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Drugs Nov 2018Bictegravir is a new integrase strand transfer inhibitor (INSTI) with a high genetic barrier to the development of HIV-1 resistance. The drug is co-formulated with the... (Review)
Review
Bictegravir is a new integrase strand transfer inhibitor (INSTI) with a high genetic barrier to the development of HIV-1 resistance. The drug is co-formulated with the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (AF) in a single-tablet regimen (STR) for the once-daily treatment of HIV-1 infection in adults (bictegravir/emtricitabine/tenofovir AF; Biktarvy). In phase 3 trials, bictegravir/emtricitabine/tenofovir AF was noninferior to dolutegravir-based therapy (dolutegravir/abacavir/lamivudine or dolutegravir plus emtricitabine/tenofovir AF) in establishing virological suppression in treatment-naïve adults through 96 weeks' treatment and, similarly, was noninferior to ongoing dolutegravir/abacavir/lamivudine or boosted elvitegravir- or protease inhibitor (PI)-based therapy in preventing virological rebound over 48 weeks in treatment-experienced patients. No resistance emerged to any of the antiretrovirals in the STR. Bictegravir/emtricitabine/tenofovir AF is generally well tolerated, requires no prior HLA-B*5701 testing (making it more suitable for 'rapid start' treatment), fulfils the antiretroviral regimen requirement for patients with hepatitis B virus (HBV) co-infection (i.e. contains tenofovir AF and emtricitabine, both of which are active against HBV) and can be used in renally impaired patients with creatinine clearance (CR) ≥ 30 mL/min. Thus, although cost-effectiveness analyses would be beneficial, current data indicate that bictegravir/emtricitabine/tenofovir AF is a convenient initial and subsequent treatment option for adults with HIV-1 infection, including those co-infected with HBV, and provides the first non-pharmacologically boosted, INSTI-based, triple-combination STR suitable for patients with CR 30-50 mL/min.
Topics: Adenine; Adult; Alanine; Amides; Anti-HIV Agents; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Combinations; Emtricitabine; HIV Infections; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; Humans; Lamivudine; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome
PubMed: 30460547
DOI: 10.1007/s40265-018-1010-7 -
Antiviral Therapy Apr 2022The advent of antiretroviral combination therapy has significantly impacted the HIV/AIDS epidemic. No longer a death sentence, HIV infection can be controlled and... (Review)
Review
The advent of antiretroviral combination therapy has significantly impacted the HIV/AIDS epidemic. No longer a death sentence, HIV infection can be controlled and suppressed using cocktail therapies that contain two or more small molecule drugs. This review aims to highlight the discovery, development, and impact of one such molecule, namely, emtricitabine (FTC, emtriva), which is one of the most successful drugs in the fight against HIV/AIDS and has been taken by over 94% of individuals infected with HIV in the USA. We also pay tribute to Dr. John C. Martin, former CEO and Chairman of Gilead Sciences, who unexpectedly passed away in 2021. A true visionary, he was instrumental in delivering FTC, as part of combination therapy with TDF (tenofovir, viread) to the global stage. As the fight to eradicate HIV marches on, we honor Dr. Martin's legacy of collaboration, achievement, and hope.
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Emtricitabine; HIV Infections; HIV-1; Humans; Male; Tenofovir
PubMed: 35491570
DOI: 10.1177/13596535211067599 -
PloS One 2023Integrase strand transfer inhibitors (INSTI) are one of the most prescribed drug classes for the treatment of HIV infection worldwide. Emtricitabine/Tenofovir...
INTRODUCTION
Integrase strand transfer inhibitors (INSTI) are one of the most prescribed drug classes for the treatment of HIV infection worldwide. Emtricitabine/Tenofovir Alafenamide/ Bictegravir (FTC/TAF/BIC) has been evaluated in randomized clinical trials; few studies have verified tolerability and safety in clinical practice. Our aim was to investigate the metabolic and hepatic safety in a real-life setting of FTC/TAF/BIC.
MATERIALS AND METHODS
Consecutive people living with HIV infection (PLWH) enrolled in the SCOLTA project, switching to or initiating their first antiretroviral treatment with FTC/TAF/BIC were included. PLWH with HBV co-infection were excluded. Metabolic and hepatic variables were collected at T0 and T1, were defined as baseline and 6-month follow-up respectively, and their modifications were analysed using the paired t-test and the analysis of variance.
RESULTS
Five hundred and thirty-nine PLWH with at least one follow-up visit were included in the analysis. Mean age was 48 years (±12.1), 74% were male, 16.1% were naïve to antiretrovirals (ART). At T1, ART-experienced PLWH showed a significant reduction of total cholesterol (TC) and triglycerides, and a slight increase in blood glucose (BG) and ALT. On the contrary, in ART-naïve PLWH blood lipids significantly increased, although with an unaffected TC/high density lipoprotein (HDL)-c ratio, while alanine aminotransferase (ALT) decreased significantly, mainly in those with altered baseline level. The treatment interruptions were 45 (8.4%) over the whole observation period, 13 (2.4%) due to AEs. The most frequent AEs were related to the central nervous system (6 events of depression, insomnia, headache, agitation) and 3 PLWH discontinued the regimen because of grade 1-2 weight gain.
CONCLUSIONS
In ART-experienced PLWH switching to FTC/TAF/BIC a significant improvement of lipid profile occurred but with significant BG and ALT variation without clinical relevance. In ART-naïve PLWH, blood lipids increased even though lipid profile did not worsen, and a trend towards normalization of liver enzymes was suggested. FTC/TAF/BIC is well tolerated in the real life setting.
Topics: Male; Humans; Middle Aged; Female; HIV Infections; Anti-HIV Agents; Emtricitabine; Alanine; Heterocyclic Compounds, 3-Ring; Pyridones; Anti-Retroviral Agents; Lipoproteins, HDL
PubMed: 37556481
DOI: 10.1371/journal.pone.0289132 -
Current Opinion in HIV and AIDS Jan 2016To discuss nondaily preexposure prophylaxis (PrEP) modalities that may provide advantages compared with daily PrEP in cost and cumulative toxicity, but may have lower... (Review)
Review
PURPOSE OF REVIEW
To discuss nondaily preexposure prophylaxis (PrEP) modalities that may provide advantages compared with daily PrEP in cost and cumulative toxicity, but may have lower adherence forgiveness.
RECENT FINDINGS
Animal models have informed our understanding of early viral transmission events, which help guide event-driven PrEP dosing strategies. These models indicate early establishment of viral replication in rectal or cervicovaginal tissues, so event-driven PrEP should rapidly deliver high mucosal drug concentrations within hours of the potential exposure event. Macaque models have demonstrated the high biological efficacy for event-driven dosing of oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) against both vaginal and rectal virus transmission. In humans, the IPERGAY study demonstrated 86% efficacy for event-driven oral TDF/FTC dosing among men who have sex with men (MSM), while no similar efficacy data are available on women or heterosexual men. The HPTN 067 study showed that certain MSM populations adhere well to nondaily PrEP, whereas other populations of women adhere more poorly to nondaily versus daily regimens. Pharmacokinetic studies following oral TDF/FTC dosing in humans indicate that TFV-diphosphate (the active form of TFV) accumulates to higher concentrations in rectal versus cervicovaginal tissue, but nonadherence in trials complicates the interpretation of differential mucosal drug concentrations.
SUMMARY
Event-driven dosing for TFV-based PrEP has promise for HIV prevention in MSM. Future research of event-driven PrEP in women and heterosexual men should be guided by a better understanding of the importance of mucosal drug concentrations for PrEP efficacy and its sensitivity to adherence.
Topics: Administration, Oral; Animals; Anti-HIV Agents; Chemoprevention; Clinical Trials as Topic; Disease Models, Animal; Disease Transmission, Infectious; Emtricitabine; Female; HIV Infections; Humans; Macaca; Male; Pre-Exposure Prophylaxis; Tenofovir
PubMed: 26633641
DOI: 10.1097/COH.0000000000000213 -
Journal of Acquired Immune Deficiency... Aug 2016Studies of tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC)-based preexposure prophylaxis (PrEP) have not focused on transgendered women who are at... (Review)
Review
Studies of tenofovir disoproxil fumarate (TDF)-emtricitabine (FTC)-based preexposure prophylaxis (PrEP) have not focused on transgendered women who are at disproportionate risk of HIV acquisition. Concerns exist for drug interactions between cross-sex therapy (estradiol, progestins, and spironolactone) with tenofovir disoproxil fumarate-emtricitabine. This review assessed the experimental and theoretical risk for such drug interactions. It was found that none of these medications are implicated as major perpetrators of drug interactions, and the classes use different metabolic pathways for clearance, suggesting a low likelihood for interactions in either direction. Subanalyses of transgender women in Preexposure Prophylaxis Initiative suggested PrEP efficacy if adherence was high. Nevertheless, several research gaps were identified, particularly the need for controlled interaction studies in transgendered women, including effects on renal clearance, intracellular tenofovir diphosphate and emtricitabine triphosphate in target cells, as well as hormone effects on HIV susceptibility and immunity. PrEP should continue to be offered to transgender women while additional research is planned or pending.
Topics: Anti-HIV Agents; Delivery of Health Care, Integrated; Directive Counseling; Emtricitabine; Female; HIV Infections; Health Status Disparities; Humans; Male; Medication Adherence; Pre-Exposure Prophylaxis; Tenofovir; Transgender Persons
PubMed: 27429188
DOI: 10.1097/QAI.0000000000001105 -
Current Opinion in HIV and AIDS Jul 2022We review macaque models for preexposure prophylaxis (PrEP) for HIV prevention and highlight their role in advancing currently approved and novel PrEP agents. (Review)
Review
PURPOSE OF REVIEW
We review macaque models for preexposure prophylaxis (PrEP) for HIV prevention and highlight their role in advancing currently approved and novel PrEP agents.
RECENT FINDINGS
The development of the repeat low dose simian HIV (SHIV) challenge models represented a significant advancement in preclinical PrEP modeling that has allowed the investigation of PrEP under conditions that better mimic HIV exposures in humans. These models incorporate relevant drug pharmacology to inform drug correlates of PrEP protection. Models of rectal, vaginal, and penile infection are now available and have been found to predict clinical efficacy of all the currently approved PrEP strategies including daily oral PrEP with the combination of emtricitabine and tenofovir disoproxil fumarate or tenofovir alafenamide, and a long-acting formulation of the integrase inhibitor cabotegravir. These models are being used to test new PrEP modalities including the nucleoside reverse transcriptase-translocation inhibitor islatravir and long-acting capsid inhibitors. The SHIV models have also been supplemented by sexually transmitted infection co-infections with Chlamydia trachomatis, Treponema pallidum or Trichomonas vaginalis to assess the impact of inflammation on PrEP efficacy.
SUMMARY
Clinical efficacy validated current PrEP macaque models supporting their continued use to advance novel PrEP agents to improve global PrEP coverage.
Topics: Animals; Anti-HIV Agents; Emtricitabine; Female; HIV Infections; Humans; Macaca; Pre-Exposure Prophylaxis
PubMed: 35762371
DOI: 10.1097/COH.0000000000000738 -
The Lancet. HIV Dec 2023Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083...
BACKGROUND
Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study.
METHODS
The HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094.
FINDINGS
Of the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation.
INTERPRETATION
Long-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance.
FUNDING
Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.
Topics: Male; Female; Humans; Adolescent; HIV Infections; Tenofovir; Emtricitabine; Anti-HIV Agents; Transgender Persons; Retrospective Studies; HIV-1; Acquired Immunodeficiency Syndrome; Pre-Exposure Prophylaxis
PubMed: 37952550
DOI: 10.1016/S2352-3018(23)00261-8 -
Current Opinion in HIV and AIDS Jan 2016The review describes the European epidemic and the challenges in moving from clinical trials of preexposure prophylaxis (PrEP) to routine practice. (Review)
Review
PURPOSE OF REVIEW
The review describes the European epidemic and the challenges in moving from clinical trials of preexposure prophylaxis (PrEP) to routine practice.
RECENT FINDINGS
Two European trials conducted in gay and other MSM and transgender women reported a high and consistent reduction in HIV incidence using oral PrEP with tenofovir/emtricitabine (TDF/FTC). The incidence of HIV infection in the control group was much higher than anticipated, based on routine surveillance data in MSM, in spite of the highest standard of HIV prevention available.
SUMMARY
Recent results have highlighted the urgent need to make PrEP available to key populations in Europe as an additional prevention tool. Gilead has not yet submitted an application to use TDF/FTC as PrEP in Europe. Although regulatory approval would accelerate implementation, countries are already dispensing TDF/FTC as postexposure prophylaxis without this. Services for prevention are diverse across countries ranging from free, walk-in services for the diagnosis and treatment of HIV and other sexually transmitted infections, to insurance-dependent reimbursement of private clinical services. Momentum is gathering in Europe with PrEP demonstration projects in MSM and a growing demand from community organizations. Each Member State urgently needs to identify their key populations and determine the service best placed to provide this new prevention strategy within a comprehensive prevention package.
Topics: Anti-HIV Agents; Chemoprevention; Disease Transmission, Infectious; Emtricitabine; Europe; Female; HIV Infections; Humans; Male; Pre-Exposure Prophylaxis; Tenofovir; Treatment Outcome
PubMed: 26599164
DOI: 10.1097/COH.0000000000000223 -
Antimicrobial Agents and Chemotherapy Aug 2020The altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased...
The altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence decreases FTC-triphosphate (FTCtp) concentrations. The effects of age and inflammation on the ratio of intracellular metabolites (IMs; tenofovir diphosphate [TFVdp] and FTCtp) to their endogenous nucleotides (ENs; dATP and dCTP), a potential treatment efficacy marker, were assessed among participants of the Women's Interagency HIV Study (WIHS), who ranged from 25 to 75 years. Samples from women receiving TDF-FTC with viral loads of <200 copies/ml were dichotomized by age at collection into two groups (≤45 years and ≥60 years). IM/EN concentrations were measured in peripheral blood mononuclear cell (PBMC) pellets; interleukin-6 (IL-6) and sCD163 were measured in plasma; senescent CD8 T cells were measured in viable PBMCs. The TFVdp:dATP and FTCtp:dCTP ratios had statistically significantly different distributions in older and younger women (log-rank test, = 0.0023 and = 0.032, respectively); in general, IM and EN concentrations were higher in the older women. After adjusting for potential confounders, these findings were not significant. In women aged ≤45 years, TFVdp was negatively associated with IL-6 and sCD163, while FTCtp was positively associated with sCD163 and IL-6 in women aged ≥60 years. Body mass index (BMI) was positively associated with IL-6 in both age groups and negatively associated with TFVdp in women aged ≤45 years. After adjustment, age remained significant for sCD163, while black race, BMI, and renal function remained significant for several IMs and ENs, suggesting that factors associated with aging, but not age itself, govern intracellular TDF-FTC pharmacology.
Topics: Adult; Aged; Anti-HIV Agents; CD8-Positive T-Lymphocytes; Emtricitabine; Female; HIV Infections; Humans; Leukocytes, Mononuclear; Middle Aged; Tenofovir
PubMed: 32631821
DOI: 10.1128/AAC.00177-20 -
Journal of Acquired Immune Deficiency... Dec 2019Tenofovir disoproxil fumarate coformulated with emtricitabine (TDF/FTC) was shown to be effective in preventing HIV acquisition when used for pre-exposure prophylaxis... (Review)
Review
BACKGROUND
Tenofovir disoproxil fumarate coformulated with emtricitabine (TDF/FTC) was shown to be effective in preventing HIV acquisition when used for pre-exposure prophylaxis (PrEP), but questions have arisen regarding optimal PrEP implementation strategies.
METHODS
A narrative review of literature since 2010 regarding PrEP effectiveness, implementation, and new prevention modalities was undertaken to summarize lessons learned, and to review potential benefits and challenges.
RESULTS
Although daily TDF/FTC is safe, well tolerated, and highly effective in preventing HIV transmission, it has been initiated by only 200,000 Americans, and a comparable number of individuals in other countries, meaning that 80%-90% of those at greatest risk globally have not benefitted yet. Barriers to PrEP uptake have included medication and care costs, anticipated side effects, stigma, and unsupportive health care systems. Innovations to increase PrEP uptake and adherence have included engaging nonmedical staff (eg, pharmacists, social workers, and peer navigators), economic assistance programs, and new technologies (eg, text messaging support and dedicated apps). Pericoital PrEP dosing seems to be effective in preventing HIV transmission among men who have sex with men, but has not been evaluated in women. Investigational PrEP approaches include antiretrovirals delivered by injection, implant, vaginal rings, rectal douches, and immunoprophylaxis. Some of these approaches may allow for infrequent dosing, whereas others may be more congruent with patterns of sexual behavior.
CONCLUSIONS
PrEP has been shown to be safe and effective when used consistently, but new approaches to enhance uptake, adherence, and convenience with less-frequent dosing are under study, suggesting that new models and modalities will evolve to optimize impact.
Topics: Anti-HIV Agents; Behavioral Risk Factor Surveillance System; Cognitive Behavioral Therapy; Drug Therapy, Combination; Emtricitabine; HIV Infections; Health Promotion; Humans; Pre-Exposure Prophylaxis; Sexual Behavior; Social Stigma; Tenofovir
PubMed: 31658197
DOI: 10.1097/QAI.0000000000002169