Viral hepatitis in resource-limited countries

Barriers and Needs to reduce the burden of disease

Maud Lemoine

Department of Hepatology St Mary’s Hospital

Imperial College London, UK

MRC, The Gambia Unit, West Africa

PEOPLE INFECTED WITH VIRAL HEPATITIS LIVE IN RESOURCE-LIMITED COUNTRIES

Ott JJ, Vaccine 2012

270 MILLION OF HBSAg CHRONIC CARRIERS

Global prevalence of chronic HBV infection worldwide, 2005

15 million in Europe

60 million in SSA

93 million in China 1.4 million USA

CDC, 2013 Hanafiah M, Hepatol 2013

170 million of HCV-infected subjects worldwide

6 million in Egypt 2 million in SSA

9-10 million in Western Europe 61 million in South Asia and South East Asia

PEOPLE INFECTED WITH VIRAL HEPATITIS LIVE IN RESOURCE-LIMITED COUNTRIES

Messina, Hepatol 2014 (in press)

• HBV and HCV: 75% cirrhosis in RLC • Main cause of HCC: HBV: 60% of HCC and HCV: 15-25% of HCC • HCC: Third commonest cancer in RLC The first commonest cancer in males in Africa, Second in females

VIRAL HEPATITIS ARE A LEADING CAUSE OF DEATHS IN RLC

Kirk,G J Hepatol 2004 Globocan 2008 Jemal, A Cancer, 2012

Mean age of presentation: 43.5 years Tumor size ≥ 5 cm in 88.4 % ; HBV: 66% of HCC; HCV: 6%; Delta: 6% Median survival: 61 days Prolifica preliminary data/ The Gambia; n=69 HCC

1-Insufficient immunization coverage (HBV) 2- Poor screening 3- Difficult assessment of the liver disease 4- No access to treatment at affordable prices 5- Immobilism of the national & international public actors

MULTIPLE BARRIERS

Chiang CJ, JAMA 2013

VACCINE AGAINST HBV IS HIGHLY EFFECTIVE

YET, A POOR IMMUNISATION COVERAGE

Courtesy of Stefan Wiktor WHO, 2014

A FIRST DOSE RECOMMENDED WITHIN THE 24 HOURS OF LIFE

BUT birth dose is given at 6 weeks within the Extended Programme of Immunization (EPI)

Yes (Birth dose) (94 countries or 48%) Not available

Source: WHO/UNICEF coverage estimates 2012 revision, July 2013

no

IN AFRICA 24% children receive a birth dose within 24 hours of life

IMMUNISATION CANNOT BE THE UNIQUE ANSWER TO THE EPIDEMIC

HBV immunization led to a significant decrease in HBsAg in children in China HOWEVER 93 MILLION PEOPLE REMAIN INFECTED

Adapated from Yang W, Vaccine 2013

TREATMENT OF INFECTED SUBJECTS IS

CRITICAL FOR THE CONTROL OF THE EPIDEMIC

NO TREATMENT

WITHOUT SCREENING

1) PREGNANT WOMEN No systematic screening for HBV in SSA HBsAg in pregnant women: 2.5 to 25% in SSA Howell J, J Viral Hepatitis 2014

2) BLOOD BANKS 24% of blood banks are not systematically screened for HBV/HCV in RLC From WHO, 2014

SCREENING IS POOR IN RLC

MAIN BARRIERS - Lack of sensitization of the population and healthcare workers - Cost of the screening (4,000 to 10,000 CFA= 6-15 euros) - Irregular supply of test kits

In Gambia in 2013: 18.7% (1,273 /6,832) for blood donors were not tested for HBsAg => Shortage of test kits during the last months of the year

ASSESSMENT OF THE LIVER DISEASE IS CHALLENGING

1) HBV DNA and HCV RNA quantification - Require good quality laboratory facilities and well-trained Lab Technicians - High cost of the PCR: 70-150 euros - Paradoxically more expensive than in Western countries 2) Assessment of the liver fibrosis Difficult in routine Liver biopsy: costly and invasive Non invasive markers ? Fibroscan®, Fibrotest®, Fibromètre® ⇒ Expensive and FM and FT parameters impossible to assess in routine ⇒ Any alternative ? : Nonpatended simple biochemical tests: APRI? FIB-4?

EASL 2014

n= 135 patients with chronic hepatitis B Double reading Gambia and UK

AST/Platelets

AST,age,Plat, ALT

ACCESS TO TREATMENT

2- HCV treatment: Almost no treatment programme in RLC Peg-IFN has been listed as an essential medicine by WHO (July 2013) Still expensive Not adapted to the African setting -> cold storage -> side-effects -> individuals infected with Genotype 1 or 4 -> non CC IL28B Second generation of DAA and IFN-free regimens: particularly adapted for RLC BUT COSTS are not affordable

1- HBV treatment: Second generation of analogues nucleos(t)idiques: not available at low price Tenofovir at generic price is still restricted to HIV patients (Global Fund and PEPFAR)

ANY ACCESS AT LOW PRICE FOR HEP C ?

Gilead press release. Expanding access to hepatitis C treatment. February2014, available at www.gilead.com. Accessed February 28th 2014.

GILEAD ACCESS PROGRAMME: Negociations with 60 countries : Sofosbuvir $300 à 350/28 pills = $900 -1,000 12 weeks

HIV Malaria TB

Neglected Diseases Schistosomiasis Filariasis Hookworm Leishmaniasis Onchocerciasis Cystercercosis Trypanosomiasis Leprosy Dengue ….

Lemoine M, Thursz M, Liver Inter 2013

INERTIA OF THE PUBLIC ACTORS

Even not neglected: forgotten

LIVER DISEASE WILL BECOME AN IMPORTANT CAUSE OF DEATHS IN HIV PATIENTS LIVING IN RLC

HIV-Viral Hepatitis coinfection is frequent ARV coverage has greatly improved and AIDS-related mortality is decreasing

AIDS-related mortality

DAD study group, AIDS 2010

IN VIETNAM HIV-HCV patients

Variables Number of participants (n=104)

Male sex (M/F) 100/4 (96%)

Median age (years) 37 (27-67)

Child-Pugh A/B/C 102 (98%)/2 (2%)/0 (0%)

Median fasting LSM value (kPa) 6.7 (3.5-75)

LSM n (%) F0-F1/F2/F3/F4 60 (57%)15 (14.4%) 16 (15.4%)12 (11.5%)

Median cd4 (mm3) 504 (203-1280)

Undetectable HIV viral load 98 (94.2%)

Positive HCV RNA (%) 103 (89%)

Median HCV RNA (cp/mL) 347,964,000 (71,137-342 666.109)

Genotyping 1(65), 6( 31%), 3 (6%),

41.3% with significant liver fibrosis 26.9% F3F4

Prevention Of Liver Fibrosis and Cancer in Africa

EC-FP7 project 2011-2016 Gambia, Senegal, Nigeria MRC The Gambia Unit/Imperial College London/INSERM France Le Dantec (Dakar) Université de Thiès MOH of Gambia & Senegal Chief Investigator: Prof. Mark Thursz, Imperial College

DATA ON VIRAL HEPATITIS IN RLC ARE URGENTLY NEEDED

PRIMARY OBJECTIVE

To assess the impact of a tenofovir-based therapy on the incidence of

HCC in West Africa (Senegal/Gambia)

GAMBIA

1- To assess the prevalence of HBV infection in the Gambian and Senegalese adult population AT THE COMMUNITY LEVEL using a Point-of-care test 2- To evaluate the proportion of subjects with significant liver disease who meet the international (EASL) treatment criteria 3-To demonstrate that HBV replication can be effectively suppressed with tenofovir 4- To assess whether screening and treatment are COST-EFFECTIVE 4- To evaluate whether the European treatment guidelines are applicable in West Africa

SECONDARY OBJECTIVES

COMMUNITY-BASED SCREENING

USING A HBsAg POINT-OF-CARE TEST

GAMBIA: Randomisation of 100 rural and urban areas SENEGAL: Screening in Factories and Villages

METHODS

5 year-regular FOLLOW-UP

Treated cohort Untreated cohort

LIVER ASSESSMENT (physical exam, Fibroscan, US, Blood and Virological tests, +/- Liver Biopsy

Treatment provided (Tenofovir) EASL criteria

Subjects tested Positive

FACILITY-BASED TESTING

GAMBIA: blood banks SENEGAL: hospitals

SCREENING-RESULTS (1) NOV 2011-DEC 2013

Country n individuals screened

n HBsAg Pos. subjects

HBsAg prevalence

COMMUNITY

GAMBIA 5, 980 495 8.5 %

SENEGAL 3,523 328 9.3%

Total 9,503 823 9.1%

Country n individuals screened

n HBsAg Pos. subjects

HBsAg prevalence

COMMUNITY

GAMBIA 5, 980 495 8.5 %

SENEGAL 3,523 328 9.3%

FACILITY Total 9,503 823 9.1%

GAMBIA Blood bank-2013

5,559 644 11.6%

SCREENING –RESULTS (2)

1- RESPONSE TO SCREENING: - attendance rate to screening: 72%; varied from 48.9 to 95.1% - higher in rural population - higher in women (75.5%) than in men (60.0%, p<0.001) 2- REASONS FOR NON ATTENDANCE: the most common reason for non participation in the screening was the absence of benefit perceived 3- ATTENDANCE RATE TO LIVER CLINICS: 78% (Gambia) ; 87.2% (Senegal) 4- COST-EFFECTIVNESS UNDER PROCESS

ASSESSMENT OF THE LIVER DISEASE

72%

26%

2% 0%

Inactive chronic carriers: HBe Ag neg, normal transaminases, HBV DNA<2000IU/mL, no significant fibrosisActive chronic carriers: transaminases>normal and/or viral load>2000 IU/mL

Immunotolerant carriers : HBe pos, normal transaminases,no fibrosis, HBVDNA>10 7 IU/mL

About 8% (Gambia) 14% (Senegal) of patients are eligible to treatment (preliminary data)

Cohort of ≈1,400 HBV infected patients in Gambia/Senegal PRELIMINARY DATA

25% had a significant fibrosis on liver biopsy

The TAC (Treatment in Africa for Hepatitis C) PROJECT

Budget:€ 705,000 Funded by ANRS Chief Investigator: Dr K. Lacombe, Paris, France

The TAC (Treament in Africa for Hepatitis C) PROJECT

PRIMARY OBJECTIVE To evaluate the efficacy of an interferon-free regimen combining sofosbuvir (400 mg/d) and weight-dose ribavirin, in treatment-naïve patients infected with HCV genotype 1 (24-week course) Genotype 2 (12-week course) or 4 (24-week course) in West and Central Africa (Senegal, Côte d’Ivoire, Cameroon) STUDY DESIGN PILOT STUDY (n= 120; 40 per genotype) Including HIV-HCV coinfected And HCV monoinfected START DATE: Sept 2014

CONCLUSIONS

1) Viral hepatitis B and C are responsible for a burden of disease in resource-limited countries

2) Education, screening and treatment are urgently needed with the support of the local governments, international policy makers and drug companies 3) Research and operational programmes on viral hepatitis should be implemented to provide better data

No Global Fund or “PEPFAR” to fight Viral Hepatitis Integration of screening and treatment of viral hepatitis within the current HIV/AIDS or Malaria and TB programmes ? The next Millennium Development Goals (2015) should include viral hepatitis

PERSPECTIVES

Acknowledgement France

Isabelle Chemin Maimuna Mendy

Pierre-Marie Girard Karine Lacombe

Jean-François Delfraissy/ANRS Gilles Raguin

Christopher Wild Fabien Zoulim

UK (Imperial College London) Mark

Thursz Simon Taylor-Robinson

Helen Holmes Debbie Garside Graham Cooke Mary Crossey

Shevanthi Nayagam Torben Kimhofer

The Gambia Umberto D‘alessandro Tumani Corrah Ramou Njie Harr Njai Gibril Ndow Yusuke Shimakawa Saydiba Tamba Mavis Foster-Nyako Abdullah Jatta Makie Taal Mustapha Khalil Ignatius Baldeh Senegal Mourtalla Ka Souleyman Mboup Coumba Toure-Kane Souleymane Toure Amina Sow Madoky Diop Pierre Ndaye

Nigeria Nimzing Ladep Marie Duguru Yakubu Fiyaktu Virginia Sale Solomon Banwat Edwin Adoga Côte d‘Ivoire Xavier Anglaret Allain Attia Serge Eholie Christine Danel Raoul Moh Vietnam Thuy Bui Huong Dong Didier Laureillard Tam Nguyen