A case series from 4 US academic medical centers (UCSF Ward 86, UCSD Owen Clinic, MetroHealth’s HIV Clinic [Cleveland, OH], and UPenn Clinic [Philadelphia, PA]) reported outcomes of patients receiving CAB LA + LEN (± RPV LA). All patients had oral antiretroviral therapy (ART) options available but reported challenges to taking oral ART which led to use of these off-label treatments. For inclusion in the case series, at least 1 viral load after starting LEN must have been available.

The primary outcome was the proportion of patients who achieved virologic suppression (HIV RNA < 75 copies/mL) after initiation of CAB LA + LEN (± RPV LA). From February to October 2023, 34 patients were included; 76% were male, 24% cis/trans female, 41% Black, with median (range) age of 47 (28–75) years; 47% (16/34) had virologic suppression prior to initiating CAB LA + LEN (± RPV LA). Most patients received every-2-month CAB (71% [24/34]) and had RPV included in the regimen (68% [23/34]).

Reported reasons for use of CAB LA + LEN were attributed to: documented or suspected non-nucleoside reverse transcriptase mutations (n = 21 [59%]), integrase strand transfer inhibitor (INSTI) mutations (n = 5 [15%]), high viral load (n = 6 [18%]), and continued viremia on CAB + RPV LA alone (n = 4 [12%]). One patient was started on CAB LA + RPV LA + LEN due to high body mass index; another patient was started on LEN due to intolerance to RPV LA (flu-like reaction).

Overall, 94% (32/34) of patients had virologic suppression (HIV-1 RNA < 75 copies/mL) after a median (range) of 8 (4–16) weeks from starting CAB LA + LEN (± RPV LA). Among patients who were not suppressed at baseline, 89% (16/18) achieved virologic suppression. Virologic suppression was achieved or maintained in all patients with documented or suspected non-nucleoside reverse transcriptase inhibitor mutations (n = 21; 11 suppressed at baseline).

Injection site reactions (ISRs) on LEN were observed in 44% of patients (grade 1: 32%, grade 2: 12%); two patients discontinued LA LEN due to ISRs. Additional safety information was not reported.

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.

Long-acting injectable (LAI) antiretroviral therapy (ART) is a promising option for people with HIV who face persistent adherence challenges, though literature to support its use in cases of integrase strand transfer inhibitor (INSTI) resistance remains limited.

We describe a 36-year-old man with advanced HIV-1, long-standing nonadherence to oral medications, and virologic failure who harbored both an INSTI major mutation (E92Q) and accessory mutation (E157Q). Given persistent nonadherence and viremia, he was started on dual LAI lenacapavir plus cabotegravir/rilpivirine. His viral load declined to 143 copies/mL within 6 weeks after initiation of injectable ART and has remained undetectable thereafter.

This case suggests that dual LAI ART may be effective in certain cases of underlying INSTI resistance and highlights the need for further study of this novel regimen in treatment-experienced individuals.

Case series from UMMC's Adult Special Care Clinic, presented alongside related multi-centre data.Rationale: Standard long-acting cabotegravir/rilpivirine (CAB/RPV) may fail in patients with NNRTI resistance-associated mutations (RAMs), which affect >10% prevalence in some populations, or with cabotegravir/INSTI resistance. This builds on an earlier 34-patient, 4-centre case series (Gandhi et al., OFID 2024) reporting 94% suppression with LEN/CAB, which called for a dedicated clinical trial in this population.

Intervention: PLHIV with viraemia and CAB or RPV RAMs, alongside chronic adherence challenges, were switched to combined long-acting therapy: intramuscular CAB/RPV plus subcutaneous lenacapavir (LEN, dosed every 26 weeks).

Rationale for LEN addition: LEN is a capsid inhibitor with a distinct resistance profile, offering antiviral cover where NNRTI or INSTI activity is compromised.

Population characteristics: Selected PLHIV had a history of poor long-term adherence to oral or standard injectable regimens.

Outcome: The regimen achieved virologic suppression in this real-world population despite pre-existing resistance and adherence barriers.

Significance: Supports LAI CAB/RPV + SC LEN as a viable "triple long-acting" salvage strategy for adherence-challenged people with HIV and dual-class resistance, reinforcing the need for prospective trial data.

The National Clinician Consultation Center is a US-based clinical resource that offers provider-to-provider tele-consultation, education, and capacity-building. Calls received from December 1, 2022 through August 30, 2024 were identified in which providers were considering potential ART changes to LEN + CAB, LEN + CAB/RPV, or LEN + RPV. Case providers were provided an 18-question survey to inquire about long-acting ART changes. Potential overlap between cases reported here and other cohorts cannot be ruled out.

Overall, 10 cases were identified in which ART was switched to LA LEN + CAB ± RPV with follow-up information available. The mean age (standard deviation) was 51 (14) years, 60% were cisgender men, and 30% were Black/African American. Seven cases reported a history of NNRTI mutations and 6 reported INSTI mutations.

Six cases received CAB monthly and 4 were on every-2-month dosing. Reasons for ART change included: detectable viral load on oral ART (n = 6), documented/suspected NNRTI resistance (n = 3), inability/refusal to take oral ART (n = 3), documented/suspected INSTI mutations (n = 2), and persistent viremia on CAB + RPV LA alone (n = 2). Within a median (range) of 56 (29–166) days, viral load decreased by a mean of 3.88 log10 copies/mL. Viral load was < 200 copies/mL in 8 individuals; the remaining 2 individuals’ viral loads decreased from 2,640,00 copies/mL to 313 copies/mL and 4,280,000 copies/mL to 210 copies/mL after 48 and 153 days, respectively.

Five individuals reported ISRs to either CAB + RPV, LEN, or all three; all were rated by the provider as “not at all” or “slightly” problematic. One individual had delayed/missed CAB/RPV injection and none had delayed/missed LEN injections.

All individuals (except for one case due to patient death for unstated reason) reported wanting to continue with the LA regimen.

A retrospective case series described 27 viremic patients treated with LA ART, 7 of which received LA LEN + CAB ± RPV. Of the overall cohort, 52% were male, 67% Black, 41% had perinatal HIV, 56% had CD4 cell count < 200 cells/mm3 (26% had CD4 < 50 cells/mm3). At baseline, all patients receiving LA LEN + CAB ± RPV had baseline NNRTI and/or INSTI mutations. All patients in the LA LEN + CAB ± RPV achieved virologic suppression (HIV-1 RNA < 200 copies/mL); median time to suppression was 7.9 weeks. All 7 patients remained on treatment at 24 weeks.