AIDS 2016: High-Dose Rifampicin for TB May Improve Survival of HIV+ People with Low CD4 Counts


More aggressive tuberculosis (TB) treatment using a high dose of rifampicin, in addition to antiretroviral therapy (ART), could reduce mortality among people with HIV/TB coinfection who are severely immunocompromised, according to results from the 3-arm RAFA trial presented at the 21st International AIDS Conference (AIDS 2016) last month in Durban.

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TB remains the leading infectious cause of death among people living with HIV. Even when a person with HIV develops drug-susceptible TB that appears to respond to the standard 6-month treatment, 12-month mortality is often poor. To improve outcomes, the World Health Organization recommends initiating ART as soon as possible after starting TB treatment.

But perhaps TB treatment is also suboptimal in people with advanced immunosuppression, making TB harder to treat. So Corinne Merle from the London School of Hygiene and Tropical Medicine and colleagues designed the RAFA trial to determine whether more intensive TB treatment might help to reduce mortality.

The trial randomized ART-naive individuals diagnosed with TB (bacteriological or molecular confirmation) and HIV with CD4 counts >50 cells/mm3 to one of the following 3 arms:

Arm A: Early ART initiation (week 2) with standard TB treatment;

Arm B: Delayed ART (week 8) with standard TB treatment;

Arm C: Delayed ART (week 8) with high-dose rifampicin (15 mg/kg) during the intensive phase of TB treatment and standard TB therapy during the continuation phase.

The study was conducted in Benin, Guinea, and Senegal. The endpoints were morbidity and mortality at 2 and 12 months post-randomization, with a total follow-up of 18 months post-randomization. There was also a nested pharmacokinetic study using a sub-sample of participants.

A total of 778 individuals were randomized in the study, but 31 were excluded because they had multidrug-resistant TB (MDR-TB), CD4 cell counts that were too low, or for other reasons. Baseline characteristics were well matched between arms.

Survival at 12 months was fairly high overall in the study, with no significant difference between the arms -- perhaps because the trial excluded people with less CD4 counts less than 50 CD4 cells/mm3 at baseline.

Among the 159 participants with less than 100 cells/mm3, however, there was a marked difference in 12-month survival in favor of Arm C:

Arm A: 12-month survival 0.81, hazard ratio (HR) 0.61 compared to Arm B (95% CI 0.27-1.37);

Arm B: 12-month survival 0.72 (Arm B served as the reference arm);

Arm C: 12-month survival 0.96, HR 0.12 (95% CI 0.03-0.55) compared to Arm B and HR 0.20 (95% CI 0.04-0.9) compared to Arm A.

"When looking at the difference in survival between [arms] A and C, there is a significant difference between the 2 groups in favor of the high-dose rifampicin regimen," said Merle. But she noted there was no difference between treatment arms when CD4 cell counts were above 100 cells/mm3.

Of interest, except at the 2-month time point, there were similar improvements in most participants’ CD4 cell counts at 6 months and 18 months after treatment. Viral load and TB responses seemed similar across arms. There was no evidence of an increased risk of liver toxicity with higher dosage of rifampicin.

Merle concluded that further study would be needed in order to explain these results more precisely, adding that the pharmacokinetic sub-study results will be important to consider.

While there did not seem to be any significant difference in TB smear or culture positivity at month 2, these may not be the most critical measures to predict long-term treatment success or survival.

According to a presentation by Clifton Barry of the U.S. National Institutes of Health and the University of Cape Town, a key reason for drug-sensitive TB treatment failure is the persistence of TB bacteria within some types of lesions in the lungs despite standard treatment, because the drug pharmacokinetics in those lesions is different from that in plasma. Boosting the dose of rifampicin may better reach TB within those hard-to-treat lesions.



CS Merle, S Floyd, A Ndiaye, et al. High-dose rifampicin tuberculosis treatment regimen to reduce 12-month mortality of TB/HIV co-infected patients: the RAFA trial results. 21st International AIDS Conference. Durban, July 18-22, 2016. Abstract WEAB0205LB.