Background

Injectable cabotegravir (CAB)/rilpivirine (RPV) is the only combination long-acting (LA) antiretroviral regimen approved for HIV. RPV may not be effective among individuals with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, which has >10% prevalence in many countries. Lenacapavir (LEN) is an LA capsid inhibitor given every 6 months, but has not been studied in combination with other LA agents.

Methods

We assembled a case series from 4 US academic medical centers where patients with adherence challenges were prescribed LEN subcutaneously every 26 weeks/CAB (+/− RPV) intramuscularly every 4 or 8 weeks. Descriptive statistics, including viral load (VL) outcomes, were summarized.

Results

All patients (n = 34: 76% male; 24% cis/trans female; 41% Black; 38% Latino/a; median age [range], 47 [28–75] years; 29% and 71% on CAB every 4 or 8 weeks) reported challenges adhering to oral ART. The reasons for using LEN/CAB with or without RPV were documented or suspected NNRTI mutations (n = 21, 59%), integrase mutations (n = 5, 15%), high VL (n = 6, 18%), or continued viremia on CAB/RPV alone (n = 4, 12%). Injection site reactions on LA LEN were reported in 44% (32% grade I, 12% grade 2). All patients but 2 (32/34; 94%) were suppressed (VL <75 copies/mL) after starting LEN at a median (range) of 8 (4–16) weeks, with 16/34 (47%) suppressed at baseline.

Conclusions

In this case series of 34 patients on LEN/CAB, high rates of virologic suppression (94%) were observed. Reasons for using LEN/CAB included adherence challenges and underlying resistance, mostly to NNRTIs. These data support a clinical trial of LEN/CAB among persons with NNRTI resistance.

Although viral suppression is attained for most adults living with diagnosed HIV in East, Central, Southern and West Africa (ECSWA), challenges remain with sustained adherence to daily oral pill taking for some in the population. Here, we evaluate the potential effectiveness and cost-effectiveness of introduction of a new combination of long-acting injectable drugs of lenacapavir + cabotegravir to increase levels of sustained viral suppression. We find there is potential for a significant impact on HIV deaths and disability adjusted life years, including due to a decrease in mother to child transmission. If lenacapavir + cabotegravir can be sourced at a cost of around $ 80 per year or less, our analysis suggests there is potential for a policy to introduce it to be cost-effective in settings in ECSWA. Recognising the limitations of a modelling study, we suggest that implementation studies be conducted to confirm the viability of these approaches.

Background: Long-acting injectable (LAI) antiretroviral therapy (ART) represents a breakthrough in managing HIV, providing an alternative to daily oral ART, especially for PLWH with adherence challenges. However, the use of LAI-cabotegravir (CAB) in association with LAI-rilpivirine (RPV) is contraindicated in PLWH with previous RPV-associated resistance mutations. LAI-lenacapavir (LEN) may help address barriers to treatment adherence among PLWH with RPV-resistant virus.

Methods: In this series, we report on eight pretreated virally suppressed (plasma viral load [pVL] <50 copies/ml) adult PLWH with RPV-resistant virus, who started LAI-ART with CAB plus LEN between January 2021 and August 2023, after approval by a multidisciplinary committee in two French hospitals. CAB and LEN were started on the same day: oral loading dose of LEN 600 mg on day 1 and day 2, and subcutaneous LEN 927 mg on day 1 and then every 6 months, in combination with intramuscular CAB 600 mg on day 1, week 4, and then every 8 weeks. Antiretroviral plasma concentrations (Cpl) were routinely determined by UPLC-MS/MS at each visit.

Results: Patients were four women and four men; median age (IQR 25–75) 56 years (44–58); duration from ART initiation 25 years (18–32); duration of viral suppression 32 months (7–59); four had CD4 counts below 200/mm3. All had difficulty accepting their illness and had adherence problems. All patients were monitored for at least 6 months, and three for 12 months, with a median of 3 pVL measurements per patient (range 1–4). No virological failures were observed during follow-up, as all pVL remained below 50 copies/ml. No serious adverse events or discontinuations were reported. All LEN trough Cpl were >15.5 ng/ml (4xPA-IC95 in MT-4 cells) and median (IQR 25–75) CAB Cpl was 1829 ng/ml (1483–2166) approximately 58 days after the last intramuscular injection. Despite the expected moderate injection site reactions, all patients expressed a preference for this treatment over oral ART.

Conclusions: CAB plus LEN maintained effective viral suppression with good tolerability. It holds great promise for vulnerable PLWH struggling with oral ART adherence, particularly when RPV is not an option anymore, and merits prospective evaluation in a large, randomized trial.

BACKGROUND: Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 3 study among participants with multidrug-resistant HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen (OBR) received through the compassionate access in France.METHODS: Participants with previous multidrug failure were prospectively enrolled between January 1st, 2021 and December 31st, 2023. Following a 2-week oral lenacapavir, they received subcutaneous lenacapavir every W26 with an OBR. A retrospective efficacy analysis was performed with the primary end point as the percentage of participants with HIV-1 viral load (VL) < 50copies/ml at W26. Secondary endpoints were virological outcomes at end of follow up, emergence of lenacapavir resistance in case of virological failure and tolerance.RESULTS: Thirty-three participants (11/33 females) were analysed with a median (IQR) age of 56 (41-59) years. At lenacapavir initiation, median CD4 cells count was 330 (106-500) cells/µL with 11/27 (41%) participants having less than 200 cells per µL. VL was 2.54 (1.48-4.27) log10 copies/ml with 14/33 (42%) having VL below 50 copies/ml. OBR included mainly darunavir/r (n=13), dolutegravir (n=11), cabotegravir (n=10), fostemsavir (n=12), maraviroc (n=8), ibalizumab (n=7) and enfuvirtide (n=4). At W26 (W22 to W30), a VL < 50 copies/ml was reported in 66.7% (CI95% 48.2-82.0) of the participants with a mean increase in the CD4+ count of +92 cells/µL.HIV-1 capside sequencing was performed in 7 participants with virological failure and the Q67H mutation conferring resistance to lenacapavir was evidenced in one case. There were no grade 3 or 4 treatment-related adverse events (included two deaths). Injection site reactions were reported for 11/33 (33%) participants without treatment discontinuation.CONCLUSIONS: In this real-life cohort of highly treatment-experienced HIV-1 participants, lenacapavir in combination with an OBR resulted in a high level of virological suppression up to 26 weeks, even increasing throughout the end of follow-up.