A recent guideline endorsed by various human immunodeficiency virus (HIV) consensus groups and the American College of Clinical Pharmacy recommends use of long-acting (LA) ibalizumab and/or lenacapavir as an addition to optimized background regimen (OBR) for heavily treatment-experienced adults with multidrug-resistant HIV-1 with limited anticipated activity from oral antiretroviral (ART) agents alone. In general, ibalizumab or lenacapavir for HIV-1 treatment are indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 failing their current ART regimen. Evidence to support the use of lenacapavir in highly treatment-experienced people with multidrug-resistant HIV-1 is supported by the Phase 3 CAPELLA trial (see Table 1). Of note, lenacapavir has low systemic clearance, resulting in a half-life longer than 1 week for the oral product, and greater than 2 months for the subcutaneous injection due to slow-release kinetics. Oral lenacapavir is being studied in combination with other oral antiretrovirals for the treatment of naive patients, while injectable lenacapavir is being studied as a single agent administered subcutaneously every 6 months for pre-exposure prophylaxis (PrEP). [1]
Clinicians should reserve lenacapavir for individuals in whom a suppressive ART regimen cannot be constructed based on available alternatives, have access to the medication, and are able to receive subcutaneous administration every 6 months. More research is necessary to determine the optimal timing and frequency of efficacy monitoring for people with HIV-1 receiving LA ART treatment with lenacapavir. Additionally, resistance testing, if available, in cases of self-discontinued LA lenacapavir, or among individuals lost to follow-up, is recommended to evaluate susceptibility to the background ART regimen. If lenacapavir requires discontinuation due to adverse events, it may remain detectable in the systemic circulation for a prolonged period of up to nine months after discontinuation. To minimize risk of developing viral resistance, an alternative antiretroviral should replace lenacapavir in the fully suppressive regimen no later than 28 weeks after the final injection of lenacapavir. [1]
The PURPOSE trials are an ongoing series of trials that aim to evaluate the safety and efficacy of twice-yearly long-acting subcutaneous lenacapavir compared to emtricitabine/tenofovir alafenamide (Descovy®) or emtricitabine/tenofovir disoproxil fumarate (Truvada®) for HIV PrEP in a variety of populations at risk for HIV infection. In the PURPOSE 1 trial, study participants were randomized in a 2:2:1 ratio to lenacapavir, Descovy, or Truvada, respectively. According to a press release by Gilead Sciences, Inc., the manufacturer of lenacapavir, an interim analysis of the PURPOSE 1 trial found lenacapavir twice yearly to demonstrate 100% efficacy for PrEP in cisgender women. PURPOSE 1 also met its key efficacy endpoints of superiority over once-daily oral Truvada and background HIV incidence. There were 0 incidence cases of HIV infection among 2,134 women in the lenacapavir group compared to 16 incidence cases among 1,068 women in the Truvada group (p<0.001). For this reason, the independent data monitoring committee recommended that Gilead stop the blinded phase of the trial and offer open-label lenacapavir to all participants. Gilead expects results in late 2024/early 2025 from the program’s PURPOSE 2 trial, which is assessing twice-yearly lenacapavir for PrEP among cisgender men who have sex with men, transgender men, transgender women, and gender non-binary individuals who have sex with partners assigned male at birth. [2], [3], [4], [5], [6], [7]
One ongoing phase 2 trial will aim to evaluate the combination of lenacapavir with broadly neutralizing antibodies (teropavimab and zinlirvimab) in virologically suppressed adults with HIV-1 infection. This trial comes after a randomized, blinded, phase 1b proof-of-concept study in which adults with a plasma HIV-1 RNA concentration <50 copies/mcL who had at least 18 months on oral ART and CD4 counts of ≥500 cells/mcL stopped their oral ART and were randomized to receive one dose of 927 mg subcutaneous lenacapavir plus an oral loading dose, 30 mg/kg intravenous teropavimab, and 10 mg/kg or 30 mg/kg intravenous zinlirvimab on day 1. No serious adverse events occurred; however, two grade 3 adverse events occurred, including lenacapavir injection-site erythema and injection-site cellulitis, both of which resolved. The most common adverse events were symptoms of injection-site reactions, reported in 17 (85%) of 20 participants who received subcutaneous lenacapavir. One participant in the zinlirvimab 10 mg/kg experienced viral rebound, but overall, HIV-1 suppression for at least 26 weeks was deemed to be feasible and generally well tolerated with this regimen at either zinlirvimab dose in selected people with HIV-1. The phase 2 trial to follow this phase 1b study is scheduled to be completed in December 2029. Another phase 2 trial will aim to evaluate the efficacy of oral weekly islatravir in combination with lenacapavir in virologically suppressed people with HIV; however, the trial is also not scheduled to be complete until November 2027. [8], [9], [10], [11]
An ongoing phase 2/3 multi-center, randomized, open-label, active-controlled study is assessing the safety and efficacy of bictegravir/lenacapavir versus stable baseline regimens (SBR) for those with HIV-1. In the phase 2 period, patients will be randomized to receive bictegravir/lenacapavir 75 mg/25 mg daily, bictegravir/lenacapavir 75 mg/50 mg daily, or a stable baseline regimen for at least 24 weeks. If receiving lenacapavir, patients will receive 600 mg daily loading dose for 2 days. In all groups and after 24 weeks, patients will have the option of enrolling in the extension period, where their regimen can be optimized to receive bictegravir/lenacapavir 75 mg/50 mg fixed dose combination (FDC) tablets. In the phase 3 period, patients will be randomized to either continue SBR or switch to SBR bictegravir/lenacapavir 75 mg/50 mg FDC for at least 48 weeks. An extension enrollment period is offered in this study as well. [12]
This phase 2/3 study led to an ongoing phase 3, randomized, double-blinded, parallel trial which aims to evaluate the effectiveness of switching to bictegravir/lenacapavir FDC versus current therapy bictegravir/emtricitabine/tenofovir alafenamide FDC in virologically suppressed people with HIV-1. Patients will be randomized in parallel in one of two treatment groups during the blinded phase for at least 48 weeks. Group 1 patients currently on bictegravir/emtricitabine/tenofovir alafenamide FDC will switch to bictegravir/lenacapavir 75 mg/50 mg FDC and placebo to match bictegravir/emtricitabine/tenofovir alafenamide FDC. Group 2 patients will continue with bictegravir/emtricitabine/tenofovir alafenamide FDC and start placebo to match bictegravir/lenacapavir. Participants in both treatment groups will be given the option to continue bictegravir/lenacapavir FDC treatment during the open-label phase. The primary outcome of both studies is the proportion of patients with HIV-1 RNA ≥50 copies/mL at week 24 and week 48, respectively. Anticipated study completion of the phase 2/3 and phase 3 study is by November 2028 and December 2029, respectively. [12], [13]