nouveaux barrages hydroélectriques au Cameroun, les responsables

des projets devraient déjà concevoir dans leurs activités opérationnelles, des plans de lutte contre les mouches

noires, vecteurs de la maladie, afin d’être prêts à gérer tout imprévu relatif à une croissance exponentielle de la

population de S. damnosum après la construction des barrages. Les principaux fleuves du Cameroun devraient

également être la cible des activités de lutte contre la mouche noire puisqu'ils contribuent tous à la reproduction du

vecteur. Aussi, une recherche opérationnelle s’avère nécessaire en vue de déterminer les seuils à partir desquelles

la lutte contre le vecteur s’impose. Par ailleurs, il est important d’inclure dans les projets de lutte antivectorielle,

une composante environnementale sur l’effet des larvicides sur la flore et la faune aquatique.

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Traitement par ivermectine sous directives communautaires

L’ivermectine (Mectizan) offert par Merck & Co, a été introduit en 1987 pour le traitement en masse de

l’onchocercose. L’APOC a mis sur pied en 1996, la stratégie de Traitement à l’Ivermectine sous Directives

Communautaires (TIDC). L’ivermectine est un microfilaricide puissant et son utilisation a réduit de façon

significative la morbidité de l’onchocercose dans différentes communautés. On espérait que l’ivermectine pouvait

éliminer la maladie en interrompant la transmission, mais tel n’est pas le cas. Ceci pourrait être dû aux facteurs

épidémiologiques, sociologiques et logistiques qui rendent difficile l’élimination de l’onchocercose à l’aide de

l’ivermectine uniquement dans certain foyers.

La principale limite de l’ivermectine réside dans le fait que ce médicament a un effet limité sur les vers adultes qui

continuent de produire les microfilaires, soulignant ainsi la nécessité de traitements biannuels une ou deux fois

par an. Un autre obstacle à la lutte contre l’onchocercose à l’aide de l’ivermectine reste la survenue des effets

secondaires graves dans des zones co‐endémiques avec la loase.

A la lumière de ce qui précède, nous suggérons que le TIDC soit amélioré en tenant compte des propositions

suivantes :

• Il est nécessaire que les structures de recherche dans le domaine de la santé au Cameroun mènent des

études sur les facteurs épidémiologiques, sociologiques et logistiques qui contribuent à maintenir des

prévalences élevées de l'onchocercose, après plus de 15 années de traitement à l'ivermectine.

• Le Programme National de Lutte contre l’Onchocercose doit intensifier la communication afin d’informer

la population sur les avantages du traitement à l’ivermectine. Des efforts doivent également être déployés

pour identifier les sujets qui restent en marge du traitement de façon permanente afin de les informer, les

éduquer et les traiter convenablement.

• La stratégie du programme de lutte dans les Amériques basée sur l’administration d’au moins deux doses

par an et qui a abouti à une élimination presque totale de l’onchocercose dans cette zone devrait être

adoptée dans toutes les zones où le programme a des difficultés à éliminer la maladie (les zones où les

prévalences restent élevées malgré plusieurs années de traitements, avec des niveaux de transmission très

élevés). Les approches thérapeutiques de réduction de la charge des infections de la filariose à L. loa sont

également nécessaires pour réduire le risque d’effets secondaires graves et ainsi accroître la couverture à

l'ivermectine. Les zones hypo, endémiques doivent être incluses dans le programme de traitement si l’on

veut réellement éliminer la maladie.

Jusqu’à nos jours, il y a beaucoup de controverse autour de l’émergence de la résistance de l’O. volvulus à

l’ivermectine. En plus des suspicions phénotypiques sur la résistance, des recherches ont prouvé qu’une sélection

intervient dans certains gènes du parasite. En dépit de ces études phénotypiques et génotypiques, la preuve de la

résistance n’est pas encore établie. D’autres recherches doivent donc être effectuées afin de clarifier cette situation

et préserver les acquis programmes de lutte contre l’onchocercose.

xvi


Thérapie à base d’antibiotiques pour le traitement de l’onchocercose chez l’homme

La symbiose entre les nématodes et la bactérie intracellulaire Wolbachia a été bien étudiée chez le bétail avec le

modèle O. ochengi. La bactérie Wolbachia est une cible pour le traitement de l’onchocercose à base

d’antibiotique. Les résultats ont montré que la doxycycline est macrofilaricide. Du fait qu’O. ochengi est proche

phylogénétiquement d’O. volvulus, le traitement à base d’antibiotiques peut être également macrofilaricide chez

les êtres humains. Des essais sur l'homme ont démontré que:

• Le traitement d’O. volvulus à base d’antibiotiques abouti à la stérilisation des vers, l’inhibition du

développement larvaire et la mort du ver adulte.

• La bactérie Wolbachia n’est pas en symbiose avec L. loa, et ce fait peut être exploité pour l’administration

de l’antibiothérapie dans le traitement de l’onchocercose dans des zones où le L. loa est co‐endémique.

• L’administration à grande échelle de doxycycline pendant six semaines est réalisable dans des villages co‐

endémiques pour la loase et l’onchocercose en utilisant le schéma de traitement sous Directives

communautaires.

Vu les résultats ci‐dessus, nous recommandons que:

• Les travaux de recherche continuent, pour la détermination des schémas thérapeutiques plus court et

utilisable en traitement de masse avec moins de difficultés.

• La doxycycline soit une alternative au cas où la résistance à l’ivermectine se confirme. Un lobbying

devraient être fait par les gouvernements des pays endémiques afin d’obtenir la doxycycline à des prix

raisonnable.

Vaccination

La vaccination peut être un outil complémentaire pour les efforts actuels de lutte contre l’onchocercose dans la

mesure où elle peut permettre de protéger les groupes vulnérables, et surtout les enfants vivant dans les zones

endémiques. Elle peut aussi permettre de réduire le nombre de vers adultes et la fécondité, réduisant ainsi les

effets pathologiques causés par les microfilaires. Plusieurs groupes de recherche ont identifié un certain nombre

de vaccins contre les stades larvaires d’O. volvulus. Des essais de certains d’entre eux ont démontré l’efficacité de

la vaccination contre l’infection par les larves L3. Dans le modèle animal, il a été démontré que la vaccination

entraîne une réduction significative des charges microfilarienne. Nous recommandons par conséquent aux

bailleurs et aux gouvernements de soutenir les groupes de recherche qui ont identifié les vaccins candidats les plus

prometteurs en vue de leur développement, leur formulation et leur utilisation dans la lutte contre l’onchocercose.

Viabilité et responsabilité des programmes de lutte

Le mandat du Programme Africain de Lutte contre l’Onchocercose s’achève en principe en 2015. Il transfèrera

alors toute la responsabilité de la lutte contre l’onchocercose aux programmes nationaux de lutte. Les

gouvernements devront alors apporter une assistance technique et financière adéquate aux programmes

nationaux de lutte afin de leur permettre de prendre les responsabilités qui leurs seront confiées par l’APOC.

L’incapacité des programmes nationaux à maintenir les efforts de lutte contre la maladie pourrait avoir des

xvii


conséquences importantes puisque la résurgence de la maladie peut anéantir les acquis obtenus par les

programmes OCP et APOC pendant des années.

Afin de maintenir des efforts de lutte durable contre la maladie après le mandat d’APOC, nous recommandons aux

programme nationaux d’assurer une bonne préparation (formations des expertises nationales dans la perspective

du retrait du programme APOC), et aux différents gouvernements et autres bailleurs de ne pas renoncer à leurs

responsabilités financières qui est nécessaire afin de s’assurer que les investissements substantiels et les progrès

réalisés dans le sens de l’élimination de l'onchocercose en Afrique perdurent.

1


Background information on onchocerciasis

Introduction

Onchocerciasis is a parasitic disease caused by Onchocerca volvulus and transmitted by the bites of a black fly of

the genus Simulium. It is a debilitating dermal filariasis which is endemic mainly in tropical Africa and to a lesser

extent in Central and South America and the Arabian Peninsula, particularly in Yemen (WHO, 1995a). The clinical

and socio‐economic effects are most severe in Guinea and Sudan savanna areas where it causes blindness in

exposed humans (Leveque, 1989).

In 1875, O’Neill working with patients from the Gold Coast (Ghana) who had “craw craw”, a skin manifestation,

established the link between microfilariae and “onchocerciasis”. However, it was Leuckart in 1893 who examined

nodules extracted from patients from Gold Coast and discovered that the nodules contained adult worms which he

then named Filarial volvulus. Independently of the work of Leuckart, Theobald (1903) examined black flies from

the Democratic Republic of Congo (DRC) and named them Simulium damnosum. In spite of all the above, the

relationship between the vector and the disease remained unknown until 1926 when Blacklock working in Sierra

Leone, demonstrated the development of microfilariae into infective larvae in S. damnosum (Blacklock, 1926 a,b).

The first clinical presentation of onchocerciasis, the ocular form of the disease, was described in Guatemala

(Robles, 1919).

Global magnitude

Presently, onchocerciasis is recognised as the world’s second leading infectious cause of blindness. Figures on its

global magnitude cited in the literature are quite varied. The World Health Organization estimates that about 37

million people are currently infected with the parasite, with about 99% of them in sub‐Saharan Africa. Almost 1.5

million are visually impaired and about 500,000 are blind. A total of 90 million people are at risk of becoming

infected with the parasite (APOC, 2005; Boatin and Richards, 2006; WHO, 2011). In hyperendemic areas in Africa,

about 15 to 40% of adults could be blind because of onchocerciasis. Before the launching of the control

programme, for example in Burkina Faso, it was estimated that 46% of males and 36% of females living in

onchocerciasis hyperendemic areas became blind before their death (Prost, 1986).

The disease is endemic in Africa, Latin America and Yemen. In sub–Saharan Africa, the African onchocercal belt

extends from Senegal in the west to Ethiopia in the east involving 30 countries and as far south as Angola and

Malawi (Figure 1). The disease is also called river blindness because the blood sucking blackfly (Simulium spp)

which transmits the disease breeds in fast flowing rivers and blindness is an important clinical manifestation. In

onchocerciasis, chronic skin (dermatitis) and eye lesions are also common. It is a major public health problem in

many tropical countries (WHO, 1995a). The initial infestation often occurs in childhood, and many of the affected

individuals remain asymptomatic for long periods. A positive association has been found between river blindness

and excess mortality in infected people, either blind or not (Pion et al., 2002; Little et al., 2004).

2


Figure 1. Distribution of onchocerciasis showing current status of global onchocerciasis control Red areas represent areas receiving ivermectin treatment. Yellow areas represent areas requiring further epidemiological

surveys. The green area is the area covered by the Onchocerciasis Control Programme in West Africa. Pink zones indicate the

special intervention zones, i.e., previous OCP areas receiving ivermectin and some vector control. Map from Basáñez M.G. et al.

(2006).

Onchocerciasis in Cameroon

Onchocerciasis is an important public health problem in Cameroon. It was first described in the country by

Füllerborn (Kamgno, 2005). In the Mbam valley in Cameroon, a case control study demonstrated an association

between onchocerciasis and epilepsy (Boussinesq et al., 2002) with a huge demographic impact of this disease in

hyperendemic communities (Kamgno et al., 2003).

A Rapid epidemiological mapping of onchocerciasis (REMO) survey undertaken in Cameroon (Mace et al., 1997)

revealed that about 50% of the rural population was at risk. Other unpublished reports put this percentage at 62%,

suggesting that about 9 million people were at risk of infection, 5 million people infested by the worm, among

which 30,000 were blind. There are many fast flowing rivers in the country which favour the propagation of the

black fly vectors of the disease.

Helen Keller International’s (HKI) work to combat the disease began in Cameroon in 1992. A major milestone was

achieved in 1995, when non governmental organizations, the World Bank, the World Health Organisation, Donor

countries and endemic countries launched the African Programme for Onchocerciasis Control (APOC). APOC

figures show that by 2007 in Cameroon (Figure 2), the number of communities treated with ivermectin was 9,445

and the geographic coverage of the country was 99.5%. By the same period, the number of people treated with

ivermectin was 4,427,481 and the treatment target (in terms of number of people treated) was 5 950 489 giving at

the time, a therapeutic coverage rate of 74.4%.

3


Figure 2. Rapid epidemiological mapping of onchocerciasis in Cameroon The areas in red show where community‐directed treatment with ivermectin is needed. People affected by onchocerciasis are

shown as: Number of communities in meso/hyper endemic (red) areas (2006): 9419; Total population in meso/hyper endemic

(red) areas (2006): 5 798 818. Source of map: www.WHO.int/apoc/countries/cm_web.jpg

Bio‐ecology of S. damnosum

The role of Simulium as a vector of onchocerciasis was suspected by Robles in 1919 in Guatemala, and confirmed in

Sierra Leone a few years later (Blacklock, 1926a; Blacklock, 1926b).

S. damnosum is a Diptera belonging to the family Simuliidae. The females are haematophagous but also take plant

juices while the males feed exclusively on plant juices. The females are mainly anthropophilic (could also feed on

animals), absorbing up to one mg of blood during a meal. The proteins in the blood are necessary for egg (between

500 and 1000 can be laid) production. The adult resting place is unknown, making it difficult to control the insect

by spraying with insecticide (Bellec and Hebrand, 1980). The female can live for up to four weeks in the savanna

but for a shorter period in the forest zone. A batch of eggs is laid on the surface of submerged vegetation in fast

flowing sections of rivers 3 to 4 days after a blood meal. The eggs hatch in about 3 days and the larval stages (1 to

7) remain attached to the substrate by the terminal segment of their abdomens. The larvae feed by fanning any

drifting debris into their mouths and the digestive system using their modified mandibles. The larval stage lasts 6

to 9 days, depending on the temperature of the water, before moulting into a nymph (non feeding stage) and the

adult. The female copulates (once in its lifetime) a few hours after immerging and seeks a blood meal.

4


Life cycle of Onchocerca volvulus

Onchocerca worms survive in their natural host for several years and the adult worm life span is generally

estimated to range from 10 to 15 years (Plaisier et al., 1991; Ottesen, 1995) despite ongoing cellular immune

responses and high titres of parasite‐specific IgG and IgE antibodies. There is some evidence that an active

modulation of the host’s immune system is one of the strategies permitting long‐term survival of the parasite

(Maizels et al., 1993). Throughout its life span, the adult fertilized female worm reproduces continuously, giving

birth to millions of microfilariae that are released per day and migrate to invade the skin and eyes. In the latter

case, they provoke ocular pathology resulting in blindness in humans. During feeding on the skin, the blood‐

sucking black fly vector Simulium damnosum (Philippon, 1977) ingests the skin dwelling microfilariae which

eventually develop into the third stage infective larvae (Figure 3). When the infective black fly bites a human being

again, the infective larvae from the head of the fly enter the wound and penetrate the tissues. In this definitive

host, these infective larvae moult (Figure 4) and develop to become immature adult worms enclosed in

collagenous, subcutaneous or deeper worm bundles as palpable nodules, where they develop to maturity.

Many Simulium species have been incriminated to a greater or lesser extent in the transmission of O. volvulus

(Crosskey, 1990), their relative vectorial capacities contributing to shape diverse transmission patterns in different

endemic areas. S. damnosum concurrently transmits both O. volvulus and animal Onchocerca species such as O.

ochengi. Under field conditions humans are exposed to such animal‐derived Onchocerca spp L3 (Figure 3) but they do

not develop in them. The larvae of these flies are aquatic dwellers and occur mainly in fast‐flowing water, requiring

a minimum flow of about 50 cm/s for survival. In Africa, the S. damnosum species complex, which includes

approximately 60 cytoforms, is responsible for more than 95 percent of onchocerciasis cases (Crosskey, 1990;

Crosskey and Howard, 2004). S. Neavei whose larvae are phoretic on crabs transmits the infection in East Africa. In

Latin America, S. ochraceum, S. exiguum, S. metallicum and S. guianense are the main vectors, respectively, in

Mexico and Guatemala, Colombia and Ecuador, northern Venezuela and southern Venezuela and Brazil (Bradley et

al., 2005; WHO, 2005).

5


Figure 3. Transmission cycle of Onchocerca volvulus, O.ochengi and O. ramachandrini Wharthogs are implicated in the life cycle of O.ramachandrini. Copied with permission from Renz and Wenk

(www.riverblindness.eu)

Figure 4. Life cycle of O.volvulus Copied and modified with permission from Renz and Wenk (www.riverblindness.eu)

6


Pathology of onchocerciasis

In endemic areas, the majority of O.volvulus‐infected persons develop a generalized form of the disease which is

characterized by varying microfilariae densities and numbers of adult parasites. Most often, this is accompanied by

a low degree of inflammatory processes in the skin. Generally there is a wide spectrum of ensuing pathological

events which represent the cumulative tissue and functional outcomes of a long‐standing interplay between the

host and parasite.The adult worms are enclosed in collagenous tissues where they form palpable nodules in the

skin.The nodules in humans typically range from the size of a pea to about 1‐4cm in diameter and may contain two

to four adult worms that can reach a length of 80 cm. In bovine O.ochengi, more than 12 adult male worms have

been detected living with one female worm in one nodule (Achukwi, unpublished data). The microfilariae can

survive 2 to 3 years.

After mating, the female worm releases around 1000 microfilariae larvae a day into the surrounding tissue. It is the

microfilarial stage of the parasite that causes the pathology of onchocerciasis, comprising a variety of

dermatological manifestations and eye lessions. Microfilariae concentrate in the dermis of the skin and the eyes

and most clinical pathology is seen at these two sites. The clinical spectrum may show:

i. apparently immune, clinically normal individuals;

ii. individuals who are infected yet asymptomatic;

iii. persons with eye or skin pathology.

Blindness is the most serious complication of onchocerciasis. It has been indicated that disease progression may be

influenced by factors such as an individual’s immune response (Ottesen, 1984) and the local incidence of

infestation (Bundy et al., 1991). In general, the relative importance of ocular and skin complications varies with the

parasite strain involved. Blindness tends to predominate in savannah areas and skin disease in forest areas.

Skin lesions

The skin manifestations of onchocerciasis are highly variable. Severe itching is fairly common. In endemic areas, a

small proportion of patients often described as clinically symptomatic patients, have severe dermatological lesions

that are usually confined to distinct areas of the body (Anderson et al., 1973; Buttner et al., 1982). The mechanism

underlying the propensity of some patients to develop an extremely debilitating dermatitis known as reactive

onchodermatitis (ROD) or sowda, has been a matter of controversy (Ali et al., 2003; Gallin et al., 1995; Mackenzie

et al., 1985; Murdoch et al., 1997). The factors that predispose patients to developing ROD are not clearly defined,

although it has been observed that there is an immunogenetic basis for the spectrum of cutaneous presentations

in onchocerciasis (Murdoch et al., 1997). Sowda occurs in a small proportion of patients who exhibit a hyperactive

form of onchocerciasis characterized by very low mf densities, only a few nodules with adult worms, pronounced

cellular and humoral immune responses and the ability to eliminate the microfilariae (Büttner et al., 1982; Lucius

et al., 1986; Brattig et al., 1987). The phenomenon of low microfilariae load is thought to result from an active

down regulation of parasite burdens by the host (Büttner and Racz 1983). A clinical classification of onchocercal

dermatitis defining six different patterns has been suggested by Murdoch et al. (1993) as follows:

i. Acute papular onchodermatitis – there is an early skin change characterised by widespread eczematous

rashes with multiple small pruritic papules which progress to vesicles and pustules. This form often

affects the face, the trunk and the extremities.

7


ii. Chronic papular onchodermatitis – this has a severely itching maculopapular rash containing scattered

flat‐topped papules and hyper pigmented macules, typically affecting the shoulders, the buttocks and

the extremities early in the infestation.

iii. Lichenified onchodermatitis – it consists of hyperkeratotic and hyper pigmented confluent plaques most

often affecting the lower extremities and associated with lymphadenopathy.

iv. Onchocercal depigmentation or leopard skin – has vitiligo‐like lesions with hypo pigmented patches

containing perifollicular spots of normally pigmented skin. Onchocercal depigmentation often affects

the shins in a symmetrical pattern and is rarely associated with pruritis and excoriations.

v. Onchocercal nodules – these are asymptomatic subcutaneous nodules of variable sizes located over bony

prominence and containing the adult worms. Other classic clinical pictures include lizard skins with

dry ichthyose‐like lesions with a mosaic pattern resembling the scales of a lizard.

vi. Hanging groin – characterised by folds of atrophic inelastic skin in the inguinal region associated with

lymphadenopathy.

In a population where onchodermatitis is endemic, the most common skin manifestation is chronic papular

onchodermatitis and followed by onchocercal depigmentation (Hagan, 1998).

Eye lesions

Ocular lesions can involve all eye tissues, ranging from punctuate and sclerosing keratitis (anterior segment) to

optic nerve atrophy (posterior segment). Onchocercal ocular disease covers a wide spectrum, ranging from mild

symptoms such as pruritis, redness, pain, photophobia, diffuse keratitis and blurring of vision to more severe

symptoms of corneal scarring, night blindness, intraocular inflammation, glaucoma, visual field loss and eventually,

blindness (Enk et al., 2003).

In untreated populations, the progressive nature of onchocercal ocular disease has been found to be responsible

for the existence of entire villages in which the older population was blind and only young people had functional

vision. This phenomenon was first observed in villages in proximity of rivers, the breeding site of the Simulium

black fly, hence, the name river blindness. Ocular lesions are usually bilateral and can affect various structures of

the anterior and posterior segments of the eye (Abiose, 1998). Anterior segment disease is related to the presence

of living or dead microfilariae in the eye. In the anterior chamber, the microfilariae can be seen with a slit lamp.

A number of studies have reported a reduced vitamin A status in individuals with onchocercal infections (Mustafa

et al., 1979; Zambou et al., 1999). An unpublished survey undertaken by the World Health Organization comparing

foci in West African savannah and the forest area of Cameroon showed that lesions caused by vitamin A deficiency

were more common in villages of the savannah areas with high Onchocerca parasite prevalence than in equivalent

forest zone villages, where dietary vitamin A was not limited. Posterior eye lesions such as retinitis,

choroidoretinitis and optic nerve damage are also more common in the savannah. In Côte d’Ivoire, Lagraulet

(1971) reported that individuals with onchocerciasis had lower serum vitamin A levels than comparative control

groups. These findings are controversial given that in other studies, vitamin A levels in skin or plasma were found

not to differ significantly between infected and uninfected people (Williams et al., 1985; Stürchler et al., 1987).

8


The pathogenesis of blindness is not clearly defined but it is thought that the immune reaction to the secreted

products or to the contents of dead microfilariae is important and possibly compounded by the induction of

autoimmunity to antigens of the eye. Dead microfilariae may cause severe anterior uveitis with formation of

synaechiae, cataract and glaucoma. Confluent opacities may obscure major portions of the cornea, ultimately

leading to a sclerosing keratitis with fibrovascular pannus and marked reduction of the visual functions. Posterior

segment disease manifests as atrophy of the retinal‐pigment epithelium and is associated with choroidoretinal

scarring and subretinal fibrosis (Newland et al., 1991). Optic neuritis followed by post neuritic optic atrophy may

also occur (Abiose et al., 1993).

It is thought that in chronic onchocercal infestations, a combination of both host‐ and parasite‐mediated processes

can synergize to control aberrant immune reactivity and damage to the host. This attenuation of the immune

response tends to limit the host´s capability to clear the infection (Maizels and Yazdanbakhsh, 2003; Bourke et al.,

2011).

The role of Wolbachia bacteria in pathology

Wolbachia bacteria living as symbionts of the major pathogenic filarial nematodes of humans, including O. volvulus

have during the last decade provided a breakthrough in our understanding of the pathogenesis of onchocerciasis

with dramatic implications for treatment and prevention programmes (Hoerauf et al., 2003a). Wolbachia bacteria

belong to the order Rickettsiales and are abundant in all development stages of filarial nematodes, including the

hypodermis and reproductive tissue of adult filariae.

Wolbachia species seem to have evolved as symbionts essential for worm development, survival, induction of

inflammatory disease pathogenesis and fertility of the nematode host.Their depletion results in disruption of

embryogenesis in the female worm (Bandi et al., 2001). Wolbachia‐bacterial endosymbionts also drive the

pathogenesis through the activation and regulation of host immunity (Taylor et al., 2010). Filarial and Wolbachia

antigens elicit the release of pro‐inflammatory and chemotactic cytokines by resident cells, which induce cellular

infiltration and amplification of the inflammatory response (Hise et al., 2004). It was in the bovine O.ochengi model

at the Veterinary Research Laboratory of the Institute of Agricultural Research for Development, Wakwa –

Ngaoundere in North Cameroon that it was first shown that the elimination of Wolbachia organisms led to adult

Onchocerca worm death (Langworthy et al., 2000). Thereafter, a series of field trials against onchocerciasis and

lymphatic filariasis have demonstrated that 4–8 week courses of the antibiotic doxycycline deplete the bacteria

and result in the long‐term sterility and most importantly death of adult worms (Hoerauf et al., 2001).

Socio‐economic implications of onchocerciasis

The blindness, dermatitis and chronic disability caused by onchocerciasis remain a huge socio‐economic

development impediment as the scarce labour force is weakened, the social life of several millions of people is

compromised and poverty is sustained in affected communities.

There are high mortalities of the blind victims of onchocerciasis, particulary among male patients (Prost, 1986;

Pion et al., 2002). High microfilarial loads have been reported to negatively affect the definitive host’s life

expectancy even in non blind patients (Little et al., 2004). Clinical manifestations such as epilepsy which may

9


possibly be due to heavy infestation (Boussinesq et al., 2002) may be partially responsible for excess mortality. In

most communities, epilepsy and onchodermatitis can lead to social stigmatization (Vlassoff et al., 2000).

Onchocerciasis is believed to be responsible for the annual loss of approximately one million disability‐adjusted

life‐years (DALYs). Visual impairment and blindness account for 40% of DALYs associated with onchocerciasis.

These are healthy life‐years lost due to disability and mortality, more than half of them due to skin disease

(Remme, 2004) which greatly reduces income‐generating capacity (Oladepo et al., 1997), incurs significant health

expenditures and exerts on a long‐term basis, a very high negative socio‐economic impact on the affected

populations and their land use (Evans 1995).

In sub Saharan Africa, blindness greatly diminishes agricultural production while increasing poverty and famine. In

West African valleys, onchocerciasis is known to prevent resettlement of arable lands (Hervouet and Prost, 1979).

10


11


Treatment and control of onchocerciasis

Introduction

A combination of several strategies has been used in the attempt to treat or control onchocerciasis. These include

surgical treatment, vector control, drugs and occasional mass therapy and vector control.

Surgical treatment

Denodulization through surgery has been used to prevent high rates of blindness and eye lesions as it removes

adult worms. The effect is however limited as the microfilariae remain in the body and can still be transmitted by

biting flies to other persons. It is also difficult to remove all the adult worms as some nodules are located deeply in

the tissues.

Vector control

Historical Background

Intensive work on the biology, bionomics and distribution of S. damnosum (Crosskey, 1958) and the development

of chlorinated hydrocarbons (CHC) increased the prospects of onchocerciasis control by attacking the vector. The

breakthrough came when it was shown that Dichlorodiphenyltrichloroethane (DDT), a CHC applied at very low

dosage directly into the river or stream was effective in killing Simulium larvae, thus paving the way for the

institution of vector control by larviciding. Effective vector control requires a good knowledge of the insect’s

biology and ecology. The insecticide of choice in the early days of vector control was DDT but it was replaced quite

appropriately by Temephos around 1972 as it was beginning to go out of favour due to its adverse effects on the

environment (Leveque, 1989).

Onchocerciasis vector control activities in Africa were executed in three phases. The first phase or pre‐Onchocerca

Control Programme (OCP) phase started with bush clearing activities (1932‐1944) and was followed by the use of

CHC insecticides, especially DDT (1944‐1972). The second phase or OCP phase was characterized by the use of

Temephos, an organophosphate and other larvicides (Phoxim, Pyraclofos, Permethrin, Etofenprox, Carbosulfan

and Bacillus thuringiensis H 14). The third phase or post OCP phase consisted of the introduction of focal vector

control by the African Programme for Onchocerciasis Control (APOC). In this last phase, vector control activities

were carried out using OCP guidelines and were put in place as a means to stop transmission of onchocerciasis in

some isolated foci.

In this section, we review the use of vector control in curbing black fly nuisance and the elimination of

onchocerciasis in some parts of Africa (Brown, 1962; McMahon, 1967; Davies, 1994; Walsh 1990) and discuss the

role it can play as a complement to the efforts of the African Programme for Onchocerciasis Control (APOC) in the

elimination of this disease in Cameroon and Africa.

12


The phases of vector control in Africa

The pre OCP phase (1932 – 1972)

Simulium vector control, prior to the OCP was largely experimental as there were no reference points to guide the

activities. It was characterized by environmental modifications such as bush clearing and larviciding with DDT to

control Simulium vectors. For example, bush clearing in the Kodera district in Kenya led to the eradication of S.

neavei from a small focus in Riana (Buckley, 1951). The same action in S. damnosum larval habitats around

Kinshasa did not produce the same results (Henry and Meredith, 1990). The successful demonstration of DDT as a

larvicide against Simulium larvae led to intensive pioneering experiments in Kenya and Uganda.

The control projects of this phase were largely localized schemes which lasted for short periods while others went

on for many years. Such control schemes were carried out in West and Central Africa in countries like Chad,

Cameroon, Nigeria, Benin, Burkina Faso, Côte d’Ivoire and Mali (Duke, 1964; Davies, 1968; Hitchen and Going,

1966; Walsh, 1970).

Successful vector control projects : Some of the control projects produced good results. In Benin, treatment of the

Yerpoo River which was infested with S. damnosum with 6 rounds of DDT at a dose of 1‐4 ppm/30 min greatly

reduced the population of adult flies. In Burkina Faso, treatment of the Black Volta and its tributaries with DDT

emulsion at the rate of 0.5ppm/30min from October 1962 to February 1963 at 10 day intervals reduced the

Simulium biting densities from 700 flies/man/week to 1 fly/man/week (McMahon, 1967). Small scale Simulium

vector control schemes using DDT were successfully conducted in Cameroon between 1956 and 1966 around Tiko,

Limbe and Edea to curb biting fly nuisance especially around the plantations of the Cameroon Development

Corporation (Duke 1964; Brown 1962;). In March 1978, Temephos at the dose of 0.05 – 0.10 ppm/10 min. was

used to successfully control S. squamosum nuisance at the Songloulou dam site in the forest zone. However,

resistance to Temephos was observed in June 1980 necessitating a larvicide rotation (Chlorphaxim replaced

Temephos) in 1985 (Hougard et al., 1992).

Control activities in Ghana from 1954 to 1955 achieved complete control of S. damnosum around the Kanyanbia,

Sisili, Kamba and the Black Volta Rivers. In 1959, DDT applied at 0.1 ppm/30 min. to the Black Volta and the Kamba

Rivers led to a complete control of S damnosum for 80 km. To reduce the level of nuisance at the Akosombo dam

site, several treatments with DDT (0.1 – 0.3 ppm/30 mins) were applied. Fly biting rates reduced at variable rates

between 1962 and 1963 until the reservoir was filled up inundating the breeding sites upstream (McMahon, 1967).

In Côte d’Ivoire, two S. damnosum control schemes (northern savanna area and forest zone in the south) were

executed between 1963 and 1970. Both of them were to protect two important agricultural communities from S.

damnosum nuisance (400 flies/man/day) in the rainy season. The Bagoe and the Bandama were treated at the rate

of 0.1 to 0.5 ppm/ 30 min. The results were good (McMahon, 1967). These projects were integrated into the OCP

as from 1975.

In Uganda control activities with DDT were able to eliminate the vector from three foci: the Bundongo forest in

1954, the Victoria Nile in 1973 and the Ruwenzori falls in 1976/77 (McMahon et al., 1958; Davies, 1994).

One of the most successful vector control projects was in Kenya where onchocerciasis was eradicated as a result of

the total elimination of the vector, S. neavei (Garnham and McMahon, 1947; Garnham and McMahon, 1981;

13


McMahon, 1967; McMahon et al., 1958). The developing stages of S. neavei in Kenya remained unknown until

McMahon in 1950, found the early stages of this fly to be breeding in phoretic association with the fresh water

crab (Potamonautes niloticus) in Kipsonoi River, near Kericho. The eradication of S. neavei and consequently

onchocerciasis from Kenya benefited from very favourable conditions, namely, a single vector, foci isolated from

one another and good follow‐up of activities. Three main foci: Mount Elgon, North Nyanza (Kakamega/Kaimosi)

and South Nyanza (Kisii, Kericho, Kodera, Riana) were identified. S. neavei was eradicated from the Riana sub‐focus

by bush clearing. This vector control method has never been repeated successfully anywhere else. All the other

foci were treated with DDT. The dosages varied from 1 to 2 ppm/ 30 min every 14 days, culminating in the demise

of onchocerciasis whose prevalence was up to 45% in some communities with 10% blind (McMahon et al., 1958).

The results of the Rapid Epidemiological Mapping of Onchocerciasis (REMO) indicate that Kenya, a country which

used to be hyperendemic for the disease is still free (Noma et al., 2002).

Unsuccesful vector control projects: Other vector control schemes were complete failures. For example, the Mayo

Kebi River scheme (1955 – 1959) in Chad was carried out in a 55km stretch between Tessoko and Mayo Ligam. The

treatment targeted both adults and larvae of S. sirbanum. Six applications of gamma‐BHC at 1‐2.5 ppm/30 min

were made at 3 different points on the ground. At the same time, 10 adulticide applications were made with 2%

lindane in gas oil emitted as aerosols from Bell helicopters. Both adults and larvae disappeared one week after

treatment but the flies returned in the rainy season of the same year. The failure of the project was attributed to

factors such as adult aestivation, insufficient dosing points and reinvasion from the untreated Mayo Wemba, a

tributary of the Benoue (Brown, 1962).

Other failed schemes include those carried out in Guinea Bisau (Davies, 1994) and in Nigeria around Kaduna,

Lokoja, Enugu, Niger River and Kainji dam which succeeded in reducing the Simulium populations but did not

reduce transmission as the infective rates (ranging from 0.7% to 2.95%) and the prevalence (88.04% in 1957 to

73.71% in 1960 ‐ 1966) of the disease remained high (Davies et al., 1978; Davies, 1968; Davies, 1994).

The OCP phase (1975‐2002)

The available information on the biology, bionomics and distribution of Simulium species and the existence of

ongoing small control schemes led to the convening of a meeting, sponsored by the United States Agency for

International Development (USAID), ‘Organisation de Coordination et de Coopération pour la Lutte contre les

Grandes Endémies’ (OCCGE) and WHO in Tunis in July 1968. The purpose of the meeting was to bring together

scientists to discuss the feasibility of onchocerciasis control. The meeting concluded that a large‐scale control

campaign rather than eradication was the solution. A programme was recommended involving 10‐15 years of

aerial larvicide spraying and simultaneous revamping of the health care systems of the endemic countries. The

area selected to start the trials was the Volta River Basin and extending into Senegal, Mali and Guinea. The

Onchocerciasis Control Programme (OCP) was thus born and after all technical, financial and administrative

arrangements were completed, it was launched in 1974 under the aegis of the WHO and it was operational from

1974 to 2002. Its mandate was to eliminate onchocerciasis as a disease of public health importance and as an

obstacle to socio‐economic development.

The basic strategy of OCP was to interrupt the transmission of O. volvulus by destroying the S. damnosum at its

larval stage by aerial application of selective insecticides in infested rivers so that adult onchocercal parasites could

eventually die out naturally in the human hosts (Hougard, 1993). The first aerial treatments began in 1974 and by

the end of 1977, a total of 654,000 sq. km, spread over seven countries (Burkina Faso, Mali, Niger, Cote d’Ivoire,

14


Benin, Ghana and Togo) was covered. As the operations were going on in the original programme area,

entomological observations revealed that reinvasion of the zone was compromising the control scheme. The OCP

was therefore extended to Western Mali, South Eastern Guinea, Northern Sierra Leone, Southern basins of Cote

d’Ivoire, Benin, Ghana and Togo. The insecticide selected for the operations was Temephos, an organo‐phosphate

which selectively kills the larvae of S. damnosum but is less toxic to non target fauna.

The overall authority for policy‐making, planning, programming, implementation and financing of OCP operations

was vested in the Joint Programme Committee (JPC), composed of representatives of the participating countries,

the donors and the sponsoring agencies.The Expert Advisory Committee (EAC), made up of 12 scientists, carried

out annual, independent evaluation of OCP operations and gave technical and scientific advice to the JPC and the

Programme Director. The Committee of Sponsoring Agencies (UNDP, FAO, WHO, World Bank) monitored the

Programme operations, considered management issues and reviewed the documentation for JPC.

Aerial treatment using helicopters and fixed wing small aircrafts was supplemented by ground larviciding where

appropriate. Rigorous monitoring methodologies were put in place for the follow up of both Simulium populations

and aquatic fauna during the entire life of the programme. In the course of OCP activities, it was observed that S.

damnosum developed resistance to Temephos and other larvicides (Phoxim, Pyraclofos, Permethrin, Etofenprox,

and Carbosulfan). This led to the introduction of larvicide rotation. This method was able to check the

development of larval resistance to an individual insecticide (WHO, 1987a, b).

The OCP also set the criteria for declaring a vector control programme a success as follows:

a) The “tolerable level of onchocerciasis infection” in a community: “The attainment and maintenance of all

persons living therein who were not infected with O. volvulus in the outset of the campaign, of a zero

incidence of the serious and irreversible ocular lesions resulting from onchocerciasis”.

b) An annual transmission potential (ATP) of 100 larvae was the maximum permissible transmission level.

c) The calculation of ATPs and annual biting rates (ABRs) was based on at least four catching days in a month

throughout the year.

In the same light, the Environmental Monitoring Group was set up with the responsibility of monitoring the

environmental impact of the large quantities of larvicides on the aquatic fauna. Specifically, it:

a) organized and evaluated the long‐term monitoring of the aquatic fauna;

b) assessed the level of toxicity of new products or formulations and approved or rejected their operational

use;

c) reviewed the nature and magnitude of the ecological problems connected with the programme and with

associated economic development projects proposed in areas freed from onchocerciasis in order to

identify the environmental and human ecological implications of such developments.

OCP achievements: The success of the OCP was outstanding and this led to the cessation of larviciding and the

eventual closure of the programme in 2002 (Yameogo, 2003). The OCP was the largest vector control scheme to be

attempted and it was born out of the experience gained from several pilot projects executed in Burkina Faso, Cote

15


d’Ivoire, Mali, Ghana, Benin and Togo (Walsh et al., 1979). The success of the OCP and the standards it set make it

stand out as the reference for all other Simulium control schemes in Africa.

It has been estimated that from 1974 to 2002, skin infection and eye lesions were prevented in 40 million people in

11 countries, 600,000 cases of blindness were prevented, 25 million hectares of abandoned arable land reclaimed

for settlement and agricultural production capable of feeding 17 million people annually. The economic rate of

return was calculated at 20% (Hodgkin et al., 2007).

The post OCP phase (2002 – today)

This phase of onchocerciasis control was characterized by vector control activities pioneered by APOC. In its effort

to control the disease in Africa, APOC included focal vector control in areas where the foci were shown to be so

isolated and there was no risk of re‐invasion of the foci by migratory black flies. Three such projects were identified

in Bioko Island in Equatorial Guinea (Traore et al., 2009), Itwara in Uganda (Kipp et al., 1992; Garms et al., 2009)

and Tukuyu in Tanzania (APOC, 2005). Whereas the vector was eliminated in the first two foci, the Tukuyu focus

suffered from re‐invasion problems and larviciding was suspended.

Problems of vector control

Despite the successes mentioned above, vector control as described in this section was also plagued by problems

such as resistance of the vector to larvicides, effect of the larvicides on non target organisms and reinvasion of

control areas by the vector.

Resistance of the vector to larvicides

This generally is a result of the development of genetic resistance to the organic compounds used in the control

process. Resistance involving two of the seven species of the S. damnosum complex namely, S. sanctipauli and S.

subrense was reported against the organophosphate, Temephos, in the OCP. This is thought to have developed

through selection of resistant individuals under long and intensive larvicide treatment spreading out through

dissemination. Generally, the development of resistance can be controlled by alternating the use of different

compounds. Unfortunately this approach can result in the development of resistance to multiple compounds as

was the case against chlophoxim and temephos along the tributaries of the Niger in Mali and the upper reaches of

the Sassandra River (Norgbey, 1997; Leveque, 1989).

Effect of the larvicides on non target organisms

The larvicides used in the vector control of onchocerciasis also had adverse environmental impacts. As a result of

studies carried out early in the course of larvicide applications, organochlorine insecticides were abandoned in

favour of organophosphates that were more readily biodegradable. Even the organophosphates have been shown

to have negative environmental impacts. For example, a routine spraying operation with Temephos using (0.05‐0.1

mg/l for 10 min) can produce a massive detachment of insect fauna, which is reflected by a rise in the drift, after a

15‐45 min period of latency. The mortality rate of drifting organisms has been shown to be very high. Generally,

temephos and other insecticides cause a reduction of about 30% of invertebrate fauna (Norgbey, 1997). There is

not much data on the effects of larvicides on aquatic flora. It has however, been suggested that aquatic plants can

16


break down into microscopic parts resulting in food scarcity and then reduction in fish populations following

spraying.

The results described above which had a strong impact on invertebrate organisms were for the first applications of

temephos and chlorphoxim. However, the results obtained after many years' treatment showed little long‐term

effect of the various larvicides on the non‐target fauna. The treated rivers had fairly strong resilience and a great

capacity for recovery (Leveque, 1989).

Reinvasion of control areas by the vector

Reinvasion by insect vectors following chemical control is a common phenomenon. It is often observed in Tse‐tse

fly control activities. It was a major problem in the OCP operations where flies were often carried by prevailing

winds from untreated zones close to OCP areas. The strategy employed in controlling the problem was to expand

the control area to cover the sources of departure of reinvading flies.

Drug treatment

There was no ideal drug for treating onchocerciasis before 1987. Two microfilaricides, diethylcarbamazine (DEC)

citrate and suramin were used until the 1970s when they became unpopular because of severe side effects. The

drug of choice recommended by the WHO is ivermectin (Mectizan®). Its antiparasitic properties were discovered in

1970, but it was in 1980 that clinical trials confirmed its efficiency against O. volvulus (Diallo et al., 1986; Lariviere

et al., 1989a,b,c; Greene et al., 1985a).

Control activities by APOC have been based largely on mass drug administration using ivermectin. Here we

described the role of ivermectin in the control of onchocerciasis in Africa.

Ivermectin in the control of onchocerciasis

Ivermectin family and chemical structure

The avermectins to which ivermectin belongs are macrocyclic lactones derived from the product of fermentation

of Streptomyces avermitilis. This germ was isolated from a soil sample collected near a golf course at Katawana in

Ito city, Shizuoka Prefecture in Japan. The avermectins were isolated by solvent extraction from the mycelia

solvent partition and column chromatography (Miller et al., 1979). This process of isolation was improved using

selected strains of S. avermitilis. A selective hydrogenation of avermectin B1 led to the synthesis of two molecules,

the 22, 23‐dihydroavermectin B1a (80%) and the 22, 23‐dihydroavermectin B1b (20%). The combination of these

two molecules constitutes ivermectin (Figure 5).

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Figure 5: Chemical structure of ivermectin

Effect of ivermectin on O. volvulus

The anthelminthic activity of avermectins was first discovered in 1979 (Miller et al., 1979; Burg et al., 1979;

Egerton et al., 1979). Avermectins act at multiple sites and various species have different sensitivities (Turner and

Schaeffer, 1989). Ivermectin acts as an agonist of glutamate‐gated chloride ion channels (Glu‐Cl) and ϒ‐

aminobutyric acid (GABA)‐related chloride ion channels receptors present in nerve and muscle cells of nematodes,

insects and ticks. Interactions between ivermectin (IVM) and these receptors and/or channels prevent their

closure, thus increasing the permeability of synapse membranes to chloride ions, which leads to hyperpolarization

of the neuronal membrane and consequently to the paralysis of the somatic muscles, particularly the pharyngeal

pump (Omura and Crump, 2004). The paralyzed microfilariae are then drained through the lymphatic system and

then destroyed by the immune system, notably by macrophages at the level of the lymph nodes. This mechanism

also leads to the disruption of the ingestion of nutrients and explain the rapid drop of microfilaridermia after a

unique dose of ivermectin (Vuong et al., 1992; Knab et al., 1997). On the adult female worm, there is a prolonged

effect of ivermectin on the uterus muscles which hinders the release of microfilariae out of the uterus. These

microfilariae are accumulated in the genital tract and degenerate in situ (Wildenburg et al., 1998).

Clinical trials with Ivermectin

The efficicacy of ivermectin on O. volvulus was demonstrated for the first time in Senegal in 1982 (Diallo et al.,

1984; Aziz et al., 1982). In the trial, 32 patients with moderate microfilaridermia were randomly allocated into four

groups which received respectively, 5, 10, 30 and 50µg/kg of ivermectin. In all groups, ivermectin was well

tolerated. Neurologic, ophthalmologic and haematologic tests performed did not show any abnormality.

18


Phase two trials were conducted in Paris and in Ghana. In Paris, patients were treated with 150 and 200µg/kg. In

Ghana, patients were treated with 50, 100, 150 or 200µg/kg. The microfilaricidal effect was more important from

100µg/kg. Adverse events were described with the increase of the doses. These included swelling, Mazzoti

reactions, conjunctivitis with transitory blurred vision and the appearance of microfilariae in the anterior chamber

of the eye (Coulaud et al., 1983, 1984; Awadzi et al., 1995).

Phase three trials compared a unique dose of 200µg/kg of ivermectin to 7 to 8 days of Diethylcarbamazin in

Senegal (Diallo et al., 1986), Mali (Lariviere et al., 1985), Liberia (Albiez et al., 1988; Taylor et al., 1986; Greene et

al., 1985b) and Ghana (Awadzi et al., 1986). In general, these trials showed more pronounced effects of ivermectin

compared to DEC with less adverse events in ivermectin treated groups. The microfilaridermia remained low

(below 10%) during the year following the administration of a unique dose of ivermectin. An important

observation was the decrease of microfilariae in the anterior chamber of the eye. Another phase three trial with

larger sample sizes was carried out in Côte d’Ivoire, (Lariviere et al., 1989a,b,c), Ghana, (Dadzie et al., 1989; Awadzi

et al., 1989) Mali (Vingtain et al., 1988), Togo (Hussein et al., 1987) and Liberia (Taylor and Greene, 1989; Newland

et al., 1988; White et al., 1987). All the results of phase I, II and III indicated that ivermectin could be used for mass

treatment of onchocerciasis. The phase IV studies were then carried out with the objective of measuring the effect

of repeated treatments on microfilaridermia, the symptoms of onchocerciasis and the transmission of the disease.

African Programme for Onchocerciasis Control

In Africa, two key events marked onchorcerciasis control in 1987. In October of that year, ivermectin (Mectizan®),

which proved to be both well tolerated and efficient against O. volvulus microfilariae, was authorized for

commercialization for the treatment of human onchocerciasis in France. Soon after, Merck and Co., Inc took an

unprecedented decision to provide it free of charge as long as needed, to those who would ask for it to treat

onchocerciasis everywhere in the world. Merck took this decision, working in collaboration with renowned experts

in public health and parasitology, the World Health Organizaton and other agencies to combat the disease in the

endemic countries. This historic decision came nearly five years after the first human clinical trials in Dakar,

Senegal (Aziz et al., 1982). The Mectizan Donation Programme (MDP) was created the same year to coordinate the

activities related to the donation (Boussinesq et al., 1997). The drug donation facilitated the launching of the

African Programme for Onchocerciasis Control (APOC).

APOC objective and strategy

The objective of APOC was to control onchocerciasis as a public health problem from the 19 endemic countries

outside OCP area by establishing sustainable ivermectin‐based treatment projects in zones where onchocerciasis

was meso or hyperendemic.

The strategy was based on the Community‐Directed Treatment with Ivermectin (CDTI). This relied on the massive

participation of endemic communities. Members of these communities were invited to appoint people called

community‐directed distributors (CDDs), who were then trained by the local health officers and NGO. The CDDs’

tasks were to sensitize the population, carry out a census of the community members, distribute Mectizan®,

monitor treated individuals for SAEs and report them to the nearest health facilities. The CDDs worked under the

supervision of the local health staff (Homeida et al., 2002)..

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The objectives of MDP are to supply Mectizan® to countries in need and to ensure an adequate use of drug as well

as the appropriate medical monitoring of adverse events. The MDP also put in place an expert committee

(Mectizan® Expert Committee, MEC) made up of independent scientists who provide technical support (MEC/TCC,

2004). This committee assess the quality of Mectizan® distribution projects submitted to MDP by endemic

countries, follow Mectizan® distribution process and seek to ensure the best possible use of the drug (Alleman et

al., 2006). This drug donation led to the involvement of Non Governmental Organizations in the control of

onchocerciasis. Between 1989 and 1994, Non Governmental Development Organizations (NGDOs) set up

ivermectin distribution programmes in several onchocerciasis foci in Africa. In 1991, an NGDOs coordination group

for onchocerciasis control was born in Geneva at the WHO headquarters. In 1995, building on the OCP experience,

many international organizations launched in partnership with endemic countries, donor countries and the NGOs

coordination, the African Programme for Onchocerciais Control (APOC). The programme was based on a

partnership involving various United Nations organizations, the governments of the participating countries,

endemic countries, NGOs, donor countries and the private sector (Merck & Co., Inc through the Mectizan®

Donation Programme). About thirty NGOs are presently involved in onchocerciais control in Africa. Some of them

are: Christoffel Blinden mission, Global 2000 River blindness Programme of The Carter Centre, Healthnet

International, Helen Keller International, Inter Church Medical Assistance, Lions Club International Foundation,

l’Organisation pour la Prévention de la Cécité and Sight Savers. In some countries, local NGOs take part in APOC

activities. Examples of these include Perspectives in Cameroon, Mission to Save the Helpless in Nigeria and

Christian Association of Liberia in Liberia (Cross, 2000). WHO is the programme executing agency, with the

headquarters in Ouagadougou, Burkina Faso. The financial agent is the World Bank, which set up a special fiduciary

fund where contributions from donors were paid to finance the programme activities. The Bank coordinated

actions from all the donors and mobilized funding for the programme.The endemic participating countries are

Angola, Burundi, Cameroon, Congo, Democratic Republic of Congo, Ethiopia, Equatorial Guinea, Liberia, Malawi,

Nigeria, Uganda, Central‐African Republic, Sudan, Tanzania and Chad.

Effect of the drug on the transmission of onchocerciasis

The use of ivermectin at the usual dose induces an important reduction of microfilaridermia. This reduction

persists for three to six months (Pion et al., 2011; Basanez et al., 2008) and has an impact on the number of

microfilariae that the vector can ingest during a blood meal. The impact of treatment on the transmission was

demonstrated for the first time in Liberia (Cupp et al., 1986). These authors compared the number of microfilariae

intake by Simulium from patients treated with ivermectin, DEC and placebo three weeks before. This intake was

significantly reduced in patients treated with ivermectin. In Ghana, two months after a unique dose of ivermectin,

it was shown that transmission indicators were reduced from 85 to 65% compared to the initial value (Remme et

al., 1989). In the Vina valley in Cameroon, after five years of annual treatment with ivermectin, the prevalence of

microfilaridermia in children aged 5 to 7 years old who had never been treated was reduced to 55.4%,

demonstrating a reduction in the transmission of onchocerciasis (Boussinesq et al., 1995).

Repeated treatments with ivermectin significantly contributed to the reduction of the impact of onchocerciasis in

more than 25 countries. In addition, the transmission of the disease has been interrupted in some foci in at least

10 countries and onchocerciasis is no longer seen in children in many formerly known endemic countries.

Consequently, ivermectin monotherapy for onchocerciasis control has grown tremendously, receiving funding,

technical and logistical support from international public health donors.

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Problems associated with the use of ivermectin for onchocerciasis control

The control of onchocerciasis presently depends on mass drug distribution (MDD) using ivermectin. As at now, it is

the only drug that is being used for the mass treatment of onchocerciasis. It is given free of charge by Merck and

Co. for as long as needed.This and the use of vector control measures have been extremely effective in abating the

public health impact of onchocerciasis (Molyneux, 2005; Boatin et al., 1997). Unfortunately, there are many

problems with the use of ivermectin for onchocerciasis control. Some of these are described below:

Ivermectin is effective against the microfilariae that cause the severe manifestations of the disease. Its

main limitation is that it has little effect on the adult worms that continue to produce microfilariae and

hence re‐treatment is required at intervals that clinicians in many on‐going programmes have not

definitely determined or agreed upon. It reduces microfilariae load but does not interrupt transmission as

it is incapable of reducing the levels of infestation below those necessary to sustain transmission. At least

two treatments per year need to be continued for a long period of time. Pregnant women, breastfeeding

mothers and children below 5 years are also excluded in ivermectin treatment programmes.

There is mounting clinical and molecular evidence that resistance to ivermectin by O. volvulus is emerging

(Ardelli and Prichard, 2004; Awadzi et al., 2004a,b; Bourguinat et al., 2007; Osei‐Atweneboana et al.,

2007; Lustigman and McCarter, 2007; Canul‐Ku et al., 2011). The emergence of resistance to ivermectin

was first suggested in Ghana where sub‐optimal responses were reported in O. volvulus multi‐treated

populations (Awadzi et al., 2004a,b). Recently, it was noticed that the ability of ivermectin to suppress

microfilariae repopulation was reduced in some communities which had received mass treatment for 6 to

18 years (Osei‐Atweneboana et al., 2007, 2011). Besides these phenotypic suspicions of resistance, many

studies have revealed that selections are occurring in some genes of the parasite such as ABC transporters

(Ardelli and Prichard, 2004, 2007;Ardelli et al., 2006a), P‐glycoprotein (Ardelli et al., 2005, 2006b; Eng and

Prichard, 2005), β‐tubulin (Eng and Prichard, 2005; Eng et al., 2006; Bourguinat et al., 2006, 2007) and P‐

glycoprotein like protein (Bourguinat et al., 2008). In studies conducted in the Mbam valley, a

hyperendemic region for onchocerciasis in Cameroon, it was shown that the genetic selection induced by

ivermectin treatments was associated with a lower reproductive rate of the heterozygote female

parasites (Gardon et al., 2002).

Despite these phenotypic and genotypic studies, the unequivocal proof of resistance has yet to be established. It

was demonstrated that some confusing factors related the host immunological status (Ali et al., 2002; Babayan et

al., 2010), the drug compliance (Cabaret, 2010) and the population dynamics of the parasite (Pion et al., 2011) can

be implicated in drug failure, leading to an inaccurate conclusion of resistance.

Adverse events following treatment with ivermectin have been described, especially in patients

harbouring very high microfilarial loads. The pathogenesis of these post treatment adverse events is not

yet well described. These adverse events are categorised as follows:

• Minor and moderate adverse events

In the savanna regions, adverse events are minor or moderate. These adverse events occur after 24 to 48 hours

after treatment and consist of itching, fever, joint pain, muscle pain, headache, dizziness, general pain, oedema

and cutaneous eruption. The intensity of these adverse events depends on the intensity of infection (Whitworth et

21


al., 1991). More serious clinical adverse events (orthostatic hypotention) were described in West Africa (Awadzi,

2003; Chijioke and Okonkwo, 1992; Awadzi et al., 1989; De Sole et al., 1989a,b). The incidence of these adverse

events also depends on the prevalence of onchocerciasis and the regions. It has been reported to vary from 13 to

59.1% (Njoo et al., 1993; De Sole et al., 1989b; Kipp et al., 2003). The incidence of adverse events decreases

significantly with the years of treatments.

Immunological and pathological studies have demonstrated that minor and moderate adverse events after

treatment with ivermectin are due to inflammatory reactions associated with the destruction of microfilariae

(Wildenburg et al., 1994; Ackerman et al., 1990). It had been suggested that lipopolysaccharides (LPS) released by

endosymbiotic Wolbachia play a role in the pathogenesis of adverse events (Cross et al., 2001; Keiser et al., 2002).

It has now been shown that Wolbachia does not contain LPS and that the inflammation is driven by Wolbachia

lipoproteins (Turner et al., 2009) At the level of the eye, ivermectin provokes a transitory increase of the number

of microfilariae in the cornea, inducing a transitional blurred vision (Boussinesq, 2005). All these minor and

moderate adverse events regress spontaneously but some may need symptomatic treatment such as antalgic, anti‐

inflammatory or antihistaminic drugs.

• Severe adverse events in loaisis co‐endemic areas

The major obstacle in the control of onchocerciasis, particularly in Central Africa, is the occurrence of severe

adverse events (SAEs) after treatment with ivermectin in areas where onchocerciasis is co‐endemic with loaisis.

These post treatment reactions occur in patients harbouring high Loa loa microfilarial loads (> 8000 mf/ml)

(Boussinesq et al., 1998; Gardon et al., 1997). These adverse events are classified in two main categories, SAEs

without neurological signs and probable L. loa encephalopathies related to treatment with ivermectin.

o Adverse reactions without neurological signs

The first category corresponds to patients who do not present neurologic signs but their conditions necessitate

hospitalisation. Reactions in these patients start twelve to twenty‐four hours after treatment. Predominant

symptoms are severe headaches, fever, general pain, severe joint pains, anorexia, nausea, vomiting and diarrhoea.

These symptoms are so severe in some patients that they cannot stand up. In some patients, there are conjunctiva

and retinal haemorrhages (Fobi et al., 2000) while others develop kidney problems (Ducorps et al., 1995). The

duration of these reactions is variable. Hospitalisation is generally around 4 days but in some rare cases it has been

prolonged to two weeks. Patients with these reactions recovered without sequels. It is difficult to know if providing

prompt and proper medical care to patients with SAEs can avoid their worsening into neurological cases and

coma, but observations in some areas in Cameroon tend to confirm this hypothesis (Fokom Domgue, 2006).

Patients developing this first category of SAEs are those with 8000 mf/ml of L. loa and above.

o Probable L. loa encephalopathies related to the treatment with Ivermectin (PLERI)

PLERI are SAEs with neurological involvement occurring after treatment with ivermectin in patients with very high

microfilarial loads (> 30 000 mf/ml) ( Boussinesq et al., 1998; Gardon et al., 1997; Twum‐Danso, 2003a,b). To be

admitted as a PLERI patient, neurological symptoms should start within the week after the treatment of a healthy

individual. Four case definitions have been adopted for neurological post ivermectin SAEs (Twum‐Danso, 2003b):

22


Definite Case of Loa encephalopathy

- Encephalopathy in which brain tissue obtained by autopsy or by needle sampling has microscopic findings

consistent with L. loa encephalopathy (vasculopathy with evidence of L. loa microfilariae as a likely

aetiology);

- Onset of Central Nervous System (CNS) symptoms and signs within 7 days of treatment with ivermectin;

illness progressing to coma without remission.

Probable Case of Loa encephalopathy

- Encephalopathy (without seizures, usually with fever) in a person previously healthy and who has no

other underlying cause for encephalopathy;

- Onset of progressive CNS symptoms and signs within 7 days of treatment with ivermectin; illness

progressing to coma without remission;

- Peripheral blood L. loa > 10,000 mf/ml pre‐treatment or > 1,000 mf/ml within 1 month post‐treatment or

> 2700 mf/ml within 6 months of treatment; and/or L. loa microfilariae present in cerebrospinal fluid

(CSF) within 1 month post‐treatment.

Possible Case of Loa encephalopathy

- Encephalopathy (without seizures, usually with fever) in a person previously healthy and who has no

other underlying cause for encepahalopathy;

- Onset of progressive CNS symptoms and signs within 7 days of treatment with ivermectin; illness

progressing to coma without remission;

- Semi‐quantitative or non‐quantitative positive (i.e. +, ++, +++) L. loa microfilariae in peripheral blood

within 1 month post‐treatment.

Encephalopathy of other known aetiology

- Encephalopathy with sufficient clinical information to determine an etiology other than L. loa (e.g.

cerebral malaria)

Pathophysiology of post Ivermectin SAEs: Many hypotheses have been put forward to explain the

pathophysiology of post ivermectin SAEs. The first is the mechanical phenomenon due to the paralysis of an

important number of microfilariae in the blood stream following treatment with ivermectin. These microfilariae

are drained to the microcirculation, creating micro‐embolism and difficulty in the oxygenation of the brain and

other organs. The conjunctivae and retinal haemorrhage that occur at the level of the capillaries (Fig. 6) are in

favour of this hypothesis (Fobi et al., 2000). Another hypothesis is the passage of the microfilariae into the brain

parenchyma. The third hypothesis is the vasoconstriction of the capillaries following a complex formed by the L.

loa antigen and antibody following the death of microfilariae. The last hypothesis is the intravascular disseminated

coagulation. In some cases, it has been described as generalized haemorrhage in the brain, the kidney and the liver

(Kamgno et al., 2010).

It has also been suspected that strain variation may be responsible. Consequently, it has been hypothesized that

those who developed SAEs may be infected by a strain of Simian L. loa which has nocturnal periodicity. The

23


periodicity of L. loa was studied in cases of SAEs and controls that took the treatment but did not develop SAEs.

The periodicity was similar in cases and controls (Kamgno et al., 2009). The results of this study suggest that post‐

ivermectin SAEs are not related to an infection with a simian Loa strain. Autopsy examinations in the Adamaoua

Region of Cameroon also revealed no microfilaria in the brains or in other tissues examined. The lungs samples

showed a neutrophil infiltration of the alveolar walls and space probably due to acute pneumonia. Two major

changes were described in the brain in association with the small and medium size blood vessels. A moderate

perivascular accumulation of inflammatory cells and significant thickenings of the basement membrane and

associated pericytic layer of various size vessels (Kamgno et al., 2008). These lesions in the brain have similarities

with those described in previous reported cases of death due to L. loa following diethylcarbamazin treatment.

Figure 6. Sub‐conjunctival haemorrhage in a post ivermectin SAE case

Incidence of SAEs: A pilot study of post ivermectin SAEs which was carried out in the Lékié area of the Centre

Region of Cameroon showed an incidence of PLERI of 1.1 cases per 10,000 treatments and the non neurological

SAEs of 5 per 10,000 treatments (Gardon et al., 1997). In a recent review, a cumulative incidence of 4.2 cases of

SAEs per 100,000 treatments including PLERI and non neurological SAEs over a period of 10 years in Cameroon

(1999 to 2009) was reported (Kamgno et al., 2011).

24


In addition to all of the above, there can be acute accidental intoxication with ivermectin (7 – 8 mg/kg)

which is correlated with a clinical presentation showing vomiting, sedation and mydriasis. On the other

hand, doses of 120 mg/kg, ten times the normal adult dose for onchocerciasis treatment, was

administered to healthy subjects, without any toxicity (Guzzo et al., 2002).

There have been suggestions that ivermectine can cause teratogenic effects. However, studies have not

shown any such effects on animals treated with normal doses (Poul, 1988; Keisler et al., 1993). In

Cameroon and Liberia, a follow up of pregnant women who ignored their pregnancy status and took

ivermectin during mass treatment was conducted. No difference was found between children of

accidentally treated pregnant women and those of untreated ones (Chippaux et al., 1995; Pacque et al.,

1990).

APOC achievements

It was estimated in 2005 that 500,000 DALYs per year were averted, 177,000 communities were mobilized and a

workforce of 261,000 community distributors was trained and made available for other programmes. For the past

Quarter century (1987‐2012), over 800 million people have been treated with ivermectin for the control of

onchocerciasis in 16 countries. The economic rate of return was put at 17% and US$7 per DALY was averted

(Hodgkin et al., 2007). However, in assessing the benefits accrued through these control programmes, it is

important to also consider the number of deaths avoided in addition to the cost‐effectiveness of treatment and

the number of people prevented from becoming blind (Benton, 1998; Waters et al., 2004).

The sustained political commitment of national governments, bilateral donors, and NGDOs and the long‐term

support of onchocerciasis control coupled with the regional approach, the contribution of a diverse group of

stakeholders (Seketeli et al., 2002) and the emphasis on continued operational research contributed to a large

extent in the success levels attained by APOC.

APOC challenges

Despite the achievements of OCP and APOC, onchocerciasis has not been eradicated. Early hopes that mass

treatment with ivermectin would eradicate the disease by breaking transmission have not been realized

(Borsboom et al., 2003). Estimations based on REMO show that the mean infestation rate among countries

targeted by APOC is around 38%, with 87 million people at risk of infection (Hotez and Kamath, 2009). In 2005,

APOC estimated that in Africa, 37 million people carried O. volvulus and 90 million were at risk (APOC, 2005).

Wars and treatment complications linked to onchocerciasis and loasis co‐endemicity have been major

impediments to the expansion of APOC activities in Central Africa. In areas that are hyperendemic with L. loa,

ivermectin is contraindicated as there is a risk of (SAEs) following treatment in people who have a high

microfilaraemia of L. Loa. This can result in encephalopathy (Gardon et al., 1997; Boussinesq et al., 2006).

Furthermore, the difficult terrains in most of Africa, specific epidemiological conditions and socio‐economic

limitations have contributed in maintaining onchocerciasis in the continent. The movement of human populations

and frequent social and political upheavals in the African Region increases the risk of transmission and/or re‐

emergence of onchocerciasis.

25


Onchocerciasis control strategies in Cameroon

Introduction

Cameroon set up a national programme for onchocerciasis control in 1991. Its structure was a reflection of the

Cameroonian public health system. It has three levels: a central level made up of the central departments of the

Ministry of Public Health and the General and Central Hospitals, intermediary level made up of Regional

Delegations of Public Health and Regional Hospitals and a peripheral level comprising 189 Health Districts and

1689 Health Centres. The Health District is the basic implementation level of health programmes and projects and

hosts a district hospital. There are two dialogue structures whose members are elected by the populations at the

district level: the management Committee of the District and the District Health Committee. The health district

consists of several health areas, some of which may have Integrated Health Centres run by nurses. At the level of a

health area, there is a Health Committee and a Management Committee. These are dialogue structures

participating in the mobilization of the populations around health‐related projects and programmes.

The National Onchocerciasis Control Programme (NOCP) works under the aegis of the National Onchocerciasis Task

Force (NOTF) presided over by the Director of Disease Control of the Ministry of Public Health. The other members

of this group are: the persons in charge of health facilities in endemic areas, the representatives of the NGDOs

participating in onchocerciasis control in Cameroon, Lions Club International and members of research institutes

working on filariasis in Cameroon. In 2003, a loasis Technical Adviser in charge of the surveillance system of SAEs

events that occur after treatment with ivermectin was added to this organization and in 2005, the Centre for

Reearch on Filariasis and other Tropical Diseases (CRFilMT) was also added to it. The programme is run on a daily

basis by a Permanent Secretary who ensures its coordination.

Identification of priority populations to be treated in Cameroon

At the time of the NOCP initiation, very little data regarding onchorcerciasis endemicity were available in

Cameroon, even though the main foci were already known. As a result, a survey based on the Rapid

Epidemiological Assessment of Onchocerciasis (REA) and REMO principles was carried out in 1992 throughout the

entire Cameroonian territory (Ngoumou et al., 1994). These surveys led to the mapping of areas where

onchocerciasis was meso‐ or hyper‐endemic (that is where the nodule prevalence in men aged 20 or more is over

20%) in the country and priority areas where ivermectin should be distributed. This mapping was particularly

important in forest areas endemic for loasis where there is a risk of SAEs after treatment with ivermectin.

Consequently, it was essential to properly define onchocerciasis endemic areas in order to reduce the risk of

treated individuals developing post‐therapeutic SAEs, when the advantage associated with the treatment is not

well established. Therefore in these areas, REA was conducted to refine the distribution of onchocerciasis. Rapid

Epidemiological Assessment of Loiasis (RAPLOA) (Takougang et al., 2002; Wanji et al., 2005) and parasitological

surveys were also conducted to determine the level of endemicity of loiasis (Kamgno et al., 1997; Kamgno and

Boussinesq, 2001) and to put in place proper measures for the prevention and management of post ivermectin

SAEs) following the Technical Consultative Committee (TCC) and Mectizan Expert Committee (MEC)

recommendations. The results of these surveys as well as those achieved in the parasitological surveys (Kamgno et

26


al., 1997; Kamgno et al., 1998; Kamgno and Boussinesq, 2001) helped to determine the meso‐ and hyper‐endemic

areas eligible for CDTI as well as hypo‐endemic areas that are not CDTI‐ eligible in the whole country.

Evolution of onchocerciasis control strategies in Cameroon

Early large scale distributions

In 1987, ivermectin distribution focusing on a few thousand people was organized in the framework of phase IV

clinical drug trials. These studies were carried out in the Vina valley by ORSTOM team (currently called IRD) and in

the South West Province by a team from the Institute of Medical Research and Medicinal Plant Studies (IMPM)

(Boussinesq et al., 1993a,b; Somo et al., 1993a,b; Chippaux et al., 1999).

In 1989, the German Technical Cooperation, GTZ (Gesellshaft fur Technische Zusammenarbeit) launched the

ivermectin distribution programme in the Littoral province. Between 1992 and 1995, three NGDOs namely, the

River Blindness Foundation (RBF) (now the Carter Center), International Eye Foundation (IEF) and Helen Keller

International (HKI) signed agreements with the Ministry of Public Health to set up distribution programmes in

other provinces of Cameroon. Treatment strategies varied according to regions.

Community‐based strategies

In 1994, the NGDOs for onchocerciasis control gathered around Lions Club International Foundation (LCIF) to form

a coalition for onchocerciasis control in Cameroon. In 1995, the LCIF launched the “Sight First” project. Thereafter,

another NGDO, Sight Savers International (SSI), started a Mectizan® distribution programme in Nanga Eboko

district.

Ivermectin was distributed through two strategies described as “advanced strategy” (wherein nurses moved

around with their motor cycles from village to village to administer the drug) and “community‐based”. In the latter

case, community‐directed distributors (CDDs) appointed by the population distributed the tablets but the health

staff still had an important role to play in the process. They had to number the households, order Mectizan®,

determine the distribution period, monitor the adverse events and write up the distribution reports. Community

members helped the health staff and participated in the population mobilization. The distribution costs were still

very high and the geographic and therapeutic coverage rates were most often very low due to difficulties to reach

some communities.

The advent of the African Programme for Onchocerciasis Control in Cameroon

In 1996, APOC objectives and strategies were presented to Cameroonian authorities. The following year, a

convention covering the period from 1996 to 2001 was signed between the Ministry of Public Health and the

Directorate of APOC. The first distributions organized in the framework of APOC took place in 1999. The two

memoranda covering the period from 2001 to 2007 and the disengagement of APOC (2008‐2010) were signed in

2001. These conventions allowed different partners to submit requests for funding to APOC for CDTI projects

covering either a province of the country or a part of the province. These projects were funded up to 75 % by APOC

and the NGDO for the first year, and the remaining 25 % by Cameroon Government. APOC participation, which was

27


agreed to last 5 years, was supposed to decrease gradually while that of the government had to increase

progressively to ensure the sustainability of the programme. To date, 15 CDTI projects have been funded in

Cameroon that cover the ten regions of the country.

Difficulties related to onchocerciasis control in Cameroon

The difficulties associated with onchocerciasis control in Cameroon are: duration of treatment programmes, cost

recovery and SAEs.

i. Duration of treatment programmes

Mectizan® is a microfilaricide, with a limited effect on adult worms (Duke et al., 1991). It should be administered on

a repetitive basis each year. Mathematical simulations showed that, in order to be able to eliminate onchocerciasis

as a public health problem, 25 years of Mectizan® distribution would be necessary if programmes were able to

keep the therapeutic coverage rate at 65 %. According to previsions from developed models, if the interval

between treatments is six months rather than 12, then the duration of the programme might be halved (Winnen et

al., 2002), but this assertion is not true in all contexts.

ii. Cost recovery

The strategy for onchocerciasis control in Cameroon underwent, like the health system of the country, a number of

modifications since the NOCP was established. In 1991, when the NOCP was set up, cost recovery was a strong

principle of the Cameroon health system. As such, the NOCP adopted it. Mectizan® was received from MDP free of

charge but delivered to patients against a payment of CFA 100 (0.25 $). This cost recovery lasted until 1996 when

APOC was being established.

During the consultations with APOC officials, Cameroon expressed the wish to maintain the principle of cost

recovery despite APOC’s reticence, which dreaded its negative impact on the population’s compliance with

treatment. In this way, Cameroon unlike other countries adopted the CDTI strategy recommended by APOC but

with a particularity, the cost recovery. The CDDs received 25 F per treatment. Later on, under the pressure of

NGDOs and taking into account the fact that in some poor families, parents could afford their own drug but not

that of children, the treatment cost was reduced (10 F CFA) for children less than 15 years‐old. It was also decided

that treatment should be free of charge for poor people.

In 2002, due to a very low coverage, notably in areas where SAEs occurred, the government decided that

treatment should henceforth be free for everybody. When this decision was taken, the problem of the payment of

CDDs emerged. The Cameroon government therefore decided to pay them directly at the rate of 25 F CFA per

treated individual. This is the policy applied to date.

iii. Severe adverse events occurring after treatment with ivermectin

In Cameroon, adverse events occurring after treatment with ivermectin constitute an important obstacle

depending on the geographic areas. In areas where loasis is absent or where the prevalence and parasite load are

below 20%, adverse events are minor or moderate. On the contrary, in areas where onchocerciasis and loasis are

co‐endemic, SAEs may occur after treatment with ivermectin. These therapeutic accidents occur in people whose

parasitic loads of L. loa are very high (> 8000 mf/ml) (Gardon et al., 1997; Boussinesq et al., 1998).

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29


Chemotherapy and immunology of onchocerciasis:

insights from the bovine model

Introduction

Research in onchocerciasis particularly that concerned with chemotherapy and immunity has been limited by the

lack of suitable animal models for O. volvulus since the parasite is very host restricted and naturally infects only

humans and gorillas. Of all animal models used to date, it is only in chimpanzees that the infection closely

resembles that in humans. This is, however, impractical for use on a large scale for research due to the cost, ethical

and conservation concerns (Copeman, 1979).

O. ochengi/cattle model for onchocerciasis research

As a result of the availability of cattle Onchocerca parasites from abattoir material and their generic relationship to

O. volvulus, bovine Onchocerca species have been extensively used in comparative studies. O. gibsoni has been

used in drug evaluation (Copeman, 1979). Unfortunately, the deep anatomical location of many bovine species

makes them unsuitable for many research studies as their viability can only be assessed on a single occasion at

post‐mortem of the host (Trees et al., 1998). This difficulty does not apply to O. ochengi.

The cattle O. ochengi forms nodules that closely resemble those formed by O. volvulus (Renz et al., 1995; Achukwi

et al., 2007). The adults of O. ochengi which are widely distributed in West Africa form multiple intradermal or

subcutaneous nodules that can be enumerated non‐invasively by palpation and sequential nodulectomies

undertaken easily to study the kinetics of the response of the macrofilariae to drugs. O. ochengi also shares some

characteristics in common with O. volvulus, such as a common arthropod vector, S. damnosum (Wahl et al., 1998)

and a very close phylogenetic relationship (Bain, 1981; Xie et al., 1994). Drug activity against microfilariae can be

evaluated by skin biopsies of the abdominal skin (Trees et al., 1998; 2000). These characteristics render the readily

accessible cattle O. ochengi a favourable model system for in vivo immunological and chemotherapeutic studies on

onchocerciasis that are not possible in humans.

A lot of studies have been carried out on this model. Published results of the studies have direct relevance to the

development of complementary therapy for river blindness given the difficulties of eliminating onchocerciasis with

ivermectin alone (Borsboom, 2003) and rising concerns about suspected resistance to this drug (Awadzi, 2004a;

Bourguinat et al., 2007).

O. ochengi and chemotherapeutic studies

Chemotherapeutic studies with anthelmintics

In the early 1990s, a team of researchers from the Veterinary Research Laboratory of IRAD Wakwa‐Ngaoundere

30


and partners from the University of Tubingen (Germany) and the Liverpool School of Tropical Medicine (UK)

started to evaluate various chemotherapeutic agents in cattle naturally infected with multiple O.ochengi nodules.

The studies were financed by the WHO‐MACROFIL Programme.

As a result of the close phylogenetic relationship between O. volvulus and O. ochengi, drug activity against both

parasites would be expected to be similar. In fact, drugs with known activities against O. volvulus, have established

the predictive value of O. ochengi in cattle. It has been shown that the effects of a number of anti‐filarial

anthelmintics, including ivermectin, suramin and melarsomine on O. ochengi are similar to those against O.

volvulus (Renz et al., 1995; Trees et al., 1998). Melarsomine had lethal effects on both microfilariae and adult

worms. Suramin only had partial effects on all worms.

Ivermectin, which was originally developed for veterinary use, has been integrated in onchocerciasis control

strategies despite the fact that there is a major stage‐related change in its efficacy against O. volvulus. Even at high

doses, it is lethal only to the L1 larvae and not to the adult worms. In adults, there is induction of some

degenerative changes in some worm tissues and the abrogation of embryogenesis but this is reversible (Kläger et

al., 1993). Its effect on the infective larvae (L3) and hence its prophylactic potential is uncertain. Tchakouté et al.

(1999) assessed the prophylactic potential of ivermectin against naturally transmitted O. ochengi in a controlled

prospective study in Wakwa‐Ngaoundere involving calves. Calves exposed to natural, fly transmitted challenge

were treated monthly with ivermectin at either 200 µg/kg or 500 µg/kg for 21 months. Infection was completely

prevented in 15 treated calves while 5 out 6 untreated controls became infected and had patent

microfilaridermias. The implication of this for humans is that strategic chemotherapy at times of maximal

transmission can be considered prophylactic as well as therapeutic against O. volvulus infection. However, for this

to be applied for mass human treatment, studies are needed to establish treatment intervals and doses required

to provide prophylaxis.

The efficacy of UMF‐078, a modified flubendazole was assessed in vivo in O. ochengi at two dosage rates by

Bronsvoort et al. (2008). Following treatment at 150 mg/kg intramuscular, nodule diameter, worm motility and

worm viability declined significantly. Embryogenesis was abrogated and death of all adult worms occurred by 24

weeks post treatment. These effects were less pronounced at 50 mg/kg intramuscular. Although no toxic signs

were observed in this trial, other studies have raised concerns regarding neuro‐ and genotoxicity with UMF‐078

(Trees et al., 1998; El‐Makawy et al., 2006).

Antibiotic therapy for onchocerciasis

The Cameroonian, British and German research group at IRAD Wakwa in North Cameroon through a chance

observation found that in an animal infected with over 100 O. ochengi nodules intended for a chemotherapeutic

trial, repeated treatment with oxytetracycline for an incidental skin infection of Dermatophilus congolensis led to

the resolution of all nodules. Also, all microfilariae were cleared from the skin of a similarly treated animal being

used for infective larvae production. In this latter case, there was subsequently no uptake of mf by feeding black

flies with a resultant zero infective larvae development in the black fly. These observations and increasing

knowledge of the existence of intracellular bacteria (Wolbachia) in filarial nematodes (Kozek and Marroquin, 1977;

Henkle‐Dührsen et al., 1998; Taylor and Hoerauf, 1999) encouraged the researchers to carry out a trial. They

demonstrated that treatment with oxytetracycline was macrofilaricidal. Embryogeneis was blocked in the female

worm, and existing microfilariae in the skin eventually disappeared as they were cleared by attrition when they

31


reached the end of their natural life span. The O. ochengi intradermal nodules were also resolved by nine months

post treatment in cattle treated intermittently for six months (Langworthy et al., 2000). Serial electron‐microscopic

examination showed that the macrofilaricididal effects were related to the elimination of intracellular bacterial

organisms. The sequential changes in the physical integrity of the organisms preceded the death of worms.

Contrary to long‐term intermittent treatment, short‐term intensive treatment that is given daily for 2 weeks

induces only transient and inconsequential effects on Wolbachia pipientis numbers and is not macrofilaricidal

(Gilbert et al., 2005).

Sequencing of a fragment of the 16s rRNA gene from the O. ochengi micro‐organisms showed them to be

Wolbachia organisms of the order Rickettsiales and were closely related to that of other Onchocerca species,

particularly O. volvulus (Bandi et al., 1998; Henkle‐Duhrsen et al., 1998).

The existence of Wolbachia as obligate intracellular bacteria in O. volvulus was first described by Kozek and

Marroquin (1977). Many filarial nematodes have a mutually dependent relationship with Wolbachia bacteria.

These endosymbionts are essential for worm development, fertility, survival and induction of inflammatory disease

pathogenesis. They are also required for successful early moulting as it has been demonstrated that the crucial

moulting step from L3 to L4 larvae is blocked by exposure of Wolbachia‐infected worms to tetracycline (Smith and

Rajan, 2000). They are Rickettsia‐like, matrilineally inherited and infect many species of invertebrates (Werren et

al., 1995; Stouthamer et al., 1999; Hise et al., 2004).

Implications for chemotherapy in humans

Wolbachia, like other Rickettsial bacteria, are susceptible to the tetracycline family of antibiotics (e.g. doxycycline),

azithromycin and rifampicin (Bandi et al., 1999 a, b; Townson et al., 2000). The existence of an almost identical

Wolbachia in O. volvulus suggests that anti‐Wolbachia treatment with these antibiotics may also be

macrofilaricidal. This can augment the success of long‐established mass treatment programmes by reducing side‐

effects that may result from the release of intact bacteria and Wolbachia products from dying nematodes (Cross et

al., 2001). Pre‐treatment targeting of Wolbachia may abrogate inflammatory responses and allow a wider range of

anti‐filarial drugs to be used (Hise et al., 2004). As a result of the fact that antibiotics do not affect the Wolbachia‐

negative L. loa which can provoke serious adverse reactions following ivermectin therapy, antibiotics can present

us a new strategy for onchocerca treatment in areas of co‐endemicity with L. loa.

The greatest obstacle to the use of antibiotic therapy in the control of onchocerciasis is the long duration of

treatment. Shorter treatment regimes are necessary if tetracyclines are to find their way into routine use against

onchocerciasis. Presently at IRAD Wakwa in North Cameroon, experiments in the proven cattle model on

chemotherapy of onchocerciasis which target Wolbachia endosymbionts of O. ochengi are being carried out with

the aim of developing optimum treatment regimes using existing drugs.

Mechanism of the macrofilaricididal action of antibiotics

Supporting evidence that the effect of the antibiotic is on the bacterial endosymbiont has been provided by studies

which showed that antibiotic treatment of Acanthocheilonema viteae and L. loa which do not contain Wolbachia

had no effect on the worm development or reproduction (Hoerauf et al., 1999; Brouqui et al., 2001). Further

32


evidence showing that antibiotics act indirectly by disrupting intracellular Wolbachia symbionts has been provided

in the review by Taylor et al. (2005).

Nfon et al. (2006) provided evidence with studies involving O. ochengi in cattle which suggest that worm killing in

onchocercomas is associated with a shift in the dominant granulocyte type surrounding the parasites, from

neutrophils to eosinophils. The presence of Wolbachia provokes neutrophil infiltration into the nodules. When

Wolbachia were eliminated following antibiotic treatment, few neutrophils were seen at sites where most bacteria

were killed. On the other hand, eosinophils which are adapted to killing worms were present in increased numbers

around worms and were observed degranulating on the filarial cuticle. These observations suggest that

accumulation of degranulating eosinophils over a prolonged period is a cause rather than an effect of parasite

death, and the macrofilaricidal mechanism of antibiotics may relate to facilitation of eosinophil infiltration around

worms by ablation of Wolbachia‐mediated neutrophilia.

It is still unclear whether the eosinophils are involved in parasite killing or if they are attracted secondarily to dying

worms. Hansen et al. (2010) tried to investigate this by giving adulticidal regimens of oxytetracycline or

melarsomine regimens to cattle infected with O. ochengi. Unlike oxytetracycline, melarsomine did not directly

affect Wolbachia viability. In the oxytetracycline group, eosinophil degranulation increased significantly and

nodular gene expression of bovine neutrophilic chemokines was lowest. Moreover, intense eosinophil

degranulation was initially associated with worm vitality, not degeneration. The data suggest that Wolbachia

confers longevity on O. ochengi through a defensive mutualism, which diverts a potentially lethal effector cell

response.

The bacterial depletion by antibiotics results in sterility of worms (through the blocking of female worm

development and embryogenesis), inhibition of larval development (by impairing microfilariae development into

L3 and interfering with moulting from L4 to adults) and inhibition of adult worm viability (Hoerauf et al., 2000a;

Casiraghi et al., 2002; Arumugam et al., 2008).

O. ochengi and immunological studies

As a result of the need for more control options for onchocerciasis, there has been growing interest in

investigating the existence of protective immunity in humans and its mechanisms, in identifying candidate vaccine

antigens and seeking evidence for prophylactic immunization. Again the O. ochengi cattle model has been an

appropriate tool for understanding the immunology of O. volvulus in humans as the biological and molecular

similarities between the two parasites and the ability to induce experimental O. ochengi infections in cattle have

made it possible to study the kinetics of immune responses to various antigens and challenge infections. This is

important for the possible development of vaccines.

Putative immunity

In endemic or hyperendemic areas, there are non‐infected individuals commonly referred to as endemic normals

or putatively immune (PI). The nature of this protective immunity has been difficult to examine in humans for

ethical reasons. Hence, Tchakoute et al. (2006) carried out a series of experiments with O. ochengi in cattle to

investigate the nature of functional immunity in onchocerciasis involving either exposure to natural field challenge

33


or experimental single‐pulse challenge. In an area endemic for O. ochengi, the authors demonstrated on the basis

of adult worm burdens that putative immunity also occurs in a subset within herds of infected cattle. The PI

animals were shown to be significantly less susceptible to heavy field challenge than age matched naïve controls.

Although they did not exhibit absolute refractoriness to O. ochengi infection, the burden of both adult parasites

and microfilariae in these animals was substantially lower than that in the controls and accumulated at a slower

rate.

Zooprophylaxis

It has been hypothesized that the predominant transmission of O. ochengi by S. damnosum in some areas of sub‐

Saharan Africa could lead to the protection of humans against onchocerciasis caused by O. volvulus. In order to

provide evidence for this, Achukwi et al. (2007) investigated whether exposure to O. volvulus could protect cattle

from O. ochengi. Gudali calves were vaccinated with live O. volvulus infective larvae and subsequently challenged

with O. ochengi infective larvae whilst raised in a fly‐proof house. The vaccinated‐challenged animals had 83–87%

less adult O. ochengi parasites than non‐vaccinated challenged animals. These findings support the idea of cross‐

protection (zooprophylaxis) due to inoculation of humans with O. ochengi infective larvae under natural

transmission conditions in endemic areas. In this experiment, no O.volvulus adult worms developed in the

vaccinated group. This is either due to their host specificity or the infective larvae were recognised and destroyed

by the cattle immune system before they could have a chance to grow to adult worms. The live O. volvulus‐

infective larvae most likely behaved like irradiation‐attenuated filarial larvae of other filariae parasites reported in

jird (Lucius et al., 1991).

O. volvulus and O. ochengi exhibit extensive antigenic cross‐reactivity as indicated by the serological recognition of

O. volvulus recombinant antigens by cattle infected with O. ochengi (Achukwi et al., 2004; Graham et al., 1999).

They can also generate cross‐protective responses both experimentally (Achukwi et al., 2007) and naturally (Wahl

et al., 1998a,b). Further evidence for all of this is provided by the fact that, molecular and biochemical comparisons

between O.volvulus and O.ochengi reveal almost identical antigenic and genomic profiles (Xie et al., 1994).

Vaccination trials

As a result of the fact that O. volvulus and O. ochengi have broad antigenic cross‐reactivity and generate cross‐

protective responses (Achukwi et al., 2004, 2007; Graham et al., 1999; Wahl et al., 1998a,b), the bovine O. ochengi

system was utilised to evaluate a recombinant vaccine in a field trial in a hyperendemic area of North Cameroon

(Makepeace et al., 2009). Naïve calves, reared in fly‐proof accommodation, were immunised with eight

recombinant antigens of O. ochengi, administered separately with either Freund’s adjuvant or alum. The selected

antigens were orthologues of O. volvulus recombinant proteins that had previously been shown to confer

protection against filarial larvae in rodent models and, in some cases, were recognised by serum antibodies from

putatively immune humans. The vaccine was highly immunogenic, eliciting a mixed IgG isotype response. Four

weeks after the final immunisation, vaccinated and adjuvant treated control calves were exposed to natural

parasite transmission by the black fly vectors in an area of Cameroon hyperendemic for O. ochengi. After 22

months, all the control animals had patent infections, compared with only 58% of vaccinated cattle. This study

shows that vaccination can reduce both the pathology and transmissibility of the infection and thus suggests that a

vaccine against microfilariae to prevent development of disease in humans may be achievable. Given that the

disease is associated with the microfilarial stage in onchocerciasis and that this stage is the key to transmission, an

34


anti‐microfilarial vaccine could be a very useful control option since it can abrogate transmission.

Tchakoute et al. (2006) also reported that vaccination with irradiated L3 of O. ochengi induced significant

protection against experimental challenge. Significantly lower worm burdens were observed in vaccinated animals

compared to controls after almost 2 years of continuous exposure to intense natural challenge from infected

Simulium. This is at variance with the failure of cattle to develop immunity after drug‐abbreviated infections. O.

volvulus‐infected humans treated with suramin, also became re‐infected after chemotherapy and developed

microfilariae loads at pre‐treatment levels (Duke, 1968). It seems that parasite death is an insufficient stimulus for

the induction of protective immunity. It has been suggested that immunity induced by irradiated L3 is mediated by

activated eosinophils (Bleiss et al., 2002; Le Goff et al., 2000; Abraham et al., 2004).

35


Antibiotic therapy for the control of onchocerciasis:

current status and perspectives

Introduction

The problems associated with the use of ivermectin for onchocerciasis control especially in the forest zones of the

Central African region where several cases of adverse reactions following ivermectin treatment were reported in

patients infected with L. loa (Chippaux et al., 1996; Gardon et al., 1997) have prompted a search for new filaricides

which could substitute ivermectin in areas of co‐endemicity and/or could be used to treat onchocerciasis without

affecting L. loa. In this regard, the discovery of Wolbachia endobacteria in some pathogenic human filarial

nematodes (Taylor et al., 1999; Taylor et al., 2005) but not L. loa (Büttner et al., 2003; McGarry et al., 2003)

presented an opportunity to take a novel approach to onchocerciasis treatment based on the use of antibiotics to

target the endobacteria (Hoerauf et al., 2001; Debrah et al., 2006). Such strategies have now been shown to be

effective in both the long‐term reduction of parasite loads and morbidity (Hoerauf et al., 2001). In animal studies,

it was observed that depletion of the Wolbachia using tetracycline not only had microfilaricidal effects but also led

to the sterility of female worms (Hoerauf et al. 1999) and the death of adult worms (Langworthy et al., 2000).

Similarly in humans, a 6‐week course of doxycycline treatment against O. volvulus depleted the bacteria, resulted

in a blockage of embryogenesis and killed the adult worms. These effects were reflected in sustained reductions in

skin microfilariae (Hoerauf et al., 2003a,b). These findings have demonstrated the superior pharmacological

efficacy of doxycycline for the treatment of onchocerciasis (Hoerauf, 2006). Macrofilaricides have a higher

potential for sustainable onchocerciasis control but this can only be guaranteed through high coverage and

compliance (Brieger et al., 2007). This is particularly important for a drug such as doxycyline that must be taken on

a daily basis for 6 weeks.

In this section, we describe:

• Antibiotic therapy in onchocerciasis by highlighting the scientific basis for the use of antibiotics;

• Treatment options with different antibiotics and how antibiotic therapy could substitute ivermectin in

problem areas where there are risks of SAEs and resistance by O. volvulus to ivermectin;

• The use of antibiotics for the treatment of onchocerciasis through the community directed approach.

A new opportunity for the treatment of onchocerciasis: the endosymbiont Wolbachia

The endosymbiont Wolbachia has generally been thought to be widespread in filarial nematodes, including the

major pathogenic filariae of humans such as Wuchereria bancrofti, Brugia malayi and O. volvulus (Casiraghi et al.,

2004). However, new evidence from a recent large‐scale survey indicates that the number of Wolbachia‐free

filarial species is greater than expected among filariae of mammals (Ferri et al., 2011). They belong to the order

Rickettsiales and are closely related to the genera Ehrlichia, Cowdria and Anaplasma. They are found in the body

wall (the hypodermis), in oocytes, in all embryonic stages and in microfilariae. Wolbachia spp in filariae seem to

have evolved as symbionts essential for the fertility of their nematode hosts and are transmitted transovarially to

the next worm generation like mitochondria.

36


Among the important filarial species investigated so far using PCR, only five species, the human filaria Loa loa, the

rodent filariae Acanthocheilonema viteae and Monanema martini, the deer filaria Onchocerca flexuosa and the

horse filaria Setaria equina appear to be free of symbionts. In filarial species positive for Wolbachia, all isolates

examined have been found to harbour this bacterium, showing identical or nearly identical gene sequences

throughout the geographical distribution of the worm (Bandi et al., 1998; Fenn et al., 2004). In addition, the

phylogeny of Wolbachia endosymbionts is congruent with the phylogeny of their host nematodes. The distribution

and phylogenetic patterns of Wolbachia in filarial nematodes indicate that the association is stable and specific

and suggests a long co‐evolutionary history (Bandi et al. 1998). This suggests co‐adaptation and reciprocal

dependence between filarial nematodes and their Wolbachia. These observations encouraged researchers to

hypothesize that antibiotic treatment against Wolbachia may be detrimental to the nematode. This has been

shown in animal studies on a variety of filarial species (Langworthy et al., 2000; Smith et al., 2000; Casiraghi et al.,

2002; Rao et al., 2002). Antibiotics have been used to deplete the endosymbionts from filariae and show the

mutualistic symbiosis between filarial Wolbachia and their hosts (Hansen et al., 2010). Depletion of Wolbachia

resulted in the disruption of embryogenesis in female worms.

Anti‐Wolbachia treatment: current status

Lessons from animal models

As shown above, several reports have described the effects of antibiotics on filarial nematodes in experimental

animal models. More importantly, members of the tetracycline family (oxytetracycline, doxycycline, minocycline)

have been found to be effective against filarial worms. The modes of action of these antibiotics are generally on

bacterial RNA polymerases, protein synthesis and other processes. They may affect similar pathways in both

worms and their Wolbachia.

In several nematode infections, the antibiotics have multiple effects on worm growth and development, worm

fertility (particularly female worm embryogenesis) and worm survival, with evidence suggesting that prolonged

treatment can be detrimental to worms (Bosshardt et al., 1993; McCall et al., 1999; Casiraghi et al., 2002).

Moreover, when microfilaraemic animals are treated, their microfilarial numbers in circulation are considerably

reduced (Hoerauf et al., 1999). In contrast, in animals infected with A. viteae worms that lack Wolbachia, similar

long‐term treatment had no effect on worm biology and development, suggesting that these bacteria play a very

important role in the growth and reproduction of the filarial worms that harbour them.

Combination studies using rifampicin and doxycycline in animal models have been found to have the potential to

achieve acceptable short‐term regimen plans (Townson et al., 1999, 2000, 2006; Specht et al. 2008). Interestingly,

in addition to anti‐Wolbachia properties, tetracyclines markedly affected the normal embryogenesis profiles by

causing damage and degeneration of intrauterine embryos. Polymerase chain reaction (PCR) assay also confirmed

the clearance of Wolbachia DNA after prolonged therapy (Volkmann et al. 2003; Kramer et al., 2003). The

reduction or clearance of bacterial specific hsp60 and Wolbachia surface protein (WSP) as determined by

immunohistochemical staining indicated the absence or clearance of Wolbachia in treated worms (Kramer, 2003).

Penicillin, gentamycin, the macrolides erythromycin and azithromycin, ciprofloxacin and chloramphenicol were

shown to be ineffective against Wolbachia in the L. sigmodontis model and consequently, did not display

antifilarial activity (Hoerauf et al., 2000).

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Anti‐Wolbachia therapy: from animal models to humans

The availability of doxycycline has encouraged clinical investigators to test the hypothesis that elimination of

Wolbachia may be beneficial in reducing the human filarial infections. The fact that doxycycline is already

registered enabled a quick transition to phase IIa studies in human onchocerciasis, which have been carried out in

Ghana over the past ten years.

Patients were given doxycycline (100mg/day) for six weeks under daily supervision by a physician. The activity of

the drug against Wolbachia and adult worms was assessed from extirpated onchocercomas. Immunohistology with

antibodies to Wolbachia proteins was used to assess the presence or absence of Wolbachia and monitor changes

in embryogenesis. Nodules from patients not treated with doxycycline served as controls. Administration of

doxycycline led to depletion of Wolbachia followed by an interruption of embryogenesis in worms, which could be

observed for 18 months. In further trials using doxycycline at 200 mg/day for four or six weeks, interruption of

embryogenesis was observed for 24 months (Hoerauf et al., 2001). This was the longest period of sterility of

female worms ever achieved by an antifilarial drug without SAEs. Consistent with the blockage of embryogenesis,

after additional treatment with ivermectin, more than 90% of the patients who had received doxycycline showed

an absence of microfilaridermia after 18 months and the remaining patients showed very low numbers of

microfilariae. In contrast, patients treated with ivermectin alone showed an increase in microfilarial counts as early

as four months after administration of ivermectin.

Preliminary results with other doxycycline regimens indicate that 100 mg or 200 mg doxycycline per day for two

weeks does not eliminate the endobacteria or interrupt embryogenesis. When given at the dose of 200 mg/day for

four weeks, it gives the same efficacy as l00 mg for six weeks (Hoerauf et al., 2003a,b). In more recent studies, it

was demonstrated that doxycycline alone, given at 200 mg/day for 5 weeks could kill 60‐70% of adult worm

populations (Hoerauf et al., 2009).

Anti‐Wolbachia as alternative treatment for onchocerciasis in areas of co‐endemicity with loiasis

The first clinical trial with doxycycline in areas of co‐endemicity of onchocerciasis and loaisis was carried out in

forest villages of Cameroon (Wanji et al., 2009). The results confirmed previous findings that a dose of doxycycline

sufficient to deplete Wolbachia by 90% results in the death of adult worms. Histological and PCR analysis

confirmed that doxycycline treatment resulted in loss of Wolbachia from the adult parasites, with an extensive loss

of uterine contents reflecting a blockage of embryogenesis. Treatment with doxycycline alone is superior to

ivermectin in achieving sustained reductions in skin microfilariae. The trial indicates that doxycycline treatment is

well‐tolerated in O. volvulus patients co‐infected with low to moderate levels of L. loa. These findings support the

use of a doxycycline only regimen to treat onchocerciasis patients coinfected with L. loa.

Scaling up the anti‐Wolbachia treatment: the community‐directed delivery approach

The argument for mass treatment with doxycycline in areas of co‐endemicity with O.volvulus and L. loa relies

heavily on its selective toxicity for O. volvulus and the absence of adverse reactions due to lack of action on L. loa.

However, its acceptance as a complementary tool for mass treatment of onchocerciasis will very much depend on

the development of effective strategies for the treatment of target communities.

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In view of the above, a study was designed in Cameroon to assess the feasibility of a large scale delivery of

doxycycline using the community‐directed approach for the treatment of onchocerciasis in areas of co‐endemicity

with loiasis, with the specific objective of determining the therapeutic coverage and the compliance rate and

identifying the side effects associated with the treatment (Wanji et al., 2009).

The study was carried out in communities in the Mbanga and Melong Health Districts in the Littoral Region of

Cameroon. These communities had never received mass treatment with ivermectin prior to the study. A cascade

mechanism involving advocacy meetings with all stakeholders (health system and community members) was used

to introduce the community‐directed delivery process to the population in the onchocerciasis/loiasis co‐endemic

areas. Community health implementers selected by community members were trained to deliver doxycycline and

to document the treatment coverage, compliance and side effects. This work was carried out under the

supervision of local officials of the Ministry of Public Health.

Of the 21,355 individuals identified, 17,519 were eligible for the treatment and 12,936 of these were treated with

doxycycline, giving a general therapeutic coverage of 60.6% and a therapeutic coverage per eligible population of

73.83%. Of the 12,936 individuals that started treatment in the study area, 12,612 completed the 6 weeks

treatment without missing a single treatment, giving a compliance rate of 97.5%.

Of the 371 people who had side effects recorded during the treatment, 270 (72.8%) had side effects that are well

known and associated with doxycycline intake. These included nausea (13.74%), mild diarrhoea (12.6%), vomiting

(13.7%), loss of appetite (1.1%), mild skin rash (5.9%), joint pains (7.4%), fever (4.1%), headache (6.2%), blurred

vision (2.2%) and feeling tired (9.2%). Apart from one patient who received anti‐inflammatory drugs to treat a

swollen arm, these side effects were generally mild and subsided without any intervention or interruption of

treatment.

The high therapeutic coverage achieved in this study is a prerequisite for the success of any disease control

programme. This augured well for encouraging a subsequent implementation of a large‐scale distribution of

doxycycline for the treatment of onchocerciasis in areas co‐endemic with L. loa.

Doxycycline combines the properties of being both a macro and microfilaricide on O. volvulus with 60 to 65% of

the female worms dying following a six week treatment (Hoerauf et al., 2009). It alo retards the development of O.

volvulus larvae in the vector as microfilariae depleted of Wolbachia endosymbiotic bacteria develop poorly in

Simulium spp (Albers et al., 2012).

Complying or conforming to treatment is absolutely necessary for effective treatments to have desired effects.

High compliance to treatment is dependent on the willingness and motivation of patients to follow the regimens

prescribed which is based on the information about the medication received by the patient, the complexity of the

regimen, the side effects and the benefits they may derive from the treatment (Khalid et al., 2009). In the

Cameroon study, 97.5% of the people who started treatment effectively completed it. This compliance was high

despite the long regimen of doxycycline. This is a good indicator that doxycycline can be used on a large scale for

the control of onchocerciasis using a community directed approach. The compliance rate did not vary with age or

sex of the treated population. This is an indication of good acceptability of the drug by all categories of individuals

in the community.

Several factors accounted for the high compliance rate achieved in the Cameroon study. The social awareness

39


campaigns during which the population was well informed on the process and the role they were expected to play

contributed much to its success. The fact that each partner in the CDI process adequately played his role was an

important factor for success. The awareness of the burden of onchocerciasis and its socio‐economic impacts on the

population was a motivating factor for community adherence and compliance to treatment. The fact that the drug

was delivered by community health implementers selected by community members guaranteed some trust and

was a great motivating factor for the population’s adherence and compliance. It is known that interventions

delivered by community health workers are more accepted by the population than those delivered using the

normal health system (Gyapong et al., 2000) and that it significantly improves the accessibility of the treatment

and treatment seeking behaviour of community members.

The fact that the drug was free was also an encouraging factor for the population to accept and adhere to the

treatment. The positive effects experienced by those who took the drug motivated others to request for their own

treatment.

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41


The way forward for the elimination of onchocerciasis

The Onchocerciasis Control Programme (OCP) recognized the fact that stopping transmission could reduce the

chances of children born after the programme was initiated getting the disease but could not prevent the disease

from progressing in the adult population. Ivermectin treatment was therefore introduced to curb clinical

symptoms and halt the aggravation of ocular lesions. Chemotherapy was thus recognized as a good and less

expensive tool to control onchocerciasis and today the African Programme for the Onchocerciasis Control (APOC)

is using Community‐Directed Treatment with Ivermectin (CDTI) as its main strategy against this disease. Studies in

Mali and Senegal have established the proof‐of‐principle that onchocerciasis elimination with ivermectin

treatment is feasible in at least some endemic foci in Africa. The results have been instrumental for the current

evolution from onchocerciasis control to elimination in Africa (Traore et al., 2012). However, ivermectin has been

shown to be less effective in some communities in Ghana and transmission is still ongoing in northern Cameroon

after 17 years of ivermectin treatment (Katabarwa et al., 2011). The other problems associated with the use of

ivermectin in onchocerciasis control as listed in previous sections of this document have not disappeared.

Recently, APOC announced that it is now an elimination programme with a target date of 2025. For this to be

achieved and considering the problems identified above, it is necessary for its efforts to be accompanied by

various strategic options which should seek to be complementary. Here, we suggest some of these options.

Vector Control

The OCP which was a successful multilateral collaborative endeavour was originally based only on aerial larvicide

spraying. This approach successfully interrupted the transmission of O. volvulus in many areas. Therefore, vector

control could supplement other strategies where possible to accelerate the elimination of onchocerciasis.

Simulium control has been implemented in several areas of Cameroon as a focal activity. The on‐going

construction of new hydroelectric dams will bring human populations from all over Cameroon and beyond to settle

around these dams. This is good for the economy but has the potential of creating new health situations as the

workers come in with various transmissible diseases. The dam spillways may also constitute breeding sites for S.

damnosum, while the lakes will be breeding grounds for vectors of malaria and intermediate hosts of

schistosomiasis.

In view of the above, different control measures will need to be envisaged for various vector‐borne diseases. In the

case of onchocerciasis, vector management for black flies and drug treatment will have to be integrated for better

results. In this regard, the main rivers of Cameroon shall be targeted as they all contribute more or less to the

breeding of S. damnosum. In the savannah, where the transmission is seasonal, an S. damnosum control scheme

will go a long way to break the transmission cycle and hasten the demise of the disease. In the forest region where

transmission is perennial, the main river which is the Sanaga with its 4 dams (Edea, Song Loulou, Bamimdjin, and

Mbakaou) and soon Lom Pangal, is not new to black fly control. The Memvele dam is presently being built.

42


Recommendation 1: In view of the on‐going construction of new hydroelectric dams in Cameroon, the authorities

of the projects should already build into their operational activities, some black fly vector control components so as

to be prepared to handle any unforeseen S. damnosum population explosion after the construction. The main rivers

of Cameroon should also be the target of focal black fly control activities as they all contribute to the breeding of S.

damnosum.

A black fly control scheme as recommended above must include the following components:

1. Cartography – a good knowledge of the geography of the area with a trained team in place.

2. Hydrology – A team of hydro‐biologists with a detailed knowledge of the rivers and their seasonal

variations will monitor the larvicide treatment and its effect on the aquatic fauna.

3. Medical Entomologists – The entomologists have the duty of monitoring the black fly populations as

treatment progresses and to inform the technical team whether their work is going on well or not and to

raise an alarm in case it is not.

4. A technical team – a good technical knowledge of the treatment techniques will require persons trained

in the management of insecticides and equipment used, including aircrafts and helicopters.

Recommendation 2: Operational research is essential to improve monitoring and establish thresholds that

determine when and where vector control is needed. It is also needed to determine whether adult black flies can be

lured by attractants to insecticide treated screens as used in tsetse control, and whether insecticide treated over‐

garments or bands at the wrists and ankles could reduce the impact of the flies on field workers.

Recommendation 3: Capacity building is indispensable to increase local knowledge of vector ecology, sampling

procedures and control techniques.

The improvement of Community Directed Treatment with Ivermectin

Despite more than forty years of onchocerciasis control in Africa, the disease is still a public health concern in

many African countries. The success of OCP in West Africa led to a significant decrease of the burden of

onchocerciasis, but the disease is not yet eliminated. In APOC countries, the CDTI has improved significantly the

treatment and geographical coverage with ivermectin. The evaluation fifteen years or more after the launching of

CDTI has shown reductions in prevalence to less than 10% in some foci, and even less than 1% in some (Mas et al.,

2006; Traore et al., 2012). However, the prevalence in some other foci is still very high as shown by Katabarwa et

al. (2011) in North cameroon. It is important to understand why this is so. There may be specific epidemiological,

sociological and logistical factors that make elimination using ivermectin alone unlikely in some areas.

Recommendation 4: There is need for research organisations in charge of medical research in Cameroon to

investigate the epidemiological, sociological and logistical factors that contribute to the maintenance of high levels

of the prevalence of onchocerciasis after more than 17 years of treatment with ivermectin through the CDTI

approach in areas where loaisis is absent.

The fear of side effects in the forest communities in Cameroon where loaisis is co‐endemic has led to a reduction in

the ivermectin uptake with serious epidemiological consequences. In some surveys, it has been observed that in

43


some foci, some families had never taken Mectizan after five rounds of treatment. These families represented

about 15% of the total population. In some other areas, people who experience SAEs refuse to continue treatment.

These situations contribute to the maintenance of the transmission of the disease.

Recommendation 5: To improve the impact of treatment, the National Onchocerciasis Control Programme should

intensify communication to inform the population on the benefits of treatment with ivermectin. Efforts should also

be made to seek for permanent non compliers in order to inform, educate and properly treat them.

For CDTI in the field, the CDDs used to register the population of each village. This survey was important for the

calculation of the treatment coverage that could help in understanding the impact of the mass treatment. In the

last few years, this activity has not been taken seriously and has made it difficult to obtain accurate treatment

coverage.

Recommendation 6: To enable the collection of data which contribute to the understanding of the impact of mass

treatment, the village census should be done during CDTI field activities.

From the results of the ONCHSIM model (a microsimulation model for onchocerciasis transmission), developed by

Plaisier et al. (1990), we need more than 15 years to achieve elimination of onchocerciasis in endemic areas with

once a year treatment. With twice a year regiment, this time could be shortened by half (Winnen et al., 2002). This

could be more effective in curbing transmission since it has been shown in many studies that repopulation of

dermal microfilariae occurs as soon as four months after a single treatment with ivermectin.

Unlike the APOC strategy which used once a year treatment with ivermectin for a very long time, the treatment

frequency strategy in the Americas was established very early in the programme to be twice annually after it was

established that this would have an accelerating effect on stopping disease transmission (Cupp et al., 1992). The

MDA approach was offered at least twice each year to all eligible individuals living in all endemic communities with

the objective of reaching a minimum of 85% treatment coverage. As a result of these changes, the programme

objective in the Americas has changed from simply controlling onchocerciasis to that of completely eliminating

transmission of the disease by 2012 (Gustavsen et al., 2011).

Recommendation 7: The strategy of the control programme in the Americas which is based on at least twice yearly

treatment and which has resulted in the near elimination of onchocerciasis in that area should be adopted in all

endemic foci in general and Cameroon in particular where the results of the epidemiological evaluations are not as

good as was expected. This should be accompanied by epidemiological surveillance to detect and control disease

recurrence. Therapeutic approaches to reduce the load of L. loa infections are also necessary to increase ivermectin

coverage.

In the efforts to eliminate onchocerciasis, hypoendemic areas should not be forgotten. The present strategy

focuses on treating the meso and hyperendemic areas (with 20% and more prevalence of nodules). Areas with less

than 20% prevalence (hypoendemic areas) of nodules could constitute a reservoir of transmission, hence the

necessity for treating them. The treatment of these areas is now projected and in areas hypoendemic for

onchocerciasis and endemic for loaisis, a new strategy of “Test and Treat” is now under development.

Recommendation 8: The National Onchocerciasis Control Programme of Cameroon should adopt the new strategy

of “Test and Treat” that is being developed for hypoendemic areas.

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To date, there is a lot of controversy regarding the emergence of resistance of O. volvulus to ivermectin. In

addition to the phenotypic suspicions of resistance, many studies have revealed that selection occurs in some

genes of the parasite. Despite these phenotypic and genotypic studies, the unequivocal proof of resistance is yet to

be established.

Recommendation 9: Further studies are needed to clarify the emergence of resistance of O. volvulus to ivermectin

in order to preserve the benefits of past and current onchocerciasis control programmes.

Anti‐Wolbachia treatment

The need for new drugs for onchocerciasis to achieve elimination of transmission cannot be over emphasised in

view of the many problems associated with the use of ivermectin for onchocerciasis control. The discovery of

Wolbachia endobacteria in some pathogenic human filarial nematodes (Taylor et al., 1999, 2005) but not L. loa

(Büttner et al., 2003; McGarry et al., 2003) gave an opportunity to study another approach to onchocerciasis

treatment based on the use of antibiotics to target the endobacteria. Results of human trials using doxycycline

(Hoerauf et al., 2001; Debrah et al., 2006; Wanji et al., 2009) have been very encouraging.

The argument for mass treatment with doxycycline in areas of co‐endemicity with O.volvulus and L. loa relies

heavily on its selective toxicity for O. volvulus and the absence of adverse reactions due to lack of action on L. loa.

However, its acceptance as a complementary tool for mass treatment of onchocerciasis will very much depend on

development of effective strategies for its delivery to the target communities.

The community‐directed intervention (CDI) trials using a 6‐week course of doxycycline challenges the notion that

prolonged courses of treatment cannot be effectively delivered through CDI (Wanji et al., 2009). The Cameroon

study showed that the intake of doxycycline on a large scale is accompanied by only mild side effects which are

generally well known to be associated with doxycycline intake. This can justify the use of this drug to treat

onchocerciasis in areas where O. volvulus and L. loa co‐exist. The high compliance rate recorded was a good

indicator that the mass administration of doxycycline for the treatment of onchocerciasis in areas of co‐endemicity

of loiasis can be a sustainable activity. RAPLOA which is a rapid diagnostic tool has been used to map areas of high

risk of encephalopathy to define restricted areas where these regimens could be deployed (Wanji et al., 2001,

2012). These areas are now well known. The regimes described above, can already be considered as suitable

treatment for individual cases of onchocerciasis in patients co‐infected with L. loa and the further development of

other anti‐Wolbachia regimens compatible with MDA could offer an alternative tool for the control on

onchocerciasis in Africa.

Recoomendation 10: Given that the recently completed community‐directed intervention using a 6‐week course of

doxycycline at a 100 mg/day demonstrated that prolonged courses of treatment can be effectively delivered either

through individual or mass treatment using doxycycline, we recommend the use of doxycycline in O. volvulus and L.

Loa co‐endemic areas and in cases of ivermectin resistance.

Mathematical simulations show that macrofilaricidal drugs have higher potentials of achieving elimination of

onchocerciasis and require less number of rounds of mass drug administration (Alley et al., 2001). It can therefore

be anticipated that with a general therapeutic coverage of 60% achieved with the community‐directed

administration of doxycycline, it may require less rounds of mass drug administration to bring the community

45


microfilarial load of O. volvulus below the threshold level of transmission in a given endemic area. Nevertheless, it

is necessary to develop a mathematical model based on data generated so far to determine the number of rounds

as well as the periodicity of mass administration of doxycycline for the control of onchocerciasis.

Recommendation 11: It is necessary for epidemiologists to develop a mathematical model to determine the

number of rounds as well as the periodicity of mass administration of doxycycline for the control of onchocerciasis.

For any health intervention to achieve its goal, the intervention must be cost effective. It should be affordable to

the health system and donors or community members. Policy and decision makers are increasingly requesting for

information on cost‐effectiveness to minimise cost of interventions and to efficiently allocate health resources.

Few studies have investigated the cost effectiveness of community based interventions. In a recent multi‐country

study on community‐directed interventions for major health problems in Africa involving eight research teams

from five African countries, it was demonstrated that community‐directed interventions are more cost‐effective

than conventional delivery systems for the integrated delivery of vitamin A, insecticide treated nets and anti‐

malarial drugs to communities. With lower implementation costs, the community directed approach achieved

higher coverage than the conventional delivery system at the health district and front line health facility levels. As

shown by Wanji et al. (2009), the community‐directed approach will be more cost effective for the delivery of

doxycycline than the conventional delivery system.

One important consideration for the large scale use of doxycycline for the treatment of onchocerciasis is the fact

that this drug is not presently made available free of charge as is the case with ivermectin. The cost (purchase and

delivery) of the six week treatment per patient is estimated at $ 2.5 (Wanji et al., 2009). Given the fact that most of

the onchocerciasis patients living in endemic communities have incomes below the poverty level, this estimated

cost may be a serious barrier to their accessibility to this therapy. It would therefore be necessary for the health

systems of endemic countries to subsidize the cost of doxycycline for the end users in the large scale treatment of

onchocerciasis where appropriate.

Recommendation 12: Given that the cost of purchase and delivery of doxycycline for the six week treatment per

patient is relatively high for most onchocerciasis patients living in endemic communities, it is necessary for the

health systems of endemic countries to subsidize the cost of the drug for the end users in the large scale treatment

of onchocerciasis where appropriate.

Currently the treatment and control of onchocerciasis rely on a single drug, ivermectin which is used in mass drug

administration (MDA) either annually or biannually or for individual every 3 to six months. It is effective at reducing

microfilarial loads but is only marginally effective against adult worms and so requires sustained delivery for more

than 15 to 17 years in order to interrupt transmission (Diawara et al. 2009; Taylor et al. 2010). Also, in areas of co‐

endemicity with loiasis, the MDA with ivermectin may have limited impact because of non compliance due to fear

of severe adverse reactions by the target population (Wanji et al; unpublished data). Recent investigations with

anti‐Wolbachial drugs have demonstrated the superior efficacy of anti‐Wolbachial drugs compared with existing

anti‐onchocercal drugs through permanent sterilization and macrofilaricidal activity against adult O. volvulus. It has

been reported that more than 97% of some 13000 people from villages where the infection is endemic started and

completed a six‐week doxycycline treatment regimen after community directed explanation and organisation and

3 to 4 years after treatment, the impact of doxycycline treatment is superior to ivermectin treatment in reducing

46


the microfilarial prevalence and intensity (Wanji et al., 2009; Tamarozzi et al. 2011). This is a major step towards

the large scale implementation of antibiotic therapy against onchocerciasis in areas of onchoecerciasis‐loiasis co‐

endemicity. This should likely speed up the elimination of onchoecrciasis in those areas.

Vaccination

It is clear that the goal of onchocerciasis eradication will not be achieved in the near future if the control strategy is

based only on vector control and ivermectin distribution. While the search for an efficient macrofilaricide remains

an attractive option today, this can be complemented with additional tools, such as vaccines that can protect

vulnerable groups particularly children living in endemic areas against infection and reduce adult worm burden and

fecundity, thus reducing the pathological effects caused by the microfilariae.

Several strategic approaches have been used to search for vaccine candidates. These include the search for target

antigens or molecules that will prevent the production of microfilariae by female worms so that severe pathology

and/or transmission of microfilariae to the black fly will be abrogated and those that could stop infection by

preventing the establishment of infective L3 larvae in the definitive host to become adult worms (i.e. prevents

worm development and patency). Other strategies have used filariae infective larvae attenuated by irradiation in

various animal models (Le Goff, 1997, 2000; Babayan et al., 2006; Tchakoute et al., 2006; Allen et al., 2008),

recombinant proteins (Makepeace et al., 2009) and live infective larvae of O. volvulus in cattle (Achukwi et al.,

2007).

Many research groups have identified a number of O.volvulus larval vaccine candidates. Trials with some of them

obtained proof‐of‐principle of vaccination against L3 infection as it was shown that microfilarial load reduced

significantly in animal models (Makepeace et al., 2009; Tchakoute et al., 2006).

Recoomendation 13: Donors should provide funding for research groups which have identified promising vaccine

candidates for the purpose of vaccine design, formulation and delivery.

Sustainability and ownership of control programmes

APOC’s mandate is expected to end in 2015. At that time, it will transfer full responsibility for onchocerciasis

control to various national control programmes. Governments would be expected to provide necessary financial

support. It is also hoped that non‐governmental development organizations will continue to play their critical role.

The overall goal is to establish country‐led programmes capable of eliminating onchocerciasis as a public health

problem in all endemic countries in Africa (2008).

However, the inability of national control programmes to sustain disease control efforts can have important

ramifications as disease resurgence can reverse the gains in public health produced by both OCP and APOC over

the years. The ability to create sustainable disease control efforts beyond APOC’s mandate will depend on the

ability of national governments to provide adequate technological and financial support for national control

programmes to enable them take on the responsibilities that would be transferred from APOC. Consequently, the

international community must ensure that national control programmes and governments have the management

and technical capacities, effective larvicides, microfilaricides, macrofilaricides and funds to continue control

efforts.

47


Recommendation 14: To create sustainable disease control efforts beyond APOC’s mandate, we urge National

Programmes to develop technical and technological competence that would enable them to function properly after

the withdrawal of APOC.

Recommendation 15: We appeal to National Governments and donors not to abdicate their financial responsibility

which is needed to ensure that the substantial investments and progress made towards eliminating onchocerciasis

in Africa are sustained for the future.

48


49


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Appendices

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Appendix A

Statement of task

Research in Onchocerciasis particularly that concerned with chemotherapy and immunity has been limited by the

lack of an appropriate animal model for Onchocerca volvulus. Of all animal models used, only O. volvulus in

chimpanzees closely resembles O. volvulus in man. This is, however, impractical for use on a large scale for

research. Rodents are non‐permissive to O. volvulus. In recent years, work carried out by a team of Cameroonian,

British and German scientists in natural cattle infections at the Veterinary Research Laboratory of IRAD Wakwa,

Ngaoundere, Cameroon and in experimental infections in the University of Liverpool, United Kingdom, identified

the bovine species, O. ochengi as an analogue of O. volvulus for chemotherapeutic and immunological research.

Published results of the studies have direct relevance to the development of improved means of controlling river

blindness. In fact, another team of Cameroonian researchers working in collaboration with Ghanaian, British and

German scientists have applied these results in human trials using mass community‐directed approach. Another

leading Cameroonian scientist has studied extensively the occurrence of adverse reactions to Mectizan treatment

especially in areas of O. volvolus co‐infection with Loa loa in Cameroon, the Democratic Republic of Congo, Angola

and Sudan.

All of the above shows that Cameroonian scientists and their partners have generated a large amount of crucial

scientific data that can be useful in the control of human Onchocerciasis. A lot of the data is really groundbreaking

scientific development. Unfortunately, it is buried in different scientific journals and is not available to

stakeholders (donors, policy makers, disease control officials and nongovernmental organisations) involved in

treatment and control efforts.

In recognition of its advocacy role, the Cameroon Academy of Sciences (CAS) through its National Forum for Public

Health decided to convene an expert panel to bring together the data, analyse it and offer conclusions and

recommendations pertinent for research and policy reorientations for human Onchocerciasis. The panel

synthesized and discussed relevant evidence and knowledge based on findings from research and recommended

actions targeted at policy and decision makers, funding agencies, nongovernmental organisations, researchers and

disease control officials.

The specific aims of the study were to:

Describe the global magnitude of human Onchocerciasis and the situation in Cameroon.

Describe the pathological and socio‐economic effects of Onchocerciasis (River blindness) in humans.

Examine current treatment and control strategies and the gaps therein.

Carry out an analytical synthesis of onchocerciasis research carried out by Cameroonian scientists and

their foreign partners with particular reference to:

o Chemotherapy and immunology – using insights from the O. ochengi/cattle model.

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o Key experimental findings of the O. ochengi/cattle model that have direct relevance to the

development of improved means of controlling river blindness.

o Use of doxycycline against onchocerciasis in clinical settings and mass community‐directed

approach in West and Central Africa.

o Observations on the current use of Mectizan in the control of Onchocerca volvolus in West and

Central Africa.

Examine the effectiveness of alternative treatment and control strategies resulting from the above

studies.

Recommend strategies to improve the control and possible elimination of onchocerciasis.

It was hoped that the report of this study would present, subject to available published evidence, sound

advice and reasoning for reorientation of the current Onchocerciasis control strategies and funding for more

research and also provoke dialogue among stakeholders and draw public attention.

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Appendix B

Biographical sketch of committee members

Vincent N. TANYA, DVM, M.Sc., PhD, is Chief Research Officer with the Institute of Agricultural Research for

Development (IRAD), Cameroon and Technical Adviser No 1 in Cameroon’s Ministry of Scientific Research and

Innovation. He is also the Programme Officer for the Cameroon Academy of Sciences. He is a Fellow of the

Cameroon Academy of Sciences. In recognition of his leadership role in the O. ochengi/cattle model system for

immunological and chemotherapeutic studies on onchocerciasis and the groundbreaking results on the antibiotic

therapy of onchocerciasis, he was elected into the Third World Academy of the Sciences in 2004. He attended the

University of Ibadan, Nigeria, the University of Edinburgh, UK and the University of Florida, Gainesville, USA, and

obtained the degrees of DVM, M.Sc. and PhD respectively. As an arbovirologist/epidemiologist, he has studied and

supervised students on foot and mouth disease, bluetongue virus, rinderpest virus, avian influenza and

onchocerciasis. He has been either principal investigator or co‐investigator on research grants financed by the FAO,

DFID (formerly ODA/NRI), MACROFIL (WHO), AUF (formerly AUPELF‐UREF), Wellcome Trust and the European Union.

He has been Head of the Veterinary Research Laboratory at the IRAD Regional Research Centre of Wakwa,

Ngaoundere, the Chief of the IRAD Regional Centres at Wakwa, Ngaoundere and Bambui and the Scientific

Coordinator for Animal and Fisheries Production at IRAD Headquarters. He has 75 articles in peer‐reviewed

journals. He is Chair of the CAS Panel for this study.

Samuel Wanji, B.Sc., M.Sc., Doc. Uni., HDR, is Associate Professor of Molecular Parasitology and Entomology at the

University of Buea, Cameroon. He has degrees of B.Sc. from the University of Orleans, France, M.Sc. and Doctorate

from the University of Montpellier II, France, and HDR from the University of Nantes, France. He is Executive

Director of the Research Foundation in Tropical diseases and Environment, Buea, Cameroon. He is Member of the

American society of Tropical Medicine and Hygiene (ASTMH), the French Society of Parasitology and the

Cameroonian Society of Parasitology. He is a Consultant for the Special Programme for Research and Training in

Tropical Diseases for the World Health Organisation, in which he is involved with the development and validation

of the Rapid Assessment Procedures for Loiasis (RAPLOA) and community‐directed interventions for major health

problems in Africa. He has been involved in the mapping of Loiasis using RAPLOA in different African countries like

the Democratic Republic of Congo, Republic of Congo, Sudan, Angola, Equatorial Guinea and Cameroon for the

African Programme for Onchocerciasis Control (APOC). He has had several research grants as either principal

investigator or co‐investigator from the European Union, l’AUPELF‐UREF, UNDP/World Bank/WHO Special

Programme for Research and training in Tropical diseases, FICU, the African Programme for Onchocerciasis control

(APOC), the Volkswagen Foundation, the Wellcome Trust, Medical Research Council,UK, and DFG Germany. He has

52 articles.

Joseph KAMGNO, MD, MPH, PhD, is Senior Lecturer in the Department of Public Health, Faculty of Medicine and

Biomedical Sciences of the University of Yaoundé I, Cameroon. After graduating as a medical doctor from the same

University, he later on obtained the Diploma in epidemiology of transmissible diseases in Pasteur Institute in Paris,

the degree of Masters and PhD in Public Health and epidemiology from the University of Paris 6. He has been a

general practitioner (1994 – 1999) at the Pasteur Centre of Cameroon, Research Assistant (2000 ‐2002) at the

same Centre and Technical Adviser (2003 – present) for the National Programme for Onchocerciasis Control. He is

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the Director of Filariasis and other Tropical Diseases Research Center. He is also Adviser for the

Mectizan/Albendazole Experts Committee and member of the Committee of Expert Evaluators of the Development

of Moxidectin. He is a member of the American Society of Tropical Medicine and Hygiene. He has worked on the

effects of ivermectin on O. volvulus and problems related to co‐endemicity with loaisis, the cartography of

parasites in Cameroon and the diagnosis and handling of post ivermectin adverse events in Cameroon, Democratic

Republic of Congo, Angola and Sudan. He has many research grants from Mectizan Donation Program,

UNDP/World Bank/WHO Special Programme for Research and training in tropical diseases, Bertrand Buisson

Institute, US Lymphatic Filaria Support Center, Helen Keller International/RTI and WHO/APOC. He has 57 papers in

peer‐reviewed journals.

Daniel M. ACHUKWI, DVM, PhD, is Chief Research Officer and Director of Scientific Research with IRAD in Yaounde,

Cameroon. He obtained the degree of DVM from the University of Ibadan, Nigeria and later on the PhD from

Strathclyde University in Glasgow, UK. He is also Head of IRADs Animal Health Programme. He was IRAD’s Regional

Scientific Coordinator for the High Guinea Savanna Agro‐ecological Zone from 2006 to May 2011. He has wide

experience in local/rural agricultural production systems and tropical livestock diseases. He has attended several short

courses including specialization in research‐extension linkages, systems‐oriented management and planning basis for

the improvement of animal health in the tropics and immunology/molecular biology of vector transmitted parasitic

diseases of livestock. He teaches immunology at postgraduate level to students of the Department of Biological

Sciences, University of Ngaoundere, molecular parasitology at postgraduate level in the Faculty of Science,

University of Buea and immunology at undergraduate level in the School of Veterinary Sciences and Medicine of

the University of Ngaoundere, Cameroon. He is currently supervising 4 doctoral students. He has been either

principal investigator (PI) or co‐PI on competitive grants financed by IFS, FAO, MACROFIL (WHO), DFG, European

Union, Leverhulme Trust, and AUSAid (CORAF/WECARD) for research on protozoan diseases of economic

importance in livestock and onchocerciasis. He has 35 publications in peer‐reviewed journals.

Peter Ayuk ENYONG, Lic. es Sc., Maitrise es Sc., DEA, Doct. es Sc., was a Senior Researcher of the Institute for

Medical Research and Study of Medicinal Plants. For years, he was the Chief of the Tropical Medicine Research

Station in Kumba. He is presently Senior Research Fellow at the Research Foundation in Tropical Diseases and

Environment, Buea, Cameroon. He is holder of the degrees of Licence es Sciences (chemistry/biology), Maitrise es

Sciences (chemistry/biology), DEA (animal biology), Maitrise es Sciences (entomology) and Doct. Es Sc. from the

University of Paris‐Sud Orsay, France. In collaboration with several colleagues, he has had several grants from the

European Union, WHO/TDR, Edna McConnell Clark Foundation, AUPELF‐UREF, NIH, The Wellcome Trust, Medical

Research Council, UK, and DFG Germany. He continues to act as a consultant for the WHO and APOC and

supervises graduate students. Throughout his long career, he studied the entomology of Simulium damnosum, the

vector of O. volvolus, the biology and ecology of Anopheles gambiae, the control of nuisance of Aedes caspius in

the Langueduc canals in Southern France, the control of Culex quinquefaciatus in Kumba, Cameroon and the

malaccology of Schistosomiasis and Paragonimiasis. He is presently working on a European Union funded research

project on novel release system and bio‐based utilities for mosquito repellent textiles and garments. The project

entails the field testing of various repellent garments and bed net materials against mosquitoes (especially

Anopheles). He has 45 articles in peer‐reviewed journals.