Importance of early identification of PrEP breakthrough infections in a generalized HIV epidemic: a case report from a PrEP demonstration project in South Africa.

BACKGROUND: The World Health Organisation recommends the use of tenofovir-containing pre-exposure prophylaxis (PrEP) as an additional Human Immunodeficiency Virus (HIV) prevention choice for men and women at substantial risk of HIV infection. PrEP could fill an important HIV prevention gap, especially for sexually active young women who are limited in their ability to negotiate mutual monogamy or condom use. As PrEP is scaled up in high HIV incidence settings, it is crucial to consider the importance of early identification of HIV infection during PrEP use, to allow for rapid discontinuation of PrEP to reduce the risk of antiretroviral (ARV) resistance. The purpose of this case study is to provide this critical evidence. CASE PRESENTATION: This report describes a 20-year-old woman in a HIV sero-discordant relationship who initiated oral PrEP (tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC)) through a demonstration project (CAPRISA 084) in October 2017. Despite good adherence throughout her PrEP use, she tested HIV antibody positive at month nine of study participation. Retrospective testing showed increasing HIV viral load over time, and retrospective use of fourth-generation rapid HIV tests showed HIV detection (positive antigen/antibody) at month one. Sequencing confirmed a dominant wild type at month one with dual therapy resistance patterns emerging by month three (M184V and K65R mutations), which is suggestive of protracted PrEP use during an undetected HIV infection. The participant was referred to infectious diseases for further management of her HIV infection and was initiated on a first line, tenofovir-sparing regimen. At the time of this report (January 2020), the participant had been on ARV- therapy (ART) for 13 months and had no signs of either clinical, immunologic or virologic failure. CONCLUSIONS: This case report highlights the importance of appropriate HIV screening during wider oral PrEP scale-up in high HIV incidence settings to circumvent the consequences of prolonged dual therapy in an undiagnosed HIV infection and in turn prevent ARV resistance.

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.

Renal impairment: an unnecessary barrier to HIV prevention.

The use of tenofovir disoproxil fumarate (TDF) in combination with emtricitabine, prescribed for pre-exposure prophylaxis (PrEP), is highly effective at reducing incident sexually transmissible HIV infection among those at risk. TDF is associated with proteinuria, Fanconi syndrome and chronic kidney disease, and is not recommended for use in patients with an estimated creatinine clearance <60 mL min-1. There are currently no Pharmaceutical Benefits Scheme (PBS)-funded PrEP options for patients at risk of HIV infection with moderate renal impairment in Australia. This report describes the case of a patient who acquired HIV soon after PrEP was suspended due to moderate renal impairment. The various clinical and regulatory issues this case raises are discussed.

Review of Real-World Implementation Data on Emtricitabine-Tenofovir Disoproxil Fumarate as HIV Pre-exposure Prophylaxis in the United States.

The antiretroviral combination of emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) was approved by the U.S. Food and Drug Administration for use as pre-exposure prophylaxis (PrEP) in individuals at high risk for acquiring human immunodeficiency virus (HIV) in July 2012. Since then, Centers for Disease Control and Prevention guidelines for the use of PrEP have been published and implemented into clinical practice throughout the United States. A number of published open-label and PrEP demonstration projects have evaluated the real-world use of PrEP including analysis of the barriers to its use and addressing major concerns. Despite the approval of FTC/TDF for PrEP, its use for this indication relies on patient and provider acceptance, and its effectiveness requires patient adherence and retention in care during periods of high-risk behaviors. Concerns regarding the use of PrEP in healthy individuals persist and include medication adverse effects including renal dysfunction and bone mineral density loss; risk compensation leading to HIV infections, sexually transmitted infections, and unintended pregnancies; and the development of drug resistance in the event of seroconversion. The cost-effectiveness of PrEP continues to be assessed with the greatest cost-effectiveness remaining in those at highest risk of acquiring HIV. Additionally, cases of HIV acquisition in individuals who are adherent to PrEP highlight scenarios in which PrEP is not 100% effective including against the transmission of drug-resistant HIV strains. This review examines data on the implementation of PrEP outside the setting of clinical trials with the aim of providing clinicians with a summary of the current barriers and opportunities for PrEP use with a specific focus on the role of pharmacists in the optimization of PrEP implementation.

Effect of Vitamin D Supplementation on Bone Turnover Markers During HIV Pre-Exposure Prophylaxis Using Tenofovir Disoproxil Fumarate-Emtricitabine in Men Who Have Sex with Men.

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) reduces bone mineral density in HIV-uninfected men who have sex with men (MSM). We hypothesized that PrEP with TDF-FTC would increase bone turnover markers (BTMs) at week 24 and that vitamin D supplementation from weeks 24 to 48 would blunt this increase. Participants were from a cohort of 398 MSM and transgender women who received daily TDF-FTC for PrEP. At week 24, a prospective intervention group initiated vitamin D3 4,000 IU daily. Concurrent controls were selected from the cohort who took ≤400 IU/day of vitamin D3 matched by age, race, and body mass index. The primary endpoint was the change in procollagen-I N-terminal propeptide (P1NP) from weeks 24 to 48. Paired t-tests were used to compare changes in BTMs between intervention and controls. Among 48 intervention-control pairs, median age was 33 years. At baseline, 68.9% of the intervention group and 77.3% of controls were vitamin D sufficient (≥20 ng/mL, p = .94). P1NP, C-telopeptide, parathyroid hormone (PTH), and 25-OH vitamin D3 did not increase significantly at week 24. P1NP fell by a mean ± SD of -27.6 ± 49.9 pg/mL from weeks 24 to 48 with vitamin D and -2.5 ± 40.2 pg/mL in controls (p = .01). There were no significant between-group differences in the weeks 24-48 change in C-telopeptide, PTH, or 25-OH vitamin D3. Vitamin D3 supplementation with 4,000 IU/day resulted in a significant reduction in the BTM P1NP compared with controls, suggesting that this intervention has potential to improve bone health during PrEP.

Body composition and adipokines changes after initial treatment with darunavir-ritonavir plus either raltegravir or tenofovir disoproxil fumarate-emtricitabine: A substudy of the NEAT001/ANRS143 randomised trial.

BACKGROUND: Comparison of changes in body composition, adipokines and inflammatory markers after initial therapy with a nucleos(t)ide reverse transcriptase inhibitor (N(t)RTI)- sparing or containing regimen are scarce. DESIGN: Randomised Clinical Trial. METHODS: This is the body composition substudy of NEAT 001/ANRS 143, a randomised trial comparing darunavir/ritonavir (DRV/r) plus either raltegravir (RAL) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 805 ART naïve HIV-infected adults. The primary endpoint was percentage change in limb fat at week 96. Secondary endpoints were associations among these changes and metabolic markers (IL-6, insulin, leptin, adiponectin, FGF-23). RESULTS: 126 subjects (61 DRV/r + RAL and 65 DRV/r + TDF/FTC) were included. The rate of change in BMI between groups for RAL versus TDF/FTC at week 96 was 1.5% per 48-week period (p = 0.015). The rate of change in limb fat mass, trunk fat mass, total body fat and total lean mass was for RAL versus TDF/FTC at week 96 was 2.5% (p = 0.38), 7.3% ((p = 0.021), 4.9% (p = 0.061) and 1.3% (p = 0.12) respectively. Baseline insulin and leptin levels were correlated with baseline limb fat and trunk fat mass [r = 0.31 (p = 0.0043)/r = 0.28 (p = 0.0011) for limb fat, and r = 0.63 (p<0.0001)/r = 0.50(p<0.0001) for trunk fat]. After adjustment, a 10% faster increase in leptin between baseline and week 48 was associated with a more rapid increase in limb fat at week 48 (0.5% per 48 weeks, p<0.001), total body fat mass (0.6% per 48 weeks, p<0.001), and trunk fat mass (0.3% per 48 weeks, p = 0.0026). CONCLUSIONS: After week 96 a N(t)RTI sparing regimen of DRV/r + RAL produced a numerically greater percentage increase in body composition variables with only change in trunk fat mass and BMI being significant.

Renal function and risk factors for renal disease for patients receiving HIV pre-exposure prophylaxis at an inner metropolitan health service.

BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) significantly reduces the risk of HIV acquisition. TDF is a known nephrotoxin however, renal dysfunction from TDF is mostly reversible following discontinuation. AIMS: To describe the renal function, risk factors for renal disease and associated clinical testing practices in a cohort of PrEP patients. METHODS: A retrospective review was conducted of all PrEP patients commenced on TDF/FTC at an inner metropolitan sexual health clinic in Sydney, Australia between April 2016 and July 2017, with follow-up data obtained at 3-monthly intervals until 18 months. RESULTS: 525 patients met inclusion criteria. Patients were almost exclusively male and median age was 34 years (IQR: 28 to 42). At baseline, 1.5% had an estimated glomerular filtration rate (eGFR) <70 mL/min/1.73m2. A small significant drop in eGFR of -2.5 mL/min/1.73m2 (p<0.05) occurred between PrEP commencement and the first follow-up period, followed by a progressive decline in eGFR of -0.38 mL/min/1.73m2 per month (95%CI: -0.57 to -0.20; p<0.001). Renal impairment (eGFR <70 mL/min/1.73m2) occurred in 6.5% of patients and persisted across consecutive follow-up periods in five (1.0%) patients. Patients aged ≥40 years had a greater risk of renal impairment than younger patients (HR 3.9, 95%CI: 1.8 to 8.4; p<0.001), despite similar rates of eGFR decline (p = 0.19). PrEP was discontinued in two patients (0.4%) due to renal function concerns. CONCLUSION: PrEP use led to an initial drop in eGFR and a more gradual progressive decline subsequently, but significant renal impairment remained uncommon up to 18 months of follow-up.

Mg-supplementation attenuated lipogenic and oxidative/nitrosative gene expression caused by Combination Antiretroviral Therapy (cART) in HIV-1-transgenic rats.

We determined if HIV-1 expression in transgenic (HIV-1-Tg) rats enhanced hepatic genomic changes related to oxidative/nitrosative stress and lipogenesis during cART-treatment, and assessed effects of Mg-supplementation. A clinically used cART (atazanavir-ritonavir+Truvada) was given orally to control and HIV-1-Tg rats (18 weeks) with normal or 6-fold dietary-Mg. Oxidative/nitrosative and lipogenic genes were determined by real-time RT-PCR. cART induced a 4-fold upregulation of sterol regulatory element-binding protein-1 (SREBP-1) in HIV-1-Tg-rats, but not in controls; Tg rats displayed a 2.5-fold higher expression. Both were completely prevented by Mg-supplementation. Nrf2 (Nuclear erythroid-derived factor 2), a master transcription factor controlling redox homeostasis, was down-regulated 50% in HIV-Tg rats, and reduced further to 25% in Tg+cART-rats. Two downstream antioxidant genes, heme oxygenase-1(HmOX1) and Glutathione-S-transferase(GST), were elevated in HIV-Tg alone but were suppressed by cART treatment. Decreased Nrf2 in Tg±cART were normalized by Mg-supplementation along with the reversal of altered HmOX1 and GST expression. Concomitantly, iNOS (inducible nitric oxide synthase) was upregulated 2-fold in Tg+cART rats, which was reversed by Mg-supplementation. In parallel, cART-treatment led to substantial increases in plasma 8-isoprostane, nitrotyrosine, and RBC-GSSG (oxidized glutathione) levels in HIV-1-Tg rats; all indices of oxidative/nitrosative stress were suppressed by Mg-supplementation. Both plasma triglyceride and cholesterol levels were elevated in Tg+cART rats, but were lowered by Mg-supplementation. Thus, the synergistic effects of cART and HIV-1 expression on lipogenic and oxidative/nitrosative effects were revealed at the genomic and biochemical levels. Down-regulation of Nrf2 in the Tg+cART rats suggested their antioxidant response was severely compromised; these abnormal metabolic and oxidative stress effects were effectively attenuated by Mg-supplementation at the genomic level.

Health Care Costs in a Cohort of HIV-Infected U.S. Veterans Receiving Regimens Containing Tenofovir Disoproxil Fumarate/Emtricitabine.

BACKGROUND: Tenofovir disoproxil fumarate (TDF), a key component in many human immunodeficiency virus (HIV) treatment regimens, is associated with increased renal and bone toxicities. The contributions of such toxicities to treatment costs, as well as the relative differences in treatment costs for various TDF/emtricitabine (FTC) regimens, remains unexplored. OBJECTIVE: To estimate and compare mean overall and renal- and bone-specific costs, including total, inpatient, outpatient, and pharmacy costs in patients treated with TDF/FTC+efavirenz (EFV) compared with several non-EFV-containing TDF/FTC regimens. METHODS: We conducted a national cohort study of treatment-naive HIV-infected U.S. veterans who initiated treatment from 2003 to 2015 with TDF/FTC in combination with EFV, elvitegravir/cobicistat, rilpivirine, or ritonavir-boosted protease inhibitors (atazanavir, darunavir, or lopinavir). Outcomes of interest were quarterly total, inpatient, outpatient, and pharmacy costs using data from the Veterans Health Administration (VHA) electronic medical record and Managerial Cost Accounting System (an activity-based accounting system that allocates VHA expenditures to patient encounters). We controlled for measured confounders using inverse probability of treatment (IPT) weights and assessed differences using standardized mean differences (SMDs). For comparisons where SMDs exceeded 0.1 after IPT weighting, we used the more conservative matching weights in sensitivity analyses. For hypothesis testing, we compared IPT-adjusted differences in quarterly costs between treatment groups using Mann-Whitney U-tests and generalized estimating equation (GEE) regression models. RESULTS: Of 33,048 HIV-positive veterans, 7,222 met eligibility criteria, including 4,172 TDF/FTC + EFV recipients; mean (SD) age of the cohort was 50.0 (10.0) years; 96.7% were male; 60.1% were black; and 30.1% were white. Quarterly periods of exposure to EFV-containing regimens were 22,499 and of exposure to non-EFV-containing regimens were 11,633. After IPT weighting, absolute SMDs were < 0.1 except for a few covariates in the rilpivirine comparison. The per-patient adjusted mean total quarterly costs were $7,145 for EFV versus $8,726 for non-EFV (P < 0.001; Mann-Whitney U-test) and the per-patient adjusted mean difference in total quarterly costs was $1,419 lower for EFV versus all non-EFV combined (P < 0.001; GEE model). Corresponding values for outpatient costs ($2,656 vs. $2,942; P < 0.001; difference, -$254; P = 0.001), inpatient costs ($2,009 vs. $2,614; P < 0.001), radiology costs ($213 vs. $276; P < 0.001), and pharmacy costs ($2,480 vs. $3,170; P < 0.001; difference, -$600; P < 0.001) were all lower for EFV versus all non-EFV combined. Findings based on matching weights were qualitatively similar. Contributions of renal and bone costs to the total costs of treatment were very small, ranging between $52 and $94 per patient per quarter for renal outcomes and between $6 and $114 for bone outcomes. CONCLUSIONS: Among 7,222 HIV-treated veterans over an average follow-up of 1.2 years per patient, those patients receiving TDF/FTC + EFV had lower overall health care costs compared with those receiving non-EFV regimens. DISCLOSURES: This study was funded by Bristol-Myers Squibb. Nelson, Ma, Crook, Knippenberg, Nyman, and LaFleur are employees of the University of Utah, which received a grant from Bristol-Myers Squibb to conduct this study. Nyman also discloses honoraria for consulting from Otsuka and for writing a book chapter from Fresenius. La Fleur reports advisory board and consulting fees from Bristol-Myers Squibb outside of this study. Paul and Esker are employees of, and own stock in, Bristol-Myers Squibb.

HIV Antiretroviral Pre-Exposure Prophylaxis: Development Challenges and Pipeline Promise.

The US Food and Drug Administration (FDA) approved oral daily tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis of human immunodeficiency virus (HIV) infection in 2012 on the basis of two randomized controlled trials (RCTs), one in men who have sex with men (MSM) and another in HIV serodiscordant heterosexual couples. Subsequently, even greater efficacy has been demonstrated in MSM with rapid population-level incidence reductions in some locations. In contrast, studies of antiretroviral pre-exposure prophylaxis (PrEP) in heterosexual women showed only modest or no efficacy, largely attributed to low adherence. The mixed results of antiretroviral-based PrEP bear witness to unique drug development challenges at this complicated intersection of sexual behavior, public health, and drug development. Multiple innovative methods and formulation strategies followed to address unmet medical needs of persons struggling with daily oral PrEP adherence or preference for nonsystemic PrEP options. Clinical pharmacology plays essential roles throughout this PrEP development process, especially in early product development and through pharmacologically informed enhancement and interpretation of clinical trials.

How to do it: setting up a PrEP service in an integrated sexual reproductive health service setting.

Pre-exposure prophylaxis for HIV (PrEP) has been shown to reduce transmission of HIV in a number of trials; however, there is limited evidence regarding the optimal way to deliver PrEP through pre-existing UK services, particularly through fully integrated drop-in sexual health service models. PrEP in the form of Truvada was launched in Wales in July 2017. We set up a PrEP service to be delivered via our drop-in integrated sexual reproductive health service. In the first 5 months of PrEP service provision, we found unforeseen levels of comorbidity, polypharmacy and renal impairment in our cohort of PrEP patients. As a result, we have altered our service model and all patients are now followed up in booked appointment PrEP clinics run by members of the HIV team. Those patients with estimated glomerular filtration rate (eGFR) of 60-70 mL/min or with eGFR of 60-80 mL/min and with comorbidities impacting on renal function are monitored every 4-6 weeks initially, and PrEP has been incorporated into our pre-existing virtual HIV renal clinic for discussion with a renal physician. The PrEP team clinicians report that monitoring and managing the PrEP cohort is now easier in its appointment-only format, although some patients have reported that they would prefer a drop-in system.

Zidovudine/Lamivudine vs. Abacavir/Lamivudine vs. Tenofovir/Emtricitabine in fixed-dose combinations as initial treatment for HIV patients: a systematic review and network meta-analysis.

INTRODUCTION: Initial treatment of the HIV is based on the use of three drugs, two of which are nucleoside analog reverse-transcriptase inhibitors. There are three combinations of these drugs which have been approved by different guidelines, each with divergent results in terms of efficacy and safety. OBJECTIVE: To compare the efficacy and safety of these three combinations. METHODS: Systematic review and network meta-analysis of randomized clinical trials comparing fixed doses of Tenofovir Disoproxil Fumarate / Emtricitabine (TDF/FTC), Abacavir / Lamivudine (ABC/3TC) and Zidovudine / Lamivudine (ZDV/3TC). RESULTS: Seven clinical trials met the eligibility criteria. The results suggested higher efficacy with TDF/FTC vs. ABC/3TC at 96 weeks and vs. ZDV/3TC at 48 weeks. However, there is clinical and statistical heterogeneity. Subgroup analysis were performed by third drug and by level of viral load prior to treatment, and found no differences in virological control. Network meta-analysis could only be carried out with TDF/FTC vs. ZDV/3TC, and the proportion of patients with virological response, with no differences at 48 weeks nor at 96 weeks. Direct comparisons showed an increased risk of bone marrow suppression of ZDV/3TC vs. TDF/FTC and of ABC/3TC hypersensitivity reactions vs. ZDV/3TC. CONCLUSIONS: The results did not show differences in effectiveness among the interventions. However, due to the heterogeneity of the third drug and the follow-up time between the included studies, this result is not definitive. The results raise the need for further studies to help improve treatment recommendations in patients infected with HIV.

INTRODUCCIÓN: El tratamiento inicial de la infección por VIH se basa en el uso de tres medicamentos, dos de ellos inhibidores de transcriptasa reversa análogos de nucleósido. Existen tres combinaciones de estos medicamentos aprobadas por diferentes guías, con resultados divergentes en cuanto a eficacia y seguridad. OBJETIVO: Comparar la eficacia y seguridad de las 3 combinaciones. MÉTODOS: Revisión sistemática y metanálisis en red de ensayos clínicos con asignación aleatoria comparando dosis fijas de Tenofovir Disoproxil Fumarato/Emtricitabina (TDF/FTC), Abacavir/Lamivudina (ABC/3TC) y Zidovudina/Lamivudina (ZDV/3TC). RESULTADOS: Siete ensayos clínicos cumplieron los criterios de elegibilidad. Los resultados sugirieron mayor eficacia con TDF/FTC vs ABC/3TC a 96 semanas y vs. ZDV/3TC a 48 semanas. Sin embargo, existe heterogeneidad clínica y estadística. Se realizó análisis de subgrupos por tercer medicamento y por nivel de carga viral previa al tratamiento, sin encontrar diferencias en control virológico. Se pudo realizar metanálisis en red con TDF/FTC vs ZDV/3TC y proporción de pacientes con respuesta virológica, sin diferencias a las 48 semanas ni 96 semanas. Las comparaciones directas evidenciaron mayor riesgo de supresión de médula ósea de ZDV/3TC vs TDF/FTC y de reacciones de hipersensibilidad de ABC/3TC vs ZDV/3TC. CONCLUSIÓN: Los resultados no demostraron diferencias en efectividad entre las intervenciones; sin embargo, debido a heterogeneidad en cuanto al tercer medicamento y el tiempo de seguimiento entre los estudios incluidos, dicho resultado no es definitivo. Los resultados plantean la necesidad de realizar nuevos estudios que ayuden a mejorar las recomendaciones de tratamiento en los pacientes infectados por el VIH.

Zidovudine/Lamivudine vs. Abacavir/Lamivudine vs. Tenofovir/Emtricitabine in fixed-dose combinations as initial treatment for HIV patients: a systematic review and network meta-analysis / Zidovudina/Lamivudina vs Abacavir/Lamivudina vs Tenofovir/Emtricitabina en combinaciones de dosis fija como tratamiento inicial en pacientes con VIH: revisión sistemática y metanálisis en red

Abstract Introduction: Initial treatment of the HIV is based on the use of three drugs, two of which are nucleoside analog reverse-transcriptase inhibitors. There are three combinations of these drugs which have been approved by different guidelines, each with divergent results in terms of efficacy and safety. Objective: To compare the efficacy and safety of these three combinations. Methods: Systematic review and network meta-analysis of randomized clinical trials comparing fixed doses of Tenofovir Disoproxil Fumarate / Emtricitabine (TDF/FTC), Abacavir / Lamivudine (ABC/3TC) and Zidovudine / Lamivudine (ZDV/3TC). Results: Seven clinical trials met the eligibility criteria. The results suggested higher efficacy with TDF/FTC vs. ABC/3TC at 96 weeks and vs. ZDV/3TC at 48 weeks. However, there is clinical and statistical heterogeneity. Subgroup analysis were performed by third drug and by level of viral load prior to treatment, and found no differences in virological control. Network meta-analysis could only be carried out with TDF/FTC vs. ZDV/3TC, and the proportion of patients with virological response, with no differences at 48 weeks nor at 96 weeks. Direct comparisons showed an increased risk of bone marrow suppression of ZDV/3TC vs. TDF/FTC and of ABC/3TC hypersensitivity reactions vs. ZDV/3TC Conclusions: The results did not show differences in effectiveness among the interventions. However, due to the heterogeneity of the third drug and the follow-up time between the included studies, this result is not definitive. The results raise the need for further studies to help improve treatment recommendations in patients infected with HIV.

Resumen Introducción: El tratamiento inicial de la infección por VIH se basa en el uso de tres medicamentos, dos de ellos inhibidores de transcriptasa reversa análogos de nucleósido. Existen tres combinaciones de estos medicamentos aprobadas por diferentes guías, con resultados divergentes en cuanto a eficacia y seguridad. Objetivo: Comparar la eficacia y seguridad de las 3 combinaciones Métodos: Revisión sistemática y metanálisis en red de ensayos clínicos con asignación aleatoria comparando dosis fijas de Tenofovir Disoproxil Fumarato/Emtricitabina (TDF/FTC), Abacavir/Lamivudina (ABC/3TC) y Zidovudina/Lamivudina (ZDV/3TC). Resultados: Siete ensayos clínicos cumplieron los criterios de elegibilidad. Los resultados sugirieron mayor eficacia con TDF/FTC vs ABC/3TC a 96 semanas y vs. ZDV/3TC a 48 semanas. Sin embargo, existe heterogeneidad clínica y estadística. Se realizó análisis de subgrupos por tercer medicamento y por nivel de carga viral previa al tratamiento, sin encontrar diferencias en control virológico. Se pudo realizar metanálisis en red con TDF/FTC vs ZDV/3TC y proporción de pacientes con respuesta virológica, sin diferencias a las 48 semanas ni 96 semanas. Las comparaciones directas evidenciaron mayor riesgo de supresión de médula ósea de ZDV/3TC vs TDF/FTC y de reacciones de hipersensibilidad de ABC/3TC vs ZDV/3TC. Conclusión: Los resultados no demostraron diferencias en efectividad entre las intervenciones; sin embargo, debido a heterogeneidad en cuanto al tercer medicamento y el tiempo de seguimiento entre los estudios incluidos, dicho resultado no es definitivo. Los resultados plantean la necesidad de realizar nuevos estudios que ayuden a mejorar las recomendaciones de tratamiento en los pacientes infectados por el VIH.

Randomized controlled trial of the tolerability and completion of maraviroc compared with Kaletra® in combination with Truvada® for HIV post-exposure prophylaxis (MiPEP Trial).

Objectives: Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir. Methods: Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra ® 400/100 mg) or maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3 or 4 clinical or laboratory adverse events (AEs) related to the PEP medication. Results: Two hundred and thirteen individuals were randomized (107 to maraviroc; 106 to Kaletra ® arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the maraviroc and 64 (65%) in the Kaletra ® arm ( P = 0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3 or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra ® arm (91% versus 70%; P < 0.001). Antidiarrhoeal medication use was higher in the Kaletra ® arm (67% versus 25%; P < 0.001). There were no HIV seroconversions in the study period. Conclusions: The completion rate in the absence of grade 3 or 4 AEs was similar with both regimens. Maraviroc-based PEP was better tolerated, supporting its use as an option for non-occupational PEP.

Pre-Exposure Prophylaxis for HIV Prevention: Safety Concerns.

Available evidence supports the efficacy of pre-exposure prophylaxis (PrEP) in decreasing the incidence of human immunodeficiency virus (HIV) infection among high-risk individuals, especially when used in combination with other behavioural preventive methods. Safety concerns about PrEP present challenges in the implementation and use of PrEP. The aim of this review is to discuss safety concerns observed in completed clinical trials on the use of PrEP. We performed a literature search on PrEP in PubMed, global advocacy for HIV prevention (Aids Vaccine Advocacy Coalition) database, clinical trials registry " http://www.clinicaltrials.gov " and scholar.google, using combination search terms 'pre-exposure prophylaxis', 'safety concerns in the use of pre-exposure prophylaxis', 'truvada use as PrEP', 'guidelines for PrEP use', 'HIV pre-exposure prophylaxis' and 'tenofovir' to identify clinical trials and literature on PrEP. We present findings associated with safety issues on the use of PrEP based on a review of 11 clinical trials on PrEP with results on safety and efficacy as at April 2016. We also reviewed findings from routine real-life practice reports. The pharmacological intervention for PrEP was tenofovir disoproxil fumarate/emtricitabine in a combined form as Truvada® or tenofovir as a single entity. Both products are efficacious for PrEP and seem to have a good safety profile. Regular monitoring is recommended to prevent long-term toxic effects. The main adverse effects observed with PrEP are gastrointestinal related; basically mild to moderate nausea, vomiting and diarrhea. Other adverse drug effects worth monitoring are liver enzymes, renal function and bone mineral density. PrEP as an intervention to reduce HIV transmission appears to have a safe benefit-risk profile in clinical trials. It is recommended for widespread use but adherence monitoring and real-world safety surveillance are critical in the post-marketing phase to ensure that the benefits observed in clinical trials are maintained in real-world use.

Evaluation of the Lipid Concentrations after Switching from Antiretroviral Drug Tenofovir Disoproxil Fumarate/Emtricitabine to Abacavir Sulfate/Lamivudine in Virologically-suppressed Human Immunodeficiency Virus-infected Patients.

Objective Recently, tenofovir disoproxil fumatate (TDF)-related side effects, such as renal nephrotoxicity and reduction of bone mineral density, have been reported. Consequently, increased switching from fixed-dose tablet TDF and emtricitabine (TDF/FTC) to abacavir and lamivudine (ABC/3TC) has occurred. Interestingly, while TDF has a lipid-lowering property, one of the ABC-related side effects is hyperlipidemia. Therefore, such switching could cause lipid elevation. To evaluate the change in lipid levels associated with switching from TDF/FTC to ABC/3TC in virologically-suppressed human immunodeficiency virus (HIV)-infected patients. Methods This is a retrospective, single-center study. We included the HIV-infected patients whose therapy included a drug switch from TDF/FTC to ABC/3TC between September 2009 and December 2012 at Ryukyu University Hospital. The exclusion criteria were HIV-RNA >40 copies/mL on the switching day, and a documented therapy change to a lipid-lowering agent or any other antiretroviral agents within 3 months before or after switching. We compared the low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), and triglyceride (TG) levels before switching to three months after. Results A total of 18 patients met the inclusion criteria. The LDL, HDL, and TC levels significantly increased three months following the switch (p<0.05), with median (interquartile range) values of 17 (7, 32), 6 (2, 13), and 27 (10, 45) mg/dL, respectively. The TG values did not markedly change. Conclusion Switching from TDF/FTC to ABC/3TC resulted in significantly increased LDL, HDL, and TC levels.

Drug safety evaluation of oral tenofovir disoproxil fumarate-emtricitabine for pre-exposure prophylaxis for human immunodeficiency virus infection.

INTRODUCTION: Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are nucleoside reverse transcriptase inhibitors approved as pre-exposure prophylaxis (PrEP) against human immunodeficiency virus (HIV). Prophylactic TDF-based regimens have been shown to reduce the risk of HIV infection by 74 to 92% among participants with detectable drug levels. Adverse events observed in clinical trials include nausea, elevated creatinine and liver enzymes, and decreased bone mineral density. AREAS COVERED: This article reviews the pharmacology, pharmacokinetics, and the safety profile of TDF and FTC used as PrEP for HIV infection. EXPERT OPINION: TDF-FTC can have a large impact in preventing HIV infections among high risk individuals when taken daily. Although TDF-FTC is associated with adverse events, they can be minimized with clinician-guided monitoring.

An analysis of baseline data from the PROUD study: an open-label randomised trial of pre-exposure prophylaxis.

BACKGROUND: Pre-exposure prophylaxis (PrEP) has proven biological efficacy to reduce the sexual acquisition of the human immunodeficiency virus (HIV). The PROUD study found that PrEP conferred higher protection than in placebo-controlled trials, reducing HIV incidence by 86 % in a population with seven-fold higher HIV incidence than expected. We present the baseline characteristics of the PROUD study population and place the findings in the context of national sexual health clinic data. METHODS: The PROUD study was designed to explore the real-world effectiveness of PrEP (tenofovir-emtricitabine) by randomising HIV-negative gay and other men who have sex with men (GMSM) to receive open-label PrEP immediately or after a deferral period of 12 months. At enrolment, participants self-completed two baseline questionnaires collecting information on demographics, sexual behaviour and lifestyle in the last 30 and 90 days. These data were compared to data from HIV-negative GMSM attending sexual health clinics in 2013, collated by Public Health England using the genitourinary medicine clinic activity database (GUMCAD). RESULTS: The median age of participants was 35 (IQR: 29-43). Typically participants were white (81 %), educated at a university level (61 %) and in full-time employment (72 %). Of all participants, 217 (40 %) were born outside the UK. A sexually transmitted infection (STI) was reported to have been diagnosed in the previous 12 months in 330/515 (64 %) and 473/544 (87 %) participants reported ever having being diagnosed with an STI. At enrolment, 47/280 (17 %) participants were diagnosed with an STI. Participants reported a median (IQR) of 10 (5-20) partners in the last 90 days, a median (IQR) of 2 (1-5) were condomless sex acts where the participant was receptive and 2 (1-6) were condomless where the participant was insertive. Post-exposure prophylaxis had been prescribed to 184 (34 %) participants in the past 12 months. The number of STI diagnoses was high compared to those reported in GUMCAD attendees. CONCLUSIONS: The PROUD study population are at substantially higher risk of acquiring HIV infection sexually than the overall population of GMSM attending sexual health clinics in England. These findings contribute to explaining the extraordinary HIV incidence rate during follow-up and demonstrate that, despite broad eligibility criteria, the population interested in PrEP was highly selective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN94465371 . Date of registration: 28 February 2013.

Reversibility of Glomerular Renal Function Decline in HIV-Uninfected Men and Women Discontinuing Emtricitabine-Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis (PrEP) use is associated with a small but statistically significant decline in estimated glomerular filtration rate (eGFR). We investigated the reversibility of eGFR decline among HIV-uninfected adults discontinuing PrEP. METHODS: Data were from the Partners PrEP Study, a randomized trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among African HIV-uninfected men and women with baseline creatinine clearance ≥60 mL/min. Serum creatinine was measured quarterly while on-study medication and at month 1 and 2 after discontinuation. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Equation. RESULTS: A total of 3924 individuals had a poststudy drug serum creatinine measurement after the scheduled drug discontinuation (1271 for TDF, 1308 for FTC-TDF, and 1345 for placebo); 65% were men, median age was 35 (range 18-64) years. Median time on study drug was 33 (interquartile range 25-36) months overall, and 36 months (interquartile range 30-36) for TDF and FTC-TDF. Mean eGFR at the last on-treatment visit was 129 mL·min·1.73 m for TDF and 128 mL·min·1.73 m for FTC-TDF versus 131 mL·min·1.73 m for placebo (2-3 mL·min·1.73 m mean decline for PrEP versus placebo, P ≤ 0.01), and this difference reversed by 4 weeks after drug discontinuation (mean eGFR at the first postdrug visit: 130 mL·min 1.73 m in all groups). More than 96% of participants had a confirmed >75% eGFR rebound to baseline level by 8 weeks after drug discontinuation, with similar proportions across treatment groups. CONCLUSIONS: In this large, placebo-controlled study of TDF-based PrEP, the small reduction in mean eGFR associated with PrEP reversed within weeks after discontinuation.