Long-acting Injectable PrEP: Cabotegravir

A long-acting formulation of the investigational integrase inhibitor cabotegravir (CAB) is being studied as a single agent for HIV prevention. (CAB also has been studied, in combination with long-acting rilpivirine, as treatment for people with HIV, see Long-Acting Injectable ART: Cabotegravir + Rilpivirine; this combination has been submitted for FDA approval). At the AIDS 2020 virtual conference in July 2020, preliminary results from the HPTN 083 PrEP study were presented – these showed that CAB was more effective than daily oral TDF/FTC in preventing HIV in high-risk MSM and transgender women.

HPTN 083 is a large (n=4,570) randomized, double-blind, double-dummy international study comparing CAB with TDF/FTC in HIV-uninfected MSM and transgender women (TGW) who have sex with men. It deliberately enrolled subjects from groups who are at high risk for HIV as well as traditionally underrepresented in studies –67% of participants were <30 years of age, 12.4% were TGW, and, in the U.S. study population, 49.7% were Black/African American. Participants received either oral CAB or TDF/FTC for 4-5 weeks, then the CAB group was switched to CAB injections (600 mg IM at 4 weeks, then every 8 weeks) while the TDF/FTC group continued daily oral TDF/FTC. Throughout, the CAB group also took a daily oral placebo pill while the TDF/FTC group received placebo CAB (initially pills, then placebo IM injections).

After a median follow up time of 1.4 years (and with 6,389 person-years [PY] of follow up), there were significantly fewer HIV infections in the CAB arm (13) than in the TDF/FTC arm (39). This translated to a incidence rate of 0.41 per 100 PY with CAB and 1.22 per 100 PY with TDF/FTC, yielding a hazard ratio of 0.34 (95% confidence interval CI 0.18, 0.62; p=0.0005). Based on these data, the study was stopped by DSMB in May, after only 25% of the prespecified endpoints (HIV infections) had occurred. Participants were unblinded, and all were offered long-acting CAB.

Of the 13 persons in the CAB arm who became infected with HIV,

• 3 were infected during the CAB oral lead-in period (estimated adherence was >95%)
• 5 were infected while on CAB injections, with no interruptions in CAB
• 5 had been off CAB for some time before infection (2 of these had been switched to open label TDF/FTC)

Additionally, 2 were found to be HIV+ at baseline, but had received CAB before this was discovered.

CAB generally was well tolerated, but injection site reactions (ISR) were common (80% of CAB recipients had at least 1 ISR). These usually were mild or moderate in severity, and were less frequent after the first several doses; 2.2% stopped CAB because of ISR. More weight gain was seen in the CAB group – 1.30 kg/year vs 0.31 kg/year in the TDF/FTC group, but the difference in weight gain occurred in the first 40 weeks of treatment – the CAB recipients on average gained 1.54 kg/year while TDF/FTC recipients lost 0.51 kg/year); thereafter weight gain was the same (1.06-1.07 kg/year) in both groups.

Clinical bottom line

In a large group of MSM and TGW, both long-acting CAB and daily oral TDF/FTC were highly effective at preventing HIV, but CAB was statistically superior. This is very exciting news – long-acting injectable CAB is likely to be appealing to people who cannot or prefer not to take daily oral PrEP medication.

But before we move forward with CAB as a PrEP agent, we will need to understand more about how it failed those few people who became infected, and what the consequences of CAB failure are.

• CAB appeared to fail (though rarely) both during the oral lead-in period and during the IM phase. Many of the subjects appeared to have excellent adherence. PK studies of subjects’ CAB levels around the time of HIV infection are under way.
• We need to know whether resistance to CAB develop in these people, and (if so) how it will it affect patients’ ART options. Resistance testing is being conducted.

And, further study of long-acting CAB in other populations is needed. HPTN 084, a similar study of CAB vs oral TDF/FTC in cisgender women, is ongoing,

Reference

• Landovitz RJ, Donnell D, Clement M, et al. HPTN083 interim results: Pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB-LA) is safe and highly effective for cisgender men and transgender women who have sex with men (MSM, TGW). AIDS 2020: 23rd International AIDS Conference Virtual. July 6-10, 2020. Abstract OAXLB01