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Evaluation of Safety and Effectiveness of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Switch Followed by Ledipasvir/Sofosbuvir HCV Therapy in HIV-HCV Coinfection.

ABSTRACT: BACKGROUND:We conducted a pilot study assessing the feasibility, efficacy, and safety of a simplified combination HIV antiretroviral and hepatitis C virus (HCV) antiviral regimen in HIV-HCV coinfection. METHODS:Participants on suppressive antiretrovirals and HCV genotype 1 infection were switched to single-tablet daily-dosed elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) and 1 month later initiated single-tablet-regimen daily-dosed ledipasvir-sofosbuvir for 12 weeks. E/C/F/TAF was continued during HCV treatment and for 12 weeks after. RESULTS:Twenty-six individuals were screened, 25 enrolled, and 23 completed all HIV and HCV treatment. Participants were predominantly male, with a mean age (SD) of 55 (7.5) years. The median transient elastography score (interquartile range [IQR]) was 5.9 (5.3 to 7.6) kPa, and the mean CD4 count (SD) was 579 (223) cells/µL. The median adherence to HCV medications, assessed by pill count, was 100% (95% confidence interval [CI], 100%-100%), and HIV ranged from 99% to 100% (100%; 95% CI, 90%-100%) over the 7-month study duration. HIV undetectability was maintained in all but 1 participant enrolled with unsuspected multiclass resistance. Treatment was well tolerated, with no study medication modification due to adverse events and no serious adverse event related to the study drug. All participants achieved sustained virological response. The mean CD4 count (SD) increased to 673 (361) cells/µL, and the fibrosis score (IQR) declined to 5.2 (4.4 to 7.4) kPa by week 12 after HCV treatment. There was no treatment effect on glucose metabolism. Cholesterol increased during and after treatment. CONCLUSIONS:Provision of this 2-tablet daily HIV-HCV regimen is feasible, well tolerated, and safe, avoids drug-drug interactions between HIV and HCV medications, maintains HIV suppression in the absence of drug resistance, and is highly curative of HCV.

SUBMITTER: Doyle MA

PROVIDER: S-EPMC6667714 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Evaluation of Safety and Effectiveness of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Switch Followed by Ledipasvir/Sofosbuvir HCV Therapy in HIV-HCV Coinfection.

Doyle Mary-Anne MA Lee Terry T Singer Joel J Crawley Angela A Klein Marina M Cooper Curtis C

Open forum infectious diseases 20190701 7

<h4>Background</h4>We conducted a pilot study assessing the feasibility, efficacy, and safety of a simplified combination HIV antiretroviral and hepatitis C virus (HCV) antiviral regimen in HIV-HCV coinfection.<h4>Methods</h4>Participants on suppressive antiretrovirals and HCV genotype 1 infection were switched to single-tablet daily-dosed elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) and 1 month later initiated single-tablet-regimen daily-dosed ledipasvir-sofosbuvir fo ...[more]

PMID: 31363776

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Project description:BackgroundDespite evidence shown of dolutegravir (DTG)-related neurotoxicity, which may be more common when combined with abacavir (ABC), its reversibility has not been explored in a clinical trial.MethodsWe conducted a randomized, multicenter, open-label, pilot trial to evaluate the reversibility of patient-reported neuropsychiatric symptoms, developed or worsened on DTG/ABC/lamivudine (DTG/ABC/3TC), in virologically suppressed patients switched to cobicistat-boosted-elvitegravir/emtricitabine/tenofovir-alafenamide (EVG/COBI/FTC/TAF). Participants were randomized to immediate switch (baseline) or to defer switch (week 4), and then all completed 24 weeks of follow up on EVG/COBI/FTC/TAF. At each visit, participants completed Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression (HAD) scales and were interviewed about 11 neuropsychiatric symptoms potentially related with DTG through a questionnaire. At baseline and at the end of follow up, they also performed neurocognitive testing. Our primary objective was to compare changes in neuropsychiatric symptoms and PSQI and HAD scales between arms at week 4. Secondary objectives were to evaluate changes in neuropsychiatric symptoms and PSQI and HAD scales at weeks 4, 12, and 24 after switching to EVG/COBI/FTC/TAF and in neurocognitive performance and magnetic resonance imaging biomarkers at end of follow up.ResultsThirty-eight participants were included. Study arms were similar at baseline. At week 4, neuropsychiatric symptoms and PSQI and HAD scores remained unchanged in participants receiving DTG/ABC/3TC and improved significantly in participants receiving EVG/COBI/FTC/TAF. These significant improvements were also observed at weeks 4, 12, and 24 after all participants switched to EVG/COBI/FTC/TAF. In addition, global neurocognitive performance improved (NPZ-7) after switching to EVG/COBI/FTC/TAF.ConclusionsNeuropsychiatric symptoms in patients on DTG/ABC/3TC could resolve or improve after switching to EVG/COBI/FTC/TAF.

Project description:A fixed-dose combination consisting of darunavir (Drv), cobicistat (Cobi), emtricitabine (2',3'-dideoxy-5-fluoro-3'-thiacytidine [FTC]), and tenofovir alafenamide (Taf) has been recently approved by the European Medicines Agency for the treatment of HIV infection, and is the first ever protease-inhibitor-based single-tablet regimen. This article provides a detailed description of its pharmacokinetic, efficacy, and safety profile. The pharmacokinetics of single compounds were analyzed, with a special focus on contrasts between Drv/Cobi and Drv/ritonavir (Rtv). When comparing Cobi and Rtv, multiple interactions must be taken into account: in comparison to Rtv, Cobi is a more selective CYP3A4 inhibitor and has no clinical effect on other isoenzymes inhibited by Rtv (eg, 2C8 and 2C9). Moreover, unlike Cobi, Rtv shows in vivo induction activity on some CYP isoenzymes (eg, 1A2, 2C19, 2C8, 2C9, and 2B6), glucuronyltransferases (eg, UGT1A4), and Pgp. Drv-Cobi-FTC-Taf has recently been demonstrated to be of equal efficacy to Drv-Rtv and other protease inhibitors in both experienced (EMERALD study) and naïve (AMBER study) patients. Moreover, kidney and bone safety profiles have been shown to be good, as has central nervous system tolerance. Total cholesterol:low-density-lipoprotein cholesterol and total cholesterol:high-density-lipoprotein cholesterol ratios are generally high in Drv-Cobi-FTC-Taf vs Rtv-Drv-FTC + tenofovir disoproxil fumarate. An unlikely role of Drv in influencing cardiovascular risk in HIV infection has also been reported. Kidney safety profile is influenced by Cobi, with an increase in creatinine plasma concentration of 0.05-0.1 mg/dL and a parallel glomerular filtration-rate reduction of 10 mL/min within the first 4 weeks after Cobi introduction, which remains stable during treatment. Bone and central nervous system safety profiles were found to be good in randomized clinical trials of both experienced and naïve patients. The efficacy and safety of Drv/Cobi/FTC/Taf are comparable to other drug regimens recommended for HIV treatment.

Project description:Background Women and those with non-B subtype HIV-1 are typically underrepresented in clinical trials. WAVES (GS-US-236-0128) was a double-blind phase 3b study among treatment-naïve HIV-1-infected women that demonstrated that elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF; N = 289) was superior to atazanavir + ritonavir + FTC/TDF (ATV + RTV + FTC/TDF; N = 286) for HIV-1 RNA < 50 copies/mL by FDA snapshot analysis at week 48. Here, we describe resistance development through week 48 in women with virologic failure and determine the impact of pre-existing mutations and HIV-1 subtype on viral suppression. Methods Genotypic analyses (population and deep sequencing) and phenotypic analyses of HIV-1 protease, reverse transcriptase (RT), and integrase (IN) were performed. The resistance analysis population (participants with HIV-1 RNA ≥ 400 copies/mL at confirmed virologic failure, at discontinuation ≥ week 8, or at week 48) had genotypic and phenotypic analyses at failure and baseline. Results The proportion of women qualifying for resistance analyses was similar between treatment groups (6.2% EVG/COBI/FTC/TDF; 7.3% ATV + RTV + FTC/TDF). Emergent resistance was rare (0% EVG/COBI/FTC/TDF; 1% ATV + RTV + FTC/TDF - 3 with M184V/I in RT). Deep sequencing of HIV-1 did not detect additional resistance development. Pre-existing mutations did not lead to virologic failure; most with the polymorphic primary IN substitution T97A (92%), or with substitutions in RT (i.e. A62V, V90I, K103N, or E138A/G/K/Q; 68-82%) demonstrated virologic suppression at week 48, with no resistance development except for one patient with M184V and pre-existing K103N in the ATV + RTV + FTC/TDF group. Most participants (74%) had non-B HIV-1, and subtype did not affect outcome. Conclusions Emergent resistance to study drugs was rare in this study of women, with no resistance observed among EVG/COBI/FTC/TDF-treated participants, despite a high proportion of participants with natural or transmitted viral mutations and non-B HIV-1 subtypes.

Project description:As a simplification strategy for treatment-experienced HIV-infected patients who have achieved virologic suppression on a multi-drug, multi-class antiretroviral regimen, the aim of this study was to evaluate the safety, efficacy, and pharmacokinetics of once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) with darunavir.A single arm, open-label 48-week study was conducted of regimen simplification to E/C/F/TDF plus darunavir 800 mg daily from stable therapy including two nucleoside/nucleotide reverse transcriptase inhibitors, a ritonavir-boosted protease inhibitor, and an integrase inhibitor. Participants had plasma HIV viral load consistently < 200 copies/mL for ? 6 months, estimated glomerular filtration rate (eGFR) ? 60 mL/min, and no genotypic resistance to major components of the study regimen. Plasma viral load was measured at weeks 2 and 4, then every 4 weeks throughout the study. Safety laboratory assessments were conducted at baseline and at weeks 12, 24, 36, and 48. Antiretroviral drug concentrations were measured at baseline and once ? 2 weeks after the regimen change.Ten HIV-infected adults (8 male and 2 female; median age 50.5 years) were enrolled. All maintained virologic suppression on the new regimen for 48 weeks. One subject experienced a decrease in eGFR from 62 mL/min at baseline to 52 mL/min at week 12; study medications were continued and his eGFR remained stable (50-59 mL/min) thereafter. No subjects discontinued study medications for renal function changes or other adverse events. Darunavir trough concentration were lower on the new regimen than on darunavir/ritonavir 800/100 mg (n = 5; p < 0.05).Despite low darunavir trough concentrations, treatment simplification to a two-pill, once-daily regimen of E/C/F/TDF plus darunavir was safe and effective for 48 weeks among 10 selected treatment-experienced HIV-infected patients. Trial registration The study protocol was registered with ClinicalTrials.gov (NCT02199613) on July 22, 2014.

Dataset Information

Evaluation of Safety and Effectiveness of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Switch Followed by Ledipasvir/Sofosbuvir HCV Therapy in HIV-HCV Coinfection.

Publications

Evaluation of Safety and Effectiveness of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Switch Followed by Ledipasvir/Sofosbuvir HCV Therapy in HIV-HCV Coinfection.

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