Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial.

Lenacapavir is a long-acting HIV-1 capsid inhibitor for treatment of HIV-1 infection. We evaluated the efficacy and safety of lenacapavir in combination with an investigator-selected optimized background regimen (OBR) after 104 weeks in adults with multidrug-resistant HIV-1. This ongoing, international, Phase 2/3 trial at 42 sites included 72 adults living with multidrug-resistant HIV-1. Following a 2-week oral lenacapavir loading phase, participants received subcutaneous lenacapavir every 26 weeks with an OBR. HIV-1 RNA, CD4 cell counts, and adverse events were assessed over 104 weeks. One participant did not enter the extension phase. At Week 104, 44 of 71 participants (62%, 95% CI 50; 73) had HIV-1 RNA <50 copies/mL via US Food & Drug Administration (FDA) snapshot algorithm. When missing data (including discontinuations) were excluded, 44 of 54 participants (82%) had HIV-1 RNA <50 copies/mL at Week 104, mean CD4 cell count increased by 122 cells/µL (95% CI 80; 165), and the proportion of participants with CD4 cell count <200 cells/µL decreased from 64% (46 of 72) at Baseline to 29% (16 of 55). Fourteen participants had treatment-emergent lenacapavir resistance; seven resuppressed (HIV-1 RNA <50 copies/mL) while maintaining lenacapavir use. There were no Grade 4 or serious treatment-related adverse events. One participant discontinued study drug due to an injection site reaction. Treatment with subcutaneous lenacapavir in combination with an OBR was well tolerated and resulted in a high rate of virological suppression over 104 weeks. Lenacapavir represents an important treatment option in people with multidrug-resistant HIV-1.

Ogbuagu O ，Molina JM ，Chetchotisakd P ，Ramgopal MN ，Sanchez W ，Brunetta J ，Castelli F ，Crofoot GE ，Hung CC ，Ronot-Bregigeon S ，Margot NA ，Wang H ，Dvory-Sobol H ，Rhee MS ，Segal-Maurer S ... -  《-》

Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

Long-acting cabotegravir and rilpivirine administered monthly or every 2 months might address the challenges associated with daily oral antiretroviral therapy. The ATLAS-2M week 48 results showed non-inferiority of long-acting cabotegravir and rilpivirine administered every 8 weeks compared with that of every 4 weeks. In this study, we report the efficacy, safety, and tolerability results from the week 96 analysis. ATLAS-2M is a randomised, multicentre, open-label, phase 3b, non-inferiority trial conducted in 13 countries, evaluating the safety and efficacy of maintenance treatment with intramuscular injections of long-acting cabotegravir and rilpivirine, administered every 8 weeks versus every 4 weeks, to people living with HIV-1. Virologically suppressed adults with HIV-1, either already receiving intramuscular long-acting cabotegravir and rilpivirine every 4 weeks (ie, ATLAS study rollover participants) or oral standard of care, were randomly assigned (1:1), in an unblinded fashion, to receive either intramuscular long-acting cabotegravir (600 mg) and rilpivirine (900 mg) every 8 weeks (ie, the every 8-week dosing group) or intramuscular long-acting cabotegravir (400 mg) and rilpivirine (600 mg) every 4 weeks (ie, the every 4-week dosing group). Randomisation was generated using the GlaxoSmithKline-validated randomisation software RANDALL NG (version 1.3.3). The primary endpoint at week 48 was the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (ie, the US Food and Drug Administration [FDA] Snapshot algorithm), which has been published previously. Here, we present the week 96 results: the proportion of participants with plasma HIV-1 RNA measurements of less than 50 copies per mL (FDA Snapshot algorithm), with a non-inferiority margin of -10%; the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (FDA Snapshot algorithm), with a non-inferiority margin of 4%; the proportion of participants with protocol-defined confirmed virological failure (ie, two consecutive plasma HIV-1 RNA measurements ≥200 copies per mL); safety; pharmacokinetics; and tolerability. This study is registered with ClinicalTrials.gov, number NCT03299049, and is currently ongoing. Between Oct 27, 2017, and May 31, 2018, a total of 1149 participants were screened; of whom, 1049 (91%) were randomly assigned and 1045 (91%) initiated treatment (522 in the every 8-week dosing group and 523 in the every 4-week dosing group). The median age was 42 years (IQR 34-50). 280 (27%) of 1045 participants were assigned female at birth and 764 (73%) were white. At week 96 (FDA Snapshot algorithm), 11 (2%) of 522 participants in the every 8-week dosing group and six (1%) of 523 in the every 4-week dosing group had an HIV-1 RNA measurement of 50 copies per mL or more, with an adjusted treatment difference of 1·0 (95% CI -0·6 to 2·5), meeting the prespecified non-inferiority threshold of 4%; 475 (91%) of 522 participants in the every 8-week dosing group and 472 (90%) of 523 in the every 4-week dosing group maintained an HIV-1 RNA measurement of less than 50 copies per mL, with an adjusted treatment difference of 0·8 (95% CI -2·8 to 4·3), which met the prespecified non-inferiority threshold of -10%. One participant in the every 8-week dosing group met the confirmed virological failure criterion since the week 48 analysis at week 88, resulting in a total of nine participants in the every 8-week dosing group and two in the every 4-week dosing group having confirmed virological failure. No new safety signals were identified, and no treatment-related deaths occurred. Injection site reactions were the most common adverse event, occurring in 412 (79%) of 522 participants in the every 8-week dosing group and 400 (76%) of 523 in the every 4-week dosing group. Most injection site reactions were grade 1 or 2 (7453 [99%] of 7557 in both groups), with a median duration of 3 days (IQR 2-5). Long-acting cabotegravir and rilpivirine dosed every 8 weeks had non-inferior efficacy compared with that of every 4 weeks through the 96-week analysis, with both regimens maintaining high levels of virological suppression. These results show the durable safety, efficacy, and acceptability of dosing long-acting cabotegravir and rilpivirine monthly and every 2 months as maintenance therapy for people living with HIV-1. ViiV Healthcare and Janssen Research & Development.

Jaeger H ，Overton ET ，Richmond G ，Rizzardini G ，Andrade-Villanueva JF ，Mngqibisa R ，Hermida AO ，Thalme A ，Belonosova E ，Ajana F ，Benn PD ，Wang Y ，Hudson KJ ，Español CM ，Ford SL ，Crauwels H ，Margolis DA ，Talarico CL ，Smith KY ，van Eygen V ，Van Solingen-Ristea R ，Vanveggel S ，Spreen WR ... -  《Lancet HIV》

Efficacy of dolutegravir plus lamivudine in treatment-naive people living with HIV without baseline drug-resistance testing available (D2ARLING): 48-week results of a phase 4, randomised, open-label, non-inferiority trial.

Dolutegravir plus lamivudine has emerged as a preferred treatment for HIV; however, initiating this regimen without baseline resistance testing raises concerns about the potential presence of pretreatment lamivudine resistance. We aimed to evaluate the efficacy of dolutegravir plus lamivudine in the absence of information on baseline resistance testing in treatment-naive people with HIV. We did an open-label, non-inferiority, single-centre, phase 4, randomised controlled study (D2ARLING), designed to assess the efficacy and safety of dolutegravir plus lamivudine in treatment-naive people with HIV with no available baseline resistance testing. We included participants aged 18 years or older with HIV-1 diagnosis who were naive to antiretroviral therapy and had no baseline genotypic resistance testing result available. We randomly assigned (1:1) participants to receive dolutegravir 50 mg plus lamivudine 300 mg or a three-drug regimen including dolutegravir 50 mg plus tenofovir disoproxil fumarate 300 mg and either emtricitabine 200 mg or lamivudine 300 mg. Randomisation was stratified by baseline HIV-1 RNA (≤100 000 vs >100 000 copies per mL) and CD4 cell count (<200 vs ≥200 cells per μL). Per protocol, we performed genotypic drug-resistance testing on day 1 and it remained double-masked throughout the study, simulating a scenario of inaccessibility of baseline resistance testing. The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48 (intention-to-treat exposed analysis via the Snapshot algorithm) with prespecified non-inferiority margin of 10%. This trial is registered with ClinicalTrials.gov (NCT04549467). Between Nov 17, 2020, and Aug 31, 2022, 214 participants were randomly assigned to and treated with dolutegravir plus lamivudine (n=106) or dolutegravir plus tenofovir disoproxil fumarate and either emtricitabine or lamivudine (n=108). Median age of participants was 31 years (IQR 26-39) and 49 (23%) were female. At baseline, 66 (31%) of participants had an HIV-1 RNA viral load of more than 100 000 copies per mL, and 44 (21%) had a CD4 T-cell count of less than 200 cells per μL. At week 48, 97 (92%) of 106 participants in the dolutegravir plus lamivudine group and 96 (89%) of 108 participants in the dolutegravir plus tenofovir disoproxil fumarate with either emtricitabine or lamivudine group had HIV-1 RNA of less than 50 copies per mL (difference 2·62%; 95% CI -5·3 to 10·6), showing non-inferiority of dolutegravir plus lamivudine to the three-drug regimen. None of the participants in the dolutegravir plus lamivudine group and two in the control group had protocol-defined virological failure, and none developed treatment-emergent resistance mutations to any of the study drugs. Overall adverse event rates were similar between arms. Less than 1% of participants in both groups were discontinued due to adverse events. This study provides evidence supporting the non-inferiority of dolutegravir plus lamivudine compared with a preferred three-drug regimen in treatment-naive individuals without baseline resistance testing. These findings suggest that baseline resistance testing might not be a requirement for initiating treatment with dolutegravir plus lamivudine in settings with low frequency or suspicion of transmitted drug resistance to these drugs. ViiV Healthcare.

Cordova E ，Hernandez Rendon J ，Mingrone V ，Martin P ，Arevalo Calderon G ，Seleme S ，Ballivian J ，Porteiro N ... -  《Lancet HIV》

Safety of combined long-acting injectable cabotegravir and long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017/MOCHA): a phase 1/2, multicentre, open-label, non-comparative, dose-finding study.

Long-acting cabotegravir and long-acting rilpivirine constitute a completely intramuscular antiretroviral therapy (ART) regimen for adults with HIV. We aimed to assess the safety, antiviral activity, and pharmacokinetics of oral cabotegravir and rilpivirine followed by a combination of long-acting cabotegravir and long-acting rilpivirine in virologically suppressed adolescents with HIV. The IMPAACT 2017/MOCHA study is a phase 1/2, multicentre, open-label, non-comparative, dose-finding trial being conducted at 18 sites across Botswana, South Africa, Thailand, Uganda, and the USA. In cohort 2 of this study, adolescents (aged 12-18 years; weight ≥35 kg) with HIV and no serious comorbidities who were receiving stable combination ART with confirmed virological suppression and had either previously enrolled in the first cohort or had not previously participated in the study were eligible for inclusion. Participants stopped their background combination ART and received oral cabotegravir 30 mg once daily and oral rilpivirine 25 mg once daily orally for 4-6 weeks, followed by long-acting injectable cabotegravir 600 mg (3 mL) and long-acting injectable rilpivirine 900 mg (3 mL) intramuscularly at weeks 4 and 8, and every 8 weeks thereafter. The primary outcome was safety, including all adverse events, at week 24. Primary safety outcome measures were summarised as frequencies, percentages, and exact Clopper-Pearson 95% CIs in the evaluable analysis population, which included participants who were treated exclusively with the regimen and either completed all scheduled treatments or experienced severe adverse events, permanently discontinued the treatment, or died, whichever occurred first; and in the all-treated analysis population, which included all participants who received at least one dose of any study product. This study is registered with ClinicalTrials.gov (NCT3497676) and is ongoing. Between July 26, 2021, and Aug 27, 2022, 44 (80·0%) of 55 adolescents who participated in cohort 1 and 100 (87·0%) of 115 screened study-naive adolescents were enrolled in cohort 2. 74 (51·4%) participants were female and 70 (48·6%) were male. Overall, 15 (10·8% [95% CI 6·2-17·2]) of all 139 participants in the evaluable analysis population had at least one adverse event of grade 3 or above by week 24. Among 142 participants who received at least one injection, 43 (30%) experienced at least one injection site reaction (ISR). All 106 ISRs were either grade 1 (98 [92·5%]) or grade 2 (eight [7·5%]), and 97 (91·5%) resolved within 7 days. No participant experienced a drug-related serious adverse event or prematurely discontinued treatment due to a drug-related adverse event. Long-acting injectable cabotegravir and long-acting injectable rilpivirine, administered to adolescents at recommended adult dosages every 8 weeks, showed no unanticipated safety concerns in the 24 weeks following administration. National Institutes of Health, ViiV Healthcare, and Johnson & Johnson.

Moore CB ，Baltrusaitis K ，Best BM ，Moye JH ，Townley E ，Violari A ，Heckman B ，Buisson S ，Van Solingen-Ristea RM ，Capparelli EV ，Marzinke MA ，Lowenthal ED ，Ward S ，Krotje C ，Milligan R ，Agwu AL ，Huang J ，Cheung SYA ，McCoig C ，Yin DE ，Roberts G ，Crauwels H ，Van Eygen V ，Zabih S ，Masheto G ，Ounchanum P ，Aurpibul L ，Korutaro V ，Gaur AH ，IMPAACT 2017 Collaborators for the IMPAACT 2017 Team ... -  《Lancet HIV》

Switch to long-acting cabotegravir and rilpivirine in virologically suppressed adults with HIV in Africa (CARES): week 48 results from a randomised, multicentre, open-label, non-inferiority trial.

Long-acting injectable cabotegravir and rilpivirine is licensed for individualised treatment of HIV-1 infection in resource-rich settings. Additional evidence is required to support use in African treatment programmes where demographic factors, viral subtypes, previous treatment, and delivery and monitoring approaches differ. The aim of this study was to determine whether switching to long-acting therapy with injections every 8 weeks is non-inferior to daily oral therapy in Africa. CARES is a randomised, open-label, non-inferiority trial being conducted at eight sites in Uganda, Kenya, and South Africa. Participants with HIV viral load below 50 copies per mL on oral antiretroviral therapy and no history of virological failure were randomly assigned (1:1; web-based, permuted blocks) to receive cabotegravir (600 mg) and rilpivirine (900 mg) by intramuscular injection every 8 weeks, or to continue oral therapy. Viral load was monitored every 24 weeks. The primary outcome was week 48 viral load below 50 copies per mL, assessed with the Food and Drug Administration snapshot algorithm (non-inferiority margin 10 percentage points) in the intention-to-treat exposed population. This trial is registered with the Pan African Clinical Trials Registry (202104874490818) and is ongoing up to 96 weeks. Between Sept 1, 2021, and Aug 31, 2022, we enrolled 512 participants (295 [58%] female; 380 [74%] previous non-nucleoside reverse transcriptase inhibitor exposure). Week 48 viral load was below 50 copies per mL in 246 (96%) of 255 participants in the long-acting therapy group and 250 (97%) of 257 in the oral therapy group (difference -0·8 percentage points; 95% CI -3·7 to 2·3), demonstrating non-inferiority (confirmed in per-protocol analysis). Two participants had virological failure in the long-acting therapy group, both with drug resistance; none had virological failure in the oral therapy group. Adverse events of grade 3 or greater severity occurred in 24 (9%) participants on long-acting therapy and ten (4%) on oral therapy; one participant discontinued long-acting therapy (for injection-site reaction). Long-acting therapy had non-inferior efficacy compared with oral therapy, with a good safety profile, and can be considered for African treatment programmes. Janssen.

Kityo C ，Mambule IK ，Musaazi J ，Sokhela S ，Mugerwa H ，Ategeka G ，Cresswell F ，Siika A ，Kosgei J ，Shah R ，Naidoo L ，Opiyo K ，Otike C ，Möller K ，Kaimal A ，Wambui C ，Van Eygen V ，Mohammed P ，Addo Boateng F ，Paton NI ，CARES trial team ... -  《-》