A 54-year-old man who regularly engages in sexual encounters with men presents to clinic. He has heard from friends about a daily medication that can prevent HIV, but he confesses that he has a difficult time with medication adherence. He asks whether there are alternatives to a once-a-day medication.
“Drugs don’t work in patients who don’t take them.” As spoken by former U.S. Surgeon General Dr. C. Everett Koop, the adage is apt to describe a concern with recent advances in preexposure prophylaxis (PrEP) for HIV. Although once-daily tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) has been shown to effectively prevent HIV infection in a variety of populations, the efficacy of the medication correlates with patient adherence.
In a recent phase 2b–3, randomized, double-blind, noninferiority trial published in NEJM, researchers compared the efficacy of the long-acting injectable integrase inhibitor cabotegravir (given intramuscularly every 8 weeks) to once-daily oral TDF-FTC in preventing incident HIV infections in at-risk cisgender men and transgender women who have sex with men.
In all, 4566 participants were randomized to receive one of the two drugs with matching placebo and followed for a median of 1.4 years before the study was terminated early due to the superior efficacy of cabotegravir. Fewer participants in the cabotegravir group than in the TDF-FTC group acquired HIV infections (13 vs. 39; hazard ratio 0.34; 95% confidence interval 0.18-0.62; P<0.001), translating to a 66% lower risk of HIV infection.
Adverse events were similar in the two groups, except for injection-site reactions, which were higher in the cabotegravir group (81% vs. 31%). Despite the significant difference between groups in injection-site reactions, only 2.4% of participants who received active cabotegravir injections declined further injections.
Overall, the evidence from this study suggests that long-acting cabotegravir is a superior alternative to daily TDF-FTC for PrEP, especially for patients such as the one described above who are at risk of poor medication adherence, if he can tolerate an intramuscular injection once every 8 weeks.
The following NEJM Journal Watch summary explains more details of this study.
Long-Acting PrEP Is Here to Stay
Wendy S. Armstrong, MD, reviewing
Injectable long-acting cabotegravir was superior to TDF-FTC for prevention of HIV infection.
Although preexposure prophylaxis (PrEP) is a vital tool to prevent HIV infection, the effectiveness of oral PrEP directly correlates with adherence. In two papers, researchers now report on the HIV Prevention Trials Network 083 trial in which they assessed cabotegravir (CBV; a long-acting injectable integrase inhibitor not yet FDA-approved for PrEP) compared with oral tenofovir disoproxil fumarate–emtricitabine (TDF-FTC) in 4566 high-risk cisgender men and transgender women who have sex with men. Participants were randomized to TDF-FTC daily or long-acting injectable CBV every 8 weeks after a lead-in with daily oral CBV.
By 153 weeks, 39 participants in the TDF-FTC arm had acquired HIV versus 13 in the CBV arm — a 66% risk reduction with CBV. Injection-site reactions (ISRs) with injectable CBV were common (81%), but associated discontinuation was rare (2%). Of the 13 new HIV infections in the CBV arm, one was determined on reassessment to represent baseline infection, five were not proximate to CBV exposure, three occurred during the lead-in phase, and four occurred in participants receiving CBV injections. Among these latter seven cases, four had integrase resistance mutations (at least two of which were acquired after continued exposure to study drug). The single participant without resistance had subtherapeutic levels of CBV during lead-in therapy; all others had sufficient CBV levels. Among the 39 with new infection on TDF-FTC, 37 had inadequate tenofovir levels.
An additional finding was that diagnosis of new HIV infection was hampered by delays in detection of baseline or incident infection using antigen/antibody testing; such delays were more common (and longer) in the CBV arm (mean delay, 98 vs. 31 days). Retrospective analysis indicated that HIV RNA testing would have detected infections earlier in nearly all cases affected by delayed diagnosis.
Comment: Long-acting therapies for HIV are poised to change the landscape of care. For PrEP, several other agents also hold promise (with results in cisgender women anticipated). The opportunity to increase individual agency, decrease stigma, improve adherence, and overcome barriers to care is exciting. While this success of CBV is remarkable, the study also highlights the need to investigate other early-detection strategies such as screening with HIV RNA testing. All told, however, long-acting preventive strategies hold promise that many of us never before imagined.
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Leslie is a 2021–2022 NEJM Editorial Fellow.