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Objective: To compare the incidence of dyslipidemia in people with HIV receiving integrase inhibitors (INSTI) versus boosted protease inhibitors (PI/b) and nonnucleoside reverse transcriptase inhibitors (NNRTI) within RESPOND consortium of prospective cohorts. Methods: Participants were eligible if they were at least 18 years, without dyslipidemia and initiated or switched to a three-drug antiretroviral therapy (ART)-regimen consisting of either INSTI, NNRTI, or PI/b for the first time, between 1 January 2012 and 31 December 2018. Dyslipidemia was defined as random total cholesterol more than 240 mg/dl, HDL less than 35 mg/dl, triglyceride more than 200 mg/dl, or initiation of lipid-lowering therapy. Poisson regression was used to determine the adjusted incidence rate ratios. Follow-up was censored after 3 years or upon ART-regimen discontinuation or last lipid measurement or 31 December 2019, whichever occurred first. Results: Overall, 4577 people with HIV were eligible (INSTI = 66.9%, PI/b = 12.5%, and NNRTI = 20.6%), 1938 (42.3%) of whom were ART-naive. During 1.7 (interquartile range, 0.6-3.0) median years of follow-up, 1460 participants developed dyslipidemia [incidence rate: 191.6 per 1000 person-years, 95% confidence interval (CI) 182.0-201.7]. Participants taking INSTI had a lower incidence of dyslipidemia compared with those on PI/b (adjusted incidence rate ratio 0.71; CI 0.59-0.85), but higher rate compared with those on NNRTI (1.35; CI 1.15-1.58). Compared with dolutegravir, the incidence of dyslipidemia was higher with elvitegravir/cobicistat (1.20; CI 1.00-1.43) and raltegravir (1.24; CI 1.02-1.51), but lower with rilpivirine (0.77; CI 0.63-0.94). Conclusion: In this large consortium of heterogeneous cohorts, dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine.

Background: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. Setting: International multicohort collaboration. Methods: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. Results: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. Conclusions: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

OBJECTIVES Predictors of chronic kidney disease (CKD) amongst HIV-positive persons are well established, but insights into the prognosis after CKD including the role of modifiable risk factors are limited. DESIGN Prospective cohort study. METHODS D:A:D participants developing CKD (confirmed, >3 months apart, eGFR ≤ 60 ml/min per 1.73 m or 25% eGFR decrease when eGFR ≤ 60 ml/min per 1.73 m) were followed to incident serious clinical events (SCE); end stage renal and liver disease (ESRL and ESLD), cardiovascular disease (CVD), AIDS-defining and non-AIDS-defining malignancies (NADM), other AIDS or death, 6 months after last visit or 1 February 2016. Poisson regression models considered associations between SCE and modifiable risk factors. RESULTS During 2.7 (IQR 1.1-5.1) years median follow-up 595 persons with CKD (24.1%) developed a SCE [incidence rate 68.9/1000 PYFU (95% confidence interval 63.4-74.4)] with 8.3% (6.9-9.0) estimated to experience any SCE at 1 year. The most common SCE was death (12.7%), followed by NADM (5.8%), CVD (5.6%), other AIDS (5.0%) and ESRD (2.9%). Crude SCE ratios were significantly higher in those with vs. without CKD, strongest for ESRD [65.9 (43.8-100.9)] and death [4.8 (4.3-5.3)]. Smoking was consistently associated with all CKD-related SCE. Diabetes predicted CVD, NADM and death, whereas dyslipidaemia was only significantly associated with CVD. Poor HIV-status predicted other AIDS and death, eGFR less than 30 ml/min per 1.73 m predicted CVD and death and low BMI predicted other AIDS and death. CONCLUSION In an era where many HIV-positive persons require less monitoring because of efficient antiretroviral treatment, persons with CKD carry a high burden of SCE. Several potentially modifiable risk factors play a central role for CKD-related morbidity and mortality.

OBJECTIVE Lower serum albumin (sAlb) has been associated with an increased risk of mortality and AIDS among people living with HIV and may be associated with the development of serious non-AIDS events (SNAEs). We evaluated the long-term association between sAlb and the risk of SNAEs. DESIGN Prospective multinational cohort study. METHODS D:A:D participants without SNAEs were followed from first routine sAlb value to the first of a new SNAE [cardiovascular disease (CVD), end-stage liver disease (ESLD), end-stage renal disease (ESRD), non-AIDS malignancy (NADM), death from non-AIDS cause], AIDS-death, 6 months after last visit or 01/02/2016. Poisson regression was used to determine associations between sAlb and a new i) SNAE, ii) CVD or iii) NADM event, with adjustment for potential confounders. Models additionally tested whether the associations were modified by age, follow-up time, smoking status, CD4 and viral load. RESULTS Of 16,350 participants (71.8% male, median age 44 years) 1,463 developed a SNAE (371 CVD, 200 ESLD, 40 ESRD, 553 NADM, 299 deaths from other non-AIDS causes) over 80,264 person-years. Increased sAlb was associated with a decreased risk of an SNAE (adjusted rate ratio (aRR) per 5 g/L: SNAE 0.79 [95%CI: 0.76, 0.83]; CVD 0.87 [0.80, 0.94]; NADM 0.88 [0.82, 0.95]). The association did not appear to wane with additional years of follow-up (p-interaction = 0.79) but was stronger for current smokers than for never smokers (p-interaction<0.01). CONCLUSIONS sAlb is a durable risk factor for SNAE. Future studies are needed to determine the mechanism underlying this association and to evaluate the value of sAlb in predictive tools.

BACKGROUND The relationship between body mass index (BMI) (weight (kg)/ height(m)) and serious non-AIDS events is not well understood. METHODS We followed D:A:D study participants on antiretroviral therapy from their first BMI measurement to the first occurrence of the endpoint or end of follow-up (N=41,149 followed for 295,147 person-years). The endpoints were cardiovascular disease (CVD); diabetes; non-AIDS-defining cancers (NADCs) and BMI-NADCs (cancers known to be associated with BMI in general population); and all-cause mortality. Using poisson regression models, we analysed BMI as time-updated, lagged by 1 year, and categorized at: 18.5, 23, 25, 27.5 and 30 kg/m. RESULTS Participants were largely male (73%) with the mean age of 40 years (SD 9.7) and baseline median BMI of 23.3 (IQR: 21.2-25.7). Overall, BMI showed a statistically significant J-shaped relationship with the risk of all outcomes except diabetes. The relative risk (RR) for the BMI of <18.5 and >30 (95% CI) compared to 23-25, respectively, was as follows: CVD: 1.46(1.15-1.84) and 1.31(1.03-1.67); NADCs: 1.78(1.39-2.28) and 1.17(0.88-1.54); 'BMI-NADCs': 1.29(0.66-2.55) and 1.92(1.10-3.36). For all-cause mortality, there was an interaction by gender (P<0.001): RR in males: 2.47(2.12-2.89) and 1.21(0.97-1.50); and in females: 1.60(1.30-1.98) and 1.02(0.74-1.42). RR remained around 1 for intermediate categories of BMI. The risk of diabetes linearly increased with increasing BMI (P<0.001). CONCLUSIONS Risk of CVD, a range of cancers, and all-cause mortality increased at low BMI (<18.5) and then tended to increase only at BMI>30 with a relatively low risk at BMI of 23-25 and 25-30. High BMI was also associated with risk of diabetes.

OBJECTIVE: To investigate the association between abacavir (ABC) use and recurrent myocardial infarction (MI) among HIV-positive people with a prior MI. DESIGN: International multi-cohort collaboration with follow-up from 1999-2016. METHODS: The rate of recurrent MI was described among D:A:D participants who experienced an index MI whilst in the study, and who remained under follow-up beyond 28 days after this MI. Follow-up was considered to the date of next MI, death, 01/Feb/2016 or 6 months after last clinic visit. Poisson regression models considered associations between recurrent MI and exposure to ABC (use at index MI, current post-MI exposure and cumulative exposure), before and after adjusting for calendar year. RESULTS: The 984 individuals who experienced an index MI during the study (91.3% male, median age 51 at index MI) were followed for 5312 person-years (PY) over which time there were 136 recurrent MIs (rate 2.56/100 PY, 95% Confidence Interval 2.13-2.99). Rates were 2.40 (1.71-3.09) and 2.65 (2.10-3.21)/100 PY in those who were and were not on ABC, respectively, at the index MI, and 2.90 (2.01-3.78) and 2.44 (1.95-2.93)/100 PY in those who were and were not currently receiving ABC, respectively, post-MI. No association was seen with recurrent MI and either cumulative exposure to ABC (RR=0.86 [0.68-1.10]/5 years), receipt of ABC at index MI (0.90 [0.63-1.29]) nor recent post-MI exposure to ABC (1.19 [0.82-1.71]). CONCLUSIONS: Among people with a previous MI, there was no evidence for an association between use of ABC post-MI and an elevated risk of a recurrent MI.

Objective: Nelfinavir exhibits potent anticancer properties against a range of tumours. However, in 2006/2007, nelfinavir supplies were accidently contaminated with a carcinogen. This analysis investigated the association between nelfinavir use and cancer risk in HIV-positive persons. Design: Observational cohort study. Methods: D:A:D study data was analysed using Poisson regression models to examine associations between cancer incidence and cumulative nelfinavir exposure, current nelfinavir exposure, and exposure to nelfinavir between 1 July 2006-30 June 2007. Results: A total of 42 006 individuals (50% white, 73% male) contributed 303 005 person-years of follow-up between 1 January 2004 and 1 February 2014. At study enrolment, median age was 40 [interquartile range (IQR) 33-46] years and 8305 individuals had a history of nelfinavir use [median duration 1.7 (IQR 0.7-3.4) years]. During follow-up, nelfinavir was used by 2476 individuals for a median of 1.7 (IQR 0.7-3.8) years; 1063 were exposed to nelfinavir between 1 July 2006 and 30 June 2007. Overall, 2279 cancers were diagnosed at a rate of 0.75 [95% confidence interval (95% CI) 0.72-0.78] per 100 person-years. Neither greater cumulative exposure to nelfinavir [adjusted risk ratio (aRR) 0.93 for every additional 5 years, 95% CI 0.82-1.06, P=0.26] nor current use of nelfinavir (aRR 0.98 vs other protease inhibitor use, 95% CI 0.68-1.41, P=0.92) were associated with cancer risk. The adjusted risk of cancer for participants exposed to nelfinavir between 1 July 2006 and 30 June 2007 compared to those receiving other treatment over this period was 1.07 (95% CI 0.78-1.46, P=0.68). Conclusion: Nelfinavir use was not associated with a lower cancer incidence than other protease inhibitor regimens. As of February 2014, exposure to the 2006/2007 contamination of nelfinavir does not appear to be associated with increased cancer incidence. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

OBJECTIVE Few studies have described mortality and clinical outcomes after myocardial infarction (MI) in the HIV-positive population. This study evaluated changes in short-term mortality after MI in HIV-positive individuals in the D:A:D Study, and investigated possible reasons for any changes seen. DESIGN Prospective cohort study. METHODS Demographic, cardiovascular disease (CVD)/HIV-related characteristics and CVD-related interventions (invasive cardiovascular procedures and drug interventions) were summarized at the time of and following an MI. Associations between calendar year and mortality in the first month after MI were identified using logistic regression with adjustment for confounders, including interventions received in the first month after MI. RESULTS One thousand and eight HIV-positive individuals experiencing an MI over the period 1999-2014 were included. The absolute number of MIs decreased from 214 (1999-2002) to 154 (2011-2014). Whilst the CVD risk profile remained high over time, the HIV status improved. The use of CVD-related interventions after MI appeared to increase over time. The proportion of individuals who died in the first month after MI dropped from 26.6% in 1999-2002 to 8.4% in 2011-2014. Later calendar year was associated with decreased short-term mortality; this effect was attenuated after adjusting for CVD-related interventions received in the first month after MI [odds ratio changed from 0.88 (95% confidence interval 0.83, 0.93) to 0.97 (0.91, 1.02)]. CONCLUSION Improvements in short-term survival after MI appear to be largely driven by improved medical management of CVD risk in HIV-positive individuals after MI. Efforts are still needed to treat CVD risk factors and increase access to CVD-related interventions.

An HIV-vaccine consisting of a DNA prime, recombinant fowlpox virus (rFPV) boost was evaluated in a double-blind placebo controlled trial. One milligram of pHIS-HIV-B expressing mutated gag, pol, env, vpu, tat and rev was administered at weeks 0 and 4 boosted by 5 × 107 pfu rFPV-HIV-B expressing gag/pol at week 8. The vaccine regimen was safe, but there was no difference between vaccine (n = 18) and placebo recipients (n = 6) for Gag or Pol-specific T-cell immune responses at week 9.