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IntroductionRandomized trials of new agents for HIV pre-exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well-characterized adherence-efficacy relationship for F/TDF to back-calculate the (non-PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV).MethodsThe DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non-inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV-DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV.ResultsThere were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person-years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV-negative controls, 5% of the person-time years had low, 9% had medium and 86% had high TFV-DP levels. A non-informative prior distribution for counterfactual bHIV, combined with the prior for TFV-DP level-efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV.ConclusionsBased on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non-PrEP control group in randomized, active-controlled PrEP trials that include a F/TDF-comparator group.

Background People of color are underrepresented in clinical trials. TAF has shown improved renal and bone safety vs. TDF. We pooled 7 studies to evaluate efficacy/safety of TAF vs. TDF for ART initiation/switch in Hispanic/Latinx and Black participants. Methods Data from Hispanic/Latinx and Black adults who initiated/switched to TAF or TDF in 7 randomized trials (2 treatment-naïve, 5 suppressed switch) were analyzed. TAF-based regimens (elvitegravir/cobicistat/emtricitabine [FTC]/TAF, rilpivirine/FTC/TAF, FTC/TAF, or bictegravir/FTC/TAF) were compared with TDF-based regimens. Virologic suppression (VS; HIV-1 RNA < 50 c/mL, FDA snapshot) and % change in bone mineral density (BMD) and renal tubular biomarkers urine β-2-microglobulin (B2M):creatinine (Cr) ratio and retinol binding protein (RBP):Cr ratio are reported at W96. Results The pooled population (N = 5,825) included 1138 Hispanic/Latinx and 1324 Black participants. Treatment-naïve participants (n = 1,733) were 15% female, 25% Black, 19% Hispanic/Latino, with median age 34 years, HIV-1 RNA 4.6 log10 c/mL, CD4 405 cells/mm3. Switch participants (n = 4,092) were 13% female, 22% Black, 20% Hispanic/Latino, median age 45 years, CD4 653 cells/mm3. There was no difference in VS rate with TAF vs. TDF in any group. VS rate (TAF vs. TDF) in naïve participants: 88% vs. 84% (Hispanic/Latinx); 78 vs. 79% (Black); 87% vs. 85% (overall). VS (TAF vs. TDF) was well maintained in switch participants: 91% both arms (Hispanic/Latinx); 86% vs. 87% (Black); 90% vs. 88% (overall). TAF and TDF were well tolerated with few discontinuations due to adverse events (0.6–2%) in all groups. At W96 there was less impact on renal biomarkers in all groups initiating TAF (P < 0.001; table), and decreases in BMD were smaller (P < 0.005; table) vs. TDF. All groups switching from TDF to TAF experienced decreases in tubular proteinuria and improvements in BMD (both P < 0.001; table) at W96. Conclusion Hispanic/Latinx and Black participants who initiated/switched to TAF had significantly improved bone and renal parameters vs. TDF, with similar VS rates at W96. Efficacy and biomarkers were similar to the overall study population. These data in >2,400 Hispanic/Latinx and Black PLH demonstrate noninferior efficacy and safety advantages with TAF vs. TDF. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background In human immunodeficiency virus (HIV) treatment, tenofovir alafenamide (TAF) is associated with greater increases in all fasting cholesterol subgroups compared with tenofovir disoproxil fumarate (TDF). Because lipid abnormalities may contribute to cardiovascular morbidity and mortality, cardiovascular risk assessment is integral to routine HIV care. This post hoc study evaluates the impact of lipid changes on predicted atherosclerotic cardiovascular disease (ASCVD) risk and statin eligibility in treatment-naive adults living with HIV treated with TAF or TDF. Methods Participants (N = 1744) were randomized (1:1) to initiate TAF or TDF, each coformulated with elvitegravir/cobicistat/emtricitabine (studies GS-US-292-0104 and GS-US-292-0111). Eligibility for statin therapy and estimated 10-year ASCVD risk among adults aged 40–79 years treated with TAF or TDF for 96 weeks (W96) were analyzed based on American College of Cardiology/American Heart Association Pooled Cohort Equations. Categorical shifts in 10-year ASCVD risk from <7.5% to ≥7.5% by W96 on TAF versus TDF were calculated. Results Participants initiating TAF versus TDF in the overall study population showed small but significant increases in median fasting lipid parameters at W96, including total cholesterol (191 vs 177 mg/dL; P <.001), low-density lipoprotein ([LDL] 119 vs 112 mg/dL; P <.001), and high-density lipoprotein ([HDL] 51 vs 48 mg/dL; P <.001), respectively. At baseline, 18% and 23% on TAF versus TDF had a 10-year ASCVD risk score ≥7.5%, with mean risk scores low overall for TAF versus TDF at baseline (4.9% vs 5.4%; P =.35) and W96 (6.1% vs 6.2%; P =.04). Increases in ASCVD risk from baseline to W96 were driven by both increasing age and changes in total cholesterol (TC) and HDL cholesterol. At W96, TC/HDL ratios (median) were 3.7 for both groups (P =.69). There was no difference between shifts in categorical risk for TAF versus TDF (9% vs 5%; P =.19). Eligibility for high-intensity statin therapy were similar for TAF versus TDF groups (19% vs 21%; P =.47). Conclusions Lipid changes with TAF as part of coformulated regimens do not substantively affect CVD risk profiles compared with TDF. [ABSTRACT FROM AUTHOR]

Background In the DISCOVER PrEP trial, emtricitabine/tenofovir alafenamide (F/TAF) was noninferior to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV prevention. Here we report the bone safety outcomes of F/TAF and F/TDF. Methods Men who have sex with men (MSM) and transgender women (TGW) at risk of HIV were randomized 1:1 to receive blinded F/TDF or F/TAF, taken once daily. Those on PrEP with F/TDF were eligible to enroll. Bone densitometry (DXA) of the hip and spine were performed in a subset of participants (BMD subset). Fracture events were compared in all study participants. Week 48 data are presented. Results 5387 participants were enrolled in the main study, with 383 included in the BMD subset. In the BMD subset, the median age was 37 (IQR 29, 46); 0.8% were TGW, 9.4% were black, and 20.6% were Hispanic or Latinx. Fifty-three BMD subset participants were on baseline F/TDF PrEP at enrollment, 26 of whom were randomized to F/TAF. F/TAF was associated with more favorable changes in hip and spine BMD compared with F/TDF (Table 1); these differences were similar when participants on baseline PrEP were excluded. Participants age <35 on F/TAF gained BMD, whereas those on F/TDF lost BMD (Table 1). BMD decreases of ≥3% were less frequent in the F/TAF group than the F/TDF group at the hip (3.8% vs. 18.4%, P < 0.001) and spine (10.1% vs. 26.9%, P < 0.001). Osteopenia was more frequently diagnosed in the spine in participants on F/TDF compared with F/TAF (Figure 1, P = 0.007); but not in the hip. Fracture event frequency was the same (53 [2.0%] per group, P = 1.00). One pathological fracture was reported in the F/TAF group compared with two in the F/TDF group (P = 0.57). In participants on baseline F/TDF PrEP, those randomized to F/TAF had significantly improved hip BMD compared with baseline (median percent change 1.13 [IQR −0.86, 3.47], P = 0.027), while spine BMD was unchanged. Conclusion Through 48 weeks, DXA subset participants taking F/TAF for PrEP had significantly less change in BMD than those taking F/TDF, and were less likely to develop spine osteopenia. The incidence of fracture was similar, and pathological fractures were rare. F/TAF for PrEP is effective and has a superior bone safety profile compared with F/TDF. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background In the DISCOVER PrEP trial, emtricitabine/tenofovir alafenamide (F/TAF) was noninferior to emtricitabine/tenofovir disoproxil fumarate (F/TDF) for HIV prevention. Here, we report on the renal outcomes of F/TAF and F/TDF among all DISCOVER participants and in those on baseline F/TDF PrEP who were randomized to F/TAF. Methods In total, 5387 men who have sex with men (MSM) and transgender women (TGW) at risk for HIV were randomized 1:1 to receive blinded F/TDF or F/TAF taken once daily (full cohort). Of these, 905 were on F/TDF PrEP at enrollment; of whom, 465 were randomized to F/TAF. Renal function and safety assessments included urinalysis (UA), estimated glomerular filtration rate (eGFRCG), urine protein:creatinine (Cr) ratio (UPCR), markers of proximal tubular function (β2-microglobulin:Cr ratio [β2M:Cr] and retinol-binding protein:Cr ratio [RBP:Cr]) and investigator-reported renal adverse events (AEs). Week 48 data are presented. Results In the full cohort, F/TAF was associated with more favorable changes in eGFRCG, β2M:Cr, and RBP:Cr compared with F/TDF (Table 1). Treatment-emergent proteinuria by UA was more common with F/TDF than F/TAF (24.3% vs. 21.3% P = 0.009), as were treatment-emergent elevations in UPCR >200 mg/g (35 [1.5%] vs. 16 [0.7%], P = 0.005). Compared with F/TDF, participants taking F/TAF had numerically fewer study drug-related renal AEs, severe study drug-related renal AEs, and discontinuations due to renal AEs (Table 2). Proximal renal tubulopathy (Fanconi syndrome) was reported in one participant in the F/TDF arm and none in the F/TAF arm. In participants on F/TDF PrEP at enrollment who were randomized to F/TAF, statistically significant increases in eGFRCG were apparent as early as week 4 (Table 1 and Figure 1), as were decreases in tubular proteinuria (Table 1). Renal biomarker changes in PrEP-naïve participants mirrored those in the full cohort. Conclusion Through 48 weeks, MSM and TGW taking F/TAF for PrEP had significantly better measures of renal function and fewer study-drug-related renal AEs compared with those taking F/TDF; switching from F/TDF to F/TAF was associated with improvements in eGFRCG and tubular function biomarkers. F/TAF for PrEP is effective and has a superior renal safety profile compared with F/TDF. Disclosures All Authors: No reported Disclosures. [ABSTRACT FROM AUTHOR]

Background HIV treatment for individuals with end-stage renal disease (ESRD) on hemodialysis (HD) has previously required complex dose-adjusted regimens. We evaluated the safety and efficacy of single-tablet, once-daily elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in people living with HIV (PLH) and ESRD on chronic HD. Methods Virologically suppressed adult PLH with ESRD on chronic HD for ≥ 6 months were switched to open-label E/C/F/TAF 150/150/200/10 mg once daily for 96 weeks. Efficacy was assessed as the proportion of participants who maintained virologic suppression (HIV RNA < 50 copies/mL) using the snapshot algorithm. Safety and participant satisfaction were assessed throughout the study. Results We enrolled 55 participants with median age 51 years (range 23–64) with median time on HD 6 years (range 1–17). In the per protocol analysis set, virologic suppression was maintained in 30 of 31 participants (96.8%, 95% CI [83.3%, 99.9%]) at week 96. In the full analysis set, virologic suppression was maintained in 30 of 55 participants (54.5%; 95% CI [40.6%, 68.0%]); one discontinued therapy due to lack of efficacy, and W96 data were unavailable for 24. Of the 24 participants lacking W96 data, 17 discontinued study drug early and 7 had missing data while on study drug; all had HIV RNA < 50 copies/mL at the last pre-week 96 check. Treatment-emergent AEs occurred in 53 (96.4%) participants, and study-drug-related AEs occurred in 7 (12.7%). Treatment-emergent AEs leading to premature study drug discontinuation occurred in 4 (7.3%) participants; two were considered study-drug-related (allergic pruritus and peripheral neuropathy in one participant each). No study-drug-related serious AEs were observed. 85.7% (30/35) of responding participants reported they were 'much more satisfied' with their regimen. Conclusion Single-tablet, once-daily E/C/F/TAF was effective in maintaining virologic suppression in PLH on chronic HD over 96 weeks of follow-up. E/C/F/TAF was well tolerated and was associated with improved participant satisfaction. These data demonstrate that E/C/F/TAF is a safe and effective alternative to more complicated regimens in PLH on chronic HD, with the potential to improve patient satisfaction and quality of life. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background The single tablet regimen (STR) composed of elvitegravir (E), cobicistat (C), emtricitabine (F), and tenofovir alafenamide (TAF) (E/C/F/TAF) was compared to the STR composed of E, C, F, and tenofovir disoproxil fumarate (TDF) (E/C/F/TDF) in 2 phase 3 studies in 1733 HIV-1 infected treatment-naïve adults. Superior efficacy of E/C/F/TAF compared to E/C/F/TDF was demonstrated at Week 144 with 84% treatment success compared to 80%, respectively, along with significantly better outcomes of bone and renal safety. Objectives Analyze the emergence of HIV-1 resistance in treatment-naïve adults receiving E/C/F/TAF for 144 weeks. Study design We conducted an integrated resistance analysis of the 2 Phase 3 studies, comprising pretreatment HIV-1 sequencing for all participants (N = 1733) and post-baseline HIV-1 resistance analysis for participants with virologic failure (HIV-1 RNA ≥400 copies/mL). Results Primary resistance-associated mutations (RAMs) were observed pre-treatment in 7.4% (NRTI-RAMs), 18.1% (NNRTI-RAMs), and 3.3% (PI-RAMs) of enrolled subjects. Baseline HIV-1 subtype or pre-existing RAMs did not affect E/C/F/TAF treatment response at week 144. Virologic failure resistance analyses were conducted for 28/866 (3.2%) and 30/867 (3.5%) patients in the E/C/F/TAF and E/C/F/TDF arms, respectively. Over the 3-year study, the rate of resistance emergence remained low at 1.4% in each group (12/866 in E/C/F/TAF; 12/867 in E/C/F/TDF). Resistant virus emerged in 24 patients who developed resistance to antiretrovirals in the regimens (E/C/F/TAF: M184V/I [1.3%], INSTI-RAMs [0.9%], K65R/N [0.2%]; E/C/F/TDF: M184V/I [1.0%], INSTI-RAMs [0.9%], K65R/N [0.5%]). Conclusions Resistance emergence was rare (1.4%) with similar patterns of emergent mutations in both groups. M184V/I was the most prevalent RAM (1.2% overall). [ABSTRACT FROM AUTHOR]

In 2 double-blind phase 3 trials, 1733 antiretroviralnaive adults were randomized to tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 144 weeks, TAF was superior to TDF in virologic efficacy, with 84.2% vs 80.0% having HIV-1 RNA <50 copies/mL (difference 4.2%; 95% confidence interval: 0.6% to 7.8%). TAF had less impact than TDF on bone mineral density and renal biomarkers. No participants on TAF had renal-related discontinuations vs 12 on TDF (P < 0.001), with no cases of proximal tubulopathy for TAF vs 4 for TDF. There were greater increases in lipids with TAF vs TDF, with no difference in the total cholesterol to high-density lipoprotein ratio. For initial HIV therapy, E/C/F/TAF is superior to E/C/F/TDF in efficacy and bone and renal safety. [ABSTRACT FROM AUTHOR]

Tenofovir disoproxil fumarate is associated with renal and bone toxicity. In a single-arm, open-label study of 242 virologically suppressed, HIV-infected participants with creatinine clearance 30–69 mL/min who switched to elvitegravir/cobicistat/ emtricitabine/tenofovir alafenamide, participants had stable creatinine clearance, significant and durable improvements in proteinuria, albuminuria, and tubular proteinuria (P < 0.001), and significant increases in hip and spine bone mineral density through 96 weeks (P < 0.001). Eighty-eight percent maintained HIV-1 RNA <50 c/mL at week 96. These longer-term results support the use of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in HIV-infected individuals with mild-moderately impaired renal function. [ABSTRACT FROM AUTHOR]

Background: HIV-infected, treatment-experienced adults with a history of prior resistance and regimen failure can be virologically suppressed but may require multitablet regimens associated with lower adherence and potential resistance development. Methods: We enrolled HIV-infected, virologically suppressed adults with 2-class to 3-class drug resistance and at least 2 prior regimen failures into this phase 3, open-label, randomized study. The primary endpoint was the percentage of participants with HIV-1 RNA <50 copies per milliliter at week 24 [Food and Drug Administration (FDA) snapshot algorithm]. Results: For 135 participants [elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) plus darunavir (DRV), n = 89; baseline regimen, n = 46], most of whom were taking a median of 5 tablets/d, simplification to E/C/F/TAF plus DRV was noninferior to continuation of baseline regimens at week 24 (plasma HIV-1 RNA <50 copies per milliliter: 96.6% vs. 91.3%, difference 5.3%, 95.001% CI: 23.4% to 17.4%). E/C/F/TAF plus DRV met prespecified criteria for noninferiority and superiority at week 48 for the same outcome. E/C/F/TAF plus DRV was well tolerated and had an improved renal safety profile compared with baseline regimens, with statistically significant differences between groups in quantitative total proteinuria and markers of proximal tubular proteinuria. Compared with baseline regimens, participants who switched to E/C/F/TAF plus DRV reported higher mean treatment satisfaction scale total scores and fewer days with missed doses. Conclusions: This study demonstrated that regimen simplification from a 5-tablet regimen to the 2-tablet, once-daily combination of E/C/F/TAF plus DRV has durable maintenance of virologic suppression and improvements in specific markers of renal safety. Such a strategy may lead to greater adherence and improved quality of life. [ABSTRACT FROM AUTHOR]

Coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide(E/C/F/TAF) has high efficacy and improved renal and bone safety in multiple phase 3 trials; TAF single agent is being studied in 2 phase 3 trials in patients with chronic hepatitis B. We report the results of an open-label, noncomparative switch study evaluating the efficacy and safety of E/C/F/TAF in HIV/hepatitis B virus (HBV)-coinfected adults. At 48 weeks, 91.7% of the 72 participants maintained or achieved virologic suppression (HIV-1 RNA <50 copies/mL; HBV DNA <29 IU/mL). Seroconversion occurred in 2.9% of hepatitis B surface antigen-positive participants and in 3.3% of HBV e antigen-positive participants; 40% of those with abnormal alanine aminotransferase normalized. E/C/F/TAF was associated with improved renal function and reduced bone turnover. These data support the use of E/C/F/TAF in treating HIV/HBV coinfection. [ABSTRACT FROM AUTHOR]

In 2 double-blinded Phase 3 trials, 1733 antiretroviralnaive participants were randomized to tenofovir alafenamide (TAF), a tenofovir prodrug versus tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 96 weeks, 86.6% in the TAF arm and 85.2% in the TDF arm had HIV-1 RNA <50 c/mL [difference 1.5%; (95% CI: 21.8% to 4.8%)]. With TAF, there are smaller declines in bone mineral density and more favorable changes in proteinuria, albuminuria, and tubular proteinuria, and no cases of proximal tubulopathy compared with 2 for TDF. These longer-term data support E/C/F/TAF as a safe, welltolerated, and durable regimen for initial HIV-1 treatment. [ABSTRACT FROM AUTHOR]