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Lancet (London, England) Jul 2020Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we... (Comparative Study)
Comparative Study Randomized Controlled Trial
Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.
BACKGROUND
Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention.
METHODS
This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting.
FINDINGS
Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints.
INTERPRETATION
Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate.
FUNDING
Gilead Sciences.
Topics: Adenine; Adult; Anti-HIV Agents; Double-Blind Method; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Europe; Female; HIV Infections; HIV-1; Homosexuality, Male; Humans; Male; North America; Placebos; Pre-Exposure Prophylaxis; Prevalence; Safety; Sexual and Gender Minorities; Tenofovir; Treatment Outcome
PubMed: 32711800
DOI: 10.1016/S0140-6736(20)31065-5 -
AIDS (London, England) Jul 2016Preexposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Preexposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP containing tenofovir disoproxil fumarate as an additional HIV prevention strategy in populations at substantial risk for HIV based on HIV acquisition, adverse events, drug resistance, sexual behavior, and reproductive health outcomes.
DESIGN
Rigorous systematic review and meta-analysis.
METHODS
A comprehensive search strategy reviewed three electronic databases and conference abstracts through April 2015. Pooled effect estimates were calculated using random-effects meta-analysis.
RESULTS
Eighteen studies were included, comprising data from 39 articles and six conference abstracts. Across populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared with placebo. Trials with PrEP use more than 70% demonstrated the highest PrEP effectiveness (risk ratio = 0.30, 95% confidence interval: 0.21-0.45, P < 0.001) compared with placebo. Trials with low PrEP use did not show a significantly protective effect. Adverse events were similar between PrEP and placebo groups. More cases of drug-resistant HIV infection were found among PrEP users who initiated PrEP while acutely HIV-infected, but incidence of acquiring drug-resistant HIV during PrEP use was low. Studies consistently found no association between PrEP use and changes in sexual risk behavior. PrEP was not associated with increased pregnancy-related adverse events or hormonal contraception effectiveness.
CONCLUSION
PrEP is protective against HIV infection across populations, presents few significant safety risks, and there is no evidence of behavioral risk compensation. The effective and cost-effective use of PrEP will require development of best practices for fostering uptake and adherence among people at substantial HIV risk.
Topics: Administration, Oral; Adult; Anti-HIV Agents; Chemoprevention; Female; HIV Infections; Humans; Male; Placebos; Pre-Exposure Prophylaxis; Tenofovir; Young Adult
PubMed: 27149090
DOI: 10.1097/QAD.0000000000001145 -
Antiviral Therapy Apr 2022Tenofovir alafenamide fumarate is a lipophilic prodrug of tenofovir which is preferentially metabolized in lymphatic tissue resulting in high concentrations of tenofovir...
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
PubMed: 35499175
DOI: 10.1177/13596535211067600 -
Safety and Efficacy of Long-Acting Injectable Agents for HIV-1: Systematic Review and Meta-Analysis.JMIR Public Health and Surveillance Jul 2023HIV-1 infection continues to affect global health. Although antiretrovirals can reduce the viral load or prevent HIV-1 infection, current drugs require daily oral use... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
HIV-1 infection continues to affect global health. Although antiretrovirals can reduce the viral load or prevent HIV-1 infection, current drugs require daily oral use with a high adherence level. Long-acting antiretrovirals (LA-ARVs) significantly improve medication adherence and are essential for HIV-1 prophylaxis and therapy.
OBJECTIVE
This study aimed to investigate the safety and efficacy of long-acting cabotegravir (CAB-LA) and long-acting rilpivirine (RPV-LA) in the prevention and treatment of HIV-1 infection.
METHODS
PubMed, Embase, and the Cochrane Library were searched for studies from database inception to November 12, 2022. We included studies that reported efficacy and safety data on LA-ARV intervention in people living with HIV and excluded reviews, animal studies, and articles with missing or duplicate data. Virological suppression was defined as plasma viral load <50 copies/mL 6 months after antiviral therapy initiation. We extracted outcomes for analysis and expressed dichotomous data as risk ratios (RRs) and continuous data as mean differences. Depending on the heterogeneity assessment, a fixed- or random-effects model was used for data synthesis. We performed subgroup analyses of the partial safety and efficacy outcomes of CAB-LA+RPV-LA. The protocol was registered with the Open Science Framework.
RESULTS
We included 12 trials comprising 10,957 individuals, of which 7 were prevention trials and 5 were treatment trials. CAB-LA and RPV-LA demonstrated safety profiles comparable with those of the placebo in terms of adverse event-related withdrawal. Moreover, the efficacy data showed that CAB-LA had a better effect on HIV-1 prevention than tenofovir disoproxil fumarate-emtricitabine (17/5161, 0.33% vs 75/5129, 1.46%; RR 0.21, 95% CI 0.07-0.61; I=70%). Although CAB-LA+RPV-LA had more drug-related adverse events (556/681, 81.6% vs 37/598, 6.2%; RR 12.50, 95% CI 3.98-39.23; I=85%), a mild or moderate injection site reaction was the most common reaction, and its frequency decreased over time. The efficacy of CAB-LA+RPV-LA was comparable with that of daily oral drugs at 48 and 96 weeks (1302/1424, 91.43% vs 915/993, 92.2%; RR 0.99, 95% CI 0.97-1.02; I=0%), and a high level of virological suppression of 80.9% (186/230) was maintained even after 5 years of LA-ARV use. Similar efficacy outcomes were observed in both treatment-naive and treatment-experienced patients (849/911, 93.2% vs 615/654, 94%; RR 0.99, 95% CI 0.96-1.02; I=0%). According to the questionnaires, more than 85% of people living with HIV favored LA-ARVs.
CONCLUSIONS
LA-ARVs showed favorable safety profiles for both the prevention and treatment of HIV-1 infection and were well tolerated. CAB-LA has more satisfactory efficacy than tenofovir disoproxil fumarate-emtricitabine, significantly reducing the rate of HIV-1 infection. CAB-LA+RPV-LA maintains virological suppression for a long time and may be a viable switching strategy with enhanced public health benefits by reducing transmission. However, further trials are required to confirm the efficacy of these drugs.
Topics: Humans; Anti-HIV Agents; Emtricitabine; HIV Infections; HIV-1; Tenofovir
PubMed: 37498645
DOI: 10.2196/46767 -
Current Opinion in HIV and AIDS May 2016With continued improvements to the antiviral efficacy and tolerability of antiretroviral therapy, long-term safety of antiretroviral therapy has become paramount. Low... (Review)
Review
PURPOSE OF REVIEW
With continued improvements to the antiviral efficacy and tolerability of antiretroviral therapy, long-term safety of antiretroviral therapy has become paramount. Low bone mineral density and fragility fractures are more common in HIV-infected individuals than in the general population. The aims of this review are to describe potential mechanisms underlying the adverse effects of tenofovir on bone, clinical studies of tenofovir disoproxil fumarate (TDF) and bone, and more recent bone data on tenofovir alafenamide.
RECENT FINDING
Several studies have demonstrated an approximately 1-3% greater bone mineral density loss with TDF compared with other agents. Recent studies with tenofovir alafenamide have shown improved bone (and renal) safety with similar virologic efficacy when compared to TDF.
SUMMARY
Given these findings, TDF-containing regimens may be gradually replaced with non-TDF containing regimens for the treatment of HIV infection, especially in those at higher risk for fragility fracture.
Topics: Anti-HIV Agents; Bone Diseases, Metabolic; Fractures, Bone; HIV Infections; Humans; Tenofovir
PubMed: 26859637
DOI: 10.1097/COH.0000000000000248 -
The New England Journal of Medicine Dec 2015Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen.
METHODS
We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections.
RESULTS
Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03).
CONCLUSIONS
The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT01473472.).
Topics: Adult; Condoms; Double-Blind Method; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Homosexuality, Male; Humans; Kaplan-Meier Estimate; Male; Medication Adherence; Middle Aged; Pre-Exposure Prophylaxis; Risk Factors; Sexual Behavior; Sexually Transmitted Diseases; Tenofovir
PubMed: 26624850
DOI: 10.1056/NEJMoa1506273 -
The Journal of Antimicrobial... Dec 2022Crushing or dissolving bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) tablets is not recommended because there are no data supporting this practice. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Crushing or dissolving bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) tablets is not recommended because there are no data supporting this practice.
METHODS
A crossover, randomized trial in healthy adults (NCT04244448) investigated the bioavailability of two off-label uses of BIC/TAF/FTC (50/200/25 mg), dissolved in water or crushed in apple compote, compared with the solid tablet. Pharmacokinetic (PK) parameters were estimated from sequential intensive plasma antiretroviral concentrations over a 72 h period post dose. Bioequivalence was met if the 90% CIs of the geometric least-squares means ratios comparing BIC/TAF/FTC exposures (AUC and Cmax) from the experimental phases were within 80%-125% of the reference.
RESULTS
Eighteen subjects participated in each of the three phases. Dissolved tablet Cmax geometric mean ratio (90% CI) for BIC/TAF/FTC was 105% (93-119)/97% (87-108)/96% (74-124), respectively. Dissolved tablet AUC geometric mean ratio (90% CI) for BIC/TAF/FTC was 111% (100-122)/100% (94 to 105)/99% (81 to 120), respectively. Crushed tablet Cmax geometric mean ratio (90%) CI for BIC/TAF/FTC was 110% (97 to 124)/70% (63-78)/66% (51-85), respectively. Crushed tablet AUC geometric mean ratio (90%) CI for BIC/TAF/FTC was 107% (96-118)/86% (82-91)/84% (69-103), respectively.
CONCLUSIONS
Crushing BIC/TAF/FTC tablets may lead to suboptimal emtricitabine and tenofovir alafenamide drug exposures. Dissolving BIC/TAF/FTC in water may be acceptable if the tablet cannot be swallowed whole.
Topics: Humans; Adult; Emtricitabine; Tenofovir; HIV Infections; Biological Availability; Cross-Over Studies; Adenine; Tablets; Anti-HIV Agents; Alanine
PubMed: 36322475
DOI: 10.1093/jac/dkac369 -
Clinical Infectious Diseases : An... Sep 2020Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases...
BACKGROUND
Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation.
METHODS
We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation.
RESULTS
Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine.
CONCLUSIONS
Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.
Topics: Anti-HIV Agents; Anti-Retroviral Agents; Female; HIV Infections; Humans; Risk Factors; Tenofovir; Weight Gain
PubMed: 31606734
DOI: 10.1093/cid/ciz999 -
Le Infezioni in Medicina Dec 2020Two Tenofovir pro-drugs are available for the treatment of HIV and HBV infection. Tenofovir Alafenamide (TAF) was clinically developed as a safer alternative to the...
Two Tenofovir pro-drugs are available for the treatment of HIV and HBV infection. Tenofovir Alafenamide (TAF) was clinically developed as a safer alternative to the older Tenofovir Disoproxil Fumarate (TDF) as the latter was consistently found to be associated to proximal renal tubule dysfunction and decrease in bone mineral density (BMD). As compared to TDF, the pharmacological properties of TAF are such that a more active drug is delivered into target cells while much less is measurable in general circulation. This translates into an antiretroviral action comparable to TDF with a significantly lower impact on proximal renal tubular function and bone structural integrity. The lipid-lowering effects of TDF as well as its lesser tendency to be associated to undesired body weight increase have raised some doubts about the substitution of TDF with TAF. Both issues, whose genesis is multifactorial, are strictly linked to the hypothesis of increased cardiovascular risk that might follow the switch from TDF to TAF. However, the long-term impact of decreasing renal function on cardiovascular risk must also be considered, especially in aging patients. It is thus a matter of balance: while the action on modifiable behavioural variables may well reduce lipid levels and body weight, the permanent dysfunctional pressure exerted by TDF on the proximal renal tubule could cause irreversible damage to both kidneys and bones. Therefore, all things considered, avoidance of TDF, particularly when aging patients are concerned, appears the preferable approach.
Topics: Alanine; Anti-HIV Agents; Anti-Retroviral Agents; Drug Substitution; HIV Infections; Humans; Tenofovir
PubMed: 33257626
DOI: No ID Found -
Molecules (Basel, Switzerland) Jun 2022The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe...
The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19.
Topics: Anti-HIV Agents; Emtricitabine; HIV Infections; HIV-1; Humans; Nucleosides; Nucleotides; Pandemics; RNA, Viral; RNA-Dependent RNA Polymerase; SARS-CoV-2; Tenofovir; COVID-19 Drug Treatment
PubMed: 35807457
DOI: 10.3390/molecules27134212