Kelly E. Dooley
BOSTON — Adding the HIV drug dolutegravir to rifampin-based TB therapy appeared to be safe and effective in coinfected patients, according to 24-week phase 3b data from the INSPIRING trial.
“We are pleased with the safety and efficacy of this regimen and think it will be a nice option for patients who are HIV/TB coinfected for the future, as there are relatively few available options for these patients,” Kelly E. Dooley MD, MPH, PhD, associate professor of medicine at Johns Hopkins University, said during a press conference.
The findings are in contrast to a study published last month in Clinical Infectious Diseases, which found that coadministration of dolutegravir and a regimen of once-weekly rifapentine and isoniazid — which is used for latent TB in patients with and without HIV co-infection— led to “unexpected and serious toxicities” in two healthy participants. Dooley said that the reason for these adverse events in healthy HIV-uninfected persons in the phase 1 trial are unclear. She noted that while hypersensitivity reactions to rifamycin antibiotics are more common with intermittent dosing, once-weekly dosing of isoniazid and rifapentine given for 12 weeks was very well-tolerated in the hundreds of HIV-infected participants in the phase 3 trial. It remains unknown if the adverse events in the healthy volunteer trial were related to high isoniazid drug levels in the two trial participants, a drug interaction between dolutegravir and isoniazid-rifapentine, or the fact that that study was conducted in uninfected patients.
“There is some evidence that healthy volunteers have really brisk, robust immunologic responses to rifamycins,” she told Infectious Disease News. “Testing in the patient population is really what we need to do to understand if we can use certain drugs together.”
For the INSPIRING trial, Dooley and colleagues evaluated the safety and efficacy of dolutegravir in ART-naive patients coinfected with HIV/TB. An active noncomparative efavirenz control arm was also enrolled. All participants received rifampin-based TB therapy for up to 8 weeks prior to enrollment. Of the 113 participants, 69 were randomly assigned (3:2) to receive dolutegravir dosed at 50 mg twice daily during and for 2 weeks after TB therapy, followed by 50 mg once daily.
“We know that rifampin reduces the concentrations of dolutegravir substantially, but that drug interaction can be mitigated by increasing the dose of dolutegravir to twice daily,” Dooley noted.
The remaining 44 participants were randomly assigned to 600 mg of efavirenz once daily. All participants also received two nucleoside reverse transcriptase inhibitors.
According to the researchers, the study was not powered to show a difference between the two study arms, so no formal statistical hypothesis was tested.
Results from an interim analysis showed that 81% (95% CI, 72%-90%) of patients in the dolutegravir arm and 89% (95% CI, 79%-98%) in the efavirenz arm maintained viral suppression at 24 weeks. There were no deaths in either arm, and there were no episodes of virologic nonresponse related to change in ART. Dooley noted that about half of patients receiving dolutegravir had viral suppression by 4 weeks.
Treatment was discontinued in two patients, both in the efavirenz arm, because of adverse events. Five patients receiving dolutegravir discontinued therapy for nontreatment-related reasons, according to the researchers.
TB-associated immune reconstitution inflammatory syndrome (IRIS) rates were low in both treatment groups (6% in the dolutegravir arm and 9% in the efavirenz arm). No patients discontinued therapy because IRIS or liver events, Dooley said.
Longer term, 48-week data will be presented at a future scientific meeting, according to a press release.
Constance A. Benson
“That is a very important study because dolutegravir is now being rolled out globally and is used in many HIV treatment programs around the world, particularly areas with a high burden of HIV and TB,” Constance A. Benson, MD, professor of medicine and senior attending physician in the division of infectious diseases at the University of California, San Diego, said during the press conference. “It is very important to understand how dolutegravir fits with the treatment paradigms in those areas.” – by Stephanie Viguers
Editor’s note: In the United States, dolutegravir is sold under the brand name Tivicay (ViiV Healthcare).
Brooks KM, et al. Clin Infect Dis. 2018; doi:10.1093/cid/ciy082.
Dooley K, et al. Abstract 33. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston.
Disclosures: Benson reports receiving research grants from AbbVie, Gilead Sciences and ViiV Healthcare, and is a consultant and on the data and safety monitoring board for GlaxoSmithKline and ViiV Healthcare. Dooley reports research support via her university from ViiV Healthcare.