Cardioprotective effects of early versus late initiated antiretroviral treatment in adolescents with perinatal HIV-1 infection.

Whether, and how, cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) vary with age at treatment initiation is unknown. We used magnetic resonance imaging to compare cardiac status between APHIV initiated on ART at < 5 years of age (early ART, n = 37) and ≥ 5 years of age (delayed ART, n = 34) versus HIV-uninfected peers (n = 21), reporting z-score mean differences adjusted for confounders. Relative to HIV-uninfected adolescents, APHIV with early ART had higher left ventricular (LV) global circumferential strain (GCS) [adjusted mean (95%CI) z-score: 0.53 (0.13, 0.92)] and maximum indexed left atrium volume (LAVi) [adjusted z-score: 0.55 (0.08, 1.02)]. In contrast, APHIV with delayed ART had greater indexed LV end-diastolic volume (LVEDVi) [adjusted z-score: 0.47 (0.09, 0.86)] and extracellular volume fraction [adjusted z-score: 0.79 (0.20, 1.37)], but lower GCS [adjusted z-score: -0.51 (-0.91, -0.10)] than HIV-uninfected peers. APHIV had distinct albeit subclinical cardiac phenotypes depending on ART initiation age. Changes in early ART suggested comparatively worse diastology with preserved systolic function while delayed ART was associated with comparatively increased diffuse fibrosis and LV dilatation with reduced systolic function. The long-term clinical significance of these changes remains to be determined.

Effect of prior tuberculosis on cardiovascular status in perinatally HIV-1-infected adolescents.

Whether, and how, co-occurring HIV-1 infection (HIV) and tuberculosis (TB) impact cardiovascular status, especially in adolescents with perinatally acquired HIV (APHIV), have not been examined. We hypothesized that APHIV with previous active TB have worse cardiac efficiency than APHIV without TB, which is mediated by increased inflammation. Arterial elastance (Ea) and ventricular end-systolic elastance (Ees) were assessed by cardiovascular magnetic resonance, and ventriculoarterial coupling (VAC) estimated as Ea/Ees ratio. Inflammation was measured by high sensitivity C-reactive protein (hsCRP). Previous TB in APHIV was associated with reduced cardiac efficiency, related to an altered ventriculoarterial coupling. However, we did not find evidence of hsCRP mediated effects in the association between prior TB and cardiac efficiency. The clinical significance of these findings requires further study, including a wider range of biomarkers of specific immune pathways.

Cardioprotective effects of antiretroviral treatment in adolescents with perinatal HIV infection are heterogeneous depending on age at treatment initiation.

The cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) may depend on age at ART initiation. We used cardiovascular magnetic resonance (CMR) to characterize and compare residual cardiac changes in apparently healthy APHIV with early and delayed ART initiation compared to sex- and age-similar HIV uninfected peers. We defined early and delayed ART as, respectively, treatment initiated at <5 years and ≥5 years of age. Cardiac function, mechanical deformation, geometry and tissue composition were assessed. APHIV had distinct albeit subclinical cardiac phenotypes depending on timing of ART initiation. For example, changes in early ART suggested comparatively worse diastology with preserved systolic function while delayed ART was associated with comparatively increased diffuse fibrosis and LV dilatation with reduced systolic function. The long-term clinical significance of these changes remains to be determined.

Identifying sex-specific anthropometric measures and thresholds for dysglycemia screening in an HIV-endemic rural South African population.

Valid screening and diagnostic algorithms are needed to achieve 2030 targets proposed by the WHO's Global Diabetes Compact. We explored anthropometric thresholds to optimally screen and refer individuals for diabetes testing in rural South Africa. We evaluated screening thresholds for waist circumference (WC), body mass index (BMI), and waist-hip ratio (WHR) to detect dysglycemia based on a glycated hemoglobin (HbA1C) ≥6.5% among adults in a population-based study in South Africa using weighted, non-parametric ROC regression analyses. We then assessed the diagnostic validity of traditional obesity thresholds, explored optimal thresholds for this population, and fit models stratified by sex, age, and HIV status. The prevalence of dysglycemia in the total study population (n = 17,846) was 7.7%. WC had greater discriminatory capacity than WHR to detect dysglycemia in men (p-value<0.001) and women (p<0.001). WC had greater discriminatory capacity than BMI to detect dysglycemia in women (p<0.001). However, BMI and WC performed similarly for men (p = 0.589). Whereas traditional WC thresholds for women (>81cm) performed well (sensitivity 91%, positive predictive value [PPV] 14.9%), substantially lower thresholds were needed to achieve acceptable sensitivity and PPV among men (traditional >94cm, derived >79.5cm). WC outperforms BMI as an anthropometric screening measure for dysglycemia in rural South Africa. Whereas WC guideline thresholds are appropriate for women, male-derived WC cutoffs performed better at lower thresholds. In this rural South African population, thresholds that maximize specificity and PPV for efficient resource allocation may be preferred.

Left ventricular remodeling and its correlates among adolescents with perinatally acquired HIV in South Africa.

BACKGROUND: Left ventricular (LV) remodeling and its transitions from compensatory adaptations to LV dysfunction have not been examined in adolescents with perinatally acquired HIV infection (PHIV). We used cardiovascular magnetic resonance (CMR) in a cross-sectional study to characterize PHIV-related progressive LV remodeling in adolescents in South Africa. METHODS: Adolescents with PHIV on antiretroviral treatment and their HIV uninfected peers completed 3 T CMR examination. We defined LV remodeling by LV mass/volume (M/V) ratio, modelling progressive LV remodeling as increasing M/V ratio. Linear regression models were applied to estimate the correlates of progressive LV remodeling. RESULTS: Overall, 71 adolescents with PHIV [mean age: 15.2 years; 54% male] and 36 HIV uninfected [15.1 years; 42% male] peers were enrolled. Adolescents with PHIV had lower mean LV M/V ratio (0.68 vs. 0.75 g/mL; p = 0.004) than HIV uninfected peers, without LV hypertrophy in either group. Among adolescents with PHIV, increasing M/V ratio was accompanied by increasing interstitial volume [adjusted mean change (AMC) per 0.1 g/mL M/V ratio: 1.75 mL, p < 0.001] with no change in global circumferential strain (GCS) [AMC per 0.1 g/mL M/V ratio: -0.21%, p = 0.48]. However, in HIV uninfected individuals, increasing M/V ratio was accompanied by increasing peak GCS [AMC per 0.1 g/mL M/V ratio: -1.25%, p = 0.039] with no change in interstitial volume (AMC per 0.1 g/mL M/V ratio: 1.16 mL, p = 0.32]. CONCLUSIONS: Successfully treated PHIV is associated with less severe LV remodeling in adolescence when compared to HIV uninfected controls. LV remodeling in PHIV is associated with disproportionate expansion of the non-contractile interstitium not accompanied by improved GCS.

Association between prior tuberculosis disease and dysglycemia within an HIV-endemic, rural South African population.

OBJECTIVE: Tuberculosis (TB) may predispose individuals to the development of diabetes. Such a relationship could have an outsized impact in high-prevalence TB settings. However, few studies have explored this relationship in populations heavily burdened by diabetes and TB. METHODS: We analyzed data from a community-based population cohort that enrolled adults in rural South Africa. Individuals were considered to have prior TB if they self-reported a history of TB treatment. We fitted sex-specific logistic regression models, adjusted for potential clinical and demographic confounders, to estimate relationships between dysglycemia (HBA1c ≥6.5%) and prior TB. Propensity score-matched cohorts accounted for the differential age distributions between comparator groups. We examined the interactions between sex, prior TB, and HIV status. RESULTS: In the analytic cohort (n = 17,593), the prevalence of prior TB was 13.8% among men and 10.7% among women. Dysglycemia was found in 9.1% of the population, and HIV prevalence was 34.0%. We found no difference in dysglycemia prevalence by prior TB (men OR 0.96, 95% CI 0.60-1.56: women OR 1.05, 95% CI 0.79-1.39). However, there was a qualitative interaction by HIV serostatus, such that among men without HIV, those with a history of TB had a greater prevalence of dysglycemia than those without prior TB (10.1% vs. 4.6%, p = 0.0077). An inverse relationship was observed among men living with HIV (prior TB 3.3% vs. no TB 7.3%, p = 0.0073). CONCLUSIONS: Treated TB disease was not associated with dysglycemia in an HIV-endemic, rural South African population. However, we found a significant interaction between prior TB and HIV status among men, suggesting distinct pathophysiological mechanisms between the two infections that may impact glucose metabolism. Longitudinal studies are needed to better establish a causal effect and underlying mechanisms related to resolved TB, HIV, and diabetes.

Association between HIV and Prevalent Hypertension and Diabetes Mellitus in South Africa: Analysis of a Nationally Representative Cross-Sectional Survey.

OBJECTIVES: Cardiovascular disease (CVD) burden is increasing among persons living with HIV (PLWH) in sub-Saharan Africa. It is unclear whether this reflects absolute increase in HIV-related CVD risk or unmasking by improved survival. Therefore, we examined whether HIV is associated with adverse cardiometabolic profiles among South African adults. METHODS: We analyzed a nationally representative dataset (n=6420), estimating the weighted prevalence of hypertension, diabetes, and 10-year predicted risk of incident fatal/nonfatal CVD (if aged ≥40 years). Associations between HIV and cardiometabolic indices were assessed using log-binomial regression models adjusted for sociodemographic factors. RESULTS: HIV population prevalence was 18.9%, with a median age of 36 years. Hypertension (44.2% vs 45.4%), diabetes (18.6% vs 20.4%), and overweight/obesity (body mass index ≥25 kg/m2: 54.9% vs 52.0%) prevalence did not substantially differ by HIV status, although PLWH had a lower 10-year predicted CVD risk (median: 5.1% vs 13.5%). In adjusted models, females who are HIV-negative had a 5 mm Hg higher median systolic blood pressure (128 vs 123 mmHg) than female PLWH. CONCLUSIONS: PLWH in South Africa have better cardiometabolic disease profiles than the general population, and social determinants, rather than HIV, may have a greater influence on cardiometabolic risk. Designating PLWH a CVD high-risk group in South Africa is likely unwarranted.

Linkage to HIV care and hypertension and diabetes control in rural South Africa: Results from the population-based Vukuzazi Study.

Non-communicable diseases (NCDs) account for half of all deaths in South Africa, partly reflecting unmet NCDs healthcare needs. Leveraging existing HIV infrastructure is touted as a strategy to alleviate this chronic care gap. We evaluated whether HIV care platforms are associated with improved NCDs care. We conducted a community-based screening of adults in rural KwaZulu-Natal, collecting BP, HbA1c, and health services utilization data. Care cascade indicators for hypertension and diabetes mellitus were defined as: 1) aware, if previously diagnosed, 2) in care, if seeing a provider within last 6 months; 3) treated, if reporting medication use within preceding 2 weeks; and 4) controlled, if BP<140/90mmHg or HbA1c<6.5%. We fit multivariable adjusted logistic regression models to compare successful completion of each step of the care cascade for hypertension and diabetes between people with virally suppressed HIV and HIV-negative comparators. Inverse probability sampling weights were applied to derive population-level estimates. The analytic sample included 4,933 individuals [mean age 58.4 years; 77% female]. Compared to being HIV-negative, having suppressed HIV was associated with lower adjusted prevalence of being aware (-6.0% [95% CI: -11.0, -1.1%]), in care (-5.7% [-10.6, -0.8%]), and in treatment (-4.8% [-9.7, 0.1%]) for diabetes; but higher adjusted prevalence of controlled diabetes (3.2% [0.2-6.2%]). In contrast, having suppressed HIV was associated with higher adjusted prevalence of being aware (7.4% [5.3-9.6%]), in care (8.0% [5.9-10.2%]), in treatment (8.4% [6.1-10.6%]) and controlled (9.0% [6.2-11.8%]), for hypertension. Overall, disease control was achieved for 40.0% (38.6-40.8%) and 6.8% (5.9-7.8%) of individuals with hypertension and diabetes, respectively. Engagement in HIV care in rural KwaZulu-Natal was generally associated with worse diabetes care and improved hypertension care. While further work should explore how success of HIV programs can be translated to NCD care, strengthening of primary healthcare will also be needed to respond to the growing NCDs epidemic.

Prevention of cardiovascular disease among people living with HIV in sub-Saharan Africa.

As longevity has increased for people living with HIV (PLWH) in the United States and Europe, there has been a concomitant increase in the prevalence of cardiovascular disease (CVD) risk factors and morbidity in this population. Whereas the availability of HIV antiretroviral therapy has resulted in dramatic increases in life expectancy in sub-Saharan Africa (SSA), where over two thirds of PLWH reside, if and how these trends impact the epidemiology of CVD is less clear. In this review, we describe the current state of the science on how both HIV and its treatment impact CVD risk factors and outcomes among PLWH in sub-Saharan Africa, including regional factors (unique to SSA) likely to differentiate these relationships from the global North. We then outline how current regional guidelines address CVD prevention among PLWH and which clinical and structural interventions are best poised to confront the co-epidemics of HIV and CVD in the region. We conclude with a discussion of key research gaps that need to be addressed to optimally develop an actionable public health response.

Female sex and cardiovascular disease risk in rural Uganda: a cross-sectional, population-based study.

BACKGROUND: Sex-based differences in cardiovascular disease (CVD) burden are widely acknowledged, with male sex considered a risk factor in high-income settings. However, these relationships have not been examined in sub-Saharan Africa (SSA). We aimed to apply the American Heart Association (AHA) ideal cardiovascular health (CVH) tool modified by the addition of C-reactive protein (CRP) to examine potential sex-based differences in the prevalence of CVD risk in rural Uganda. METHODS: In a cross-sectional study nested within a population-wide census, 857 community-living adults completed physical and laboratory-based assessments to calculate individual ideal CVH metrics including an eight category for CRP levels. We summarized sex-specific ideal CVH indices, fitting ordinal logistic regression models to identify correlates of improving CVH. As secondary outcomes, we assessed subscales of ideal CVH behaviours and factors. Models included inverse probability of sampling weights to determine population-level estimates. RESULTS: The weighted-population mean age was 39.2 (1.2) years with 52.0 (3.7) % females. Women had ideal scores in smoking (80.4% vs. 68.0%; p < 0.001) and dietary intake (26.7% vs. 16.8%; p = 0.037) versus men, but the opposite in body mass index (47.3% vs. 84.4%; p < 0.001), glycated hemoglobin (87.4% vs. 95.2%; p = 0.001), total cholesterol (80.2% vs. 85.0%; p = 0.039) and CRP (30.8% vs. 49.7%; p = 0.009). Overall, significantly more men than women were classified as having optimal cardiovascular health (6-8 metrics attaining ideal level) (39.7% vs. 29.0%; p = 0.025). In adjusted models, female sex was correlated with lower CVH health factors sub-scales but higher ideal CVH behaviors. CONCLUSIONS: Contrary to findings in much of the world, female sex in rural SSA is associated with worse ideal CVH profiles, despite women having better indices for ideal CVH behaviors. Future work should assess the potential role of socio-behavioural sex-specific risk factors for ideal CVH in SSA, and better define the downstream consequences of these differences.

Population Prevalence and Correlates of Prolonged QT Interval: Cross-Sectional, Population-Based Study From Rural Uganda.

OBJECTIVES: We aimed to estimate the prevalence and correlates of QT interval prolongation in rural Uganda. BACKGROUND: Major electrocardiographic abnormalities, including prolonged QT interval, have been shown to be independently predictive of adverse cardiovascular events among Western populations. Cardiovascular diseases are on the rise in sub-Saharan Africa with poorly characterized context-specific risk factors. An important question is whether ECG screening might have value in cardiovascular disease risk stratification in SSA. METHODS: We conducted a cross-sectional survey in a sample of adults participating in an ongoing whole-population cohort in Mbarara, Uganda, in 2015. Of 1,814 subjects enrolled in the parent whole-population cohort, 856 (47%) participated in the study. Participants completed 12-lead electrocardiography and cardiovascular disease risk factors assessment. We summarized sex-specific, heart rate variation-adjusted QT (QTa) defining prolonged QTa as >460 ms in women and >450 ms in men. We fit linear and logistic regression models to estimate correlates of (continuous) QTa interval length and (dichotomous) prolonged QTa. Models included inverse probability of sampling weights to generate population-level estimates accounting for study nonparticipation. RESULTS: We assessed data from 828 participants with electrocardiograms. The weighted population mean age was 38.4 years (95% confidence interval: 36.3-40.4). The weighted population was 50.4% female, 11.5% had elevated blood pressure, and 57.6% had a high-sensitivity C-reactive protein >1 mg/dl. The population mean QTa was 409.1 ms (95% confidence interval: 405.1-413.1), and 10.3% (95% confidence interval: 7.8-13.5) met criteria for prolonged QTa. Women had a higher mean QTa (421.6 ms vs. 396.3 ms; p < 0.001), and a higher proportion of women had a prolonged QTa (14.0% vs. 9.3%; p = 0.122) than did men. In multivariable-adjusted regression models, female sex and hypertension correlated with higher mean QTa and meeting criteria for prolonged QTa, respectively. CONCLUSIONS: QT interval prolongation is highly prevalent in rural Uganda and may be more common than in high-income settings. Female sex, age, and high blood pressure correlated with QT interval prolongation. Future work should assess whether genetic predisposition or environmental factors in sub-Saharan African populations contribute to prolonged QT and clarify consequences.

Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α antagonists as first-line biologic agents. We determined the overall treatment effect of Th17 pathway inhibitors compared to placebo or active control on American College of Rheumatology (ACR) 20 response at week 12 (primary objective), risk of infections, discontinuation of treatment due to adverse events, and serious adverse events during the placebo-controlled period (12-24 weeks) in adults with active PsA in published randomized controlled trials. METHODS: The SCOPUS database was searched. The Cochrane risk of bias tool was used for assessing quality. The pooled relative risk (RR) was derived from random effects models. RESULTS: Seven randomized controlled trials were included which randomized 1,718 patients to Th17 inhibitors and 840 to placebo. Patients treated with Th17 inhibitors had an RR of 2.04 (95% CI: 1.79-2.33; p < 0.001) for achieving an ACR20 response at week 12 (I2 = 0%; p = 0.89) compared to placebo-treated patients. There was no evidence of publication bias. The result was consistent for study phase and outcome (ACR50/70), mechanism of action and TNF-α naivety. RR of infections was 1.06 (0.91-1.23), that of candida infections was 3.35 (0.75-14.95), that of serious adverse events was 0.82 (0.42-1.59) and that of discontinuation of treatment was 0.54 (0.31-0.93) among treated versus placebo subjects. No incident cases of tuberculosis were reported. CONCLUSION: In patients with active PsA, biologics targeting the Th17 axis produce a clinically significant improvement in joint disease activity with acceptable safety and tolerability for short-term treatment compared to placebo.

A cross-sectional, facility based study of comorbid non-communicable diseases among adults living with HIV infection in Zimbabwe.

BACKGROUND: Increased antiretroviral therapy uptake in sub-Saharan Africa has resulted in improved survival of the infected. Opportunistic infections are declining as leading causes of morbidity and mortality. Though comprehensive data are lacking, concern has been raised about the rapid emergence of non-communicable diseases (NCDs) in the African HIV care setting. We therefore set out to characterise the NCD/HIV burden among adults living and ageing with HIV infection in Zimbabwe. METHODS: We conducted a cross-sectional study among patients receiving care in a public sector facility. We reviewed patient records and determined the prevalence of comorbid and multi-morbid NCDs. Associations with patient characteristics were evaluated using univariate and multi-variate logistic regression modelling. Significance testing was done using 2-sided p values and 95 % confidence intervals calculated. RESULTS: We recruited 1033 participants. 31 % were men. Significant gender differences included: older median age, more advanced disease at baseline, and greater use of stavudine and protease inhibitor containing regimens in men compared to women. The prevalence of comorbidity and multi-morbidity were, respectively, 15.3 % (95 % CI 13.3-17.7 %) and 4.5 % (95 % CI 3.4-6.0 %). Women had higher rates than men of both co-morbidity and multi-morbid ity: 21.8 vs. 14.9 %; p = 0.010 and 5.3 vs. 2.9 %; p = 0.025 respectively. The commonly observed individual NCDs were hypertension [10.2 %; (95 % CI 8.4-12.2 %)], asthma [4.3 % (95 % CI 3.1-5.8 %)], type 2 diabetes mellitus [2.1 % (95 % CI 1.3-3.2 %)], cancer [1.8 % (95 % CI 1.1-2.8 %)], and congestive cardiac failure [1.5 % (95 % CI 0.9-2.5 %)]. After adjusting for confounding, only age categories 45-≤55 years (AOR 2.25; 95 % CI 1.37-3.69) and >55 years (AOR 5.42; 95 % CI 3.17-9.26), and female gender (AOR 2.12; 95 % CI 1.45-3.11) remained significantly and strongly associated with comorbidity risk. CONCLUSIONS: We found a substantial burden of comorbid non-communicable diseases among HIV infected patients in a high HIV and low-income setting. Integrating non-communicable diseases care, including active screening, with HIV care is recommended.