Médecins Sans Frontières (MSF) has urged the Japanese pharmaceutical giant Otsuka to provide an access plan for South Africa that ensures people in the country with drug-resistant TB (DR-TB) can receive delamanid, one of the most promising new drugs in decades available in the fight against this deadly illness.
Such a plan would outline Otsuka’s intentions for registering delamanid with the Medicines Control Council (MCC), and providing treatment courses in the interim through a clinical access programme, along with information on pricing and licensing of patent rights.
South Africa has one of the highest burdens of TB and DR-TB in the world, with more than 20,000 people diagnosed with DR-TB in 2015. Yet the current DR-TB treatment – which consists of a combination of multiple pills and daily injections – is only successful in about half of all people who receive it. New drugs such as delamanid offer the opportunity to provide more successful, tolerable treatment regimens to patients with few options available.
According to MSF’s DR-TB specialist Dr Jennifer Hughes: “Delamanid is of particular interest in South Africa, given that it can be taken with the standard fixed-dose combination treatment for HIV, and over 70% of people diagnosed with TB here are also HIV-positive. An estimated 7,000 DR-TB patients per year in South Africa could benefit from the inclusion of delamanid in their treatment regimens, but we need Otsuka to act rapidly to register the drug and provide an interim access plan if we want people who need this drug to receive it.”
Over the past 10 months, a small number of DR-TB patients in South Africa have had delamanid included in their treatment by having their clinicians apply on a case-by-case basis for compassionate use – including 52 DR-TB patients in Khayelitsha, for whom MSF purchases the drug at a cost of $1,700 (R23,600) per six-month treatment course. The Khayelitsha patient cohort is the largest in South Africa and one of the largest in the world on delamanid.
Wider access to the drug is being hampered by a slow start to a national clinical access programme for delamanid, which the South African National Department of Health (NDOH) has proactively taken steps to establish with Otsuka. Through the programme, clinicians would prescribe the drug at select clinical sites prior to the drug’s registration.
“The eventual start of a clinical access programme nationwide will be a welcome development,” said Hughes, “though it is unclear if there will be a sufficient number of treatment courses to meet demand for delamanid prior to local registration of the drug.”
There are also delays in registering the drug at the MCC. Local registration is necessary for the NDOH to incorporate the drug into clinical guidelines, and negotiate a purchasing price for the drug. Unfortunately, Otsuka has yet to file for registration of delamanid in South Africa, a process which can take years, even when applications are expedited.
“MSF is urging Otsuka to apply for registration and for the application to be expedited by the MCC once filed. Given the timelines involved, we are also calling on Otsuka to outline their plan to ensure enough treatment courses will be available during the clinical access programme to meet demand and bridge the gap to registration,” said Hughes.
One of the first people in Khayelitsha to start treatment with delamanid is 16-year-old Sinethemba Kuse, who was diagnosed with extensively DR-TB (XDR-TB) in February this year. Her grandmother, Vuyisiwa Madubela, helped nurse her back to health, and has issued a heartfelt plea to Outsuka:
“I would ask the manufacturer of delamanid to get more drugs for other patients,” she said. “I would ask them to give it to every patient who really needs it. I see lots of TB patients at the TB clinic. If people got this drug, they could really control DR-TB. TB is a giant but not a killer. TB can be cured.”
Clinicians and researchers from MSF’s DR-TB programmes around the world, including Khayelitsha, attended the annual World Conference on Lung Health, , where delegates from more than 125 countries presented their latest research, and discussed ways to tackle the disease, which now kills more people worldwide than HIV.
MSR has shared its experience of using the new TB drugs, bedaquiline and delamanid, to treat people with drug-resistant TB in programme settings at the conference. MSF is also involved in two clinical trials to test new TB treatments, both of which will start to enrol patients soon. The trials aim to find new, more effective, shorter, and more user-friendly treatments for drug-resistant forms of tuberculosis.
“The lack of solid data and evidence on the safety and efficacy of the new TB drugs means that only the sickest people can receive them under current guidelines, and that governments are reluctant to introduce them into their national TB treatment programmes for routine use,” said Dr Catherine Hewison, MSF TB advisor. “Furthermore, very few of those eligible patients have accessed them to date. In fact, through MSF’s effort to accelerate access to and research for the new TB drugs, we now have some of the largest cohorts of patients on bedaquiline and delamanid.”
Bedaquiline and delamanid, which were approved by the US Food and Drug Administration and the European Medicines Agency in 2012 and 2014 respectively, are the first two new TB drugs developed in nearly 50 years. They represent a new hope for patients sick with the most resistant forms of TB, for whom most existing drugs do not work.
Yet as of October 2016, only 5,700 patients have been able to receive bedaquiline globally, and a mere 405 have had access to delamanid. According to the WHO’s latest estimates, 580 000 people were eligible for multi-drug resistant (MDR-TB) treatment in 2015.
Among the many reasons for this massive gap, one is the limited knowledge on how to use these drugs in combination with existing drugs, as multiple medicines are required to kill the bacteria. Early clinical research and programmatic use have shown promising results, which have led the WHO to recommend use of the drugs for some of the sickest patients.
However, far more clinical research should be conducted and published, particularly on their use in new combination treatments; on specific categories of patients (such as pregnant women, children, and HIV-positive patients); and beyond the six-month treatment currently recommended in WHO interim guidelines.
While continuing to advocate for the necessary resources and political will for greater research and development of novel regimens, MSF began its own clinical trials to contribute to knowledge of optimal regimen composition.
MSF is involved in two TB clinical trials – TB PRACTECAL and as part of the endTB partnership – to find new, shorter, more effective combination treatments for multi-drug resistant TB that include the new drugs. Patients’ needs are at the heart of both trials, which aim to find treatments that contain no injectable drugs, and have manageable side effects. Both trials are expected to enrol the first patient by the end of the year.
Within the framework of the endTB project, MSF and its partners are also collecting programmatic evidence about the use of bedaquiline and delamanid in a cohort of 2 600 patients across 15 countries.
To increase use of, and access to, more effective regimens containing the new drugs, MSF and its partners have provided delamanid to 236 patients (of which 21 are children) and bedaquiline to 781 patients. Moreover, 41 patients received a combination of both drugs, and 101 are being treated for more than 6 months.
These efforts span 12 countries in Africa, Eastern Europe, Central and Southern Asia. MSF will share experience from these programmes at the conference, including preliminary data on patients’ response to treatment.
Final results from an observational study conducted with 1,006 rifampicin-resistant tuberculosis (RR -TB) patients in nine francophone countries in Africa show high treatment success rates of 82% with limited adverse events on a nine-month treatment regimen. The study was carried out among MDR-TB patients in Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Côte d’Ivoire, Democratic Republic of the Congo, Niger and Rwanda. The results were presented at the conference.
“The francophone study is a breakthrough in the fight against drug-resistant TB,” said Dr Paula I Fujiwara, scientific director of the International Union Against Tuberculosis and Lung Disease (The Union). “These results have now been replicated in many different settings and with a large number of patients, showing conclusively that this is the most effective treatment for drug-resistant TB discovered to date.” The previous standard regimen for treating drug-resistant TB lasted 20 months or more and achieved cure rates below 55%. Based on the francophone ́s strong preliminary data presented in December 2015, the WHO in May 2016 recommended that the nine-month treatment regimen be used in place of the previous regimens.
“With strong evidence now showing that this regimen is the most effective available for treating multidrug-resistant forms of TB, the next step is for countries to begin widely implementing this new approach,” said Dr Arnaud Trébucq, a senior consultant with The Union.
Among the 1,006 patients who participated in the study, treatment was successful for 821 (82%), of whom 734 were cured, defined as patients who completed the full course of treatment without evidence of failure, and who produced samples that tested negative for the presence of TB bacteria three times before treatment completion, using a culture test. A culture test, in which colonies of TB bacteria are cultured within a growth medium, is the most rigorous test available for identifying the presence of TB. An additional 87 patients successfully completed the full course of treatment without demonstrating any signs of treatment failure but 2 had less than three negative culture results. An additional 54 patients (5%) did not respond to the treatment, 82 patients (8%) died, and 49 (5%) were lost to follow-up.
The death rate was higher among patients with HIV-infection, but among patients who survived, the regimen demonstrated similar success rates in HIV-infected and non HIV-infected patients.
The study was carried out by researchers from The Union, together with the Institute of Tropical Medicine of Anvers (Belgium), the San Raffaele Scientific Institute of Milan (Italy) and the teams of each of the nine participating countries which included clinicians, National Reference Laboratories and National Tuberculosis Control Programmes.
On 13 October, WHO published new data on the global TB epidemic, referring to drug-resistant TB as a “crisis.” In 2015, 580,000 people became sick with TB resistant to at least rifampicin, of whom 480,000 were diagnosed as having developed resistance to both rifampicin and isoniazid.
In September 2016, the UN General Assembly issued a declaration committing to take worldwide action against drug-resistant TB. The declaration recognised that within the broader context of antimicrobial resistance, resistance to antibiotics “is the greatest and most urgent global risk, requiring increased attention and coherence at the international, national and regional levels.