Prior Virological Failure Research Articles

Efficacy and safety of dolutegravir/lamivudine in virologically suppressed female participants: week 48 data from the pooled TANGO and SALSA studies.

Women represent >50% of people with HIV globally but have historically been underrepresented in clinical trials. We evaluated the efficacy and safety of switching to dolutegravir/lamivudine (DTG/3TC) vs continuing their current antiretroviral regimen (CAR) by sex assigned at birth (female and male) in virologically suppressed adults with HIV-1 without prior virological failure in a pooled analysis of two randomized controlled trials. This analysis included 48-week data from the phase 3 TANGO and SALSA studies. Primary and key secondary endpoints included proportions of participants with HIV-1 RNA ≥50 and <50 copies/mL at week 48, respectively. Safety was also assessed. Of 1234 participants, 250 (DTG/3TC, n = 133; CAR, n = 117) were female at birth. Week 48 proportions of participants with Snapshot HIV-1 RNA ≥50 copies/mL were similar regardless of sex at birth (DTG/3TC vs CAR: female, <1% [1/133] vs 2% [2/117]; male, <1% [1/482] vs <1% [3/502]). Proportions with HIV-1 RNA <50 copies/mL were high across sexes and treatment groups (DTG/3TC vs CAR: female, 91% [121/133] vs 89% [104/117]; male, 94% [455/482] vs 94% [471/502]). Immunological response with DTG/3TC was slightly higher in female participants. Incidences of adverse events leading to withdrawal and serious adverse events were low and comparable between treatment groups and across sexes. Weight gain was higher with DTG/3TC than with CAR among female participants aged ≥50 years (treatment difference 2.08 kg [95% confidence interval 0.40-3.75]). Results confirm the robustness of DTG/3TC as a switch option in virologically suppressed females with HIV-1, with outcomes similar to those in males.

A Comprehensive Literature Review of Treatment-Emergent Integrase Resistance with Dolutegravir-Based Regimens in Real-World Settings.

After a decade of dolutegravir (DTG) use in various antiretroviral therapy combinations and in diverse populations globally, it is critical to identify HIV strains with reduced drug susceptibility and monitor emergent resistance in people living with HIV who experience virologic failure while on DTG-based regimens. We searched the PubMed, Embase, and Cochrane databases to identify studies that reported DTG resistance-associated mutations (RAMs) emerging under selection pressure. Our review showed that RAMs conferring resistance to DTG were rare in 2-drug and 3-drug regimens used in real-world cohorts, corroborating data from clinical trials. The potency of DTG in maintaining virologic suppression was demonstrated, even in cases of pre-existing resistance to companion drugs in the regimen. Estimates of DTG RAMs depended on the population and certain risk factors, including monotherapy, baseline resistance or lack of genotypic testing, treatment history and prior virologic failure, and suboptimal treatment adherence. The RAMs detected after virologic failure, often in heavily treatment-experienced individuals with prior exposure to integrase strand transfer inhibitors, were G118R, E138K, G140A/C/R/S, Q148H/K/R, N155H, and R263K. Overall, these data highlight the durable effectiveness and high barrier to resistance of DTG as part of combination antiretroviral therapy in a wide variety of settings.

900. Switching to DTG/3TC Fixed-Dose Combination (FDC) Is Non-inferior to Continuing a TAF-Based Regimen (TBR) in Maintaining Virologic Suppression Through 144 Weeks (TANGO Study)

BackgroundDTG/3TC is a complete 2-drug regimen (2DR) for the treatment of HIV-1 infection. Non-inferior virologic efficacy has been proven over 3 years in treatment-naive people living with HIV (PLWH) and 2 years in a stable switch setting. MethodsTANGO, a randomized, open-label, non-inferiority study, evaluates efficacy and safety of switching to DTG/3TC in PLWH who are virologically suppressed ( > 6 months, no prior virologic failure [VF], no major NRTI/INSTI resistance) vs remaining on a 3- or 4-drug TAF-based regimen (TBR), stratified by baseline 3rd agent class. Week 144 analyses assessed non-inferiority (NI) with a 4% NI margin for Snapshot virologic failure (VF) and 8% for virologic success (VS; FDA Snapshot algorithm, intention-to-treat–exposed [ITT-E] population).ResultsOf 741 randomized/exposed pts (DTG/3TC: 369; TBR: 372), most pts entered the study on EVG/c (66%). For Week 144 Snapshot VF, switching to DTG/3TC was non-inferior to continuing TBR in the ITT-E analysis: 0.3% vs 1.3%; adjusted difference (95% CI): −1.1% (−2.4%, 0.2%) and superior to TBR in the per-protocol analysis: 0% vs 1.1%; adjusted difference: −1.1% (−2.3, −0.0); P=0.044 (2-sided). Snapshot VS was high in both arms and demonstrated non-inferiority (Table). Zero pts on DTG/3TC and 3 (0.8%) on TBR met confirmed virologic withdrawal criteria with no resistance observed. Zero pts on DTG/3TC and 6 (1.6%) on TBR discontinued for lack of efficacy. Overall AE rates were similar between arms (Table). TC, LDL-C, and triglycerides improved with DTG/3TC, HDL-C improved with TBR, with no difference in TC/HDL-C ratio between arms. Changes in eGFR (cystatin C) and proximal tubular function marker were similar across arms. Adjusted mean change from BL in weight was 2.2 and 1.7 kg in the DTG/3TC and TBR arms, respectively, and proportion of pts with > 10% weight increase was similar across arms (13% and 12%, respectively).Table. Efficacy and Key Safety Results for the ITT-E and Safety Population ConclusionSwitching to the 2-drug regimen of DTG/3TC from a TAF-based 3- or 4-drug regimen resulted in high, non-inferior efficacy with zero confirmed virologic withdrawals and good tolerability over 3 years of treatment. DTG/3TC 2DR is a robust switch option with durable efficacy, good safety and tolerability, and a high barrier to resistance.Disclosures Olayemi Osiyemi, M.D, Gilead (Advisor or Review Panel member, Speaker’s Bureau)Merck (Advisor or Review Panel member)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Fiona Bisshop, MBBBS, Gilead (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Stéphane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Joaquín Portilla, MD, AbbVie (Other Financial or Material Support)Gilead (Grant/Research Support, Other Financial or Material Support)Janssen (Grant/Research Support, Other Financial or Material Support)Merck Sharpe & Dohme (Other Financial or Material Support)ViiV Healthcare (Grant/Research Support, Other Financial or Material Support) Jean-Pierre Routy, MD, FRCPC, ViiV Healthcare (Grant/Research Support) Mounir Ait-Khaled, PhD, ViiV Healthcare (Employee) Keith Pappa, PharmD, Glaxo Smith Kline (Shareholder)ViiV Healthcare (Employee) Ruolan Wang, Master of Science, ViiV Healthcare (Employee) Peter Leone, MD, viiv healthcare (Employee) Jonathan Wright, MSc, GlaxoSmithKline (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Michael Aboud, MBChB, MRCP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kimberly Smith, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Tenofovir disoproxil fumarate and emtricitabine maintenance strategy in virologically controlled adults with low HIV-1 DNA: 48 week results from a randomized, open-label, non-inferiority trial.

Low HIV reservoirs may be associated with viral suppression under a lower number of antiretroviral drugs. We investigated tenofovir disoproxil fumarate/emtricitabine as a maintenance strategy in people living with HIV (PLHIV) with low HIV-DNA. TRULIGHT (NCT02302547) was a multicentre, open-label, randomized trial comparing a simplification to tenofovir disoproxil fumarate/emtricitabine versus a triple regimen continuation (tenofovir disoproxil fumarate/emtricitabine with a third agent, control arm) in virologically suppressed adults with HIV-DNA <2.7 log10 copies/106 PBMCs and no prior virological failure (VF). The primary endpoint (non-inferiority margin 12%) was the percentage of participants with a plasma viral load (pVL) <50 copies/mL in ITT (Snapshot approach) and PP analyses at Week 48 (W48). Of the 326 participants screened, 223 (68%) were randomized to the tenofovir disoproxil fumarate/emtricitabine arm (n = 113) or control arm (n = 110). At W48, the tenofovir disoproxil fumarate/emtricitabine and control arms maintained a pVL < 50 copies/mL in 100/113 (88.5%) and 100/110 (90.9%) participants, respectively (ITT difference 2.4%, 95% CI -5.9 to 10.7; PP difference 3.4%, 95% CI -4.2 to 11.0). Six VFs occurred in the tenofovir disoproxil fumarate/emtricitabine arm (two with emerging mutations M184V and K65R) versus two in the control arm (ITT difference 3.5%, 95% CI -1.9 to 9.4). All VFs were resuppressed after treatment modification. Although non-inferiority was shown, simplification to tenofovir disoproxil fumarate/emtricitabine should not be used for most PLHIV because of a low risk of VF with resistance.

Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1

Background Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917). Objective To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (AMBER: viral load [VL], CD4+ count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance; EMERALD: prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent). Methods Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96. Efficacy endpoints were percentage cumulative confirmed VL ≥50 copies/mL (virologic rebound; EMERALD), and VL <50 (virologic response), or ≥50 copies/mL (VF) (FDA snapshot; both trials). Results D/C/F/TAF demonstrated high Week 96 virologic responses (AMBER: 85% [308/362]; EMERALD: 91% [692/763]) and low VF rates (AMBER: 6% [20/362]; EMERALD: 1% [9/763]). In EMERALD, D/C/F/TAF showed low virologic rebound cumulative through Week 96 (3% [24/763]). Results were consistent across subgroups, including prior antiretroviral experience in EMERALD. No darunavir, primary PI, or tenofovir resistance-associated mutations were observed post-baseline. Study-drug-related serious adverse events (AEs) and AE-related discontinuations were <1% and 2%, respectively (both D/C/F/TAF arms), and similar across subgroups. eGFRcyst and bone mineral density improved or were stable and lipids increased through Week 96 across demographic subgroups, with small changes in total-cholesterol/HDL-cholesterol ratio. Conclusions D/C/F/TAF was effective with a high barrier to resistance and bone/renal safety benefits, regardless of demographic or clinical characteristics for treatment-naïve and treatment-experienced, virologically-suppressed adults.

1046. Week 48 Outcomes from the BRAAVE 2020 Study: A Randomized Switch to B/F/TAF in African American Adults with HIV

BackgroundBlack Americans are disproportionately impacted by HIV. The BRAAVE 2020 study, evaluated the safety and efficacy of switching to the guidelines-recommended single-tablet regimen bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) in Black adults through week (W) 48.MethodsAdults with HIV who self-identified as Black or African American and were virologically suppressed on 2 NRTIs plus a 3rd agent were randomized (2:1) to switch to open-label B/F/TAF once daily or stay on their baseline regimen (SBR). Prior virologic failure was allowed except failure on an INSTI. Prior resistance to NNRTIs, PIs and/or NRTIs was permitted except K65R/E/N, ≥3 thymidine analog mutations or T69-insertions. Primary INSTI-resistance was excluded. SBR participants switched to B/F/TAF at W24. Efficacy was assessed at the W24 (1○ endpoint, noninferiority margin 6%) and at W48 as the proportion with HIV-1 RNA ≥ 50 c/mL by FDA Snapshot and by changes in CD4 count. Safety was assessed by adverse events (AE) and lab results.Results495 were randomized and treated (B/F/TAF n=330, SBR n=165): 32% cis women, 2% transgender women, median age 49 y (range 18-79), 10% had pre-existing M184V/I mutation (Table 1), and 62% lived in the US South. At W24, 1% (2/328) on B/F/TAF vs 2% (3/165) on SBR had HIV-1 RNA ≥50 c/mL (difference -1.2%; 95% CI -4.8% to 0.9%) demonstrating noninferiority of B/F/TAF; 2 with pre-existing primary INSTI resistance were excluded from analysis. 163 assigned to SBR completed W24 and switched to B/F/TAF (SBR to B/F/TAF). At W48 1% (3/328) originally randomized to B/F/TAF and 0 SBR to B/F/TAF had HIV-1 RNA ≥ 50 c/mL (Table 2). The presence of baseline NRTI resistance did not affect the efficacy of B/F/TAF. No treatment emergent resistance was detected. The mean (SD) changes in CD4 were +7 cells/mm3 (189) for B/F/TAF and -8 cells/mm3 (159) for SBR to B/F/TAF. Median (IQR) weight increased 0.9 kg (-1.5, 4.1) and 0.6 kg (-1.0, 3.1) for B/F/TAF and SBR to B/F/TAF groups, respectively. Study drug-related AEs occurred in 10% of participants while on B/F/TAF; most were grade 1.Table 1. Table 2. ConclusionSwitching to B/F/TAF was highly effective for Black adults regardless of baseline regimen or pre-existing NRTI resistance and was associated with few treatment related AEs or discontinuations.Disclosures Debbie Hagins, MD, Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)Janssen (Grant/Research Support)Merck (Consultant, Grant/Research Support, Advisor or Review Panel member)Viiv Healthcare (Consultant, Grant/Research Support, Advisor or Review Panel member) Princy Kumar, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Michael Saag, MD, Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator)Merck (Consultant, Grant/Research Support)Proteus (Grant/Research Support)Viiv Healthcare (Consultant, Grant/Research Support) Anson K. Wurapa, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)GlaxoSmithKline (Grant/Research Support)Janssen (Grant/Research Support, Advisor or Review Panel member)Pfizer (Grant/Research Support) Indira Brar, MD, Gilead (Speaker’s Bureau)janssen (Speaker’s Bureau)ViiV (Speaker’s Bureau) Daniel Berger, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Olayemi Osiyemi, M.D, GlaxoSmithKline (Advisor or Review Panel member, Speaker’s Bureau)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Corrilynn Hileman, MD, Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator) Moti Ramgopal, MD FACP FIDSA, AbbVie (Speaker’s Bureau)Allergan (Speaker’s Bureau)Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Speaker’s Bureau)Janssen (Speaker’s Bureau)Merck (Consultant)Viiv Healthcare (Consultant) Cheryl McDonald, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen (Grant/Research Support)Merck (Grant/Research Support, Speaker’s Bureau)Viiv Healthcare (Grant/Research Support) Christiana Blair, MS, Gilead Sciences (Employee, Shareholder) Kristen Andreatta, MSc, Gilead Sciences (Employee, Shareholder) Sean E. Collins, MD, MS, Gilead Sciences (Employee) Diana M. Brainard, MD, Gilead Sciences (Employee) Hal Martin, MD, MPH, Gilead Sciences Inc. (Employee, Shareholder)

Simplifying ARV Therapy in the Setting of Resistance.

HIV treatment simplification is typically indicated for virologically suppressed patients with no baseline resistance-associated mutations (RAMs) or prior virologic failure (VF) to the simplification regimen. Simplification can occur to minimize pill burden, toxicities, drug-drug interactions, or costs. As most studies for treatment simplification excluded patients with baseline RAMs or prior VF, this review is aimed to critically analyze data regarding treatment simplification in treatment-experienced patients. Antiretroviral (ARV) regimens containing three-, two-, and one-drug(s) have been scarcely studied to assess virologic efficacy in treatment-experienced patients. Three-drug regimens with the most data and highest efficacy are with integrase strand transfer inhibitors (INSTIs). Regimens including dolutegravir (DTG) and bictegravir have been shown to maintain efficacy in patients with certain baseline RAMs. Dual therapy regimens include the use of DTG plus either lamivudine (3TC), rilpivirine (RPV), or other ARVs. None of these studies evaluated patients with baseline DTG resistance. Baseline RAMs to 3TC were not a predictor of VF in patients on DTG/3TC. Efficacy was seen with DTG/RPV; however, studies showed high rates of discontinuation. DTG plus boosted-protease inhibitors were studied in smaller but promising studies. Two small studies assessed the use of monotherapy with boosted darunavir or DTG, both showing virologic efficacy. Currently, three- and two-drug ARV regimens may be considered in this population with most studies evaluating the use of DTG and bictegravir without baseline INSTI RAMs. Future studies should include heavily treatment-experienced patients with a variety of baseline RAMs and a larger sample size.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-experienced, virologically suppressed patients with HIV-1: subgroup analyses of the phase 3 EMERALD study

BackgroundDarunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a once-daily, single-tablet regimen for treatment of HIV-1 infection. The efficacy/safety of switching to D/C/F/TAF versus continuing boosted protease inhibitor (bPI) + emtricitabine/tenofovir disoproxil fumarate (control) were demonstrated in a phase 3, randomized study (EMERALD) of treatment-experienced, virologically suppressed adults through week 48. The objective of this analysis was to evaluate EMERALD outcomes across subgroups of patients based on demographic characteristics, prior treatment experience, and baseline antiretroviral regimen.MethodsEMERALD patients were virologically suppressed (viral load [VL] < 50 copies/mL for ≥ 2 months at screening). Prior non-darunavir virologic failure (VF) was allowed. Primary endpoint was proportion of patients with virologic rebound (confirmed VL ≥ 50 copies/mL) cumulative through week 48. Virologic response was VL < 50 copies/mL (FDA snapshot). Safety was assessed by adverse events, renal proteinuria markers, and bone mineral density. Outcomes were examined for prespecified subgroups by age (≤/> 50 years), gender, race (black/non-black), prior number of antiretrovirals used (4/5/6/7/> 7), prior VF (0/≥ 1), baseline bPI (darunavir/atazanavir or lopinavir), and baseline boosting agent (ritonavir/cobicistat).ResultsAmong 1141 patients in the D/C/F/TAF (n = 763) and control (n = 378) arms, virologic rebound rates (2.5% and 2.1%, respectively) were similar, and this was consistent across all subgroups. Virologic response rates ranged from 91 to 97% (D/C/F/TAF) and 89 to 99% (control) across all subgroups, with differences between treatment arms of 0 and 6%. Adverse event rates were low in both arms and across subgroups. Improvements in renal and bone parameters were observed with D/C/F/TAF across demographic subgroups.ConclusionsFor treatment-experienced, virologically suppressed patients, switching to D/C/F/TAF was highly effective and safe, regardless of demographic characteristics, prior treatment experience, or pre-switch bPI.Trial registration ClinicalTrials.gov Identifier: NCT02269917. Registered 21 October 2014. https://clinicaltrials.gov/ct2/show/NCT02269917

Evaluating cabotegravir/rilpivirine long-acting, injectable in the treatment of HIV infection: emerging data and therapeutic potential.

Cabotegravir and rilpivirine long-acting injectable antiretroviral therapy for the treatment of HIV-1 infection brings promise of a new mode of delivery and potential solutions to some problems of oral therapy, but also new challenges and unanswered questions. Adding to the increasing body of evidence for newer two-drug combinations, phase II and phase III trial data to date demonstrate cabotegravir and rilpivirine combination injectable therapy to be non-inferior to selected oral triple-therapy alternatives. Most importantly, this therapy is reported to be acceptable to individuals taking the 4-weekly or 8-weekly injections, despite frequent injection-site reactions. Key outstanding questions include management of missed or delayed dosing, drug interactions and management of virological failure, as well as the efficacy of cabotegravir and rilpivirine in all HIV-1 subtypes. We describe clinical evidence to date and efficacy and challenges in selected populations, including women; those with prior virological failure; individuals with a history of difficulty adhering to oral therapy and individuals with co-infections. We await real-world data and longer-term evidence while moving forward to this new era of antiretroviral therapy.

1766. Sustained Viral Suppression with Dolutegravir and Boosted Darunavir Dual Therapy Among Highly Treatment-Experienced Individuals

BackgroundThe use of antiretroviral (ARV) dual therapy for treatment of HIV is increasing; raltegravir with boosted darunavir (bDRV) is recommended in certain clinical situations in DHHS guidelines. Dolutegravir (DTG) with bDRV has not been widely studied. We sought to determine the effectiveness of DTG/bDRV in treatment experienced patients.MethodsThis retrospective cohort study evaluated viral suppression in patients prescribed DTG/bDRV dual therapy within a large urban health system. Data collected included demographics, cumulative ARV exposure, reasons for use, regimen start/stop dates, and viral suppression (HIV-RNA ≤200). Follow-up was defined as the number of days from start of regimen until last HIV-RNA determination on the study regimen.ResultsFrom January 1, 2013 to December 31, 2017, 60 patients received DTG/bDRV dual therapy: 15% were female, median age was 56, 83% were ≥3 class ARV-experienced, and median time since starting ARVs was 20 years. Median follow-up on DTG/bDRV was 444 days (IQR 273–808). Viral suppression was achieved by 59 of 60 (98%) patients at some point on DTG/bDRV. When stratified by baseline viral suppression, 46 of 46 (100%) who had baseline viral suppression maintained viral suppression in comparison to 11 of 14 (79%) without baseline viral suppression (table). The most common reasons for DTG/bDRV were simplification in setting of prior resistance (47%), toxicity reduction (39%), and virologic failure (15%). At study end, 53 of 60 (88%) were still on DTG/bDRV and the most common reason for stopping was drug interactions.ConclusionIn a highly treatment-experienced cohort of patients, DTG/bDRV dual therapy demonstrated sustained rates of viral suppression, even in those who were failing therapy prior to initiating the regimen. Further study of this potent, simple, high-barrier dual class regimen is warranted.Table:Virologic OutcomesNFollow-up Days, Median (IQR)HIV-RNA Evera ≤200 cp/mLLastb HIV-RNA ≤200 cp/mLOverall60444 (273,808)59 (98%)57 (95%)Baseline HIV-RNA suppressed46423 (268,817)46 (100%)46 (100%)Baseline HIV-RNA not suppressed14613 (392,743)13 (93%)11 (79%)IQR, interquartile range. aEver refers to achieving suppression at any point while on DTG/bDRV. bLast refers to the last recorded HIV-RNA value while on DTG/bDRV.Disclosures S. Rowan, Gilead Sciences: Investigator, Research grant. S. C. Johnson, Viiv Healthcare: Scientific Advisor, Consulting fee.

Incidence of Postsuppression Virologic Rebound in Perinatally HIV-Infected Asian Adolescents on Stable Combination Antiretroviral Therapy

PurposeTo assess the incidence and predictors of postsuppression virologic rebound (VR) among adolescents on stable combination antiretroviral therapy in Asia. MethodsPerinatally HIV-infected Asian adolescents (10–19 years) with documented virologic suppression (two consecutive viral loads [VLs] <400 copies/mL ≥6 months apart) were included. Baseline was the date of the first VL <400 copies/mL at age ≥10 years or the 10th birthday for those with prior suppression. Cox proportional hazards models were used to identify predictors of postsuppression VR (VL >1,000 copies/mL). ResultsOf 1,379 eligible adolescents, 47% were males. At baseline, 22% were receiving protease inhibitor–containing regimens; median CD4 cell count (interquartile range [IQR]) was 685 (448–937) cells/mm3; 2% had preadolescent virologic failure (VF) before subsequent suppression. During adolescence, 180 individuals (13%) experienced postsuppression VR at a rate of 3.4 (95% confidence interval: 2.9–3.9) per 100 person-years, which was consistent over time. Median time to VR during adolescence (IQR) was 3.3 (2.1–4.8) years. Wasting (weight-for-age z-score <−2.5), being raised by grandparents, receiving second-line protease inhibitor–based regimens, starting combination antiretroviral therapy after 2005, and having preadolescent VF were independent predictors of adolescent VR. At VR, median age, CD4 cell count, and VL (IQR) were 14.8 (13.2–16.4) years, 507 (325–723) cells/mm3, and 4.1 (3.5–4.7) log10 copies/mL, respectively. ConclusionsA modest and consistent incidence of postsuppression VR was documented during adolescence in our cohort. Having poor weight, receiving second-line regimens, and prior VF were associated with an increased VR rate. Adolescents at higher risk of VR may benefit from more intensive VL monitoring to enhance adherence management.

Dual Raltegravir-Etravirine Combination as Maintenance Regimen in Virologically Suppressed HIV-1-Infected Patients.

Nucleoside reverse transcriptase inhibitor (NRTI)- and protease inhibitor (PI)-sparing antiretroviral regimens may be useful in selected human immune deficiency virus (HIV)-infected patients with resistance or intolerance to these drug classes. This was an observational prospective study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted PI who switched to a dual regimen containing raltegravir plus etravirine. Patients were required not to have prior virological failure to raltegravir and to have efficacy of etravirine shown through the genotypic resistance assay in case of prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure. As a whole, 38 patients were enrolled. The mean duration of current regimen was 4.3 years, and the reason for simplification was toxicity in 29 patients and resistance to NRTIs in 9 patients. After switching, the percentage of patients with HIV RNA <20 copies/ml at week 48 was 81.6% in the intent-to-treat-exposed analysis. The switch led to a significant reduction in the mean serum triglyceride levels (-81.2 mg/dl), in the mean total cholesterol levels (-44.3 mg/dl), and in the prevalence of tubular proteinuria (-30.2%), with a significant increase in the mean phosphoremia (+0.52 mg/dl) and in both mean lumbar and femoral neck bone mineral density (+6.5% and +4.7%, respectively). Two patients (5.2%) had virological failure due to suboptimal adherence, and five subjects (13.1%) discontinued treatment due to adverse events. In our study, simplification to the dual-therapy raltegravir plus etravirine was associated with a good efficacy and tolerability, in addition to a favorable effect on kidney, bone, and serum lipids.

Pharmacokinetics of Unboosted Atazanavir in Treatment-experienced HIV-infected Children, Adolescents and Young Adults.

HIV protease inhibitor use in pediatrics is challenging due to the poor palatability and/or toxicity of concomitant low-dose ritonavir. Atazanavir without ritonavir (unboosted) is not recommended for patients with prior virologic failure, a common problem for perinatally-infected adolescents. Atazanavir 400 mg once-daily provided suboptimal exposure. Higher unboosted doses or splitting the daily dose to twice-daily warrants investigation in this treatment-experienced population.

Characteristics associated with virologic failure in high-risk HIV-positive participants with prior failure: a post hoc analysis of ACTG 5251

Patients with prior virologic failure (VF) are at an increased risk of subsequent failure, emergence of resistance, and death. This analysis identifies outcomes and correlates of VF in a high-risk population.Methods: A5251 was designed to evaluate an enhanced adherence counseling intervention delivered by nurses from a central call site on virologic suppression. Due to slow enrollment, the study was closed prematurely and revised study endpoints were evaluated (week 24 VF (HIV-1 RNA ≥200 copies/ml) and non-perfect adherence (<100% self-reported using both the ACTG adherence questionnaire and visual analog scale (VAS)).Results: Fifty-nine participants were enrolled, 43 (73%) black non-Hispanic and 23 (39%) women. Median prior antiretroviral regimen changes were three and the co-morbidity in this population was higher than typical for HIV clinical trials. At week 24 (n = 41), 24 (59%) failed to reach virologic suppression (HIV-1 RNA <200 copies/ml) and 25 (63%) reported non-perfect adherence. Higher depression (CES-D10) and adverse illness perceptions (IPQ-B) were associated with week 24 non-adherence. Early clinical assessments (week 12 HIV-RNA ≥200 copies/mL and non-perfect adherence) as well as higher depression and adverse illness perceptions were associated with week 24 VF.Discussion: In this high-risk population, the proportion of participants with suboptimal adherence and VF was unacceptably high. Interventions to address this treatment gap are clearly needed. Depression and a higher illness perception score, failure to achieve virologic suppression by week 12, and less than perfect adherence could be used to target individuals for early interventions in treatment-experienced, high-risk individuals at high risk for VF.

Withdrawing inactive NRTIs in HIV-1 subjects with suppressed viraemia: a randomized trial.

Extensively pretreated subjects with virological failure (VF) may receive salvage regimens containing NRTIs with only residual or no activity. Once virological suppression is achieved, their contribution remains elusive. This was a multicentre, randomized, prospective study. Subjects with at least one prior VF, HIV-1 RNA <50 copies/mL for ≥6 months and receiving a regimen with at least two active drugs (one of them a boosted PI) were randomized 1:1 to stop (experimental arm) or maintain (control arm) NRTIs. EudraCT: 2012-000198-21. Ninety subjects were randomized (experimental, n = 45; and control, n = 45). The mean age was 50 years, 80% were male, the mean CD4+ cell count was 542 cells/mm(3) and the median number of prior VFs was 3. Seventy-four subjects (82%) harboured the mutation M184V/I and the median number of thymidine-associated mutations was 3 (IQR: 0-4). In the experimental arm, thirty-two (71%) subjects removed one NRTI and 13 (29%) subjects removed two. Twenty-two of 45 (49%) discontinued tenofovir disoproxil fumarate. Forty-one of 45 (91.1%, experimental arm) and 44 of 45 (97.8%, control arm) had HIV-1 RNA <50 copies/mL at 48 weeks (difference: -6.7%; 95% CI: -17.4, 4.1). In a post-hoc analysis allowing NRTI reintroduction, efficacy rates were 95.6% and 97.8%, respectively (difference: -2.2%; 95% CI: -7.2, 2.7). Rates of discontinuation at 48 weeks were 2% in both arms. One subject developed a late VF with resistance selection. In patients receiving a successful multidrug salvage regimen with at least two active drugs (one a boosted PI), the withdrawal of inactive NRTIs was safe, rates of VF were low and drug resistance was uncommon at 48 weeks in this small study. This strategy could potentially prevent long-term toxicities, reduce the number of drugs and reduce costs if non-inferiority was met in a fully powered trial.

Emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen in HIV-1 infection: a guide to its use in the EU

Emtricitabine/rilpivirine/tenofovir disoproxil fumarate (tenofovir DF) [Eviplera® (EU); Complera® (USA)] is a convenient and effective addition to the other single-tablet regimens currently available for the treatment of HIV-1 infection. Once-daily emtricitabine/rilpivirine/tenofovir DF was noninferior to once-daily emtricitabine/efavirenz/tenofovir DF in establishing virological suppression in treatment-naive adults. Switching to the once-daily single tablet maintained virological suppression and was noninferior to remaining on a more complex multiple-tablet regimen in treatment-experienced patients already virologically suppressed with an antiretroviral regimen and without prior virological failure. Emtricitabine/rilpivirine/tenofovir DF was generally well tolerated, with a more favourable overall tolerability profile than emtricitabine/efavirenz/tenofovir DF.

Efficacy and safety of a switch to rilpivirine-based regimens in treatment-experienced HIV-1-infected patients: a cohort study.

Rilpivirine (RPV) is a second-generation once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) which has shown non-inferior antiviral activity to efavirenz in treatment-naive patients. Data in treatment-experienced patients are more limited. We wished to assess the efficacy and safety of a switch to RPV-based regimens in well-suppressed treatment-experienced patients. Between September 2012 and June 2013, all antiretroviral therapy (ART)-experienced HIV-1-infected patients with a plasma HIV RNA level <50 copies/ml, and switching to an RPV-based regimen, were analysed in this retrospective observational monocentric cohort study. The primary end point was the proportion of patients with virological success defined as a plasma HIV RNA level <50 copies/ml at 12 months using the FDA snapshot algorithm. A total of 281 participants were studied and 97% received a combination of RPV/tenofovir disoproxil fumarate/emtricitabine. At month 12, the rate of virological success was 59% and increased to 72% using available data beyond month 12. Sixteen (6%) patients experienced virological failure, which was associated with the presence of the M184V/I resistance mutation in prior genotypes (P=0.02) and the use of a non-NNRTI as third agent before the switch (P=0.03). RPV-based regimens were overall well tolerated and only 23 (8%) patients discontinued ART because of adverse events, mostly neuropsychiatric adverse events. Switching to RPV was associated with significant but modest improvement of the lipid profile. In patients fully suppressed on ART, a switch to an RPV-based regimen should only be considered in the absence of prior virological failure or resistance mutations to nucleoside reverse transcriptase inhibitors and NNRTIs to avoid virological failures.

Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent

The Phase-2 C-SALVAGE study evaluated an investigational interferon-free combination of grazoprevir (a NS3/4A protease inhibitor) and elbasvir (a NS5A inhibitor) with ribavirin for patients with chronic HCV genotype-1 infection who had failed licensed DAA-containing therapy. C-SALVAGE was an open-label study of grazoprevir 100 mg and elbasvir 50 mg QD with weight-based ribavirin BID for 12 weeks in cirrhotic and non-cirrhotic patients with chronic HCV genotype-1 infection who had not attained SVR after ⩾4 weeks of peginterferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Exclusion criteria included decompensated liver disease, hepatocellular carcinoma, and HIV or HBV co-infection. The primary efficacy outcome was SVR12 defined as a HCV RNA level below the assay limit of quantification 12 weeks after the end of treatment. Of the 79 patients treated with ⩾1 dose of study drug, 66 (84%) patients had a history of virologic failure on a regimen containing a NS3/4A protease inhibitor; 12 of the other 13 patients discontinued prior treatment because of adverse experiences. At entry, 34 (43.6%) of 78 evaluable patients harbored NS3 RAVs. SVR12 rates were 76/79 (96.2%) overall, including 28/30 (93.3%) patients with genotype 1a infection, 63/66 (95.5%) patients with prior virologic failure, 43/43 (100%) patients without baseline RAVs, 31/34 (91.2%) patients with baseline NS3 RAVs, 6/8 (75.0%) patients with baseline NS5A RAVs, 4/6 (66.7%) patients with both baseline NS3 and RAVs, and 32/34 (94.1%) cirrhotic patients. None of the five reported serious adverse events were considered drug-related. Grazoprevir and elbasvir plus ribavirin for 12 weeks provides a promising new treatment option for patients after failure of triple therapy containing an earlier-generation protease inhibitor.

Perfil de resistencias y barrera genética de dolutegravir

The resistance profile of dolutegravir differs significantly from those of earlier integrase inhibitors (INI). Dolutegravir displays in vitro activity against mutant HIV-1 harboring any isolated resistance mutations selected during failures to raltegravir or elvitegravir (Y143C/H/, N155H, Q148H/K/R, E92G/Q, T66A/I/K, T97A, E138A/K, G140A/S). Its activity is only compromised by Q148X mutations combined with other mutations, particularly > 1 mutation. The drug has pharmacokinetic/pharmacodynamic properties (plasmatic t1/2 15.3 h, inhibitory quotient 19, dissociative t1/2 from the IN-DNA complex 71 h) that favor a high genetic barrier to resistance. In vitro the selection of HIV-1 resistance to dolutegravir is extremely difficult to achieve. The mutations eventually selected (R263K, H51Y and E138K) do not confer significant resistance, and induce a fitness cost that prevents HIV-1 from evading drug pressure. Suprisingly, HIV-1 is not able to compensate, leading the virus to a previously unnoticed evolutionary pathway with very low chances of developing resistance to INI or the backbone. No treatment-naïve patients starting dolutegravir therapy (+TDF/FTC o ABC/3TC) have selected resistance in IN or against the backbone. No INI- naïve patients with prior virologic failure selected phenotypic dolutegravir resistance. Only 4 out of 354 patients selected resistance mutations in IN, and rates of selection of mutations in IN or against the backbone were significantly lower than with raltegravir. In multitreated patients with widespread resistance including IN resistance, the high efficacy of dolutegravir was confirmed, irrespective of the previous pattern of IN mutations, provided that Q148X associated with other mutations was absent.

Efficacy and pharmacokinetics of the combination of etravirine plus raltegravir as novel dual antiretroviral maintenance regimen in HIV-infected patients

Novel combination antiretroviral regimens may be needed for selected HIV-infected patients with toxicity or resistance. We evaluated prospectively 25 virologically suppressed patients, largely pretreated (15.6years on therapy) with antiretroviral drug toxicity (n=19) or interactions (n=9, mainly with chemotherapy against non-Hodgkin lymphoma or anti-HCV therapy), who switched to a dual therapy with etravirine (ETR) plus raltegravir (RAL). Patients were required not to have prior virological failure or resistance to both drugs. After a median follow up of 722days (473–1088: 53.3 patients-year), there were no cases of transient virological replication or failure. Only 1 patient left therapy at day 10 due to a grade 2 rash, and therefore efficacy by intent-to-treat analysis was 96% at 48weeks. There were no cases of liver toxicity grade 3–4, and total cholesterol (TC) and triglycerides (TG) levels decrease significantly after initiation (TC, −17mg/dl; p=0.01; TG, −42mg/dl; p=0.01), as well as the TC/High density lipoprotein-cholesterol ratio (from 4.35 to 4.28). Geometric mean plasma trough level of RAL was 166ng/ml (IQR, 40–249), well above the inhibitory concentration 90 (IC90). In conclusion, a novel dual therapy with ETR plus RAL is effective and well tolerated, and it could be an option to maintain durable viral suppression in hard-to-treat HIV-infected patients.