0 Recommendations

Practice-Based Recommendations for the Management of RR/MDR-TB

By Lindsay McKenna | 21 Aug, 2019

Dear Colleagues:

Attached and below please find a statement from DR-TB STAT and Treatment
Action Group outlining practice-based recommendations for the optimal
management of RR/MDR-TB.

We hope this practical advice will help country programs implement the 2018
WHO recommendations for the management of RR/MDR-TB.

Thank you for all you are doing on behalf of people living with
drug-resistant TB. Please do not hesitate to contact us with any comments
or questions.


*Samantha Britton*

*Program Specialist, Sentinel/DR-TB STAT*

*Partners In Health | www.pih.org <http://www.pih.org/>*

*Email: <

*Skype: sbritton.pih | cell: +1 857 222-2113*

*Lindsay McKenna*, MPH
TB Project Co-Director
Treatment Action Group
90 Broad St, Suite 2503
New York, NY 10004 USA
m: (631) 258-0808
t: (212) 253-7922

Practice-Based Recommendations for Implementing the 2018 World Health
Organization Recommendations on the Treatment of Rifampicin-
Resistant/Multidrug-Resistant Tuberculosis

August 2019

*I. Introduction*
It has been one year since the World Health Organization (WHO) released its
Rapid Communication documenting significant changes in the approach to the
treatment of rifampicin-resistant/multidrug-resistant tuberculosis
(RR/MDR-TB),1 with the full guidance being released in December of 2018.2 These
recommendations represent a significant shift in RR/MDR-TB management: for
the first time, three medications were strongly recommended for the
treatment of RR/MDR-TB and all-oral regimens were recommended for a
majority of people living with the disease. The guidelines, however, offer
several possible therapeutic options for countries and programs treating
people living with RR/MDR-TB (see Table 1), creating confusion about the
conditions under which each regimen should be prescribed. Country programs
and implementation partners have requested advice to guide decision-making
and support optimal treatment outcomes for all people living with
RR/MDR-TB. The following clinical practice principles were developed based
on field experience providing direct care for people living with RR/MDR-TB,
engaging with TB programs, and listening to the perspectives from the TB

*II. WHO Recommended Regimens* Three possible approaches to initial regimen
selection are outlined in the 2018 WHO recommendations:


   The use of all-oral regimens that contain all three strongly recommended
   Group A drugs (bedaquiline, linezolid and a third-generation
   fluoroquinolone [either levofloxacin or moxifloxacin]) when possible, along
   with both Group B drugs (clofazimine and cycloserine/terizidone) for 18-20
   months. This is the preferred regimen recommended by WHO;

   The use of all-oral shorter regimens consisting of 4-5 medications and
   that contain the Group A drugs bedaquiline, linezolid and a
   third-generation fluoroquinolone (either levofloxacin or moxifloxacin) and
   Group B drugs (clofazimine) or Group C drugs (delamanid) for the treatment
   of RR/MDR-TB but administered for 9-12 months (“modified shorter regimens”)
   under operational research conditions (see section below on principles for
   operational research);

   The use of the WHO “standardized shorter regimen”* first recommended in
   2016,3 but given with amikacin instead of kanamycin and accompanied by
   routine monitoring for hearing loss.

*Four months of clofazimine, moxifloxacin (or levofloxacin), ethambutol,
pyrazinamide, high dose isoniazid, ethionamide (or prothionamide), and
amikacin, followed by five months of clofazimine, moxifloxacin (or
levofloxacin), ethambutol, and pyrazinamide

Table 1: Comparison Table for Regimens Recommended in the 2018 WHO
RR/MDR-TB Treatment Guidelines

2018 Longer Regimen

2016 Standardized Shorter Regimen

All-Oral Shorter Regimen

Date of WHO recommendation




Strength of WHO recommendation

Group A drugs§ strongly recommended

Conditionally recommended

Recommended under operational research conditions

Baseline DST necessary

Rifampin resistance and fluoroquinolone resistance at a minimum; consider
storage of baseline strains to test for resistance to components of the
regimen in the future

Rifampin, fluoroquinolone, and second-line injectable resistance

Rifampin resistance and fluoroquinolone resistance at a minimum; consider
storage of baseline strains to test for resistance to components of the
all-oral shorter regimen in the future

Evidence for efficacy

Evidence for individual drugs but not for regimen as a whole

Randomized controlled trial showed non- inferiority when compared with the
2016 WHO longer regimen (which is no longer recommended)

Limited evidence from smaller cohorts, largely from South Africa

Efficacy risks

Could have higher rates of loss to follow up given length of regimen

Higher rates of poor bacteriologic outcomes (most benefit is seen
in reducing loss to follow up)

Could have higher rates of recurrence/relapse, with relapse
being identified through genetic testing

Safety risks

Largely associated with linezolid; requires clinical and laboratory
monitoring that is reasonably easy to access; partially reversible

Hearing loss from injectable; often difficult to monitor; irreversible

Largely associated with linezolid; requires clinical and laboratory
monitoring that is reasonably easy to access; partially reversible

Other possible benefits

Lower mortality reported with the use of bedaquiline in some settings

Short-term costs could be lower

Lower mortality reported with the use of bedaquiline in some settings

Other possible risks

Use of medications to which there may be resistance

High pill burden; daily injections; use of medications to which there may
be resistance

Use of medications to which there may be resistance

Maximum number of Group A drugs§




Maximum number of Group B drugs§




§Group A drugs: bedaquiline, linezolid, and levofloxacin or moxifloxacin;
Group B drugs: clofazimine and cycloserine/terizidone

*III. Principles for Regimen Selection*
Recently, the WHO and its Civil Society Task Force announced that they
“that all countries transition to an all-oral regimen for drug-resistant TB
by World TB Day 2020.”4 In light of this, the following best practices are
suggested for optimal regimen selection for persons living with RR/MDR-TB:

   - All-oral regimens should be given to a MAJORITY of people with
   RR/MDR-TB and these regimens should include all three of the Group A
   medications unless there is a non-modifiable clinical contraindication;
   - Countries should consider offering all-oral shorter regimens
   (“modified shorter regimens”) under closely monitored conditions that allow
   them to collect effectiveness and safety data (e.g. operational research),
   especially in populations that are usually excluded from studies (e.g.
   children, pregnant women, people living in prisons). These regimens should
   utilize the Group A drugs (bedaquiline, linezolid, either levofloxacin
   or moxifloxacin) and Group B drugs (clofazimine, cycloserine/terizidone) or
   Group C drugs (delamanid, ethambutol if there is documented susceptibility,
   pyrazinamide if there is documented susceptibility);
   - Injectables should only be used in patients with no other treatment
   options (e.g. salvage therapy), when there is formal assessment and monthly
   monitoring of hearing; the person living with RR/MDR-TB has been informed
   about the risks of the injectable drugs (permanent hearing loss, renal
   failure, electrolyte abnormalities); and consent is given to receive the
   - The 2016 standardized shorter regimen should be phased out in favor of
   all-oral regimens which are either 18-20 months in duration or shorter and
   administered under carefully monitored conditions;
   - The 2016 standardized shorter regimen should only be given to people
   who have no documented resistance to the injectable and no documented
   resistance to the fluoroquinolone since the phase III randomized,
   controlled study to evaluate the standardized shorter regimen used these
   criteria.5 Additionally, it is unethical to expose people to medicines
   to which they are resistant and carry risks of toxicities without potential
   benefit. If the shorter regimen is to be given, amikacin should be used,
   there must be baseline and monthly assessments of hearing, and there must
   be documented consent that the patient agrees to receive the injectable
   after being counseled about the risks of permanent hearing loss and renal

*IV. All-Oral Regimen Design and Adjustment to Support Optimal Treatment
Outcomes *

   - All countries need to urgently scale up laboratory testing to detect
   resistance to rifampicin and the fluoroquinolones;
   - Children over the age of six years can receive bedaquiline and should
   receive this drug unless it is contraindicated. Children over the age of
   three years should receive delamanid instead of bedaquiline. Additional
   dosing and safety data on these drugs in younger children will be
   forthcoming soon; in the meantime, younger children can receive these drugs
   on a case-by-case basis;
   - There are limited data on the use and safety of all second-line drugs
   during pregnancy and breastfeeding. Animal studies suggest there are no
   teratogenic effects of bedaquiline, and delamanid is in the same safety
   category as most of the other second-line drugs. Since injectable agents
   are contraindicated in pregnant women, they should receive all-oral
   regimens. Pregnancy is not a reason to deny women access to drugs with a
   proven mortality benefit, including bedaquiline, linezolid, and the
   third-generation fluoroquinolones;
   - The 24-week administration period for both bedaquiline and delamanid
   was selected so clinical trials could be completed in a shorter time
   period, not because of any evidence of cumulative toxicity or risk if
   either drug is administered for longer than 24 weeks.6 Individuals
   receiving these medications may need to take them for longer than 24 weeks
   for a variety of reasons, including (but not limited to) toxicity to
   another medication in the regimen leading to discontinuation of that
   medication, resistance to one or more of the Group A drugs, delayed culture
   conversion, or if the person living with RR/MDR-TB has severe disease;
   - Initial hesitation to give bedaquiline and delamanid together had to
   do with a theoretical risk of additive or synergistic cardiotoxicity. Data
   from observational studies and from a randomized controlled trial show
   there is no increased risk of cardiotoxicity and therefore bedaquiline and
   delamanid can be given in combination in patients who need both of these
   drugs. Data supporting the safe co-administration of bedaquiline and
   delamanid come from observational cohorts7—including the endTB study8—and
   a randomized controlled designed specifically to look at cardiotoxicity of
   giving bedaquiline and delamanid in combination (ACTG5343);9
   - All-oral regimens are the preference for a majority of people living
   with RR/MDR-TB, and some countries may simply wish to use the 2016
   standardized shorter regimen and simply replace the injectable with
   bedaquiline. This regimen, however, includes ethionamide (a drug that is
   now only recommended for salvage regimens) and only utilizes two of the
   Group A drugs; additionally, if fluoroquinolone resistance is not ruled
   out, use of this modification could lead to amplification of resistance to
   its other components, including bedaquiline and/or clofazimine. Therefore,
   simply replacing the injectable with bedaquiline may not be ideal;
   - Monitoring and management of adverse events associated with the Group
   A and B drugs is essential to ensure the best possible outcomes for people
   living with RR/MDR- TB and the programs treating them. This included
   baseline/monthly monitoring of the complete blood count, visual acuity, and
   screening for peripheral neuropathy while on linezolid and baseline/monthly
   monitoring for potassium and the QTcF interval while on bedaquiline,
   clofazimine, or moxifloxacin;

   If drug adjustments are needed for toxicity, there are several options,
   including prolongation of bedaquiline, dose adjustments for linezolid, or
   the use of Group C agents, of which delamanid is preferred given its safety

*V. Principles for Operational Research*

   - Operational research is not meant to replicate clinical trials but
   rather to help countries answer questions about optimal implementation in
   the populations they are treating in every day practice;
   - Sample protocols for modified, all-oral shorter regimens have been
   developed by multiple groups, including the WHO Tropical Diseases Research
   (TDR) Program, the US Agency for International Development (USAID), and the
   Harvard Medical School Dubai Center for Global Health Delivery and these
   can be adapted to local country settings with support for planning,
   implementing and analyzing the results of such protocols provided by
   in-country partners, including academic institutions;
   - While there are multiple, ongoing clinical trials to assess all-oral,
   shortened RR/MDR-TB regimens,11 there is also a need to collect and
   analyze data on the implementation of such regimens under field conditions;
   - Well-conducted observational cohort studies have been used to support
   policy change at both national and international levels and have the added
   benefit of assessing feasibility as well.13,14
   - Table 2 below reviews the medications that should be prioritized in
   all-oral shorter regimens.

Table 2: Priority Medications for All-Oral Shorter Regimens


Phase completed and regulatory approval status

Summary of study results

Adverse events

Drug-drug interactions and overlapping toxicities

Access and pricing15

Ongoing trials16

Bedaquiline 17,18,19,20

US, Europe, South Africa, multiple other countries

Significantly faster time to culture conversion, significantly higher rates
of culture conversion, and significantly improved treatment outcomes when
compared with placebo

QTc prolongation (moderate), hepatitis

Cannot use with efavirenz or rifampin

Use with protease inhibitors results in increased bedaquiline levels but
clinical significance not clear

Caution when used with other QTc prolonging agents

USD 66.6 per month via Global Drug Facility (GDF)


Clofazimine 21

No registered TB indication, approved for treatment of leprosy

Significantly faster time to and higher rates of culture conversion,
significantly improved treatment outcomes, non- placebo- controlled studies

Skin discoloration, QTc prolongation

Caution when used with other QTc prolonging agents

USD 30.00 per month via GDF


Delamanid 22,23,24,25,26,27

Europe, Japan, South Africa, limited number of additional countries

Faster time to culture conversion (p=0.052) compared with placebo: no
differences in final outcomes, but study not powered to detect these

QTc prolongation (mild), generally well tolerated

No significant drug-drug interactions

USD 283.20 per month via GDF



No registered TB indication, approved for treatment of other bacterial

Considered a core drug in the treatment of RR- TB based on observational

QTc prolongation (mild), tendinitis, tendinopathy, generally well tolerated

No significant drug-drug interactions

USD 12.00 per month via GDF

endTB, NeXT, Opti-Q, MDR- END,


2B, 3
No registered TB indication, approved for treatment of other bacterial

Significantly higher rates of and faster times to culture conversion and
improved outcomes in delayed-start trial and non-placebo- controlled trials

Bone marrow toxicity, peripheral neuritis, optic neuritis

Caution when used in persons on AZT due to overlapping bone marrow toxicity

Caution when given with other drugs causing peripheral neuropathy (i.e.
INH) or causing optic neuritis or neuropathy (i.e. ethambutol)

USD 39.00 per month via GDF


*VI. Programmatic Considerations*

   - Countries will need to ensure they have adequate stocks of newer drugs
   (bedaquiline and delamanid) as well as other companion drugs (clofazimine,
   linezolid, levofloxacin, and possibly moxifloxacin);
   - While identifying and managing adverse events during treatment are
   crucial activities, systems for reporting serious, severe, and other
   adverse events of interest should be developed or strengthened within the
   country to serve all persons living with RR/MDR- TB regardless of their
   treatment regimen. This active Drug Safety Monitoring and Management should
   be done according to WHO principles30 and national guidelines;
   - While countries may consider rolling out all-oral shorter regimens or
   “modified shorter regimens” in selected locations or provinces, scale-up of
   all-oral shorter regimens containing group A and B medications needs to
   take place on a national level and implementation plans must be in place
   for equitable and widespread access.

The WHO Guideline Development Group will be meeting at the end of 2019 to
update recommendations on the treatment of RR/MDR-TB, including the use of
all-oral shorter regimens. It is anticipated that these new recommendations
will be available in the second quarter of 2020. More frequent updates to
the WHO recommendations are anticipated in the coming years as more
evidence emerges. This is a welcome development that reflects the improving
science in RR/MDR-TB treatment and is common in other diseases/WHO
guidelines such as for HIV management. Countries should develop systems to
rapidly update their national guidelines and implementation plans as better
treatment data emerges; this is necessary to “End TB” and to ensure that a
patient-centered, human right-based approach to RR/MDR-TB is available to
all affected by the disease.


1 World Health Organization. Rapid communication: key changes to treatment
of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). August,

2 World Health Organization. WHO consolidated guidelines on drug-resistant
tuberculosis treatment. March, 2019.

3 World Health Organization. WHO treatment guidelines for drug-resistant
tuberculosis. 2016 Update. October, 2016.

4 World Health Organization. Joint statement by the WHO Director General
with the WHO Civil Society Task Force. July 24, 2019.

5 Nunn, A., Philips, P., Meredith, S., et al. A trial of a shorter regimen
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6 Guglielmetti, L., Jaspard, M., Le Du, D., et al. Long-term outcome and
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7 Ferlazzo, G., Mohr, E., Laxmeshwar, C., et al. Early safety and efficacy
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8 endTB. Interim analysis report. July, 2018.

9 Dooley, K., Rosenkranz, S., Conradie, F., et al. QTc effects of
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10 Von Groote-Bidlingmaier, F., Patientia, R., Sanchez, E., et al. Efficacy
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11 RESIST-TB. Clinical Trials Progress Report.
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13 Khan, F., Salim, H., du Cros, P., et al. Effectiveness and safety of
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14 World Health Organization. A 2016 review of available evidence on the
use of bedaquiline in the treatment of multidrug-resistant tuberculosis.
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15 Global Drug Facility. Product catalogue. Available at
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16 RESIST-TB. Clinical Trials Progress Report. Available at
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20 Schnippel K, Ndjeka N, Maartens G, et al. Effect of bedaquiline on
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21 Tang S, Yao L, Hao X, et al. Clofazimine for the treatment of
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30 World Health Organization. Active drug-safety monitoring and management:
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