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.