Union letter to WHO regarding treatment guidelines

The Union has sent a letter to Dr Tedros Adhanom Ghebreyesus, Director-General of the World Health Organization (WHO) in response to concerns raised by partner organisations over the latest drug-resistant tuberculosis (DR-TB) guidelines issued by the WHO.

That letter is printed in full here below:


Dear Dr Tedros,

We are aware of an open letter from Partners in Health, Médecins Sans Frontiers, Treatment Action Group, DR-TB STAT, The Sentinel Project and the Global TB CAB sent on 23 April 2019 expressing concern regarding the latest DR-TB guidelines from the WHO.

The current WHO DR-TB guidelines leave the choice between two different approaches to DR-TB. First, an individualised all-oral long regimen approach relying on the most effective drugs as established by meta-analysis of individual patient data, some of which have potentially toxic side effects. This recommendation has a very low certainty in the estimates of effect. Second, the shorter 9-12 -month standardised treatment regimen, the first complete treatment regimen to have evidence on its use from a phase three randomised control trial. This second recommendation is based on a low certainty of effect. In addition, the results of this trial closely match the programmatic experience of using this regimen. Although it contains an injectable agent, it represents an important step towards shorter and more programmatically friendly regimens with significantly better adherence.

We would like to share our perspectives on the following technical concerns related to short regimens raised by the open letter:

1. False equivalence between shorter and new longer, all-oral regimens.

It is unknown how the new all-oral regimen performs in real life. There are no trials underway or planned nor programmatic data available using this approach. In addition, most of the data on the use of bedaquiline and linezolid come from high and higher-middle income countries, while data for shorter regimens are from low and lower-middle income countries with weaker health systems. The risk of unfavourable outcomes (failures/relapses/deaths) by using a new all-oral regimen (shorter or longer) might be higher in low and lower-middle income countries for reasons not necessarily linked to TB treatment but health systems-related issues. However, the lost to follow up rate was significantly lower for patients treated with shorter regimens in programmatic conditions.

Drugs Susceptibility Tests (DST) for bedaquiline, linezolid (Group A) and clofazimine (Group B) may not be accessible in resource limited settings.

2. The recommendation for the shorter regimen fails to emphasize that it should not be used in patients with confirmed or suspected drug resistance to any of the drugs in the regimen, except isoniazid.

This statement is at best controversial. It is critical to indicate that phenotypic DST for ethambutol and prothionamide/ethionamide may not be accurate and reproducible. There are clear WHO warnings about these tests1. Excluding patients from the shorter regimen based on an unreliable result of resistance to one of these drugs can thus not be justified.  

The success of short regimen is based on the action of main drugs, such as fluoroquinolones, second-line injectables and clofazimine.  The role of other drugs is supportive in preventing development of acquired resistance and they should not be ‘counted’.

The shorter regimen is given successfully under programmatic conditions in several African and Asian countries to thousands of patients with very good results for over 10 years.

Treatment outcomes are far better than reported for the previous WHO recommended long regimen in similar programmatic conditions.

3. Technical manual for drug susceptibility testing of medicines used in the treatment of tuberculosis. WHO/CDS/TB/2018.24

Good quality of clinical care must to offered to ALL patients, not only to those on the shorter treatment regimen, including an informed consent, complete side effects monitoring and not just audiometry, as stated in the letter point 5.

4. Minimising the benefits of shorter, all-oral regimens under operational research conditions.

While robust clinical trials into shorter, less toxic all-oral regimens are underway, the effectiveness of shorter, all-oral regimens remains unknown.

The role of good quality operational research into all-oral regimens will play a vital role in supporting future WHO guidance. We agree that national TB programmes (and funders) should be encouraged to pilot shorter, all-oral regimens under operational research conditions.

We welcome WHO’s renewed focus on universal health coverage so that TB programmes can be more accessible, with shorter delays for diagnosis and treatment, better quality of clinical care and follow-up of patients, and strengthened infection control, preventing development of drug resistance and its transmission. Integrating DR-TB management into routine TB programmes and not managing DR-TB as a separate project is also required to ensure sustainability. The shorter regimen, used in line with the current WHO recommendations offers an important effective treatment option for MDR-TB patients using fewer resources in high prevalence settings while we await data on shorter all oral regimens.

We have entered a period of dynamic change in the treatment of DR-TB and as such WHO needs to be ready to support this with timely updates and examining the evidence on its merits.  As organisations supporting National TB programmes we hope that this guidance from WHO will be evidence based without bias and serve the needs of the majority of patients living in low- and middle-income countries.


José Luis Castro
Executive Director, The Union