clinical guidelines & standard operating procedure for the ... · resistant tb (mdr-tb) are...

1

CHIEF DIRECTORATE: HEALTH PROGRAMMES

Acting Chief Director: Mr James Kruger

Enquiries: Dr Vanessa Mudaly/ Ms Razia Vallie

Ref: 19/5/1/11/1

Clinical Guidelines & Standard Operating Procedure for

the Implementation of the Short & Long DR-TB regimens

for Adults, Adolescents and Children

Updated November 2018

(In accordance with “Interim Clinical Guidance for the implementation of injectable-free

regimens for Rifampicin-resistant tuberculosis in adults, adolescents and children”

published by National Department of Health- South Africa: September 2018)

2

Compiled by

Dr Vanessa Mudaly & Ms Jacqueline Voget

Acknowledgements

We acknowledge the invaluable contributions received from members of the National & Provincial

DR-TB Clinical Advisory Committee (NCAC & PCAC), Western Cape DR-TB Task Team, National Health

Laboratory Service (NHLS) and Paediatric DR-TB experts, particularly Prof Gary Maartens, Prof

Graeme Meintjes, Prof Keertan Dheda, Dr Anja Reuter, Dr Jenny Hughes, Dr Julian Te Riele, Ms

Chantal Fourie, Dr Lenny Naidoo, Ms Judy Caldwell, Dr Natalie Beylis, Prof Simon Schaaf and Dr

Anthony Garcia-Prats. Special thanks to the City of Cape Town for use of the DR-TB medicine dosing

and clinical monitoring tools.

3

Contents 1. Introduction ................................................................................................................................................... 7

1.1 DR-TB Definitions.......................................................................................................................................... 7

1.1.1 Mono-resistant TB ................................................................................................................................. 7

1.1.2 Poly-drug resistant TB ........................................................................................................................... 7

1.1.3 Rifampicin resistant TB (RR-TB) ............................................................................................................ 7

1.1.4 Multidrug-resistant TB (MDR-TB) .......................................................................................................... 7

1.1.5 Pre XDR-TB ............................................................................................................................................. 7

1.1.6 Extensively drug-resistant TB (XDR-TB)................................................................................................ 7

1.1.7 Heteroresistant TB infection ................................................................................................................ 7

1.2 Background ................................................................................................................................................. 8

1.3 Current Treatment Regimens for RR/MDR-TB in South Africa ............................................................... 9

1.4 New Short & Long Treatment Regimens for DR-TB in SA ....................................................................... 9

2. Overview of the Short Regimen for RR/MDR-TB Treatment .................................................................. 10

2.1Eligibility Criteria ......................................................................................................................................... 10

2.1.1 Inclusion Criteria ................................................................................................................................. 10

2.1.2 Exclusion Criteria ................................................................................................................................ 10

2.2 Treatment duration .................................................................................................................................. 11

2.3 Anti-TB Medicines included in the Short Regimen ............................................................................... 11

2.4 Treatment regimen for Adults & Adolescents ≥12 yrs (>30kg) ........................................................... 13

2.5 Treatment regimens for Children <12 yrs (<30kg) ................................................................................ 13

2.5.1 Short Regimen for Children 6-12 years (15-30kg) .......................................................................... 14

2.5.2 Short Regimen for Children <6years (<15kg) ................................................................................. 14

3. Overview of Long Treatment Regimens for RR/MDR TB ........................................................................ 15

3.1 Long standardized treatment regimen for RR/MDR-TB with FLQ sensitivity ...................................... 15


3.1.2 Exclusion Criteria ................................................................................................................................ 15

3.1.3 Treatment Duration ........................................................................................................................... 16

3.1.4 Treatment regimen for Adults & Adolescents ≥12 yrs (>30kg) ..................................................... 16

3.1.5 Treatment regimen for Children <12 yrs (<30kg) ........................................................................... 17

3.2 Long regimen for RR/MDR-TB with FLQ resistance ............................................................................... 18


3.2.2 Exclusion Criteria................................................................................................................................ 18

3.2.3 Treatment regimen for Adults & Adolescents ≥12 yrs (>30kg) ........................................................ 18

3.2.4 Treatment regimen for Children <12 yrs (<30kg) ........................................................................... 19

3.3 Long regimen for RR/MDR-TB with CNS Disease .................................................................................. 20

3.3.1 Principles of Management………………………………………………………………………………..20

3.3.2 Treatment regimen for Adults & Adolescents ≥12 yrs (>30kg) with ............................................ 21

4

RR/MDR-TB CNS Disease ............................................................................................................................ 21

3.3.3 Treatment regimen for Children <12yrs (<30kg) with RR/MDR-TB CNS Disease ........................ 21

3.4 Other long individualized regimens for RR/MDR-TB ............................................................................. 22

4. Clinical Guidelines for Initiation of the Short or Long regimen ............................................................. 23

4.1 Sputum Collection for diagnosis ............................................................................................................. 23

4.2 Laboratory-based Drug Sensitivity Tests (DSTs) ..................................................................................... 23

4.3 Baseline Assessment ................................................................................................................................. 25

4.4 Baseline Investigations ............................................................................................................................. 25

4.5 Initiation of Treatment .............................................................................................................................. 26

5. Management of RR/MDR-TB Patients Co-infected with HIV ................................................................ 27

5.1 Key principles ............................................................................................................................................ 27

5.2 Initiation of ART in ART-naïve patients.................................................................................................... 27

5.3 Re-starting ART in patients previously on ART, but currently not on ART ........................................... 28

5.4 Management of patients currently on ART .......................................................................................... 28

6. Monitoring of Patients on Short & Long RR-TB Regimens ...................................................................... 29

6.1 Clinical & sputum monitoring ................................................................................................................. 29

6.2 Monitoring of Bloods ................................................................................................................................ 29

6.3 Monitoring of ECG .................................................................................................................................... 29

7. Switching from Intensive Phase to Continuation Phase ........................................................................ 31

7.1 Switching treatment phases in Short Regimen..................................................................................... 31

7.2 Switching treatment phases in Long Regimens ................................................................................... 32

8. Discordance or lack of GXP confirmation .............................................................................................. 32

9. Medicine substitution for Patients on Short or Long Regimens ............................................................ 33

10. Reporting of Adverse Drug Reactions ................................................................................................... 33

11. Patient education/ Counselling ............................................................................................................. 33

12. Post- Treatment Monitoring for TB Relapse ........................................................................................... 34

13. Management of Other Forms of DR-TB ................................................................................................. 35

13.1 INH Mono-resistant TB ............................................................................................................................. 35

13.2 RIF Heteroresistant TB.............................................................................................................................. 35

14. Recording and reporting ........................................................................................................................ 36

15. Role of DR-TB Provincial & National Clinical Advisory Sub-Committees ........................................... 36

(PCAC/NCAC) & Provincial DR-TB Review Committee ............................................................................ 36

16. References ................................................................................................................................................ 38

5

List of Boxes

Box 1: Short Treatment Regimen for RR/MDR TB for Adults, Adolescents ≥12 yrs (>30kg) ........................ 13

Box 2: Short Regimen for RR/MDR Treatment in Children6-12 years (15-30kg) .......................................... 14

Box 3: Short Regimens for RR/MDR Treatment in Children<6 years (<15kg) ............................................... 14

Box 4: Long Treatment Regimen for RR/MDR with FLQ sensitivity for

Adults & Adolescents ≥12yrs (>30kg) ............................................................................................................... 16

Box 5: Long Treatment Regimen for RR/MDR with FLQ sensitivity for Children <12 yrs (<30kg) ............... 17

Box 6: Long Treatment Regimen for RR/MDR TB with FLQ Resistance for

Adults & Adolescents≥12yrs (>30kg) ................................................................................................................ 18

Box 7: Long Treatment Regimen for RR/MDR TB with FLQ resistance Children <12 yrs (<30kg) .............. 19

Box 8: Long Individualized Treatment Regimen for FLQ sensitive RR/MDR CNS Disease in

Adults & Adolescents≥12yrs (>30kg) ................................................................................................................ 21

List of Tables

Table 1: Laboratory-based Drug Sensitivity Tests (DSTs) ................................................................................ 24

Table 2: Amending treatment on short regimen with 1st & 2nd line LPA results .......................................... 26

Table 3: Adjusting ART regimen for short or long DR-TB regimen containing BDQ & LZD ......................... 28

Table 4: Monitoring QTcF on ECG when using BDQ ...................................................................................... 30

List of Annexures

Annexure 1: RR/MDR-TB Treatment Algorithm ......................................................................................................... 40

Annexure 2: RR/MDR-TB Medicine Dosing Chart for Adolescents ≥ 12 years and Adults ........................... 41

Annexure 3: RR/MDR-TB Medicine Dosing Chart for Children <12 years and weight <30kg ..................... 42

Annexure 4: Revised WHO Classification of Medicines for use in RR-TB Regimens ....................................... 43

Annexure 5: Contraindications to Bedaquiline ....................................................................................................... 44

Annexure 6: Schedule of Clinical Reviews & Management in Short Regimen .............................................. 45

Annexure 7: Clinical Monitoring Chart for Short & Long DR-TB Regimens ....................................................... 47

Annexure 8: Smear Monitoring in Short RR/MDR-TB Regimen ............................................................................. 48

Annexure 9: Snellen Chart ............................................................................................................................................. 49

Annexure 10: Ishihara Chart ......................................................................................................................................... 51

Annexure 11: Severity & Grading of Medicine-related Adverse Events .......................................................... 52

Annexure 12: ADR Reporting Form for MIC in Western Cape ............................................................................. 53

Annexure 13: Management of RIF sensitive INH Monoresistant TB .................................................................... 54

Annexure 14: Treatment Outcomes Definitions for Short RR/MDR-TB Regimen ............................................. 55

Annexure 15: Treatment Outcome Definitions for Long RR/MDR-TB Regimens ............................................. 56

Annexure 16: Form for Submission of Applications to PCAC and NCAC ........................................................ 57

6

Abbreviations & Acronyms

ART Anti-Retroviral Treatment

BDQ Bedaquiline

CNS Central Nervous System

CFZ Clofazimine

DLM Delamanid

DR-TB Drug Resistant Tuberculosis

DST Drug Susceptibility Test

E Ethambutol

ECG Electro-cardiogram

EDST Extended Drug Susceptibility Test

EPTB Extra-Pulmonary Tuberculosis

ETO Ethionamide

FBC Full Blood Count

FLQ Fluoroquinolone

GXP GeneXpert

HIV Human Immunodeficiency Virus

INH/ INHhigh dose Isoniazid/ Isoniazid high dose

INJ Injectable agent

IRIS Immune Reconstitution Inflammatory Syndrome

KM Kanamycin

LFX Levofloxacin

LPA Line Probe Assay

LZD Linezolid

MO Medical Officer

MFX Moxifloxacin

MDR Multi-Drug Resistant

NCAC National Clinical Advisory Committee

NDoH National Department of Health

PCAC Provincial Clinical Advisory Committee

RIF Rifampicin

RR Rifampicin Resistant

SAHPRA South African Health Products Regulatory Authority

TRD Terizidone

XDR Extensively Drug Resistant

WHO World Health Organization

Z Pyrazinamide

7

1. Introduction

1.1 DR-TB Definitions

Drug-Resistant tuberculosis (DR-TB) refers to active tuberculosis disease caused by

Mycobacterium tuberculosis (Mtb) bacilli that are resistant to one or more anti-TB medicines.

1.1.1 Mono-resistant TB

Resistance to only one first line anti-TB medicine, without resistance to other anti-TB medicines:

o Rifampicin(RIF) monoresistant TB- resistant to RIF only

o Isoniazid (INH) monoresistant TB- susceptible to RIF and resistant to INH only (section 13.1)

1.1.2 Poly-drug resistant TB

Resistance to more than one anti-TB medicine, other than both RIF and INH.

1.1.3 Rifampicin resistant TB (RR-TB)

Resistance to at least RIF, with or without resistance to other anti-TB medicines. Includes

RIF- mono-resistant TB, MDR-TB, pre-XDR-TB and XDR-TB

1.1.4 Multidrug-resistant TB (MDR-TB)

Resistance to both RIF and INH with or without resistance to other anti-TB medicines

1.1.5 Pre XDR-TB

Resistance to both RIF and INH (MDR-TB) with additional resistance to either a fluoroquinolone or

any one of the second-line injectable medicines (kanamycin, amikacin or capreomycin)

1.1.6 Extensively drug-resistant TB (XDR-TB)

Resistance to both RIF and INH (MDR-TB) with additional resistance to both a fluoroquinolone

and any one of the second-line injectable medicines

1.1.7 Heteroresistant TB infection (section 13.2)

Heteroresistance is defined as the occurrence of drug-resistant and susceptible TB bacteria in

the same patient sample. It is detected by laboratory tests. Heteroresistance can be due to:

development of drug-resistant sub-populations through mutations in original Mtb population

presence of mixed TB infection- more than one clonally distinct Mtb strain, either through

one transmission event involving more than one distinct strain or through multiple

transmission events during a single disease episode

8

1.2 Background

Rifampicin-resistant tuberculosis (RR-TB) has been declared a public health crisis by the World

Health Organization (WHO). In contrast to the six-month fixed-dose combination treatment

regimen offered to people with drug susceptible TB, people diagnosed with RR-TB or multi-drug

resistant TB (MDR-TB) are treated with variable combinations of first and second-line anti-

tuberculosis drugs, usually for 18 months or more. Numerous studies to investigate shorter, more

effective and less toxic treatment regimens are ongoing in an attempt to improve outcomes in

children and adults with RR/MDR-TB in South Africa.

The WHO’s 2016 DR-TB treatment guidelines include recommendations on the use of a shorter

regimen (9-11 months) for patients with RR/MDR-TB under specific conditions [1]. These

recommendations were based on studies carried out in multiple countries, including

Bangladesh, Benin, Burkina Faso, Burundi, Cameroon, Senegal and Swaziland, that showed a

high rate of successful treatment outcomes in selected patients receiving a standardized

shorter regimen for <12 months.

South Africa has the 9th highest incidence of RR-TB in the world, with 14,000 cases estimated in

2017 [2]. Encouragingly, among the 30 high MDR-TB burden countries, South Africa has one of

the highest levels of treatment coverage; about 73% of estimated incident cases initiated

second-line TB treatment in 2017. However, RR/MDR-TB treatment success rates remain low, with

successful outcomes reported in only 55% of cases started on treatment in 2015 [2]. The National

Department of Health (NDoH) has been at the forefront of programmatic introduction of new

and repurposed drugs for RR-TB since the Bedaquiline Clinical Access Programme (BCAP)

began in 2013 [3]. As at January 2018, roughly 15,000 patients with RR-TB have received

Bedaquiline (BDQ) under programmatic conditions. By the end of 2017, 68 countries reported

having started using BDQ however, 79% of patients treated with BDQ globally were reported by

only two countries – South Africa and the Russian Federation [2].

NDoH provided a policy framework for introduction of new and repurposed medicines for

which made provision for substitution of the injectable agent with BDQ [4]. This substitution was

done for long and short treatment regimens. A retrospective analysis of patients treated in the

Western Cape has shown improved treatment outcomes with BDQ when substituted for

second-line injectable agents in MDR-TB patients [5]. Another retrospective analysis of the

impact of access to BDQ on RR/MDR-TB outcomes within South Africa demonstrated its use was

associated with an almost four times reduction in mortality [6]. Thus, in June 2018 the NDoH took

the unprecedented decision to make BDQ routinely available within injectable-free regimens

for patients presenting with RR -TB.

9

On 15 August 2018 the WHO released a Rapid Communication: Key changes to treatment of

multidrug and rifampicin-resistant tuberculosis (MDR/RR-TB) [7]. This document issues new

guidance on treatment based on a meta-analysis of over 12 000 individual patient RR/MDR-TB

records, and includes changes to the categorization of medicines used to treat RR-TB.

Consolidated, updated and more detailed WHO policy guidelines on RR-TB treatment will be

provided by the end of 2018.

1.3 Current Treatment Regimens for RR/MDR-TB in South Africa

There are several treatment regimens currently being offered for RR/MDR-TB across South Africa:

Most patients with RR/MDR-TB are still receiving the old long regimen made up of KM – MFX

– ETO – TRD – Z (18-20 months duration)

Some patients with RR/MDR-TB have started the short (9-11 months) MDR-TB regimen with an

injectable agent: (4-6) KM – MFX – ETO – INHhd – CFZ – Z – E / (5) MFX – CFZ – Z – E

Some patients have received BDQ to substitute the injectable agent in cases of toxicity or

intolerance, within a short or long RR/MDR-TB regimen

Patients with pre-XDR-TB and XDR-TB currently receive long, individualized regimens

containing new and repurposed medicines.

1.4 New Short & Long Treatment Regimens for DR-TB in SA

Injectable-free regimens are being phased in routinely in South Africa. A document entitled

“Bedaquiline Expansion Plan” [8] was initially circulated to all provinces in July 2018 and this was

followed by the more comprehensive document entitled: “Interim Clinical Guidance for the

Implementation of Injectable-Free Regimens Rifampicin-Resistant Tuberculosis in Adults,

Adolescents and Children” [9] that was circulated in September 2018. In the Western Cape,

injectable-free regimens will be routinely available to treat RR/MDR-TB in adults, adolescents and

children of all ages at all DR-TB treatment sites with the implementation of these new guidelines.

A short injectable-free regimen of 9-11 months may be used for RR/MDR-TB provided specific

criteria are met. Adults and children who do not meet inclusion criteria for the short regimen will be

offered a long injectable-free regimen of 18-20 months. Some patients may initiate treatment with

a short regimen but then switch to a long regimen once further diagnostic or other relevant

information becomes available. Eligibility criteria for the short and the long regimens are listed

under relevant chapters but Annexure 1 gives an overview of eligibility criteria and various

treatment options available for patients with RR-TB. Recommendations on duration of the short

and long treatment regimens are based on WHO guidance on the short course regimen [1] and

new data presented in the Lancet on optimal duration for long treatment regimens [10].

10

2. Overview of the Short Regimen for RR/MDR-TB Treatment

2.1Eligibility Criteria

2.1.1 Inclusion Criteria

o Patients with Rifampicin (RIF) resistant TB (RR-TB) and no prior exposure (>1month) to

second-line anti-TB medicines- this includes

o RIF-resistant TB- diagnosis based on initial GXP result only, while awaiting further

genotypic 1st & 2nd line LPA results

o RIF- mono-resistant TB -resistant to RIF only, sensitive to INH and sensitive to

Fluoroquinolones(FLQ) & Injectables (INJ)

o Multidrug resistant TB (MDR-TB)- resistant to RIF and INH with either InhA or KatG

mutation but not both, and sensitive to FLQ & INJ

o Uncomplicated RR/MDR Extra pulmonary TB (EPTB) – i.e. lymphadenopathy, pleural

effusion, etc.(with or without PTB)

o People living with HIV: already on ART or due to start/ restart ART

o Pregnant women- if PTB / uncomplicated EPTB, eligible for short regimen, but must be

reviewed by NCAC (see sect 14)

o Children < 12 years: younger children with confirmed or presumed RR/MDR-TB are

eligible for a short regimen and should be treated without an injectable agent - discuss

with paeds DR-TB expert and send application to PCAC (see sect 14)

2.1.2 Exclusion Criteria

o Any previous exposure to second–line anti-TB medicines (i.e. treatment for RR-TB) for

more than 1 month regardless of treatment outcome

o Hb <8 g/dL (unable to tolerate addition of LZD): consult PCAC for further advice

o MDR-TB with both InhA & KatG mutations present

o All Pre-XDR and XDR TB

o Any additional suspected resistance to second-line TB medicines (excluding Z & E):

o close contacts of patients with pre-XDR or XDR-TB,

o close contacts of patients with MDR- TB with both InhA & KatG mutations

o close contacts of patients in whom RR/MDR-TB treatment has failed

o Complicated and/or severe forms of extra-pulmonary RR/MDR-TB disease – e.g.

meningitis, osteo-articular, pericardial effusion, abdominal –use long regimen

o RR/MDR-TB with extensive disease e.g. extensive bilateral cavitatory disease on CXR

o Any other situation in which the clinician is uncertain of a patient’s eligibility for the short

treatment regimen

11

2.2 Treatment duration

A short duration of treatment of 9-11 months should be used to treat adults, adolescents and

children with newly diagnosed RR/MDR-TB if they are eligible according to specified criteria (refer

sect 2.1). The intensive phase is usually 4 months, but may be extended to 6 months if sputum

result remains smear positive at the end of month 4. The continuation phase is fixed at 5 months.

2.3 Anti-TB Medicines included in the Short Regimen

The following medicines are included (see annexure 2 & 3 for dosing):

Bedaquiline (BDQ) replaces the injectable agent in the short regimen and is given for a

minimum duration of 6 months (regardless of duration of intensive phase), unless withdrawn

early due to related toxicity or other contra-indications. Studies suggest that BDQ is superior

to the injectable in terms of safety and efficacy in treatment of RR/MDR-TB [7,10], thus a

modified short regimen including BDQ is considered more effective than the previous

injectable-containing short regimen.

Linezolid (LZD) is routinely included in the regimen up front to protect BDQ in the early

stages of treatment, particularly in cases of RR-TB where sensitivity to a quinolone has not

yet been confirmed. South Africa has a high burden of pre-XDR and XDR-TB and

inadequate regimens at the start of treatment can drive the acquisition of further drug

resistance. Linezolid will be given for the first 2 months only and will contribute to a robust

intensive phase with four core drugs (LZD, BDQ, LFX, CFZ) that are highly likely to be

effective against RR/MDR-TB at the beginning of treatment. Most cases of peripheral

neuropathy associated with LZD occur after 2 months of exposure; however,

myelosuppression tends to occur sooner so there must be close monitoring of FBC including

neutrophil count. Linezolid must be withdrawn in the event of severe haematological side

effects (Hb < 8 g/dl, neutrophils < 0.75 x109/L, platelets < 50 x109/L). Concerns regarding

toxicity must be balanced with the efficacy of LZD.

Delamanid (DLM) is the preferred replacement for the injectable children 6-12 years old (15-

30kg). DLM is not yet registered by SAHPRA, however, it is available through the Delamanid

Clinical Access Programme (DCAP) for children >6 years (as per WHO recommendations

[15] at DCAP-approved sites. This still requires application to the NCAC for use in each

individual case – if approved, DLM is given for a full 6 months. PAS may be used to

substitute the injectable in this age group if DLM is not available

Levofloxacin (LFX) replaces Moxifloxacin (MFX) to reduce the risk of QT prolongation when

used with both BDQ & CFZ

Clofazimine (CFZ) is included for the full duration of treatment and is a key medicine in the

short regimen

12

High dose Isoniazid (INHhd) is included in the short regimen for the duration of the intensive

phase, regardless of which INH mutation (inhA or katG) is detected.

Para-aminosalicylic acid (PAS) should be used to substitute the injectable in children<6

years (<15kg), but other options include LZD (with close FBC monitoring), and potentially

BDQ & DLM in the future.

Pyrazinamide (Z) and Ethambutol (E) are included for the full duration of treatment.

Although it is estimated that >50 % of RR/MDR-TB isolates in South Africa are also resistant to

either Z or E; the proportion that are resistant to both medicines is lower, and therefore there

is still some efficacy benefit in offering these medicines routinely. While both are generally

well tolerated, they do not have to be substituted if they are withdrawn due to toxicity or

intolerance.

A Rifamycin may be included in RR/MDR-TB treatment regimens where RIF

heteroresistant TB infection is reported by the laboratory. Rifabutin (RBT) should be given

for a total duration of 6 months, with monthly monitoring for side effects of

neutropaenia, uveitis (eg. visual disturbances, painful inflamed eye, photophobia) and

hepatitis(section 13.2). Rifampicin must not be coadministered with BDQ.

The following medicines are excluded from the short regimen:

Ethionamide (ETO) is no longer included in the short regimen, and is replaced with LZD. At

least 30 % of MDR-TB isolates detected in the national Drug Resistance Survey [11] were

found to have an inhA mutation which confers resistance to ETO. In some provinces, the

incidence of this mutation was >50% and therefore ETO is likely to cause more harm than

benefit when offered routinely for treatment of RR/MDR-TB, particularly in view of the limited

efficacy of this medicine as reported in the recent IPD meta-anlaysis in the Lancet [10]. In

addition, ETO is one of the main contributors to poor adherence to treatment due to the

common side effect of severe nausea and vomiting, which may also lead to sub-optimal

absorption of other TB medicines.

Kanamycin / Amikacin / Capreomycin:

Kanamycin & Capreomycin are no longer recommended in the treatment of RR/MDR-TB

due to recent analyses indicating that use of these injectable agents was associated with

poor TB treatment outcomes [10] and severe adverse events, including reports of

ototoxicity in up to 60% of patients receiving the drug [12]. Amikacin shares a similar toxicity

profile, however it appears to be associated with slightly better treatment outcomes. It may

be considered as an option for drug substitution in the short or long regimen, and may be

the injectable agent of choice in exceptional cases where treatment options are severely

limited.

13

2.4 Treatment regimen for Adults & Adolescents ≥12 yrs (>30kg)

The short standardized treatment regimen is shown in box 1. There are 7 medicines in the

intensive phase and 4 medicines in the continuation phase.

Box 1: Short Treatment Regimen for RR/MDR TB for Adults, Adolescents ≥12 yrs (>30kg)

4-6 months (intensive phase):

BDQ6months-LZD2months-LFX-CFZ-Z-INHhigh-dose-E

+

5 months (continuation phase):

Continue INHhd for 2 months (extend intensive phase from 4 to 6 months) if smear

remains positive by month 4 of treatment. Dosage:10 mg/kg daily.

Duration of treatment with BDQ may be extended to 9 months :

o if smear remains positive by month 4 of treatment

o if 2nd line LPA uninterpretable or not done, and no phenotypic 2nd line DST results

available

o slow clinical response to treatment

o extensive bilateral cavitatory disease

If smear remains positive after month 4, consider possibility of treatment failure

2.5 Treatment regimens for Children <12 yrs (<30kg)

It has been agreed that children <12yrs with confirmed or presumed RR/MDR-TB should also have

access to a short, injectable-free regimen, as discussed in the document entitled: “Statement on

Injectable-Free Regimens for Children under the Age of 12 Years with Rifampicin-Resistant

Tuberculosis” [14 ]. This position statement was released in July 2018 by the Sentinel Project on

Paediatric DR-TB, in collaboration with the Treatment Action Group (TAG) and paediatric TB

experts at the Desmond Tutu TB Centre at Stellenbosch University.

Recommended options for replacement of the injectable agent within the short regimen for

children <12 years will depend on availability of specific drugs (e.g. DLM) and experience of the

treating clinician- see box 2 & 3. Always consult a paediatric DR-TB expert or PCAC before

initiating treatment. Children of any age (<12 years) with suspected or confirmed RR-TB meningitis

or osteo-articular or disseminated/miliary RR-TB disease are not eligible for treatment with a short

regimen, and require a long regimen as recommended by a paediatric DR-TB expert.

14

2.5.1 Short Regimen for Children 6-12 years (15-30kg)

Box 2: Short Regimen for RR/MDR Treatment in Children6-12 years (15-30kg)


LZD2months-DLM*6months- LFX- CFZ-INHhigh-dose -Z-E

+


LFX-CFZ-Z-E

*Refer section 2.3

o Recommended dosing for DLM is as follows:

> 35kg: 100 mg twice daily; 20-35 kg: 50 mg twice daily; 10-20 kg: 25 mg twice daily

PAS may be used if DLM is not accessible

Use AMI or BDQ only if recommended by paediatric DR-TB expert, present to NCAC

LZD may be omitted from the short regimen, at the clinician’s discretion, in children with

non-severe RR/MDR-TB disease (i.e. no bacteriological confirmation, unilateral

pulmonary TB disease, non-cavitatory TB disease)

Dose of LZD in children >15 kg is 10mg/kg once daily

2.5.2 Short Regimen for Children <6years (<15kg)

Box 3: Short Regimens for RR/MDR Treatment in Children<6 years (<15kg)


LZD2months -PAS- LFX- CFZ-INHhigh-dose -Z-E

+


LFX-CFZ-Z-E

LZD may be omitted from the short regimen, at the clinician’s discretion, in children with

non-severe RR/MDR-TB disease (i.e. no bacteriological confirmation, unilateral

pulmonary TB disease, non-cavitatory TB disease). If LZD is used, FBC should be

monitored carefully. Dose of LZD in children 5-15kg is 15mg/kg once daily

Potentially more effective alternatives to PAS include DLM and BDQ – however, dosing is

not currently known in children <3 years and therefore these medicines should not yet

be used routinely in this age group, except in individual cases and in consultation with a

paediatric DR-TB expert and approval from the NCAC. This is likely to change in the near

future as more data become available from ongoing paediatric pharmacokinetic

studies on these medicines.

15

3. Overview of Long Treatment Regimens for RR/MDR TB

Patients who are not eligible for the short regimen must be offered a long regimen. The

composition of the long regimen is determined by the TB resistance pattern and previous

treatment history. The WHO has recently reviewed its grouping of medicines recommended for use

in long regimens (see annexure 4) [7] . Long regimens that may be offered are:

o Long standardized regimen for RR/MDR-TB with FLQ sensitivity (without CNS disease)

o Long individualized regimen for RR/MDR-TB with FLQ resistance (without CNS disease)

o Long individualized regimen for RR/MDR-TB with CNS disease

o Long individualized regimen for RR/MDR-TB with previous exposure to new or repurposed

anti-TB medicines or treatment failure

3.1 Long standardized treatment regimen for RR/MDR-TB with FLQ sensitivity


o Previous exposure to second–line anti-TB medicines (i.e. previous treatment for RR-TB) for

more than 1 month regardless of treatment outcome. If previously exposed to new or

repurposed TB medicines ( BDQ/DLM/LZD or CFZ), request extended phenotypic DST (table

1) and consult PCAC for further advice

o Hb <8 g/dL, neutrophils <0.75 x109/L or platelets <50 x109/L at baseline or while exposed

to LZD during the first 2 months of the short regimen

o MDR-TB with both InhA & KatG mutations but susceptible to FLQ

o Complicated extra pulmonary TB (eg. abdominal, osteoarticular, pericardial and miliary)

o RR/MDR-TB with extensive disease e.g. extensive bilateral pulmonary cavitation

o Close contacts of patients with RR/MDR-TB with both katG and inhA mutations but

susceptible to FLQ

o Pre-XDR TB with resistance to INJ but susceptible to FLQ

o Any other situation in which the clinician is uncertain of a patient’s eligibility for the short

treatment regimen


o FLQ resistance on 2nd line LPA or phenotypic DST

o CNS disease

o history of any previous RR-TB with exposure to new and repurposed medicines (BDQ,

CFZ, DLM, LZD)> 1 month without a successful treatment outcome or with exposure to

any 2nd line anti-TB medicines > 1 month with a successful outcome, but a relapse is

considered to be likely. These cases should be presented to PCAC.

o close contact of a patient failing any RR/MDR-TB treatment

16

3.1.3 Treatment Duration

The long regimen is given for a total duration of 18-20 months. The intensive phase will usually

be 6 months but may be extended to 8 months in the following situations:

o At the clinician’s discretion in cases of slow clinical response to treatment (i.e. poor

weight gain, ongoing TB symptoms, poor resolution on CXR, delayed smear or culture

conversion)

o Bilateral pulmonary disease with extensive cavitations

o Delayed culture conversion (i.e. positive MTB cultures at month 4)

o Cases where 2nd line LPA results are indeterminate/FLQ sensitivity is not confirmed

The continuation phase is fixed at 12 months.

3.1.4 Treatment regimen for Adults & Adolescents ≥12 yrs (>30kg)

This long regimen is standardized and is based on WHO’s updated classification of anti-TB

Medicines (see annxure 4) [7]. It consists of 5 medicines in the intensive phase and 3 medicines in

the continuation phase- see box 4.

Box 4: Long Treatment Regimen for RR/MDR with FLQ sensitivity for Adults & Adolescents ≥12yrs (>30kg)

Both BDQ and LZD are included in the intensive phase

In cases of contra-indication or toxicity to one of the five core drugs in the intensive

phase, other drugs from WHO Category C may be used for substitution (see Annexure

6). Two new drugs that are considered to be effective should be used to substitute one

of the five recommended core drugs in the long regimen.

LZD should be stopped if Hb <8g/dL, neutrophils <0.75x10 9/L or platelets <50 x109/L at

baseline or during treatment. Replace LZD with two category C drugs- present to PCAC

for advice.

TRD may be substituted with two category C drugs if there is a history of psychosis or

patient develops psychosis on treatment

Rifabutin may be included for 6 months if RIF hetero-resistant disease is detected (refer

sect 2.3)


LZD-BDQ-LFX-CFZ-TRD

+


LFX-CFZ-TRD

17

3.1.5 Treatment regimen for Children <12 yrs (<30kg)

The recommendations for the long regimen for children <12yrs with RR/MDR-TB (see box 5)

depends on:

Severity of TB disease (culture-negative presumed RR/MDR may possibly be treated for

shorter duration e.g. 15 months total depending on effective drugs)

Availability/approval of new drugs (DLM and BDQ) for specific age groups. Once BDQ dose

and safety is established in children <12 years of age, this should be routinely included in the

long regimen for children, as for adults. Until such time, DLM is the preferred option and

should be used in place of BDQ in children 6-12 years if possible (in settings where DLM is

available through DCAP). In all other cases where neither BDQ nor DLM is available for use

in children <12 years, PAS should be included in the long regimen for RR/MDR-TB until the

newer drugs become available. PAS can be continued for the full duration of treatment, if

tolerated (does not have to be withdrawn at the end of the intensive phase)

Effective drugs in the regimen. Given the uncertainty of access to new drugs for children

<12 years, INHhigh-dose or ETO should be included in the long regimen for the full duration of

treatment, if tolerated, especially if neither BDQ nor DLM are included. The choice of

INHhigh-dose or ETO will depend on the INH mutation present. If inhA mutation only, use INH

15-20mg/kg/day. If KatG mutation only, use ETO at the usual paediatric dose. If both inhA

and KatG mutations are present, do not use either drug in the regimen.

Box 5: Long Treatment Regimen for RR/MDR with FLQ sensitivity for Children <12 yrs (<30kg)


LZD-(BDQ or PAS or DLM)-LFX-CFZ-TRD-(INHhigh-dose or ETO)

+


PAS (if used in IP)-LFX-CFZ-TRD-(INHhigh-dose or ETO)

LZD must be used with very careful monitoring of FBC & diff in children

Always consult a paediatric DR-TB expert or PCAC before initiating treatment

18

3.2 Long regimen for RR/MDR-TB with FLQ resistance


o Pre-XDR TB with FLQ resistance

o XDR- TB (resistance to both INJ & FLQ)

o Close contacts of patients with Pre-XDR TB with FLQ resistance or XDR- TB


o CNS disease

o history of any previous RR-TB with exposure to 2nd line anti-TB medicines including new and

repurposed medicines(BDQ, CFZ, DLM, LZD)> 1 month without a successful outcome; these

cases should be presented to NCAC.

o history of any previous RR/MDR-TB with exposure to 2nd line anti-TB medicines > 1 month with

a successful outcome, but a relapse is considered to be likely. These cases should be

presented to NCAC.


3.2.3 Treatment regimen for Adults & Adolescents ≥12 yrs (>30kg)

A treatment regimen for a FLQ resistant Pre-XDR-TB and XDR-TB should be long and individualized,

considering the patients treatment history, DST results and drug toxicity and intolerance. An

intensive phase should include a minimum of 4 medicines that are known or predicted to be

effective. This is followed by a continuation phase that includes a minimum of 3 medicines that

are known or predicted to be effective- see box 6.

Box 6: Long Treatment Regimen for RR/MDR TB with FLQ Resistance for Adults & Adolescents≥12yrs (>30kg)


LZD-BDQ-(DLM* or PAS)-CFZ-TRD-Z-(INHhigh-dose or ETO)

+


LZD-CFZ- Z-(INHhigh-dose or ETO)-TRD

* preferred if available, apply through NCAC

FLQs are not included if there is FLQ resistance on genotypic DST (LPA)

The usual dose of LZD is 600mg daily, but may be reduced to 300mg daily if toxicity occurs

INHhd or ETO usage will depend on the INH mutation present. If only InhA mutation present,

use INH 10mg/kg/day. If only KatG present, use ETO at same dose of RR/ MDR-TB regimen.

If both InhA and KatG mutations present, do not include either of the medicines

19

Do not include TRD if previously exposed to it in a failing regimen >12 months

Z is included in this regimen as it has a low rate of adverse event, however clinicians should

have a low threshold for stopping this medicine if a related adverse event occurs. If Z

resistance is demonstrated on phenotypic DST, Z should be stopped.

Rifabutin (RBT) may be included for 6 months if RIF heteroresistant TB infection is detected

(refer sect 13.2)

If one or more core drugs needs to be omitted or cannot be relied upon as susceptible,

then an alternate agent needs to be added to the regimen. This should be presented to

NCAC for review and recommendation

All patients should have intensive adherence counseling and have challenges to

adherence addressed before starting treatment. Adherence and adverse effects should

be revisited throughout treatment.

If the patient has been on treatment for RR/MDR- TB with either the short or the long regimen

for longer than one month when the diagnosis of FLQ resistance is made, consult NCAC for

a treatment regimen

3.2.4 Treatment regimen for Children <12 yrs (<30kg)

The principles discussed in section 3.2.3 are applicable. All children <12 years should be discussed

with a paeds DR-TB expert before initiating treatment.

Box 7: Long Treatment Regimen for RR/MDR TB with FLQ resistance Children <12 yrs (<30kg)


PAS-(BDQ or DLM*)-LZD-CFZ-TRD-Z-(INHhigh-dose or ETO)

+


PAS-LZD-CFZ-TRD-Z-(INHhigh-dose or ETO)

*if available, apply though NCAC

FLQs are not included if there is FLQ resistance on genotypic DST (LPA)

LZD must be used with very careful monitoring of FBC and neutrophil count

INHhd or ETO usage will depend on the INH mutation present. If only InhA mutation present, use

INH 15-20mg/kg/day. If only KatG present, use ETO at same dose of RR/ MDR-TB regimen. If

both InhA and KatG mutations present, do not include either of the medicines

20

3.3 Long regimen for RR/MDR-TB with CNS Disease

3.3.1 Principles of Management

RR/MDR-TB CNS disease (TB meningitis or tuberculomas) is associated with a high mortality

Clinicians should have a low threshold for performing investigations (e.g. CT brain scan or

lumbar puncture) to diagnose CNS TB disease in patients people with headaches/

neurological signs with possible immune compromise (i.e. HIV, children) and with symptoms of

CNS disease

As cerebrospinal fluid findings can be highly variable with TB meningitis and it can be

challenging to differentiate between bacterial, tuberculosis (or mixed) meningitis it is

recommended to include antibiotic cover (for example ceftriaxone 2 g IV) for 10 days or

until bacterial meningitis is ruled out. Co-infection with cryptococcal meningitis should be

ruled out with a CSF CrAg.

Steroids are given with TB medications and are tapered down over 6-8 weeks

Every effort should be made to ascertain TB drug sensitivity results for CNS disease (contact

history, sending cerebrospinal fluid for GeneXpert/LPA/culture and sensitivity as well as

taking TB diagnostic samples from other sites (sputum’s, lymph nodes etc)

Many TB drugs have poor CNS penetration. Thus, the recommended treatment is based on

the inclusion of the second line drugs with the best CNS-perfusion at optimized dosages and

is for the longer duration of treatment

In patients co-infected with HIV and not yet on antiretroviral therapy (ART): ART should be

initiated 4-6 weeks after TB treatment (to minimize the risk of life threatening intracranial IRIS)

Patients already on ART should continue ART throughout TB treatment.

21

3.3.2 Treatment regimen for Adults & Adolescents ≥12 yrs (>30kg) with

RR/MDR-TB CNS Disease

The recommended regimen for FLQ sensitive disease is shown in box 7.

Box 8: Long Individualized Treatment Regimen for FLQ sensitive RR/MDR CNS Disease in Adults &

Adolescents≥12yrs (>30kg)


LZD-BDQ-LFX-CFZ-TRD-Z-(INHhigh-dose* or ETO)

PLUS: Dexamethasone 12 mg IVI (0.4mg/ kg/ day) bi-daily 12 hourly followed

by Prednisone 120mg per oral daily.

After 1 week gradually taper dose over 6-8 weeks

+


LFX-CFZ-TRD-Z-(INHhigh-dose* or ETO)

*INH dose 15mg/kg/day

Addition of DLM can be considered (good CNS perfusion in rat models) where available

Change from intensive phase to continuation phase is based on clinical response

If LZD is well tolerated and ongoing close monitoring (for haematological, optic and peripheral

neuropathy) is possible, LZD can be extended into the continuation phase

Repeat CT brain scan may be used to monitor response of tuberculomas to treatment.

Residual lesions may be present at end of treatment and do not necessarily represent

treatment failure

All patients with presumed or confirmed FLQ resistant CNS TB must be presented to NCAC for

expert advice, as there is a very high risk of mortality. In addition to the regimen shown in box 7,

DLM should be included, and an intravenous carbepenem may be recommended.

3.3.3 Treatment regimen for Children <12yrs (<30kg) with RR/MDR-TB CNS

Disease All children with CNS disease should be discussed with an experienced paediatric and/or DR-TB

clinician (NCAC can be consulted). For TB meningitis and miliary TB in children, treatment of both

MDR and XDR-TB should include sufficient drugs that penetrate the CSF (LFX; LZD; TRD; Z; INHhd;

ETO)

22

3.4 Other long individualized regimens for RR/MDR-TB

An individualized long regimen should be used in the following scenarios:

o history of any previous RR/MDR-TB with exposure to 2nd line anti-TB medicines including

new and repurposed medicines (BDQ, CFZ, DLM, LZD)> 1 month without a successful

outcome

o history of any previous RR/MDR-TB with exposure to 2nd line anti-TB medicines > 1 month

with a successful outcome, but a relapse is considered to be likely


An individualized long regimen is constructed according to the previous RR/MDR-TB history and

exposure to 2nd line anti-TB medicines. Send sputum sample for individualized extended

phenotypic DST (see table 1).

Consult PCAC or NCAC for advice before initiating treatment (refer sect 15).

23

4. Clinical Guidelines for Initiation of the Short or Long regimen

4.1 Sputum Collection for diagnosis

For all patients who have one or more signs or symptoms of TB, collect two sputum

specimens at least one hour apart

The first sputum specimen will be used for GXP testing

If Rifampicin resistance is detected on GXP, the second sputum specimen will be used

for smear microscopy, 1st line & 2nd line LPA and TB culture

Record the above results as “baseline” results

It is no longer necessary to routinely collect a 3rd sputum specimen (previously referred

to as baseline sputum) before initiating treatment

However, an additional sputum specimen must be submitted if the initial sample is

inadequate or has leaked, results are inconclusive, or if requested by the lab

4.2 Laboratory-based Drug Sensitivity Tests (DSTs)

Choice of regimen and duration of treatment is guided by the results of laboratory-

based genotypic & phenotypic DSTs (see table 1)

1st and 2nd genotypic test (LPA) will be conducted routinely on all specimens with GXP

positive RIF resistant results.

1st and 2nd line LPA’s will be repeated on culture isolates if initial results are inconclusive

Phenotypic DST for INH will be routinely performed on culture isolates if 1st line LPA

indicates INH sensitivity- this will detect phenotypic resistance to INH that may not be

identified on targeted genotypic testing, which has a sensitivity of 86% ( meaning that

about 14% are actually phenotypically resistant) [12]. Phenotypic DST results will not

provide information about the associated mutation if INH resistance is detected.

2nd line phenotypic DST will be done routinely if there is FLQ sensitivity on 2nd line LPA

Extended 2nd line phenotypic DST detects resistance to Bedaquiline, Clofazimine,

Levofloxacin, Linezolid, and Moxifloxacin. This test will routinely be conducted on culture

isolates if resistance to FLQ is detected by routine 2nd line LPA. This is a reflex test and it is

not necessary to send additional specimens. These Pre-XDR and XDR cases are not

eligible for the shorter regimen and should receive individualized longer regimens. The

purpose of carrying out this extended phenotypic DST is to provide the clinician with a

greater repertoire of drugs that MAY be effective in treating Pre-XDR (FLQ) and XDR

cases (the results will be available after a minimum of 14 days)

Repeat LPAs and extended 2nd line phenotypic DST must be requested for patients with

a smear positive result at month 4. Contact the lab to request test on previous culture

positive specimen and follow up for results.

24

Table 1: Laboratory-based Drug Sensitivity Tests (DSTs)

Type of test When done Result

Genotypic

1st line LPA

GXP pos/RIF resistant

GXPneg/HIVpos if

culture positive

Susceptibility to

Rif & INH, and INH

mutation(s)

2nd

line LPA

GXP pos/RIF resistant

GXPneg/HIVpos &

LPA Rif resistant

on culture isolate

Susceptibility to

FLQ & INJ

Phenotypic INH

In-lab reflex when RIF

resistant but

susceptible to INH on

1st line LPA

To confirm

susceptibility to

INH- no mutation

Phenotypic FLQ

In-lab reflex test for all

2nd line LPA results

that indicate FLQ

susceptibility

Susceptibility to

LFX/MFX 0.25

ug/ml

2nd line Phenotypic DST

In-lab reflex test when

resistance to FLQ or

INJ detected on

2nd

line LPA Susceptibility to

LFX/LZD/

MFX 0.25 & 1.0

ug/ml

(to include BDQ &

CFZ in 2019)

Requested by

clinician if 2nd line LPA

is susceptible but

resistance to 2nd

line

TB medicines is

suspected (eg due to

previous unsuccessful

RR-TB treatment, or

XDR contact)

Individualized

Extended Phenotypic DST

(from NICD)

Requested by

clinician when RR-TB

treatment fails, and

patient had been

previously exposed to

2nd

line medicines

Susceptibility to

multiple 2nd line TB

medicines; results

will be used to

construct a

salvage regimen

25

4.3 Baseline Assessment

Obtain full medical history and assess clinical condition of the patient

Enquire about HIV status and any previous ART exposure

Enquire about close RR/MDR-TB contacts

Screen for non-communicable diseases (hypertension, diabetes mellitus, mental health)

Screen for substance use using available validated screening tool

Enquire about history of cardiac disease and cardiac symptoms (chest pain, palpitations,

dizziness, syncope)

Screen for contraindications to use of BDQ (see annexure 5) and other 2nd line TB medicines

Consult Provincial Clinical Advisory Committee (PCAC) if BDQ contraindicated, or if

significant cardiac history or symptoms present

Pregnant women with newly diagnosed RR/MDR-TB are eligible for treatment with the short

DR-TB regimen- an application should be submitted to the (NCAC), but this should not

delay initiation of treatment in patients with uncomplicated first episode of DR-TB

Breastfeeding women are also eligible for treatment with the BDQ-containing short or long

regimens. The benefits of breastfeeding must be weighed against the risks of transmission of

TB to the baby. Manage risk of transmission with appropriate infection control measures.

Always consult a paeds DR-TB expert before initiating treatment for RR/MDR-TB for

children<12 years old. An application should be submitted to PCAC.

4.4 Baseline Investigations

ECG: must be done before treatment with BDQ is initiated. However, do not delay initiating

treatment in patients where this might result in worse outcome eg. very

immunocompromised or very ill patients. Consult an expert if unsure.

Blood tests: Full blood count (FBC) & differential, ALT, Creatinine, Sodium, Potassium,

Magnesium, TSH, HBsAg

A point-of-care Hb may be used to determine whether LZD can be included in regimen. An

FBC & diff must still be submitted to the lab for baseline testing

Do HIV rapid test if HIV status unknown or previously tested HIV negative

If HIV positive (regardless of ART status): baseline CD4 (if not done in previous 3 months) and

VL (if not done or found to be >1000 in previous 3 months)

If CD4<100, a reflex cryptococcal antigen test (CrAg) will be performed

If female: pregnancy test; ensure adequate contraception if not pregnant

Audiometry assessment should be done at baseline for all patients even if not using

injectable agent. This must not delay initiation of treatment.

Baseline chest X-ray

26

4.5 Initiation of Treatment

If GXP Pos + Rif resistant, consider history and assess eligibility for short or long regimen

Review results of baseline investigations

Review ECG result: baseline QTcF must be <450ms in order to initiate treatment with BDQ

If baseline QTcF>450ms, address any contributing causes: stop any concomitant QT-

prolonging medicines, correct electrolytes, treat abnormal TSH. Repeat ECG – if QTcF still

>450ms, consult PCAC for advice on regimen (sect 15).

Initiate treatment according to algorithm shown in Annexure 1

Follow up for 1st and 2nd line LPA results after 7-14 days and confirm eligibility for the short or

long regimen with patient if results are conclusive

If on short regimen, amend treatment regimen as shown in table 2

If on long regimen, or if switching from short to long regimen, amend treatment regimen as

discussed in sect 3

Table 2: Amending treatment on short regimen with 1st & 2nd line LPA results

1st line LPA Result Action

RIF Susceptible continue DR-TB regimen, discuss discordance with lab

RIF Resistant continue DR-TB regimen with INHhd

,

modify according to other LPA results

InhA mutation only continue DR-TB regimen with INHhd

KatG mutation only continue DR-TB regimen withINHhd

Both InhA & KatG

mutations

switch to long regimen

(patient is no longer eligible for the short regimen)

Susceptible to INH continue DR-TB regimen with INHhd

and wait for INH

phenotypic DST result

o if confirmed susceptible to INH, decrease INH to

normal dose

o if resistant to INH, continue with INHhd

2nd

line LPA Result Action

Susceptible to FLQ continue with DR-TB regimen with 2 months LZD.

Follow up results of phenotypic DST for LFX/MFX 0.25 ug/ml

Resistant to FLQ Switch to longer individualised DR-TB regimen

Follow up results of phenotypic DST for LFX/MFX 0.25, MFX 1.0,

LZD (BDQ and CFZ in 2019)

27

5. Management of RR/MDR-TB Patients Co-infected with HIV

5.1 Key principles

Patients with HIV and RR/MDR TB are considered to have advanced ( stage 4) HIV disease

and are at high risk of mortality, especially if not on ART [16,17]

Patients with HIV are more at risk of poor outcomes due to:

o immunocompromised status & risk of IRIS

o high pill burden & risk of drug-drug interactions & toxicities

o co-morbid opportunistic infections

Aggressively diagnose and manage co-morbid opportunistic infections

In adults with CD4 < 100, review CrAg test result before initiation of ART. If symptomatic, refer to

hospital for lumbar puncture and IV anti-fungal treatment, which will be followed by oral anti-

fungal therapy with Fluconazole ≥ 1 year (discontinue when CD4 > 200 taken 6 months

apart). Monitor for QTcF prolongation with concomitant use of BDQ and fluconazole.

Bactrim prophylaxis reduces mortality and (unless contraindicated or hypersensitivity

present)should be given with TB treatment regardless of CD4 count [17]. Bactrim can be

used with LZD; regular FBC and neutrophils count monitor for bone marrow suppression

Initiate ART within 2 weeks of starting RR/MDR-TB for patients not on ART (except if CNS

disease present), and optimize treatment for those already on ART

Treatment with the short or long regimen is the same for all patients regardless of HIV status.

However, choice of ART regimens may need to be modified according to the medicines in

the short or long regimen

5.2 Initiation of ART in ART-naïve patients

Timing of ART Initiation:

o initiate ART within 2 weeks of starting treatment [18]

o If TBM or CM, initiate ART 4-6 weeks after starting TB medication due to risk of

intracranial IRIS [19]

Choice of ART regimen:

o Efavirenz (EFV)cannot be used concurrently with BDQ, therefore:

If female & CD4<250 or male & CD4<350 initiate ART with TDF/FTC/NVP.

Use ABC instead if TDF contraindicated. Lead-in dose of NVP is required.

If female & CD4≥250 or male & CD4≥350 initiate ART with TDF/FTC/LPV/r. Use

ABC instead if TDF contraindicated

o On completion of treatment with course of BDQ, switch to EFV-based regimen if

virologically suppressed

28

5.3 Re-starting ART in patients previously on ART, but currently not on ART

o If previously on 1st line ART, initiate a 2nd line PI-based regimen

o If previously on 2nd line ART, address reasons for treatment interruption and restart same

regimen. If GI side effects experienced with LPV/r and TB meds, consider switch to ATV/r.

Repeat VL after 3 months

5.4 Management of patients currently on ART

o Review recent VL (baseline or within last 3 months)- see table 3

o If VL<400, adjust ART as shown in table 3. Switch back to starting regimen once BDQ

course is completed

o If VL≥400 on 1st line ART, switch to 2nd line ART. If using LZD, avoid using AZT and use

TDF instead. If contra-indication to TDF use ABC.

o If VL≥400 on 2nd line ART, continue 2nd line ART, assess adherence and apply for

genotyping test if VL remains unsuppressed

Table 3: Adjusting ART regimen for short or long DR-TB regimen containing BDQ & LZD

*Consider switching to ATV/r if GI side effects present or to reduce pill burden

Current ART

Regimen

Proposed ART Regimen

VL<400 VL≥400

TDF/ FTC/ EFV TDF/ FTC/ NVP TDF/ 3TC/ LPV/r

ABC/ 3TC/ EFV ABC/ 3TC/ NVP ABC/ 3TC/ LPV/r

TDF/ FTC/ LPV/r TDF/ FTC/ LPV/r*

ABC/ 3TC/ LPV/r ABC/ 3TC/ LPV/r*

AZT/ 3TC/ LPV/r TDF/ FTC/ LPV/r*

29

6. Monitoring of Patients on Short & Long RR-TB Regimens

6.1 Clinical & sputum monitoring

Medical officer must review patient at 2 weeks, 4 weeks, 8 weeks and then monthly

(annexure 6)

Follow up for outstanding DST results and modify regimens accordingly

Monitor clinically for side effects including cardiac symptoms(chest pain, palpitations,

dizziness, syncope), gastrointestinal symptoms (nausea, vomiting, diarrhea),

hepatotoxicity (nausea, fatigue, jaundice), anaemia, optic neuropathy and peripheral

neuropathy

Monitor for side effect of optic neuritis monthly on LZD using Snellen chart (annexure 9)

and Ishihara chart (annexure 10). Stop LZD and refer to ophthalmologist if changes

detected.

Monitor clinically for side effect of uveitis monthly on RBT- visual disturbances, painful

inflamed eye, photophobia. Stop RBT and refer to ophthalmologist if symptoms

detected.

Routine sputum collection monthly for smear & culture

Optimize management of concurrent non-communicable diseases

Repeat audiometric assessment monthly if on injectable agent- stop injectable and refer

for further audiological management if ototoxicity detected

Repeat audiometric assessment 3 monthly even if not on injectable agent-refer for

further audiological management if hearing deficits detected.

Refer to annexure 5 for schedule of clinical review &management in short regimen

6.2 Monitoring of Bloods

• Standard monitoring blood tests according to DR-TB guidelines (annexure 7)

o Check FBC & diff (Hb & neutrophil count)) at 2 weeks, 4 weeks, 8 weeks and then

monthly if using LZD

o Check ALT monthly if using RBT or more frequently if hepatic disease is suspected.

6.3 Monitoring of ECG

Monitor QTcF on ECG monthly until course of BDQ completed or until QTcF <470ms if it was

prolonged >470ms at the end of 6 months of BDQ

Manage according to Table 4

30

Table 4: Monitoring QTcF on ECG when using BDQ

QTcF on ECG at baseline Action

<450 ms = normal

Start BDQ and repeat ECG after 2 weeks

(If QTcF>450ms, address any contributing causes

eg. stop any concomitant QT-prolonging

medicines, correct electrolytes, treat abnormal

TSH. Repeat ECG and consult PCAC for regimen)

QTcF on follow-up ECG done at

2 weeks then monthly Action

<450 ms = normal Cont BDQ with routine QTcF monitoring

450-469 ms or

increase in interval <30 msec

= mild prolongation

Cont BDQ with routine QTcF monitoring

470-499 ms or

increase in interval 30-50 msec

= moderate prolongation

Exclude other causes of QT prolongation

(medicines, electrolyte disturbances,

hypothyroidism) and manage appropriately.

Enquire about cardiac symptoms (chest pain,

palpitations, dizziness, syncope). If any present,

discuss with expert. If none, continue BDQ and

repeat ECG within 1 week

>500 ms or

increase in interval >50 msec

= severe prolongation

Stop LFX, BDQ & CFZ, and any other QT prolonging

medicines.

Enquire about cardiac symptoms (chest pain,

palpitations, dizziness, syncope). If any present,

discuss with expert. Exclude other causes of QT

prolongation (electrolyte disturbances,

hypothyroidism) and manage appropriately.

Repeat ECG after 48 hours. If QTcF decreasing,

monitor weekly. When QTcF <470ms, restart LFX,

BDQ & CFZ sequentially, with QTcF monitoring in

between.

Consult an expert if QTcF remains elevated >470ms

at 2 weeks after stopping QT-prolonging

medicines.

31

7. Switching from Intensive Phase to Continuation Phase

7.1 Switching treatment phases in Short Regimen

The duration of the intensive phase of treatment is dependent on the clinical condition

and timing of smear conversion (annexure 2)

Medical officer must assess clinical condition and smear & culture results of patient at

month 4 to decide if intensive phase should change to continuation phase at this stage, or

if intensive phase should be prolonged for another 2 months (note that it is likely that the

month 3 and month 4 culture results will not be available at that point, and therefore the

decision is based on the clinical condition of patient and monthly smear results)

Switch to continuation phase when the following apply:

o Patient who started treatment being smear positive: If smear negative at the end of

month 4 and patient is clinically improving

o Patient who started treatment being smear negative: if TB smear remains smear

negative up until month 4 of treatment and patient is clinically improving

If patient has not shown signs of clinical improvement, or is deteriorating after initial clinical

improvement, discuss with PCAC regardless of smear results

If the month 4 smear is still positive (has not changed from being positive at baseline),

suspect potential treatment failure. Assess adherence, substance use, co-morbidities and

side effects. Review monthly culture results, and request reflex DST on the latest positive

culture. Prolong the intensive phase to 6 months, and consult PCAC as it will be necessary

to extend course of BDQ. At 6 months, review monthly culture results. Switch to

continuation phase only if culture conversion has occurred by month 4. If culture

conversion does not occur by month 4, consult NCAC for advice on longer individualized

regimen.

If the 4 month sputum has become smear positive after initially being negative at baseline,

or reverted to being smear positive after becoming negative, assess adherence, optimize

management of co-morbidities and request LPA and phenotypic DST on latest sputum

sample. As this is a higher risk of treatment failure, present case to PCAC as soon as

possible

32

7.2 Switching treatment phases in Long Regimens

Medical officer must assess clinical condition and culture results of patient at month 6 to

decide if intensive phase should change to continuation phase at this stage, or if intensive

phase should be prolonged for another 2 months

If patient has not shown signs of clinical improvement by 2 months, or is deteriorating after

initial clinical improvement, discuss with PCAC regardless of smear or culture results

Switch to continuation phase when the following apply:

o For patient who started treatment being culture positive: culture negative result for

sputum sent at the end of month 4 and patient is clinically improving

o For patient who started treatment being culture negative or indeterminate: all culture

results remain negative including that of sputum sent at the end of month 4 and patient

is clinically improving

If intensive phase is prolonged to 8 months, duration of treatment with BDQ should also be

extended to 8 months- submit application to PCAC

If culture conversion does not occur during extended intensive phase, assess adherence,

substance use, co-morbidities and side effects, and prepare to present to NCAC as

treatment failure

8. Discordance or lack of GXP confirmation

In situations where RR-TB is detected on GXP only and resistance pattern is not confirmed on

LPA or DST (e.g. sample contaminated, sample leaks or results are indeterminate), every

effort should be made to collect another sample as early as possible to obtain confirmation

of drug resistance patterns. Include both BDQ & LZD in the intensive phase.

These patients may have started the short or long regimen, according to clinical history

If patient is on the short regimen, and sensitivity to FLQ & INJ is not confirmed on LPA or DST,

but all other eligibility criteria are met(e.g. patient is not a close contact of XDR, etc.), then

they may still continue with the short regimen

If discordant results are obtained, repeat sputum culture as soon as the discordance is

observed; continue with RR-TB treatment regimen and contact the lab and DR-TB expert or

PCAC to discuss regimen and duration of treatment.

33

9. Medicine substitution for Patients on Short or Long Regimens

Patients who are currently on a short or long Kanamycin (Km)-containing regimen, are

eligible for medicine substitution with BDQ- consult PCAC

BDQ must be given for a minimum duration of 6 months regardless of when it is started in

the intensive phase

Repeat audiometric assessments at 3 and 6 months after stopping the injectable agent

Patients who develop intolerance or toxicity to any of the core medicines (BDQ-LFX-ETO-

CFZ-INH) in the short regimen, are eligible for substitution with DLM, TRD, PAS and / or LZD.

However, they will have to be switched to a long individualized regimen.

Patients who develop intolerance or toxicity to any of the medicines in a long regimen

are also eligible for substitution- options may include DLM, PAS, ETO, Amikacin and/or an

Imipenem etc.

Applications for medicine substitution in short or long regimens must be submitted to

PCAC (refer sect 15)

10. Reporting of Adverse Drug Reactions

An adverse drug reaction is one type of adverse event, defined as any untoward medical

occurrence that may present during treatment with a pharmaceutical product, but which

does not necessarily have a causal relationship with this treatment

Reporting of serious ADRs provides important information that enables improvement in

the quality of patient care

ADRs may be graded according to the severity of the symptoms (see annexure11)

Medical officers, nurses or pharmacists must report at least grade 3-5 ADRs to the MIC

(see annexure 12), SAHPRA via NDOH APP or via Sinjani

11. Patient education/ Counselling

Counselling of patients with regard to DR-TB treatment should be modified to include

new information about the short regimen, and continue as per current protocols

Patients should be counselled at baseline about their eligibility for the standard short

regimen treatment which is for 9-11 months and this should be confirmed with them

once the results of their LPA’s and/ or DST are available.

All patients should be counseled on the clinical monitoring requirements including

monthly ECGs while on BDQ or DLM, as well as key symptoms to report urgently (i.e.

cardiac symptoms, visual problems, peripheral neuropathy or extreme lethargy)

34

The clinician’s responsibility

o Detailed focused history which should include:

Previous exposure to anti-TB medicines

Co-morbidities including cardiovascular diseases

Family history of cardiac diseases or sudden death

Close contacts on TB treatment or with symptoms suggestive of TB

Other medication usage including ART & contraception

Screening for substance use

Screening for depression & other mental illness

o Discuss frequency and type of investigations to be done:

Baseline & monitoring bloods

Audiology test

Pregnancy test

Monthly ECGs

o Discuss potential side effects / adverse drug reactions – with strong focus on

symptoms to report urgently

o Discuss infection control practices and cough hygiene

Identify & screen close contacts

Counsellor/ TB nurse responsibility

o Provide counseling on:

HIV support and ART

Disease course and treatment journey

Adherence support and enabling tools such as schedules

Infection control practices

Contact tracing

Addressing substance abuse and mental illness

12. Post- Treatment Monitoring for TB Relapse

It is of utmost importance that patients completing the short DR-TB regimen be monitored

for subsequent relapse of TB disease

Give patients appointments for clinical assessments at 6 monthly intervals for 1 year after

successful completion of treatment

The assessment must include review of clinical condition, CXR and collection of sputum

sample for smear & culture.

35

13. Management of Other Forms of DR-TB

13.1 RIF Susceptible INH Monoresistant TB

The conventional management of RIF-susceptible TB with 2 months of rifampicin, isoniazid,

pyrazinamide and ethambutol followed by 4 months of rifampicin and isoniazid (2RHZE/4HR) is

more likely to fail in patients who have INH monoresistance compared to those who are INH

susceptible [1, 22]. Therefore, WHO now recommends the addition of Levofloxacin(LFX) for this

group of patients, provided Rifampicin resistance has been excluded (annexure13).

According to the South African Tuberculosis Drug Resistance Survey 2012-2014, the prevalence of

INH monoresistance among TB patients in the Western Cape is 10.8% (CI 8.5-13.7) [23]. Genotypic

DST (1st line LPA) is currently not routinely performed for patients with RIF-susceptible TB(by Xpert),

instead it must be requested for patients who are not improving clinically or who still have smear

positive sputum results at 7 weeks or at any time thereafter. If INH resistance is detected and RIF

resistance has been excluded with 1st line LPA, the new recommendation is to continue RHZE for a

further 6 months with the addition of LFX (see dosing charts- annexure 2 & 3). If only an InhA

mutation is detected (ie. no KatG mutation), a higher dose of INH may be beneficial [24]. The

dose of INH may be augmented to total 10mg/kg/day. The decision to treat with INHhd should be

individualized: consider benefits versus risk of toxicity and increased medicine burden. Consult

PCAC if unsure.

The treatment duration with addition of LFX (with or without INHhd) may be extended beyond 6

months if INH resistance is detected later than 2 months in the course of treatment, or in patients

with extensive disease [22] - discuss with PCAC. Monthly monitoring of sputum smear and culture

results should be performed until treatment is completed. All RIF susceptible INH monoresistant TB

patients should be recorded in the DR TB register and captured in the EDRWeb.

13.2 RIF Heteroresistant TB

Studies show that a significant proportion of RR-TB isolates may still have in-vitro susceptibility to

Rifabutin [25]. Furthermore, treatment outcomes in patients with Rifabutin- susceptible RR-TB can be

improved with the addition of Rifabutin. Therefore, Rifabutin should be added to treatment regimens

for adolescents>12 years and adults where RIF heteroresistant infection is detected by genotypic DST,

for a total of 6 months. Monitor monthly for side effects of neutropaenia, uveitis (visual disturbances,

painful inflamed eye, photophobia) and hepatitis (see annexure 6). Dosing (annexure 2) must be

adjusted when using ART containing protease inhibitors. Submit application to PCAC before adding

Rifabutin to regimen.

36

14. Recording and reporting

Recording and reporting will continue as per norm. Stationery has been revised to include

the short and long regimens

Folders, registers and drug prescription charts should be marked to differentiate between

the short and long regimen:

- Green sticker to indicate the short regimen

- Orange sticker to indicate the long regimen

Data will be captured on the EDRWeb

The Medical Officers are responsible for assigning DR-TB outcomes once a patient has

completed treatment (annexures 15 & 16)

15. Role of DR-TB Provincial & National Clinical Advisory Sub-Committees

(PCAC/NCAC) & Provincial DR-TB Review Committee

The Provincial DR-TB Clinical Advisory Committee (PCAC) provides clinical governance and

support for clinicians managing DR-TB patients in the Western Cape. It is no longer

necessary to submit applications for all DR-TB patients initiating BDQ in the shorter regimen.

However, applications should still be submitted for the following:

o New episode of Pre-XDR or XDR TB

o Patient unable to tolerate LZD: Hb <8 g/dL, neutrophils <0.75 x109/L or platelets

<50 x109/L at baseline or while exposed to LZD during the first 2 months of the

short regimen

o Children & adolescents <12 years old

o Patients with treatment failure on MDR-TB regimen

o Patients who are still on Kanamycin in a short or long regimen and require

medicine substitution

o Requests for medicine substitution for any of the medicines in the short or long

regimens

o Requests for extension of BDQ treatment beyond 6 months

o Complicated clinical scenarios requiring expert advice

o RIF heteroresistant TB

37

The National DR-TB Clinical Advisory Committee (NCAC) provides inputs for

development of national DR-TB policies and guidelines and provides clinical

governance and support for clinicians managing DR-TB patients nationally. Applications

should be submitted for:

o Patients with contraindications to BDQ or other 2nd line TB medicines, or significant

cardiac disease or symptoms

o All pregnant patients initiating RR-TB treatment

o Exposure to standard short RR/MDR TB regimen>1 month before FLQ and/or INJ

resistance detected

o Patients failing treatment on pre-XDR/XDR-TB regimen

o Unable to construct a regimen with at least two of the following four medicines:

BDQ, LZD, FLQ (MFX or LFX), AMI

o Patients who interrupted treatment >2 months on regimens containing BDQ, DLM,

CFZ or LZD and present for restart of treatment

o Patient previously treated for any RR- TB with a successful outcome but present

with a new episode of RR-TB that may be a relapse of previous disease

o Requests for treatment with DLM or extension of DLM treatment beyond 6 months

via the Delamanid Clinical Access Programme (DCAP)

Submission to PCAC or NCAC must be made using the form contained in annexure 17.

This form must emailed to:

PCAC: [email protected]

NCAC : [email protected]

(Please add patient folder number and reason for application/nature of query in

subject line, and cc the treating clinician if possible)

The Provincial DR-TB Review Committee is a multi-disciplinary team that reviews

management of patients in whom DR-TB treatment is failing despite optimization of

treatment options. Patients who have multiple episodes of treatment interruption, or are

estimated to be taking <75% of doses of their TB medicines should be presented to the

DR-TB Review Committee to support a decision to withdraw out-patient treatment.

Patients requiring presentation to the Provincial DR-TB Review Committee should be

discussed with Provincial HAST office ([email protected])

mailto:[email protected]

mailto:[email protected]

38

16. References

1. World Health Organization. WHO treatment guidelines for drug-resistant tuberculosis 2016 update.

World Health Organization; 2016.

2. World Health Organization. Global Tuberculosis Report. Geneva : 2018

3. Ndjeka N et al. Treatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence

setting: an interim cohort analysis. The International Journal of Tuberculosis and Lung Disease. 2015;

19:979-85. doi :10.5588/ijtld.14.0944

4. Directorate Drug-Resistant TB, TB & HIV. Introduction of new drugs, drug regimens and

management for drug-resistant TB in South Africa: Policy framework. 1.1. Pretoria: National

Department of Health; 2015.

5. Zhao et al. Improved treatment outcomes with bedaquiline when substituted for second-line

injectable agents in multi-drug resistant tuberculosis: a retrospective cohort study. Clinical Infectious

Diseases, ciy 727, http://doi.org/10.1093/cid/ciy727. Published 24 August 2018.

6. Schnippel Ket al. Effect of bedaquiline on mortality in South African patients with drug-resistant

tuberculosis: a retrospective cohort study. Lancet Respir Med 2018; 2600:1-8. doi : 10.1016/S2213-

2600(18)30235-2.

7. World Health Organization. Rapid communication: key changes to treatment of multidrug and

rifampicin-resistant tuberculosis (MDR/RR-TB). World Health Organization; August 2018.

8. Directorate Drug-Resistant TB, TB & HIV. Bedaquiline Expansion Plan. June 2018

9. Interim Clinical Guidance for the implementation of injectable-free regimens for Rifampicin-

resistant tuberculosis in adults, adolescents and children. National Department of Health ; 2018

10. The Collaborative Group for the Meta-analysis of Individual patient Data in MDR-TB treatment

2017; Ahmed N et al. Treatment correlates of successful outcomes in pulmonary multidrug-reistant

tuberculosis; an individual patient data meta-analysis. Lancet2018; 392:821-34.

11. Ismail N et al. Prevalence of drug-resistant tuberculosis and imputed burden in South Africa: a

national and sub-national cross-sectional survey. Lancet Infect Dis 2018. Published online 20 April

2018.

12. Seddon J A et al. Hearing loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J

2012; 40: 1277–1286.

13. Zignol M et al. Genetic sequencing for surveillance of drug resistance in tuberculosis in hihly

endemic countries: a multi-country population-based study. Lancet Infect Dis. 2018. Pii:S1473-

3099(18)30072-2. doi :10.1016/S1473-3099(18)30072-2.

14. Sentinel Project. Statement on Injectable Free Regimens for Children under the Age of 12 Years

with Rifampicin-Resistant Tuberculosis. Available at http://sentinel-project.org/wp-

content/uploads/2018/07/Recommendations-for-Injectible-Free-Regimens-in-Children-with-Rif-

Resistant-TB.pdf.

http://doi.org/10.1093/cid/ciy727

http://sentinel-project.org/wp-content/uploads/2018/07/Recommendations-for-Injectible-Free-Regimens-in-Children-with-Rif-Resistant-TB.pdf



39

15. World Health Organization. The use of delamanid in the treatment of multidrug-resitant

tuberculosis in children and adolescents: Interim policy guidance 2016.

16. Gandhi NR et al. Risk factors for mortality among MDR-and XDR-TB patients in a high HIV

prevalence setting. The International Journal of Tuberculosis and Lung Disease. 2012 Jan 1;16(1):90-7.

17. Schnippel K C et al. Persistently high early mortality despite rapid diagnostics for drug-resistant

tuberculosis cases in South Africa. Int J Tuberc Lung Dis. 2017;21(10):1106

18. World Health Organization. Guidelines for managing advanced HIV disease and rapid initiation of

antiretroviral therapy, July 2017.

19. Torok ME et al. Timing of initiation of antiretroviral therapy in Human immunodeficiency virus (HIV)

associated tuberculous meningitis. Clin Infect Dis. 2011;52:1374–1383.

20. Paton NI et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. New

England Journal of Medicine 2014. 371(3):234-47.

21. World Health Organization. WHO Treatment Guidelines for Isoniazid-resistant tuberculosis.

Supplement to the WHO Treatment Guidelines for drug-resistant Tuberculosis. 2017.

22. Compendium of WHO guidelines and associated standards: ensuring optimum delivery of the

cascade of care for patients with tuberculosis. Version 1. November 2017.

23. National institute for communicable Diseases- Division of the National Health Laboratory Service.

South African Tuberculosis Drug Resistance Survey 2012–14 http://www.nicd.ac.za/assets/files/K-

12750%20NICD%20National%20Survey%20Report_Dev_V11-LR.pdf

24. World Health Organization . Frequently asked questions on the WHO treatment guideline for

isoniazid- resistant tuberculosis. 24 April 2018.

25. Lee et al. Treatment outcomes of rifabutin-containing regimens for rifabutin-sensitve multidrug-

resistant pulmonary tuberculosis. Int J Inf Dis. 65 (2017) 135-141.

-

40

Annexure 1: RR/MDR-TB Treatment Algorithm

41

Annexure 2: RR/MDR-TB Medicine Dosing Chart for Adolescents ≥ 12 years and

Adults

42

Annexure 3: RR/MDR-TB Medicine Dosing Chart for Children <12 years and

weight <30kg

43

Annexure 4: Revised WHO Classification of Medicines for use in RR-TB Regimens

GROUP MEDICINE Abbreviation

Group A Include all three medicines (unless they cannot be used)

Levofloxacin OR LFX

Moxifloxacin MFX

Bedaquiline BDQ

Linezolid LZD

Group B Add both medicines (unless they cannot be used)

Clofazimine CFZ

Cycloserine OR Terizidone

CS TRD

Group C Add to complete the regimen and when medicines from Groups A and B cannot be used

Ethambutol E

Delamanid DLM

Pyrazinamide Z

Imipenem-cilastin OR Meropenem

Ipm-Cln Mpm

Amikacin (OR Streptomycin)

Am (S)

Ethionamide OR Prothionamide

ETO PTO

p-aminosalicyclic acid PAS

44

Annexure 5: Contraindications to Bedaquiline

*Consult NCAC if any present

Contraindications to Bedaquiline*

1. Patient refuses consent

2. History of torsades de pointes or cardiac ventricular arrhythmias

3. Severe coronary artery disease

4. Prolonged QT syndrome or family history of prolonged QT syndrome

5. History of allergies, hypersensitivity or tolerance to BDQ

6. Medicines:

o Class 1a or Class III anti-arrhythmic medicines (such as amiodarone,

sotalol, procainamide, dysopyramide and quinidine)

o Tricyclic anti-depressants, including amitriptyline, doxepin, despipramine,

imipramine, clomipramine;

o The non-sedating anti-histamines astemizole and terfenadine

o Neuroepileptics such as phenothiazine, thioridazine, haloperidol,

chlorpromazine, trifluoperazine, percycline, prochlorperazine, fluphenazine,

sertindole and pimozide

o Prokinetic cisapride

o Quinolone antimalarial (e.g. chloroquine and quinacrine)

45

Annexure 6: Schedule of Clinical Reviews & Management in Short Regimen

Review visit Key Actions

Baseline Review all available sputum results, baseline blood results (FBC&diff, HIV

test, viral load, CD4 count, Cr, Mg, K, ALT results

Do pregnancy test and ECG and review both results → discuss

contraception

Review inclusion and exclusions criteria for short regimen and decide if

patient is eligible

If eligible, HB ˃8g/dL and baseline QTcF<450, start regimen and adjust

ART as needed

Do baseline visual screening (Annexure 9 &10)

Refer for baseline audiometry assessment

Screen for smoking and substance use

Screen for mental health disorders

Identify support structures for patient; initiate RR/MDR-TB counselling

2 weeks Review LPA results- if conclusive, amend regimen if indicated

Repeat FBC& diff

Review baseline audiology screening results

4 weeks Review LPA results if not previously available and amend regimen if

indicated

Review FBC&diff result: if Hb<8g/dL, neutrophils <0.75 x109/L or platelets

<50 x109/L, drop LZD and switch to longer regimen.

repeat FBC and neutrophil count

Repeat ECG and review QTcF result (see sect 6.3)

8 weeks Check initial sputum smear and culture result - if 1st & 2nd line LPAs were

initially uninterruptable, check results of repeat LPAs done on culture

isolate should be available.

If LPA FLQ results were susceptible – review phenotypic FLQ susceptibility.

If resistance detected change to individualized long regimen.

Review FBC and neutrophil count and repeat.

Stop LZD


Sputum sample for smear & culture should be submitted and results reviewed monthly.

ECG’s should be done and reviewed monthly until BDQ completed.

Adherence, change in substance use, and mental health should be assessed regularly.

4 months

Review all smear & culture results.

o If smear conversion (from positive to negative) has occurred, or if

smears have remained negative since treatment start, stop INHhd –

this is the switch to continuation phase

o If no smear conversion has occurred at this stage, continue all

treatment for another 2 months (i.e. continue intensive phase)

If smears are positive at 4 months this is a risk for treatment failure. Request

extended DST, reassess clinical condition and prepare to present to NCAC

for input


6 months Review all monthly smear and culture results

Consider eligibility for extension of BDQ to 9 months- refer section 3.5

If latest available smears and cultures are negative, and not eligible

for BDQ extension, stop BDQ.

Stop INHhd

Repeat VL if on ART

If on EFV-based 1st line ART with viral suppression at baseline, may

revert to this regimen if latest VL suppressed.

46

9 months Review all monthly smear and culture results

Stop treatment if there was no delay in smear conversion (at Month 4)

and patient is clinically well and meets criteria for cure or treatment

completion

If intensive phase was extended to 6 months and BDQ extended to 9

months, then stop BDQ (if applicable) and continue Z / E / LFX / CFZ

for another 2 months


11 months

(for

patients

who had

their

intensive

phase

extended)

Review all monthly smear and culture results

Stop treatment if patient is clinically well and meets criteria for cure or

treatment completion

If there are any concerns, present case to PCAC / NCAC


6 months &

12 months

post-

completion

of

treatment

Monitor for signs & symptoms of relapse- assess clinically, do CXR and

send sputum for smear & culture.


47

Annexure 7: Clinical Monitoring Chart for Short & Long DR-TB Regimens

48

Annexure 8: Smear Monitoring in Short RR/MDR-TB Regimen

49

Annexure 9: Snellen Chart

51

Annexure 10: Ishihara Chart

52

Annexure 11: Severity & Grading of Medicine-related Adverse Events

Mild

(Grade 1)

Symptoms cause no or minimal interference with usual, age

appropriate, social and functional activities (e.g. going to work,

shopping, cooking, using transport, hobbies)

Moderate

(Grade 2)

Symptoms cause greater than minimal interference with usual, age

appropriate, social and functional activities (e.g. going to work,

shopping, cooking, using transport, hobbies)

Severe

(Grade 3)

Symptoms cause inability to perform usual, age appropriate, social

and functional activities (e.g. going to work, shopping, cooking,

using transport, hobbies)

Potentially life-

threatening

(Grade 4)

Symptoms cause inability to perform basic, age-appropriate, self-

care functions (e.g. bathing, dressing, toileting, continence,

feeding, movement); OR

Medical or operative intervention required to prevent permanent

impairment, persistent disability, or death

Death

(Grade 5)

53

Annexure 12: ADR Reporting Form for MIC in Western Cape

DOB: Gender: Male Female

Height (cm):

Yes No Unknown N/A

Dose Date Started

D ate

sto pped Dose D ate Started D ate sto pped

Hb:

Lipoatrophy Death

Neutropenia

Other Describe:

Died RecoveredNot yet

recoveredHospita-

lised

Regimen change

- specify:

Tel: Cell:

Western Cape Adverse Drug Reaction Reporting Form for patients on ARV & / or TB treatment

MEDICATION HISTORY (circle suspected medicines)

Date event started:

Patient Initials:

MedicineMedicine

Pancreatitis

Creatinine (µmol/L):Renal toxicity

Skin reaction

Other o utco me-

specify:

Congenital anomaly/ Pregnancy exposure/ foetal death

Date completed:

Email:

Name:

ADVERSE REACTION DETAILS

Anaemia requiring transfusion

OUTCOME

Cholestatic hepatitis

Hyperuricaemia

Hypersensitivity reaction

Description of reaction:

Lipohypertrophy (Abnormal fat accumulation)

Submit to Manager: Pharmaceutical Services

Investigations (including other relevant medical history):

Please include additional information that you may deem necessary in your report (use additional paper)

Management of adverse event:

Qualifications:

Ototoxicity

(Neutrophils less than 0.5 X 10⁹/L)

SJS/TEN

Gynaecomastia

Permanent

damage/

disability

(Fat loss)

Lactic acidosis (Metabolic acidosis and lactate>2mmol/L) Transaminitis (gr 3=5-10XULN, gr 4>10XULN)/ symp hepatitis

Suspected cause of death:

Symptomatic hyperlactataemia (lactate>2 and symptoms)

REPORTING DOCTOR / PHARMACIST / PROFESSIONAL NURSE

OFFICE USE ONLY: Database reference no:

Starting CD4 (if HIV+):

List all medication patient was receiving at the time of the reaction including herbal, traditional and OTC medication

ICD 10 code(s) or disease(s):

Treatment facility name:

Pregnant? Current CD4 (if HIV+):

District/sub-district:

Folder no:

Weight (kg):

Signature:

54

Annexure 13: Management of RIF sensitive INH Monoresistant TB

55

Annexure 14: Treatment Outcomes Definitions for Short RR/MDR-TB Regimen

OUTCOME DEFINITION

Cured 1. A patient who has TB culture converted. 2. Received treatment for a total duration of 9 months or more 3. Has at least 3 consecutive negative TB cultures during continuation

phase (at least 30 days apart) 4. No evidence of clinical deterioration

Treatment completed

(success)

1. A patient who has TB culture converted 2. Received treatment for a total duration of 9 months or more 3. Has less than 3 consecutive negative TB cultures during continuation

phase (at least 30 days apart) 4. No evidence of clinical deterioration

Loss to follow up

(previously known as

defaulter)

1. A patient with treatment interrupted

- >= 2 consecutive months

- Any reason without medical approval

Treatment failure 1. A patient who failed to culture convert by month 6 2. In the initial 6 months of treatment

- >= 2 of 5 cultures are positive

- Clinical condition deteriorating

3. Treatment stopped on clinical grounds 4. More than 2 new drugs added because of poor clinical response 5. Was discussed at the Provincial Review Committee and the decision to

terminate any further DR-TB treatment taken

Moved 1. Referred from one facility to another facility within the same district

to continue treatment. This is not an outcome, but serves to match

patient moving within the district in order to prevent double

counting

2. The treatment outcome is reported by the facility where the patient

is newl registered

Transferred Out 1. Referred from one facility to another reporting and recording facility

in another district, province or country to continue treatment

2. The treatment outcome is reported by the facility where the patients

is newly registered

Died A patient who died for any reason during the course of treatment

Still on treatment Still on treatment after prescribed period

Not evaluated A patient recorded in the register and who does not have the necessary

recorded data to enable classification of any outcome.

56

Annexure 15: Treatment Outcome Definitions for Long RR/MDR-TB Regimens

OUTCOME DEFINITION

Cured 1. A patient who has TB culture converted. 2. Received treatment for at least 12 months after TB culture conversion 3. Has at least 3 consecutive negative TB cultures during continuation phase 4. Total duration of treatment not to be less than 18 months 5. No evidence of clinical deterioration

Treatment completed (success)

1. A patient who has TB culture converted. 2. Received treatment for at least 12 months after TB culture conversion 3. Has less than 3 consecutive negative TB cultures during continuation phase 4. Total duration of treatment not to be less than 18 months 5. No evidence of clinical deterioration

Loss to Follow Up 1. A patient with treatment interrupted

- >= 2 consecutive months

- Any reason without medical approval

Treatment Failure 1. A patient who failed to culture convert by month 6 2. In the final 12 months of treatment

- >= 2 of 5 cultures are positive

- Clinical condition deteriorating

3. Treatment stopped on clinical grounds 4. More than 2 new drugs added because of poor clinical response 5. Was discussed at the Provincial Review Committee and the decision to

terminate any further DR-TB treatment taken

Moved 1. Referred from one facility to another facility within the same district to continue treatment. This is not an outcome, but serves to match patient moving within the district in order to prevent double counting

2. The treatment outcome is reported by the facility where the patient is newly registered

Transferred Out 1. Referred from one facility to another reporting and recording facility in another district, province or country to continue treatment

2. The treatment outcome is reported by the facility where the patients is newly registered

Died Patient who dies for any reason during the course of treatment

Still on treatment Still on treatment after prescribed period

Not Evaluated A category IV patient recorded in the register and did not receive any of the above outcomes

57

Annexure 16: Form for Submission of Applications to PCAC and NCAC

clinical guidelines & standard operating procedure for the ... · resistant tb (mdr-tb) are...

Documents