A three-drug regimen trialled on South African tuberculosis patients, half of whom were also HIV positive, has delivered results described as a ‘phenomenal breakthrough’ in treating extensively drug-resistant tuberculosis (XDR-TB). The study was presented at the Union World Conference on Lung Health.
At a press conference on research results on drug-resistant TB (DR-TB), Dr Francesca Conradie, South Africa, shared the interim results of a clinical study using three drugs for the treatment of XDR-TB. This three-drug regimen was trialled on patients in South Africa, half of whom were also HIV positive.
“XDR-TB is TB that is resistant to the four main TB drugs that we have and the mortality rate is very high, with four out of five patients dying,” said Dr Conradie, “Prior XDR-TB treatment consisted of the kitchen sink approach; we just gave every drug that we had.”
Conradie presented initial results showing that out of 50 patients, 30 patients have been completely cured, 17 patients are being successfully treated, and there have been just three deaths (and those patients had advanced TB before entering the study).
Conradie described these results as a “phenomenal breakthrough in treating XDR-TB” and that this felt to her like the early days of treating HIV, where there is suddenly hope for dying patients. “This is the most rewarding protocol I’ve worked on, because patients go home and get better. We’re actually in a little bit of trouble because our wards are empty, but I think that’s a good thing.”
“DR-TB is one of the most challenging diseases any person could ever face. But we’re starting to see promise in shorter, more effective treatments that have the hope of eliminating some of the most difficult parts of the treatment experience,” said Dr Paula I Fujiwara, scientific director of the International Union Against Tuberculosis and Lung Disease (The Union).
Additionally, at the press conference the researchers demonstrated promising results from experimental treatments and models of providing health care to patients suffering from multidrug-resistant TB (MDR-TB). They also announced new data showing that TB drug resistance can develop quickly, and that a significant percentage of patients who are diagnosed with DR-TB could have been diagnosed earlier. Late diagnosis is more likely to lead to treatment complications and worse treatment outcomes.
These trials all use the shorter treatment regimen, which reduces the length of treatment from 20 or more months to only nine months, and is recommended by the World Health Organisation as the new standard approach to treat MDR-TB.
Erika Mohr from Médecins Sans Frontières (MSF) discussed the missed opportunities for rapid diagnosis of DR-TB in South Africa. The researchers found there were missed opportunities for diagnosing DR-TB earlier in 28 percent of cases. Earlier diagnosis improves patient outcomes and reduces TB transmission within the community.
Animesh Sinha, MSF Russia, shared results about the effectiveness of TB treatment regimens for DR-TB in the Chechen Republic.
Esther Casas, MSF Swaziland, delivered results from implementing the short-course regimen for MDR-TB in a high HIV prevalence setting. Dr Casas described how the study treated patients in their home, in a clinic and in an outreach setting, with an emphasis on psycho-social support. These measures demonstrated high rates of treatment success: Of the 80 patients who completed treatment, 75% were treated fully. One patient in the study said, “I’m so glad that I chose to be treated using the shorter treatment; the mobile team has been so supportive. Since I completed my treatment I can even play soccer again.”
Conradie, who works for Right to Care and the Clinical HIV Research Unit said about her study: “This treatment is not without side-effects but the patients who died already had advanced TB and their deaths were unrelated to the drugs.” People taking the NIX-TB regimen only take three oral drugs, bedaquiline, linezolid and pretomanid.
Health-e News reports that this is instead of an average of eight toxic drugs in the current treatment, which can include thousands of pills, six months or more of daily painful injections, and debilitating side-effects like deafness and blindness. “XDR-TB is resistant to the four main anti-TB drugs we have. One in five of our patients are still alive after treatment at five years,” said Conradie.
That means that 80% of these patients die, even if they have access to treatment, and are able to endure more than 20 months of the toxic mix of painful injections and nauseating tablets.
As so few options are available to treat these patients, physicians have to use a “kitchen sink” approach where every possible drug is given in the hopes that some will have an effect on the disease, said Conradie – “but more drugs for more time means more side-effects”.
Although only 30 patients have completed the regimen and only 17 have been TB-free for over a year post-treatment, the TB Alliance said these results were so promising they were already in talks with regulatory authorities like the South African Medicines Control Council, the US Food and Drug Administration and the European Medicines Agency.
“We are talking to them about how many patients treated successfully are needed to make a regulatory file for approval. And we’ve got encouragement with the NIX data we have right now that potentially we could file within a year,” said TB Alliance’s Dr Daniel Everitt.
The trial aims to enrol 200 patients, so it is only just a quarter way there but Everitt said that “perhaps if 45 patients met the primary end point” of six months post-treatment while remaining TB-free, the NIX team could file for regulatory approval and the life-saving treatment can be incorporated into WHO guidelines. But regulators have not yet confirmed just how many cured patients are needed.
No guidelines exist currently and Conradie said physicians treating people with XDR-TB have to rely on expert opinion or luck: “There’s never been a trial like this before. Up until now it’s been a matter of trying our hardest and crossing our fingers,” she said. Healthcare workers entrusted to care for these patients are often frustrated. She said “doctors practice medicine because they don’t want patients to die. Especially not young patients who we now have a chance of curing.”
The average age of the patients taking part in this research, being conducted at Sizwe Hospital in Johannesburg and the Brooklyn Chest Hospital in Cape Town, is 35 years.
About 1,500 people are diagnosed with XDR-TB in South Africa every year, which is small in comparison to the approximately 300 000 new TB infections that occurred in 2015. But the costs associated with the XDR-TB care – sometimes as high as $21,000 per patient – and the risk of spreading resistant strains make even a handful of cases a huge concern
Everitt said the NIX regimen, should it be adopted, has the potential to significantly lower treatment costs regardless of how much countries will have to pay to procure these novel drugs. “The biggest reduction in cost is getting people out of the hospital quickly. Getting them back to work,” he said.
His “optimistic” projection is to receive regulatory approval somewhere in the world within the next two years and TB Alliance is also “exploring the possibility of setting up compassionate access programmes” so that as many people around the world as possible can benefit.
But Conradie warned that the side-effects of one of the drugs, linezolid, needs to be monitored closely throughout treatment. The good news is that these side effects, related to bone marrow and nerve problems, have all been resolved in time in the NIX-TB patients who experienced them.
“While only 20% of patients typically survive past five years, this new treatment would mean a full cure after only six months of treatment with only three drugs and with no injections and no hearing loss,” said TB activist David Bryden, from the organisation, Results. “It really shows the battle to end TB is gathering strength. Now is the time for funders and policy makers to get on board and invest in ending this epidemic. People need to know it might take some time to become available but I think Dr Conradie should get the Nobel prize for this.”
Overview: People suffering from XDR-TB have very few treatment options – cure rates are extremely low and mortality rates are extremely high. Nix-TB is the world’s first clinical trial to study an XDR-TB drug regimen with only pills – no injections – and minimal pre-existing resistance. The trial tests a three-drug regimen consisting of bedaquiline, pretomanid, and linezolid.
Nix-TB enrolls participants at XDR-TB at three sites in South Africa. It includes patients as young as 14 and those who are co-infected with HIV with a CD4 count of 50 or higher. Nix-TB is an open-label trial that enables participants to be assessed at regular intervals with the aim of being cured in six to nine months. After completing treatment, participants are monitored for two years to ensure they do not relapse. The trial has an adaptive design; if improved treatments become available during the course of the study, they can be incorporated into the trial. The trial is designed to accommodate up to 200 patients.
Nix-TB is a partnership between TB Alliance, the sponsor of the trial; Janssen Pharmaceuticals, the discoverer of bedaquiline; and the sites in South Africa where the study is being conducted (Sizwe Hospital, TASK at Brooklyn Chest Hospital, and THINK at Doris Goodwin Hospital). The study may expand to include other partners and sites.
About the New Treatment(s): The Nix-TB regimen consists ofbedaquiline, which received conditional regulatory approval in several high-TB disease burden countries; the novel antibacterial drug compound pretomanid, which is being tested in multiple clinical trials for TB; and linezolid, an oxazolidinone that has been used off-label to treat TB. This combination is predicted to be able to cure XDR-TB in six to nine months.
If successful, the injection-free regimen being tested in Nix-TB could transform XDR-TB treatment, with patients being cured by taking a relatively short, simple, and effective regimen. Importantly, the regimen being tested could reduce the complexity and cost of the treatment to a fraction of what it is today, facilitating the global implementation of XDR-TB treatment in resource-poor nations.
Timeline: Nix-TB began in Q2 2014. Nix-TB is scheduled to report findings on an ongoing basis at predetermined milestones.