Reassuring Data for TB Therapies in Resource-Limited Settings

SEATTLE — Multiple therapies to treat tuberculosis were well tolerated in both HIV infected and uninfected patients, according to researchers here.

First, co-administration of dolutegravir and 3HP (short-course preventive tuberculosis therapy with 12 once-weekly rifapentine/isoniazid doses) was well tolerated, and the effectiveness of dolutegravir to treat HIV infection was maintained, reported Kelly Dooley, MD, of Johns Hopkins University in Baltimore.

Both studies were late-breaking trials, and presented at the Conference on Retroviruses and Opportunistic Infections.

Constance Benson, MD, of the University of California at San Diego, who moderated the press conference, but was not involved with the research, characterized both studies as “subtle in context,” but said that each had the potential for major impact in how to approach the prevention and treatment of tuberculosis disease.

Benson explained to MedPage Today separately that she thought that both trials could have an impact on World Health Organization (WHO) guidelines. She pointed out that the WHO recommends dolutegravir as first-line therapy for people with HIV infection in resource-limited settings, and in previous studies there was the suggestion of increased toxicity with rifapentine given for preventive therapy.

“This study was very reassuring,” Benson told MedPage Today. “We’re sure it will be taken into consideration by the WHO recommendations, saying that it’s safe to use dolutegravir if you’re going to use 3HP to prevent tuberculosis.”

Dooley and colleagues examined 60 HIV-infected adults with undetectable viral loads and currently on efavirenz-based regimens, who received dolutegravir instead of efavirenz for 8 weeks, and then began 3HP. A total of 70% of the participants were women, median age was 40, and all were African black.

There were three adverse events that were ≥Grade 3 (two elevated creatinine and one hypertension). Participants’ viral loads at baseline, at day 58 (pre-HP), day 72 (third HP dose), and day 168 (post-HP) were all <40 copies/ml.

Dooley said drug concentrations were “somewhat reduced” by 3HP, but that all but one participant who had a suppressed viral load at the beginning of the study remained suppressed on 3HP.

No Prolongation of QT Interval with New MDR TB Drugs

In the second study, there was a no more than additive effect on QT prolongation (a heart rhythm disorder that could cause serious arrhythmia) when giving both delamanid and bedaquiline to treat multi-drug resistant (MDR) tuberculosis, reported Gary Maartens, MD, of the University of Cape Town in South Africa.

Delamanid and bedaquiline were described as two new drugs for MDR tuberculosis, which as Maartens said at the press conference was “very rare — we haven’t had new drugs for a very long time.”

But the researchers said that because the drugs have long half-lives, each prolongs the QT interval with “maximum effects weeks after drug initiation,” and the cardiac safety of these drugs has not yet been established.

Benson told MedPage Today that these findings also had the potential to impact WHO recommendations, given the “epidemic of multi-drug resistant tuberculosis globally” that is increasing, even as overall background rates of tuberculosis are decreasing.

“When you have two new drugs that people were reluctant to use together in treating multi-drug resistant tuberculosis, showing we can safely do that regardless of whether people are HIV infected or not, that is a huge step in making recommendations for how to shorten the course of MDR TB and use more effective drugs together [for treatment],” Benson said.

The DELIBERATE trial was a phase II open-label trial of 84 HIV infected and uninfected patients. Three-quarters were men, mean age was 34, and 37% were HIV-positive. They were randomized to receive delamanid, bedaquiline, or both for 24 weeks. Three electrocardiograms were performed at baseline, at week 24, and at week 28, the authors said.

Importantly, there were no Grade 3 or Grade 4 QT interval prolongation events, and Maartens noted at the press conference that no participant achieved ≥Grade 2 prolongation.

“The QT issue in drug-resistant TB is a real one, and the community is reckoning to deal with how to properly monitor that,” Maartens said, adding that he was still a little concerned about “the addition of other drugs and monitoring implications.”