BackgroundDespite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts.MethodsIn HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower “usual” levels of IL-6 and D-dimer.ResultsOver 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower “usual” IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal.ConclusionsBoth IL-6 and D-dimer are independently associated with serious non-AIDS conditions or death among HIV-positive adults with suppressed virus. This suggests that treatments that reduce IL-6 and D-dimer levels might substantially decrease morbidity and mortality in patients on suppressive ART. Clinical trials are needed to test this hypothesis.
BackgroundThe sieve analysis for the Step trial found evidence that breakthrough HIV-1 sequences for MRKAd5/HIV-1 Gag/Pol/Nef vaccine recipients were more divergent from the vaccine insert than placebo sequences in regions with predicted epitopes. We linked the viral sequence data with immune response and acute viral load data to explore mechanisms for and consequences of the observed sieve effect.MethodsNinety-one male participants (37 placebo and 54 vaccine recipients) were included; viral sequences were obtained at the time of HIV-1 diagnosis. T-cell responses were measured 4 weeks post-second vaccination and at the first or second week post-diagnosis. Acute viral load was obtained at RNA-positive and antibody-negative visits.FindingsVaccine recipients had a greater magnitude of post-infection CD8+ T cell response than placebo recipients (median 1.68% vs 1.18%; p = 0·04) and greater breadth of post-infection response (median 4.5 vs 2; p = 0·06). Viral sequences for vaccine recipients were marginally more divergent from the insert than placebo sequences in regions of Nef targeted by pre-infection immune responses (p = 0·04; Pol p = 0·13; Gag p = 0·89). Magnitude and breadth of pre-infection responses did not correlate with distance of the viral sequence to the insert (p>0·50). Acute log viral load trended lower in vaccine versus placebo recipients (estimated mean 4·7 vs 5·1) but the difference was not significant (p = 0·27). Neither was acute viral load associated with distance of the viral sequence to the insert (p>0·30).InterpretationDespite evidence of anamnestic responses, the sieve effect was not well explained by available measures of T-cell immunogenicity. Sequence divergence from the vaccine was not significantly associated with acute viral load. While point estimates suggested weak vaccine suppression of viral load, the result was not significant and more viral load data would be needed to detect suppression.
Background Heart failure is a prominent cardiovascular disease (CVD) manifestation in sub-Sarahan Africa. Myocardial fibrosis is a central feature of heart failure that we aimed to characterize among persons with human immunodeficiency virus (PWH) in South Africa. Methods Cardiovascular magnetic resonance (CMR) imaging was performed among PWH with viral suppression and uninfected controls, both free of known CVD. Plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured. Comparisons by human immunodeficiency virus (HIV) status were made using linear and logistic regression, adjusted for age, sex, and hypertension. Results One hundred thirty-four PWH and 95 uninfected persons completed CMR imaging; age was 50 and 49 years, with 63% and 67% female, respectively. Compared with controls, PWH had greater myocardial fibrosis by extracellular volume fraction ([ECV] absolute difference, 1.2%; 95% confidence interval [CI], 0.1–2.3). In subgroup analyses, the effect of HIV status on ECV was more prominent among women. Women (vs controls) were also more likely to have elevated NT-proBNP levels (>125 pg/mL; odds ratio, 2.4; 95% CI, 1.0–6.0). Among all PWH, an elevated NT-proBNP level was associated with higher ECV (3.4% higher; 95% CI, 1.3–5.5). Conclusions Human immunodeficiency virus disease may contribute to myocardial fibrosis, with an effect more prominent among women. Research is needed to understand heart failure risk among PWH within sub-Saharan Africa.
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