Novel TB regimen shortens treatment time for HIV-infected patients

A 4-month regimen containing the combination of rifapentine (RPT) and moxifloxacin (MOX) can effectively treat tuberculosis (TB) in HIV-positive patients, performing just as well as the 6-month standard of care, according to a subgroup analysis of the landmark phase III S31/A5349 trial.

This shortened regimen represents a major milestone in the pursuit of shorter TB treatment courses for people living with HIV, said study co-author Dr April Pettit from the Vanderbilt University Medical Center, US, during a virtual presentation at the Conference on Retroviruses and Opportunistic Infections (CROI) 2021 Annual Meeting.

In S31/A5349, 2,516 patients with newly diagnosed DS-TB from 34 sites in 13 countries in Asia, the Americas, Africa, and Europe were enrolled. Of these, 214 (8 percent; median age, 36 years) had HIV, with a median CD4+ count of 344 cells/mL³; all but nine patients were already or initiated on efavirenz-based antiretroviral therapy.

The patients were assigned to one of the following treatment groups: control (n=829/71 HIV+; 8 weeks of daily treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol, followed by 18 weeks of daily treatment with rifampicin and isoniazid), RPT (n=838/71 HIV+; 8 weeks of daily treatment with high-dose RPT, isoniazid, pyrazinamide, and ethambutol, followed by 9 weeks of daily treatment with RPT and isoniazid), or RPT-MOX (n=849/72 HIV+; 8 weeks of daily treatment with high-dose RPT, isoniazid, pyrazinamide, and MOX, followed by 9 weeks of daily treatment with high-dose RPT, isoniazid, and MOX).

Noninferiority

In terms of the primary endpoint of TB disease-free survival 12 months after randomization (favourable outcome) in the overall population, RPT-MOX demonstrated noninferioriority to control in an analysis limited to patients with pulmonary TB susceptible to isoniazid, rifampin, and fluoroquinolones (microbiologically eligible population; absolute difference [AD], 1 percent, 95 percent confidence interval [CI], –2.6 to 4.5 percent).

The same held true in the assessable analysis population, which involved the microbiologically eligible but excluded patients lost to follow-up after a final negative chest X-ray, those who died during the study period, who discontinued treatment due to pregnancy, and who experienced TB reinfection (AD, –6.6 percent, 95 percent CI, –18.3 to 5 percent).

Results were consistent in the HIV subgroup, where the shorter RPT-MOX proved just as effective as the control regimen. In fact, favourable outcomes occurred more often with the former than the latter in both the microbiologically eligible (85 percent vs 78 percent; AD, –7.5 percent, 95 percent CI, –20.8 to 6.1 percent) and assessable (91 percent vs 85 percent; AD, –6.6 percent, 95 percent CI, –18.3 to 5 percent) analysis populations.

For those in the assessable population who completed at least 95 percent of assigned treatment, favourable outcomes occurred more frequently among HIV-positive patients who received the control treatment, although not markedly different relative to the RPT-MOX arm (98 percent vs 96 percent), Pettit said.

Meanwhile, the 4-month RPT arm failed to meet the efficacy noninferiority criteria, she added.

Not a safety risk

Safety data indicated that the shorter experimental regimens posed no greater risk than currently used standard of care. Specifically, there were fewer severe (grade 3–5) or serious adverse events reported among patients receiving RPT or RPT-MOX. Furthermore, while more HIV-positive patients in the RPT vs control arm died, none of those in the RPT-MOX arm did.

“There was no evidence of an interaction between HIV status and treatment arm in the efficacy analysis,” according to Pettit.

Current national and international guidelines recommend a 6-month regimen containing isoniazid, rifampicin, pyrazinamide, and ethambutol to treat drug-susceptible pulmonary TB (DS-TB), she said.

But shorter treatment courses should be able to improve adherence and minimize healthcare cost, which are extremely beneficial in both resource-limited settings and rich countries. As such, research efforts have been undertaken to reduce the duration of TB treatment. [Eur Respir J 2014;43:554-565]

TB elimination

A collaboration between the US Centers for Disease Control and Prevention (CDC) TB Trials Consortium (TBTC) and the US National Institutes of Health (NIH) AIDS Clinical Trials Group (ACTG), the S31/A5349 trial was lauded for its inclusivity. That is, it enrolled a diverse population, including adolescents aged 12–17 years, HIV-positive patients with low CD4 cell counts, and people with cavitary TB (indicating more serious disease).

“Considering that this was a publicly funded study, the results should be considered as a public good made available to all. We further encourage funders and researchers to fill remaining data gaps so that this new, shorter regimen can be used in children under 12, in pregnant women, and in people with comorbidities not included in Study 31/A5349,” said Mike Frick, TAG’s TB Project Co-Director in a press statement.

Dr Philip LoBue, director of CDC’s Division of Tuberculosis Elimination, chimed in, saying that the S31/A5349 trial data should serve as a huge leap towards their goal of TB elimination.