BOSTON — A shorter duration of preventive therapy for tuberculosis (TB) in HIV-positive individuals was comparable to the lengthier usual-care regimen for rates of TB and death, a late-breaking phase III randomized trial presented here found.
A 1-month course of isoniazid/rifapentine, an antibiotic regimen for TB prevention, was found to be safe and effective when compared with the usual 9-month course of isoniazid alone in people with HIV infection, reported Richard E. Chaisson, MD, of Johns Hopkins University in Baltimore.
Constance Benson, MD, of the University of California San Diego, who moderated the press conference at the Conference on Retroviruses and Opportunistic Infections (CROI), but was not involved in the research, characterized these findings as having “the potential to immediately change clinical practice.”
In a separate statement released by the National Institutes of Health, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, agreed, saying that these results “offer people living with HIV who are at risk of developing active [TB] an additional, shorter-duration prevention option that is safe, effective and more convenient.”
At the press conference, Chaisson said that while prevention of TB with isoniazid is effective, “uptake has been appallingly bad.” He added that the longer the course of the therapy is, the more people stop taking it, and described “a sense of futility” among clinicians about this problem.
A shorter, 4-week course of rifapentine and isoniazid had shown promise in animal studies, the authors said, so they hypothesized it would be non-inferior to the usual 9-month standard of care. “The bottom line is,” Chaisson added, “it was.”
Participants were eligible if they were HIV-infected individuals age 13 or older with no evidence of active TB, who had either a positive TB skin or blood test (Interferon Gamma Release Assay, or IGRA) or lived in an area with a high burden of TB (prevalence ≥60/100,000 population). They were stratified by CD4-positive cell count and antiretroviral therapy (ART) use at entry.
After randomization, patients received either 300-mg isoniazid plus 450- to 600-mg rifapentine once daily for 4 weeks or 300-mg isoniazid daily for 9 months. They were then followed for 3 years after the last participant was enrolled. ART with efavirenz or nevirapine was permitted.
Overall, 1,488 patients in the intervention group and 1,498 patients in the control group were included in the analysis. More than half were women, two-thirds were black and median body mass index was 23.5. Median CD4 count was 470 cells/mm³, and half were on ART at entry. Around 20% had a positive TB skin or blood test. The primary endpoint was the incidence rate ratio of active TB, TB death, or death due to an unknown cause, and the non-inferiority margin was 1.25 per 100 person-years.
The intervention group had an incidence of 0.65 per 100 person-years and the control group had an incidence of 0.67 per 100 person-years (IRR difference 0.023, 95% CI -0.30 to 0.35).
Rates of the primary outcome were higher for patients not on ART at entry and those with a positive TB skin or blood test, but no difference between treatments was noted, the authors said. In addition, rates were higher in the intervention group among those with baseline CD4 counts of ≤250 mm3, but the difference was not statistically significant.
Serious adverse events occurred in 5.6% of patients in the intervention group and 7.1% of the controls, but the difference was not significant. The authors noted that safety was “similar” in both arms, with more hematologic toxicity in the intervention group and more liver and neurotoxicity in the control group.
Chaisson said that the study was unlikely to be replicated, but characterized this as a “large enough, clear enough answer that it can be acted upon.” He added that he hoped this therapy would be studied in people without HIV.
The next steps would be incorporating these findings into guidelines. Chaisson said that he shared his results with the World Health Organization and encouraged them to incorporate this into new guidelines, perhaps as an amendment, “as quickly as possible.”
Chaisson disclosed support from Otsuka.
Sanofi supplied study medications for this trial.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner