OBJECTIVES:Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is an effective treatment for HIV-1 infection; however, clinical trial data in older people living with HIV (PLWH) are lacking. The primary 24-week and secondary 48-week analyses of study GS-US-380-4449 (NCT03405935), which assessed the efficacy and safety of switching to B/F/TAF in older PLWH, have been published. Here we report the results of the final 96-week analyses from the study.METHODS:In this 96-week, phase 3b, open-label, single-arm trial, virologically suppressed PLWH aged ≥65 years switched from elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or a tenofovir disoproxil fumarate-based regimen to B/F/TAF. Viral suppression, resistance, immune response, safety, tolerability and adherence were evaluated through week 96.RESULTS:Of 90 participants screened, 86 were enrolled and switched to B/F/TAF. No participants had HIV-1 RNA ≥50 copies/ml (by FDA Snapshot algorithm) at weeks 72 or 96; virologic suppression rates were 94.2% (81/86; 95% CI 87.0-98.1) and 74.4% (64/86; 95% CI 63.9-83.2), respectively. No treatment-emergent resistance was observed, and CD4 counts remained stable. There were no study drug-related serious adverse events. Three participants experienced drug-related treatment-emergent adverse events that led to premature drug discontinuation. There were no clinically relevant changes from baseline to week 96 in fasting lipid parameters, and the median change in body weight at week 96 was 0.0 kg (IQR -2.3, 2.0). Median self-reported adherence was 100% (IQR 100-100%).CONCLUSIONS:Switching to B/F/TAF is an effective long-term option for virologically suppressed adults ≥65 years of age, with favourable safety and tolerability profiles in this population.

We report the 48-week results of an ongoing study to assess the efficacy and safety of switching older people with HIV to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). This was a 96-week, phase 3b, open-label, single-arm study (GS-US-380-4449; NCT03405935). Virologically suppressed individuals aged ≥ 65 years receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or a tenofovir disoproxil fumarate-based regimen were switched to B/F/TAF. Primary endpoint was the percentage of participants with HIV-1 RNA < 50 copies/ml at week 24. Eighty-six participants (median age 69 [range 65–80] years; 87% male; 95% white) were enrolled and treated in five European countries. Rates of virologic suppression were 97.7% at week 24 and 90.7% at week 48; none had HIV-1 RNA ≥ 50 copies/ml, and 100% had virologic suppression by missing = excluded analysis at both time points. No treatment-emergent resistance was observed. There were no grade 3–4 study drug-related adverse events (AEs) or study drug-related serious AEs or deaths. Three AEs led to premature discontinuation; one (moderate abdominal discomfort) was attributed to the study drug by the investigator. At week 48, median changes from baseline in weight and estimated glomerular filtration rate were + 0.1 kg (interquartile range [IQR] − 1.0, 2.3) and − 6.0 ml/min (IQR − 10.2, 0.0), respectively. There were no clinically relevant changes from baseline to week 48 in fasting lipid parameters. Treatment satisfaction improved, and health-related quality of life was maintained from baseline through week 48. Median adherence to the study drug was 98.6% (IQR 96.0, 100). Switching to B/F/TAF was effective and well tolerated through 48 weeks in virologically suppressed adults aged ≥ 65 years. ClinicalTrials.gov identifier, NCT03405935.

Background: The ability of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) to maintain virologic suppression in participants with M184V and/or M184I resistance mutations from historical genotypic reports when switching from a tenofovir disoproxil fumarate–based or abacavir (ABC)-based regimen was investigated. Setting: Phase IIIb, 48-week, open-label, single-arm, multicenter, clinical trial (NCT02616029). Methods: Virologically suppressed adults with HIV and documented M184V/I on historical genotypic records switched to E/C/F/TAF from a tenofovir disoproxil fumarate–based or ABC-based regimen. The primary end point was HIV-1 RNA of <50 copies per milliliter at week 12 using pure virologic response (PVR). Secondary end points included HIV-1 RNA of <50 copies per milliliter at weeks 24/48 (PVR) and at weeks 12, 24, and 48 (Food and Drug Administration snapshot algorithm), and change in CD4+ count at weeks 12, 24, and 48. Results: M184V alone was reported in 82.8% of 64 participants; 9.4% and 7.8% had M184I and M184V/I, respectively, and 43.8% had archived M184V/I (baseline DNA). All (62/62 with available data, 100%, 95% confidence interval 94.2% to 100%) participants maintained PVR at weeks 12, 24, and 48. By Food and Drug Administration snapshot algorithm, one participant had HIV-1 RNA of ≥50 copies per milliliter (week 12); confirmatory HIV-1 RNA was <50 copies per milliliter. No significant changes were observed in CD4+ cell count. Drug-related adverse events (AEs) were reported by 10 (15.6%) participants. Six (9.4%) and 5 (7.8%) participants had grade 3–4 AEs or serious AEs, respectively (none drug related). Conclusions: The presence of the resistance mutations M184V/I did not jeopardize the efficacy of switching to E/C/F/TAF in virologically suppressed adults. High rates of virologic suppression were maintained throughout 48 weeks of therapy and treatment was well tolerated.

INTRODUCTION:Guidelines advocate the treatment of HCV in all HIV/HCV co-infected individuals. The aim of this randomized, open-label study (ClinicalTrials.gov identifier: NCT02707601; https://clinicaltrials.gov/ct2/show/NCT02707601) was to evaluate the safety/efficacy of ledipasvir/sofosbuvir (LDV/SOF) co-administered with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/F/TAF (R/F/TAF) in HIV-1/HCV co-infected participants.METHODS:Participants with HIV-1 RNA <50 copies/mL and chronic HCV-genotype (GT) 1 (HCV treatment-naïve ± compensated cirrhosis or HCV treatment-experienced non-cirrhotic) were randomized 1:1 to switch to E/C/F/TAF or R/F/TAF. If HIV suppression was maintained at Week 8, participants received 12 weeks of LDV/SOF. The primary endpoint was sustained HCV virologic response 12 weeks after LDV/SOF completion (SVR12).RESULTS:Of 150 participants, 148 received ≥1 dose of HIV study drug and 144 received LDV/SOF (72 in each F/TAF group; 83% GT1a, 94% HCV treatment-naïve, 12% cirrhotic). Overall, SVR12 was 97% (95% confidence interval: 93-99%). Black race did not affect SVR12. Of four participants not achieving SVR12, one had HCV relapse, one had HCV virologic non-response due to non-adherence, and two missed the post-HCV Week 12 visit. Of 148 participants, 96% receiving E/C/F/TAF and 95% receiving R/F/TAF maintained HIV suppression at Week 24; no HIV resistance was detected. No participant discontinued LDV/SOF or E/C/F/TAF due to adverse events; one participant discontinued R/F/TAF due to worsening of pre-existing hypercholesterolemia. Renal toxicity was not observed in either F/TAF regimen during LDV/SOF co-administration. In conclusion, high rates of HCV SVR12 and maintenance of HIV suppression were achieved with LDV/SOF and F/TAF-based regimens.CONCLUSION:This study supports LDV/SOF co-administered with an F/TAF-based regimen in HIV-1/HCV-GT1 co-infected patients.

In general, HIV-negative men who have sex with men (MSM) have been considered to be at low risk for hepatitis C virus (HCV) infection.1, 2 HIV-negative MSM who access pre-exposure prophylaxis (PrEP) have reported sexual behaviours that could place them at high risk of HCV, including high partner numbers, chemsex and injecting drug use.3, 4 Early diagnosis of HCV infection allows early linkage to treatment and care, and reduction in onward transmission of infection.5 Data from European PrEP trials and cohort studies of PrEP users have reported high baseline HCV prevalence and incidence during follow-up.6-8 In contrast, studies from North America have generally found low levels of HCV endemicity among PrEP users.9-11 The PROUD study was an open-label trial of HIV PrEP among 544 HIV-negative MSM.12, 13 As there were no data on HCV incidence in HIV-negative MSM using PrEP in the UK, we implemented routine quarterly screening during the long-term follow-up phase when all participants had access to PrEP. We report HCV prevalence and incidence among participants in the PROUD study. PROUD was an open-label, wait-list trial design that randomized MSM attending participating sexual health centres in England to receive HIV PrEP immediately or after a deferral period of 1 year (the deferred phase). Five hundred and forty-four participants were recruited between November 2012 and April 2014, and follow-up continued to October 2016. The protocol was modified in November 2014 following an interim analysis which showed PrEP to be highly effective, resulting in some participants in the deferred arm being offered PrEP earlier than one year (N = 163).13 The initial PROUD protocol followed national guidelines on HCV testing, with screening 'on indication'. Screening at enrolment was not mandated. The tests used during the trial varied by site, and the use of antibody, antigen or viral load tests depending on whether the participant had a prior history of HCV. Information on HCV was collected in a number of ways. At enrolment, participants self-reported a diagnosis with HCV in the previous 12 months, and the clinician reported whether the participant had ever been screened for, and if so, diagnosed with HCV. At each visit, the number of HCV screens and positive screens (although not distinguishing the type of test) since the previous visit was recorded. For all new infections, clinics were asked to provide detailed clinical and laboratory information, including dates of last positive and last negative test (for all assays), HCV viral load test results, liver function test results and history of injecting drug use. In March 2015, additional funding was acquired which allowed screening at every quarterly study visit; at this time, all participants had access to PrEP and the trial was closed to further recruitment. If the first HCV antibody (anti-HCV) test was negative, the participant was assumed to be seronegative at enrolment. If the first test was positive, the Trial Management Group determined whether infection was most likely acquired before enrolment (and thus contributed to the seroprevalence analysis) or after enrolment (and thus contributed to the incidence analysis) based on alanine transaminase and HCV viral load measurements, in relation to time since randomization. The cumulative incidence of HCV infection (time to diagnosis) was estimated using Kaplan-Meier analysis and randomized groups compared with the log-rank test, censoring at the time of the last screen for HCV. Estimation of incidence by calendar year was complicated by the highly variable time between the last negative test and the first positive test which, in some cases, could span adjacent calendar years. To address this, the date of infection was imputed 1000 times assuming a uniform distribution, and calculating the incidence for each calendar year within each imputed dataset.14 Estimates were obtained by averaging across the imputed datasets, and confidence intervals derived using Rubin's rule.15 All analyses were done in STATA version 15.1. Characteristics of the 544 study participants have been previously described.13 Figure 1 illustrates the hepatitis C screening and infection among study participants. One hundred and thirty-three (24.4%) participants were screened for HCV at enrolment, and 499 (91.7%) were tested at least once during follow-up. Nine participants were only screened at baseline and therefore could not contribute to an incidence analysis. A HCV screen was conducted at 54.0% (3213/5946) of visits (higher during the phase of routine quarterly screening [80.6%] compared to the earlier phase of testing on indication [34.9%]), with a median of 6 (IQR: 3-8) screens per participant. Of the 45 participants who were never tested, 14 participants were also missing information on HCV history collected at enrolment. The seroprevalence at enrolment was 2.1% (11/530; 95% CI: 1.0%-3.7%). The 11 cases were identified as follows: eight participants were reported by the clinician at enrolment to have had a previous diagnosis of HCV; two were diagnosed with HCV a few days before enrolment; two participants had HCV viraemia detected at their first post-enrolment test (they were not tested at enrolment), of which one was judged to have acquired infection before enrolment. HCV incidence is based on the 490 participants who were considered HCV seronegative at enrolment, or who had previously cleared HCV infection prior to enrolment, and had at least one post-enrolment HCV test. Table 1 presents baseline characteristics of these participants and indicates a cohort with high-risk behaviours: 226 (47.6%) reported use of chemsex-associated drugs in the past three months, 282 (57.6%) were diagnosed with any STI in the past 12 months, 170 (36.9%) reported using post-exposure prophylaxis in the past 12 months, and the median number of partners in the past three months was 10. N (%) (Total = 490) The median follow-up (enrolment to last HCV test) was 2.6 (IQR: 2.1-3.0) years, with a total follow-up of 1188.8 person-years (PY). Overall, 25 participants had a new HCV infection, yielding an incidence rate of 2.1 per 100 PY (25/1188.8; 95% CI: 1.4-3.1). Three of these were re-infections (the previous infections had cleared spontaneously or with treatment before enrolment), and one participant experienced two infections during follow-up (only the first infection was included in the incidence calculation). Two HCV infections were acquired after diagnosis of HIV whilst the participant was no longer on PrEP but was being actively followed up. Excluding these cases from the HCV incidence calculation reduced the estimate only slightly (1.9 per 100 PY [95% CI: 1.2-2.9]). Use of nonprescribed injected drugs was reported by 11 participants at the suspected time of HCV infection, was denied by 12 and was unknown for two. Figure 2 shows the cumulative incidence of time to a new HCV diagnosis, stratified by randomized arm (P-value log-rank test = 0.87). As only three infections (one immediate, two deferred) were observed during the deferred phase of the study (ie the period before the DEF arm had access to PrEP), the trial essentially provides no randomized information of whether access to PrEP affects the risk of acquiring HCV infection. Accounting for uncertainty in the time of acquisition of HCV infection, HCV incidence appeared to increase over calendar time (Table 2), reaching an estimated 4.0 per 100 PY in 2016 (95% CI: 2.0-8.1, P-value for trend = 0.09). This analysis demonstrates a high overall incidence of hepatitis C infection (2.1 per 100 PY) in the PROUD trial. This is higher than, although compatible with, the incidence reported in other contemporaneous PrEP studies in Europe. In the AmPrEP study, HCV incidence during follow-up was 1.9 per 100 PY (95% CI: 1.1-3.4). The incidence rate of primary infection was 1.0 per 100 PY (95% CI: 0.5-2.2) and of re-infection 25.5 per 100 PY (95% CI: 11.5-56.8).6 In the ANRS IPERGAY study of on-demand PrEP, HCV incidence was estimated to be 1.4 per 100 PY (95% CI: 0.7-2.4).7 A large French cohort estimated HCV incidence to be 1.2 per 100 PY for HIV-negative MSM PrEP users.8 In contrast, demonstration and implementation cohorts of PrEP users in North America have reported lower incidence of HCV infection. An incidence of 0.7 per 100 PY (95% CI: 0.08-2.4) was reported from a San Francisco clinic.10 A retrospective cohort study in a Montreal sexual health clinic that compared the incidence of STIs prior to, and in 12 months following, the prescription of PrEP in 109 MSM found no incident cases of HCV during either time period.9 The disparity in HCV incidence seen between European and North American PrEP studies could be due to a different risk of exposure to the virus (ie variation in the prevalence of active infection among MSM) or differences in the extent of high-risk sexual behaviours. PROUD participants were at the far end of this spectrum, reporting an average of 10 sexual partners in the three months before enrolment and 37% having used post-exposure prophylaxis in the previous 12 months (Table 1). Few studies have estimated HCV incidence in general HIV-negative MSM populations. A meta-analysis by Ghisla et al estimated incidence to be 0.43 per 1000 PY (95% CI: 0.01-0.86).2 A cohort in Amsterdam did not observe any HCV infections in HIV-negative participants during 7808 PY of follow-up (0 per 1000 PY, 95% CI: 0.0-0.5).16 In a UK (Brighton) hospital, HCV incidence was estimated at 0.15 per 100 PY (95% CI: 0.05-0.35)17 among 57% of eligible participants who were tested. The difference in HCV incidence between HIV-negative MSM in general and those seeking PrEP is likely to be explained by the lower sexual risk behaviours and lower testing rates in the former group. Although the increase in HCV incidence over calendar timein PROUD was not conventionally statistically significant, the low seroprevalence at enrolment (2.1%, coincidently identical to the overall incidence of 2.1% per year) suggests that the increasing incidence is genuine. This increase occurred despite an overall decline in HCV prevalence in England in recent years.18 Phylogenetic analysis of HCV infections in the AmPrEP study and a cohort of HIV-negative and HIV-positive MSM in a French clinic19, 20 suggest that there was substantial sexual mixing between HIV-negative and HIV-positive populations, who have high HCV prevalence21 and incidence,2, 22 and it is likely that PrEP facilitates this mixing. Although the frequency of HCV testing increased part way through the study and probably resulted in more rapid diagnosis of infections, we used an imputation method that should correct for any bias arising from this. The 2.1% seroprevalence of HCV in PROUD participants at enrolment was considerably lower than that reported in the AmPrEP demonstration project (4.8%).19 The IPERGAY study reported only one HCV infection at enrolment.7 However, HCV seroprevalence changes rapidly in the context of a high incidence and comparisons between studies will be affected by the calendar time over which seroprevalence was calculated. Our study has two major limitations. First, the small number of incident HCV infections limited our ability to examine risk factors for the acquisition of HCV, including geographical region. The second limitation is around the generalizability of our findings. PROUD participants were at much higher risk of acquiring HIV infection than other MSM attending sexual health clinics in the same time period, and the same may apply to HCV infection. The use of nonprescribed injected drugs was reported by 11 of the 25 incident cases, and this cannot be excluded as a possible route of transmission. However, qualitative research indicates that sharing of needles is uncommon among MSM injecting chemsex drugs in the UK, with high awareness of the risks of doing so.23 Even if these 11 cases are discounted, the estimated incidence is still high, suggesting that HCV is highly transmissible through sexual contact, with the risk of epidemic spread of the infection in certain populations. Regular care for PrEP provides an opportunity to screen for and provide early intervention for HCV. The increasing availability of HCV antigen/antibody testing makes screening in this population more feasible.24 The high incidence of HCV that we observed in PROUD supports the 2018 BHIVA/BASHH recommendation for quarterly HCV testing among HIV-negative MSM using PrEP in the UK, in line with other STIs.25 Also, a recent modelling study has indicated that screening and treating PrEP users for HCV at least every 12 months can reduce HCV incidence by 67.3% (uncertainty range 52.7%-79.2%).26 However, HCV incidence can vary markedly by location and time, and guidance in the UK and other countries27, 28 should be regularly reviewed in the light of local evidence. Gilead Sciences awarded a grant to fund the increased quarterly screening of hepatitis C. The PROUD study was supported by ad hoc funding from the MRC Clinical Trials Unit at University College London and an innovations grant from Public Health England, and most clinics received support through the UK National Institute of Health Research Clinical Research Network. Gilead Sciences provided Truvada PrEP for the PROUD study. We thank the PROUD participants who recognized the need for the study design, the dedication of the clinic teams and the oversight that the governance committees provided as the study evolved. The PROUD study was provided drug free of charge by Gilead Sciences plc. that also distributed it to participating clinics and provided funds for additional diagnostic tests for HCV and drug levels. EW university fees and stipend funded by Gilead Science plc. SM reports grants from the European Union H2020 scheme, EDCTP 2, the National Institute of Health Research and Gilead Sciences; other support from Gilead Sciences and the Population Council Microbicide Advisory Board; and is Chair of the Project Advisory Committee for USAID grant awarded to CONRAD to develop tenofovir-based products for use by women (nonfinancial). DTD has received fees for participation on advisory boards and educational workshops from ViiV Healthcare and Gilead Sciences. AC has received consultancy fees from Gilead and ViiV/GSK, and travel bursaries to education events from Gilead. DP is an employee of Gilead Sciences. NV has received conference support from Gilead and Janssen. MD, DW, AS, MG, JF, CL and RG have no conflicts to declare.

Background: The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) was analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naive and ART-experienced Asian participants infected with human immunodeficiency virus (HIV)-1 through 96 or 144 weeks.Objective: In Asian population requiring treatment, it is imperative to have data specific to this group, particularly as there is a general concern that Asians with lower body weight have increased risk of tenofovir disoproxil fumarate (TDF)-related renal dysfunction.Methods: Studies -104 and 111 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naive participants, comparing E/C/F/TAF versus E/C/F/TDF. Study 109 was a randomized, open-label, 96-week study conducted in virologically suppressed, ART-experienced participants, who switched to E/C/F/TAF from ritonavir/cobicistat-boosted atazanavir ATV+(RTV or COBI) + F/TDF regimens, from non-nucleoside reverse transcriptase inhibitors (NNRTI) + F/TDF regimens, or from E/C/F/TDF. Study 112 was a single arm, open-label, 144-week study conducted in HIV suppressed, ART-experienced participants with mild-moderate renal impairment, who switched to E/C/F/TAF.Results: Asian participants in these studies had sustained efficacy safety and tolerability. In Study 104/111, Asian participants achieved 93% virologic suppression on TAF vs 88% on TDF at week 144. At baseline, there were numerically more Asians with median CD4 counts < 200 cells/uL and VL > 100,000 c/mL. In Study 109, 95% of Asians on TAF vs 86% on TDF maintained virologic suppression at week 96. Lastly, in Study 112, 91% maintained virologic suppression at week 144. There were no discontinuations due to renal AE, no cases of PRT or Fanconi syndrome in any of the studies.

OBJECTIVETo evaluate the efficacy and safety of switching from an abacavir/lamivudine (ABC/3TC)-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet regimen in virologically suppressed, HIV-1-infected adults.DESIGNRandomized, open-label, noninferiority study.METHODSParticipants with HIV-1 RNA levels less than 50 copies/ml receiving ABC/3TC plus a third agent for at least 6 months were randomized 2 : 1 to switch immediately to E/C/F/TAF (immediate-switch group) for 48 weeks or to continue receiving ABC/3TC plus a third agent for 24 weeks followed by E/C/F/TAF for 24 weeks (delayed-switch group). The primary endpoint was HIV-1 RNA less than 50 copies/ml at Week 24 by Food and Drug Administration Snapshot algorithm (-12% noninferiority margin).RESULTSBaseline characteristics of 274 participants (183 in immediate-switch group and 91 in delayed-switch group) were similar. Virologic response was maintained at Week 24 by 93.4 and 97.8% of participants in the immediate-switch and delayed-switch groups, respectively, with a treatment difference of -4.4% (95% confidence interval: -9.4 to 1.9%), confirming noninferiority. Adverse events of any grade were similar between groups through Week 24 (66% E/C/F/TAF, 64% ABC/3TC); adverse event-related drug discontinuations occurred in 4% of participants switching to E/C/F/TAF (no discontinuations because of renal events) and no participants continuing ABC/3TC. Renal biomarkers of urine albumin:creatinine and beta-2-microglobulin:creatinine ratios significantly improved on E/C/F/TAF. Self-reported treatment satisfaction was significantly higher with E/C/F/TAF.CONCLUSIONSwitching to E/C/F/TAF was noninferior to continuing ABC/3TC plus a third agent for maintenance of HIV RNA suppression at Week 24. This study supports E/C/F/TAF as an efficacious and well tolerated option for participants switching from ABC/3TC-based regimens.

Background Tenofovir alafenamide is associated with less renal and bone toxicity than tenofovir disoproxil fumarate and might improve the long-term safety of antiretroviral therapy. We aimed to investigate the effect on bone mineral density of switching from a regimen containing tenofovir disoproxil fumarate to one containing tenofovir alafenamide in participants aged 60 years and older. Methods We did a prospective, open-label, multicentre, randomised trial in 36 European centres. Participants were virologically suppressed (HIV-1 RNA <50 copies per mL), aged 60 years or older, on a tenofovir disoproxil fumarate-containing regimen and were randomly assigned (2:1) via an interactive web-response system to open-label elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg), and tenofovir alafenamide (10 mg) daily or continued therapy containing tenofovir disoproxil fumarate (300 mg). Participants were stratified by spine and hip bone mineral density categories. Primary endpoints were change from baseline to week 48 in spine and hip bone mineral density with a null hypothesis of zero between-group difference tested at a significance level of 0.05. This study was registered with ClinicalTrials.gov, NCT02616783. Findings Between Dec 22, 2015, and March 21, 2018, 167 participants were randomly assigned to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (n=111 [66%]) or tenofovir disoproxil fumarate (n=56 [34%]). One participant in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group did not receive treatment and was excluded from all analyses. At week 48, the mean percentage change in spine bone mineral density was 2.24% (SD 3.27) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and -0.10% (3.39) in the tenofovir disoproxil fumarate group (between-group difference 2.43% [95% CI 1.34-3.52]; p<0.0001), and mean percentage change in hip bone mineral density was 1.33% (2.20) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and -0.73% (3.21) in the tenofovir disoproxil fumarate group (difference 2.04% [1.17-2.90]; p<0.0001). The most common adverse events were nasopharyngitis (12 [11%]), back pain (nine [8%]), and diarrhoea (eight [7%]) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and bronchitis (six [11%9, vitamin D deficiency (four 17%1), and arthralgia (four [7%]) in the tenofovir disoproxil fumarate group. 22 (20%) participants in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and one (2%) participant in the tenofovir disoproxil fumarate group had an adverse event that was considered to be related to treatment. No treatment-related serious adverse events were observed. The proportions of adverse events leading to premature treatment discontinuation were similar between groups (four [4%] in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and one (2%) in the tenofovir disoproxil fumarate group). Interpretation The significantly improved bone mineral density, overall safety, and efficacy data show the feasibility of switching from a regimen containing tenofovir disoproxil fumarate to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV aged 60 years or older. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

We address a data gap identified by Adams et al. [1], of virological efficacy outcomes and emergent drug resistance in HIV-1-infected, antiretroviral treatment (ART)naive participants with baseline (BL) viral loads (VL) >1,000,000 copies/ml. Initial ART regimens including an integrase strand transfer inhibitor (INSTI) cause a rapid decline in VL. In two cases described [1], the VL response on the single tablet regimen (STR) of co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) was <2 log10 copies/ml and associated with emergent drug resistance [1]. Double-blind, Phase III studies of EVG/COBI/FTC/TDF (Studies 102/103 and 128), and co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (EVG/COBI/FTC/TAF; Studies 104/111), have investigated the efficacy and safety of both EVG-containing STRs in ART-naive participants [2–10]. We present a post hoc analysis of efficacy of these STRs in participants with VL ≥1,000,000 copies/ml. Participants (n=64) analysed with VL ≥1,000,000 copies/ml were treated with either EVG/COBI/FTC/ TDF (n=32), EVG/COBI/FTC/TAF (n=9) or other ART regimens (efavirenz/emtricitabine/ tenofovir disoproxil fumarate [EFV/FTC/TDF, n=6], or atazanavir + ritonavir + fixed dosed TDF/FTC [ATV+RTV+FTC/TDF, n=17]). Virological success (VS) was achievement of HIV-1 RNA <50 copies/ml (Snapshot). Genotypic sensitivity to FTC and TDF was required, and to EFV or ATV (Studies 102, or 103 and 128, respectively). Integrase genotyping was performed at screening in Studies 104/111 [11]. Post-BL resistance testing was performed when VL [3] 400 copies/ml was confirmed at virological failure (VF). Adherence was monitored by pill count. BL VLs in the subgroup ranged from 1,030,000– 11,000,000 copies/ml, and 72% of participants had BL CD4+ T-cell count <200 cells/mm3 (Table 1). VL curves of participants through week (W) 48 are shown (Figure 1). By W4, participants randomized to either EVG-containing STR had median changes in VL from BL >-3.0 log10 copies/ml in all studies versus <-3.0 log10 copies/ml for participants on the other ART regimens (Table 1). In participants on either EVG-containing STR, the first achievement of HIV-1 RNA <50 copies/ml had occurred in 33% by W12, 67% by W24 and 97% by W48 (range W4–W60). Overall, 35/41 (85%) on EVG-containing STRs had HIV-1 RNA <50 copies/ml at W48. 38 of 41 (93%) participants on EVG-containing STRs achieved HIV-1 RNA <50 copies/ml by last available time point, although 2 participants discontinued the study (Table 1). Sixteen participants (39%) never had any subsequent blips in VL ≥50 copies/ml, 20 (49%) had at least one transient VL ≥50 to <400 copies/ ml and re-suppressed, and 2 (5%) had VL >400 copies/ ml and re-suppressed. 3 of 41 (7%) participants on the EVG-containing STRs (EVG/COBI/FTC/TDF [2] and EVG/COBI/FTC/TAF [1]) had VF, and met resistance Letter

Objective: Assess the performance of HIV-1 RNA repeat testing of stored samples in cases of low-level viremia during clinical trials. Design: Prospective and retrospective analysis of randomized clinical trial samples and reference standards. Methods: To evaluate assay variability of the Cobas AmpliPrep/Cobas TaqMan HIV-1 Test, v2.0, three separate sources of samples were utilized: the World Health Organization (WHO) HIV reference standard (assayed using 50 independent measurements at six viral loads <200 copies/ml), retrospective analysis of four to six aliquots of plasma samples from four clinical trial participants, and prospective repeat testing of 120 samples from participants in randomized trials with low-level viremia. Results: The TaqMan assay on the WHO HIV-1 RNA standards at viral loads <200 copies/ml performed within the expected variability according to assay specifications. However, standards with low viral loads of 36 and 18 copies/ml reported values of ≥ 50 copies/ml in 66 and 18% of tests, respectively. In participants treated with antiretrovirals who had unexpected viremia of 50–200 copies/ml after achieving <50 copies/ml, retesting of multiple aliquots of stored plasma found <50 copies/ml in nearly all cases upon retesting (14/15; 93%). Repeat testing was prospectively implemented in four clinical trials for all samples with virologic rebound of 50–200 copies/ml (n = 120 samples from 92 participants) from which 42% (50/120) had a retest result of less than 50 copies/ml and 58% (70/120) retested ≥ 50 copies/ml. Conclusion: The TaqMan HIV-1 RNA assay shows variability around 50 copies/ml that affects clinical trial results and may impact clinical practice. In participants with a history of viral load suppression, unexpected low-level viremia may be because of assay variability rather than low drug adherence or true virologic failure. Retesting a stored aliquot of the same sample may differentiate between assay variability and virologic failure as the source of viremia. This retesting strategy could save time, money, and anxiety for patients and their providers, as well as decrease follow-up clinic visits without increasing the risk of virologic failure and resistance development.

Abstract Background Higher rates of neuropsychiatric events among patients on dolutegravir (DTG) compared with other integrase inhibitors (INSTIs) have been reported from clinic cohorts and one blinded trial. We compared select neurological and psychiatric events in a large sample of patients treated with different INSTIs. Methods The Quintiles IMS database, which includes pharmacy and medical claims records, was examined for HIV infected patients treated from 2006 to 2016 with DTG (TIVICAY/TRIUMEQ), elvitegravir (EVG, STRIBILD), or raltegravir (RAL, ISENTRESS). The dependent variable outcomes were insomnia/sleep disturbance and depression. A propensity score was created to adjust for variables associated with treatment with a particular INSTI including age, gender, year of initial INSTI exposure, and enrollment time. Multivariate Poisson mixed models were used to generate incidence rate ratios (IRRs). Results Records for 54,151 distinct HIV-infected patients treated with DTG, EVG, or RAL were identified. In the multivariate model the rate of insomnia/sleep disturbance events was significantly higher for patients treated with DTG vs. EVG (IRR 1.21 [95% CI 1.09–1.33, P < 0.001]), but was not significantly different when comparing DTG to RAL (IRR 1.04 [95% CI 0.94–1.14, P = 0.459]). Likewise, the rate of incident depression was significantly higher for patients treated with DTG vs. EVG (IRR 1.18 [95% CI 1.09–1.27, P < 0.001], but not when comparing DTG to RAL (IRR 0.93 [95% CI 0.87 – 1.01, P = 0.068]). Conclusion In this analysis using a large healthcare database, significantly higher adjusted rates of both incident insomnia/sleep disturbances (21% more) and depression (18% more) were found among patients treated with DTG compared with EVG. In contrast, a significant difference in the rates of either outcome was not observed when comparing DTG and RAL. Further studies are warranted to determine the risk of neuropsychiatric events in patients treated with different INSTIs. Disclosures D. Wohl, Gilead Sciences: Consultant and Investigator, Consulting fee and Research grant; Viiv: Consultant and Investigator, Consulting fee and Research grant; Janssen: Consultant, Consulting fee; Bristol-Myers Squibb: Consultant, Consulting fee; A. Mills, Gilead Sciences: Consultant, Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; Viiv: Consultant and Investigator, Consulting fee and Research grant; Merck: Consultant, Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; Janssen: Investigator, Research grant; Bristol-Myers Squibb: Investigator, Research grant; Sangamo Bio Sciences: Investigator, Research grant; R. Mera, Gilead Sciences: Employee and Shareholder, Salary; D. Piontkowsky, Gilead Sciences: Employee and Shareholder, Salary

Background: HIV-1-infected, virologically suppressed adults wanting to simplify or change their non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may benefit from switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF). Objective: We examined differences in the proportion of participants with HIV-1 RNA < 50 copies/mL (Snapshot analysis), change in CD4 cell count, safety, and patient-reported outcomes in participants switching to E/C/F/TDF from an NNRTI + FTC/TDF (TVD) regimen. Methods: STRATEGY-NNRTI was a 96-week, phase 3b, randomized, open-label, study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF in virologically suppressed individuals (HIV-1 RNA < 50 copies/mL) on an NNRTI + TVD regimen. Participants were randomized to switch or remain on their NNRTI-based regimen (no-switch). Results: At Week 96, 87% (251/290) of switch and 80% (115/143) of no-switch participants maintained HIV-1 RNA < 50 copies/mL (difference 6.1%; 95% CI −1.3 to 14.2%; p = 0.12) according to the FDA-defined snapshot algorithm. Both groups had similar proportions of subjects with virologic failure (2.8% switch, 1.4% no-switch). Discontinuations resulting from adverse events were infrequent (3% [9/291] switch, 2% [3/143] no-switch). Three switch participants (1%) discontinued due to renal adverse events (2 of the 3 before Week 48). Switch participants reported significant improvements in neuropsychiatric symptoms by as early as Week 4, and which were maintained through Week 96. Conclusions: E/C/F/TDF is safe and effective and reduces NNRTI-associated neuropsychiatric symptoms for virologically suppressed HIV-positive adults switching from an NNRTI plus FTC/TDF-based regimen.

The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naive and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naive subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively. Studies GS-US-236-115 and GS-US-236-121 were randomized, open-label, 96-week long conducted in ART-experienced subjects, who switched to E/C/F/TDF from ritonavir-boosted protease inhibitors (PI+RTV)+F/TDF, or non-nucleoside reverse transcriptase inhibitors (NNRTI)+F/TDF regimens. The E/C/F/TDF appeared to have sustained efficacy and safety and was well tolerated in the small number of ART-naive and ART-experienced Asian subjects..

[This corrects the article DOI: 10.1371/journal.pone.0155406.].

Cobicistat and ritonavir are structurally distinct compounds that both potently inhibit cytochrome P450 (CYP) 3A, the metabolizing enzyme primarily responsible for the elimination of several antiretroviral medications, and, as such, are pharmacokinetic boosters for antiretroviral agents that require longer dosing intervals. Recently, cobicistat was approved for the treatment of HIV-1 infection in treatment-naive adults as a component of a single-tablet regimen consisting of cobicistat-boosted elvitegravir plus emtricitabine and tenofovir disoproxil fumarate. While studies have demonstrated that boosting with either cobicistat or ritonavir results in comparable plasma exposure of the target antiretroviral agent, a better understanding of drug-drug interactions between cobicistat- and ritonavir-boosted antiretrovirals and other medications will inform treatment decisions in HIV-infected patients. In connection with their distinct structural properties, COBI and RTV differ with respect to their drug-drug interaction profiles. Compared with ritonavir, cobicistat lacks induction potential and is a more specific inhibitor of 3A and therefore, has reduced effects on other CYP isoforms. To date, more studies have assessed ritonavir drug-drug interactions with other medications than have assessed cobicistat drug-drug interactions. The objective of this article is to review the drug-drug interactions when cobicistat- or ritonavir-boosted elvitegravir, cobicistat, or elvitegravir/cobicistat/emtricitabine/tenofovir are coadministered with antiretroviral therapies or drugs that are either substrates, inducers, or inhibitors of the CYP3A metabolic pathway, as well as with drugs that alter intra-gastric pH or are substrates of P-gp, in order to inform the proper use of elvitegravir/cobicistat/emtricitabine/tenofovir.