HIV, HAART and cardiac risk

The first reports of premature heart attack and coronary artery disease among people taking protease inhibitors emerged in the late 1990s.^{1 2} The most important evidence to date comes from the D:A:D (Data collection on Adverse events of antiretroviral Drugs) study. D:A:D is a unique collaborative effort begun in 1999, which has pooled data from eleven cohorts of HIV-positive people (eight European, one multinational, one Australian, and one North American) in order to track the long-term toxicity of HIV therapies.

The D:A:D study has collected data on adverse events in 23,347 HIV-positive patients (three quarters of whom are male, median age 39) for up to six years, beginning in 1999. At entry, over half the cohort were smokers, approximately 20% had raised total cholesterol levels (above 6.3 mm), over a third raised triglyceride levels (above 2.3 mm), and a quarter had low levels of the cardio-protective HDL cholesterol.³ Nineteen per cent had taken no antiretroviral drugs, 67% had never taken a protease inhibitor, and 34% had never taken a non-nucleoside reverse transcriptase inhibitor (NNRTI).

When D:A:D results were published in 2004, during 36,145 person years of follow-up, 38 people had a stroke, and 126 people had a heart attack, 36 of whom died. After the data were adjusted for the effects of known cardiovascular risk factors (for example age, gender, and smoking status), each year of exposure to antiretroviral therapy increased the risk of heart attack by 26%. The ‘traditional’ cardiac risk factors were significant. In fact, some were more significant predictors of heart attack risk than antiretroviral exposure, such as raised cholesterol at study entry, which increased risk by 60%.⁴

Extended results published in 2007 have shown a 16% increased risk of heart attack for each year of exposure to protease inhibitors, up to six years. After adjusting for the effect of elevated lipids, this declined to a 10% per year additional risk for PI exposure. This is similar to the risk attributable to smoking or diabetes. There was no significant risk for people exposed to NNRTIs, and the study was not able to distinguish between individual PIs.⁵

The researchers have cautioned that cohort studies cannot prove causality, only association, and note that the overall risk of heart disease remains low when weighed against the marked effectiveness of combination antiretroviral therapy in preventing HIV-related complications.

Further analysis of the D:A:D cohort, focusing on NRTIs and cardiovascular risk, found that patients exposed to abacavir, and to a lesser extent ddI, had an elevated risk of heart attack. For the study as a whole, the risk of heart attack was 1 in 64 over five years. Abacavir increased this risk by 90%, but the increase in risk was most concentrated among those with moderate to high cardiovascular risk.⁶ A similar analysis of participants in the SMART treatment interruption trial found that participants who took abacavir had a fourfold higher risk of heart attack and a 1.8-fold higher risk of any cardiovascular events. A sub-study showed that those who received abacavir had significantly higher levels of high sensitivity C-reactive protein and interleukin-6, markers of inflammation. A study in an HIV-positive Danish cohort also found that beginning or switching to abacavir roughly doubled the risk of heart attack. Although this was also a non-randomised cohort study, the difference remained after controlling for confounding factors.⁷

However an analysis carried out by abacavir’s manufacturer GlaxoSmithKline found no evidence of an elevated risk of cardiovascular events in those who received abacavir in the company’s own studies (this analysis covered 14,683 people). Furthermore, data from one particular trial (HEAT) showed no difference in inflammatory markers between those who received abacavir and those who received tenofovir.^{8 9 10}

In a second prospective study, all HIV-positive patients admitted with an acute myocardial infarction to a Los Angeles hospital between 1998 and 2000 were monitored and matched with HIV-negative controls. Twenty-four HIV-positive patients experienced heart attacks during that time. Over 15 months of follow-up, the HIV-positive patients had a much higher incidence of second acute myocardial infarction (20 vs 4%) and rehospitalisation for a coronary event (45 vs 11%) than sex- and age-matched controls. The investigators observed that protease inhibitors did not seem to be solely responsible for abnormally high blood lipids seen in 24 patients who had had heart attacks. Consequently, the authors attributed the higher rate of secondary cardiac events among HIV-positive patients to HIV infection itself, rather than PI therapy.¹¹

Retrospective study findings have been varied:

• An analysis of the US Veterans Administration (VA) cohort, which included 36,666 patients who received HIV care between 1993 and 2001 did not find any increase in the incidence of cardiovascular events after the introduction of HAART.¹²
• A database of individuals involved in the Kaiser Permanente health care plan showed an increased rate of heart attack and coronary artery disease in people with HIV compared with adults without HIV in an age-matched analysis, but no relationship to type of treatment.^{13 14} The analysis did not control for other cardiovascular risk factors, and may be inaccurate due to people dropping out of analysis.
• The HIV Outpatient Study (a US database covering 5,676 patients, with 17,712 years of patient follow-up) found that individuals taking a protease inhibitor (PI) were at least three times more likely to experience a heart attack compared to those not taking a PI, but had no increased risk for angina or stroke.¹⁵
• A review of the Johns Hopkins University HIV cohort reported a two to three times higher incidence of angina, myocardial infarction and stroke in 2671 patients followed for 7330 person-years, compared with an age and race matched control population.
• A review of the Insight database of 7542 US patients found that one year of protease inhibitor treatment increased the risk of subsequent cardiovascular events by 60% over a median of 3.5 years of follow-up.¹⁶
• A review of the French Hospital Database on HIV found that people who had been taking PIs for more than 30 months had a threefold increase in risk of heart attack.¹⁷ Compared to the general, age-matched French population, the risk of heart attack was increased by 50% for HIV-positive men and by 170% for women with HIV.¹⁸
• A review of patient data at Boston’s two largest hospitals from 1996 to 2004 found that HIV-positive patients had a 50% increased risk of heart attack compared to HIV-negative patients. HIV-positive women, however, were at triple the risk (see Cardiac risk in women). ¹⁹

A recent editorial in the British Medical Journal has argued that cardiovascular risk should be taken into account when considering when a patient should start antiretroviral therapy. They advocate that patients with a risk of more than 20% over ten years should delay starting HAART until the CD4 cell count has fallen to near 200 cells/mm³, allowing them time to undertake lifestyle changes and possibly take lipid-lowering medication, rather than starting HAART when their CD4 cell count is closer to the upper recommended limit of 350 cells/mm³.²⁰