Patients with HIV exposed to abacavir may have an increased risk of cardiovascular disease. There is debate whether this association arises because of a channelling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. The effect of exposure to abacavir on the risk of cardiovascular disease events was assessed in the Swiss HIV Cohort Study. A new marginal structural Cox model was used to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and cardiovascular disease. Cardiovascular disease event was defined as the first occurrence of either a myocardial infarction, an invasive cardiovascular procedure or a cardiovascular related death. Each event was documented. Follow-up was divided into consecutive one-month periods. Multivariate models were adjusted on time-fixed covariates for demographic characteristics (age, sex, likely transmission through injection drug use, Caucasian ethnicity) and cardiovascular risk factors (family history of coronary heart disease, previous cardiovascular event); and time-varying covariates for cardiovascular disease risk factors (smoking status and body mass index, updated at each follow-up visit), calendar year, and cumulative exposure to 15 other antiretroviral drugs (with a separate covariate for each drug updated each month). In the marginal structural Cox models, time-varying covariates are also accounted (hypertension, dyslipidaemia, diabetes) indicators for three Framingham risk score categories, and continuous measures of CD4 cell count and log10 HIV RNA.
11,856 patients were followed for a median of 6.6 years; 365 patients had a cardiovascular event (4.6 events per 1,000 patient-years). In the conventional Cox model, recent but not cumulative, exposure to abacavir increased the risk of a cardiovascular event. In the new marginal structural Cox model, continued exposure to abacavir during the past four years increased the risk of a cardiovascular event (hazard ratio 2.06, 95% confidence interval 1.43-2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6 to 36 months caused the greatest increase in risk.
In conclusion, abacavir increases the risk of a cardiovascular event. The effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.
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