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Relationships between distinct antiretroviral therapy (ART) adherence patterns and risk of drug resistance are not well understood.We conducted a nested case-control analysis within a longitudinal cohort study of individuals initiating efavirenz-based ART. Primary outcomes of interest, measured at 6 and 12 months after treatment initiation, were: 1) virologic suppression, 2) virologic failure with resistance, and 3) virologic failure without resistance. Our primary exposure of interest was ART adherence, measured over the 6 months before each visit with electronic pill monitors, and categorized in three ways: 1) 6 months average adherence; 2) running adherence, defined as the proportion of days with average adherence overWe analyzed data from 166 individuals (107 had virologic failure during observation and 59 had virologic suppression at 6 and 12 months). Average adherence was higher among those with virologic suppression (median 83%, IQR 58-96%) versus those with virologic failure with resistance (median 35%, IQR 20-77%, pairwiseAverage adherence patterns, but not the assessed frequency of treatment gaps, differentiated failure with versus without drug resistance among individuals initiating efavirenz-based ART. Future work should explore adherence-resistance relationships for integrase inhibitor-based regimens.

Background Data on low bone mineral density (BMD) in people living with HIV (PLWH) are mainly derived from younger adults; little is known about how antiretroviral therapy (ART) and alterations in the renal-bone axis relate to BMD in older PLWH. Methods Cross-sectional study of men > 50 years and post-menopausal women with HIV. Antiretroviral therapy exposure was stratified into four groups based on use of tenofovir disoproxil fumarate (TDF) and protease inhibitors (PI): non-TDF/non-PI, non-TDF/PI, TDF/non-PI, and TDF/PI. Bone mineral density was measured by dual X-ray absorptiometry (DXA). Bone turnover/regulatory markers and renal tubular function were analysed in stored plasma and urine samples. The association of ART exposure and bone/renal biomarkers on BMD was explored using logistic regression models. Results 247 individuals (median [IQR] age 57 [53, 65] years; 47% female; 13% of Black ethnicity; CD4 count 643 [473, 811] cells/mm3; and 98% with HIV RNA < 200 copies/mL) were included. Bone turnover and renal tubular function differed significantly by ART exposure. In analyses adjusted for demographic and traditional renal/bone risk factors, exposure to TDF and PI was associated with a fourfold greater risk of low BMD at the femoral neck and exposure to TDF and/or PI with a threefold greater risk of low BMD at the lumbar spine. The relationship between ART and low BMD was not altered by further adjustment for bone turnover or renal tubular function markers. Conclusions The associations between low BMD and ART exposure (TDF vs. non-TDF and boosted vs. unboosted third agents) were minimally affected by adjustments for bone and kidney biomarkers.

Background Information on HIV drug resistance (HIVDR) prevalence in people newly diagnosed with HIV is limited. We implemented a cross-sectional study to estimate HIVDR prevalence among pregnant women recently infected with HIV in Malawi. Methods The HIVDR study was nested within a routine antenatal clinic (ANC) sentinel surveillance survey. Dried blood spot samples were tested for recent infection using a limiting antigen antibody assay together with HIV viral load testing. HIV-1 protease and reverse transcriptase were sequenced using Sanger sequencing. Drug susceptibility was predicted using Stanford HIVdb algorithm (version 8.9). Weighted analysis was performed in Stata 15.1. Results Of the 21,642 pregnant women enrolled in the ANC survey, 8.4% (1826/21,642) tested HIV positive. Of these, 5.0% (92/1826) had recent HIV infection, and 90.2% (83/92) were tested by PCR. The amplification and sequencing success rate was 57.8% (48/83). The prevalence of any HIVDR was 14.6% (5/45) (95% CI: 4.7–36.8%), all of which indicated HIVDR to nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIVDR to nucleoside reverse transcriptase inhibitors was 7.9% (2/45) (95% CI: 1.4–34.6%). Resistance to protease inhibitors currently in use in Malawi was not observed. Conclusions Despite the low number of cases with presumed TDR, our study hints that resistance to NNRTIs was high, above the 10% target for regimen change. Further investigation is needed to establish the exact magnitude of presumed TDR among women recently infected with HIV. These findings support the transition to an integrase inhibitor-based first-line regimen for patients initiating or on ART.

Introduction Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that retains activity against common NNRTI resistance mutations. In this study, we aimed to investigate the prevalence of DOR resistance mutations compared with that of resistance mutations for other NNRTIs among HIV-1-infected treatment‐experienced and -naïve patients from Poland. Methods Resistance to DOR and other NNRTIs was assessed in two datasets: 1760 antiretroviral treatment-naïve HIV-1 patients and 200 treatment‐experienced patients. All 1960 sequences were derived from the patients using bulk sequencing. For resistance analyses, Stanford HIV drug resistance database scores were used. Results Overall, DOR resistance was present in 32 patients (1.62%), of whom 13 (0.74%) were naïve and 19 (9.50%) were treatment-experienced. The most common DOR resistance mutations observed among the naïve patients were A98G and K101E (0.2% each), and those among cART-experienced patients were L100I (2.0%), K101E, V108I, H221Y, and P225H (1.5% each). Furthermore, among the naïve patients, less common resistance to DOR (0.7%) compared with that to nevirapine (NVP) (2.1%; p = 0.0013) and rilpivirine (5.40%; p < 0.0001) was observed. For sequences obtained from treatment-experienced patients, the frequency of resistance to DOR (9.5%) was lower than that for efavirenz (25.5%; p < 0.0001) and NVP (26.0%; p < 0.0001). Conclusions The frequency of transmitted drug resistance to DOR is low, allowing for effective treatment of antiretroviral treatment-naïve patients and rapid treatment initiation. In cART-experienced patients, this agent remains an attractive NNRTI option with a higher genetic barrier to resistance.

Background Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for HIV-1 infection treatment. Because of its genetic barrier, DOR appears to be a good alternative in switch strategies compared to other NNRTI. Our aim was to evaluate the percentage of people living with HIV (PLWHIV) followed in our center who could be eligible to a DOR-based regimen. Methods We collected data from all treatment-experienced PLWHIV, never exposed to DOR and with a demonstrated virological suppression. We analyzed previous genotypic analyses, clinical history, and previous exposure to NNRTIs. Results We analyzed data from 653 patients, whose characteristics are shown in Table 1. 59% of them presented no resistance mutation (RAM) at genotypic analysis. The most common DOR-related RAM were V106A, Y181V, and Y188L. We also analyzed RAM that can possibly interfere with combination therapy (mostly K65R and M184V). In the end, 81.8% of our patients results to be eligible for a DOR-based therapy regimen. Conclusions DOR represents a good option for switch strategies in virological suppressed PLWHIV. It seems to have a higher genetic barrier and a lower risk for resistance mutation development compared to other NNRTI. In our cohort, we found 81.8% of patients who could be eligible for a regimen containing DOR and almost 2/3 of patients who can be treated with the fixed-dose combination DOR/3TC/TDF.

A co-formulated, one pill once a day antiretroviral regimen (single-tablet regimen), containing efavirenz, emtricitabine, and tenofovir disoproxyl fumarate ( Atripla), revolutionized the antiretroviral therapy landscape. Single-tablet regimens provide not only dosing convenience but help optimize adherence and persistence with antiretroviral therapy to achieve durably suppressed viremia with both individual and societal benefits. Given the many excellent options available now, single-tablet regimens are the preferred choice for initiating antiretroviral therapy in almost all patients with rare exceptions for drug interactions and pregnancy, and for simplification of more complex antiretroviral therapy to a single-tablet regimen. In this special commemorative article, we celebrate this astounding advancement in antiretroviral therapy, championed by John C. Martin while CEO of Gilead Sciences, and its transformative impact on HIV care nationally and globally.

The advent of antiretroviral combination therapy has significantly impacted the HIV/AIDS epidemic. No longer a death sentence, HIV infection can be controlled and suppressed using cocktail therapies that contain two or more small molecule drugs. This review aims to highlight the discovery, development, and impact of one such molecule, namely, emtricitabine (FTC, emtriva), which is one of the most successful drugs in the fight against HIV/AIDS and has been taken by over 94% of individuals infected with HIV in the USA. We also pay tribute to Dr. John C. Martin, former CEO and Chairman of Gilead Sciences, who unexpectedly passed away in 2021. A true visionary, he was instrumental in delivering FTC, as part of combination therapy with TDF (tenofovir, viread) to the global stage. As the fight to eradicate HIV marches on, we honor Dr. Martin’s legacy of collaboration, achievement, and hope.

Background To evaluate the long-term safety and efficacy of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in human immunodeficiency virus (HIV)–infected patients. Methods RPV-treated HIV-infected patients from phase 2b or 3 studies rolled-over into this phase 3, open-label study and received RPV 25 mg once daily (QD) with choice of two NRTIs. Adverse events (AEs), plasma viral load, CD4+ cell count, and antiviral resistance were evaluated. Results Of the 482 patients treated, 437 (>90%) patients discontinued study treatment; 371 (77%) had switched to commercially available RPV, 14 (2.9%) discontinued due to AEs, and 6 (1.2%) had virologic failure. In this rollover study, patients were followed up to week 336, although data was limited beyond 288 weeks. Forty-five (9.3%) patients were still undergoing treatment at the time of data cut-off for the current analysis (8 February 2018). The most frequently reported AEs were pregnancy in 7 (1.5%) patients and syphilis in 5 (1.0%) patients. Grade 3–4 AEs were reported in 17 (3.5%) patients, and AEs possibly related to RPV in 23 (4.8%) patients. Over 288 weeks of treatment, 80.1% (95% CI: 74.9%; 84.3%) of patients maintained virologic suppression (HIV-1 RNA + cell count increased over time until week 192 and remained constant thereafter. Conclusions RPV 25 mg QD in combination with an investigator-selected background regimen of two NRTIs demonstrated sustained long-term virologic suppression. The treatment was well-tolerated with no new safety findings.

Background Few pharmacokinetic data were reported on dispersible tablets despite their increasing use. One hundred fifty HIV-infected children receiving lamivudine were enrolled in the MONOD ANRS 12,206 trial. Three galenic forms were administered: liquid formulation, tablet form and dispersible scored tablet. Method HIV-infected children Results One hundred and fifty children (age: 2.5 years (1.9–3.2), weight 11.1 (9.5–12.5) kg (median (IQR)) were included in this study. Over the study period, 79 received only the syrup form, 29 children switched from syrup form to tablet 3TC/AZT form, 36 from syrup to the orodispersible ABC/3TC form and two from the 3TC/AZT form to the orodispersible ABC/3TC form. The 630 lamivudine concentrations were best described by a two-compartment model allometrically scaled. Galenic form had no significant effect on 3TC pharmacokinetic. Conclusion This trial provided an opportunity to compare three galenic forms (liquid formulation, tablet form and dispersible scored tablet) of lamivudine in the target population of young HIV–1-infected children. Galenic form had no significant effect on lamivudine pharmacokinetics.

Background Viral suppression in patients on antiretroviral treatment (ART) is critical to reducing HIV transmission and HIV-related mortality. Although many studies have evaluated factors associated with viral suppression, few have assessed the extent to which missing viral load data may bias results. Methods We included data on all patients starting ART from 2005 to 2019 in eight South African cohorts participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) collaboration. Multivariable logistic regression models were used to determine factors associated with having a viral load measurement within 2 months of a scheduled testing date and having a viral load Results Viral load tests were scheduled in 603,549 and 77,423 intervals in adults and children, respectively, but test results were recorded in only 40.7% and 41.2%, respectively. The proportion of recorded results suppressed was 85.7% in adults and 72.4% in children. After imputation of missing viral load measurements, viral suppression reduced slightly in adults (85.3%) and increased in children (73.2%). Predictors of virological suppression in adults, which included female sex, older age, higher baseline CD4+ T-cell count and recent testing year, were similar in the main analysis and after imputing missing viral loads. Conclusions Although viral load information was frequently missing in the South African setting, estimates of viral suppression and predictors of viral suppression did not change substantially after adjusting for missing data.

BackgroundHair antiretroviral concentration has served as an innovative and objective measure of antiretroviral adherence. However, some factors (for example, pharma-cokinetics and hair characteristics) may contribute to the variability of hair antiretroviral concentration that may threaten the validity and reliability of the hair measure as a biomarker of adherence. This study aimed to examine the potential factors that may influence the measure of hair antiretroviral concentration.MethodsHair samples from a cohort of 372 people living with HIV (PLHIV) receiving lamivudine (300 mg/day) in Guangxi, China. Lamivudine concentration was analysed using liquid chromatography-tandem mass spectrometry. Multivariable linear regression was used to evaluate the associations of hair lamivudine concentration with age, sex, ethnicity, height, weight, body mass index, duration of HIV diagnosis, duration of current regimen, dosing schedule, concomitant antiretroviral medications, frequency of hair washing, hair care products use, hair cosmetic treatment and self-reported adherence.ResultsMultivariable models revealed that frequency of hair washing (β=-0.221, P=0.001), dosing schedule (β=0.141, P=0.036) and self-reported adherence (β=0.160, P=0.002) were associated with hair lamivudine concentration.ConclusionsWe observed that, among those potential factors, hair lamivudine concentration was influenced by frequency of hair washing and dosing schedule. Therefore, frequency of hair washing and dosing schedule should be considered in future research using hair lamivudine concentration as a measure of lamivudine exposure and bio-marker of adherence.

Background Pharmacokinetic (PK) changes can affect antiretroviral (ARV) systemic exposure for critically ill patients living with HIV (CI-PLWH). Studies to guide ARV adjustments in this population are limited. Methods A PK analysis was conducted in a 44-year-old CI-PLWH who presented for a heart and lung transplant on veno-arterial extracorporeal membrane oxygenation (VA ECMO). Home ARV therapy (ART) of co-formulated abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) was continued. ARV serum concentrations were obtained during and after VA ECMO. Two blood levels were drawn at 1 h, for maximum serum concentration (Cmax) and a serum trough (Ct). ARVs were given as a single tablet crushed via nasogastric tube. Results Area under the concentration–time curve (AUC0–t) was calculated using non-compartmental analysis. Cmax and AUC0–t were higher during VA ECMO compared with post-decannulation. The Cmax of ABC was >2.5-fold higher than the mean in the reference. Cmax and Ct post VA ECMO were within range of referenced literature for all ARVs. Cmax and AUC0–t of DTG post VA ECMO was approximately four- to fivefold lower than referenced literature. HIV virological suppression was maintained throughout the hospitalization. Conclusions ART adjustments would not be required for this patient. Additional studies are needed to assess effects of VA ECMO and crushed tube administration of ARVs in CI-PLWH.

Background Neuropsychiatric AEs (NPAEs) leading to dolutegravir (DTG) discontinuation were seen more frequently in real-world use than in randomized clinical trials (RCTs). The recently approved fixed-dose combination bictegravir plus emtricitabine and tenofovir alafenamide (BIC/F/TAF) has shown comparable NPAE rates but some favourable patient-reported outcomes in RCTs compared with DTG. We were interested in its neuropsychiatric tolerability in clinical practice. Methods All patients starting BIC/F/TAF from June 2018 in a single centre (two subcentres) were followed retrospectively. Discontinuation rates due to any AEs and NPAEs were compared with those of patients initiating DTG-based regimens. Results As of May 2019, a total of 943 patients (852 males, 76 females, 15 transgender and gender diverse) initiated BIC/F/TAF outside RCTs. After a median follow-up of 6.2 months, 50 (5.3%) and 31 (3.3%) patients had discontinued BIC/F/TAF due to any AEs or to NPAEs, respectively. In multivariate analysis, a pre-existing depression and subcentre remained predictive for NPAEs, but not age, gender, ethnicity or prior DTG-related AEs. Compared with 1,043 patients treated with DTG-based regimens, the estimated NPAE-related discontinuation rate with BIC/F/TAF was comparable during the first 6 months ( P=0.36). Cross-intolerance was low, and only 5/55 patients with prior DTG intolerability had to discontinue BIC/F/TAF due to NPAEs. Conclusions Short-term tolerability of BIC/F/TAF was comparable to DTG-containing regimens. As seen with DTG, discontinuation rates were higher than in RCTs. A pre-existing depression but also physician's awareness may have an impact on tolerability and continuation of BIC/F/TAF. In contrast, prior intolerability of DTG was of limited predictive value.

We report a case of an infant with HIV receiving raltegravir granules for oral suspension and rifampicin-based TB prophylaxis. Raltegravir trough levels remained subtherapeutic and viral load increased during concurrent rifampicin therapy despite using double-dosed raltegravir. Even after rifampicin therapy, a higher dose was needed. This highlights the importance of therapeutic drug monitoring and dose adjustments of raltegravir in infants with rifampicin as comedication.

Background: To compare effectiveness and safety of initial antiretroviral therapy (ART) among premenopausal and postmenopausal women living with HIV aged 45-60 years from the cohort of the Spanish HIV/AIDS Research Network (CoRIS) who initiated ART between 2004 and 2015. Methods: Multivariable regression models were used to compare post- versus premenopausal women regarding viral suppression (≤50 copies/ml), change in CD4+ T-cell count and time to treatment change (TC) at 48 and 96 weeks after ART initiation. Results: Among 230 women, 154 (67%) were premenopausal at ART initiation. The most frequent initial regimen was tenofovir disoproxil fumarate/emtricitabine/efavirenz prescribed in 49 (32%) premenopausal and 22 (29%) postmenopausal women. The proportion of TC was 35.7% and 30.3% at 48 weeks and 51.3% and 47.4% at 96 weeks, for pre- and postmenopausal women, respectively. There were no significant differences in CD4+ T-cell count changes from ART initiation, viral load suppression, time to TC or reason for TC between both groups. The main reason for TC was occurrence of an adverse event, followed by simplification, in both groups. Conclusions: ART effectiveness and safety did not differ significantly between pre- and postmenopausal women. Instituto de Salud Carlos III a través de la Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 y RD16/0002/0006) ISCIII-Subdirección General de Eval-uación y el Fondo Europeo de Desarrollo Regional (FEDER) y Acción Estratégica en Salud Intramural (PI15CIII/00027) 2.400 JCR (2020) Q3, 204/276 Pharmacology & Pharmacy 0.747 SJR (2020) Q2, 139/208 Infectious Diseases No data IDR 2020 UEM

A concept of “all or nothing” inspired the innovation of a one-pill-once-daily HIV treatment. Atripla® was the one pill that combined efavirenz, emtricitabine, and tenofovir disoproxil fumarate to become the first daily single tablet regimen that forever simplified HIV treatment to enhance patient compliance and thus, sustained viral suppression. The making of Atripla incorporated dry granulation and bilayer compression technologies to achieve stability and bioequivalence in an optimal pill size. In 2011, there lacked a standard of care for chronic hepatitis C infections that was safe, simple, short, free of interferon and ribavirin, and with high cure rates. A fixed-dose combination of ledipasvir and sofosbuvir was developed and approved in 2014 to be the first complete daily single tablet regimen for CHC genotype 1 infection. A spray-drying process for particle morphology engineering in a polymer matrix was used for improving bioavailability.

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

Vesatolimod (VES; GS-9620) is a Toll-like receptor 7 (TLR7) agonist that directly activates human plasmacytoid dendritic cells (pDCs) and B lymphocytes resulting in direct and indirect production of cytokines and immune activation. VES is being evaluated in HIV-1-infected people as part of an HIV remission strategy. Here we investigated the potential of VES to trigger indirect activation of HIV-specific CD8Peripheral blood mononuclear cell (PBMC) cultures derived from HIV+ donors virologically suppressed on stable antiretroviral therapy (n=31) were isolated and treated with VES or vehicle for 24 h. Cells were stained with surface and intracellular fluorescent conjugated antibodies and HIV-specific pentamers, and analysed by flow cytometry.Treatment of PBMCs with VES resulted in all 31 donors demonstrating a concentration dependent increase in CD8This study demonstrates that VES treatment can induce the activation of functional HIV-specific CD8

Cofactors associated with persistently abnormal CD4Clinic-based study in a tertiary, university hospital in Madrid. People with HIV starting a first-line ART regimen (January 2006-June 2017) were included in a prospective national multicentre cohort (CoRIS). People with controlled HIV-infection within the first year of ART initiation and complete CD4The study included 557 subjects. During follow-up (median 5.24 years), 44% of participants achieved a ratio of 1 within a median of 1.49 years. In a multivariate PH model, pre-ART factors negatively associated with ratio normalization were the pre-ART CD4In summary, our study showed that higher pre-ART CD4

Background We conducted a systematic review and meta-analysis (CRD#42017070552) to quantify the impact of oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) on bone mineral density (BMD) and the risk of osteoporosis, low bone mass and fractures, among people taking it as pre-exposure prophylaxis (PrEP), HIV treatment and HBV treatment. Methods We searched MEDLINE and EMBASE for randomized controlled trials published from 1997–2018 reporting BMD, osteoporosis, low bone mass and/or fractures in treatment-naive patients taking compared with not taking TDF for 48 ±4 weeks. We pooled outcomes using DerSimonian random-effects models. Results Our search yielded 5,178 abstracts, representing 3,865 articles, with 25 meeting the inclusion criteria. TDF was associated with greater BMD decline when taken as PrEP (lumbar spine: mean difference [MD]=-0.82%, 95% CI=-1.28, -0.37%, I2=38%; total hip: MD=-0.81%, 95% CI=-1.22, -0.40%, I2=48%) and HIV treatment (lumbar spine: MD=-1.62%, 95% CI=-2.30, -0.95%, I2=93%; total hip: MD=-1.75%, 95% CI=-2.08, -1.42%, I2=83%; femoral neck: MD=-1.26%, 95% CI=-2.15, -0.38%, I2=43%) in comparison to those not taking TDF. Eight studies reported on incident osteoporosis or low bone mass, with variable results. Pooled results from five PrEP studies showed that TDF was not associated with increased fractures compared with no PrEP (RR=1.12, 95% CI=0.752, 1.74, I2=26%). Conclusions TDF caused greater decreases in BMD than did comparators when used for all three indications and the magnitude of this decrease was larger for HIV treatment compared with PrEP. Fractures were not increased among PrEP patients. The clinically significant BMD decline caused by TDF and current expansion of PrEP use suggest attention to the adverse bone effects of TDF will increase in importance.

Tenofovir-based pre-exposure prophylaxis (PrEP) revolutionized the global HIV prevention landscape. Prior to the proof-of concept trial in 2010, which demonstrated that tenofovir (TFV) could prevent sexual transmission of HIV, prevention options were largely limited to behavior change, condoms, and circumcision. Several subsequent studies evaluating oral tenofovir disoproxil fumarate (TDF) or the TDF/emtricitabine (FTC) combination as PrEP for HIV prevention provided evidence for regulatory approval and inclusion in national and international guidelines. By 2021, 1.5 million people had initiated oral tenofovir-based PrEP, contributing to declines in HIV incidence in some regions. Here we reflect on how oral tenofovir-based PrEP became an important component of combination HIV prevention programs across the globe.

Background Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor available as a single tablet and a three-drug combination with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) to treat HIV-1 infection. These analyses assessed pharmacokinetic (PK) interactions with coadministration. Methods Two trials were conducted. Study 1: two-period, fixed-sequence; eight healthy participants; Period 1, DOR 100 mg followed by ≥7-day washout; Period 2, TDF 300 mg once daily for 18 days, coadministration of DOR 100 mg on day 14. Study 2: three-period, crossover, 15 healthy participants; Treatment A, DOR 100 mg; Treatment B, 3TC 300 mg + TDF 300 mg; Treatment C, DOR 100 mg + 3TC 300 mg + TDF 300 mg; ≥7-day washout between periods. Results Study 1: geometric mean ratios (GMRs; 90% confidence interval [CI]) of DOR area under the concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and observed plasma concentrations at 24 h post-dose (C24 h; DOR+TDF/DOR) were 0.95 (0.80, 1.12) and 0.94 (0.78, 1.12), respectively. Study 2: GMRs (90% CI) of DOR AUC0–∞ and C24 h (DOR+3TC+TDF/DOR) were 0.96 (0.87, 1.06) and 0.94 (0.83, 1.06), respectively. GMRs (90% CI) of 3TC and tenofovir AUC0–∞ (DOR+3TC+TDF/3TC+TDF) were 0.94 (0.88, 1.00) and 1.11 (0.97, 1.28), respectively. Study drugs were generally well tolerated. Conclusions Multiple doses of TDF did not have a clinically meaningful effect on DOR PK. The PK of DOR were similar when administered alone or in combination with 3TC and TDF. DOR had no meaningful effect on the PK of 3TC and tenofovir.

BackgroundSentinel surveillance of transmitted HIV drug resistance (TDR) among recently infected populations within a country was recommended by the World Health Organization from 2004 to 2015.MethodsSerum specimens collected as part of the 2010, 2011 and 2012 National Antenatal Sentinel HIV Prevalence Surveys were used to estimate provincial and national TDR prevalence in South Africa.ResultsModerate (5–15%) levels of transmitted non-nucleoside reverse transcriptase inhibitor (NNRTI) drug class resistance were detected in three of five provinces surveyed in 2010 and 2011 (Eastern Cape, Free State and KwaZulu-Natal). Inclusion of all nine of South Africa's provinces in the 2012 survey enabled calculation of a national TDR point prevalence estimate: TDR to the NNRTI drug class was 5.4% (95% CI 3.7, 7.8%), with K103N and V106M being the most frequently detected mutations. TDR estimates for the nucleoside reverse transcriptase inhibitor (NRTI) drug class were 1.1% (95% CI 0.5, 2.4%) and 0.6% (95% CI 0.1, 1.6%) for protease inhibitors (PI).ConclusionsThese data provide national TDR estimates for South Africa in 2012 and indicate that levels of TDR were low to moderate for the NNRTI drug class and low for NRTIs and PIs in the population surveyed.

Background To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART. Methods SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2–3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group). 210 participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: thymidine analogue (ta-NRTI) + lamivudine/emtricitabine (3[F]TC; ta-NRTI group); tenofovir (TDF)+3(F)TC (TDF group); TDF+ta-NRTI ±3(F)TC (TDF+ta-NRTI group); RAL. Changes in fasted total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression methods were used. Results We analysed 454 participants. Participants in RAL group had greater TC increases, TC (adjusted mean difference [aMD]=0.65, 95% CI 0.33, 0.96), LDL-c (aMD=0.38, 95% CI 0.15, 0.61) and glucose (aMD=0.47, 95% CI -0.01, 0.92) compared to TDF group, and had greater increases in TC (aMD=0.65, 95% CI 0.28, 1.03), HDL-c (aMD=0.12, 95% CI 0.02, 0.23) and LDL-c (aMD=0.41, 95% CI 0.13, 0.69) compared to TDF+ta-NRTI group. TC/HDL ratio and triglycerides increased in all groups without significant differences between groups. A 1 kg increase in trunk fat mass was associated with an increase in TC. Conclusions We observed metabolic changes of limited clinical significance in the relatively young population enrolled in this study. However, the metabolic changes observed may have greater clinical significance in older people living with HIV or those with other concomitant cardiovascular risks.

Triumeq is a single-tablet regimen for patients with HIV infection comprising dolutegravir, abacavir and lamivudine. Overdoses with Triumeq have not been reported previously. We present a case of a 26-year-old man who presented to our hospital after intentionally ingesting 30 tablets of Triumeq. An intoxication with Triumeq can lead to several side effects. An overdose of abacavir and lamivudine can cause mitochondrial toxicity and lactic acidosis. An intoxication with dolutegravir appears to be relatively harmless. As Triumeq will be used on a regular basis as treatment for patients with HIV-1 infection, these intoxications are expected to be encountered more often.

Background Efavirenz has been a mainstay of antiretroviral therapy (ART) for over 15 years in the US. Its association with neuropsychiatric side effects may influence clinical prescribing and management. Methods We included HIV-infected adults enrolled in care at seven sites across the US, who initiated combination ART between 1999 and 2015. We examined the proportion initiating and continuing on efavirenz, overall and by mental health status. Log binomial and Cox models were used to estimate associations between mental health, clinical and sociodemographic characteristics and initiating or switching from efavirenz as first-line ART. Results Of the 8,230 participants included, 3,710 (45%) initiated efavirenz. In multivariable analyses, prior mono-or dual-ART, ART initiation after 2006, being female, intravenous drug use, antidepressant prescription, previous mental health diagnosis and baseline CD4+ T-cell count >350 cells/mm3 were inversely associated with initiating efavirenz. Participants initiating efavirenz had a faster time to a regimen switch, compared with those initiating an efavirenz-free regimen ( P-value Conclusions Multiple clinical factors, including mental health diagnoses, appeared to influence efavirenz use. While mental health diagnosis status and more recent treatment starts were associated with shorter duration of efavirenz therapy, a previous mental health diagnosis did not preclude efavirenz initiation or continuation in many participants.

Pre-exposure prophylaxis (PrEP), using tenofovir disoproxil fumarate (TDF), can effectively prevent HIV acquisition. However, TDF can cause changes in bone mineral density (BMD). There is little information on the use of PrEP among patients with bone disease. We present a case report of a female with pre-existing osteoporosis who was prescribed PrEP. Over the course of 9 months of consistent PrEP use, verified by dried blood spot testing, we report a lack of BMD changes on serial dual-emission X-ray absorptiometry scans in this patient. This case can inform PrEP care for patients with pre-existing bone disease.

Background Persons infected with HIV often have altered lipid profiles that may be affected by antiretroviral therapies (ART). Traditional lipid measurements may be insufficient to assess cardiovascular disease (CVD) risk in this population. Methods We report results from 39 ART-naive participants in a substudy of A5248, a single-arm study of raltegravir, emtricitabine/tenofovir administration. Samples were collected at baseline, 12, 24 and 48 weeks after ART initiation. We performed advanced lipid phenotyping using nuclear magnetic resonance spectroscopy (Liposcience, Raleigh, NC, USA) for lipid particle size and number, and examined high-density lipoprotein (HDL) function measuring reverse cholesterol transport using J774 macrophages. Results We report significant increases in total cholesterol (13 mg/dl; P0.1 all time points). HDL levels were increased over baseline levels at all time points ( PConclusions HDL increases were associated with increases in beneficial HDL particles and HDL cholesterol efflux capacity, which may reduce future CVD events. Persistent inflammation in these HIV+ participants, may be a cause or consequence of oxLDL levels, and may contribute to declining levels of HDL over time. Clinicaltrials.gov NCT00660972.

Background Renal toxicity is a common side effect during tenofovir (TDF)-use in HIV-infected, but not necessarily HBV-infected, patients. Nevertheless, little is known regarding TDF-use on renal impairment during HIV–HBV coinfection. We aimed to evaluate the progression and determinants of renal impairment in coinfected patients undergoing TDF. Methods A total of 175 coinfected patients initiating TDF-containing antiretroviral therapy were prospectively followed. Estimated glomerular filtration rates (eGFR) were calculated at baseline and every 6–12 months. Determinants of eGRF change from baseline (ΔeGFR) were evaluated using mixed-effect linear regression and progression towards renal impairment using proportional-hazards regression. Results At baseline, average eGFR was 96.7 ml/min per 1.73m2 (95% CI 93.8, 99.6). During a median 58.3 months (IQR 33.7–92.1) of treatment, eGFR decreased a monthly average of -0.14 ml/min per 1.73m2 (95% CI -0.16, -0.12). Significantly faster ΔeGFR was associated with baseline eGFR>90 ( P=0.002), male gender ( P=0.04), previous AIDS-defining illness at baseline ( P=0.03), baseline liver cirrhosis ( P=0.03) and concomitant protease inhibitor use ( P=0.005). Between respective baseline and end of follow-up visits, the proportion of patients with renal impairment increased: normal function, 65.7% to 53.1%; mild impairment, 32.6% to 40.0%; moderate impairment, 1.7% to 6.9%. Higher age ( P=0.01) and previous AIDS-defining illness ( P=0.02) at baseline were independent risk-factors for developing impairment, while undetectable HBV DNA on-treatment was protective ( P=0.006). Five (2.9%) patients permanently discontinued TDF after a renal event. Conclusions Severe HIV-related and HBV-related morbidity negatively affects renal function in coinfected patients undergoing long-term TDF. Although most patients only developed mild/moderate impairment, close renal monitoring is warranted for this particular population.

Background In Western countries, viral rebound on antiretroviral therapy (ART) appears to occur more frequently in migrants. We aimed to assess the respective roles of socioeconomic factors and migration on viral rebound in people living with HIV (PLHIV) in France. Methods We included PLHIV in France, enrolled from 2004 to 2008 in the French ANRS-COPANA cohort, who started a first ART and achieved undetectability (Results Of 499 included individuals, 288 were born in France, 158 in sub-Saharan Africa (SSA) and 53 in another country. Kaplan–Meier probabilities of viral rebound-free survival were similar for men having sex with men (MSM) and heterosexuals born in France, and lower in migrants from SSA or other countries ( PConclusions Socioeconomic factors affect outcomes on ART, even in the context of free access to HIV care and treatment. Patient-centred strategies should be encouraged with the intervention of social workers to address basic needs and promote social support for more socially vulnerable individuals.

Background Cobicistat (COBI), a CYP3A inhibitor, is a pharmacokinetic enhancer that increases exposures of the HIV protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV). The potential drug interaction between COBI-boosted PIs and hormonal contraceptives, which are substrates of intestinal efflux transporters and extensively metabolized by CYP enzymes, glucuronidation and sulfation, was evaluated. Methods This was a Phase I, open-label, two cohort ( n=18/cohort), fixed-sequence study in healthy females that evaluated the drug–drug interaction (DDI) between multiple-dose ATV+COBI or DRV+COBI and single-dose drospirenone/ethinyl estradiol (EE). DDIs were evaluated using 90% confidence intervals of the geometric least-squares mean ratios of the test (drospirenone/EE+boosted PI) versus reference (drospirenone/EE) using lack of DDI boundaries of 70–143%. Safety was assessed throughout the study. Results 29/36 participants completed the study. Relative to drospirenone/EE alone, drospirenone area under the plasma concentration versus time curve extrapolated to infinity (AUCinf) was 1.6-fold and 2.3-fold higher, and maximum observed plasma concentration (Cmax) was unaltered, upon coadministration with DRV+COBI and ATV+COBI, respectively. EE AUCinf decreased 30% with drospirenone/EE + DRV+COBI and was unchanged with ATV+COBI + drospirenone/EE, relative to drospirenone/EE alone. Study treatments were generally well tolerated. The majority of adverse events were mild and consistent with known safety profiles of the compounds. Conclusions Consistent with COBI-mediated CYP3A inhibition, drospirenone exposure increased following coadministration with COBI-containing regimens, with a greater increase with ATV+COBI. Thus, clinical monitoring for drospirenone-associated hyperkalaemia is recommended with DRV+COBI and ATV+COBI should not be used with drospirenone. Lower EE exposure with DRV+COBI may be attributed to inductive effects of DRV on CYP enzymes and/or intestinal efflux transporters (that is, P-gp) involved in EE disposition.

Background Pretreatment and acquired drug resistance mutations (DRMs) can limit antiretroviral therapy effectiveness. Methods We review prevalence of DRMs with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), focusing on lamivudine and rilpivirine, from 127 articles with >100,000 individuals with HIV-1 infection. Results Estimated global prevalence of pretreatment resistance to any NRTI was 4% and to any NNRTI was 6%. Most prevalent DRMs resistant to lamivudine or rilpivirine were at positions E138 (4%), V179 (1%) and M184 (1%). Estimated acquired DRM prevalence was 58% for any NRTIs and 67% for any NNRTIs, most frequently at positions M184 (58%) and Y181 (21%). Conclusions This review suggests low risk of lamivudine-or rilpivirine-resistant mutations in treatment-naive, HIV-1-infected individuals.

Background HIV viral load (VL) and resistance testing are limited in sub-Saharan Africa, so individuals may have prolonged time on failing first-line antiretroviral therapy (ART). Our objective was to describe the evolution of drug resistance mutations among adults failing first-line ART in Zambia. Methods We analysed data from a trial of VL monitoring in Lusaka, Zambia. From 2006 to 2011, 12 randomized sites provided either routine VL monitoring (intervention) or discretionary (control) after ART initiation. Samples were collected prospectively following the same schedule in each arm but analysed retrospectively in the control group. For those with virological failure (VF; >400 copies/ml), HIV genotyping was performed retrospectively on baseline (BL) and on all subsequent specimens until censored due to study completion, withdrawal or death. Results Of 1,973 enrollees, 165 (8.4%) developed VF. 464 genotype results were available including 132 (80%) at BL, 116 (70%) at VF and 125 (76%) had at least one result between VF and censoring. Major nucleoside reverse transcriptase inhibitor (NRTI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations increased from 26% (BL) to 82% (VF) to 89% at last genotype (LG). M184 mutations increased from 2% to 59% to 71%; K65R from 2% to 11% to 13%; 2 or more thymidine analogue mutations from 1% to 3% to 12%. Among those on a failing tenofovir disoproxil fumarate (TDF)-based regimen, TDF resistance increased from 42% to 58%. Conclusions We found substantial resistance to NRTIs and NNRTIs at VF with incremental increases after VF while still on a failing first-line ART; this resistance may compromise attainment of the UNAIDS 90-90-90 goals.

Background Cabotegravir (CAB) is an integrase strand transfer inhibitor in development as a long-acting injectable formulation, with an oral formulation used during a safety lead-in period. Tuberculosis (TB)–HIV coinfection is common, often requiring simultaneous treatment. Rifabutin (RBT) is an alternative antimycobacterial agent for TB and a moderate inducer of cytochrome P450 and UDP-glucuronosyltransferase isoenzymes. This study evaluated the impact of RBT on the pharmacokinetics (PK) of oral CAB. Methods In this Phase I, single-centre, open-label, two-period, fixed-sequence, drug interaction study, subjects received oral CAB 30 mg once daily for 14 days in period 1, and oral CAB plus RBT 300 mg once daily for 14 days in period 2. Serial PK sampling was performed on days 14 and 28. Geometric least squares (GLS) mean ratios with associated 90% CIs were calculated to compare CAB non-compartmental PK parameters following CAB+RBT versus CAB alone. Safety was also assessed. Results A total of 15 male subjects were enrolled and 12 completed all treatments. Comparing CAB+RBT with CAB alone, the GLS mean ratios (90% CIs) for CAB area under the concentration–time curve from time zero to the end of the dosing interval (AUC0–τ), maximum observed plasma concentration (Cmax) and concentration at the end of the dosing interval (Cτ) were 0.79 (0.74, 0.83), 0.83 (0.76, 0.90) and 0.74 (0.70, 0.78), respectively. 11 subjects reported 24 adverse events (AEs); 22 were reported with CAB+RBT (3 drug-related) and 2 with CAB alone (not drug-related). All AEs resolved by study end. Conclusions RBT had a modest impact on plasma CAB exposure following oral coadministration, resulting in overall plasma CAB trough exposures above the 10 mg oral dose shown to maintain viral suppression in HIV-1-infected subjects. Oral CAB can be coadministered with RBT without dosage adjustment.

Background Ageing HIV-infected patients present an increased incidence of cardiovascular diseases, endothelial dysfunction being an early alteration. Some protease inhibitors (PIs) have been shown to increase the risk of cardiovascular disease. We evaluated here the effects of CCR5 or integrase inhibitors as compared to PIs on endothelial functions in vitro. Methods Human coronary artery endothelial cells (HCAEC) from adult and old non-HIV-infected donors were treated for 15 days with the CCR5 inhibitor mara-viroc, the integrase inhibitors dolutegravir or raltegravir or the ritonavir-boosted PIs, darunavir (DRV/r) or atazanavir (ATV/r), all at Cmax concentrations. We evaluated endothelial function, secretion of adhesion molecules and cytokines, inflammation, oxidative stress and senescence. Results In endothelial cells from adult donors, we con-firmed that ATV/r and DRV/r adversely affected all assessed endothelial functions and enhanced senescence, these effects being mild for DRV/r. Raltegravir had no effect and maraviroc a mild anti-inflammatory effect. Dolutegravir decreased inflammation, by inhibiting the NFκB pathway, and senescence, by repressing the p21 pathway. Moreover, HCAEC from an old donor presented, constitutively, a high level of senescence. Raltegravir mildly affected inflammation and senescence while maraviroc and dolutegravir decreased oxidative stress, inflammation and senescence and improved endothelial dysfunction. Conclusions We report here that the integrase inhibitor dolutegravir and the CCR5 inhibitor maraviroc reduced inflammation of human adult endothelial cells to different extents while raltegravir was neutral. Dolutegravir also reduced senescence, while PI/r increased inflammation and senescence. It is important to address the clinical relevance of these results.

We report a case of therapeutic drug monitoring guided raltegravir use for the prevention of vertical HIV transmission in a premature neonate born to a woman living with perinatally acquired HIV and documented resistance to multiple HIV drugs. Maternal viral load was above 1,000 copies/ml at delivery. This case demonstrates delayed raltegravir elimination in a neonate born at 33 weeks gestational age and a need for less frequent raltegravir dosing than is used in older infants and children.

Background Failure to achieve complete viral suppression with antiretroviral drugs (ARV) may lead to uncontrolled HIV replication, ARV resistance and negative outcomes. Monitoring and reporting of HIV resistance trends is important but problematic. We examined prevalent resistance rates in an HIV population over 20 years and document how rates may appear to vary greatly based solely on which parameters are utilized. Methods We determined the annual use of geno-typic antiretroviral resistance testing (GART) from 1995 to 2014 for all patients receiving HIV care in southern Alberta, Canada, and the presence of resistance mutations in those tested. The impact on prevalent resistance rates of using cumulative or latest GART was also determined. Results Between 1995 and 2014, the number of patients with GART increased from Conclusions While prevalence resistance rates are decreasing, the precise rates being reported may vary due to increasing number of patients tested annually, using either the entire population as denominator or only patients with GART, and using either last or cumulative GART. Defining these parameters is critical if prevalence is to be compared over time or between HIV populations.

Background We assessed whether women who acquired HIV during tenofovir gel prophylaxis trials can be safely and effectively treated with tenofovir-containing anti-retroviral therapy (ART). Methods Between May 2011 and October 2014, HIV seroconvertors from two tenofovir gel trials were recruited when eligible for ART (CD4+ T-cell count Results Fifty-nine women were enrolled and followed-up for median 18 months (IQR 6–24). Twenty-nine women (7 tenofovir gel exposed, 22 tenofovir gel unexposed) were randomized to a tenofovir-containing and 30 (9 tenofovir gel exposed, 21 tenofovir gel unexposed) to a tenofovir-sparing regimen. Median baseline CD4+ T-cell count and viral load (VL) were 345 cells/ml (IQR 280–423) and 4.5 log copies/ml (sd 0.79), and did not differ by ART assignment. Overall VL suppression rates were 88.0% and 78.3% at 6 months ( P=0.454) and 85.7% and 79.0% at 12 months ( P=0.689) in women on the tenofovir-containing and tenofovir-sparing regimens, respectively. Toxicity-related drug switches were more frequent in women on the tenofovir-sparing than tenofovir-containing regimen (36.7% versus 0.0%, PConclusions Preliminary data show that tenofovir-containing ART was effective and more tolerable in HIV seroconvertors from tenofovir gel prophylaxis trials and may be considered for use in women with prior tenofovir gel exposure. Clinical trials.gov NCT01387022.

Background Studies in healthy volunteers have shown that the recently approved HIV integrase inhibitor dolutegravir has limited drug-to-drug interaction profile. Here we carried out a pharmacokinetic survey in HIV-infected patients given dolutegravir as part of their antiretroviral therapy. Methods Dolutegravir plasma trough concentrations were measured in 78 HIV-infected patients given the drug in combination with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or abacavir/lamivudine. Drug concentrations were assessed by high performance liquid chromatography method with UV-detection. Results All patients were given dolutegravir at 50 mg once daily, with median trough drug concentrations of 1,096 (664–2,356) ng/ml (interindividual coefficient of variation: 85.3%). Patients given dolutegravir with atazanavir had significantly higher drug concentrations compared with those given darunavir, rilpivirine or abacavir/lamivudine (2,399 [1,929–4,070] versus 738 [552–1,048], 603 [432–1,373] or 1,045 [856–1,115] ng/ml; PConclusions Atazanavir coadministration significantly inhibited dolutegravir metabolism, ultimately resulting in a two- to fourfold increase in drug disposition compared with other antiretroviral drugs. This boosting effect of atazanavir could be used to optimize dolutegravir dosing in particular clinical settings.

BackgroundThis study compared time to virological suppression and rebound between Indigenous and non-Indigenous individuals living with HIV in Canada initiating combination antiretroviral therapy (cART).MethodsData were from the Canadian Observational Cohort collaboration; eight studies of treatment-naive persons with HIV initiating cART after 1/1/2000. Fine and Gray models were used to estimate the effect of ethnicity on time to virological suppression (two consecutive viral loads [VLs] 200 copies/ml at least 3 months apart) following suppression.ResultsAmong 7,080 participants were 497 Indigenous persons of whom 413 (83%) were from British Columbia. The cumulative incidence of suppression 1 year after cART initiation was 54% for Indigenous persons, 77% for Caucasian and 80% for African, Caribbean or Black (ACB) persons. The cumulative incidence of rebound 1 year after suppression was 13% for Indigenous persons, 6% for Caucasian and 7% for ACB persons. Indigenous persons were less likely to achieve suppression than Caucasian participants (aHR=0.58, 95% CI 0.50, 0.68), but not more likely to experience rebound (aHR=1.03, 95% CI 0.84, 1.27) after adjusting for age, gender, injection drug use, men having sex with men status, province of residence, baseline VL and CD4+T-cell count, antiretroviral class and year of cART initiation.ConclusionsLower suppression rates among Indigenous persons suggest a need for targeted interventions to improve HIV health outcomes during the first year of treatment when suppression is usually achieved.

Background Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds directly to HIV-1 gp120, blocking initial viral attachment and entry into host CD4+ T-cells. Efficacy, safety and dose-response data of fostemsavir in treatment-experienced, HIV-1-infected subjects, through week 48, are reported. Methods AI438011 is an ongoing Phase IIb, randomized, active-controlled trial (NCT01384734). Subjects were randomized 1:1:1:1:1 into five arms: fostemsavir (400 mg twice daily, 800 mg twice daily, 600 mg once daily or 1,200 mg once daily) and a reference arm (ritonavir-boosted atazanavir [ATV/r] 300/100 mg once daily), each with a backbone of raltegravir 400 mg twice daily plus tenofovir disoproxil fumarate 300 mg once daily. Results In total, 251 subjects were treated. Through week 48, the proportion of fostemsavir subjects with HIV-1 RNA + T-cell count increases from baseline were 145-186 cells/μl and 142 cells/μl for the ATV/r arm. Fostemsavir doses were generally well tolerated and no fostemsavir-related adverse events led to discontinuation. Conclusions Through week 48, fostemsavir continued to be well tolerated and showed similar efficacy to ATV/r. These results support the ongoing Phase III trial in heavily treatment-experienced adults with limited therapeutic options (≤2 classes of active antiretrovirals remaining). ClinicalTrials.gov identifer: NCT01384734.

Background We aimed to measure the effect of raltegravir (RAL) on insulin sensitivity and surrogates of cardiovascular risk in healthy HIV-seronegative volunteers compared to that of lopinavir/r (LPV/r), a positive control. Methods An open-label, two phase crossover study in HIV-negative male subjects randomized 1:1 to receive either 2 weeks of LPV/r followed by a 2-week washout period and 2 weeks of RAL, or RAL initially followed by LPV/r. A hyperinsulinaemic euglycaemic clamp was performed prior to and following each 2-week dosing phase. Fasting samples for lipids, adiponectin, leptin, vascular inflammatory biomarkers and CD36 were also taken. Results A total of 16 subjects completed the study. At the baseline visit the mean insulin-stimulated glucose disposal per unit insulin (M/I) was 7.97 and 8.30 for LPV/r and RAL, respectively. The mean (sem) percentage change from baseline was -16.10% (3.84) after 2 weeks of LPV/r and -0.43% (4.83) after 2 weeks of RAL. Absolute M/I was 25% lower for LPV/r than for RAL ( P=0.001). Triglycerides and total cholesterol rose significantly with LPV/r (+0.5 mmol/l, P=0.002 and +0.4 mmol/l, PConclusions RAL was not associated with measurable change in glycaemic, metabolic or inflammatory effects.

Background Antiretroviral (ART) drugs have been associated with higher triglycerides (TG), higher total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-C) levels. Associations between lipid levels with HIV viraemia and immunosuppression in the presence of ART remain unclear. Methods Participants from the D:A:D study with at least one TG/TC/HDL-C measurement were included. Linear mixed effect models were used to determine the association of ART, viral load (VL), nadir and current CD4+ T-cell count and previous AIDS diagnosis with lipids. Results Of 49,717 participants, 90%, 92% and 80% contributed at least one TG/TC/HDL-C measurement (median follow-up 6.8, 6.8 and 5.0 years, respectively). Predicted mean (95% CI) baseline levels for TG, TC and HDL-C (mmol/l), were 2.10 (2.05, 2.14), 4.94 (4.91, 4.98) and 1.08 (1.07, 1.10), respectively. Lopinavir was associated with the worst TG profile, (27.2% higher levels compared to atazanavir; 95% CI 25.2%, 29.2%), and darunavir had a similar profile as atazanavir. The nucleoside pair lamivudine/tenofovir was associated with the most favourable TG profile (-2.8%; -3.5%, -2.0%) compared with emtricitabine/tenofovir, whereas lamivudine/abacavir (+10.2%; +9.3%, +11.2%) and lamivudine/ stavudine (+8.0%; +6.9%, +9.0%), were associated with the worst. Raltegravir was associated with lower TG (-5.2%; -6.4%, -3.9%), and nevirapine had a more favourable HDL-C profile (+11.3%; +10.8%, +11.7%) than efavirenz (+5.3%; 5.0%, 5.7%), compared to atazanavir. Higher VLs were associated with lower TG/TC/HDL-C, whereas higher CD4+ T-cell counts were associated with higher TG/TC/HDL-C. Conclusions TG, TC and HDL-C levels, which generally improved over time, are dependent on ART, viraemia and, to a lesser extent, immunosuppression.