Bictegravir/emtricitabine/tenofovir alafenamide in older individuals with HIV: Results of a 96-week, phase 3b, open-label, switch trial in virologically suppressed people ≥65 years of age.

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.

Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People with HIV Aged ≥ 65 Years: Week 48 Results of a Phase 3b, Open-Label Trial.

INTRODUCTION: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: Switching to B/F/TAF was effective and well tolerated through 48 weeks in virologically suppressed adults aged ≥ 65 years. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03405935.

Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in Adults With HIV and M184V/I Mutation.

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.

HIV/HCV therapy with ledipasvir/sofosbuvir after randomized switch to emtricitabine-tenofovir alafenamide-based single-tablet regimens.

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.

Bone mineral density in virologically suppressed people aged 60 years or older with HIV-1 switching from a regimen containing tenofovir disoproxil fumarate to an elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide single-tablet regimen: a multicentre, open-label, phase 3b, randomised trial.

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%]), vitamin D deficiency (four [7%]), 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. FUNDING: Gilead Sciences.

Randomized study evaluating the efficacy and safety of switching from an an abacavir/lamivudine-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide single-tablet regimen.

OBJECTIVE: To 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. DESIGN: Randomized, open-label, noninferiority study. METHODS: Participants 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). RESULTS: Baseline 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. CONCLUSION: Switching 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.

Efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide in Asian participants with human immunodeficiency virus 1 infection: A sub-analysis of phase 3 clinical trials.

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.

Repeat testing of low-level HIV-1 RNA: assay performance and implementation in clinical trials.

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.

Switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir DF from non-nucleoside reverse transcriptase inhibitor plus coformulated emtricitabine and tenofovir DF regimens: Week 96 results of STRATEGY-NNRTI.

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.

Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in Asian Subjects with Human Immunodeficiency Virus 1 Infection: A Sub-Analysis of Phase 3 Clinical Trials.

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)-naïve 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-naïve 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-naïve and ART-experienced Asian subjects.

Correction: An Indirect Comparison of Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate and Abacavir/Lamivudine + Dolutegravir in Initial Therapy.

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

An Indirect Comparison of Efficacy and Safety of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate and Abacavir/Lamivudine + Dolutegravir in Initial Therapy.

OBJECTIVES: The objective of this analysis is to perform an indirect comparison of elvitegravir, cobicistat, emtricitabine and tenofovir DF (E/C/F/TDF) to abacavir/lamivudine and dolutegravir (ABC/3TC + DTG) by using 2 trials evaluating each of these regimens in comparison to efavirenz, emtricitabine and tenofovir DF (EFV/FTC/TDF). METHODS: An indirect comparison was performed by using a generalization of Bucher's methodology to calculate risk differences. Two phase III clinical trials (GS-US-236-0102 and SINGLE-described above) were used. RESULTS: Results of the indirect comparison showed no statistically significant risk difference of the efficacy endpoint of achieving HIV RNA < 50 copies/mL between E/C/F/TDF and ABC/3TC + DTG for the ITT population at weeks 48, 96 and 144: respectively -3.7% (CI95% = [-10.8%; 3.4%]), -5.2% (CI95% = [-13.2%; 2.8%]) and -3.1% (CI95% = [-12.0%; 5.7%]). There was no statistically significant differences in the risk difference for serious adverse events (5.7% (CI95% = [-2.2%; 12.3%])), drug related adverse event (2.7% (CI95% = [-7.0%;12.4%])), drug related serious adverse event (0.8% (CI95% = [-1.6%;3.2%])) and death (0.5% (CI95% = [-0.8%;1.8%])), respectively, between E/C/F/TDF and ABC/3TC + DTG. A significant difference was found for discontinuation due to adverse events with a higher rate for E/C/F/TDF (difference = 8.6% (CI95% = [3.3%; 13.9%])). There was also no statistically significant risk difference of the viral resistance of 1.2% (CI95% = [-1.2; 3.7]) between E/C/F/TDF and ABC/3TC + DTG at week 48, 1.7% at week 96 (CI95% = [-1.1; 4.5]) and 2.2% (CI95% = [-1.0; 5.4]) at week 144.

Drug Interactions with Cobicistat- or Ritonavir-Boosted Elvitegravir.

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.

Rilpivirine vs. efavirenz-based single-tablet regimens in treatment-naive adults: week 96 efficacy and safety from a randomized phase 3b study.

OBJECTIVES: To compare efficacy, safety, tolerability, and patient-reported outcomes between two single-tablet regimens, rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults. DESIGN: This was a phase 3b, 96-week, randomized, open-label, international, noninferiority trial. METHODS: A total of 799 participants were randomized (1 : 1) to receive RPV/FTC/TDF or EFV/FTC/TDF. The primary efficacy endpoint evaluated proportions of participants with HIV-1 RNA less than 50 copies/ml using the Snapshot algorithm. Additional assessments included CD4 cell counts, genotypic/phenotypic resistance, adverse events, patient-reported outcomes, and quality of life questionnaires. RESULTS: At week 96, trial completion rates were 80.2% (316/394; RPV/FTC/TDF) and 74.0% (290/392; EFV/FTC/TDF). Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF [HIV-1 RNA <50 copies/ml: 77.9 vs. 72.4%, respectively; difference -5.5; 95%CI (-0.6, 11.5); P = 0.076]. RPV/FTC/TDF was significantly more efficacious compared with EFV/FTC/TDF in participants with baseline HIV-1 RNA equal to or less than 100 000 copies/ml (78.8 vs. 71.2%; P = 0.046) and in those with CD4 cell count greater than 200 cells/µl (80.6 vs. 73.0%; P = 0.018). There was no significant between-group difference in the CD4 cell count increase (278 ±â€Š189 vs. 259 ±â€Š191 cells/µl; P = 0.17). Few participants developed resistance after week 48 (1.0% RPV/FTC/TDF; 0.3% EFV/FTC/TDF). Compared with EFV/FTC/TDF, RPV/FTC/TDF was associated with fewer adverse event-related discontinuations (3.0 vs. 11.0%; P<0.001), significantly fewer adverse events due to central nervous system issues and rash, greater improvements in patient-reported symptoms, and significant improvements in the SF-12v2 quality of life questionnaire mental health composite score (P = 0.014). CONCLUSION: In treatment-naive, HIV-1-infected participants, 96-week RPV/FTC/TDF treatment demonstrated noninferior efficacy and better tolerability than EFV/FTC/TDF.

Discontinuation of tenofovir disoproxil fumarate for presumed renal adverse events in treatment-naïve HIV-1 patients: meta-analysis of randomized clinical studies.

BACKGROUND: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected and noninfected patients. This meta-analysis explored the frequency of discontinuation attributed to renal adverse events (AEs) in randomized, controlled clinical studies that used TDF-containing regimens for ART-naïve, HIV-infected patients. METHODS: A literature search of 4 electronic databases through October 31, 2013 was utilized. RCTs included were limited to randomized, prospective, comparative design in ART treatment-naïve adults with HIV-1 infections receiving ART. Studies included trials containing TDF treatment regimens, with or without a non-TDF control group. Study design, follow-up, size of study population, treatment group, patient demographics, number of patients exposed to TDF or non-TDF control, baseline characteristics, investigator-defined criteria for renal AEs, and number of discontinuations due to a presumed renal AEs were extracted. RESULTS: Twenty-one clinical studies met the selection criteria. Treatment duration ranged from 48 to 288 weeks. Renal AEs led to study drug discontinuation in 44 of 10,129 patients exposed to TDF (0.43%; 95% CI, 0.32%-0.58%) and 2 of 2,013 patients exposed to non-TDF-containing regimens (0.10%; 95% CI, 0.01%-0.36%). In 5 randomized, controlled studies that included a non-TDF comparator, the estimated risk difference between the treatment groups (TDF vs non-TDF) was 0.50% (95% CI, 0.13%-0.86%; P = .007). CONCLUSIONS: In clinical studies using TDF-containing regimens, the rate of discontinuations due to renal AEs was low, but was slightly higher than in studies using non-TDF comparators.

Long-term efficacy and safety of E/C/F/TDF vs EFV/FTC/TDF and ATV+RTV+FTC/TDF in HIV-1-infected treatment-naïve subjects ≥50 years.

INTRODUCTION: In high-income countries, ≥30% of HIV-infected patients are ≥50 years (yrs) old (UNAIDS 2013). In two phases, three clinical trials (Studies 102 and 103) elvitegravir/cobicistat/emtricitabine/tenofovir DF (E/C/F/TDF; STB) had non-inferior efficacy and favourable safety vs efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF; ATR) or ritonavir-boosted atazanavir (ATV+RTV)+FTC/TDF (TVD) in HIV-infected, treatment-naïve subjects at Week 144. The efficacy and safety of STB in subjects < or ≥50 yrs is described. MATERIALS AND METHODS: Post hoc analysis of efficacy, tolerability and safety in subjects < or ≥50 yrs at Week 144. RESULTS: Subjects ≥50 yrs in Study 102: STB: 14% (49/348), ATR: 16% (56/352); in Study 103: STB: 14% (48/353), ATV+RTV+TVD: 14% (48/355). Efficacy, safety and tolerability by age and study endpoint are shown in Table 1. Regardless of age, STB had robust efficacy at Week 144 with similar virologic outcomes vs ATR or ATV+RTV+TVD. Discontinuations (DC) due to AE on STB were similar to the comparators, most occurred by Week 48. Median changes in eGFR on STB were similar by age; DC with renal PRT was rare [STB: 4 (0.6%); ATV: 3 (0.8%); ATR: 0], 2 and 1 in ≥50 yrs old strata, respectively. CONCLUSIONS: STB compared to ATR or ATV+RTV+TVD, is an efficacious, well-tolerated and safe regimen for HIV-1-infected, treatment-naïve subjects

An indirect comparison of efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir and dolutegravir + abacavir/lamivudine.

BACKGROUND: Integrase strand transfer inhibitors (INSTI) are the standard of care for naïve HIV-infected individuals due to their favourable efficacy and safety profile. The newest INSTIs, elvitegravir and dolutegravir, have not been evaluated in a head to head study; however, both have been compared to efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF) in phase III trials. Elvitegravir/cobicistat/emtricitabine/tenofovir DF (E/C/F/TDF) was compared to EFV/FTC/TDF for 144 weeks in Gilead Study 102 (GS-102), while dolutegravir (DTG) with the abacavir/lamivudine fixed-dose combination (ABC/3TC) was compared to EFV/FTC/TDF for 96 weeks in the SINGLE study. The objective of this analysis is to perform an indirect comparison at 48 and 96 weeks of E/C/F/TDF to DTG+ABC/3TC by using the two trials evaluating each of these regimens compared to EFV/FTC/TDF. METHODS: An indirect comparison was performed by using Bucher's methodology to calculate risk differences based on the two phase III clinical trials described above. RESULTS: At week 48 (snapshot analysis), 88% of the patients on E/C/F/TDF and DTG+ABC/3TC had HIV RNA <50 c/mL, while 84% and 81% of patients on EFV/FTC/TDF were suppressed in GS-102 and SINGLE, respectively. At week 96, 84% of patients receiving E/C/F/TDF compared with 80% of patients receiving DTG+ABC/3TC remained suppressed, while 82% and 72% on EFV/FTC/TDF maintained HIV RNA <50 c/mL in GS-102 and SINGLE. At week 144 80% of patients on E/C/F/TDF remained suppressed (vs. 75% of the patients on EFV/FTC/TDF). RESULTS of indirect comparison showed a risk difference of HIV RNA <50 copies per mL between E/C/F/TDF compared with DTG+ABC/3TC of -4% (CI 95%=-11 to 3) for the ITT 48 weeks (p=0.3) and -5% (95% CI=-13 to 3) for the ITT 96 weeks (p=0.2). In regards to safety, there was no significant difference between E/C/F/TDF and DTG+ABC/3TC for any adverse event (AE) (p=0.3), serious AEs (0.13), drug related AEs (0.7), or drug-related serious AEs (0.6). CONCLUSIONS: In GS-102 and SINGLE, 88% of the patients on E/C/F/TDF and DTG+ABC/3TC were virologically suppressed at week 48. At week 96, these proportions were 84% for E/C/F/TDF and 80% for DTG+ABC/3TC. The indirect efficacy comparisons between EVG/COBI/FTC/TDF and DTG+ABC/3TC at week 48 and 96 revealed no statistically significant differences.

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

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