SEATTLE – A long-acting, injectable combination of the novel integrase inhibitor cabotegravir (CAB) and the second-generation nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV) was noninferior to dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) in one phase 3 study (FLAIR) and to three-drug oral antiretroviral therapy (ART) more broadly in the companion ATLAS phase 3 study. Patient acceptance of the injectable formulation was surprisingly high, although researchers admitted there was likely some selection bias because patients already interested in receiving an injection would have been predisposed to entering the trials.
Still, the numbers were impressive: 99% of patients who received the intramuscular injection expressed more satisfaction with it than with their previous oral regimen in the FLAIR study, and 98% expressed a similar opinion in the ATLAS study. Circumstantial evidence also suggests there may be some demand, according to, professor of medicine at the University of North Carolina at Chapel Hill, who commented during a press conference at the Conference on Retroviruses & Opportunistic Infections. “These studies didn’t take a long time to accrue. People were very interested, so it wasn’t as if people had to go around and beat the bushes to try to find people [to participate],” said Dr. Eron, who was not an author on either report.
“My patients tell me that they like not having to worry about taking their pills every day. There may be some relief from the stigma of HIV. You don’t have to think about it,”, medical director of the Specialty Care Clinic at the University of Nebraska Medical Center in Omaha and first author of the ATLAS trial, said during the press conference.
There were some injection site reactions, but they were generally mild and most resolved within 7 days. In the ATLAS study, 75% of participants reported injection site pain, and 1% discontinued as a result. In the FLAIR study, 82% in the CAB/RPV arm experienced an injection site reaction, with a median duration of 3 days; 99% of reactions were grade 1 or 2.
Should the combination achieve regulatory approval, it remains to be seen how challenging it will be to manage patients with monthly injections and ensure they stick to the schedule. The injections must be administered by a health care provider.
“In terms of generalizability outside of the study, it would be a paradigm shift in our therapy,”, said at a press conference. Dr. Orkin is the first author on the FLAIR trial report and a consultant in HIV Medicine at Barts Health National Health Service Trust. She pointed to the example of injectable contraception. “It can be done. It’s just that we haven’t done it. It will require some thought,” Dr. Orkin added.
In the ATLAS study, 616 participants taking two nucleoside reverse transcriptase inhibitor (NRTIs) and an integrase inhibitor, a non-NRTI, or a protease inhibitor, were randomized 1:1 to continue their regimen (CART arm) or switch to CAB/RPV, following a 4-week safety monitoring period of oral CAB/RPV. After 48 weeks, 1.6% in the CAB/RPV arm and 1.0% in the CART arm had HIV-1 RNA greater than or equal to 50 copies/mL, which met the prespecified noninferiority margin. Of patients in the CAB/RPV arm, 93% had HIV-1 RNA less than 50 copies/mL at week 48 versus 95% in the CART arm, and the difference was not statistically significant. Grade 3 or 4 events were seen in 11% of CAB/RPV and 7% of CART patients.
The FLAIR study randomized 566 ART-naive patients to receive either CAB/RPV or DTG/ABC/3TC after a 20-week induction phase, followed by a 4-week safety monitoring period for those going into the CAB/RPV arm. At week 48, 2.1% in the CAB/RPV arm and 2.5% in the DTG/ABC/3TC arm had HIV-1 RNA greater than or equal to 50 copies/mL, which met the prespecified noninferiority margin, while 94% in the CAB/RPV arm and 93% in the DTG/ABC/3TC arm had HIV-1 RNA less than 50 copies/mL. Confirmed virologic failure occurred in four patients (1.4%) in the CAB/RPV arm, and three of those patients had mutations in the NNRTI+INSTI domains, while the fourth patient was not tested. Three failures occurred in the DTG/ABC/3TC arm, and none of those patients had INSTI resistance mutations. A total of 82% of CAB/RPV patients had injection site reactions, 99% of which were grade 1 or 2, and the median duration was 3 days.
The ATLAS and FLAIR studies were sponsored by ViiV. Janssen and GlaxoSmithKline were collaborators.
SOURCES: Swindells S et al. CROI 2019, Abstract . Orkin C et al. CROI 2019, Abstract .