HIV and antiretroviral therapy increase risk of cardiovascular disease, shows meta-analysis

People with HIV have an increased risk of cardiovascular disease, and the risk is higher still for those taking antiretroviral therapy, results of a meta-analysis published in HIV Medicine show.

Overall, infection with HIV increased the relative risk of cardiovascular disease by 61%, and the risk was doubled for those taking HIV treatment. The risk differed between classes of antiretrovirals and specific anti-HIV drugs.

However, most of the increased risk was due to higher rates of coronary heart disease (CHD). The investigators note that this “refers to atherosclerosis of the coronary arteries. It is important to note this distinction from other manifestations of CVD [cardiovascular disease], especially as there is less evidence on the impact of ART associated with other CVD events than CHD.” Moreover, the majority of cardiovascular events associated with HIV treatment “were confined to patients who were already at increased risk of CVD”.

Cardiovascular disease is an increasingly important cause of death in people with HIV. There is no consensus about the reasons for this, especially the role of antiretroviral therapy.

Because of this lack of certainty, investigators from Sydney, Australia, conducted a systematic review and meta-analysis of studies comparing the risk of cardiovascular disease between HIV-positive and HIV-negative individuals; studies comparing the risk between people taking antiretroviral therapy and those who were treatment naive; research comparing the risk between classes of antiretroviral drugs; and studies exploring the association between specific drugs and the risk of cardiovascular disease.

Observational studies and randomised-controlled trials involving adults, conducted before August 2010, were eligible for inclusion in the analysis. Cardiovascular disease was defined as heart attack, ischaemic heart disease, cardiovascular and cerebrovascular events and coronary heart disease. 

A total of 23 studies, including two randomised-controlled trials, met the investigators’ inclusion criteria.

Three studies looked at the overall cardiovascular risk of HIV-positive people. Their pooled results showed that, compared to HIV-uninfected controls, HIV-positive people had a higher relative risk of cardiovascular disease (RR = 1.61; 95% CI, 1.43-1.81;  < 0.001).

A further three studies compared risk between people taking antiretroviral therapy and HIV-negative controls. Their pooled results showed that participants taking HIV treatment had twice the relative risk of cardiovascular disease (RR = 2.00; 95% CI, 1.70-2.37; p < 0.001). “In summary,” comment the investigators, “the risk of CVD is two times higher among ART-treated PLHIV [people living with HIV] than HIV-uninfected people.”

The results of eight studies were used to compare the risk of heart disease for people taking HIV therapy compared to HIV-positive study participants who were treatment naive. Their pooled results showed that treatment-experienced participants had an increased risk (RR = 1.52; 95% CI, 1.35-1.70; p = 0.001). “PLHIV who are on ART have a 52% higher risk of CVD compared with PLHIV unexposed to any ART,” comment the authors.

Next, they compared the risk of cardiovascular disease between people taking each of the three main classes of antiretrovirals and treatment-naive patients.

Analysis of specific NRTIs showed that abacavir (Ziagen, also in Kivexa), non-abacavir and ddI (Videx)-containing regimens were all associated with an increase in risk (all p < 0.001).

Risk was also compared between types of HIV therapy.

Pooled results of four studies showed that treatment containing a protease inhibitor resulted in a higher risk of cardiovascular disease than non-protease inhibitor regimens (RR = 1.41; 95% CI, 1.21-1.65; p < 0.001).

Duration of treatment was also an important risk factor. Each year of therapy with a protease inhibitor increased the risk by 11% (RR = 1.01-1.10) and each additional year of treatment with NRTIs was associated with a 5% increase in risk (RR = 1.05; 95% CI, 1.01-1.10).

Cumulative exposure to specific anti-HIV drugs also increased the risk. Each year of therapy with the protease inhibitor lopinavir/ritonavir (Kaletra) increased the relative risk by almost a fifth (RR = 1.19; 95% CI, 1.03-1.39; p = 0.022), whereas each year of therapy with abacavir was associated with a 9% increase in risk (RR = 1.05; 95% CI, 1.02-1.16).

The investigators stress that it is important to place their results within wider contexts and to understand potential confounders. “Despite being a risk factor for CVD, ART use has increased the quality and length of life of PLHIV…it is possible that the use of ART increases life expectancy and hence increases the average age of those taking ART in comparison to the reference group, which may lead to confounding of results.”

They conclude: “The reasons for the excess risk of CVD among HIV-infected people are not very well known and require considerable attention as CVD is likely to be on of the major conditions to be confronted in the future by populations of PLHIV.”

Islam FM et al. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med 13: 453-68, 2012.