HIV PrEP and Treatment: Long-Acting Injectable Cabotegravir and Lenacapavir

Long-Acting Cabotegravir for PrEP: HPTN 083 and HPTN 084

The single most important lesson from two decades of oral HIV pre-exposure prophylaxis is that a drug only works if the patient takes it. Daily oral TDF/FTC is remarkably effective when taken consistently, but adherence in real-world settings — particularly among the populations at highest risk — falls short of what trials demonstrate under close monitoring. Long-acting injectable PrEP was developed to solve this problem, and the results have exceeded expectations. For the infectious disease physician, primary care provider, or public health clinician involved in PrEP delivery, understanding the long-acting options is now essential because they represent a fundamental advance in how we think about HIV prevention.

Injectable cabotegravir (600 mg IM every 2 months) was evaluated in two landmark PrEP trials. HPTN 083 enrolled 4,566 cisgender men who have sex with men and transgender women, demonstrating 69% superiority over daily oral TDF/FTC (HR 0.34, 95% CI 0.18-0.62)[1]. HPTN 084 enrolled 3,224 cisgender women in sub-Saharan Africa, showing 89% superiority (HR 0.11, 95% CI 0.04-0.31)[2]. The incidence of HIV infection was 0.41 per 100 person-years with cabotegravir versus 1.22 with oral PrEP in HPTN 083, and 0.20 versus 1.85 per 100 person-years in HPTN 084.

Why Injectable Was Superior to Oral — Not Just Non-Inferior

The superiority of injectable cabotegravir over oral TDF/FTC is driven primarily by adherence, not by pharmacologic superiority. Cabotegravir levels remain protective for the full dosing interval regardless of patient behavior between injections, while oral PrEP efficacy depends on the patient taking a pill every day. In both trials, the infections that occurred in the oral PrEP arms were overwhelmingly in participants with low drug levels — evidence of non-adherence. The injectable removes the daily decision point entirely. For the clinician counseling a patient about PrEP options, this is the key message: if the patient can reliably attend bimonthly injection appointments, injectable PrEP provides a level of protection that daily oral adherence rarely matches in real-world practice.

Lenacapavir: Twice-Yearly PrEP

Lenacapavir, a first-in-class capsid inhibitor administered subcutaneously every 26 weeks, demonstrated remarkable PrEP efficacy in the PURPOSE 1 trial among cisgender women in South Africa and Uganda. The incidence of HIV was 0 per 100 person-years (0 infections in 2,134 participants) in the lenacapavir arm versus 2.41 per 100 person-years in the background incidence cohort, translating to 100% efficacy[3] during the blinded phase. The PURPOSE 2 trial, enrolling cisgender men, transgender individuals, and non-binary persons, confirmed superiority over oral TDF/FTC with a 96% reduction in HIV incidence.

What Zero Infections Means — And What It Does Not

The PURPOSE 1 result — zero infections among 2,134 participants — is one of the most striking outcomes in modern prevention science. However, interpreting it requires context. Zero infections in a trial of this size does not prove that lenacapavir is literally 100% effective; it means that with the sample size and exposure period of this trial, no breakthrough infections were observed. As the agent is used in larger populations over longer periods, some infections will inevitably occur. What the data do demonstrate convincingly is that twice-yearly subcutaneous lenacapavir provides an extraordinary level of protection that exceeds what any daily oral regimen achieves in practice. For the patient who cannot or will not take a daily pill and struggles with bimonthly injection appointments, a twice-yearly visit represents a genuinely transformative prevention option.

Injectable Treatment: Cabotegravir/Rilpivirine (Cabenuva)

Cabotegravir/rilpivirine (Cabenuva) is the first complete long-acting injectable ART regimen, administered as two IM injections monthly or every 2 months. The ATLAS and FLAIR trials demonstrated non-inferiority of monthly injections to daily oral three-drug regimens, with virologic suppression rates of 93-94% at week 48[4]. ATLAS-2M established that every-2-month dosing was non-inferior to monthly dosing (virologic failure 1.0% vs 0.2%)[5]. Patient satisfaction scores were significantly higher with injectable versus oral therapy across all studies.