Richard Elion

Ombitasvir, Paritaprevir Co-dosed With Ritonavir, Dasabuvir, and Ribavirin for Hepatitis C in Patients Co-infected With HIV-1: A Randomized Trial

IMPORTANCEnPatients 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.nnnOBJECTIVEnTo 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.nnnDESIGN, SETTING, AND PARTICIPANTSnTURQUOISE-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.nnnINTERVENTIONSnOmbitasvir/paritaprevir/r, dasabuvir, and ribavirin for 12 or 24 weeks of treatment as randomized.nnnMAIN OUTCOMES AND MEASURESnThe primary assessment was the proportion of patients with sustained virologic response (HCV RNA <25 IU/mL) at posttreatment week 12 (SVR12).nnnRESULTSnAmong 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.nnnCONCLUSIONS AND RELEVANCEnIn 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.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT01939197.

Weight loss as a predictor of survival and disease progression in HIV infection

Severe weight loss in HIV is associated with decreased length of survival. It is unclear whether mild weight loss is associated with an increased risk of death or opportunistic complications of HIV. Participants in four interventional studies (n = 2382) conducted by a community-based clinical trials network were evaluated for percentage change in weight during their first 4 months in the study. Proportional hazards models were performed for the occurrence of opportunistic complications and death subsequent to the 4-month visit. The relative risk of death and opportunistic complications for those with 5% to 10% weight loss over 4 months was 2.22 (p < .001) and 1.89 (p < .001), respectively, and 1.26 (p < .01) and 1.19 (p < .01) among those who lost 0% to 5% of their body weight, respectively, when compared with those with no weight loss. Among those who lost 5% to 10% of their body weight, the relative risk of individual opportunistic complications increased significantly, including Pneumocystis carinii pneumonia (PCP) (1.61; p < .01), cytomegalovirus (CMV) (2.33; p < .001), and Mycobacterium avium complex (MAC) (1.81; p < .01). As little as 5%t weight loss over a 4-month period is associated with increased risk of death and opportunistic complications in HIV. A weight loss of 5% to 10% is also associated with an increased risk of individual opportunistic complications.

Preexposure Prophylaxis for HIV Infection Integrated With Municipal- and Community-Based Sexual Health Services

IMPORTANCEnSeveral randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM).nnnOBJECTIVEnTo assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States.nnnDESIGN, SETTING, AND PARTICIPANTSnDemonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015.nnnINTERVENTIONSnA combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring.nnnMAIN OUTCOMES AND MEASURESnConcentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition.nnnRESULTSnOverall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with ≥4 doses/wk) at follow-up visits. African American participants (56.8% of visits; Pu2009=u2009.003) and those from the Miami site (65.1% of visits; Pu2009<u2009.001) were less likely to have protective levels, whereas those with stable housing (86.8%; Pu2009=u2009.02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; Pu2009=u2009.01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion.nnnCONCLUSIONS AND RELEVANCEnThe incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP.

Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: A randomized phase 2 study

Objectives:To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of a single-tablet regimen (STR) for the initial treatment of HIV-1 infection. Design:Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study. Methods:Antiretroviral naive adults with HIV-1 RNA ≥5000 copies per milliliter and a CD4 count ≥50 cells per microliter were randomized 2:1 to receive an STR of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo for 48 weeks. Results:Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates of virologic suppression (<50 HIV copies per milliliter) at week 24 (86.6%; 89.7%) and at week 48 (88.4%; 87.9%), and had similar improvements in CD4 at week 48 (177; 204), respectively. Both treatments were well tolerated, and most adverse events were self-limiting and of mild to moderate severity. Compared with patients on E/C/F/TDF, patients on E/C/F/TAF had smaller reductions in estimated creatinine clearance (−5.5 vs. −10.1 mL/min, P = 0.041), significantly less renal tubular proteinuria, and smaller changes in bone mineral density for hip (−0.62% vs. −2.39%, P < 0.001) and spine (−1.00% vs. −3.37%, P < 0.001). Patients on E/C/F/TAF had higher increases in total cholesterol, low-density lipoprotein, and high-density lipoprotein, but the total cholesterol/high-density lipoprotein ratio was unchanged for both. Conclusions:Treatment-naive patients given the STR that contained either TAF or TDF achieved a high rate of virologic success. Compared with those receiving TDF, patients on E/C/F/TAF experienced significantly smaller changes in estimated creatinine clearance, renal tubular proteinuria, and bone mineral density.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study

BACKGROUNDnAntiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate.nnnMETHODSnIn this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736.nnnFINDINGSnBetween April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6-6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group.nnnINTERPRETATIONnSwitching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes.nnnFUNDINGnGilead Sciences.

High interest in preexposure prophylaxis among men who have sex with men at risk for HIV infection: baseline data from the US PrEP demonstration project.

Background:Preexposure prophylaxis (PrEP) is the first biomedical intervention with proven efficacy to reduce HIV acquisition in men who have sex with men (MSM) and transgender women. Little is known about levels of interest and characteristics of individuals who elect to take PrEP in real-world clinical settings. Methods:The US PrEP Demonstration Project is a prospective open-label cohort study assessing PrEP delivery in municipal sexually transmitted disease clinics in San Francisco and Miami and a community health center in Washington, DC. HIV-uninfected MSM and transgender women seeking sexual health services at participating clinics were assessed for eligibility and offered up to 48 weeks of emtricitabine/tenofovir for PrEP. Predictors of enrollment were assessed using a multivariable Poisson regression model, and characteristics of enrolled participants are described. Results:Of 1069 clients assessed for participation, 921 were potentially eligible and 557 (60.5%) enrolled. In multivariable analyses, participants from Miami (adjusted Relative Risk [aRR]: 1.53; 95% confidence interval [CI]: 1.33 to 1.75) or DC (aRR: 1.33; 95% CI: 1.2 to 1.47), those who were self-referred (aRR: 1.48; 95% CI: 1.32 to 1.66), those with previous PrEP awareness (aRR: 1.56; 95% CI: 1.05 to 2.33), and those reporting >1 episode of anal sex with an HIV-infected partner in the last 12 months (aRR: 1.20; 95% CI: 1.09 to 1.33) were more likely to enroll. Almost all (98%) enrolled participants were MSM, and at baseline, 63.5% reported condomless receptive anal sex in the previous 3 months. Conclusions:Interest in PrEP is high among a diverse population of MSM at risk for HIV infection when offered in sexually transmitted disease and community health clinics.

Inflammatory biomarkers and abacavir use in the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study.

Objective:To assess associations between abacavir (ABC) use and systemic inflammation. Design:Nested case–control study. Methods:The Multicenter AIDS Cohort Study (MACS) and Womens Interagency HIV Study (WIHS) cohort participants who initiated ABC were matched, using propensity score methods, to ABC-unexposed persons. Levels of high-sensitivity C-reactive protein (hsCRP) (μg/ml), interleukin-6 (IL-6) (pg/ml), and D-dimer (μg/ml) were measured from pre-HAART and on-HAART plasma. Random-effects models compared markers by ABC exposure and by changes from pre-HAART levels. Results:Biomarkers were measured in N = 508 matched pairs (328 women; 180 men). Pre-HAART levels did not differ by exposure group except that hsCRP levels were higher among WIHS women who subsequently used ABC (P = 0.04). Regardless of ABC use, mean hsCRP increases and D-dimer reductions were seen when comparing pre-HAART to on-HAART levels, in the overall group (28 and −27%), for MACS men (28 and −31%) and for WIHS women [29 and −24%, P < 0.01 for all]; IL-6 levels declined in MACS men (P = 0.02). No adjusted biomarker level differences existed by ABC exposure at the on-HAART visit. HIV RNA reductions correlated with D-dimer (r = 0.14, P < 0.01) and IL-6 (r = 0.12, P < 0.01) reductions. Associations between ABC use and mean biomarker levels were modified by pre-HAART antiretroviral therapy experience. Renal dysfunction was equally likely among non-ABC and ABC recipients. Discussion:ABC use was not associated with plasma elevations in hsCRP, IL-6, and D-dimer. Mechanisms other than increased systemic inflammation may account for ABCs reported association with increased cardiovascular disease. HAART-associated reductions in D-dimer and IL-6 were apparent regardless of ABC use and were correlated with HIV RNA reductions.

Rilpivirine versus efavirenz in HIV-1-infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE Studies.

Abstract Objectives: Week 96 efficacy and safety of the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV) was compared to efavirenz (EFV) in subset of 1,096 subjects who received emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in pooled data from 2 phase 3 studies. Methods: ECHO and THRIVE are double-blind, double-dummy, randomized, active-controlled, non-inferiority phase 3 studies of RPV versus EFV plus 2 NRTIs in antiretroviral-naïve adult subjects. The primary and secondary endpoints were the proportion of subjects with HIV-1 RNA <50 copies/mL using an intent-to-treat, time to loss of virologic response (ITT-TLOVR) analysis at weeks 48 and 96, respectively. Safety, tolerability, immunologic response, adherence level, and other measures were also evaluated. Results: At week 48, noninferior efficacy of RPV+FTC/TDF over EFV+FTC/TDF was established, and at week 96 RPV+FTC/TDF remained noninferior (77% overall response rate in both groups). Through week 96, rates of virologic failure were higher in the RPV+FTC/TDF group, with low and similar rates of virologic failure and resistance mutations occurring during the second year of follow-up. Treatment with RPV+FTC/TDF was associated with a lower rate of discontinuation due to adverse events and grade 2–4 adverse events including dizziness, abnormal dreams/nightmares, rash, and lipid abnormalities. Conclusions: The pooled ECHO and THRIVE studies demonstrated noninferiority of RPV+FTC/TDF in achieving virologic response with safety and tolerability advantages over EFV+FTC/TDF through 96 weeks. Higher rates of virologic failure in the RPV+FTC/TDF group were balanced with higher rates of discontinuations due to adverse events in the EFV+FTC/TDF group.

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

BACKGROUNDnCabotegravir (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.nnnMETHODSnWe 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.nnnFINDINGSnBetween 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.nnnINTERPRETATIONnDespite 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.nnnFUNDINGnViiV Healthcare.

Once-Daily Abacavir/Lamivudine and Ritonavir-Boosted Atazanavir for the Treatment of HIV-1 Infection in Antiretroviral-Naïve Patients: A 48-Week Pilot Study

Abstract Purpose: To assess the efficacy and safety of a once-daily (QD) regimen consisting of the co-formulation of abacavir/lamivudine (ABC/3TC) and atazanavir plus ritonavir (ATV-RTV) in antiretroviral (ART)-naïve patients with plasma HIV-1 RNA >5,000 copies/mL. Method: This open-label, multicenter study conducted between September 2004 and June 2006 included 112 patients who received ABC 600 mg/3TC 300 mg and ATV 300 mg-RTV 100 mg QD. Drug switches were permitted for ABC hypersensitivity and ATV-related hyperbilirubinemia. Primary endpoints were proportion of patients achieving HIV-1 RNA <50 copies/mL at Week 48 and treatment discontinuation due to study drugs. Results: A total of 111 patients were treated. At Week 48, the proportion of patients achieving HIV-1 RNA <50 copies/mL was 77% (85/111) by intent-to-treat (ITT) missing=failure, switch included response rate. Drug substitutions occurred in 8 (7%) patients for suspected ABC hypersensitivity reaction (HSR) and in 6 (5%) patients for ATV-related toxicities; only 1 patient discontinued study due to ABC HSR. Four patients met confirmed virologic nonresponse (HIV RNA ⩾400 copies/mL). Treatment-emergent drug resistance was rare, and no patient had virus that developed reduced susceptibility to ATV. Median change from baseline (95% confidence interval) in fasting lipids at Week 48 was 39 (26–66) mg/dL for triglycerides, 28 (22–38) mg/dL for total cholesterol (C), 14 (10.5–16) mg/dL for HDL-C, and 8 (2–16.5) mg/dL for LDL-C. Conclusion: ABC/3TC and ATV-RTV QD is an effective and well-tolerated regimen in ART-naïve patients through 48 weeks, with a modest impact on fasting lipids.