HIV PrEP and Treatment: Long-Acting Injectable Cabotegravir and Lenacapavir
Long-Acting Cabotegravir for PrEP: HPTN 083 and HPTN 084
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). HPTN 084 enrolled 3,224 cisgender women in sub-Saharan Africa, showing 89% superiority (HR 0.11, 95% CI 0.04-0.31). 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.
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 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.
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. ATLAS-2M established that every-2-month dosing was non-inferior to monthly dosing (virologic failure 1.0% vs 0.2%). Patient satisfaction scores were significantly higher with injectable versus oral therapy across all studies.
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Implementation Considerations
Long-acting injectables require infrastructure adaptations: cold chain storage, trained injection staff, appointment tracking systems, and protocols for missed visits. Cabotegravir has a prolonged pharmacologic tail (detectable drug levels for 12+ months after discontinuation), creating a window for resistance if HIV is acquired during the tail period. Rilpivirine resistance mutations (particularly E138K and K101E) have been observed in virologic failures on Cabenuva, predominantly in patients with baseline BMI >30 kg/m2 who received every-2-month dosing. An oral lead-in period (cabotegravir 30 mg + rilpivirine 25 mg daily for 4 weeks) is recommended to assess tolerability before initiating injections.
Practical PrEP Selection in 2026
The PrEP landscape now includes daily oral TDF/FTC, daily oral TAF/FTC (for MSM and transgender women), event-driven 2-1-1 dosing (MSM only), injectable cabotegravir every 2 months, and twice-yearly subcutaneous lenacapavir. Selection should be guided by patient preference, adherence patterns, renal function (avoid TDF with CrCl <60 mL/min), and access to injection services. Lenacapavir's twice-yearly schedule offers the most favorable adherence profile but cost and access remain barriers. All PrEP modalities require HIV testing before initiation and at regular intervals (every 3 months for oral, at each injection visit for injectables) to prevent inadvertent monotherapy of undiagnosed infection.
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