Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

BACKGROUND: Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing. METHODS: ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing. FINDINGS: Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred. INTERPRETATION: The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1. FUNDING: ViiV Healthcare and Janssen.

Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression.

BACKGROUND: Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence. METHODS: In this phase 3, open-label, multicenter, noninferiority trial involving patients who had had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy, we randomly assigned participants (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, determined with the use of the Food and Drug Administration snapshot algorithm. RESULTS: Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group. CONCLUSIONS: Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal. (Funded by ViiV Healthcare and Janssen; ATLAS ClinicalTrials.gov number, NCT02951052.).

Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial.

IMPORTANCE: Patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are at high risk for liver disease progression. However, interferon-based treatments for HCV infection have significant toxicities, limiting treatment uptake. OBJECTIVE: To assess the all-oral 3 direct-acting antiviral (3D) regimen of ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), dasabuvir, and ribavirin in HCV genotype 1-infected adults with HIV-1 co-infection, including patients with cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: TURQUOISE-I is a randomized, open-label study. Part 1a of this pilot study was conducted at 17 sites in the United States and Puerto Rico between September 2013 and August 2014 and included 63 patients with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naive or had history of prior treatment failure with peginterferon plus ribavirin therapy. The study allowed enrollment of patients, including those with cirrhosis, with a CD4+ count of 200/mm3 or greater or CD4+ percentage of 14% or more and plasma HIV-1 RNA suppressed while taking a stable atazanavir- or raltegravir-inclusive antiretroviral regimen. INTERVENTIONS: Ombitasvir/paritaprevir/r, dasabuvir, and ribavirin for 12 or 24 weeks of treatment as randomized. MAIN OUTCOMES AND MEASURES: The primary assessment was the proportion of patients with sustained virologic response (HCV RNA <25 IU/mL) at posttreatment week 12 (SVR12). RESULTS: Among patients receiving 12 or 24 weeks of 3D and ribavirin, SVR12 was achieved by 29 of 31 (94%; 95% CI, 79%-98%) and 29 of 32 patients (91%; 95% CI, 76%-97%), respectively. Of the 5 patients who did not achieve SVR, 1 withdrew consent, 2 had confirmed virologic relapse or breakthrough, and 2 patients had clinical history and phylogenetic evidence consistent with HCV reinfection. The most common treatment-emergent adverse events were fatigue (48%), insomnia (19%), nausea (18%), and headache (16%). Adverse events were generally mild, with none reported as serious or leading to discontinuation. No patient had a confirmed HIV-1 breakthrough of 200 copies/mL or greater during treatment. CONCLUSIONS AND RELEVANCE: In this open-label, randomized uncontrolled study, treatment with the all-oral, interferon-free 3D-plus-ribavirin regimen resulted in high SVR rates among patients co-infected with HCV genotype 1 and HIV-1 whether treated for 12 or 24 weeks. Further phase 3 studies of this regimen are warranted in patients with co-infection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01939197.

Switch to Stribild versus continuation of NVP or RPV with FTC and TDF in virologically suppressed HIV adults: a STRATEGY-NNRTI subgroup analysis.

INTRODUCTION: Switch to Stribild (STB) was non-inferior to continuation of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir DF (FTC/TDF) at week 48 in virologically suppressed HIV adults (1). We report the Week 48 efficacy and safety of STB versus nevirapine (NVP) or rilpivirine (RPV) with FTC/TDF in suppressed subjects. MATERIALS AND METHODS: Virologically suppressed subjects on an NNRTI with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB versus continue their NNRTI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV-1 RNA <50 copies(c)/mL at Week 48 by FDA snapshot algorithm (12% non-inferiority margin). Subgroup analysis by non-EFV NNRTI use (NVP [74]; RPV [19]; etravirine [3]) at screening was pre-specified. RESULTS: The mITT population included 433 subjects who were randomized and treated. In the non-EFV NNRTI subgroup, 59 switched to STB; 37 continued a non-EFV NNRTI (27 NVP, 10 RPV) with FTC/TDF. At week 48, 97% STB versus 95% non-EFV NNRTI maintained HIV-1 RNA <50 c/mL. No emergent resistance was detected in either group. No difference in median increases from baseline in CD4 count at week 48 (cells/µL): 25 STB versus 55 non-EFV NNRTI (p=0.78). No discontinuation due to adverse events; no cases of proximal renal tubulopathy. As expected, there were no significant changes in the frequency of neuropsychiatric symptoms (i.e. anxiety, insomnia, dizziness, vivid dreams, weird/intense dreams, and nightmares) reported on the HIV Symptom Index at week 48 compared to baseline after switching to STB. There was a greater but non-progressive decrease from baseline in eGFR in the STB versus non-EFV NNRTI group; median changes (mL/min) at week 48: -9.1 versus -1.4. Switch to STB was associated with a higher treatment ease (convenience, flexibility, demand, lifestyle, understanding) score (range: -15 to 15) at week 4 (median: 14 vs 11; p=0.047) and week 24 (median: 14 vs 12.5; p=0.038). CONCLUSIONS: In this small group of virologically suppressed subjects, switch to STB vs continuation of NVP or RPV with FTC/TDF was safe, well-tolerated, and associated with a high rate of virologic suppression at week 48. There was more treatment ease with STB use.

Role of GB virus C in HIV-1-infected and hepatitis C virus-infected hemophiliac children and adolescents.

BACKGROUND: GB Virus C (GBV-C) has been associated with a better prognosis of HIV-1 disease in adults. Little is known about prevalence and interaction between GBV-C, HIV-1, and/or hepatitis C virus (HCV) in hemophiliac children and adolescents. METHODS: A well-characterized cohort of HIV-1-infected and HIV-1-uninfected hemophiliac children and adolescents followed in the Hemophilia Growth and Development Study (HGDS) were evaluated using quantitative reverse transcription polymerase chain reaction to detect GBV-C RNA in samples from baseline and last follow-up visit. RESULTS: HIV-1-infected (n = 202) and HIV-1-uninfected (n = 119) patients had a low prevalence of GBV-C infection at baseline (0.9 and 0%), which increased at time of last follow-up visit to 25.2% and 26.3%, respectively. In addition, at the time of the follow-up GBV-C measurement, those GBV-C infected had been followed longer and had higher CD4(+) cell counts and lower HIV-1 viral loads than those GBV-C uninfected. These beneficial effects of GBV-C were no longer significant after controlling for CD4(+) cell count and HIV-1 RNA at baseline. HCV RNA clearance was more common amongst those who were not GBV-C infected than those who became GBV-C viremic. CONCLUSIONS: This study confirms a positive association of GBV-C with milder course of HIV-1 infection. GBV-C infection was associated with a higher likelihood of persistent HCV infection.