Traditional and HIV-specific risk factors for cardiovascular morbidity and mortality among HIV-infected adults in Brazil: a retrospective cohort study

With successful antiretroviral therapy (ART), HIV infection has been transformed into a chronic disease [1]. Worldwide and in Brazil, AIDS-related morbidity and mortality has declined, whereas the burden of non-communicable diseases, such as cardiovascular disease (CVD), has increased [2‐6]. Specifically, CVD risk is up to two-fold higher among HIV-infected persons compared with HIV-uninfected individuals, even after adjusting for traditional CVD risk factors [7‐9]. And, while higher frequencies of traditional CVD risk factors have been reported in HIV-infected persons, the impact of HIV on CVD is most prominent in traditionally low-risk demographic groups [10‐13], suggesting CVD risk in treated HIV infection may also be mediated by non-traditional factors.

In Brazil, CVD incidence has risen more rapidly among HIV-infected persons than the general population [14], and hospitalization costs for myocardial infarctions have surpassed those for AIDS-related illnesses [15]. However, the dual burden of CVD and HIV in low- and middle-income countries is understudied [16, 17]. Discerning modifiable CVD risk factors in treated HIV infection may help prevent and treat CVD, reducing disease burden and health system costs while improving quality of life.

While ART is critical to successful control of HIV infection, several observational studies have reported associations between specific antiretroviral agents and increased CVD risk [18‐24]. Data are conflicting, however, and the evidence is predominantly derived from U.S. and European cohorts, whose relevance to low- and middle-income countries that routinely use ART with poorer metabolic profiles remains unclear. Understanding whether commonly used ART regimens may be contributing to CVD risk is a critical component of long-term HIV management that may both inform global ART guidelines and improve clinical practice in resource-limited settings. This analysis aims to define traditional and HIV-specific risk factors for CVD in a large cohort of HIV-infected adults on ART in Rio de Janeiro, Brazil, including whether specific antiretroviral agents and classes confer additional risk of CVD morbidity and mortality.

We sought to clarify the link between traditional and HIV-specific risk factors and cardiovascular morbidity and mortality in a large, well-characterized cohort of HIV-infected adults on ART in a middle-income country. We observed a significant burden of traditional CVD risk factors compared with the general Brazilian population [31]. Notably, our cohort was young relative to previously-studied cohorts, with 61 % under 40 years of age [22, 23]. Similarly, although age 40 and over was associated with increased CVD event risk in multivariate analysis, 41 % of events occurred in persons less than 40 years of age (IR, 4.46 per 1000 PY; 95 % CI, 3.33–5.98). Additionally, 61 % of participants had at least one traditional CVD risk factor. While these rates are comparable to other studies of HIV-infected persons in Brazil and Latin America [32, 33], the risk factor burden for age is greater than previously observed CVD risk factor frequencies in the United States and Europe [22, 24, 34, 35].

HIV-specific risk factors were more strongly associated with incident CVD morbidity and mortality than traditional CVD risk factors, including nadir CD4⁺ T lymphocyte count ≤50 cells/mm³ and detectable HIV-1 RNA in the year prior to the event. These factors remained independently associated with incident CVD after controlling for time on ART, consistent with literature citing low nadir CD4⁺ T lymphocyte count and ongoing HIV replication as risk factors for CVD [36‐39], but countering the belief that traditional CVD risk factors account for the majority of CVD risk in the setting of HIV infection [40]. Even though ART is universally available through Brazil’s public health system at no cost, late diagnosis remains a problem, as evidenced by low nadir CD4⁺ T lymphocyte counts [41]. Moreover, virologic suppression rates were sub-optimal at 60 %, and poorer adherence may be related to the toxicity of the available first and second line regimens [42].

Low nadir CD4⁺ T lymphocyte count and ongoing HIV replication are linked to chronic immune activation and inflammation in HIV-infected persons, contributing to atherosclerosis development via HIV-mediated endothelial injury and the promotion of a pro-thrombotic state [43]. Even though venous thromboembolism may traditionally be viewed as a distinct pathophysiologic entity from atherosclerotic CVD, there is an increasing body of evidence suggesting that patients with unprovoked venous thromboembolism are at a higher risk of arterial cardiovascular events than matched controls, and that venous and arterial thrombosis may instead be “two aspects of the same disease” [44‐47]. The seemingly bi-directional relationship between coagulation and inflammation becomes significant in HIV infection since, in addition to a two-fold increased risk of myocardial infarction (MI), patients infected with HIV are at a two-to-ten-fold increased risk for a venous thromboembolic event [48‐51]. Interestingly, levels of pro-thrombotic monocyte and tissue factor activation in HIV-infected persons with uncontrolled viremia mirror levels in HIV-uninfected persons experiencing acute coronary syndrome [52]. And, although some biomarkers of inflammation and immune activation decrease significantly with ART-induced virologic suppression, residual monocyte/macrophage activation persists and independently predicts mortality and disease burden in this population [53‐59]. In light of the potential pathophysiologic link between these disease states, particularly in the chronic inflammatory state of HIV infection, the inclusion of thromboembolic events is a unique strength of this study.

We also examined associations between ART exposure during the study period and the risk of CVD events. Cumulative NRTI, NNRTI, and/or PI exposure were associated with a 12–23 % decreased CVD event incidence per additional year of exposure. Cumulative tenofovir and atazanavir use had the strongest associations, and these associations persisted both when hospitalizations and deaths were analyzed separately and when recent use was examined. In contrast, recent stavudine, nevirapine, high-dose ritonavir, unboosted nelfinavir, and unboosted indinavir exposure were associated with increased CVD event incidence. Neither cumulative nor recent abacavir exposure were significantly associated with CVD event incidence, although only 7 % of participants had abacavir exposure due to the high cost of HLA B5701 testing and the lack of generic formulations in Brazil. Our findings are in contrast to prior observational studies that detected an association between PI use and CVD [19, 23, 60‐62]. Additionally, the D:A:D study group reported an increased risk of MI associated with cumulative indinavir and lopinavir-ritonavir exposure, as well as recent abacavir and didanosine exposure [20, 22]. Since then, results regarding CVD risk and abacavir and other ART exposure have been conflicting [24, 34, 35, 63, 64]. Interestingly, recently published data from the Swiss Cohort suggests that risk from recent abacavir exposure may confer cumulative risk, but only for a limited period, with exposure during the past six to 36 months causing the greatest increase in risk [65]. Coupled with their finding of a rapid early harmful effect for didanosine followed by a protective effect, these results suggest that there may be different processes mediating ART-associated CVD risk that are drug-specific [65].

This cohort differs from previously studied U.S. and European cohorts in that it is from a developing country setting with universal access to ART, but with a limited choice of agents that differs from what is commonly used in higher income settings. Until 2013, a zidovudine (AZT) backbone was the standard first line therapy, typically with lamivudine. Alternatives to AZT were didanosine or tenofovir. Abacavir was, and remains, rarely used due to its higher cost relative to other NRTIs, as is the case for emitricitabine. First line ART remains primarily NNRTI-based, with efavirenz being the preferred NNRTI, although PI use is allowed and commonly used as second line therapy. Lopinavir/ritonavir is the first choice PI, and atazanavir/ritonavir can be used as an optional PI. Third line and salvage therapy are also available and mostly based on agents such as darunavir, raltegravir, etravirine and enfuvirtide. The availability of such drugs has been expanded along the years, according to their availability in the market and their affordability in the Brazilian public health system. These results stress the importance of enhancing access to ART regimens with improved metabolic profiles as first and second line treatment in low- and middle-income settings, especially in the context of advanced HIV disease.

This study has several limitations, most significantly its observational design, which limited our ability to control for unknown sources of confounding and bias. Known sources of confounding were controlled for whenever possible, and treatment selection bias was minimized as physicians must prescribe in accordance with algorithmic Brazilian HIV treatment guidelines. We could not fully account for the effects of chronic kidney disease as time-updated glomerular filtration rates were not available. BMI was not available for all participants, and standardized screening was not present for family and social history variables, including substance use. Although we were not able to control for obesity due to missing BMI data, we observed a trend towards increased risk of CVD events with lower BMI (data not shown), and this trend remained consistent when weight tertiles were used. We were not able to control for concurrent ART use in our models given the limited number of events, and we were underpowered to fully discern sex differences in CVD risk (although our analysis included 35 % women). We only captured hospitalizations at the INI hospital, which could underestimate CVD morbidity in this cohort. However, as one of the largest public health reference centers for HIV care and research in Rio de Janeiro, it is also the hospital that HIV-infected persons experiencing serious hospitalizations are referred to, minimizing missing data due to hospitalizations outside of INI. It is important to note that the hospital is located within the same campus as ambulatory care and that patients’ records are linked by a unique ID. While only 10 % of the hospitalizations were randomly reviewed for adjudication, given the high observed agreement, no further quality control comparisons were conducted. Similarly, given that the Rio de Janeiro State mortality database routinely tracks vital statistics on all residents, the loss to follow up in this cohort is expected to be minimal. Lastly, evaluating the contribution of specific ART agents and classes to CVD risk is complicated by the fact that regimens typically include three or more agents, regimen changes are common, and ART use is inherently linked to virologic suppression. Important strengths of this study include the well-characterized nature of this cohort, its diversity of race and sex, use of both hospitalization and death data, and the characterization of acute CVD events beyond myocardial infarctions.

Our data are the first to evaluate the association between HIV infection and ART exposure with CVD risk in Latin America. CVD in treated HIV infection is an increasingly prevalent comorbidity whose origins are not fully understood; however, traditional CVD and HIV-specific risk factors must both be considered as prevention and treatment strategies are developed. We found that traditional, virological and immunological risk factors all strongly predicted incident CVD, with ART use and subsequent virologic suppression generally associated with a decreased incidence of CVD events. Our findings support other literature suggesting an overall benefit of ART (and subsequent virologic suppression) on CVD risk [66‐69]; however, our data are unique in that they document CVD events occurring in a young population with a high traditional CVD risk burden, supporting resource allocation towards risk factor reduction efforts at all ages to prevent CVD events in HIV-infected persons. Our data also highlight the importance of early HIV diagnosis and treatment, as well as the need for availability of metabolically-neutral first- and second-line ART in resource-limited settings.