New England Journal of Medicine NOVEMBER 27, 2024

Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons

Kelley CF, Acevedo-Quiñones M, Agwu AL, et al. for the PURPOSE 2 Study Team

Bottom Line

In the Phase 3 PURPOSE 2 trial, twice-yearly subcutaneous lenacapavir demonstrated superior efficacy to daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF) and significantly reduced HIV incidence compared to background rates among cisgender men and gender-diverse individuals.

Key Findings

1. Lenacapavir reduced HIV infections by 96% compared to background HIV incidence, with only 2 incident cases among 2,179 participants (incidence of 0.10 per 100 person-years; 95% CI, 0.01 to 0.37).

2. Twice-yearly lenacapavir demonstrated statistical superiority to daily oral F/TDF, with an 89% relative risk reduction in HIV incidence (incidence rate ratio 0.11; 95% CI, 0.02 to 0.51; P=0.002).

3. Adherence to the study regimen was high, with 92.8% of participants receiving on-time injections at one year, contrasting with declining adherence to oral daily F/TDF over the same period.

4. The safety profile was generally favorable, with injection-site reactions (ISRs) being the most common adverse event (reported in 83.2% of the lenacapavir group), though most were mild to moderate in severity.

Study Design

Design

RCT

Double-Blind

Sample

3,265

Patients

Duration

52 wk

Median

Setting

Multicenter, International

Population HIV-negative cisgender gay, bisexual, and other men, transgender women, transgender men, and gender nonbinary individuals who have condomless receptive anal sex with partners assigned male at birth.

Intervention Subcutaneous lenacapavir (twice-yearly) plus daily oral placebo.

Comparator Daily oral F/TDF plus subcutaneous placebo every 26 weeks.

Outcome Incidence of HIV-1 infection in the lenacapavir group compared to background HIV incidence in the screened population.

Study Limitations

• The trial was stopped early for efficacy, which may limit the collection of long-term data on rare adverse events or potential resistance development.

• The high frequency of injection-site reactions may pose a barrier to real-world uptake and retention for some individuals.

• The study compared lenacapavir against an active control that, while standard, had documented challenges with adherence in real-world settings compared to the strictly monitored clinical trial environment.

Clinical Significance

The results establish twice-yearly subcutaneous lenacapavir as a highly effective, long-acting PrEP option for populations at high risk for HIV. Its reduced dosing frequency compared to daily oral or bimonthly injectable options (like cabotegravir) could significantly improve adherence, expand accessibility, and offer a more discreet prevention modality for diverse communities.

Historical Context

The PURPOSE 2 trial builds upon the success of the PURPOSE 1 study, which demonstrated the efficacy of lenacapavir in cisgender women in sub-Saharan Africa. These studies represent a major advancement in the HIV prevention landscape, moving from daily oral medications to long-acting injectable agents, addressing persistent challenges related to pill burden, adherence, and social stigma.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the unique mechanism of action of lenacapavir compared to traditional reverse transcriptase inhibitors like F/TDF, and how does its pharmacological profile support twice-yearly dosing?

Key Response

Lenacapavir is a first-in-class capsid inhibitor that targets multiple stages of the HIV-1 lifecycle, including capsid-mediated nuclear uptake of pre-integration complexes, virus assembly, and capsid shell formation. Its low solubility and slow release from a subcutaneous injection site allow for a prolonged half-life, enabling the 26-week dosing interval observed in the PURPOSE 2 trial.

Resident

In the context of the PURPOSE 2 trial results, how should a clinician manage a patient who missed their scheduled 6-month lenacapavir injection by more than four weeks, particularly regarding the risk of HIV acquisition and resistance?

Key Response

The trial demonstrated high efficacy, but the 'long tail' of lenacapavir means that subtherapeutic levels persist for months after a missed dose. If a patient is exposed during this window and seroconverts, there is a theoretical risk of developing capsid-inhibitor resistance (e.g., the Q67H mutation). Clinicians must emphasize the importance of the 26-week window and consider bridging with oral PrEP if an injection is significantly delayed.

Fellow

The PURPOSE 2 trial included cisgender men, transgender women, transgender men, and nonbinary individuals. How do the pharmacokinetic and efficacy data from this diverse cohort address previous concerns regarding PrEP efficacy in gender-diverse populations on hormone therapy?

Key Response

Historically, concerns existed about drug-drug interactions between PrEP (specifically tenofovir) and gender-affirming hormone therapy (GAHT). PURPOSE 2 demonstrated that lenacapavir's efficacy was consistent across these subgroups, suggesting that the subcutaneous delivery and capsid-targeting mechanism are not significantly impacted by GAHT, providing a robust prevention option for gender-diverse individuals.

Attending

Given that lenacapavir demonstrated superiority over daily oral F/TDF in this trial, how does this shift the 'adherence paradigm' in HIV prevention, and what are the system-level barriers to its implementation in a standard primary care or infectious disease clinic?

Key Response

Lenacapavir shifts the burden from daily patient behavior to biannual clinical encounters. While this solves daily adherence issues, it requires robust clinic infrastructure for tracking appointments and managing cold-chain or storage (though lenacapavir is stable at room temperature, logistics of subcutaneous administration and insurance billing for injectables remain hurdles). It effectively turns HIV prevention into a 'vaccine-like' scheduled medical procedure.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of a 'counterfactual' background HIV incidence (bHIV) as the primary comparator in PURPOSE 2. What are the statistical risks of using recency-weighted incidence from screened individuals versus a traditional randomized placebo control?

Key Response

Using a bHIV is an innovative response to the ethical impossibility of using a placebo when effective PrEP (F/TDF) already exists. However, it assumes the screening population—those who tested negative but were screened—accurately reflects the risk profile of the trial participants. This methodology must account for 'screening effects' and potential shifts in regional epidemiology that could lead to an over- or under-estimation of the drug's relative risk reduction.

Journal Editor

The PURPOSE 2 trial reported only 2 infections in the lenacapavir group versus 9 in the F/TDF group. While statistically significant, how should the editor interpret the fragility of these results given the extremely low event rate, and what are the implications for the trial's external validity?

Key Response

With only 2 events in the intervention arm, the point estimate for efficacy is high (99.9%), but the absolute number of events is tiny. A reviewer would flag the 'fragility' of the result—if only a few more infections had occurred due to late injections or outliers, the superiority margin might have narrowed significantly. However, the consistency with the PURPOSE 1 trial (in cisgender women) reinforces the biological plausibility and robustness of the findings.

Guideline Committee

Based on the PURPOSE 2 findings, should lenacapavir be elevated to a 'preferred' status alongside or above cabotegravir (CAB-LA) in upcoming PrEP guidelines, and what specific evidence-based criteria would justify this change?

Key Response

Current guidelines (e.g., CDC/WHO) recommend CAB-LA every 2 months. Lenacapavir's 6-month dosing offers a clear logistical advantage. The committee must evaluate the PURPOSE 2 data against CAB-LA's HPTN 083/084 data. If lenacapavir is proven superior to F/TDF and potentially more convenient than CAB-LA, it likely warrants a Grade 1A recommendation for MSM and gender-diverse populations, provided cost-benefit analyses support the transition.

Clinical Landscape

Noteworthy Related Trials

2010

iPrEx Trial

n = 2,499 · NEJM

Tested

Daily oral emtricitabine/tenofovir disoproxil fumarate

Population

MSM and transgender women

Comparator

Placebo

Endpoint

Incidence of HIV infection

Key result: Daily oral PrEP reduced the risk of HIV acquisition by 44% compared to placebo. It established the proof of concept for oral PrEP in high-risk populations.

2020

HPTN 083 Trial

n = 4,566 · NEJM

Tested

Injectable cabotegravir every 8 weeks

Population

Cisgender MSM and transgender women

Comparator

Daily oral emtricitabine/tenofovir disoproxil fumarate

Endpoint

Incidence of HIV infection

Key result: Injectable cabotegravir was superior to daily oral PrEP in reducing HIV incidence by 66%. This demonstrated the viability of long-acting injectable agents for prevention.

2021

HPTN 084 Trial

n = 3,224 · NEJM

Tested

Injectable cabotegravir every 8 weeks

Population

Cisgender women in sub-Saharan Africa

Comparator

Daily oral emtricitabine/tenofovir disoproxil fumarate

Endpoint

Incidence of HIV infection

Key result: Cabotegravir was highly effective and superior to daily oral PrEP in cisgender women. It solidified the global utility of long-acting injectable PrEP.

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