Since 1999, there has been a general worsening of the CVD risk factor profile among HIV-infected individuals in the DAD study. Individuals have aged, and possibly as a result, some have developed diabetes mellitus, hypertension, and/or dyslipidaemia or have undergone invasive procedures for CVD. There has been an encouraging decrease in the proportion of smokers since 2002, and individuals (particularly those at high risk of CVD) are more likely to be receiving lipid-lowering drugs. This targeted use of interventions among those at high risk of CVD has undoubtedly had a positive impact on the overall incidence of MI, largely as a result of improved lipid profiles among these individuals. However, any decreases in MI incidence attributable to improved patient treatment appear to have been offset by a gradual worsening of the CVD risk profile of the cohort as patients have aged. Thus, overall, we have not seen as great a reduction in the incidence of MI over time as might have been expected.
Although there are some guidelines for the use of lipid-lowering therapy for individuals with HIV infection [13
], evidence to support their effectiveness in the prevention of CVD in this population is lacking. The overall conclusions regarding the use of lipid-lowering therapy have often been confusing [14
]. Our results from this current analysis suggest that clinicians have become increasingly willing to initiate lipid-lowering therapy for patients with abnormal lipid levels, diabetes, and other risk factors for CVD, although other work from our group [17
] suggests that the use of lipid-lowering therapy in those with existing CVD remains suboptimal. Interestingly, the peak of initiation of lipid-lowering therapy occurred in 2001, with a subsequent decrease thereafter, possibly reflecting an early rapid uptake of these drugs among those with the greatest need for cART after the initial reports of a relationship between cART and MI and/or possible underuse of these drugs in later years. Unfortunately, the study did not collect information regarding the class of lipid-lowering drugs used (e.g., fibrates or statins). Because these different drug classes may have different effects on lipid levels, models that include these variables may be difficult to interpret. However, exclusion of the lipid parameters from these models led to similar conclusions regarding the other parameters in the model. It should be noted that injection drug users were less likely to receive lipid-lowering therapy after controlling for other confounding factors. Although we are unable to comment on whether this was a result of failure on the part of treating physicians to offer these drugs in the first place or of refusal by the patient to accept the drugs when offered, this highlights the importance of assessing risk factors in all HIV-infected persons and ensuring patient access to potentially beneficial interventions. It should be noted that injection drug use (and other covariates in our models, including risk factor and ethnicity) may also act as a surrogate for socioeconomic status; this information is not captured directly in the DAD study.
The proportion of patients undergoing invasive cardiovascular procedures in the cohort increased over time, both among those who had experienced a previous cardiovascular event and among those who had not experienced such an event. However, the correct interpretation of these findings is not clear. Although the proportion of individuals who require invasive procedures will likely increase as the risk of CVD among the cohort increases, the use of these procedures as pre-emptive interventions prior to the development of clinical CVD could become more attractive, because expected survival of HIV-infected patients has improved.
We have not considered changes to antiretroviral therapy in this analysis. However, it is recognized that some antiretroviral drugs are associated with more-deleterious lipid profiles than others [18
], and switching antiretroviral regimens to those perceived to be more “lipid friendly” has generally been associated with improvement in lipid parameters [22
]. Preliminary results from the DAD study have suggested that clinicians are increasingly likely to make such changes [25
]; further detailed analyses of these findings are ongoing.
The DAD study includes a large, geographically diverse, and representative population of individuals with HIV infection who are from clinics that encompass a wide variety of treatment practices. To minimize bias, a number of standardized definitions for data collection have been introduced, and data quality checks are regularly performed. All cardiovascular events and deaths are centrally validated to ensure that they meet the stringent protocol-defined criteria.
A number of limitations of our study should be acknowledged. First, in some cohorts, the date of starting lipid-lowering therapy was estimated using the information available regarding the use of these drugs at consecutive DAD study visits. Second, information on changes in risk factors such as smoking may have relied on a patient's self-reported behavior. Although this information has been collected since the start of the DAD study, the quality of the information may have improved, which may introduce bias. Similarly, because clinicians and patients have become more aware of the relationship between cART and CVD, information on some variables (e.g., family history of CVD) may have been more actively sought, leading to a potential apparent increase in such reports. Third, because investigators at sites participating in the DAD study are likely to be particularly interested in CVD risk, they may have more vigorously promoted risk reduction through behavioral and therapeutic interventions; thus, changes in risk factors in this cohort may be greater than those elsewhere. Fourth, the DAD study does not collect information regarding other behavioral factors, such as diet and exercise, although any changes to these factors would, to some extent, be reflected in changes to lipid levels. Fifth, despite the rigorous procedures in the DAD study to ensure that all end points are captured in a timely manner, the possibility that our results regarding MI incidence may have been affected by ascertainment bias must be considered, particularly in the most recent calendar period. It might be anticipated that clinicians may be less likely to report MIs as the study duration increases, contributing to an apparent decrease in incidence over time; however, because all centers are visited yearly and a substantial proportion of patients receiving follow-up are monitored, we believe that the risk of this should be minimal. Finally, because the DAD study is a closed cohort and patient follow-up for the analysis of MI incidence is censored after an individual develops an MI, there may be an artificial reduction in the incidence of MI as those patients at highest risk of MI drop out of the risk set.
In conclusion, our findings suggest that, although the CVD risk profile among patients observed in the DAD study has deteriorated since 1999, MI incidence rates have remained relatively stable. This is possibly a result of a more aggressive targeted approach to managing the risk of CVD.