Long-Term Efficacy, Safety, and Durability of Cabotegravir and Rilpivirine as 2-Drug Oral Maintenance Therapy After 6 Years of Study.

Background: In the LATTE study, daily oral cabotegravir + rilpivirine demonstrated higher rates of efficacy than efavirenz + 2 nucleoside reverse-transcriptase inhibitors (NRTIs) through Week 96 in antiretroviral therapy (ART)-naive adults with human immunodeficiency virus (HIV)-1. We present the results from 6 years of continued treatment with oral cabotegravir + rilpivirine. Methods: LATTE was a phase IIb, randomized, multicenter, partially blinded, dose-ranging study in ART-naive adults with HIV-1. After a 24-week induction phase with cabotegravir + 2 NRTIs, participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL were randomized to receive cabotegravir (10, 30, or 60 mg) + rilpivirine (25 mg) in the maintenance phase through Week 96 and switched to cabotegravir 30 mg + rilpivirine 25 mg in the open-label phase through Week 312. Results: Of 160 participants who entered the maintenance phase, 111 completed the study at Week 312. At Week 312, 105 (66%) participants maintained HIV-1 RNA <50 copies/mL, 15 (9%) had HIV-1 RNA ≥50 copies/mL, and 40 (25%) had no virologic data. Eight participants met protocol-defined virologic failure criteria through Week 312, 2 of whom met protocol-defined virologic failure criteria after Week 144. Six participants developed treatment-emergent resistance to 1 or both agents during the study, 3 of whom developed integrase inhibitor resistance substitutions. Two participants (1%) reported drug-related serious adverse events. Few adverse events led to withdrawal during the open-label phase (n = 5, 3%). Conclusions: Oral cabotegravir + rilpivirine demonstrated efficacy in the majority of participants and an acceptable safety profile through 6 years of treatment, demonstrating its durability as maintenance therapy for HIV-1.

Satisfaction and acceptability of cabotegravir long-acting injectable suspension for prevention of HIV: Patient perspectives from the ECLAIR trial.

BACKGROUND: Cabotegravir (GSK1265744) is an integrase strand transfer inhibitor in development as a long-acting (LA) intramuscular injectable suspension for HIV-1 pre-exposure prophylaxis (PrEP). OBJECTIVE: We report participant outcomes from the phase IIa ECLAIR study related to tolerability, acceptability, and satisfaction of cabotegravir LA. METHODS: The ECLAIR study (ClinicalTrials.gov identifier, NCT02076178) was a randomized, placebo-controlled study in healthy men not at high risk of acquiring HIV-1. Participants were randomized (5:1) to once-daily oral cabotegravir 30 mg or placebo tablets for 4 weeks, followed by gluteal intramuscular injections of cabotegravir LA 800 mg or saline placebo every 12 weeks. The primary objective was to evaluate the safety of cabotegravir LA over three injection cycles (to Week 41). Secondary objectives assessed the tolerability, satisfaction, and acceptability of cabotegravir LA. RESULTS: Among 115 participants who received injections in the cabotegravir (n = 94) and placebo (n = 21) groups, 93% (n = 87) and 95% (n = 20) completed the injection phase, respectively. Injection intolerability led to withdrawal in 4 participants (4%) receiving cabotegravir LA. The most frequently reported Grade ≥2 adverse event was injection-site pain. Most participants (74% [n = 67]) receiving consecutive injections favored cabotegravir LA vs oral cabotegravir. Most participants were satisfied with cabotegravir LA (75% [n = 64]), were willing to continue (79% [n = 68]), and would recommend (87% [n = 75]) the therapy. CONCLUSIONS: While Grade ≥2 injection-site pain was common, most participants reported overall satisfaction with and preference for cabotegravir LA, with few discontinuations due to injection intolerance. These findings support investigation of cabotegravir LA as an alternative to daily oral PrEP regimens.

HIV prevention trial design in an era of effective pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) has demonstrated remarkable effectiveness protecting at-risk individuals from HIV-1 infection. Despite this record of effectiveness, concerns persist about the diminished protective effect observed in women compared with men and the influence of adherence and risk behaviors on effectiveness in targeted subpopulations. Furthermore, the high prophylactic efficacy of the first PrEP agent, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), presents challenges for demonstrating the efficacy of new candidates. Trials of new agents would typically require use of non-inferiority (NI) designs in which acceptable efficacy for an experimental agent is determined using pre-defined margins based on the efficacy of the proven active comparator (i.e. TDF/FTC) in placebo-controlled trials. Setting NI margins is a critical step in designing registrational studies. Under- or over-estimation of the margin can call into question the utility of the study in the registration package. The dependence on previous placebo-controlled trials introduces the same issues as external/historical controls. These issues will need to be addressed using trial design features such as re-estimated NI margins, enrichment strategies, run-in periods, crossover between study arms, and adaptive re-estimation of sample sizes. These measures and other innovations can help to ensure that new PrEP agents are made available to the public using stringent standards of evidence.

Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial.

BACKGROUND: Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection. METHODS: We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA. Healthy men (aged 18-65 years) deemed not at high risk of acquiring HIV-1 at screening were randomly assigned (5:1), via computer-generated central randomisation schedules, to receive cabotegravir or placebo. Participants received oral cabotegravir 30 mg tablets or matching placebo once daily during a 4 week oral lead-in phase, followed by a 1 week washout period and, after safety assessment, three intramuscular injections of long-acting cabotegravir 800 mg or saline placebo at 12 week intervals. Study site staff and participants were masked to treatment assignment from enrolment through week 41 (time of the last injection). The primary endpoint was safety and tolerability from the first injection (week 5) to 12 weeks after the last injection. We did analysis in the safety population, defined as all individuals enrolled in the study who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov identifier, NCT02076178. FINDINGS: Between March 27, 2014, and Feb 23, 2016, we randomly assigned 127 participants to receive cabotegravir (n=106) or placebo (n=21); 126 (99%) participants comprised the safety population. Most participants were men who have sex with men (MSM; n=106 [83%]) and white (n=71 [56%]). 87 (82%) participants in the cabotegravir group and 20 (95%) participants in the placebo group completed the injection phase. Adverse events (n=7 [7%]) and injection intolerability (n=4 [4%]) were the main reasons for withdrawal in the cabotegravir group. The frequency of grade 2 or higher adverse events was higher in participants in the long-acting cabotegravir group (n=75 [80%]) than in those in the placebo group (n=10 [48%]; p=0·0049), mostly due to injection-site pain (n=55 [59%]). No significant differences were noted in concomitant medications, laboratory abnormalities, electrocardiogram, and vital sign assessments. Geometric mean trough plasma concentrations were 0·302 µg/mL (95% CI 0·237-0·385), 0·331 µg/mL (0·253-0·435), and 0·387 µg/mL (0·296-0·505) for injections one, two, and three, respectively, indicating lower than predicted exposure. The geometric mean apparent terminal phase half-life estimated after the third injection was 40 days. Two (2%) MSM acquired HIV-1 infection, one in the placebo group during the injection phase and one in the cabotegravir group 24 weeks after the final injection when cabotegravir exposure was well below the protein-binding-adjusted 90% inhibitory concentration. INTERPRETATION: Despite high incidence of transient, mild-to-moderate injection-site reactions, long-acting cabotegravir was well tolerated with an acceptable safety profile. Pharmacokinetic data suggest that 800 mg administered every 12 weeks is a suboptimal regimen; alternative dosing strategies are being investigated. Our findings support further investigation of long-acting injectable cabotegravir as an alternative to orally administered pre-exposure prophylaxis regimens. FUNDING: ViiV Healthcare.

Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial.

BACKGROUND: In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. METHODS: In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01641809. FINDINGS: Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 [87%] of 60, 51 [85%] of 60, and 53 [87%] of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77-88) patients in the cabotegravir groups (48 [80%; 70-90], 48 [80%; 70-90], and 53 [87%; 78-95] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60-82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69-82) receiving cabotegravir (41 [68%; 57-80], 45 [75%; 64-86], and 51 [84%; 74-93] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51-75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 [47%], 32 [53%], and 33 [54%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one [2%], one [2%], and four [7%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group. INTERPRETATION: Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection. FUNDING: ViiV Healthcare and Janssen Research and Development.