The association between hypertension (HTN) and inflammatory biomarkers (interleukin-6 [IL-6] and high-sensitivity C-reactive protein [hsCRP]) in HIV-positive persons with CD4+ count >500 cells/mm3 is unknown.We studied HTN in participants of the Strategic Timing of AntiRetroviral Treatment (START) trial of immediate vs. deferred antiretroviral therapy (ART) in HIV-positive, ART naive adults with CD4+ count > 500 cells/mm3. HTN was defined as having a systolic blood pressure (BP) ≥140 mmHg, a diastolic BP ≥90 mmHg, or using BP-lowering therapy. Logistic and discrete Cox regression models were used to study the association between baseline biomarker levels with prevalent and incident HTN.Among 4,249 participants with no history of cardiovascular disease, the median age was 36 years, 55% were nonwhite, and the prevalence of HTN at baseline was 18.9%. After adjustment for race, age, gender, body mass index (BMI), diabetes, smoking, HIV RNA and CD4+ levels, associations of IL-6 and hsCRP with HTN prevalence were not significant (OR per twofold higher:1.10, 95% confidence interval [CI]: 0.99, 1.20 for IL-6 and 1.05, 95% CI: 0.99, 1.10 for hsCRP). Overall incidence of HTN was 6.8 cases/100 person years. In similarly adjusted models, neither IL-6 (Hazard ratios [HR] per twofold higher IL-6 levels: 0.97, 95% CI: 0.88, 1.08) nor hsCRP (HR per twofold higher hsCRP levels: 0.97, 95% CI: 0.92, 1.02) were associated with risk of incident HTN. Associations did not differ by treatment group. Age, race, gender, and BMI were significantly associated with both the prevalence and incidence of HTN.Traditional risk factors and not baseline levels of IL-6 or hsCRP were associated with the prevalence and incidence of HTN in START.
Abstract Background HIV viremia has been considered a cardiovascular disease (CVD) risk factor, but many studies have had insufficient data on potential confounders. We explored the association between viremia and CVD after adjusting for established risk factors and analyzed whether consideration of viremia would improve CVD prediction. Methods Adults from RESPOND were followed from the first date with available data until the first of rigorously defined CVD, loss to follow-up, death, or administrative censoring. We first analyzed the associations between 6 measures of viremia (time-updated, before antiretroviral therapy [ART], viremia category, and measures of cumulative viremia) and CVD after adjusting for the variables in the D:A:D CVD score (age, sex/gender, smoking, family history, diabetes, recent abacavir, CD4 count, blood pressure, cholesterol, high-density lipoprotein, cumulative use of stavudine, didanosine, indinavir, lopinavir, and darunavir). We subsequently compared predictive performance with and without viremia in 5-fold internal cross-validation. Results A total of 547 events were observed in 17 497 persons (median follow-up, 6.8 years). Although some viremia variables were associated with CVD in univariable analyses, there were no statistically significant associations after adjusting for potential confounders, neither for measures of current viral load, pre-ART viral load, highest viremia category during ART, nor cumulative viremia (modeled both as total cumulative viremia, cumulative viremia during ART, and recent cumulative viremia). Consistently, none of the viremia variables improved prediction capacity. Conclusions In this large international cohort, HIV viremia was not associated with CVD when adjusting for established risk factors. Our results did not show viremia to be predictive of CVD among people with HIV.
Abstract Background Switching from boosted PIs to dolutegravir in people living with HIV (PLWH) with high cardiovascular risk improved plasma lipids at 48 weeks in the NEAT022 trial. Whether this strategy may have an impact on cardiovascular biomarkers is unknown. Methods We assessed 48 week changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury, and glomerular and tubular kidney injury. Results Of 415 PLWH randomized in the NEAT022 study, 313 (75.4%) remained on allocated therapy and had paired samples available. Soluble CD14 (–11%, P < 0.001) and adiponectin (–11%, P < 0.001) significantly declined and high-sensitive C-reactive protein (–13%, P = 0.069) and oxidized LDL (–13%, P = 0.084) tended to decrease with dolutegravir. Switching to dolutegravir remained significantly associated with soluble CD14 and adiponectin reductions after adjustment for baseline variables. There were inverse correlations between soluble CD14 and CD4 count changes (P = 0.05), and between adiponectin and BMI changes (P < 0.001). Conclusions Switching from boosted PIs to dolutegravir in PLWH with high cardiovascular risk led to soluble CD14 and adiponectin reductions at 48 weeks. While decreasing soluble CD14 may entail favourable health effects in PLWH, adiponectin reduction may reflect less insulin sensitivity associated with weight gain.
Abstract Background In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. Methods PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. Results Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. Discussion After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.
The level of evidence for HIV transmission risk through condomless sex in serodifferent gay couples with the HIV-positive partner taking virally suppressive antiretroviral therapy (ART) is limited compared with the evidence available for transmission risk in heterosexual couples. The aim of the second phase of the PARTNER study (PARTNER2) was to provide precise estimates of transmission risk in gay serodifferent partnerships.The PARTNER study was a prospective observational study done at 75 sites in 14 European countries. The first phase of the study (PARTNER1; Sept 15, 2010, to May 31, 2014) recruited and followed up both heterosexual and gay serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex, whereas the PARTNER2 extension (to April 30, 2018) recruited and followed up gay couples only. At study visits, data collection included sexual behaviour questionnaires, HIV testing (HIV-negative partner), and HIV-1 viral load testing (HIV-positive partner). If a seroconversion occurred in the HIV-negative partner, anonymised phylogenetic analysis was done to compare HIV-1 pol and env sequences in both partners to identify linked transmissions. Couple-years of follow-up were eligible for inclusion if condomless sex was reported, use of pre-exposure prophylaxis or post-exposure prophylaxis was not reported by the HIV-negative partner, and the HIV-positive partner was virally suppressed (plasma HIV-1 RNA <200 copies per mL) at the most recent visit (within the past year). Incidence rate of HIV transmission was calculated as the number of phylogenetically linked HIV infections that occurred during eligible couple-years of follow-up divided by eligible couple-years of follow-up. Two-sided 95% CIs for the incidence rate of transmission were calculated using exact Poisson methods.Between Sept 15, 2010, and July 31, 2017, 972 gay couples were enrolled, of which 782 provided 1593 eligible couple-years of follow-up with a median follow-up of 2·0 years (IQR 1·1-3·5). At baseline, median age for HIV-positive partners was 40 years (IQR 33-46) and couples reported condomless sex for a median of 1·0 years (IQR 0·4-2·9). During eligible couple-years of follow-up, couples reported condomless anal sex a total of 76 088 times. 288 (37%) of 777 HIV-negative men reported condomless sex with other partners. 15 new HIV infections occurred during eligible couple-years of follow-up, but none were phylogenetically linked within-couple transmissions, resulting in an HIV transmission rate of zero (upper 95% CI 0·23 per 100 couple-years of follow-up).Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV.National Institute for Health Research.
Mortality among people with human immunodeficiency virus (HIV) declined with the introduction of combination antiretroviral therapy. We investigated trends in mortality in people with HIV from 1999 through 2020. Data were collected from the Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) cohort between January 1999 through January 2015 and the International Cohort Consortium of Infectious Disease (RESPOND) from October 2017 through December 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV, were calculated. Poisson models were used to assess mortality over time. Among 55 716 participants followed for median 6 years (interquartile range, 3-11), 5263 died (mortality rate [MR], 13.7/1000 person-years of follow-up [PYFU]; 95% confidence interval [CI], 13.4-14.1). Changing mortality was observed: AIDS mortality was most common between 1999-2009 (n = 952; MR, 4.2/1000 PYFU; 95% CI, 4.0-4.5) and non-AIDS-defining malignancy (NADM) between 2010-2020 (n = 444; MR, 2.8/1000 PYFU; 95% CI, 2.5-3.1). In multivariable analysis, all-cause mortality declined (adjusted mortality rate ratio [aMRR], 0.97 per year; 95% CI, .96-.98), mostly 1999-2010 (aMRR, 0.96 per year; 95% CI, .95-.97) but was stable 2011-2020 (aMRR, 1.00 per year; 95% CI, .96-1.05). Mortality due to all known causes except NADM also declined. Mortality among people with HIV in the D:A:D and/or RESPOND cohorts declined between 1999-2009 and was stable over the period 2010-2020. This decline in mortality was not fully explained by improvements in immunologic-virologic status or other risk factors.
BackgroundMaternal pertussis vaccination with Tdap vaccine is recommended to protect newborns from severe postnatal infection. HIV-exposed uninfected (HEU) infants have a higher incidence of pertussis infection and may particularly benefit from maternal immunization. The impact of HIV infection on the quality of IgG and memory B cell (MBC) responses to Tdap vaccination in pregnant women (PW) living with HIV (PWH) is unknown.MethodsIn this observational study, humoral immune responses to Tdap vaccination, including IgG levels, Fc-dependent effector functions, and MBC frequencies, were measured before and after vaccination in 40 PWH and 42 HIV-uninfected PW. Placental transfer of IgG and avidity were assessed in cord blood (CB). Soluble and cellular immune activation markers were quantified at baseline.FindingsOne month after vaccination, PWH had lower frequencies of MBC compared with HIV-uninfected PW. At delivery, PWH had attenuated pertussis-specific IgG levels and Fc-dependent effector functions. Reduced levels of maternal vaccine polyfunctional IgG and IgG avidity were transferred to HEU as compared to HIV-unexposed newborns. After adjustment with ethnicity, maternal antibody levels and gestational age at vaccination, HIV infection was independently associated with decreased levels of PT specific-IgG in CB. Both maternal and neonatal pertussis-specific IgG responses as well as PT-specific IgG avidity were inversely correlated with maternal sCD14 levels before vaccination among PWH.InterpretationMaternal HIV infection is associated with attenuated humoral immune responses to Tdap vaccination that correlate with sCD14. Suboptimal transfer of maternal immunity may further increase the risk of severe pertussis infection in HEU infants.FundingThis work was supported by IRIS Fund managed by the Foundation Roi Baudouin [2017J1820690206902], Association Vésale pour la Recherche Médicale and the Medical Council of CHU Saint-Pierre and has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, under Award No. U19AI145825. N.D. is a clinical researcher and A.M. is Research Director at the Fonds de la Recherche Scientifique (F.R.S.-FNRS), Belgium. M.E.A. was partially supported by NIH NIAID 1U19AI14825. This article is published with the support of the Fondation Universitaire of Belgium.
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