ObjectiveCardiovascular disease (CVD) is one of the leading non-AIDS-defining causes of death among HIV-positive (HIV+) individuals. However, the evidence surrounding specific components of CVD risk remains inconclusive. We conducted a systematic review and meta-analysis to synthesise the available evidence and establish the risk of myocardial infarction (MI) among HIV+ compared with uninfected individuals. We also examined MI risk within subgroups of HIV+ individuals according to exposure to combination antiretroviral therapy (ART), ART class/regimen, CD4 cell count and plasma viral load (pVL) levels.DesignSystematic review and meta-analysis.Data sourcesWe searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews until 18 July 2018. Furthermore, we scanned recent HIV conference abstracts (CROI, IAS/AIDS) and bibliographies of relevant articles.Eligibility criteriaOriginal studies published after December 1999 and reporting comparative data relating to the rate of MI among HIV+ individuals were included.Data extraction and synthesisTwo reviewers working in duplicate, independently extracted data. Data were pooled using random-effects meta-analysis and reported as relative risk (RR) with 95% CI.ResultsThirty-two of the 8130 identified records were included in the review. The pooled RR suggests that HIV+ individuals have a greater risk of MI compared with uninfected individuals (RR: 1.73; 95% CI 1.44 to 2.08). Depending on risk stratification, there was moderate variation according to ART uptake (RR, ART-treated=1.80; 95% CI 1.17 to 2.77; ART-untreated HIV+ individuals: 1.25; 95% CI 0.93 to 1.67, both relative to uninfected individuals). We found low CD4 count, high pVL and certain ART characteristics including cumulative ART exposure, any/cumulative use of protease inhibitors as a class, and exposure to specific ART drugs (eg, abacavir) to be importantly associated with a greater MI risk.ConclusionsOur results indicate that HIV infection, low CD4, high pVL, cumulative ART use in general including certain exposure to specific ART class/regimen are associated with increased risk of MI. The association with cumulative ART may be an index of the duration of HIV infection with its attendant inflammation, and not entirely the effect of cumulative exposure to ART per se.PROSPERO registration numberCRD42014012977.

BackgroundNon-HIV/AIDS-related diseases are gaining prominence as important causes of morbidity and mortality among people living with HIV. The purpose of this study was to characterize and compare changes over time in mortality rates and causes of death among a population-based cohort of persons living with and without HIV in British Columbia (BC), Canada.MethodsWe analysed data from the Comparative Outcomes And Service Utilization Trends (COAST) study; a retrospective population-based study created via linkage between the BC Centre for Excellence in HIV/AIDS and Population Data BC, and containing data for HIV-infected individuals and the general population of BC, respectively. Our analysis included all known HIV-infected adults (≥ 20 years) in BC and a random 10% sample of uninfected BC adults followed from 1996 to 2012. Deaths were identified through Population Data BC – which contains information on all registered deaths in BC (BC Vital Statistics Agency dataset) and classified into cause of death categories using International Classification of Diseases (ICD) 9/10 codes. Age-standardized mortality rates (ASMR) and mortality rate ratios were calculated. Trend test were performed.Results3401 (25%), and 47,647 (9%) individuals died during the 5,620,150 person-years of follow-up among 13,729 HIV-infected and 510,313 uninfected individuals, respectively. All-cause and cause-specific mortality rates were consistently higher among HIV-infected compared to HIV-negative individuals, except for neurological disorders. All-cause ASMR decreased from 126.75 (95% CI: 84.92-168.57) per 1000 population in 1996 to 21.29 (95% CI: 17.79-24.79) in 2011-2012 (83% decline; p < 0.001 for trend), compared to a change from 7.97 (95% CI: 7.61-8.33) to 6.87 (95% CI: 6.70-7.04) among uninfected individuals (14% decline; p < 0.001). Mortality rates from HIV/AIDS-related causes decreased by 94% from 103.85 per 1000 population in 1996 to 6.72 by the 2011–2012 era (p < 0.001). Significant ASMR reductions were also observed for hepatic/liver disease and drug abuse/overdose deaths. ASMRs for neurological disorders increased significantly over time. Non-AIDS-defining cancers are currently the leading non-HIV/AIDS-related cause of death in both HIV-infected and uninfected individuals.ConclusionsDespite the significant mortality rate reductions observed among HIV-infected individuals from 1996 to 2012, they still have excess mortality risk compared to uninfected individuals. Additional efforts are needed to promote effective risk factor management and appropriate screening measures among people living with HIV.

This exploratory follow-up of the HELP Trial suggests that supervised aerobic exercise may be associated with improved PFS in lymphoma patients. Larger trials designed to answer this question are needed.

Genome-wide association studies (GWASs) have identified low-penetrance common variants (i.e., single nucleotide polymorphisms, SNPs) associated with breast cancer susceptibility. Although GWASs are primarily focused on single-locus effects, gene-gene interactions (i.e., epistasis) are also assumed to contribute to the genetic risks for complex diseases including breast cancer. While it has been hypothesized that moderately ranked (P value based) weak single-locus effects in GWASs could potentially harbor valuable information for evaluating epistasis, we lack systematic efforts to investigate SNPs showing consistent associations with weak statistical significance across independent discovery and replication stages. The objectives of this study were i) to select SNPs showing single-locus effects with weak statistical significance for breast cancer in a GWAS and/or candidate-gene studies; ii) to replicate these SNPs in an independent set of breast cancer cases and controls; and iii) to explore their potential SNP-SNP interactions contributing to breast cancer susceptibility. A total of 17 SNPs related to DNA repair, modification and metabolism pathway genes were selected since these pathways offer a priori knowledge for potential epistatic interactions and an overall role in breast carcinogenesis. The study design included predominantly Caucasian women (2,795 cases and 4,505 controls) from Alberta, Canada. We observed two two-way SNP-SNP interactions (APEX1-rs1130409 and RPAP1-rs2297381; MLH1-rs1799977 and MDM2-rs769412) in logistic regression that conferred elevated risks for breast cancer (P interaction<7.3×10−3). Logic regression identified an interaction involving four SNPs (MBD2-rs4041245, MLH1-rs1799977, MDM2-rs769412, BRCA2-rs1799943) (P permutation = 2.4×10−3). SNPs involved in SNP-SNP interactions also showed single-locus effects with weak statistical significance, while BRCA2-rs1799943 showed stronger statistical significance (P correlation/trend = 3.2×10−4) than the others. These single-locus effects were independent of body mass index. Our results provide a framework for evaluating SNPs showing statistically weak but reproducible single-locus effects for epistatic effects contributing to disease susceptibility.

Adopting a comprehensive biologically informed candidate-pathway approach identified GEI effects on colon cancer. Findings may have important implications for public health and personalized medicine targeting prevention and therapeutic strategies. Findings from this study need to be validated in other studies.