April 12, 2024

endTB: Ministry of Health of Peru implements shortened treatment against tuberculosis

Socios En Salud is part of a global consortium that managed to shorten the treatment for patients with multidrug-resistant tuberculosis to nine months and without the use of injectables. A new regimen that 112 Peruvian patients are already receiving and that the World Health Organization (WHO) is evaluating for use as a therapy guideline.

Being a tuberculosis (TB) patient is a draining experience. Some 52,000 people who contract this disease every year in Peru know it well and, in addition to suffering its social stigmas and economic costs, they must receive harsh treatment. Curing a typical form of TB requires four to six months of therapy, but if someone becomes infected with multidrug-resistant (MDR-TB) or extensively drug-resistant (XDR-TB), then they can spend 18 to 24 months taking up to 14,000 pills and receiving painful daily injections. This difficult scenario, however, is nearing its end. The answer is called endTB. A consortium led by Partners In Health, Interactive Research and Development and Médecins Sans Frontières, and funded by Unitaid, has tested five new shortened, all-oral, nine-month treatment regimens for MDR-TB over the past decade. This is not, of course, a miracle. This result is the fruit of a long collaboration with several scientific studies at different stages, in which Partners In Health (SES) has played a crucial role, as have several institutions around the globe. Therefore, the following is a story of hope in modern science, but also in human bonds.

Two drugs, one way

It was 2012 when the U.S. Food and Drug Administration (FDA) approved the use of bedaquiline to treat TB. Nearly 50 years had passed since the last time the U.S. agency had given the green light to a new drug to treat this disease. Just two years later, the European Union did the same with a new drug: delamanid. "We had two drugs to treat resistant tuberculosis, but for various reasons no country implemented them," says Dr. Leonid Lecca, general director of Socios En Salud (SES) and instructor at Harvard University. Faced with this scenario, endTB set out to operate under two research arms: one observational and the other experimental. The first, according to Lecca, sought to advocate and accompany at the institutional level so that each country would integrate these two new drugs into their standard treatment regimens for multidrug-resistant forms of tuberculosis. During those years, SES met with various Peruvian health authorities to "achieve authorization for the use of the new drugs," according to Antonieta Alarcón, now executive director of the Tuberculosis Prevention and Control Directorate (DPCTB) of the Ministry of Health (MINSA).

Thanks to this initiative, Peru became the first Latin American country to introduce bedaquiline in the treatment of TB. This milestone was soon followed by the entry of the first batches of delamanid into our country, as well as the reintroduction of a drug that had ceased to be used at the beginning of the new century: clofazimine. "We started the intervention with part of these drugs and this operational arm of endTB in eight hospitalized patients with XDR-TB, to whom another treatment was administered intravenously (...) We greatly reduced the percentage of deaths, to the point that now the rate is between 17% and 18%, and we reached almost 80% cure rate", says Alarcón. With 267 people enrolled in the observational study, endTB had achieved one of its objectives, but it still had a long way to go: the experimental one. "We not only wanted to show that the drugs improved the cure rate, but also that shorter regimens improved the cure and people's experience," Lecca emphasizes. 

"endTB proposed to advocate and accompany at the institutional level so that each country integrates new drugs into their standard treatment regimens for multidrug-resistant TB."

A global effort: the endTB clinical trial

In 2017, endTB launched its five-arm clinical trial of regimens to reduce TB treatment duration. The initiative enrolled 754 patients in seven countries on four continents: Peru, Georgia, Lesotho, Pakistan, South Africa, India and Kazakhstan. Almost 40% of the participants were Peruvian nationals. "To choose the countries, it was necessary for them to have a significant burden of MDR-TB," says Carole Mitnick, PIH research director for the endTB project, co-principal investigator of the study and professor of global health and social medicine at Harvard Medical School's Blavatnik Institute. Mitnick notes that they also sought "a diverse group of participants," since people with MDR-TB have "significant comorbidities, such as HIV, diabetes, alcohol and drug use." "In clinical trials, they tend to exclude somewhat complicated participants so as not to threaten good outcomes, but for us these are part of the group of patients we want to help," she highlights.  

In Peru, patients from the Hipolito Unanue, Dos de Mayo and Sergio E. Bernales national hospitals participated in the clinical trial, which was supported by researchers and physicians from Harvard Medical School and other research centers around the world. "The five arms of the clinical trial were nine months in duration and all used oral medications. In addition to other drugs, two of these arms included bedaquiline, two others delamanid, and one arm bedaquiline and delamanid. The clinical trial enrollment took place between February 2017 and October 2021," Lecca says. Thus, in October 2023, endTB presented its results at the latest edition of the Union World Conference on Lung Health, held in Paris (France): three of the five arms evaluated in the clinical trial achieved effectiveness and high cure rates (~85%), as well as shortening MDR-TB treatment and freeing it from injections. New hope was emerging for the half a million people around the world who are infected with this form of TB every year. 

MINSA implements endTB shortened schemes

Far from France, another milestone occurred between October and December 2023 in Peru. The endTB had shared its results with MINSA, and the latter soon implemented in 46 MDR-TB patients the new shortened, oral treatment regimen proposed by arm two of the clinical trial. The therapy comprises the intake of bedaquiline, clofazimine, linezolid, levofloxacin and pyrazinamide for nine months. According to Alarcón, the fact that almost 40% of the participants in the clinical trial were Peruvians was "strong evidence that we, as a country, can introduce this type of drug". "The implementation was in Lima and Callao, above all, because it is closer to us to work in one way or another on these processes," she indicates. "It has helped us a lot to shorten treatment regimens. The consultant pulmonologists who have participated in the endTB process have found it very easy to adopt and I think it is something we urgently needed. It was a demand from patients to stop using injectables," says the MINSA representative.

Unlike other short-course therapies, Alarcón emphasizes that the regimens proposed by endTB can be applied in patients as young as 0 years of age, with comorbidities and even in pregnant women. "This 2024 we already have 66 more patients recruited. A total of 112 have started treatment with shortened oral regimens," she reports.

Arm one of the endTB clinical trial is also being implemented in Peru. The executive director of the DPCTB hopes that with these regimens, treatment abandonment rates will decrease and "adherence rates" will increase. At the end of March they will have "a cohort of the first patients who entered in October to analyze their bacteriological conversion".

Meanwhile, MINSA has a pending task: to update the technical health standard for the comprehensive care of the person affected by tuberculosis, family and community. "We are including (these regimens) within the new version, mainly arm two and one, which will be written as proposals," Alarcón points out.

Likewise, the head of the DPCTB states that the government has already ordered the purchase of more drugs to expand the shortened endTB treatment to other regions of Peru. "The country is grateful for these boosts to research that allow us to make decisions and changes in public policy," she says. 

"The treatment regimens proposed by endTB can be applied in patients from 0 years of age, with comorbidities and even in pregnant women."

endTB at WHO

As of 2018, says the general director of Socios En Salud, the World Health Organization (WHO) placed bedaquiline and delamanid, in addition to other drugs, among the medications that should be used in therapies for the different forms of tuberculosis. "Since that year, it has recommended not to use injectables," Lecca points out. Currently, according to Carole Mitnick, Partners In Health (PIH) is collaborating with the WHO so that next June its findings on endTB will be considered for inclusion in the world guidelines for treating multidrug-resistant TB. "This step is important because many countries rely on WHO recommendations to prepare their own guidelines. In addition, donors such as the Global Fund require that grant activities be endorsed by this organization," he notes. Although all these initiatives are giant steps forward in the fight against the spread of Koch's bacillus, the Harvard Medical School professor emphasizes that there are still barriers. "One of them is the cost of treatment," she warns. That is why PIH is already working to convince the pharmaceutical industry to release patents on certain drugs.  

But in the meantime, millions of people can see the light at the end of the tunnel.

Link to the original article (in Spanish): https://sociosensalud.org.pe/noticias/endtb-ministerio-de-salud-del-peru-implementa-tratamiento-acortado-contra-la-tuberculosis

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