fumarates and HIV-Infections

fumarates has been researched along with HIV-Infections* in 34 studies

Reviews

3 review(s) available for fumarates and HIV-Infections

ArticleYear
Evaluating the combination of emtricitabine/ tenofovir alafenamide fumarate to reduce the risk of sexually acquired HIV-1-infection in at-risk adults.
    Expert opinion on pharmacotherapy, 2021, Volume: 22, Issue:10

    Pre-exposure prophylaxis with a single daily pill of emtricitabine (F) plus tenofovir disoproxil fumarate (TDF) is highly efficacious at preventing HIV acquisition. Tenofovir alafenamide (TAF) is another tenofovir prodrug that delivers higher intracellular levels of active tenofovir diphosphate in blood cells and has an improved safety profile compared to TDF. Given the recent regulatory approval of the F/TAF combination for prophylaxis, it is important to review its safety and efficacy.. In this review, the author examines the safety and efficacy of F/TAF for pre-exposure prophylaxis. Both published manuscripts and conference papers are reviewed. F/TAF is non-inferior to F/TDF at preventing HIV acquisition in men and transgender women with a trend toward superiority. F/TAF has yet to be tested against HIV exposure via injection or vaginal intercourse.. Within these limitations, F/TAF may be particularly advantageous for older individuals thanks to improved kidney safety compared to F/TDF. F/TAF did not possess the hypolipidemic properties of F/TDF and was associated with weight gains.

    Topics: Adenine; Adult; Alanine; Anti-HIV Agents; Emtricitabine; Female; Fumarates; HIV Infections; HIV-1; Humans; Male; Tenofovir

2021
Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy.
    Critical reviews in immunology, 2013, Volume: 33, Issue:4

    The persistence of chronic immune activation and oxidative stress in human immunodeficiency virus (HIV)-infected, antiretroviral drug-treated individuals are major obstacles to fully preventing HIV disease progression. The immune modulator and antioxidant dimethyl fumarate (DMF) is effective in treating immune-mediated diseases and it also has potential applications to limiting HIV disease progression. Among the relevant effects of DMF and its active metabolite monomethyl fumarate (MMF) are induction of a Th1 to Th2 lymphocyte shift, inhibition of pro-inflammatory cytokine signaling, inhibition of NF-κB nuclear translocation, inhibition of dendritic cell maturation, suppression of lymphocyte and endothelial cell adhesion molecule expression, and induction of the Nrf2-dependent antioxidant response element (ARE) and effector genes. Associated with these effects are reduced lymphocyte and monocyte infiltration into psoriatic skin lesions in humans and immune-mediated demyelinating brain lesions in rodents, which confirms potent systemic and central nervous system (CNS) effects. In addition, DMF and MMF limit HIV infection in macrophages in vitro, albeit by unknown mechanisms. Finally, DMF and MMF also suppress neurotoxin production from HIV-infected macrophages, which drives CNS neurodegeneration. Thus, DMF might protect against systemic and CNS complications in HIV infection through its effective suppression of immune activation, oxidative stress, HIV replication, and macrophage-associated neuronal injury.

    Topics: Animals; Antioxidants; Central Nervous System Diseases; Dimethyl Fumarate; Fumarates; HIV Infections; Humans; Virus Replication

2013
Dimethyl fumarate - only an anti-psoriatic medication?
    Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2012, Volume: 10, Issue:11

    Fumaric acid esters have been used successfully in the therapy of psoriasis vulgaris since 1959. In the last 17 years, many of the underlying mechanisms of anti-psoriatic action, such as a Th1/Th2 shift, a suppression of important leukocyte adhesion molecules, the induction of pro-apoptotic pathways in T-cells and recently anti-angiogenic action, have been discovered. Based on the knowledge of these immunomodulatory characteristics, fumaric acid esters have been shown to be effective or potentially effective in a multitude of dermatological as well as non-dermatological diseases. The range of new therapeutic targets reaches from multiple sclerosis to illnesses such as necrobiosis lipoidica, granuloma annulare and sarcoidosis. Experimental approaches offer promising, although preliminary, results on the treatment of cancer, malaria, chronic inflammatory lung diseases, and Huntington disease, to name but a few. This valued and well-known drug mainly prescribed by dermatologists is now experiencing a renaissance far beyond dermatologic applications.

    Topics: Dermatologic Agents; Dimethyl Fumarate; Fumarates; Granuloma Annulare; HIV Infections; Humans; Immunosuppressive Agents; Multiple Sclerosis; Necrobiosis Lipoidica; Neoplasms; Off-Label Use; Sarcoidosis

2012

Trials

4 trial(s) available for fumarates and HIV-Infections

ArticleYear
First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023, 09-18, Volume: 77, Issue:6

    We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial.. Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults.. Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors.. In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children.. ISRCTN22964075.

    Topics: Adult; Anti-HIV Agents; Antiviral Agents; Atazanavir Sulfate; Child; Darunavir; Emtricitabine; Fumarates; HIV Infections; Humans; Lopinavir; Protease Inhibitors; Ritonavir; Tenofovir

2023
INSTIs for the management of HIV-associated TB (INSIGHT study): a phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a combination of bictegravir, emtricitabine and tenofovir alafenamide fumarate for the treatment of HIV-1 infection i
    BMJ open, 2022, 11-10, Volume: 12, Issue:11

    Cotreatment of HIV and tuberculosis (TB) reduces morbidity and mortality in coinfected patients. Availability of antiretroviral treatment (ART) drug options, including within drug classes, is important, particularly in high HIV/TB burden low and middle-income countries.. This is a phase 2b, open-label, non-comparative randomised controlled trial to assess the antiretroviral activity of a fixed-drug, single tablet, combination of bictegravir (BIC) 50 mg/emtricitabine (FTC) 200 mg/tenofovir alafenamide (TAF) 25 mg (Biktarvy). The primary objective is to determine the efficacy, safety and pharmacokinetics of two times per day, coformulated BIC 50 mg/FTC 200 mg/TAF 25 mg in HIV-positive ART-naïve patients with TB who are receiving a rifampicin-based treatment regimen and to characterise viral suppression rates at week 24 through to week 48 in the BIC/FTC/TAF arm. We will enrol 120 patients randomised in a 2:1 ratio to the intervention or control arm of the study. A non-comparative contemporaneous control arm in which participants receive a dolutegravir-based regimen (standard of care) will also be enrolled.. The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC/00001300/2020 and SAHPRA 20200810). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.. Clinicaltrials.gov; Trial registration number: NCT04734652; South African National Clinical Trials Register (SANCTR DOH-27-012021-6789).

    Topics: Adenine; Anti-HIV Agents; Anti-Retroviral Agents; Emtricitabine; Fumarates; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Pyridones; Rifampin; Tuberculosis

2022
Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques.
    EBioMedicine, 2022, Volume: 86

    Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities.. PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12).. Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%-98.8%) and 100% (95% CI = undefined), respectively.. Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women.. Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.

    Topics: Adenine; Animals; Anti-HIV Agents; Female; Fumarates; HIV Infections; Macaca; Pre-Exposure Prophylaxis; Tenofovir

2022
Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021, 07-01, Volume: 73, Issue:1

    Doravirine (DOR) is a nonnucleoside reverse-transcriptase inhibitor. In the phase 3 DRIVE-AHEAD trial in treatment-naive adults with human immunodeficiency virus type 1 (HIV-1) infection, DOR demonstrated noninferior efficacy compared with efavirenz (EFV) and superior profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96.. DRIVE-AHEAD is a phase 3, multicenter, double-blind, noninferiority trial in antiretroviral treatment-naive adults with HIV-1 RNA ≥1000 copies/mL. Participants were randomized to a daily fixed-dose tablet of DOR (100 mg), lamivudine (3TC; 300 mg) and tenofovir disoproxil fumarate (TDF; 300 mg) (DOR/3TC/TDF) or EFV (600 mg), emtricitabine (FTC; 200 mg) and TDF (300 mg) (EFV/FTC/TDF). The efficacy end point of interest at week 96 was the proportion of participants with HIV-1 RNA levels <50 copies/mL (Food and Drug Administration Snapshot Approach) with a predefined noninferiority margin of 10% to support week 48 results. Safety end points of interest included prespecified neuropsychiatric adverse events and the mean change in fasting lipids at week 96.. Of 734 participants randomized, 728 received study drugs and were included in analyses. At week 96, HIV-1 RNA <50 copies/mL was achieved by 77.5% of DOR/3TC/TDF vs 73.6% of EFV/FTC/TDF participants, with a treatment difference of 3.8% (95% confidence interval, -2.4% to 10%). Virologic failure rates were low and similar across treatment arms, with no additional resistance to DOR observed between weeks 48 and 96. Prespecified neuropsychiatric adverse events and rash were less frequent in DOR/3TC/TDF than in EFV/FTC/TDF participants through week 96. At week 96, fasting low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol (HDL-C) levels increased in the EFV/FTC/TDF group but not in the DOR/3TC/TDF group; the mean changes from baseline in total cholesterol/HDL-C ratio were similar.. NCT02403674.

    Topics: Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Emtricitabine; Fumarates; HIV Infections; HIV-1; Humans; Lamivudine; Pyridones; Tenofovir; Treatment Outcome; Triazoles

2021

Other Studies

27 other study(ies) available for fumarates and HIV-Infections

ArticleYear
Renal profile of patients treated with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate and dolutegravir/abacavir/lamivudine: 120-week results from a real-world cohort.
    European journal of hospital pharmacy : science and practice, 2023, Volume: 30, Issue:4

    Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (EVG/c/FTC/TAF) and dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) are currently available for HIV patients.. This study evaluated modifications in the renal safety profile in a large real-world cohort of patients who had received EVG/c/FTC/TAF or DTG/ABC/3TC.. A retrospective observational study of HIV-infected patients who received EVG/c/FTC/TAF or DTG/ABC/3TC between March 2015 and June 2019 at a reference hospital in north-western Spain was conducted. Epidemiological, clinical, immunovirological data and information regarding antiretroviral therapy were recorded. The statistical differences between treatments were calculated.. A total of 457 patients were evaluated, 266 using EVG/c/FTC/TAF and 191 using DTG/ABC/3TC. Up to week 120, serum creatinine improved in both study groups among experienced patients (EVG/c/FTC/TAF 1.01±0.24 vs 0.91±0.19, p<0.001; DTG/ABC/3TC 1.08±0.24 vs 1.02±0.31, p<0.001), while in naïve patients serum creatinine remained stable compared with baseline. Statistically significant differences were found in serum creatinine when comparing both treatments at week 48 in experienced (0.94±0.21 vs 1.09±0.28, p<0.001) and naïve patients (0.89±0.16 vs 1.06±0.20, p=0.001), and among experienced patients at week 120 (0.91±0.19 vs 1.02±0.31, p=0.015) for the EVG/c/FTC/TAF and DTG/ABC/3TC groups, respectively. During the follow-up, 39 patients in EVG/c/FTC/TAF and 33 in DTG/ABC/3TC (p=0.449) discontinued treatment. The main reason for stopping treatment was adverse events, which were similar in both groups.. During the follow-up, patients experienced changes that were not clinically relevant in both treatment groups. Differences in renal events were not found.

    Topics: Anti-HIV Agents; Cobicistat; Creatinine; Emtricitabine; Fumarates; HIV Infections; Humans; Lamivudine

2023
Effect of P-glycoprotein and Cotreatment with Sofosbuvir on the Intestinal Permeation of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate.
    Pharmaceutical research, 2023, Volume: 40, Issue:9

    We aimed to compare the effects of P-glycoprotein (ABCB1) on the intestinal uptake of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), and metabolites, tenofovir isoproxil monoester (TEM) and tenofovir (TFV), and to study the molecular mechanism of drug-drug interaction (DDI) between sofosbuvir (SOF) and TDF/TAF.. Bidirectional transport experiments in Caco-2 cells and accumulation studies in precision-cut intestinal slices prepared from the ileal segment of rodent (rPCIS) and human (hPCIS) intestines were performed.. TDF and TAF were extensively metabolised but TAF exhibited greater stability. ABCB1 significantly reduced the intestinal transepithelial transfer and uptake of the TFV. TDF and TAF likely produce comparable concentrations of TFV-equivalents in the portal vein and the extent of permeation is reduced by the activity of ABCB1. DDI on ABCB1 can thus potentially affect TDF and TAF absorption. SOF does not inhibit ABCB1-mediated transport of TDF and TAF but does stabilise TDF, albeit without affecting the quantity of TFV

    Topics: Adenine; Alanine; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caco-2 Cells; Fumarates; HIV Infections; Humans; Sofosbuvir; Tenofovir

2023
Prophylaxis by doravirine-lamivudine-tenofovir disoproxil fumarate or elvitegravir-cobicistat-emtricitabine-tenofovir alafenamide after sexual exposure to HIV.
    BMC infectious diseases, 2023, Sep-04, Volume: 23, Issue:1

    HIV post- exposure prophylaxis (PEP) is a prevention tool for individuals with a recent potential exposure to HIV. Doravirine has been available since 2019 in combination with tenofovir disoproxil fumarate and lamivudine and has not been evaluated as a PEP. DOR/3TC/TDF is our department's most commonly prescribed PEP treatment since 2021. This study evaluates the completion rate of the DOR/3TC/TDF as compared to EVG/c/FTC/TAF for PEP, which was the regimen prescribed until 2020 in our hospital.This retrospective observational study was conducted between January 2020 and September 2021. The subjects included consecutively were adults who consulted for an HIV sexual exposure accident and for whom DOR/3TC/TDF in 2021 or EVG/c/FTC/TAF in 2020 was prescribed. The outcomes were the completion rate to the end of treatment (28 days), the seroconversion rate, and the description of side effects.During the study period, 311 people were included: 140 treated with DOR/3TC/TDF and 171 treated with EVGc/FTC/TAF. Considering subjects with a follow-up visit, the completion rate was 96.8% (90/93) in the DOR/3TC/TDF group, and 94.6% (123/130) in the EVG/c/FTC/TAF group (p-value: 0.53). The number of people lost to follow-up was nearly equivalent in both groups: 27.1% (38/140) in the DOR/3TC/TDF group and 23.4% (40/171) in the EVG/c/FTC/TAF group (p-value: 0.45). A side effect was described for 38% (36/94) in the DOR/3TC/TDF group, and 29.7% (38/128) in the EVG/c/FTC/TAF group. No cases of seroconversion were observed.DOR/3TC/TDF appears to have a similar safety profile to EVG/c/FTC/TAF. Due to its lower cost, it seems to be a treatment option for consideration in the context of HIV-exposure accidents.

    Topics: Adult; Anti-HIV Agents; Cobicistat; Drug-Related Side Effects and Adverse Reactions; Emtricitabine; Fumarates; HIV Infections; Humans; Lamivudine; Tenofovir

2023
Use of Tenofovir Alafenamide Fumarate for HIV Pre-Exposure Prophylaxis and Incidence of Hypertension and Initiation of Statins.
    JAMA network open, 2023, 09-05, Volume: 6, Issue:9

    Pre-exposure prophylaxis (PrEP) is an important tool for preventing HIV infection. However, PrEP's impact on cardiometabolic health is understudied.. To examine the risk of incident hypertension and statin initiation among adult (age ≥18 years) health plan members starting PrEP with tenofovir alafenamide fumarate (TAF) compared with propensity score-matched adults taking tenofovir disoproxil fumarate (TDF).. This retrospective cohort study used electronic health records (EHRs) from Kaiser Permanente Southern California. Adult members starting PrEP in Kaiser Permanente Southern California between October 2019 and May 2022 were included. Propensity score matching with multiple imputation (50 matched data sets) was conducted to generate 1 TAF:4 TDF matched data sets with balanced baseline covariates.. PrEP initiation with either TAF or TDF during the study period.. Incident hypertension and statin initiation within 2 years of PrEP initiation were ascertained through blood pressure and outpatient pharmacy records, respectively. Risk differences and odds ratios (ORs) were estimated using logistic regression and g-computation.. A total of 6824 eligible individuals were identified (mean [SD] age, 33.9 [10.3] years; 6618 [97%] male). This pool was used to generate 2 cohorts without baseline hypertension or statin use for matching (hypertension: n = 5523; statin: n = 6149) In both cohorts, those starting PrEP with TAF were older and were more likely to be non-Hispanic White compared with those starting with TDF. In matched analysis adjusting for baseline covariates, TAF use was associated with elevated risk of incident hypertension (TAF: n = 371; risk difference, 0.81 [95% CI, 0.12-1.50]; OR, 1.64 [95% CI, 1.05-2.56]). TAF use was also associated with elevated risk of statin initiation (TAF: n = 382; risk difference, 0.85 [95% CI, 0.37-1.33]; OR, 2.33 [95% CI, 1.41-3.85]). Subgroup analyses restricted to individuals 40 years and older at PrEP initiation showed similar results with larger risk difference in statin initiation (risk difference, 4.24 [95% CI, 1.82-6.26]; OR, 3.05 [95% CI, 1.64-5.67]).. In this study of people taking PrEP, TAF use was found to be associated with higher incident hypertension and statin initiation compared with TDF use, especially in those 40 years or older. Continued monitoring of blood pressure and lipids for TAF users is warranted.

    Topics: Adenine; Adolescent; Adult; Female; Fumarates; HIV Infections; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Incidence; Male; Pre-Exposure Prophylaxis; Retrospective Studies; Tenofovir

2023
Analytical Lifecycle Management (ALM) and Analytical Quality by Design (AQbD) for analytical procedure development of related substances in tenofovir alafenamide fumarate tablets.
    Journal of pharmaceutical and biomedical analysis, 2022, Jan-05, Volume: 207

    Analytical procedure development for quantifying 10 impurities in Tenofovir Alafenamide Fumarate (TAF) tablets was a challenge for analytical and formulation researchers. The aim of this paper was to develop a robust, regulatory-flexible, application-specific Ultra Performance Liquid Chromatography (UPLC) analytical procedure using the Analytical Lifecycle Management (ALM) and the Analytical Quality by Design (AQbD) for the estimation of the TAF tablets. In this work, the Analytical Target Profile (ATP) for the analytical procedure and the Critical Analytical Attributes (CAAs) were identified. Through the risk assessment studies, the high-risk analytical conditions were found, and they were screened and optimized by the Design of Experiment (DoE) to obtain the Design Space (DS) and identify the working point. The prediction intervals were used to examine the robustness of the analytical procedure. And the procedure performance qualification and the continued procedure performance verification were used to ensure routine application of analytical procedure. Finally, the 10 impurities were separated within 20 min by UPLC. The success of this study demonstrates the usefulness of using ALM and AQbD for analytical procedure development and provides a reference for the analytical procedure development for other drugs.

    Topics: Adenine; Alanine; Anti-HIV Agents; Chromatography, Liquid; Fumarates; HIV Infections; Humans; Tablets; Tenofovir

2022
Effect of switching from tenofovir disoproxil fumarate to tenofovir alafenamide on estimated glomerular filtration rate slope in patients with HIV: A retrospective observational study.
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 2022, Volume: 28, Issue:3

    There is limited data on the effects of switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) on estimated glomerular filtration rates (eGFR) slope in patients with human immunodeficiency virus (HIV) infection. This study aimed to compare the eGFR slope when administering TDF and TAF and to investigate the predictors of improvement in eGFR slope after switching from TDF to TAF.. We conducted a single-center, retrospective, observational study in Japanese patients with HIV infection who switched the antiretroviral drug from TDF to TAF. eGFR was calculated using serum cystatin C. The eGFR slope was defined as the regression coefficient between eGFR and time. Differences between eGFR slope during TDF and TAF administration were compared using Wilcoxon signed rank test. A stepwise logistic regression model was used to examine the associations between improvement of eGFR slope after switching from TDF to TAF and various parameters.. The results suggest that patients with poor renal function and those with progressive worsening during TDF administration would benefit from switching to TAF.

    Topics: Alanine; Anti-HIV Agents; Fumarates; Glomerular Filtration Rate; HIV Infections; Humans; Retrospective Studies; Tenofovir

2022
Doravirine/tenofovir disoproxyl fumarate/lamivudine-induced alopecia: A case report.
    International journal of STD & AIDS, 2022, Volume: 33, Issue:7

    Topics: Alopecia; Anti-HIV Agents; Anti-Retroviral Agents; Emtricitabine; Fumarates; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Pyridones; Tenofovir; Triazoles; Viral Load

2022
Tenofovir alafenamide fumarate.
    Antiviral therapy, 2022, Volume: 27, Issue:2

    Tenofovir alafenamide fumarate is a lipophilic prodrug of tenofovir which is preferentially metabolized in lymphatic tissue resulting in high concentrations of tenofovir (TFV) and its active diphosphate metabolite inside the cells that replicate HIV. Due to its selectivity for these tissues, lower total doses of TAF can be administered relative to tenofovir disoproxil fumarate (TDF) which results in improved bone and renal biomarkers. Tenofovir alafenamide fumarate has become the "backbone" of multiple combination products for the treatment of HIV, combined with emtricitabine for PreP and as a monotherapy for the treatment or HBV.

    Topics: Adenine; Alanine; Anti-HIV Agents; Fumarates; HIV Infections; HIV-1; Humans; Tenofovir

2022
Weight changes in patients with sustained viral suppression switching tenofovir disoproxil fumarate to tenofovir alafenamide.
    Obesity (Silver Spring, Md.), 2022, Volume: 30, Issue:6

    Switching from tenofovir disoproxil fumarate (TDF)- to tenofovir alafenamide (TAF)-containing antiretroviral therapy may negatively influence weight, cholesterol, and atherosclerotic cardiovascular disease risk. The extent of these changes and their association with TAF remain unclear.. This retrospective cohort evaluated metabolic changes in virologically suppressed patients with HIV infection who switched from TDF to TAF without switching other antiretroviral therapy medications. Adult patients on TDF and with no HIV viral load values >200 copies/mL for ≥2 years prior to and following a TAF switch were included. Weight and other variables were collected for 2 years before and after the switch. Longitudinal linear mixed-effects models evaluated changes at 1 and 2 years after the switch.. In the unadjusted analysis, there were increases in weight, BMI, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, fasting glucose, and atherosclerotic cardiovascular disease risk scores 2 years after switching to TAF (each p ≤ 0.03). However, only increases in total and low-density lipoprotein cholesterol were associated with TAF and were significantly different from expected changes predicted in the adjusted longitudinal models.. Despite observing significant unadjusted metabolic changes after switching to TAF, only changes in cholesterol were associated with TAF and were different from changes expected in time-trend adjusted models.

    Topics: Adenine; Adult; Alanine; Anti-HIV Agents; Cardiovascular Diseases; Cholesterol; Drug Substitution; Fumarates; HIV Infections; Humans; Retrospective Studies; Sustained Virologic Response; Tenofovir; Weight Gain

2022
Pill related oesophagitis due to tenofovir disproxil fumarate/emtricitabine (Truvada) HIV pre-exposure prophylaxis.
    Internal medicine journal, 2022, Volume: 52, Issue:6

    Topics: Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Esophagitis; Fumarates; HIV Infections; Humans; Pre-Exposure Prophylaxis; Tenofovir

2022
Effect of alcohol exposure on the efficacy and safety of tenofovir alafenamide fumarate, a major medicine against human immunodeficiency virus.
    Biochemical pharmacology, 2022, Volume: 204

    Human immunodeficiency virus (HIV) continues to be a major health concern. AIDS-related deaths (acquired immunodeficiency syndrome) have decreased recently, but chronic liver disease is now a major cause of mortality among HIV patients. Widespread alcohol use is recognized to be a major contributing factor. Tenofovir alafenamide fumarate (TAF), one of the most used HIV drugs, requires hydrolysis followed by phosphorylation to produce tenofovir diphosphate, the ultimate anti-HIV metabolite. Carboxylesterase-1 (CES1), established to hydrolyze TAF, is known to catalyze transesterification in the presence of ethanol. The aim of the study was to test the hypothesis that metabolism-based interactions between TAF and ethanol negatively impact both efficacy and safety of TAF. To test this hypothesis, the metabolism of TAF was determined in human primary hepatocytes and with a large number of human liver samples (S9 fractions) in the presence or absence of ethanol. The metabolism was monitored by LC-MS/MS (liquid chromatography with tandem mass spectrometry) and the level of CES1 or CES2 was determined by Western blotting. Consistent with the hypothesis, TAF underwent transesterification in the presence of ethanol accompanied by decreased hydrolysis. The formation of tenofovir diphosphate (the therapeutically active metabolite) was significantly decreased. In addition, TAF but not its hydrolytic metabolite, was found to increase intracellular lipid retention, and the increase was enhanced by ethanol. These findings conclude that alcohol consumption, beyond commonly accepted poor adherence to HIV medications, directly impacts the efficacy and safety of TAF.

    Topics: Adenine; Alanine; Alcohol Drinking; Anti-HIV Agents; Carboxylic Ester Hydrolases; Chromatography, Liquid; Ethanol; Fumarates; HIV; HIV Infections; Humans; Lipids; Organophosphates; Tandem Mass Spectrometry; Tenofovir

2022
Understanding the Actual Use of Anti-HIV Drugs in Japan from 2016 to 2019: Demonstrating Epidemiological Relevance of NDB Open Data Japan for Understanding Japanese Medical Care.
    International journal of environmental research and public health, 2022, 09-25, Volume: 19, Issue:19

    The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan is helpful for attaining simple and comprehensive understanding of medical care in Japan. Herein, we investigated the transition of anti-HIV-drug use in Japan over a 4-year period from fiscal year (FY) 2016 to FY 2019 using data on anti-HIV drugs that were extracted from the 3rd, 4th, 5th, and 6th NDB Open Data Japan. Then, the data were stratified by mechanism of action, single-tablet regimen (STR) or non-STR, age groups, and sex and analyzed. Throughout the study period, the prescription volume for tenofovir alafenamide fumarate as the backbone drug and integrase strand transfer inhibitors as the anchor drug increased. In FY 2019, STRs constituted approximately 44% of the total combination antiretroviral therapy regimens, 1.6 times higher than that in FY 2016 (27%). With the advent of newer drugs and regimens, the differences in anti-HIV drugs prescribed to patients of different ages and sex gradually diminished; however, differences were unremarkable in the first period, especially between sexes. The NDB Open Data Japan made it relatively easy to evaluate recent trends in anti-HIV prescription in Japan, indicating its usefulness for continuous surveys in this field.

    Topics: Anti-HIV Agents; Fumarates; HIV Infections; Humans; Integrases; Japan; Tablets; Tenofovir

2022
Pharmacokinetics and efficacy of topical inserts containing tenofovir alafenamide fumarate and elvitegravir administered rectally in macaques.
    EBioMedicine, 2022, Volume: 86

    Topical on-demand forms for HIV pre-exposure prophylaxis (PrEP) may be a desirable alternative for people that prefer not to use daily PrEP. CONRAD has developed inserts containing tenofovir alafenamide (TAF) and elvitegravir (EVG) for on-demand vaginal or rectal pericoital use. We assessed the pharmacokinetics (PK) and pre-exposure efficacy of rectally applied TAF/EVG inserts in macaques.. PK was assessed in 12 pigtailed macaques. Tenofovir (TFV) and EVG levels were assayed in rectal biopsies and secretions, and tenofovir-diphosphate (TFV-DP) levels in biopsies and peripheral blood mononuclear cells (PBMC). Drug biodistribution was evaluated in 10 animals at necropsy 4 h post-dosing. For efficacy assessments, one or two TAF/EVG inserts were administered to macaques (n = 6) 4 h before repeated rectal SHIV162p3 challenges.. One TAF/EVG insert resulted in rapid and high EVG and TFV-DP in rectal tissue 4 h after application. Adding a second insert led to a 10-fold increase in EVG and TFV-DP in rectal tissue. Efficacy of one and two TAF/EVG inserts were 72.6% (CI 24.5%-92.6%) and 93.1% (CI 73.3%-99.2%), respectively.. Although high TFV-DP and EVG levels were observed with one rectal TAF/EVG insert, it only conferred partial protection from rectal SHIV challenges. Adding a second insert led to an increase in TFV and EVG in rectal tissues resulting in higher (>90%) efficacy. These results highlight the high efficacy of TAF/EVG inserts as topical on-demand rectal PrEP, as well as the need for appropriate drug coverage in the deep rectum and colon to achieve high protection.. The work related to animal studies was funded by CDC intramural funds and an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002). The work related to the insert formulation was funded by U.S. PEPFAR through USAID under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. The findings and conclusions of this manuscript are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention (CDC), USAID, President's Emergency Plan for AIDS Relief (PEPFAR), Eastern Virginia Medical School (EVMS), or the US government.

    Topics: Alanine; Animals; Anti-HIV Agents; Female; Fumarates; HIV Infections; Leukocytes, Mononuclear; Macaca; Tenofovir; Tissue Distribution

2022
Doravirine/lamivudine/tenofovir disoproxil fumarate-induced hypertriglyceridemia in a newly diagnosed AIDS patient.
    AIDS (London, England), 2022, 12-01, Volume: 36, Issue:15

    Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Emtricitabine; Fumarates; HIV Infections; Humans; Hypertriglyceridemia; Lamivudine; Tenofovir

2022
Renal function in Japanese HIV-1-positive patients who switch to tenofovir alafenamide fumarate after long-term tenofovir disoproxil fumarate: a single-center observational study.
    AIDS research and therapy, 2021, 12-07, Volume: 18, Issue:1

    Tenofovir disoproxil fumarate (TDF) has a strong antiviral effect, but TDF is known to cause renal dysfunction. Therefore, we are investigating preventing renal dysfunction by replacing TDF with tenofovir alafenamide fumarate (TAF), which is known to be relatively safe to the kidneys. However, the changes in renal function under long-term use of TAF are not known. In this study, we evaluated renal function in Japanese HIV-1-positive patients switching to TAF after long-term treatment with TDF.. A single-center observational study was conducted in Japanese HIV-1-positive patients. TDF was switched to TAF after at least 48 weeks of the treatment so we could evaluate the long-term use of TDF. The primary endpoint was the estimated glomerular filtration rate (eGFR) at 144 weeks of TAF administration. In addition, we predicted the factors that would lead to changes in eGFR after long-term use of TAF.. Of the 125 HIV-1-positive patients who were prescribed TAF at our hospital during the study period, 70 fulfilled the study criteria. The eGFR at the time of switching from TDF to TAF was 81.4 ± 21.1 mL/min/1.73 m. In this study, it was confirmed that switching to TAF was effective for Japanese HIV-1-positive patients who had been taking TDF for a long period of time and had a reduced eGFR. It was also found that the transition status depended on the eGFR and weight at the time of switch. Since HIV-1-positive patients in Japan are expected to continue taking TAF for a long time, renal function and body weight should be carefully monitored.

    Topics: Alanine; Anti-HIV Agents; Fumarates; HIV Infections; HIV-1; Humans; Japan; Kidney; Tenofovir

2021
Outcomes associated with treatment change from tenofovir disoproxil fumarate to tenofovir alafenamide in HIV-1-infected patients: a real-world study in Japan.
    HIV medicine, 2021, Volume: 22, Issue:6

    To investigate the impact of switching from tenofovir disoproxil fumarate (TDF)- to tenofovir alafenamide (TAF)-containing regimens on bone, kidney, serum lipids and body weight among Asian patients.. A prospective, multicentre, observational cohort study was conducted at three centres for HIV infection in Japan during 2017-2019. HIV-infected adults previously treated with TDF-containing regimens and scheduled to switch to TAF-containing regimens were included. Bone mineral density (BMD), renal markers, lipids and weight were measured consecutively from 12 months before to 12 months after the switch.. Among 118 patients evaluated, the mean percentage change to spine BMD during 1 year of TAF treatment was higher than that during 1 year of TDF treatment (mean difference = 1.9%; 95% confidence interval (CI): 0.8-3.1). Urine protein and β. Among predominantly Japanese HIV-infected patients, BMD and renal tubular markers improved, while lipid profiles worsened significantly after the switch. Weight gain during the TAF period was larger than that during the TDF period. Concurrent use of INSTI with TAF may act synergistically to gain body weight.

    Topics: Adult; Alanine; Anti-HIV Agents; Fumarates; HIV Infections; HIV-1; Humans; Japan; Prospective Studies; Tenofovir

2021
Hypophosphatemia in people with HIV: no benefit when switching from tenofovir disoproxil fumarate to tenfovir alafenamide.
    AIDS (London, England), 2021, 07-15, Volume: 35, Issue:9

    Treatment with tenofovir disoproxil fumarate (TDF) has been associated with hypophosphatemia mainly because of injury of the renal proximal tubulus. Studies on the impact of tenfovir alafenamide (TAF) on phosphate homeostasis in people with HIV (PWH) are limited. Prompted by a patient with phosphate wasting under tenofovir but no other evidence for tubular dysfunction, a retrospective cohort analysis with 102 PWH revealed that hypophosphatemia remained largely unchanged after switching from TDF to TAF.

    Topics: Anti-HIV Agents; Fumarates; HIV Infections; Humans; Hypophosphatemia; Retrospective Studies; Tenofovir

2021
Changes in alanine aminotransferase levels after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in HIV-positive people without viral hepatitis in the Swiss HIV Cohort Study.
    HIV medicine, 2021, Volume: 22, Issue:7

    We previously demonstrated an association between tenofovir disoproxil fumarate (TDF) and chronic liver enzyme elevation in the D:A:D study. The objective of the study was to assess changes in alanine aminotransferase (ALT) levels after switching from TDF to tenofovir alafenamide (TAF).. We included Swiss HIV Cohort Study participants who switched from TDF to TAF with two or more ALT values in the 24 months before and two or more values in the 24 months after replacing TDF with TAF. Individuals with replicating viral hepatitis were excluded. Uni- and multivariable linear mixed models were used to explore changes in ALT values associated with switching from TDF to TAF, and to assess potential modifying effects.. A total of 1712 participants were included, contributing 6169 ALT values before and 5482 after switching. Median (interquartile range, IQR) age was 50 (42-57) years, and 75% were male. Median (IQR) ALT was 28 (22-38) U/L before and 24 (19-32) U/L after replacing TDF with TAF. ALT values decreased by 3.7 U/L (95% confidence interval: 3.2-4.2) after the switch. The median drop was larger in patients with chronic ALT elevation (defined as two or more elevated values for ≥ 6 months) compared with patients with normal ALT values (17.8 vs. 3.3 U/L, P < 0.001). We did not identify any major effect modifications of the ALT change with any of the potential variables studied.. Replacing TDF with TAF in HIV-monoinfected people led to a significant decrease in ALT values. Findings were not significantly affected by known risk factors for hepatotoxicity.

    Topics: Alanine; Alanine Transaminase; Anti-HIV Agents; Cohort Studies; Fumarates; Hepatitis, Viral, Human; HIV Infections; Humans; Male; Middle Aged; Switzerland; Tenofovir

2021
Changing trends in lipid profile and biomarkers of renal function and bone metabolism before and after switching from tenofovir disoproxil fumarate to tenofovir alafenamide: a prospective observational study.
    AIDS research and therapy, 2021, 05-27, Volume: 18, Issue:1

    Antiretrovirals, including tenofovir, can suppress human immunodeficiency virus (HIV) infection but cannot completely eradicate it. Patients with HIV infection are administered antiretroviral drugs over a long term; thus, managing consequent adverse drug reactions, such as renal dysfunction and bone mineral loss, is important. Currently, highly sensitive biomarkers that can detect adverse drug reactions early have not been well studied.. This single-center, prospective, observational study explored changes in the biomarkers of renal function, bone metabolism, and lipid profile before and after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with HIV infection.. All 31 enrolled patients had been treated with antiretrovirals for more than 5 years. The rate of proteinuria decreased significantly after starting TAF-containing antiretroviral regimen. The urinary liver-type fatty acid binding protein (L-FABP)/creatinine ratio was significantly decreased at 3 and 6 months after switching to TAF compared with that before switching to TAF (- 0.5 μg/g Cr at 3 months, and - 0.8 μg/g Cr at 6 months; p < 005 for both at 3 and 6 months). The urinary N-terminal telopeptide (NTx)/creatinine ratio decreased over the study period, and the ratios were significantly different between 3 and 6 months (- 11 nmol/mmol Cr at 3 months, - 15.2 nmol/mmol Cr at 6 months; p = 0.0069 at 3 months, p < 0.0001 at 6 months). Low density lipoprotein-cholesterol level significantly increased at 3 (+ 26 mg/dL) and 6 months (+ 13 mg/dL) compared with that at the baseline (p < 0.0001).. Switching from TDF to TAF decreased the levels of renal and bone biomarkers, such as urinary L-FABP and NTx, but increased low density lipoprotein-cholesterol levels. Future studies should evaluate if these biomarkers, such as urinary L-FABP and NTx, truly detect serious adverse drug reactions early.

    Topics: Alanine; Anti-HIV Agents; Biomarkers; Fumarates; HIV Infections; Humans; Kidney; Lipids; Prospective Studies; Tenofovir

2021
A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques.
    Antimicrobial agents and chemotherapy, 2020, 02-21, Volume: 64, Issue:3

    Topics: Adenine; Alanine; Animals; Anti-HIV Agents; Delayed-Action Preparations; Drug Implants; Female; Fumarates; HIV Infections; Humans; Inflammation; Macaca mulatta; Male; Necrosis; Polyurethanes; Rabbits; Subcutaneous Tissue; Tenofovir

2020
The switch from tenofovir disoproxil fumarate to tenofovir alafenamide determines weight gain in patients on rilpivirine-based regimen.
    AIDS (London, England), 2020, 05-01, Volume: 34, Issue:6

    To investigate whether the switch from tenofovir disoproxil fumarate/emtricitabine/rilpivirine (TDF/FTC/RPV) to tenofovir alafenamide (TAF)/FTC/RPV is associated with weight gain in people living with HIV (PLWHIV).. Retrospective single-centre study.. All PLWHIV on TDF/FTC/RPV who switched to TAF/FTC/RPV from January 2017 to December 2018 were considered if they had at least two weight measures in the year before and two after the switch. The weight trend across the study was evaluated by a generalized linear model for repeated measures, with pair comparison performed by Bonferroni adjustment.. Two hundred and fifty-two patients on TDF/FTC/RPV were included, 65% men, mean age 51.2 years (±9.6), history of 18 (±18.2) years of HIV infection and CD4 T-cell count of 744 (±329) cells/μl. All had HIV-RNA <50 copies/ml. Twelve months before the switch, baseline weight was 73.8 (±14.3) kg, and remained stable to 73.8 (±14.3) kg in the following 6 months. A weight increase was noticed 3 and 6 months after the switch, to 77.7 (±42.3) and 75.5 (±14.5) kg, respectively (P < 0.0001). A significant weight change exactly within the timeframe of the switch (between 6 months before and 3 months after) was found in women, patients with higher BMI (>25 kg/m), lower CD4 T-cell count (≤500 cells/μl) and history of previous drug abuse. The frequency of BMI greater than 25 kg/m rose from 122/252 patients (48.4%), to 133/252 (52.8%) (P < 0.0001).. TAF appears to have an impact on weight gain, similarly to what observed in naïve patients, also in experienced PLWHIV with good virologic control.

    Topics: Adenine; Adult; Alanine; Anti-HIV Agents; Emtricitabine; Female; Fumarates; HIV Infections; HIV-1; Humans; Male; Middle Aged; Retrospective Studies; Rilpivirine; RNA, Viral; Tenofovir; Treatment Outcome; Viral Load; Weight Gain

2020
Tenofovir Alafenamide Fumarate Therapy for HIV Treatment: Cardiometabolic and Renal Safety.
    AIDS research and human retroviruses, 2020, Volume: 36, Issue:9

    Antiretroviral treatment based on tenofovir alafenamide fumarate (TAF) is increasingly recommended, as it maintains the viral suppression and improves renal function and bone density in comparison with tenofovir disoproxil fumarate (TDF). We carried out a retrospective cohort study including experienced patients who switched treatment from TDF to TAF. Serum lipids and glucose, renal function, body mass index (BMI), and cardiovascular risk were evaluated before and 3 and 6 months after the initiation of TAF-based treatment. We identified 85 patients on TAF-based treatment. The majority were men (82.9%), smokers (70%), and older than 40 years. Significant increases in lipids and BMI were noted, but cardiovascular risk remained <7.5%. Renal function remained normal with a notable improvement among patients with renal impairment. These results suggest that TAF has no significant effect on glucose and does not meaningfully increase cardiovascular risk, despite an elevation in serum lipids. It also exhibits renal safety. However, the increase of BMI was significant. Further studies are needed to confirm these findings in larger patient series and over longer follow-up periods.

    Topics: Alanine; Anti-HIV Agents; Cardiovascular Diseases; Female; Fumarates; HIV Infections; Humans; Kidney; Male; Retrospective Studies; Tenofovir

2020
Interspecies Differences in Tenofovir Alafenamide Fumarate Stability in Plasma.
    Antimicrobial agents and chemotherapy, 2020, 08-20, Volume: 64, Issue:9

    Tenofovir (TFV) alafenamide fumarate (TAF) is an antiretroviral that has been evaluated in alternative drug delivery systems in several species. The

    Topics: Adenine; Alanine; Animals; Anti-HIV Agents; Dogs; Fumarates; HIV Infections; Rabbits; Sheep; Tenofovir

2020
Population Pharmacokinetic and Pharmacodynamic Analysis To Evaluate a Switch to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in People Living with HIV-1.
    Antimicrobial agents and chemotherapy, 2020, 10-20, Volume: 64, Issue:11

    Doravirine is a non-nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus type 1 (HIV-1) infection. A population pharmacokinetic (PK) model for treatment-naive participants in doravirine clinical studies was updated with data from switch participants in the DRIVE-SHIFT trial and used to estimate individual

    Topics: Anti-HIV Agents; Emtricitabine; Fumarates; HIV Infections; HIV-1; Humans; Lamivudine; Pyridones; Tenofovir; Triazoles

2020
Pharmacokinetics of tenofovir disoproxyl fumarate/emtricitabine in a client on pre-exposure prophylaxis after a total gastrectomy.
    AIDS (London, England), 2020, 11-01, Volume: 34, Issue:13

    Topics: Adolescent; Adult; Anti-HIV Agents; Emtricitabine; Fumarates; Gastrectomy; HIV Infections; Humans; Middle Aged; Pre-Exposure Prophylaxis; Tenofovir; Young Adult

2020
The Female Genital Tract Microbiome Is Associated With Vaginal Antiretroviral Drug Concentrations in Human Immunodeficiency Virus-Infected Women on Antiretroviral Therapy.
    The Journal of infectious diseases, 2017, 11-15, Volume: 216, Issue:8

    The female genital tract (FGT) microbiome may affect vaginal pH and other factors that influence drug movement into the vagina. We examined the relationship between the microbiome and antiretroviral concentrations in the FGT.. Over one menstrual cycle, 20 human immunodeficiency virus (HIV)-infected women virologically suppressed on tenofovir (TFV) disoproxil fumarate/emtricitabine and ritonavir-boosted atazanavir (ATV) underwent serial paired cervicovaginal and plasma sampling for antiretroviral concentrations using high-performance liquid chromatography-tandem mass spectrometry. Analysis of 16S ribosomal RNA gene sequencing of cervicovaginal lavage clustered each participant visit into a unique microbiome community type (mCT).. Participants were predominantly African American (95%), with a median age of 38 years. Cervicovaginal lavage sequencing (n = 109) resulted in a low-diversity mCT dominated by Lactobacillus (n = 40), and intermediate-diversity (n = 28) and high-diversity (n = 41) mCTs with abundance of anaerobic taxa. In multivariable models, geometric mean FGT:plasma ratios varied significantly by mCT for all 3 drugs. For both ATV and TFV, FGT:plasma was significantly lower in participant visits with high- and low-diversity mCT groups (all P < .02). For emtricitabine, FGT:plasma was significantly lower in participant visits with low- vs intermediate-diversity mCT groups (P = .002).. Certain FGT mCTs are associated with decreased FGT antiretroviral concentrations. These findings are relevant for optimizing antiretrovirals used for biomedical HIV prevention in women.

    Topics: Adenine; Adolescent; Adult; Anti-Retroviral Agents; Cohort Studies; Deoxycytidine; Emtricitabine; Female; Fumarates; Genitalia, Female; HIV Infections; Humans; Microbiota; Middle Aged; Organophosphonates; Prospective Studies; Tenofovir; Young Adult

2017
Heme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disorders.
    The Journal of clinical investigation, 2014, Volume: 124, Issue:10

    Heme oxygenase-1 (HO-1) is an inducible, detoxifying enzyme that is critical for limiting oxidative stress, inflammation, and cellular injury within the CNS and other tissues. Here, we demonstrate a deficiency of HO-1 expression in the brains of HIV-infected individuals. This HO-1 deficiency correlated with cognitive dysfunction, HIV replication in the CNS, and neuroimmune activation. In vitro analysis of HO-1 expression in HIV-infected macrophages, a primary CNS HIV reservoir along with microglia, demonstrated a decrease in HO-1 as HIV replication increased. HO-1 deficiency correlated with increased culture supernatant glutamate and neurotoxicity, suggesting a link among HIV infection, macrophage HO-1 deficiency, and neurodegeneration. HO-1 siRNA knockdown and HO enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with nonselective pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. Furthermore, IFN-γ, which is increased in CNS HIV infection, reduced HO-1 expression in cultured human astrocytes and macrophages. These findings indicate that HO-1 is a protective host factor against HIV-mediated neurodegeneration and suggest that HO-1 deficiency contributes to this degeneration. Furthermore, these results suggest that HO-1 induction in the CNS of HIV-infected patients on antiretroviral therapy could potentially protect against neurodegeneration and associated cognitive dysfunction.

    Topics: Adult; Aged; Antioxidants; Astrocytes; Brain; Central Nervous System; Cognition Disorders; Cohort Studies; Dimethyl Fumarate; Female; Fumarates; Heme Oxygenase-1; HIV Infections; HIV-1; Humans; Inflammation; Linear Models; Macrophages; Male; Microglia; Middle Aged; Nervous System Diseases; Oxidative Stress; Prefrontal Cortex; RNA, Small Interfering; Virus Replication

2014