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Background Drug resistance may be acquired in people starting human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) during undiagnosed infection. Population-based estimates of PrEP-related resistance are lacking. Methods We used New York City surveillance and partner services data to measure the effect of PrEP use (tenofovir disoproxil fumarate/tenofivir alafenamide fumarate with emtricitabine) history on the baseline prevalence of M184I/V mutations in people with HIV diagnosed in 2015–2022. PrEP use was categorized as "recent" (defined as PrEP stopped ≤90 days before diagnosis), "past" (PrEP stopped >90 days before diagnosis), or "no known use." Resistance-associated mutations were determined using the Stanford algorithm. We used log binomial regression to generate the adjusted relative risk (aRR) of M184I/V by PrEP use history in people with or without acute HIV infection (AHI). Results Of 4246 people with newly diagnosed HIV and a genotype obtained within ≤30 days of diagnosis, 560 (13%) had AHI; 136 (3%) reported recent and 124 (35%) past PrEP use; and 98 (2%) harbored M184I/V. In people with AHI, recent PrEP use was associated with a 6 times greater risk of M184I/V than no known use (aRR, 5.86 [95% confidence interval, 2.49–13.77]). Among people without AHI, the risk of M184I/V in recent users was 7 times that in people with no known use (aRR, 7.26 [95% confidence interval, 3.98–13.24]), and in past users, it was 4 times that in those with no known use (4.46 [2.15–9.24]). Conclusions PrEP use was strongly associated with baseline M184I/V in New York City, regardless of AHI status. Ordering a nucleic acid test when indicated after assessment of exposure, antiretroviral history, and AHI symptoms can decrease PrEP initiation in people with undetected infection. [ABSTRACT FROM AUTHOR]

We estimate the effectiveness of antiretroviral therapy (ART) among individuals receiving HIV care in Rio de Janeiro, Brazil. Adults (18y+) initiating ART between Jan/2008 and Dec/2018 (follow-up through Dec/2020) were included. First-line ART (two nucleoside reverse transcriptase inhibitors plus one antiretroviral from another class) was categorized into four categories: non-nucleoside reverse transcriptase inhibitor/NNRTI-based, protease inhibitor/PI-based, integrase strand transfer inhibitor/INSTI-based, and single-tablet regimen (STR, Tenofovir 300mg + Lamivudine 300mg + Efavirenz 600mg). Effectiveness (viral load ≤50 copies/µL) was evaluated at 6(3–9) and 12(9–15) months from ART initiation. Bayesian logistic regression models were used to quantify the association between exposure and outcomes while accounting for missing data. Overall, 1863(57%), 652(19.9%), 412(12.6%), and 342(10.5%) individuals used, respectively, NNRTI-based, PI-based, INSTI-based regimens, and STR. Compared to NNRTIs, the odds of viral suppression with INSTI-based regimens was 76% higher (adjusted OR:1.76, 95%CI:1.23–2.51) at six months but no higher at 12 months. Older age, higher education, CD4 count ≥500 cells/mm3 and viral load <100,000 copies/µL at ART initiation increased the odds of viral suppression. Viral suppression at six months was the strongest predictor of viral suppression at 12 months. These results highlight population groups that could benefit from close monitoring during the first year of ART. [ABSTRACT FROM AUTHOR]

The rise of HIV‐1 drug resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) threatens the long‐term success of NNRTI‐based therapies. Our study aims to describe the circulation of major resistance‐associated mutations (RAMs) for NNRTIs in people living with HIV (PLWH) in Italy from 2000 to 2020. We included 5982 naïves and 28 505 genotypes from 9387 treatment‐experienced PLWH from the Antiviral Response Cohort Analysis (ARCA) cohort. Transmitted drug resistance (TDR) was found in 12.5% and declined from 17.3% in 2000–2003 to 10.9% in 2016–2020 (p = 0.003). Predictors of TDR were viral subtype B [vs. non‐B, adjusted odds ratio (aOR) = 1.94, p < 0.001], zenith viral load (VL) (per 1 log10 higher, aOR = 0.86, p = 0.013), nadir CD4 cell count (per 100 cells/μL increase aOR = 0.95, p = 0.013). At least one RAM for NNRTIs among treatment experienced PLWH was detected in 33.2% and pre‐treatment drug resistance (PDR) declined from 43.4% in 2000–2003 to 20.9% in 2016–2020 (p < 0.001). Predictors of PDR were sexual transmission route (vs. others, aOR = 0.78, p < 0.001), time since HIV diagnosis (per 1 month longer, aOR = 1.002, p < 0.001), viral subtype B (vs. non B, aOR = 1.37, p < 0.001), VL (per 1 log10 higher, aOR = 1.12, p < 0.001), nadir CD4 count (per 100 cells/μL increase, aOR = 0.91, p < 0.001), previous exposure to any NNRTI (aOR = 2.31, p < 0.001) and a more recent calendar year sequence (any time span > 2008 vs. 2000–2003, any aOR <1, p < 0.001). Circulation of RAMs to NNRTIs declined during the last 20 years in Italy. NNRTIs remain pivotal drugs for the management of HIV‐1 due to safety concerns and long‐acting options. [ABSTRACT FROM AUTHOR]

Background Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice-daily dolutegravir dosing when coadministered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed human immunodeficiency virus type 1 (HIV-1) RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). Methods We conducted a randomized, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (2 consecutive HIV-1 RNA ≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA <50 copies/mL at week 24. This study was not powered to compare arms. Results One hundred thirty participants were randomized (65 to each arm). Median baseline HIV-1 RNA was 4.0 log10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and 2 were lost to follow-up. At week 24, 55 of 64 (86% [95% confidence interval {CI}: 75%–93%]) in the supplementary dolutegravir arm and 53 of 65 (82% [95% CI: 70%–90%]) in the placebo arm had HIV-1 RNA <50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of 6 participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. Conclusions Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. Clinical Trials Registration NCT03991013. [ABSTRACT FROM AUTHOR]

Background & Objective: Many different combination regimens have been used for the treatment of patients infected with human immunodeficiency viruses (HIV). This study aimed to compare the efficacy of two antiviral drugs for the treatment of HIV-infected patients. Materials & Methods: This cross-sectional study was performed on HIV-positive patients in Fasa, Southwest Iran. Eighty patients were enrolled in the investigation who were then randomly divided into two groups and treated plus vonavir (teno - fovir-emtricitabine-efavirenz) and cobavir (lamivudine-zidovudine) with efavirenz for six months. Blood samples collected from all patients were examined for viral load every six months using Real-time PCR and CD 4 changes by flow cytometry. Result: During the six months of treatment, the CD 4 response was not significantly increased in group one, treated with vonavir. In contrast, the CD 4 value showed a significant increasing trend during the treatment course in group two treated with cobavir-efavirenz (P=0.003). However, overall, there was no statistically significant difference between the CD4 responses of the two groups (P=0.361). In addition, the plasma viral load was significantly suppressed in both regimens (P< 0.05). Conclusion: Hence, the two regimens (cobavir-efavirenz, and vobavir) showed the same efficacy on HIV patients according to the same suppression of viral load, and CD 4 response in this region. However, inclusion of more samples is needed and more studies are suggested in order to confirm our results as well. [ABSTRACT FROM AUTHOR]

Background 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. Methods 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. Results 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. Clinical Trials Registration NCT02403674. [ABSTRACT FROM AUTHOR]

Ilex paraguariensis (mate) is one of the plants more traditionally used to elaborate infusions in South America countries. It has won prestige in world markets, including United States, Asia and Europe for their benefits in the glucose metabolism and also to present properties hypocholesterolemic, anti-inflammatory, anti-obesity, hepatoprotective and antioxidant. To report a clinical case with observed adverse reactions reduction during the concomitant consumption of mate infusion with Atripla (emtricitabine, efavirenz and tenofovir (disoproxil fumarate)) treatment. The masculine patient's clinical history assisted in external consult of the Institute of Tropical Medicine "Pedro Kourí" was revised for check evolution during one year. Accrual literature related to the case was reviewed. The presentation of a patient case that has improved its quality of life after ingestion of mate infusion when some of the Atripla adverse reactions that the patients experience with HIV diminishing without pharmacological interaction or the appearance of other side effects. It is important the patients orientation by medical personnel during antiretroviral treatment as Atripla about the benefits of mate infusion consumption as safe nutraceuticals therapeutic strategy. [ABSTRACT FROM AUTHOR]

Background Doravirine (DOR) demonstrated noninferior efficacy to darunavir plus ritonavir (DRV+r) and efavirenz (EFV) in 2 ongoing phase 3 trials: DRIVE-FORWARD (NCT02275780) and DRIVE-AHEAD (NCT02403674). Methods This prespecified analysis pooled efficacy data through the first 48 weeks of DRIVE-FORWARD and DRIVE-AHEAD from the DOR groups (DOR/lamivudine [3TC]/tenofovir disoproxil fumarate [TDF] or DOR [100 mg daily] with emtricitabine [FTC]/TDF or abacavir [ABC]/3TC [n = 747]) compared with DRV+r (800/100 mg daily) with FTC/TDF or ABC/3TC (n = 383) or EFV/FTC/TDF (600/200/300 mg daily; n = 364). Efficacy assessments included the proportion of participants with human immunodeficiency virus type 1 (HIV-1) RNA <50 copies/mL and change in CD4+ T-cell count. Results At week 48, DOR demonstrated noninferior efficacy to DRV+r and EFV, with 84.1% of DOR-treated participants achieving HIV-1 RNA <50 copies/mL compared with 79.9% of the DRV+r and 80.8% of the EFV groups. Results were similar across demographic/prognostic subpopulations, including baseline plasma HIV-1 RNA, gender, race, and HIV-1 subtype. Mean increases from baseline in CD4+ T-cell count through 48 weeks were 195.5 cells/mm3 for DOR, 185.6 cells/mm3 for DRV+r, and 188.4 cells/mm3 for EFV/FTC/TDF. Conclusions DOR, as a single entity (in combination with other antiretroviral agents) and as a fixed-dose combination (DOR/3TC/TDF), demonstrated noninferior efficacy to DRV+r and EFV as assessed by the proportion of HIV-1-infected, treatment-naive adults with HIV-1 RNA <50 copies/mL. Clinical Trials Registration NCT02275780 and NCT02403674. [ABSTRACT FROM AUTHOR]

Background Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression (VS; <50 copies/mL) in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial. Methods Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation. Results PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years (interquartile range, 0.91–2.13), mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32; 95% confidence interval [CI], 0.12–0.86), while there was no difference between those with only NNRTI PDR vs no PDR (aHR, 1.05; 95% CI, 0.82–1.34) at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance. Conclusions NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone. Clinical T rials T egistration NCT01509508; South African National Clinical Trials Register: DOH-27-0512-3974. [ABSTRACT FROM AUTHOR]

Background Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. Methods DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment–naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). Results Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) (-3.83 vs +13.26 mg/dL) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (−1.6 vs +8.7 mg/dL and −3.8 vs +13.3 mg/dL, respectively). Conclusions In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non–HDL-C compared with EFV/FTC/TDF. Clinical Trials Registration NCT02403674 [ABSTRACT FROM AUTHOR]

Introduction: Data are lacking regarding overdose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF).Material and methods: We present the first report of suicidal attempt with E/C/F/TAF in a Human Immunodeficiency Virus-infected subject.Results: A reversible acute renal failure with no proximal tubulopathy and neuropsychiatric issues are discussed. E/C/F/TAF withdrawal resulted in favourable renal and neuropsychiatric outcomes. The suicide attempt seemed unrelated to the integrase strand transfer inhibitor, being evenly explained within the context of stressful personal conflicts.Conclusion: A suicidal attempt with an E/C/F/TAF overdose in an HIV-infected patient, resulted in a favourable outcome from a renal and neuropsychiatric standpoint. [ABSTRACT FROM AUTHOR]

Gilead Sciences has developed a single tablet anti-HIV-1 medication (Biktarvy®) combining the novel integrase strand transfer inhibitor (INSTI) bictegravir with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) emtricitabine and tenofovir alafenamide. This fixed dose combination has demonstrated efficacy as treatment for both anti-retroviral naïve and virologically suppressed HIV-1 infection in patients switching therapy, and was recently approved in the USA. This article summarizes the milestones in the development of bictegravir leading to this first approval of bictegravir/emtricitabine/tenofovir alafenamide as treatment for HIV-1 infection. [ABSTRACT FROM AUTHOR]

Highly active anti-retroviral therapy has proved successful in reducing morbidity and mortality associated with HIV infection though it has been linked to increased risk of cardiovascular disease. To date, the direct effects of the anti-retroviral drugs Efavirenz, Tenofovir and Emtricitabine on the vasculature relaxant response have not been elucidated, which impaired may predispose individuals to cardiovascular disease. Increased cellular oxidative stress and overactivation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) have been identified as central mediators of vascular dysfunction. The aim of this study was to investigate whether exposure to Efavirenz, Tenofovir or Emtricitabine directly causes endothelial cell dysfunction via overactivation of PARP. Exposure of ex vivo male rat aortic rings or in vitro endothelial cells to Efavirenz but not Tenofovir or Emtricitabine impaired the acetylcholine-mediated relaxant response, increased cellular oxidative stress and PARP activity, decreased cell viability and increased apoptosis and necrosis. Pharmacological inhibition of PARP protected against the Efavirenz-mediated impairment of vascular relaxation and endothelial cell dysfunction. Oestrogen exposure also protected against the Efavirenz-mediated inhibition of the vascular relaxant response, cell dysfunction and increased PARP activation. In conclusion, Efavirenz directly impairs endothelial cell function, which may account for the increased risk of developing cardiovascular complications with anti-retroviral therapy. [ABSTRACT FROM AUTHOR]

Background. Antiretroviral drugs with a lower potential to induce hepatic steatosis in human immunodeficiency virus (HIV) infection need to be identified. We compared the effect of switching efavirenz (EFV) to raltegravir (RAL) on hepatic steatosis among HIV-infected patients with nonalcoholic fatty liver disease (NAFLD) receiving EFV plus 2 nucleoside analogues. Methods. HIV-infected patients on EFV plus tenofovir/emtricitabine or abacavir/lamivudine with NAFLD were randomized 1:1 to switch from EFV to RAL (400 mg twice daily), maintaining nucleoside analogues unchanged, or to continue with EFV plus 2 nucleoside analogues. At baseline, eligible patients should show controlled attenuation parameter (CAP) values ≥238 dB/m. Changes in hepatic steatosis at 48 weeks of follow-up over baseline levels were measured by CAP. Results. Overall, 39 patients were included, and 19 of them were randomized to switch to RAL. At week 48, median CAP for the RAL group was 250 (Q1–Q3, 221–277) dB/m and 286 (Q1–Q3, 269–314) dB/m for the EFV group (P = .035). The median decrease in CAP values was –20 (Q1–Q3, –67 to 15) dB/m for the RAL arm and 30 (Q1–Q3, –17 to 49) dB/m for the EFV group (P = .011). CAP values <238 dB/m at week 48 were observed in 9 (47%) patients on RAL and 3 (15%) individuals on EFV (P = .029). Conclusions. After 48 weeks, HIV-infected individuals switching EFV to RAL showed decreases in the degree of hepatic steatosis, as measured by CAP, compared with those continuing with EFV. In addition, the proportion of patients without significant hepatic steatosis after 48 weeks was greater for those who switched to RAL. [ABSTRACT FROM AUTHOR]

Objectives Tenofovir disoproxil fumarate/emtricitabine ( TDF/ FTC) is approved for pre-exposure prophylaxis (Pr EP) against HIV infection. Adherence is critical for the success of Pr EP, but current adherence measurements are inadequate for real-time adherence monitoring. We developed and validated a urine assay to measure tenofovir ( TFV) to objectively monitor adherence to Pr EP. Methods We developed a urine assay using high-performance liquid chromatography coupled to tandem mass spectrometry with high sensitivity/specificity for TFV that allowed us to determine TFV concentrations in log10 categories between 0 and 10 000 ng/ mL. We validated the assay in three cohorts: (1) HIV-positive subjects with undetectable viral loads on a TDF/ FTC-based regimen, (2) healthy HIV-negative subjects who received a single dose of TDF/ FTC, and (3) HIV-negative subjects receiving daily TDF/ FTC as Pr EP for 24 weeks. Results The urine assay detected TFV with greater sensitivity than plasma-based measures and with a window of measurements within 7 days of the last TDF/ FTC dose. Based on the urine log-linear clearance after the last dose and its concordance with all detectable plasma levels, a urine TFV concentration > 1000 ng/ mL was identified as highly predictive of the presence of TFV in plasma at > 10 ng/ mL. The urine assay was able to distinguish high and low adherence patterns within the last 48 h (> 1000 ng/ mL versus 10-1000 ng/ mL), as well as nonadherence (< 10 ng/ mL) extended over at least 1 week prior to measurement. Conclusions We provide proof of concept that a semiquantitative urine assay measuring levels of TFV could be further developed into a point-of-care test and be a useful tool to monitor adherence to Pr EP. [ABSTRACT FROM AUTHOR]

Background: In January 2014, the European Medicines Agency issued a marketing authorization for dolutegravir (DTG), a second-generation integrase strand transfer inhibitor for HIV treatment. The study aimed at determining the incremental cost-effectiveness ratio (ICER) of the use of DTG+backbone compared with raltegravir (RAL)+backbone, darunavir (DRV)+ritonavir(r)+backbone and efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) in HIV- positive treatment-naïve patients and compared with RAL+backbone in treatment-experienced patients, from the Italian National Health Service's point of view. Materials and methods: A published Monte Carlo Individual Simulation Model (ARAMIS- DTG model) was used to perform the analysis. Patients pass through mutually exclusive health states (defined in terms of diagnosis of HIV with or without opportunistic infections [OIs] and cardiovascular disease [CVD]) and successive lines of therapy. The model considers costs (2014) and quality of life per monthly cycle in a lifetime horizon. Costs and quality-adjusted life years (QALYs) are dependent on OI, CVD, AIDS events, adverse events and antiretroviral therapies. Results: In treatment-naïve patients, DTG dominates RAL; compared with DRV/r, the ICER obtained is of 38,586 €/QALY (6,170 €/QALY in patients with high viral load) and over EFV/ TDF/FTC, DTG generates an ICER of 33,664 €/QALY. In treatment-experienced patients, DTG compared to RAL leads to an ICER of 12,074 €/QALY. Conclusion: The use of DTG+backbone may be cost effective in treatment-naïve and treatment- experienced patients compared with RAL+backbone and in treatment-naïve patients compared with DRV/r+backbone and EFV/TDF/FTC considering a threshold of 40,000 €/QALY. [ABSTRACT FROM AUTHOR]

Background. Adherence to antiretroviral therapy (ART) is crucial to preventing mother-to-child transmission of human immunodeficiency virus (HIV) and ensuring the long-term effectiveness of ART, yet data are sparse from African routine care programs on maternal adherence to triple ART. Methods. We analyzed data from women who started ART at 13 large health facilities in Malawi between September 2011 and October 2013. We defined adherence as the percentage of days "covered" by pharmacy claims. Adherence of ≥90% was deemed adequate. We calculated inverse probability of censoring weights to adjust adherence estimates for informative censoring. We used descriptive statistics, survival analysis, and pooled logistic regression to compare adherence between pregnant and breastfeeding women eligible for ART under Option B+, and nonpregnant and nonbreastfeeding women who started ART with low CD4 cell counts or World Health Organization clinical stage 3/4 disease. Results. Adherence was adequate for 73% of the women during pregnancy, for 66% in the first 3 months post partum, and for about 75% during months 4-21 post partum. About 70% of women who started ART during pregnancy and breastfeeding adhered adequately during the first 2 years of ART, but only about 30% of them had maintained adequate adherence at every visit. Risk factors for inadequate adherence included starting ART with an Option B+ indication, at a younger age, or at a district hospital or health center. Conclusions. One-third of women retained in the Option B+ program adhered inadequately during pregnancy and breastfeeding, especially soon after delivery. Effective interventions to improve adherence among women in this program should be implemented. [ABSTRACT FROM AUTHOR]

Background:Tenofovir disoproxil fumarate (TDF) is a component of many combinations of antiretroviral treatment (ART) regimens. Although potent and generally well tolerated, TDF may cause renal and bone toxicity. The magnitude of off-target side effects is proposed to be related to tenofovir plasma concentrations, which are affected by food and drug–drug interactions with concomitant antiretrovirals. Objective:To perform a systematic literature review and qualitatively report on renal and bone safety outcomes associated with efavirenz (EFV), emtricitabine (FTC), and TDF (EFV+FTC+TDF) ART. Methods:Embase and PubMed databases were searched for randomized clinical trials and observational cohort studies reporting on HIV treatment with EFV+FTC+TDF. Relevant articles were hand-searched for renal (Grade 3–4 serum creatinine/estimated glomerular filtration rate elevations, renal adverse events [AEs], discontinuation due to renal AEs, and urinary biomarkers) and bone outcomes (bone mineral density [BMD] reductions, bone turnover markers, and fracture), and results compiled qualitatively. Results:Of 337 retrieved articles, 29 reporting renal and 11 reporting bone outcomes met the review criteria. EFV+FTC+TDF was associated with a low frequency of renal AEs and treatment discontinuations due to renal AEs. Renal AEs were more frequent when TDF was taken with protease inhibitor (PI)- or cobicistat-containing ART. EFV+FTC+TDF was associated with reduced BMD and increased bone turnover markers, but BMD reductions were less than with PI-containing ART. No treatment-related bone fractures were identified. Conclusions:EFV+FTC+TDF appeared to have a more favorable renal safety profile than TDF administered with a PI or cobicistat. BMD decreased with EFV+FTC+TDF, but no treatment-related fractures were identified. [ABSTRACT FROM PUBLISHER]

Objectives The aim of the study was to assess the cost-effectiveness of the four regimens studied in the AIDS Clinical Trials Group ( ACTG) 5202 clinical trial, tenofovir/emtricitabine ( TDF/ FTC) or abacavir/lamivudine ( ABC/3 TC) in combination with efavirenz ( EFV) or atazanavir/ritonavir ( ATV/r), for treatment-naïve adults with HIV-1 infection in the UK. Methods A Markov model with six health states based on CD4 cell count ranges was developed to predict long-term costs and health outcomes for individuals on first-line therapy. Head-to-head efficacy data comparing TDF/ FTC + EFV, TDF/ FTC + ATV/r, ABC/3 TC + EFV, and ABC/3 TC + ATV/r were obtained from ACTG 5202 for up to 192 weeks. Antiretroviral drug costs were based on current list prices. Other medical costs (2013 UK pounds sterling), utility values, and mortality rates were obtained from published sources. Base-case, sensitivity, and subgroup analyses (by baseline viral load) were conducted. Results Individuals using TDF/ FTC-based regimens were predicted to remain on first-line therapy longer and accrue more quality-adjusted life-years ( QALYs) than individuals using ABC/3 TC-based regimens. At a willingness-to-pay threshold of £30 000 per QALY gained, TDF/ FTC-based regimens were predicted to be cost-effective compared with ABC/3 TC-based regimens, with incremental cost-effectiveness ratios of £23 355 for TDF/ FTC + EFV vs. ABC/3 TC + EFV and £23 785 for TDF/ FTC + ATV/r vs. ABC/3 TC + ATV/r. Results were generally robust in subgroup, sensitivity, and scenario analyses. Conclusions In an analysis of the regimens studied in ACTG 5202 for treatment-naïve adults with HIV-1 infection in the UK, TDF/ FTC-based regimens yielded more favourable health outcomes and were generally predicted to be cost-effective compared with ABC/3 TC-based regimens. These results confirm that TDF/ FTC-based regimens are not only clinically effective but also cost-effective. [ABSTRACT FROM AUTHOR]

Objectives Simplification of antiretroviral therapy enhances a patient's adherence but a new formulation could also lead to new adverse events and changes in daily routine. This study compared medication adherence, tolerance and satisfaction among subjects switching from a two-tablet tenofovir/emtricitabine/efavirenz regimen to a one-tablet regimen. Methods Clinical and sociodemographic data were collected and three surveys were administered at month 0 (=switch), and then 1 and 4-6 months after the switch: the Beliefs about Medicines Questionnaire, the HIV-symptom index questionnaire, the Short HIV Treatment Satisfaction Questionnaire, the Swiss HIV Cohort Study ( SHCS) two-item adherence questionnaire, and a questionnaire on daily combination antiretroviral therapy ( cART) management. Medication adherence of a subgroup of subjects was routinely monitored using an electronic device ( MEMS™). Results Eighty-eight subjects gave informed consent to participate in the study. The subjects' back-switch rate was 7% (six of 88). Subjects who did not back-switch preferred the one-tablet regimen (median = 2; IQR = 1.3-2.5; on a −3 to 3 scale), but no change in adherence was found (10 of 46 nonadherent subjects; P = 1.00). The perception of treatment necessity score decreased ( P = 0.004), the efavirenz blood level increased (14%; P = 0.04), and association/dissociation of cART with food intake evolved ( P = 0.01) after the switch. Subjects listed equivalent numbers of symptoms during the three visits. Conclusions The one-tablet regimen was preferred but the number of back-switches was not negligible. The perception of treatment necessity score decreased with the simplification of the regimen from a two-tablet to a one-tablet formulation, which could negatively impact adherence. Switching is a sensitive time in a patient's treatment life and professionals should pay particular attention to patient's perceptions of treatment during such a transition. [ABSTRACT FROM AUTHOR]

Background: HIV-infected patients with TB need simplified, effective and well-tolerated antiretroviral regimens.Methods: The French ANRS 129 BKVIR open trial evaluated the once-daily tenofovir DF/emtricitabine and efavirenz combination, started within 12 weeks after TB treatment initiation, in antiretroviral-naive HIV-1-infected patients. Success was defined as an HIV-1 RNA <50 copies/mL and TB cure at 48 weeks.Results: TB was confirmed microbiologically (90%) or histologically (10%) in 69 patients (71% male; median age 43 years; 54% born in Africa). The median time between TB treatment initiation and antiretroviral therapy was 8 weeks (range 1-22 weeks). At baseline, median HIV-1 RNA was 5.4 log10 copies/mL and median CD4 cell count 74 cells/mm(3). In the ITT analysis, combined success at week 48 was achieved in 57/69 patients (83%, 95% CI 74-92). Twelve patients did not achieve virological success, and TB was not cured in one of them. Among the 47 patients who fully adhered to the strategy, the success rate was 96% (95% CI 90-100) and was not affected by low rifampicin and isoniazid serum concentrations. Forty-nine serious adverse events were reported in 31 patients (45%), and 11 led to antiretroviral drug interruption. All adverse events resolved. The immune reconstitution inflammatory syndrome occurred in 23 patients (33%, 95% CI 22-44), and was associated with a low baseline BMI (P = 0.03) and a low haemoglobin level (P = 0.02).Conclusion: These results support the use of tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients with TB. [ABSTRACT FROM AUTHOR]

This 96-week, randomized, open-label study was designed to assess the efficacy and safety of two single-tablet regimens in treatment naïve HIV-1-infected adults: rilpivirine (RPV) + emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and efavirenz (EFV) + FTC/TDF. Assessments included patient-reported Medication Adherence Self-Report Inventory, SF-12v2 Quality of Life assessment, HIV Treatment Satisfaction Questionnaire, and HIV Symptom Index Questionnaire through Week 48. Additional evaluations included study drug discontinuations due to treatment-emergent adverse events (TEAEs). A total of 786 participants (n=394 RPV/FTC/TDF, n=392 EFV/FTC/TDF) were included. Fewer RPV/FTC/TDF-treated than EFV/FTC/TDF-treated participants discontinued study drug due to TEAEs (2.5% vs. 8.7%), with 41% (14/34) TEAE-related discontinuations in the EFV/FTC/TDF group occurring within the first four weeks of treatment. Treatment adherence and satisfaction remained high through Week 48 and quality of life improved from baseline in both groups. There were no significant between-group differences in virologic success (HIV-1 RNA <50 copies/mL) regardless of adherence (<95% or ≥95%). Significant between-group differences favouring RPV/FTC/TDF were observed for the HIV SIQ symptoms of difficulty falling or staying asleep (p = .022) and diarrhea or loose bowel movements (p = .002). In conclusion, 48-week treatment with RPV/FTC/TDF or EFV/FTC/TDF was associated with high adherence, high treatment satisfaction, and improved quality of life. TEAE-related discontinuations and patient-reported symptoms indicate that RPV/FTC/TDF may be somewhat better tolerated than EFV/FTC/TDF. [ABSTRACT FROM PUBLISHER]

Summary Background The week 48 primary analysis of the ENCORE1 trial established the virological non-inferiority and safety of efavirenz 400 mg compared with the standard 600 mg dose, combined with tenofovir and emtricitabine, as first-line HIV therapy. This 96-week follow-up of the trial assesses the durability of efficacy and safety of this treatment over 96 weeks. Methods ENCORE1 was a double-blind, placebo-controlled, non-inferiority trial done at 38 clinical sites in 13 countries. HIV-infected adult patients (≥16 years of age) with no previous antiretroviral therapy, a CD4 cell count of 50–500 cells per μL, and plasma HIV-1 viral load of at least 1000 copies per mL were randomly assigned (1:1) by an electronic case report form to receive fixed-dose daily tenofovir 300 mg and emtricitabine 200 mg plus efavirenz either 400 mg daily or 600 mg daily. Participants, physicians, and all other trial staff were masked to treatment assignment. Randomisation was stratified by HIV-1 viral load at baseline (≤ or >100 000 copies per mL). The primary endpoint was the difference in the proportions of patients in the two treatment groups with a plasma HIV-1 viral load below 200 copies per mL at week 96. Treatment groups were deemed to be non-inferior if the lower limit of the 95% CI for the difference in viral load was above −10% by modified intention-to-treat analysis. Non-inferiority was assessed in the modified intention-to-treat, per-protocol, and non-completer=failure (NC=F) populations. Adverse events and serious adverse events were summarised by treatment group. This study is registered with ClinicalTrials.gov , number NCT01011413 . Findings Between Aug 24, 2011, and March 19, 2012, 636 eligible participants were enrolled and randomly assigned to the two treatment groups (324 to efavirenz 400 mg and 312 to efavirenz 600 mg). The intention-to-treat population who received at least one dose of study drug comprised 630 patients: 321 in the efavirenz 400 mg group and 309 in the efavirenz 600 mg group. 585 patients (93%; 299 in the efavirenz 400 mg group and 286 in the 600 mg group) completed 96 weeks of follow-up. At 96 weeks, 289 (90·0%) of 321 patients in the efavirenz 400 mg group and 280 (90·6%) of 309 in the efavirenz 600 mg group had a plasma HIV-1 viral load less than 200 copies per mL (difference −0·6, 95% CI −5·2 to 4·0; p=0·72), which suggests continued non-inferiority of the lower efavirenz dose. Non-inferiority was recorded for thresholds of less than 50 and less than 400 copies per mL, irrespective of baseline plasma viral load. Adverse events were reported by 291 (91%) of 321 patients in the efavirenz 400 mg group and by 285 (92%) of 309 in the 600 mg group (p=0·48). The proportions of patients reporting an adverse event that was definitely or probably related to efavirenz were 126 (39%) for efavirenz 400 mg and 148 (48%) for efavirenz 600 mg (p=0·03). The number of patients who reported serious adverse events did not differ between the groups (p=0·20). Interpretation Our findings confirm that efavirenz 400 mg is non-inferior to the standard dose of 600 mg in combination with tenofovir and emtricitabine as initial HIV therapy over 96 weeks. Fewer efavirenz-related adverse events were reported with the 400 mg efavirenz dose than with the 600 mg dose. These findings support the routine use of efavirenz 400 mg. The coadministration of rifampicin and efavirenz 400 mg needs further investigation. Funding Bill & Melinda Gates Foundation, and UNSW Australia. [ABSTRACT FROM AUTHOR]

Medication adherence is a major determinant of antiretroviral (ARV) treatment success and a significant challenge for HIV-positive patients, yet a well-defined adherence threshold to maintain virologic suppression on current ARV regimens remains unclear. The present study evaluated 1915 Kaiser Permanente Southern California HIV-positive patients on one of three regimen types: (1) emtricitabine-tenofovir-efavirenz (FTC-TDF-EFV); (2) emtricitabine-tenofovir (FTC-TDF) and raltegravir (RAL); and (3) FTC-TDF and a boosted protease inhibitor, either darunavir (DRV) or atazanavir (ATV), to compare virologic failure rates between patients with varying levels of adherence to the regimens. Medication possession ratios (MPRs) were calculated to determine adherence, and HIV RNA PCR levels drawn 12-18 months after the initial pharmacy claim for the measured drug were used to determine virologic failure, which was defined as two consecutive HIV RNA PCR measurements ≥200 copies/mL. Adherence was inversely related to virologic failure, with an 80-90% MPR threshold resulting in no more than 3.5% virologic failure rate. In comparison, ≥90% MPR yielded no more that 1.1% virologic failure rate. Although the gold-standard adherence threshold for older ARV regimens has been 95%, an 80-90% MPR appears sufficient to maintain virologic suppression in patients treated with these three ARV regimen types. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to evaluate HIV-1 viral load ( VL) and inflammatory markers in cerebrospinal fluid ( CSF) and neurocognitive performance in patients with neurocognitive impairment ( NCI) while they were receiving tenofovir ( TDF)/ emtricitabine ( FTC)/efavirenz ( EFV) and after switching to a regimen with enhanced central nervous system ( CNS) penetrability. Methods This was a prospective, single-arm pilot study. HIV-1-infected patients with plasma viral suppression and HIV-associated NCI on a regimen including TDF/ FTC/ EFV were switched to abacavir ( ABC)/lamivudine ( 3TC)/maraviroc ( MVC). The Global Deficit Score ( GDS) was used to score cognitive function at baseline and 48 weeks after treatment switch. Both CSF and blood samples were taken at baseline and between weeks 24 and 36 after switching. HIV-1 RNA in plasma and CSF was determined by quantitative reverse transcriptase−polymerase chain reaction ( qRT-PCR). Inflammatory biomarkers in CSF were measured by enzyme-linked immunosorbent assay ( ELISA). Results A total of 71 patients receiving TDF/ FTC/ EFV were screened. Twelve of them (17%) had documented NCI, lacked the human leucocyte antigen ( HLA)- B*57:01 haplotype and harboured Chemokine Receptor Type-5 ( CCR5)-tropic virus. Eight patients had detectable HIV-1 RNA (between 2.7 and 41.6 HIV-1 RNA copies/mL) in CSF at baseline. All participants had elevated levels of neopterin and Monocyte Chemoattractant Protein 1 ( MCP-1) in CSF at baseline. Eight out of 12 patients completed their follow-up assessment after treatment switch. The GDS decreased from 0.55 to 0.4 ( P = 0.085). Median HIV-1 RNA in CSF decreased from 3.49 to 2.20 ( P = 0.23). Among the inflammation markers in CSF, tumour necrosis factor ( TNF)-α decreased significantly from median 0.51 to 0.35 pg/mL ( P = 0.027), showing a correlation with the changes in neopterin, interferon ( IFN)-γ and interleukin ( IL)-6. Conclusions Most patients with NCI receiving TDF/ FTC/ EFV had low-level viraemia and/or increased inflammatory markers in CSF. Treatment switching to an MVC-containing regimen with better CNS penetration resulted in a trend towards improvement in neurocognitive status and reduced TNF-α concentrations in CSF. [ABSTRACT FROM AUTHOR]

Background: STaR (GS-US-264-0110) was a 96-week phase 3b study evaluating the safety and efficacy of two single-tablet regimens, rilpivirine/emtricitabine/tenofovir DF (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF) in treatment-naive, HIV-1-infected subjects. Methods: Genotypic analyses (population sequencing) of HIV-1 protease (PR) and reverse transcriptase (RT) were performed at screening; subjects with pre-existing resistance to study drugs were excluded. The protocol-defined resistance analysis population had genotypic/phenotypic analyses at failure and baseline for PR and RT. Results: Through week 96, the resistance analysis population included 24/394 subjects (6.1%) receiving RPV/FTC/TDF and 9/392 subjects (2.3%) receiving EFV/FTC/TDF. In the RPV/FTC/TDF arm, HIV-1 isolates from 21/394 subjects (5.3%) developed non-nucleoside reverse transcriptase inhibitor (NNRTI) and/or nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations and 20/21 isolates had both NNRTI and NRTI genotypic and/or phenotypic resistance. In the EFV/FTC/TDF arm, isolates from 4/392 subjects (1.0%) developed NNRTI and/or NRTI resistance mutations. Resistance development after week 48 was infrequent (1.0% RPV/FTC/TDF; 0.3% EFV/FTC/TDF). When stratified by baseline HIV-1 RNA ≤ or >100 000 copies/ml, 9/260 (3.5%) versus 12/134 (9.0%) RPV/FTC/TDF-treated subjects and 3/250 (1.2%) versus 1/142 (0.7%) EFV/FTC/TDF-treated subjects developed resistant isolates, respectively. Pre-existing NRTI- and NNRTI-associated resistance mutations (not related to study drugs) did not impact treatment response to either regimen. Conclusions: Resistance development to RPV/FTC/TDF consisted of NNRTI and NRTI mutations and was more frequent than resistance development to EFV/FTC/TDF through week 96. Emergent resistance after week 48 was infrequent in both arms. Within the RPV/FTC/TDF arm, resistance development was more frequent in subjects with baseline HIV-1 RNA >100 000 copies/ml compared to baseline HIV-1 RNA ≤ 100 000 copies/ml. [ABSTRACT FROM AUTHOR]

The once daily, single-tablet regimen (STR) combining rilpivirine (RPV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) provides a simplified treatment option for antiretroviral therapy (ART)-naïve patients with baseline HIV-1 RNA (BLVL) of ≤100,000 copies/mL. The aim of this analysis is to compare long-term efficacy, safety, and tolerability of RPV+FTC/TDF vs. efavirenz (EFV)+FTC/TDF as individual components in subjects with BLVL ≤100,000 copies/mL. Week 96 efficacy and safety data from subjects with BLVL ≤100,000 copies/mL, who received daily RPV 25 mg or EFV 600 mg with FTC/TDF in the phase 3, randomized, double-blind, double-dummy, active-controlled, registrational trials ECHO and THRIVE, were analyzed. Virologic response was evaluated by intent-to-treat, time to loss of virological response (ITT-TLOVR), and Snapshot algorithms. Through Week 96, RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF (84% vs. 81%, respectively; ITT-TLOVR) in 543 subjects with BLVL ≤100,000 copies/mL, and overall rates of virologic failure (VF) were 5.9% vs. 2.4%, respectively. Resistance development was lower in Year 2 than Year 1. Subjects in both arms with suboptimal adherence (≤95%) had lower virologic responses (63% vs. 62%, respectively). Treatment with RPV+FTC/TDF was associated with significantly fewer treatment-related adverse events (AEs), grade 2-4 AEs, neurological and psychiatric AEs (including dizziness and abnormal dreams/nightmares), and rash. Additionally, grade 2-4 treatment-emergent laboratory abnormalities and grade 1-3 lipid abnormalities were significantly less common with RPV+FTC/TDF than EFV+FTC/TDF. RPV+FTC/TDF demonstrated non-inferior efficacy to EFV+FTC/TDF in ART-naïve subjects with BLVL ≤100,000 copies/mL and was associated with a higher rate of VF but a more favorable safety and tolerability profile through Week 96. [ABSTRACT FROM AUTHOR]

Objectives An increasing number of HIV-infected patients are combating HIV infection through the use of antiretroviral drugs, including reverse transcriptase inhibitors. Oral complications associated with these drugs are becoming a mounting cause for concern. In our previous studies, both protease inhibitors and reverse transcriptase inhibitors have been shown to change the proliferation and differentiation state of oral tissues. This study examined the effect of a nonnucleoside and a nucleoside reverse transcriptase inhibitor on the growth and differentiation of gingival epithelium. Methods Organotypic (raft) cultures of gingival keratinocytes were treated with a range of efavirenz and tenofovir concentrations. Raft cultures were immunohistochemically analysed to determine the effect of these drugs on the expression of key differentiation and proliferation markers, including cytokeratins and proliferating cell nuclear antigen ( PCNA). Results These drugs dramatically changed the proliferation and differentiation state of gingival tissues when they were present throughout the growth period of the raft tissue as well as when drugs were added to established tissue on day 8. Treatment with the drugs increased the expression of cytokeratin 10 and PCNA and, conversely, decreased expression of cytokeratin 5, involucrin and cytokeratin 6. Gingival tissue exhibited increased proliferation in the suprabasal layers, increased fragility, and an inability to heal itself. Conclusions Our results suggest that efavirenz and tenofovir treatments, even when applied in low concentrations for short periods of time, deregulated the cell cycle/proliferation and differentiation pathways, resulting in abnormal epithelial repair and proliferation. Our system could be developed as a potential model for studying the effects of HIV and highly active antiretroviral therapy ( HAART) in vitro. [ABSTRACT FROM AUTHOR]

Study Background: Vitamin D has wide-ranging effects on the immune system, and studies suggest that low serum vitamin D levels are associated with worse clinical outcomes in HIV. Recent studies have identified an interaction between antiretrovirals used to treat HIV and reduced serum vitamin D levels, but these studies have been done in North American and European populations. Methods: Using a prospective cohort study design nested in a multinational clinical trial, we examined the effect of three combination antiretroviral (cART) regimens on serum vitamin D levels in 270 cART-naïve, HIV-infected adults in nine diverse countries, (Brazil, Haiti, Peru, Thailand, India, Malawi, South Africa, Zimbabwe and the United States). We evaluated the change between baseline serum vitamin D levels and vitamin D levels 24 and 48 weeks after cART initiation. Results: Serum vitamin D levels decreased significantly from baseline to 24 weeks among those randomized to efavirenz/lamivudine/zidovudine (mean change: −7.94 [95% Confidence Interval (CI) −10.42, −5.54] ng/ml) and efavirenz/emtricitabine/tenofovir-DF (mean change: −6.66 [95% CI −9.40, −3.92] ng/ml) when compared to those randomized to atazanavir/emtricitabine/didanosine-EC (mean change: −2.29 [95% CI –4.83, 0.25] ng/ml). Vitamin D levels did not change significantly between week 24 and 48. Other factors that significantly affected serum vitamin D change included country (p<0.001), season (p<0.001) and baseline vitamin D level (p<0.001). Conclusion: Efavirenz-containing cART regimens adversely affected vitamin D levels in patients from economically, geographically and racially diverse resource-limited settings. This effect was most pronounced early after cART initiation. Research is needed to define the role of Vitamin D supplementation in HIV care. [ABSTRACT FROM AUTHOR]

Background and Objectives Alcohol abuse complicates treatment of HIV disease and is linked to poor outcomes. Alcohol pharmacotherapies, including disulfiram (DIS), are infrequently utilized in co-occurring HIV and alcohol use disorders possibly related to concerns about drug interactions between antiretroviral (ARV) medications and DIS. Method This pharmacokinetics study ( n = 40) examined the effect of DIS on efavirenz (EFV), ritonavir (RTV), or atazanavir (ATV) and the effect of these ARV medications on DIS metabolism and aldehyde dehydrogenase (ALDH) activity which mediates the DIS-alcohol reaction. Results EFV administration was associated with decreased S-Methyl- N- N-diethylthiocarbamate (DIS carbamate), a metabolite of DIS ( p = .001) and a precursor to the metabolite responsible for ALDH inhibition, S-methyl- N, N-diethylthiolcarbamate sulfoxide (DETC-MeSO). EFV was associated with increased DIS inhibition of ALDH activity relative to DIS alone administration possibly as a result of EFV-associated induction of CYP 3A4 which metabolizes the carbamate to DETC-MeSO (which inhibits ALDH). Conversely, ATV co-administration reduced the effect of DIS on ALDH activity possibly as a result of ATV inhibition of CYP 3A4. DIS administration had no significant effect on any ARV studied. Discussion/Conclusions ATV may render DIS ineffective in treatment of alcoholism. Future Directions DIS is infrequently utilized in HIV-infected individuals due to concerns about adverse interactions and side effects. Findings from this study indicate that, with ongoing clinical monitoring, DIS should be reconsidered given its potential efficacy for alcohol and potentially, cocaine use disorders, that may occur in this population. (Am J Addict 2014;23:137-144) [ABSTRACT FROM AUTHOR]

Objectives: Statins are lipid-lowering drugs that exhibit anti-Inflammatory and immune-modulatory properties, leading to a reduction of serum levels of C-reactive protein (CRP) in the general population. Design: To assess the anti-inflamatory effects of statins in HIV-infected patients, because very limited data are available today. Methods: Longitudinal, observational study of HIV-infected adult patients naive to antiretroviral therapy who started tenofovir/emtricitabine/efavirenz and were followed-up for 48 weeks. Patients with baseline normal cholesterol level and taking only antiretroviral drugs (group A) were compared to those with baseline hypercholesterolemia who received rosuvastatin (10 mg daily) in association with antiretroviral treatment (group B). The primary observation was change in serum markers of inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], interleukin-8 [IL-8]) and tumor necrosis factor-α [TNF- α]) in both groups, whereas secondary observations include variations in CD4 lymphocyte count, HIV viral load, and occurrence of adverse events. Results: Eighty-six patients were enrolled into the study: 46 in group A and 40 in group B. After 48 weeks, patients treated with antiretroviral therapy plus rosuvastatin had significantly greater decreases in serum concentrations of all Inflammatory markers than those taking antiretroviral therapy only. Changes in mean levels of hsCRP and TNF-α were -35.1% and -22.4% in group B and -8.2% and 5.4% in group A, respectively (P < .001, for both parameters). No significant differences in immunovirological parameters and safety profile were reported across the compared groups. Conclusions: Our findings suggest that tenofovir/emtricitabine/efavirenz plus rosuvastatin has a greater antiInflammatory effect than antiretroviral drugs only. [ABSTRACT FROM AUTHOR]

The fixed-dose combination efavirenz, emtricitabine, and tenofovir (EFV/FTC/TDF) is a first-line agent for the treatment of HIV. We report the case of a 40-year-old female with a history of HIV acquired through heterosexual contact who initiated EFV/FTC/TDF. Hepatitis B and C serologies were negative, CD4 cell count was 253 cells per cubic millimeter (15.8%), and HIV viral load was 67,373 copies per milliliter. Eight months later she developed transaminitis and severe right upper quadrant pain. Neither illicit drug abuse nor hepatotoxic medication such as acetaminophen was reported. After evaluation including negative acute viral hepatitis studies, EFV/FTC/TDF was discontinued; both her transaminitis and pain resolved. Hepatotoxicity is most often associated with efavirenz. Rarely, fulminant hepatic failure occurs. Efavirenz-related hepatotoxicity is thought to result from a cellular self-digestion process known as autophagy. This is the first report to our knowledge of EFV/FTC/TDF-related hepatotoxicity. [ABSTRACT FROM AUTHOR]

Background: Due to ongoing neuropsychiatrie adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcrip-tase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a sin-gle-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. Objective: This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. Methods: This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (>3 months duration) to RPV/FTC/TDF. Virologie suppression (HIV-1 RNA <50 cop-ies/mL), safety, and EFV and RPV pharmacokinetics were assessed. Results: At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologie failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. Conclusions: Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR. [ABSTRACT FROM AUTHOR]

Background: Prepubertal gynecomastia is a rare condition and most frequently classified as idiopathic. In HIV-infected adults gynecomastia is a recognised but infrequent side-effect of antiretroviral treatment (ART) and mostly attributed to efavirenz use. Gynecomastia should be distinguished from pseudogynecomastia as part of the lipodystrophy syndrome caused by Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to avoid incorrect substitution of drugs. In the medical literature only five cases of prepubertal gynecomastia in children taking ART are described and underlying pathogenesis was unknown. The occurrence of adverse effects of ART may interfere with therapy adherence and long-term prognosis and for that reason requires attention. We report the first case of prepubertal gynecomastia in a young girl attributed to efavirenz use. Case presentation: A seven-year-old African girl presented with true gynecomastia four months after initiation on ART (abacavir, lamivudine, efavirenz). History, physical examination and laboratory tests excluded known causes of gynecomastia and efavirenz was considered as the most likely cause. Six weeks after withdrawal of efavirenz the breast enlargement had completely resolved. Conclusions: Efavirenz-induced gynecomastia may occur in children as well as in adults. With the increasing access to ART, the possibility of efavirenz-exposure and the potential occurrence of its associated side-effects may be high. In resource-poor settings, empirical change from efavirenz to nevirapine may be considered, providing no other known or alarming cause is identified, as efavirenz-induced gynecomastia can resolve quickly after withdrawal of the drug. Timely recognition of gynecomastia as a side-effect of efavirenz is important in order to intervene while the condition may still be reversible, to sustain adherence to ART and to maintain the sociopsychological health of the child. [ABSTRACT FROM AUTHOR]

Objectives The pharmacokinetics ( PK) of antiretrovirals ( ARVs) in older HIV-infected patients are poorly described. Here, the steady-state PK of two common ARV regimens [tenofovir ( TFV)/emtricitabine ( FTC)/efavirenz ( EFV) and TFV/ FTC/atazanavir ( ATV)/ritonavir ( RTV)] in older nonfrail HIV-infected patients are presented. Methods HIV-infected subjects ≥55 years old not demonstrating the frailty phenotype were enrolled in an unblinded, intensive-sampling PK study. Blood plasma (for TFV, FTC, EFV, ATV and RTV concentrations) and peripheral blood mononuclear cells [ PBMCs; for tenofovir diphosphate ( TFV-DP) and emtricitabine triphosphate ( FTC-TP) concentrations] were collected at 11 time-points over a 24-hour dosing interval. Drug concentrations were analysed using validated liquid chromatography-ultraviolet detection ( LC-UV) or liquid chromatography tandem mass spectrometry ( LC-MS/MS) methods. Noncompartmental pharmacokinetic analysis was used to estimate PK parameters [area under the concentration-time curve over 24 h ( AUC0-24h) and maximal concentration ( Cmax)]. These parameters were compared with historical values from the general HIV-infected population. Results Six subjects on each regimen completed the study. Compared with the general population, these elderly subjects had 8-13% decreased TFV AUC0-24h and Cmax, and 19-78% increased FTC and RTV AUC0-24h and Cmax. Decreased ATV AUC0-24h (12%) and increased Cmax (9%) were noted, while EFV exposure was unchanged (5%) with a 16% decrease in Cmax. Intracellular nucleoside/tide metabolite concentrations and AUC are also reported for these subjects. Conclusions This study demonstrates that the PK of these ARVs are altered by 5-78% in an older HIV-infected population. Implications of PK differences for clinical outcomes, particularly with the active nucleoside metabolites, remain to be explored. This study forms the basis for further study of ARV PK, efficacy, and toxicity in older HIV-infected patients. [ABSTRACT FROM AUTHOR]

The once-daily, single-tablet regimen of emtricitabine/rilpivirine/tenofovir disoproxil fumarate (Eviplera™ [EU]; Complera™ [US]) provides a convenient option for antiretroviral therapy in treatment-naive patients with HIV-1 infection. In well designed trials in this patient population, rilpivirine plus emtricitabine/tenofovir disoproxil fumarate was noninferior to efavirenz plus emtricitabine/tenofovir disoproxil fumarate in terms of reducing viral HIV-1 RNA level to <50 copies/mL and was generally better tolerated than efavirenz plus emtricitabine/tenofovir disoproxil fumarate. [ABSTRACT FROM AUTHOR]

Objective: Changes in endothelial function, measured as flow-mediated dilation (FMD) of the brachial artery, has not been systematically assessed beyond 6 months of initiation of antiretroviral therapy (ART) when drug-related effects might offset initial improvements with virologic control. Design: We assessed 6 and 12 month changes in FMD [presented as median (quartile 1, quartile 3)] and circulating HIV and cardiovascular biomarkers in 23 subjects initiating ART. Results: There were no significant changes in FMD at 6 or 12 months overall despite significant increases in CD4 cell count and HDL-C and reductions in HIV RNA level, MCP-1, IP-10, sVCAM-1, sTNFR2, and sCD14. However, there were significant differences (P = 0.04) in the changes in FMD between those receiving efavirenz [N = 12; 23.50% (24.90%, 0.68%)] vs. protease inhibitors at 12 months [N= 11; 1.50% (20.86%, 4.56%)]. The differences in changes in FMD between those receiving and not receiving emtricitabine/tenofovir/efavirenz were more pronounced and were significantly different at both 6 and 12 months (P,0.02 for both). Additional studies showed no significant differences in changes in 25-(OH)-vitamin D, PTH, FGF-23, of F2-isoprostane levels between efavirenz and PI use or between those receiving and not receiving emtricitabine/tenofovir/efavirenz. Conclusion: Efavirenz use was associated with reduced FMD at 12 months compared to PI-based regimens while emtricitabine/tenofovir/efavirenz was associated with reduced FMD at both 6 and 12 months compared to those not receiving this combination. Long-term effects of antiretrovirals on endothelial function may play an important role in the risk of cardiovascular disease in HIV-infected patients. [ABSTRACT FROM AUTHOR]

We compared 4 years of antiretroviral therapy with tenofovir/emtricitabine and either raltegravir or efavirenz from the ongoing STARTMRK study of treatment-naïve HIV-infected patients. Through 192 weeks, raltegravir produced durable and consistent viral suppression and immune restoration compared with efavirenz irrespective of baseline demographic and prognostic factors, including in patients with high viral loads. [ABSTRACT FROM AUTHOR]

Most patients (80-90%) newly diagnosed with HIV are started on the antiretroviral regimen efavirenz, emtricitabine, and tenofovir (EFV/FTC/TDF). Existing studies of patient tolerability, however, are limited. We compared symptom experiences of patients on EFV/FTC/TDF, and the subsequent impact on health-related quality of life, with those of patients on other combination antiretroviral therapy (cART). We conducted a cross-sectional analysis of the Veterans Aging Cohort Study from February 2008 to August 2009 to compare the symptom experiences of patients on EFV/FTC/TDF vs. other cART, unadjusted and then adjusted for treatment characteristics, and comorbid disease severity. We then assessed the association between EFV/FTC/TDF use and health-related quality of life. Among the 1,759 patients in our analytic sample, EFV/FTC/TDF use was associated with fewer symptoms than was other cART. The use of EFV/FTC/TDF was independently associated with health-related quality of life, and this association was at least partially explained by symptom burden. [ABSTRACT FROM AUTHOR]

There are few data on the impact of antiretroviral therapy (ART) regimen factors on adherence in ART-naïve HIV patients on contemporary once- or twice-daily regimens. Ninety-nine newly diagnosed patients in a prospective observational cohort study completed a visual analogue scale to assess their ART adherence. Adherence by type of ART and dosing frequency were compared by Brown-Mood median tests. Participants taking once-daily regimens had higher adherence (n = 70, 99.5%) compared with participants taking twice-daily regimens (n = 29, 94%; P = 0.01). Adherence of participants taking the fixed dose combination efavirenz-emtricitabine-tenofovir (n = 34, 100%) compared with those taking once-daily regimens of two or more pills was no different (n = 36, 99.3%; P = 0.34). Among a cohort of newly diagnosed ART-naïve patients, once-daily dosing of ART resulted in higher adherence than twice-daily dosing. Pill burden among once-daily regimens did not predict adherence, suggesting that factors other than pill burden should drive regimen selection. [ABSTRACT FROM AUTHOR]

Background Etravirine is approved for use in treatment-experienced patients at a dose of 200 mg twice daily. Efavirenz has been associated with greater increases in serum lipids compared with other non-nucleosides in randomized trials of first-line treatment. Methods In this double-blind, placebo-controlled trial, 157 treatment-naive patients with HIV RNA >5000 copies/mL were randomized 1 : 1 to either 400 mg of etravirine once daily (n = 79) or 600 mg of efavirenz once daily (n = 78) plus two nucleoside analogues (either abacavir/lamivudine, zidovudine/lamivudine or tenofovir/emtricitabine) for 48 weeks. Lipids were measured under fasting conditions at baseline and all visits to Week 48. Clinicaltrials.gov identifier: NCT00903682. Results Overall, the patients had a median baseline CD4 count of 302 cells/mm3 (range 74–722) and a median HIV RNA of 4.8 log10 copies/mL (range 3.5–6.6). Both the non-nucleosides and the nucleoside analogues used caused changes in serum lipids. In the efavirenz arm, patients showed significantly larger increases in high-density lipoprotein (HDL) (+0.15 mmol/L, P = 0.004), low-density lipoprotein (LDL) (+0.35 mmol/L, P = 0.005), total cholesterol (+0.61 mmol/L, P < 0.0001) and triglycerides (+0.33 mmol/L, P = 0.03) at Week 48 compared with the etravirine arm. Across the two arms, patients taking abacavir/lamivudine showed greater increases in total cholesterol (+0.47 mmol/L, P = 0.005) compared with patients taking tenofovir/emtricitabine. There were fewer grade 3/4 elevations in total cholesterol, LDL and triglycerides in the etravirine arm (2 patients, 1 patient and 0 patients, respectively) versus the efavirenz arm (8 patients, 6 patients and 2 patients, respectively). Conclusions In the SENSE trial, first-line treatment with 400 mg of etravirine once daily plus two nucleoside analogues led to fewer grade 3 or 4 lipid elevations compared with efavirenz plus two nucleoside analogues. [ABSTRACT FROM PUBLISHER]

Objectives We designed two different studies to evaluate two different combination antiretroviral therapy (cART) stopping strategies namely a ‘staggered stop’ approach (STOP 1 study) and a ‘protected stop’ approach (STOP 2 study) to find the best ‘universal stop’ strategy. Patients and methods Patients who stopped cART for any reason were recruited. In STOP 1, 10 patients on efavirenz continued dual nucleos(t)ide reverse transcriptase inhibitors (NRTIs) for 1 week after discontinuing efavirenz. Efavirenz concentrations were measured weekly for up to 3 weeks. In STOP 2, 20 patients stopped their cART and replaced it with two tablets of lopinavir/ritonavir (Kaletra) (100/50 mg) twice daily for 4 weeks. Lopinavir, efavirenz, nevirapine and tenofovir concentrations were measured weekly for up to 4 weeks. Virological and resistance testing were performed. Results In STOP 1 five patients still had efavirenz present (median t1/2 = 148.4 h) 3 weeks after stopping. In STOP 2, 15/20 patients had a viral load (VL) of <40 copies/mL and 3/20 patients had a reduction in VL by 4 weeks. Six patients opted not to stop lopinavir/ritonavir and still had <40 copies/mL at week 8. Week 1–4 median trough lopinavir concentrations were well above the EC95. Six patients still had detectable concentrations of original cART persisting for >1 week after stopping. No patients developed new resistance mutations. Conclusions Plasma efavirenz concentrations can persist up to 3 weeks after patients stop efavirenz-containing regimens. This suggests a strategy of stopping efavirenz only 1 week before NRTIs may not be long enough for some individuals. The use of lopinavir/ritonavir monotherapy for a 4 week period may be an alternative pharmacologically and virologically effective universal stopping strategy which warrants further investigation. [ABSTRACT FROM PUBLISHER]

Drug-drug interactions involving efavirenz are of major concern in clinical practice. We evaluated the effects of multiple doses of efavirenz on omeprazole 5-hydroxylation (CYP2C19) and sulfoxidation (CYP3A). Healthy volunteers (n = 57) were administered a single 20 mg oral dose of racemic omeprazole either with a single 600 mg oral dose of efavirenz or after 17 days of administration of 600 mg/day of efavirenz. The concentrations of racemic omeprazole, 5-hydroxyomeoprazole (and their enantiomers), and omeprazole sulfone in plasma were measured using a chiral liquid chromatography-tandem mass spectrometry method. Relative to single-dose treatment, multiple doses of efavirenz significantly decreased (P < 0.0001) the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of racemic-, R- and S-omeprazole (2.01- to 2.15-fold) and the corresponding AUC0-∞ metabolic ratio (MR) for 5-hydroxyomeprazole (1.36- to 1.44-fold) as well as the MR for omeprazole sulfone (∼2.0) (P < 0.0001). The significant reduction in the AUC of 5-hydroxyomeprazole after repeated efavirenz dosing suggests induction of sequential metabolism and mixed inductive/inhibitory effects of efavirenz on CYP2C19. In conclusion, efavirenz enhances omeprazole metabolism in a nonstereoselective manner through induction of CYP3A and CYP2C19 activity. [ABSTRACT FROM AUTHOR]

Abstract: Our goal was to determine the contribution of HIV-1 reverse transcriptase tryptophan repeat motif residues to virion maturation. With the exception of W402A, we found none of the single substitution mutations exerted major impacts on virus assembly or processing. However, all mutants except for W410A exhibited significant decreases in virus-associated RT, presumably a result of unstable RT mutant degradation. Mutations W398A, W401A and W406A decreased the enhancement effect of efavirenz on PR-mediated Gag processing efficiency, which is in agreement with their destabilizing RT effects. Furthermore, combined double or triple W398, W401 and W406 mutations significantly affected virus processing and Gag–Pol packaging. Further analyses suggest that inefficient PR-mediated Gag cleavage partly accounts for the virion processing defect. Our results support the idea that in addition to playing a role in RT heterodimer stabilization, the RT Trp repeat motif in the Gag–Pol context is also involved in PR activation via Gag–Pol/Gag–Pol interaction. [Copyright &y& Elsevier]

We investigated the effect of food on the steady-state pharmacokinetics of a proprietary fixed-dose combination (FDC) tablet containing tenofovir disoproxil fumarate (TDF)/emtricitabine/efavirenz. Fifteen Ugandan HIV-1 patients at steady-state dosing with TDF/emtricitabine/efavirenz were admitted for 24-hour intensive pharmacokinetic sampling after dosing in the fasting state. Blood sampling was repeated seven days later with TDF/emtricitabine/efavirenz administered with food (19 g fat). Drug concentrations in plasma were determined by liquid chromatography and tandem mass spectrometry. Geometric mean ratios (GMRs) and confidence intervals (CIs) of parameters were calculated (reference, fasting). For efavirenz, GMRs (90% CIs) for Cmax, AUC0-24, and C24 were 1.47 (1.24-1.75), 1.13 (1.03-1.23), and 1.01 (0.91-1.11), respectively. Corresponding GMRs were 1.04 (0.84-1.27), 1.19 (1.10-1.29), and 0.99 (0.82-1.19) for tenofovir, 0.83 (0.76-0.92), 0.87 (0.78-0.97), and 0.91 (0.73-1.14) for emtricitabine. Stable patients may take the FDC without meal restrictions. The FDC should be taken without food by patients experiencing central nervous system toxicities. [ABSTRACT FROM AUTHOR]

Abstract: We herein report the 5α-reductase inhibitors, antiviral and anti-tumor activities of some synthesized heterocyclic cyanopyridone and cyanothiopyridone derivatives fused with steroidal structure. Initially the acute toxicity of the compounds was assayed via the determination of their LD50. All the compounds, except 3b, were interestingly less toxic than the reference drug (Prednisolone®). Seventeen heterocyclic derivatives containing a cyanopyridone or cyanothiopyridone rings fused to a steroidal moiety were synthesized and screened for their 5α-reductase inhibitors, antiviral and anti-tumor activities comparable to that of Anastrozole, Bicalutamide, Efavirenz, Capravirine, Ribavirin, Oseltamivir and Amantadine as the reference drugs. Some of the compounds exhibited better 5α-reductase inhibitors, antiviral and anti-tumor activities than the reference drugs. The detailed 5α-reductase inhibitors, antiviral and anti-tumor activities of the synthesized compounds were reported. [Copyright &y& Elsevier]

Abstract: A simple and rapid isocratic, high performance liquid chromatography (HPLC) assay employing solid phase extraction (SPE) for the simultaneous determination of the anti HIV drug, efavirenz, the anti-tuberculosis drug, rifampicin and the desacetyl metabolite of rifampicin in plasma from HIV/tuberculosis infected patients has been developed. Using a Zorbax SB-Phenyl reverse-phase analytical column with UV detection, good separation and detection of the drugs was attained within a 10min run time. Intra- and inter-assay precision RSD values were found to be less than 15% at the concentrations examined (0.1–20μg/mL). The LOQ was found to be 0.1μg/mL for each agent and the assay was found to generate a linear response up to 20μg/mL. This low cost assay can accurately detect efavirenz and rifampicin concentrations within a clinically relevant concentration range using standard chromatography equipment, making it particularly applicable to resource-limited settings. [Copyright &y& Elsevier]

Objective: To determine factors affecting serum levels of Efavirenz and Nevirapine and analyze the effect of Rifampicin on Nevirapine drug levels. Methods: A cross-sectional study was conducted on 30 HIV infected children on Antiretroviral therapy (ART) with Nevirapine or Efavirenz. Patients on simultaneous Rifampicin and Nevirapine were given higher doses of Nevirapine with regular monitoring of liver function tests. Trough levels (before morning dose of Nevirapine) and levels after 2 hours of administration of Nevirapine and levels of Efavirenz were assessed using HPLC and were checked to see if they fall within the therapeutic range. Results: Thirty patients (14 males) were enrolled in the study with 20 on Nevirapine and 10 (33.3%) on Efavirenz. Seven (23.3%) patients were simultaneously taking rifampicin. The mean Nevirapine dose given to the patients was 350.9±59.8mg/m²/day (on simultaneous rifampicin) and 309.2±54.6mg/m²/day (not on concurrent rifampicin). Thirteen (81.3%) of the 16 patients with trough Nevirapine had values in the normal range, 1 (6.3%) had low Nevirapine trough levels and 2 (12.5%) had high Nevirapine trough levels. Of the post 2 hours Nevirapine levels, 1 (5%) had low levels and 3 (15%) had high Nevirapine blood levels. Factors like age (P=0.4, P=0.4087), nourishment (P=0.2679, P=0.4132), ART combination (P=0.4199, P=0.4132), form of the drug (tablet/syrup) (P=0.1964, P=0.4696) or if it was being given as single or in a fixed dose combination (P=0.4179, P=0.4696) and even concurrent rifampicin administration (P=0.284, P=0.472) did not significantly affect the trough and post 2 hours Nevirapine values, respectively. All the five patients being given concurrent rifampicin had normal trough and post 2 hours levels of Nevirapine. The Efavirenz drug levels were 1.9±1.1 g/mL. Of the 10 patients on Efavirenz, 2 (20%) had high and 1 (10%) had low blood levels. Conclusion: Concurrent Rifampicin administration does not alter blood levels of Nevirapine; provided the dose of Nevirapine is increased by 20-30%. Formulation of drugs does not alter the blood levels provided drug administered is in the recommended dose. [ABSTRACT FROM AUTHOR]

Background Efavirenz is among the most widely used antiretroviral drugs. Increased efavirenz exposure has been associated with CNS side effects and also with the chance of emergence of resistance upon treatment interruptions. The objective of this study was to evaluate factors associated with efavirenz plasma concentrations in a cohort of HIV-infected individuals. Methods From July 2009 to March 2010, HIV-infected patients with efavirenz as part of antiretroviral therapy (600 mg at night), undetectable viral load for at least 1 year and CD4 cell count >200 cells/mm3 were consecutively enrolled at the HIV/AIDS ambulatory care unit in southern Brazil. Plasma samples were taken 18–23 h after efavirenz last dose and analysed by validated ultra-performance liquid chromatography. Results Forty-one subjects were included (21 females). Mean age and weight were 45.4 years and 70.9 kg, respectively. Mean efavirenz plasma concentration was 2.20 ± 2.17 mg/L. Most plasma concentrations (73%) were within the therapeutic window (1–4 mg/L); 17% were below and 10% above the limits. There were no significant associations between efavirenz concentration and age, CD4 cell count, time on antiretroviral treatment and gender. There was significant and inverse correlation between efavirenz concentrations and body weight (P = 0.013) and body mass index (P = 0.001). Conclusions In this cohort of well-controlled HIV-positive individuals, patients with lower weight or body mass index had a higher chance of presenting elevated plasma concentrations of efavirenz. Therapeutic drug monitoring to adjust dose might be a helpful tool to decrease efavirenz dose in order to minimize costs and adverse effects. [ABSTRACT FROM PUBLISHER]

Background. We compared 3 years of antiretroviral therapy with raltegravir or efavirenz as part of a combination regimen in the ongoing STARTMRK study of treatment-naive patients infected with human immunodeficiency virus (HIV). Methods. Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies/mL and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind, noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. Outcomes included viral suppression, adverse events, and changes from baseline metabolic parameters. Dual energy X-ray absorptiometry scans were obtained on a convenience sample of patients at prespecified time points to assess changes in body fat composition. Results. At week 156 counting noncompleters as failures, 212 (75.4%) of 281 versus 192 (68.1%) of 282 had vRNA levels <50 copies/mL in the raltegravir and efavirenz groups, respectively [Δ (95% CI) 5 7.3% (20.2, 14.7), noninferiority P < .001]. Mean changes from baseline CD4 count were 332 and 295 cells/mm3 in the raltegravir and efavirenz arms, respectively [Δ (95% CI) 5 37 (4, 69)]. Consistent virologic and immunologic efficacy was maintained across prespecified demographic and baseline prognostic subgroups for both treatment groups. Fewer drug-related clinical adverse events (49% vs 80%; P <.001) occurred in raltegravir than efavirenz recipients, with discontinuations due to adverse events in 5% and 7%, respectively. Elevations in fasting lipid levels (including LDL- and HDL-cholesterol) were consistently lower in the raltegravir than efavirenz group (P < .005). Fat gain was 19% in 25 raltegravir recipients and 31% in 32 efavirenz recipients at week 156. Conclusions. When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir produced durable viral suppression and immune restoration that was at least equivalent to efavirenz through 156 weeks of therapy. Both regimens were well tolerated, but raltegravir was associated with fewer drug-related clinical adverse events and smaller elevations in lipid levels. [ABSTRACT FROM AUTHOR]