\u00a0<\/span>\u2265400 copies\/mL) who had documented resistance to at least two ARV drugs from at least three of the four main classes (nucleoside RT inhibitors, non-nucleoside RT inhibitors, integrase strand transfer inhibitors and protease inhibitors), and no more than two fully active ARV drugs from the four main classes that could be effectively combined.<\/p>\nChanges in plasma HIV-1 RNA levels between the screening and cohort selection visits, which occurred 14\u201330 days apart, were used to divide participants into two distinct cohorts. Cohort 1 consisted of the first 36 participants with an HIV-1 RNA level of\u00a0<\/span>\u2265400 copies\/mL and a decline of <0.5 log10<\/sub>\u00a0copies\/mL between the screening and cohort selection visits. In this cohort, participants were randomly assigned in a 2:1 ratio to receive oral LEN (600 mg on days 1 and 2 and 300 mg on day 8) or a matching placebo while continuing their failing therapy (double-blind). In the maintenance phase, which started on day 15, participants in the LEN group received subcutaneous LEN (927 mg) once every 6 months plus OBR. Participants in the placebo group received oral LEN (600 mg on days 15 and 16 and 300 mg on day 22), followed by subcutaneous LEN plus OBR.<\/p>\nCohort 2 was designed to include participants with a decrease of\u00a0<\/span>\u22650.5 log10<\/sub>\u00a0copies\/mL between screening and cohort selection visits, a viral load of\u00a0<\/span>\u2264400 copies\/mL or both. All participants in this cohort received open-label oral LEN (600 mg on days 1 and 2 and 300 mg on day 8) with OBR on day 1, followed by subcutaneous LEN every 6 months starting on day 15.<\/p>\nPrimary and secondary efficacy endpoints were evaluated in cohort 1. The primary efficacy endpoint was the proportion of participants with a decrease in plasma HIV-1 RNA of at least 0.5 log10<\/sub>\u00a0copies\/mL from baseline by day 15 (the end of the functional monotherapy). Secondary endpoints were the proportion of participants with a viral load of <50 copies\/mL and the proportion of those with a viral load of <200 copies\/mL at week 26 following initiation of subcutaneous LEN. Other key efficacy endpoints included changes in viral load and CD4+ counts.<\/p>\nA total of 72 participants were enrolled in the CAPELLA study. Of these, 36 were enrolled in cohort 1 (12 of whom were assigned to receive placebo during the functional monotherapy period and 24 to receive LEN), and 36 were enrolled in cohort 2. Participants in cohort 1 had received a median of 9 ARV treatments prior to enrollment, and their median overall susceptibility score for failing regimens was 0.8.10<\/span><\/sup>\u00a0The drug susceptibility score for an individual ARV drug was calculated using an algorithm that assigned a value of 1.0 for full susceptibility, 0.5 for partial susceptibility and 0.0 for no susceptibility; the overall susceptibility score was the sum of the individual susceptibility scores.<\/p>\n<\/span>Participants in cohort 2 had similar characteristics (e.g. demographics, characteristics of HIV infection, viral resistance and immunovirological profiles) to participants in cohort 1.<\/p>\nIn cohort 1, the primary efficacy endpoint (-0.5 log10<\/sub>\u00a0copies\/mL HIV-1 RNA at day 15) was achieved in 21\/24 (88%) participants in the LEN group and 2\/12 (17%) participants in the placebo group during the functional monotherapy period (absolute difference 71%, 95% confidence interval [CI] 35\u201390; p<0. 001). At week 26, 29\/36 participants from this cohort had HIV-1 RNA <50 copies\/mL (81%;95% CI 64\u201392), and 32\/36 participants had <200 copies\/mL (89%; 95% CI 74\u201397. In cohort 2, 30\/36 (83%) participants and 31\/36 (86%) participants had viral loads of <50 copies\/mL and <200 copies\/mL, respectively, at week 26.<\/p>\n<\/sup>When considering both the randomized and non-randomized cohorts, 56\/72 (78%) participants had a viral load of <50 copies\/mL, 11\/72 (15%) had HIV-1 RNA levels of >50 copies\/mL and 5\/72 (7%) had no virologic data at week 52.11<\/sup><\/span>\u00a0Of the 72 participants, 59 (82%) had a 52-week viral load of <200 copies\/mL, 8 (11%) had an HIV-1 RNA level of >200 copies\/mL and 5 (7%) had no virologic data. At week 52, 27\/34 (79%) participants treated with two active ARVs in combination with LEN had a viral load of <50 copies\/mL, while 20\/26 (77%) participants with only one active ARV had a viral load of <50 copies\/mL and 9\/12 (75%) with no active ARV in combination with LEN had a viral load of <50 copies\/mL. In addition, efficacy at week 52 was similar in different subgroups according to demographic characteristics (e.g. sex at birth, age and race), baseline CD4 count and HIV-1 RNA levels (although a trend toward a higher rate of virologic response was seen in those with lower viraemia and a higher CD4 cell count), and OBR characteristics.27<\/sup><\/span><\/p>\nIn terms of safety, a combined analysis of cohorts 1 and 2 at week 26 showed that 7\/72 (10%) participants experienced serious adverse events (AEs), none of which were considered to be related to LEN by the investigator.10<\/sup><\/span>\u00a0After excluding injection site reactions (ISRs), the most common AEs were diarrhoea (11%) and constipation (11%). A total of 45\/72 (63%) participants experienced at least one ISR. The ISRs included pain (31%), swelling (31%), erythema (25%) and nodule occurrence (24%). Most ISRs, including pain, were grade 1 and resolved within a few days. No grade 4 ISRs were reported.<\/p>\nAfter 52 weeks of follow-up, no study drug-related AEs occurred in >5% of participants, and no study drug-related serious AEs occurred.11<\/sup><\/span>\u00a0Three-quarters or more of the study participants had no ISRs after the first and second subcutaneous doses of LEN, and no grade 4 ISRs were reported. The three grade 3 reactions were swelling and erythema in one participant, which resolved in 4 and 8 days, respectively, and pain in another participant, which resolved in 1 day.11<\/sup><\/span>\u00a0Two participants died during follow-up: one from non-Hodgkin\u2019s lymphoma and the other from acute respiratory failure; neither death was related to LEN.10,11<\/sup><\/span><\/p>\nThe efficacy of LEN was also evaluated in treatment-na\u00ef<\/span>ve PLWH in the CALIBRATE study (ClinicalTrials.gov identifier: NCT04143594).14,28,29<\/sup><\/span>\u00a0In this study, participants were randomized into four groups: group 1 and group 2 received 927 mg subcutaneous LEN every 26 weeks (after 2 weeks of oral LEN dosing) with oral\u00a0tenofovir alafenamide\/emtricitabine for the first 28 weeks of the study, then switched to oral tenofovir alafenamide<\/span>\u00a0(group 1) or bictegravir (BIC) (group 2); group 3 received oral daily LEN with emtricitabine and\u00a0tenofovir alafenamide<\/span>; and group 4 received oral daily BIC, emtricitabine and\u00a0tenofovir alafenamide<\/span>. Subcutaneous LEN showed good overall efficacy in groups 1 and 2. At week 54, an HIV-1 RNA level of <50 copies\/mL was achieved in 47\/52 (90%) participants in group 1 (difference with oral tenofovir alafenamide\/emtricitabine and BIC comparator arm -2.6%, 95% CI -18.4 to 13.2) and 45\/53 (85%) participants in group 2 (difference with the tenofovir alafenamide\/emtricitabine\/BIC comparator arm -7.1%, 95% CI -23.4 to 9.3).14<\/sup><\/span>\u00a0At week 80, the proportion of participants with viral suppression was 85% and 75% in groups 1 and 2, respectively, compared with 92% in the tenofovir alafenamide\/emtricitabine and BIC control arm.28<\/sup><\/span><\/p>\nThe phase Ib trial of teropavimab and zinlirvimab in combination with lenacapavir<\/h2>\n
According to the pharmacokinetic characteristics of the subcutaneous formulation of LEN, combining LEN with other drugs characterized by long half-lives could allow to design ARV regimens with 6-monthly dosing that could benefit HTE-PLWH. In a phase Ib clinical trial (ClinicalTrials.gov identifier: NCT04811040), Eron et al. evaluated a regimen of LEN and two broadly neutralizing antibodies, teropavimab and zinlirvimab (Gilead Sciences, Inc.,\u00a0Foster City<\/span>, CA, USA), administered every 6 months in ART-experienced PLWH with viral suppression.30<\/sup><\/span>\u00a0Teropavimab is a broadly neutralizing antibody that targets the CD4 binding site on HIV gp120, while zinlirvimab is a broadly neutralizing antibody that targets a non-overlapping epitope of the V3 glycan of HIV envelope glycoprotein. Both antibodies have been modified to extend their half-life and allow for 6-month dosing.<\/p>\nThis phase Ib clinical trial enrolled 21 PLWH on ART with viral suppression for at least 18 months, with a baseline CD4+ count of\u00a0<\/span>>\u00a0<\/span>500 cells\/mm3<\/sup>\u00a0and a nadir CD4+ count of <350 cells\/mm3<\/sup>.30<\/sup><\/span>\u00a0All study participants had a virus that was susceptible to both antibodies. At baseline, active ART was stopped, and all participants received an oral loading dose of 600 mg of LEN (repeated on day 2). Participants received two subcutaneous injections for a total of 927 mg of LEN and an intravenous infusion of teropavimab (30 mg\/kg). They were also randomized to receive either 10 mg\/kg or 30 mg\/kg of zinlirvimab. In both groups, 10 participants received all scheduled doses and were included in the analysis. Although the study was originally designed to last 52 weeks, it was shortened to 26 weeks due to a clinical hold on the subcutaneous LEN formulation.<\/p>\nLEN, teropavimab and zinlirvimab (at both doses) remained above therapeutic levels (5 ng\/mL for LEN and 2\u00a0\u03bcg<\/span>\/mL for teropavimab and zinlirvimab) for up to 26 weeks. At the end of the study, 90% of participants in both groups maintained viral suppression. One participant in the 30 mg\/kg zinlirvimab group withdrew from the study at week 12. Another participant in the 10 mg\/kg group experienced a viral rebound, which was suppressed after restarting the baseline regimen. Treatment was safe and generally well tolerated. No serious or life-threatening AEs or clinically significant laboratory abnormalities were observed, and there were no discontinuations due to AEs. The most common AEs were ISRs.30<\/sup><\/span><\/p>\nMutations associated with resistance to<\/span>\u00a0lenacapavir<\/span><\/h1>\nIn vitro<\/em><\/h2>\nIn vitro<\/em>\u00a0resistance selection assays have shown that Q67H and N74D are the main resistance-associated mutations (RAMs) in the\u00a0gag<\/em>\u00a0gene associated with LEN exposure.9,31\u201333<\/sup><\/span>\u00a0Additional mutations include L56I, M66I, K70N, Q67H\/N74S, and Q67H\/T107N.9,31\u201333<\/sup><\/span>\u00a0These mutations, alone or in combination, confer reduced susceptibility to LEN (6- to >3,200-fold resistance compared with the wild type). Moreover, all but the low-level resistant variant Q67H (6-fold resistance to LEN relative to the wild-type virus) have been associated with a reduced replication capacity\u00a0in vitro<\/em>.34<\/sup><\/span><\/p>\nLEN retains potent antiviral activity against HIV-1 site-directed mutants and clinical isolates resistant to currently approved ARV agents, including nucleoside RT inhibitors, non-nucleoside RT inhibitors, integrase strand transfer inhibitors, protease inhibitors, entry inhibitors (fostemsavir, ibalizumab and maraviroc) and the experimental drug islatravir (Merck\u00a0& Co., Inc., Rahway, NJ USA<\/span>).32,35,36<\/sup><\/span>\u00a0Due to its first-in-class nature, LEN is expected to be fully active regardless of the patient\u2019s treatment history. In a sample of 1,500 PLWH, including treatment-na\u00ef<\/span>ve and treatment-experienced individuals, none of the LEN resistance mutations identified during the\u00a0in vitro<\/em>\u00a0selection experiments were detected.31<\/sup><\/span><\/p>\nIn vivo<\/em><\/h2>\nIn this section, we present resistance data from the CAPELLA and CALIBRATE trials, which assessed the efficacy and safety of LEN in HTE- and treatment-na\u00efve PLWH, respectively.10,11,14,28,37<\/sup><\/span>\u00a0The analysis of potential treatment-emergent resistance to LEN in the CAPELLA trial was carried out during the study\u2019s maintenance phase when all participants received LEN plus OBR. Participants were tested for genotypic and phenotypic resistance to LEN and OBR components in the event of virological failure.10<\/sup><\/span>\u00a0By week 52, 21\/72 (29%) participants met the criteria for resistance analysis, 9\/72 (13%) developed LEN RAMs in the CA, and 12\/72 (17%) did not meet the criteria for resistance analysis. Four major patterns of LEN RAMs were observed, including M66I \u00b1 other substitutions were the most common patterns, with 6\/72 (8%) participants attesting M66I mutations and a median LEN phenotypic fold change (FC) of 234 in patients with M66I mutations compared with the wild type; the Q67H + K70R combination was found in 1\/72 (1%) participants and was associated with a LEN FC of 15 compared with the wild type; and a K70H mutation was found in 1\/72 (1%) participants and was associated with a LEN FC of 265 compared with the wild type.37<\/sup><\/span>\u00a0Eventually, the isolated LEN Q67H mutation emerged in a single participant at week 52, with an associated LEN FC of 6 compared to wild type.11<\/sup><\/span>\u00a0No participant with LEN resistance experienced the emergence of additional RAMs to the components of OBR.<\/p>\nOf the participants who did not develop resistance to LEN, 3\/12 (25%) remained viraemic throughout the study without acquiring new OBR resistance. Ultimately, 9\/12 (75%) participants suppressed their HIV-1 RNA level to <50 copies\/mL without changing OBR, including two who initially experienced RAMs on their OBR.10<\/sup><\/span>\u00a0Of the 9 participants who developed resistance, 4 (44%) with LEN-associated CA RAM emergence were on functional LEN monotherapy and did not have fully active ARVs on their OBR.11<\/sup><\/span>\u00a0These participants had few treatment options based on baseline resistance analyses; however, two of them were able to resuppress their HIV-1 RNA level to <50 copies\/mL after switching to active or partially active agents while maintaining LEN, and two participants experienced viral rebound to levels similar to baseline. The other five participants who developed LEN RAMs received at least two fully active OBRs. However, blood samples obtained during the development of LEN resistance revealed undetectable levels of several OBR drugs (darunavir, dolutegravir, emtricitabine and tenofovir), indicating poor adherence to oral ART.10,11<\/sup><\/span><\/p>\nIn the CALIBRATE study, three treatment-na\u00efve PLWH developed resistance.14,28<\/sup><\/span>\u00a0At week 10 (during treatment with tenofovir alafenamide\/emtricitabine<\/span>\u00a0plus subcutaneous LEN), the LEN-associated Q67H and K70R CA substitutions and the M184M\/I RT mutation were detected in the first participant. Emtricitabine and tenofovir concentrations were consistent with expected pharmacokinetics, and LEN plasma concentrations were within target ranges (>3.87 ng\/mL).38<\/sup><\/span>\u00a0At week 54, a second participant treated with\u00a0emtricitabine\/tenofovir alafenamide<\/span>\u00a0+ oral LEN (group 3) experienced virologic rebound with the emergence of LEN resistance (Q67H mutation) and the subsequent emergence of the K70R mutation.28<\/sup><\/span>\u00a0Finally, a third participant receiving oral tenofovir alafenamide + subcutaneous LEN (group 1) developed the Q67H + K70R combination at week 80.28<\/sup><\/span>\u00a0A summary of the LEN RAMs selected\u00a0in vitro<\/em>\u00a0and\u00a0in vivo<\/em>\u00a0from the CAPELLA and CALIBRATE studies is provided in\u00a0Table 1<\/span><\/em>.11,14,28,34,37<\/sup><\/span><\/p>\n<\/p>\n
Role of\u00a0lenacapavir<\/span>\u00a0in the management of eavily treatment-experienced people living with HIV<\/span><\/span><\/b><\/span><\/h1>\nThe current article reviewed results from on-going clinical trials that,\u00a0despite the limited sample size,<\/span>\u00a0have shown the efficacy and safety of LEN in HTE-PLWH. In the CAPELLA trial, virologic efficacy of 78% was achieved at 52 weeks, with a limited proportion of participants experiencing grade 3\u20134 AEs.10,11<\/sup><\/span>\u00a0In addition, ISRs, albeit frequent, were mostly mild to moderate in intensity.10,11<\/sup><\/span><\/p>\nThe long-acting, subcutaneous LEN formulation, which can be administered every 6 months, is a significant addition to the HIV treatment armamentarium due to its unique characteristics. However, despite data demonstrating the efficacy of regimens containing LEN as the only active drug, LEN should not be misused in the HTE population.11<\/sup><\/span>\u00a0Although it is often difficult to design regimens with at least two active drugs for HTE patients with failing ART, the add-on strategy (where an active drug is added to a failing regimen) should be strongly discouraged for LEN.6,39<\/sup><\/span>\u00a0Fortunately, new therapies from new drug classes have become available in recent years (e.g. fostemsavir and ibalizumab) or may be available soon (islatravir and broadly neutralizing antibodies).7,40<\/sup><\/span>\u00a0Consequently, LEN should be combined with an OBR that includes, when feasible, at least a second active agent that takes into account both new and existing classes.6,39<\/sup><\/span>\u00a0Therefore, a reassessment of the complete drug history and cumulative viral genotypes and, if available, of the use of phenotypic resistance testing to determine the best possible treatment is recommended in HTE-PLWH on a failing ART.