Population Pharmacokinetic and Pharmacodynamic Analysis To Evaluate a Switch to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in People Living with HIV-1.
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SUBMITTER: Vaddady P
PROVIDER: S-EPMC7577165 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
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Project description:Oral pre-exposure prophylaxis (PrEP) containing tenofovir disoproxil fumarate (TDF) co-formulated with emtricitabine (FTC) or lamivudine (3TC) is recommended as an additional prevention option for persons at substantial risk of HIV infection by both the World Health Organization (WHO) and the US President's Emergency Plan for AIDS Relief (PEPFAR). The WHO and PEPFAR consider 3TC clinically interchangeable with FTC for PrEP given comparable pharmacologic equivalence, resistance and toxicity patterns, and indirect clinical trial evidence from TDF-containing studies. Globally, FTC/TDF has been widely used in clinical trials, open-label extension studies and demonstration projects. Thus, most PrEP efficacy and safety data are based on FTC/TDF use in heterosexual women and men, men who have sex with men, and people who inject drugs. However, generic 3TC/TDF is less expensive than FTC/TDF, is already available in supply chains for HIV drugs, and has 60-70% of the global adult market share, making it particularly appealing in settings with limited availability or affordability of FTC/TDF. Compelling indirect evidence suggests that scaling up use of 3TC/TDF is potentially cost saving for HIV programs in settings where restricting drug choice to FTC/TDF would delay PrEP implementation. Guideline committees and public health decision-makers in countries should encourage flexibility in PrEP drug selection, support off-label use of 3TC/TDF, and approve use of generic formulations to decrease the cost of PrEP medications and accelerate PrEP delivery through the public and private sectors.
| S-EPMC7710557 | biostudies-literature
Project description:Background:Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. Methods:DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ?1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). Results:Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (-1.6 vs +8.7 mg/dL and -3.8 vs +13.3 mg/dL, respectively). Conclusions:In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF. Clinical Trials Registration:NCT02403674.
| S-EPMC6355823 | biostudies-literature
Project description:BACKGROUND:Doravirine is a novel, nonnucleoside reverse transcriptase inhibitor with demonstrated efficacy in treatment-naive adults with HIV-1. METHODS:In this open-label, active-controlled, noninferiority trial, adults with HIV-1 virologically suppressed for ?6 months on 2 nucleoside reverse transcriptase inhibitors plus a boosted protease inhibitor, boosted elvitegravir, or a non-nucleoside reverse transcriptase inhibitor were randomized (2:1) to switch to once-daily, single-tablet doravirine 100 mg with lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF) or to continue their current therapy (Baseline Regimen) for 24 weeks. The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies/mL (defined by the FDA Snapshot approach), with the primary comparison between DOR/3TC/TDF at week 48 and Baseline Regimen at week 24 and a secondary comparison between the groups at week 24 (noninferiority margin, -8%). RESULTS:Six hundred seventy participants (447 DOR/3TC/TDF, 223 Baseline Regimen) were treated and included in the analyses. At week 24, 93.7% on DOR/3TC/TDF vs 94.6% on Baseline Regimen had HIV-1 RNA <50 copies/mL [difference -0.9 (-4.7 to 3.0)]. At week 48, 90.8% on DOR/3TC/TDF had HIV-1 RNA <50 copies/mL, demonstrating noninferiority vs Baseline Regimen at week 24 [difference -3.8 (-7.9 to 0.3)]. In participants on ritonavir-boosted protease inhibitor at entry, mean reductions in fasting LDL-C and non-HDL-C at week 24 were significantly greater for DOR/3TC/TDF vs Baseline Regimen (P < 0.0001). Adverse events occurred in 68.9% on DOR/3TC/TDF and 52.5% on Baseline Regimen by week 24, leading to treatment discontinuation in 2.5% and 0.4%, respectively. CONCLUSIONS:Switching to once-daily DOR/3TC/TDF is a generally well-tolerated option for maintaining viral suppression in patients considering a change in therapy. REGISTRATION:ClinicalTrials.gov NCT02397096.
| S-EPMC6905402 | biostudies-literature
Project description:This study was designed to assess the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) responses to rectal administration of tenofovir (TFV) 1% vaginally formulated gel and oral tenofovir disoproxil fumarate (TDF). This study was designed as a phase 1, randomized, two-site (United States), double-blind, placebo-controlled study of sexually abstinent men and women. Eighteen participants received a single 300-mg exposure of oral TDF and were then randomized 2:1 to receive a single and then seven daily exposures of rectal TFV or hydroxyethyl cellulose (HEC) placebo gel. Safety endpoints included clinical adverse events (AEs) and mucosal safety parameters. Blood and colonic biopsies were collected for PK analyses and ex vivo HIV-1 challenge. No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use "if somewhat protective" was ?75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C(max) 30?min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK-PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations.
| S-EPMC3484811 | biostudies-literature
Project description:Tenofovir is the representative treatment for human immunodeficiency virus and hepatitis B virus infection. This study was conducted to assess the pharmacokinetics (PKs) and safety characteristics after a single administration of tenofovir disoproxil phosphate compared to tenofovir disoproxil fumarate in healthy male subjects. An open-label, randomized, single administration, two-treatment, two-sequence crossover study was conducted in 37 healthy volunteers. Serial blood samples were collected up to 72 hours. Non-compartmental analysis was used to calculate the PK parameters. The 90% confidence intervals (90% CIs) of the geometric mean ratio (GMR) were calculated for comparing tenofovir disoproxil phosphate to tenofovir disoproxil fumarate. Safety assessments were performed including clinical laboratory tests, adverse events, etc. during the study. The GMR and 90% CIs were 1.0514 (0.9527-1.1603) for Cmax and 1.0375 (0.9516-1.1311) for AUClast, respectively, and both fell within the conventional bioequivalence range of 0.8-1.25. Both tenofovir salt forms were tolerable. This study demonstrated that tenofovir disoproxil phosphate (292 mg) was bioequivalent to tenofovir disoproxil fumarate (300 mg).
| S-EPMC8020360 | biostudies-literature
Project description:To compare the distribution of tenofovir in sheep vaginal lumen, tissue, and plasma following topical delivery of the antiretroviral drug from intravaginal rings, either as tenofovir or the disoproxil fumarate prodrug.Comparative pharmacokinetic study in sheep.Intravaginal rings formulated to achieve equivalent release rates of tenofovir and its disoproxil fumarate prodrug were evaluated for 28 days in sheep, with four animals in each group. Drug concentrations were measured by high-performance liquid chromatography-mass spectrometry.Tenofovir levels in cervicovaginal lavage were indistinguishable (P?>?0.30) in both groups, but tissue levels in animals receiving the prodrug were 86-fold higher than those receiving tenofovir, and approximately 50 times higher than the level shown to be protective of HIV infection in the CAPRISA 004 trial.This is the first study to compare the pharmacokinetics of tenofovir and its disoproxil fumarate prodrug administered topically to the vaginal tract. These in-vivo data show that the prodrug leads to significantly higher drug tissue levels than tenofovir, a finding that may have important implications for the development of preexposure prophylaxis strategies based on topical delivery of antivirals to the female genital tract.
| S-EPMC3855348 | biostudies-literature
Project description:The efficacy of switching to tenofovir disoproxil fumarate (TDF) monotherapy from lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy (stable switching) in patients with LAM-resistant chronic hepatitis B (CHB) and undetectable hepatitis B virus (HBV) DNA is not clear.In this non-inferiority trial, patients with LAM-resistant CHB and undetectable serum HBV DNA (<20 IU/mL) for >6 months after initiating LAM+ADV combination therapy were randomized (1:2) either to continue the combination therapy (LAM+ADV group, n = 58) or switched to TDF monotherapy (TDF group, n = 111). They were followed-up with serum biochemistry tests and HBV DNA measurement at 12-week intervals for 96 weeks. The primary endpoint of this study was the proportion of patients with viral reactivation at week 96.Patients with CHB enrolled in this study (n = 169) included 74 patients with compensated liver cirrhosis. In total, 9 patients (4 in the LAM+ADV group and 5 in the TDF group) dropped-out from the study. After a mean follow-up period of 96 weeks, the proportion of HBV reactivation observed was 6.8% (4/58) in the LAM+ADV group and 4.5% (5/111) in the TDF group by using intention-to-treat analysis (difference, -2.3%; 95% CI, -9.84-5.24%). None of the subjects in either group experienced viral reactivation based on per protocol analysis. No serious adverse reactions were observed. In the subgroup analysis for estimated glomerular filtration rate (eGFR) before and after treatment, decreased eGFR was observed only in the TDF group with cirrhosis (85.22 vs. 79.83 mL/min/1.73 m2, p = 0.000).Stable switching to TDF monotherapy yielded non-inferior results at 96 weeks compared to the results obtained with LAM+ADV combination therapy in patients with LAM-resistant CHB and undetectable HBV DNA. However, TDF monotherapy in patients with cirrhosis requires close attention with respect to renal function.ClinicalTrials.gov NCT01732367.
| S-EPMC5766122 | biostudies-literature
Project description:BackgroundTenofovir disoproxil fumarate (TDF)-induced nephrotoxicity is related to high plasma tenofovir concentrations. Tenofovir alafenamide (TAF) is a tenofovir prodrug with 90% lower plasma tenofovir concentrations. The aim of this study was to evaluate changes in tenofovir-induced nephrotoxicity in Human Immunodeficiency Virus (HIV)-positive patients who switched from TDF to TAF.Materials and methodsWe identified all HIV-positive patients who switched from elvitegravir/cobicistat/emtricitabine/TDF to elvitegravir/cobicistat/emtricitabine/TAF at a tertiary hospital. We assessed tubulopathy and renal dysfunction before TDF administration, at the time TAF was used following at least 3 months of TDF use, and 3 months after TAF administration. Tubulopathy was defined by the presence of at least three abnormalities in fractional excretion of phosphate, fractional excretion of uric acid, urinary β2-microglobulin, urinary N-acetyl-β-D-glucosaminidase, glucosuria or proteinuria. Renal dysfunction was defined as decreased by more than 25% in the estimated glomerular filtration rate (eGFR) relative to baseline.ResultsIn 80 patients, the mean eGFR was 96.8 mL/min/1.73 m² before administration of TDF, 81.2 (P <0.001) at the time of change to TAF, 90.9 (P <0.001) after TAF administration. Renal dysfunction occurred in 19 patients (23.8%) after TDF use for a median 15 months, 11 (57.9%) of these patients recovered from renal dysfunction after TAF administration. Six patients (7.5%) had tubulopathy before TDF administration, 36 (45.0%) after TDF administration (P <0.001), 12 (15.0%) after TAF administration (P = 0.002).ConclusionTenofovir-induced nephrotoxicity in HIV-positive patients receiving TDF was mostly reversible after changing to TAF. Thus, TAF-containing regimens can be administered safely to HIV-positive patients with tenofovir-induced nephrotoxicity.
| S-EPMC7533205 | biostudies-literature
Project description:OBJECTIVE:Bone mineral density (BMD) loss, a risk factor for osteoporosis, has been attributed to HIV infection and antiretroviral therapy (ART), including regimens containing tenofovir disoproxil fumarate. DESIGN:Study 202094 is an open-label, parallel-group, sub-study of the phase III SWORD-1 and SWORD-2 studies (ClinicalTrials.gov identifier, NCT02478632). METHODS:HIV-1-infected adults with HIV-1 RNA less than 50 copies/ml who received ART containing tenofovir disoproxil fumarate for at least 6 months were randomized to receive dolutegravir with rilpivirine or continue current ART regimen. Total hip and lumbar spine BMD were measured by dual-energy X-ray absorptiometry (DXA) scans. The primary endpoint was percentage change from baseline in total hip BMD. RESULTS:DXA scans were evaluable for 81 participants at baseline and Week 48. Percentage increase in total hip BMD was significantly greater in participants who switched to dolutegravir with rilpivirine (1.34%) compared with participants who continued current ART (0.05%; treatment difference, +1.29%; 95% CI 0.27-2.31; P?=?0.014). Lumbar spine BMD significantly increased in the dolutegravir with rilpivirine group by 1.46% (95% CI 0.65-2.28) compared with 0.15% (95% CI -0.79 to 1.09) in the current ART group (treatment difference, 1.32; 95% CI 0.07-2.57; P?=?0.039). Participants in the dolutegravir with rilpivirine group experienced significantly greater reductions in bone formation and resorption biomarkers compared with the current ART group. CONCLUSION:Switch to dolutegravir with rilpivirine was associated with significant improvement in BMD and bone turnover markers compared with tenofovir-based three-drug regimens, providing a robust option for preserving bone health while continuing suppressive ART.
| S-EPMC5802259 | biostudies-literature
Project description:Tenofovir disoproxil fumarate (TDF) monotherapy has proven superior antiviral efficacy in chronic hepatitis B (CHB) patients; however, whether the combination of TDF and emtricitabine (FTC) exerts a significant advantage remains controversial. A meta-analysis was performed to comprehensively compare the therapeutic effects of FTC/TDF combination with TDF alone in CHB patients. Five studies involving 614 patients were identified, and subgroup analysis was performed based on the nucleos(t)ide treatment history. Our results revealed that in patients with nucleos(t)ide-naïve treatment, there were no significant differences between the treatment groups with TDF alone and FTC/TDF combination after 12 and 24 weeks; however, the FTC/TDF combination showed better viral suppression efficacy versus TDF alone after 48 (OR = 2.16, 95% CI = 1.06-4.41, P = 0.03), 96 (OR = 2.76, 95% CI = 1.29-5.92, P = 0.009) and 192 weeks (OR = 2.60, 95% CI = 1.21-5.56, P = 0.01). In patients with nucleos(t)ide treatment history, no differences were noted between the two treatment groups after 12, 24, 48 and 96 weeks. Our results indicated that FTC/TDF combination showed better viral suppression efficacy versus TDF alone in CHB patients with nucleos(t)ide-naïve treatment, while both treatments provided similar viral suppression efficacy in CHB patients with nucleos(t)ide treatment history.
| S-EPMC4499796 | biostudies-literature