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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)
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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.
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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
3.1.1 Inclusion Criteria ................................................................................................................................. 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
3.2.1 Inclusion Criteria ................................................................................................................................. 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
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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
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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
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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
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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
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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
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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)
4-6 months (intensive phase):
LZD2months-DLM*6months- LFX- CFZ-INHhigh-dose -Z-E
+
5 months (continuation phase):
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)
4-6 months (intensive phase):
LZD2months -PAS- LFX- CFZ-INHhigh-dose -Z-E
+
5 months (continuation phase):
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
3.1.1 Inclusion Criteria
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
3.1.2 Exclusion Criteria
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)
6-8 months (intensive phase):
LZD-BDQ-LFX-CFZ-TRD
+
12 months (continuation phase):
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)
6-8 months (intensive phase):
LZD-(BDQ or PAS or DLM)-LFX-CFZ-TRD-(INHhigh-dose or ETO)
+
12 months (continuation phase):
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
3.2.1 Inclusion Criteria
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
3.2.2 Exclusion Criteria
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.
o close contact of a patient failing any RR/MDR-TB treatment
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)
6-8 months (intensive phase):
LZD-BDQ-(DLM* or PAS)-CFZ-TRD-Z-(INHhigh-dose or ETO)
+
12 months (continuation phase):
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)
6-8 months (intensive phase):
PAS-(BDQ or DLM*)-LZD-CFZ-TRD-Z-(INHhigh-dose or ETO)
+
12 months (continuation phase):
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)
6-8 months (intensive phase):
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
+
12 months (continuation phase):
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
o close contact of a patient failing any RR/MDR-TB treatment
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: Vanessa.mudaly@westerncape.gov.za
NCAC : ncac@witshealth.co.za
(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 (Razia.vallie@westerncape.gov.za)
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.
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
Repeat ECG and review QTcF result (see sect 6.3)
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
Repeat ECG and review QTcF result (see sect 6.3)
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
Repeat ECG and review QTcF result (see sect 6.3)
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
Repeat ECG and review QTcF result (see sect 6.3)
6 months &
12 months
post-
completion
of
treatment
Monitor for signs & symptoms of relapse- assess clinically, do CXR and
send sputum for smear & culture.
Repeat ECG and review QTcF result (see sect 6.3)
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
50
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
58
59
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