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Whether the epidemiological association between antiretroviral therapy and increased blood pressure is of a causal nature remains largely unknown. The transition from association to causation could represent a fundamental step for taking preventive measures against hypertension and its untoward effects. Such preventive measures are especially crucial for people living with HIV in sub-Saharan African countries, where HIV is most widespread, trends in cardiovascular disease risk factors are rising persistently, and antiretroviral treatment coverage rates are rapidly increasing. Aims and objectives • To review the evidence for the epidemiological associations of antiretroviral therapy with increased blood pressure and other cardiovascular disease risk factors, and to obtain comprehensive estimates of the strengths of these associations in people living with HIV worldwide (Evidence synthesis). • To examine the epidemiological association between antiretroviral therapy and increased blood pressure using Hill’s criteria of causation (mini-review). • To investigate a plausible causal link between antiretroviral therapy and increased blood pressure among HIV-infected patients in a sub-Saharan setting using appropriate statistical methods (primary data analysis). Methods Evidence synthesis: A series of systematic reviews with meta-analyses were conducted to examine the associations of antiretroviral therapy with cardiovascular disease risk factors. Studies were sought from electronic databases and cross-references of relevant articles. Studies in which blood pressure and other cardio-metabolic outcomes were compared between HIV-infected adults naïve and exposed to antiretroviral therapy were eligible for the meta-analyses. The data from these studies were combined using random-effects meta-analyses to obtain pooled estimates of the associations between antiretroviral therapy and each cardio-metabolic outcome. Mini-review: Each of Hill’s criteria of causation was examined separately with regards to the association between antiretroviral therapy and increased blood pressure. Primary data analysis: Four hundred and six HIV-infected adults―306 antiretroviral-exposed and 100 antiretroviral-naïve―were recruited from a tertiary HIV clinic in semi-urban Nigeria between August and November 2014 as part of a cross-sectional study. To assess if antiretroviral therapy improves the prediction of hypertension, candidate logistic regression models for predicting hypertension were compared using Nagelkerke’s R2 and parameter estimates. Structural equation models were fitted to determine the indirect effects of antiretroviral therapy on blood pressure through body mass index, waist circumference, blood glucose level, and sleep quality, while controlling for socio-demographic and clinical characteristics. A propensity score matching model was fitted to examine the average treatment effects on the treated (ATT) of antiretroviral therapy on systolic and diastolic blood pressure. Results Evidence synthesis: Ninety-one observational studies comprising data for 83,669 HIV-infected patients were included in the meta-analyses. Cardio-metabolic measures were significantly higher among antiretroviral-exposed patients, compared to their naïve counterparts as shown in the forest plots below: Summary estimates of the pooled associations between antiretroviral therapy and cardio-metabolic outcomes (continuous) ART, antiretroviral therapy; CI, confidence interval; N, number of studies included in the meta-analyses. Summary plot shows ART is significantly associated with increases in all cardio-metabolic outcome measures. Summary estimates of the pooled associations between antiretroviral therapy and cardio-metabolic outcomes (categorical) CI, confidence interval; N, number of studies included in the meta-analyses. With the exception of combined overweight/obesity, ART is significantly associated with increased risk of cardio-metabolic disorders. Mini-review: The association between antiretroviral therapy and increased blood pressure fulfilled all of Hill’s criteria of causation, with the exception of ‘specificity’. Nonetheless, one would not expect the exposure to be specific in the context of a multifactorial condition, such as high blood pressure. Primary data analysis: Of 400 HIV-infected patients with reported hypertension status, 60 (15%) were diagnosed as hypertensive. Other important findings of primary data analysis include the following: • Without considering antiretroviral treatment status, the best parsimonious model for predicting hypertension comprised age, body mass index, family history of hypertension, and sleep quality (R2 = 0.265). The extent to which these variables fit within the predictive model was improved slightly when antiretroviral treatment status was included (R2 = 0.274). • The indirect effects of antiretroviral therapy on systolic (coefficient = 0.94, 95% CI = 0.73 to 2.43) and diastolic blood pressure (coefficient = 0.64, 95% CI = 0.16 to 2.09) through waist circumference remained statistically significant after adjusting for age, sex, lifestyle factors, CD4 cell count, and HIV infection duration. • After propensity score-matching, 25% of the initial population sample were dropped, so that 229 patients on antiretroviral therapy were matched to 74 antiretroviral-naïve patients. In this propensity score-matched sample, the estimated ATT of the effects of antiretroviral therapy on systolic (7.85 mmHg, 95% CI = 3.72 to 15.68) and diastolic blood pressure (7.45 mmHg, 95% CI = 4.99 to 13.61) remained statistically significant after achieving a balanced distribution of baseline covariates between antiretroviral-naïve and exposed patients. Conclusion Overall, antiretroviral therapy is potentially the single most consistent correlate of high blood pressure (and other cardiovascular disease risk factors) in people living with HIV. These findings also suggest a high probability that the epidemiological association between antiretroviral therapy and increased blood pressure may be causal. People living with HIV in sub-Saharan African countries may benefit from regular hypertension screening and other cardiovascular risk assessments after the commencement of antiretroviral therapy. Future studies should identify what phenotypes on the HIV clinical spectrum are most susceptible to the effects of antiretroviral therapy on blood pressure and other cardio-metabolic parameters, as well as the efficacies of targeted iinterventions on these phenotypes. |
