The advent of triple combination therapy for HIV disease, while associated with substantial reductions in morbidity and mortality among those living with HIV and AIDS [1–3], has also been associated with significant adverse effects on patient lipid profiles, specifically increases in both total cholesterol and triglyceride levels [4–7]. The widespread occurrence of these metabolic abnormalities has led to speculation as to whether the use of the highly active triple therapy regimens will result in an increased risk of cardiovascular disease in the HIV-positive, therapy-exposed population.
Cases of cardiovascular events or predisposing cardiovascular abnormalities among persons exposed to triple therapy regimens have been reported. However, there are limited data regarding actual risk of cardiovascular events or procedures among HIV-infected individuals undergoing highly active antiretroviral therapy (HAART) or comparison with non-exposed HIV-positive or HIV-negative populations [8–10].
In this report, we describe temporal trends in cardiovascular interventional procedures and calculate rates of these outcomes in a large population-based observational cohort of antiretroviral treatment recipients and compare these rates with those of the general British Columbia population. Moreover, we identify sociodemographic, clinical and treatment characteristics associated with the occurrence of interventional cardiovascular procedures among HIV-positive individuals treated with antiretroviral drugs.
The distribution of antiretroviral therapy in the province of British Columbia has been described elsewhere [2,3]. In brief, antiretroviral medications have been distributed at no cost to eligible HIV-infected individuals since 1986. In 1992, the distribution of antiretroviral agents was centralized through the British Columbia HIV/AIDS Drug Treatment Programme. Antiretroviral therapy is distributed according to specific guidelines commensurate with internationally devised treatment recommendations [11–14].
The British Columbia Cardiac Registries (BCCR) was initiated in 1990 as a joint project between the province's cardiac surgeons and the Ministry of Health. The project developed and implemented a software system that collected information on surgical waiting lists as well as data from the cardiac surgical event in sufficient detail to be used to produce the official medical record for the event. Since January 1991, all cardiac surgeries performed in British Columbia (in excess of 3000 per year) have been registered using this system and their operative reports generated by it. Specific data were collected through the BCCR regarding diagnostic and therapeutic procedures, notably coronary angioplasties, open-heart surgeries and, since 1999, coronary diagnostic and therapeutic catheterizations.
Using anonymous linkage, the two databases (British Columbia HIV/AIDS Drug Treatment Programme and the BCCR) were linked to determine the number of individuals who have taken antiretroviral therapy and who have also had a cardiac procedure since 1993. For the purposes of this analysis, an interventional cardiovascular procedure was defined as open-heart surgery, coronary angioplasties, and coronary diagnostic or therapeutic catheterizations.
HIV-positive population figures were based on the number of programme participants actively on antiretroviral therapy. Crude rates are expressed as events (cardiovascular procedures) per 1000 active treatment programme participants and were calculated per year over the period 1995 to 2000 inclusively. The crude general population rates were calculated similarly, but using the total population of the province of British Columbia for the years 1995 through 2000 . Data for 2001 are not yet available. Age-adjusted rates were calculated using direct age standardization techniques and applying HIV–age-specific rates to British Columbia general population figures per 1000 population aged 20 to 64 years. Age groupings used were 20–34, 35–49 and 50–64 years. Linear regression was used to calculate the slope of the trends over time. Event rates are calculated using all individuals who had an event.
To describe sociodemographic and clinical characteristics associated with undergoing a cardiovascular procedure, chi-square tests were used for dichotomous variables (gender, AIDS diagnosis at baseline, HIV risk category), Wilcoxon rank sum tests for non-normal continuous variables (months on antiretroviral therapy, adherence to antiretroviral therapy, number of antiretroviral drugs started), and Student's t-tests for normal continuous variables (age at baseline, CD4 cell count at baseline, plasma viral load at baseline). All variables significant at the 0.05 level were entered into a logistic regression model to determine factors independently associated with experiencing an interventional cardiovascular procedure.
Patients were conservatively defined as adherent or non-adherent using prescription refill compliance . The definition of adherence was based on the ratio of time that medication dispensed would last as a proportion of follow-up time. This calculation was restricted to each patient's first year on therapy to avoid reverse causation that could occur among patients who cease antiretroviral therapy after they have become too sick to take medication. It has been previously demonstrated how this estimate strongly predicts virological response  and survival , and how it can adjust for the potentially confounding effect of treatment interruption . Non-adherence was defined if patients picked up less than 95% of their required antiretroviral medications during the first 12 months of therapy.
Of the 5082 individuals registered in the Drug Treatment Programme since 1995, 63 (1%) individuals were recorded in the BCCR. Of the total population in the Drug Treatment Programme, patient consent was obtained to examine the records of 3148, including 44 of the individuals who had had an interventional cardiac procedure.
The majority of all the cardiac procedures [70 (72%)] occurred since 1999. There were 30 open-heart surgeries (53% since 1999), 31 coronary angioplasties (58% since 1999) and 36 diagnostic coronary catheterizations (100% since 1999 as the Registry only began collecting these data in 1999). After excluding the diagnostic catheterizations, procedures since 1999 still represented 56% of all cardiac procedures among HIV-positive individuals on antiretroviral drugs.
The crude event rates per year per 1000 individuals on antiretroviral drugs were 3.37 in 1995, 1.65 in 1996, 0.34 in 1997, 1.57 in 1998, 3.54 in 1999 and 6.18 in 2000. Linear regression determined an increase of 1.95 procedures per 1000 active participants per year (P = 0.013) in the crude event rate.
Age-adjusted rates are summarized in Fig. 1. Among the HIV-positive population, the adjusted rates by year are 5.25 in 1995, 1.23 in 1996, 0.39 in 1997, 1.72 in 1998, 3.61 in 1999 and 6.52 in 2000 (P for trend 0.015). Among the general population, the age-adjusted rates were 3.76 in 1995, 3.78 in 1996, 3.69 in 1997, 3.68 in 1998, 3.78 in 1999 and 5.08 in 2000 (P for trend 0.191).
Of the sociodemographic and clinical characteristics examined, being older age at baseline (median 45 versus 37 years; P < 0.001) and median months on antiretroviral therapy (56 versus 38 months; P < 0.001) were associated with having had a cardiac procedure. Non-significant (P > 0.05) variables examined were gender, AIDS, CD4 cell count, plasma viral load at baseline, number of drugs started, HIV risk group and adherence. In multivariate analysis, age at baseline per 10 year increase (adjusted odds ratio 2.4; 95% confidence interval, 1.8–3.4) and months on therapy per 10 month increment (adjusted odds ratio 1.2; 95% confidence interval, 1.0–1.3) remained significant (Table 1).
Our data suggest that there is a significantly increasing rate of interventional cardiovascular procedures among HIV-infected individuals undergoing antiretroviral therapy. This trend becomes particularly evident since the widespread introduction of triple drug therapy in 1997, and by the year 2000, age-adjusted rates of cardiac procedures among HIV-positive individuals receiving antiretroviral therapy exceeded the rate of cardiac procedures among the general population of British Columbia. The trend of increasing cardiac procedures among HIV-positive individuals is statistically significant, while there is no such trend in the general population. Further, our data suggest that, even after controlling for age, the cumulative number of months on antiretroviral therapy is independently associated with experiencing an event. These data have important implications on the cost and complexity of managing HIV disease in the HAART era.
Our data add to the mounting body of evidence suggesting that antiretroviral therapy, through its effects on lipids, is predisposing individuals towards experiencing an increase in cardiovascular disease [4–6,8–10]. However, the relatively low crude rate of events (maximum 6.2 per 1000 active participants) suggests that the benefits of antiretroviral therapy outweigh the risks. It should be noted that rates of cardiac procedures will probably increase over time, given that people are living longer with HAART and that the population of HAART users is aging.
Our data have a number of salient features. One, this is a population-based analysis, reflecting population-based rates and characteristics. Two, the event data are physician reported and not self-report, increasing the validity of the results. Three, we have been able to examine the rates over time, and particularly pre- and post-HAART eras, enabling us to compare the impact of HAART on the outcome of interest. Four, by calculating a rate per 1000 active participants, we are able to control for increased uptake of antiretroviral therapy over time. Five, we have adjusted for age in our analyses.
There are also limitations that must be taken into account. Although our sample size is relatively large, the number of events is small and this limits the power of the analysis to detect differences. Also, we do not have data on either smoking history or family history of cardiovascular disease. Finally, we are unable to control for the potential confounding effect of more aggressive management of cardiovascular disease among HIV-infected individuals as a result of improved life expectancy in the era of HAART.
There are a number of potential alternative explanations for the increased rate of interventional cardiac procedures. For example, it is possible that HIV itself may cause metabolic changes that could impact on lipid profiles , and this effect can actually be observed now that patients have improved longevity. A more significant potential confounding factor is increased survival related to antiretroviral therapy. Improved survival may mean that physicians are more likely to consider a cardiac intervention worthwhile and cost-effective. The decrease in rates observed between 1995 and 1997 may be the converse result: that because individuals with HIV infection had such a short life expectancy, any sign of cardiovascular disease that would ordinarily warrant an intervention would have been viewed as a secondary priority to HIV infection. This, however, would not explain why there was a fall from 1995. It is more likely that individuals were already beginning to benefit from dual and triple therapy (the latter through expanded access programmes), and that this benefit conferred improved health, which extended to cardiovascular health. If our hypothesis is correct, that antiretroviral therapy has contributed to an increase in interventional cardiac procedures, then a time-lag of 2 or 3 years would be expected before seeing a population-level increase in interventions, such as we have observed.
Although at this time, the benefits of antiretroviral therapy, especially for individuals with more advanced infection, outweigh the risks, our data do suggest that careful monitoring of individuals on HAART is warranted, and that the management of alterable risk factors (e.g. smoking, diet, exercise) are important as a means of mitigating the adverse effects of antiretroviral therapy. These trends merit further longitudinal monitoring; as further events accumulate, further evaluation of the type of antiretroviral regimen(s) associated with such events will need to be evaluated.
The authors would like to express their gratitude to the staff of the Drug Treatment Programme for support of this project, including Dianne Campbell, Bonnie Devlin, Elizabeth Ferris, Nada Gataric, Myrna Reginaldo, Peter Vann and Benita Yip. We would also like to acknowledge the BCCR for collaboration on this project.
Sponsorship: This work was supported by the Canadian Institutes of Health Research (CIHR) through an Investigator Award to R. Hogg and through a Doctoral Fellowship to P. Braitstein. This work was also supported by the Michael Smith Foundation for Health Research through a Senior Scholar Award to R. Hogg, a Doctoral Fellowship to P. Braitstein and a Postdoctoral Fellowship to K. V. Heath.
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