Bedaquiline and Delamanid are the first new drugs for TB treatment to receive approval from the United States and European authorities for more than 40 years. Both Delamanid and Bedaquiline have novel and different mechanisms of action, and there is no cross resistance with existing TB drugs. This is heartening news to all those affected by drug-resistant TB (DR-TB), including patients, healthcare workers and researchers. Encouragingly there are several other new drugs that are in clinical development, including a drug from the same class as Delamanid named PA-824 (see Table 1 for the currently commercially available drugs that may be used in regimens to treat MDR-TB). New drugs, when incorporated into new treatment regimens, offer the hope of much improved chances of cure for patients with DR-TB disease,

Limitations of current DR-TB treatment

Globally, close to a half a million people are estimated to develop multidrug-resistant TB (MDR-TB, defined as resistance to Rifampicin and Isoniazid) annually, yet less than 20% of these currently receive recommended treatment and only a half of these are successfully treated. The figures from South Africa are improved over the global average with about half of all diagnosed cases estimated to receive treatment. Indeed South Africa is to be commended for the expansion of access to DR-TB treatment and efforts to decentralise treatment further and improve access.

However, only 40% of these successfully complete treatment. Treatment success is even poorer for patients infected with extensively-drug-resistant TB strains (defined as MDR-TB plus resistance to the most important classes of second-line drugs; the fluoroquinolones and the injectable agents). Nationally, less than 20% of XDR-TB patients are cured and long-term outcomes are even poorer. Currently recommended treatment regimens for DR-TB are lengthy, associated with significant side effects, costly, and poorly efficacious. These regimens result in poor outcomes for patients, with high rates of treatment failure, death, and failure to complete the full regimen (treatment default).

DR-TB clinical trials

Both Bedaquiline and Delamanid show promising results in phase 2 trials (designed to show improved efficacy, but not overall cure) in MDR-TB patients, with improvements in conversion of sputum culture from positive to negative. Phase 3 trials, designed to assess final treatment outcomes, are either planned or underway. Such trials are designed to demonstrate individual drug efficacy, with a view to drug approval and registration. They are not, however, designed to identify the best possible treatment regimen to achieve large-scale effectiveness. The approach in these pharmaceutical company sponsored studies, which add new drugs to the existing, long, toxic, complex regimens, is extremely unlikely to improve treatment access or outcomes substantially. More ambitious trials that include novel drug combinations and shorter treatment durations are clearly needed.

There are several multicentre trials being implemented or planned that aim to test combinations of new and existing drugs for MDR-TB. The ongoing STREAM study (ISRCTN78372190), which is examining shorter nine-month regimens using existing and re-purposed (see box) drugs, is considering the addition of new trial arms that include Bedaquiline. Somewhat more ambitiously, the MARVEL study (ACTG 5319) aims to conduct a phase 2 trial of new, existing and re-purposed drugs, including Bedaquiline and PA-824, although the study design is still under discussion. In addition, a study funded by the SA MRC will shortly evaluate an injection free six-month regimen for MDR-TB (NExT RCT). These trials aim to create shorter, better-tolerated and more effective regimens that have the potential to increase access to treatment in a range of settings.

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ANDILE’S STORY

Andile Ndomile closes his eyes, catches his breath and continues sharing his story. “I had normal TB in 2012, but I just never felt well, so I went back to the clinic where they told me I had MDR-TB.”

Ndomile is skeletal, but his eyes are full of fight as he struggles to breath. He is currently living at the Lizo Nobanda step-down facility in Khayelitsha. He is unable to live with his seamstress mother because the bureaucracy involved in getting oxygen at his house is proving to be a stumbling block.
“My lungs are damaged and I have oxygen at my side all the time,” he explains. How does he cope with taking 22 tablets every day, including his antiretrovirals?
“Yho! I take four at a time and they make you so nauseous and you just want to vomit and sleep.
“My pills are like my food, I have to believe that to make it easier.”
Ndomile finds the nights long and often lonely.
“Sometimes I wake up in the middle of the night, short of breath and I tell myself: Let me live to do the things I want to do and I watch the night turn into day.”[/box]

Re-purposed drugs: The fluoroquinolones, clofazimine and Linezolid

Re-purposed drugs are drugs that were designed and tested for diseases other than tuberculosis, but have then been found to be useful in TB treatment. The fluoroquinolones are broad spectrum antibiotics used for a wide range of diseases. They now form the backbone of DR-TB treatment. Clofazimine is an old drug that has been used for the treatment of leprosy for many decades, but is now under investigation for TB treatment.

In contrast, Linezolid is a much newer drug, used for the treatment of highly resistant bacterial strains often acquired in hospital settings. There is now good evidence (including a well conducted clinical trial) emerging that Linezolid may be useful for the treatment of DR-TB, particularly for XDR-TB patients, where there are limited other treatment options. There are two potential barriers to more widespread use of Linezolid in South Africa. The first is that long-term use (required for TB treatment) is associated with significant side effects that require close clinical monitoring. The second is cost. As Linezolid is a newer drug, still under patent in South Africa, it is very expensive. However, given the potential to cure many more XDR-TB patients and thus reduce community transmission, this investment is likely to be worthwhile.

The unfortunate reality is that clinical trials for TB are also extremely slow. In recent TB trials, the time taken from first patient randomised to release of trial results has ranged from 5-11 years. This excludes the considerable time taken in trial design, planning and seeking regulatory approval. Even if the limited number of trials currently in process and planning produce promising results, it is unlikely that we will have data to guide regimen formulation for programmatic use until at least 2020 and possibly beyond (see figure 1 on next page).
Given the urgent need for expanded and improved MDRTB treatment, this timeline is unacceptable, and prompts
questioning of how new drugs should be used and the extent of use in the interim period.

Incorporating new drugs into DR-TB treatment

Given the delay in accumulating clinical trial evidence, an innovative approach to how these new drugs can be best employed in the field in the short term is required. Such an approach would aim to increase access to urgently needed treatment, while contributing to the evidence base on use in the settings where treatment is most needed. Currently shortened MDR-TB treatment with existing drugs, based on the Bangladesh MDR-TB treatment regimen (a nine month shortened regimen which showed impressive results in Bangladesh and includes clofazimine), is being assessed in several observational studies, in addition to the more stringent STREAM trial. The approach to study novel DR-TB regimens in observational studies with closer patient monitoring during and beyond treatment than is the case for standard care, with ethical review, has been endorsed by the World Health Organization as it will contribute to the evidence base.

Incorporating new drugs, initially Bedaquiline and the repurposed drug, Linezolid, into modified regimens, particularly for patients infected with XDR-TB, is possible in the immediate future. Indeed the World Health Organization is currently facilitating access to Bedaquiline for high burden countries for this purpose.

It is also possible to incorporate new drugs into regimens, which are adapted to take into account toxicity and tolerability, for all MDR-TB patients across South Africa in a phased manner. This approach has the potential to both improve access to treatment and improve patient outcomes. In addition, such observational programmes can contribute key safety data unlikely to be gained from smaller randomised controlled trials, where the likelihood of rare events is low. This approach has the possibility to increase access to these newer, potentially more efficacious TB drugs much more rapidly, while ensuring safety and simultaneously contributing to the evidence-base of use in programme settings.

Balancing risks and benefits

There is considerable concern in the TB world about indiscriminate use of new drugs leading to widespread resistance in a short space of time. This concern is behind efforts to restrict the use of new drugs to small, well-functioning programmes and to restrict patient eligibility criteria. However the development of resistance due to accelerated and widespread use is an untested assumption for which there is little or no direct evidence. Although resistance to some TB drugs has emerged rapidly, the mechanisms and drivers for drug resistance remain poorly understood. Recent data now suggests that poor adherence may not be a principal driver for TB drug resistance, as dogma would suggest. Rather, prescription of inadequate regimens may be an important factor. Therefore, accelerated access to new drugs may actually reduce the risk of resistance amplification by improving treatment regimens for the majority of patients. Finally, continuous monitoring of resistance over time can assess risk.

There is also concern about potentially very small but serious risks from the drugs themselves. This concern can be used by some to restrict access to drugs until further safety data is available. However, these potential risks need to be balanced against the thousands of individuals who die currently from DR-TB in South Africa. Similarly, recognition must also be made of the considerable side effects of existing, older DR-TB drugs.

Permanent hearing loss due to the injectable agents is common, as is the mortality risk associated with renal toxicity and electrolyte abnormalities with capreomycin and the aminoglycosides.

Conclusions

The potential availability of new drugs provides a glimmer of hope for the thousands of individuals in South Africa in whom DR-TB emerges each year. However, individual new drugs are not enough; we need to know how to use these drugs in the most effective way to reduce mortality and interrupt ongoing transmission. Clinical trials that test different drug combinations and treatment durations with new, existing and repurposed drugs, while avoiding injectables are required. But, given the time taken to conduct such trials and the critical need to scaleup access to treatment and improve patient outcomes, largescale programme studies are urgently needed to complement clinical trials.

Dheda is professor of respiratory medicine and head of the Lung Infection and Immunity Unit at the University of Cape Town (UCT) Lung Institute and the Department of Medicine.

Maartens is the chief specialist physician at Groote Schuur Hospital and a professor at UCT, where he is head of the Division of Clinical Pharmacology.

Cox is senior researcher at the Division of Medical Microbiology, UCT.

Goemaere is the coordinator of the TB/HIV unit support within MSF South Africa, supporting MSF programmes in most SADC countries. He is an honorary senior lecturer in the School of Public Health and Family Medicine at UCT.