A large study of US patients with HIV has concluded that people taking abacavir had an increased risk of heart disease and stroke, but also found a modestly increased risk of heart failure in people taking tenofovir.
The study, which analysed patient data from the Veterans Administration Clinical Case Registry, was published this month in the journal AIDS.
The study found that the proportion of patients who experienced a heart attack while taking abacavir was approximately one in 16, compared to one in 30 among those taking tenofovir, a 50% higher risk. The risk did not seem to be greater in people with existing risk factors for heart disease.
There has been controversy for some years over the possible role of abacavir in cardiovascular disease in people with HIV, since the D:A:D cohort study found that recent abacavir treatment increased the risk of heart attack by 90%.The effect appeared to be most pronounced in people who already had other risk factors for heart disease, or who had an existing heart condition.
While several other cohort studies have also found that people who took abacavir as part of their antiretroviral regimen had a higher risk of heart attack, other studies – including a meta-analysis of clinical trials of the drug – found no increased risk of cardiovascular events in people taking the drug.
Less attention has been paid to heart failure, a progressive condition caused by weakening of the heart, attributable both to the same risk factors as heart attack and atherosclerosis, but also to the toxicity of HIV or drugs to the heart muscles.
The study published this month analyses cardiovascular events in 10,931 largely male HIV-infected patients receiving care through Veterans Health Administration hospitals in the United States who started antiretroviral therapy between 1997 and 2007, and who had viral load, CD4 count and kidney function data available.
The kidney function data were important, authors noted, because most previous studies have not controlled for an important potential bias: patients with kidney disease may be steered away from tenofovir due to its potential toxic effect to the kidney tubules, and placed instead on abacavir-based treatment. However people with kidney disease are at higher risk of cardiovascular disease, and this could lead to an apparent increase in the risk of cardiovascular events that might not be caused by abacavir.
A previous analysis of the Veterans data, presented at the International AIDS Society conference in 2009, found no elevated risk of heart attack or stroke in patients taking abacavir, in patients treated between 1996 and 2004.
This analysis compared treatment outcomes in 3235 patients treated with abacavir, 4314 treated with tenofovir and 9122 who received regimens containing other antiretroviral drugs.
The average duration of exposure to abacavir was 1.6 years and to tenofovir 1.3 years.
Conditions strongly implicated in the development of cardiovascular disease were common in this cohort: around half smoked, around 40% had high blood pressure, 16-19% had diabetes and one-fifth already had a diagnosis of cardiovascular disease at the time they started either abacavir or tenofovir.
Impaired kidney function was somewhat more common in the abacavir-treated patients compared to tenofovir-treated patients (10% vs 6%).
During 60,588 person-years of follow-up there were 194 cases of heart failure, while in 59,578 person-years of follow-up there were 501 atherosclerotic cardiovascular events.
Abacavir treatment was associated with a 50% increase in the risk of a cardiovascular event when compared to tenofovir or other treatment (13.4 events vs 9.4 events per 100 person years, p<0.01; hazard ratio 1.49 (95% confidence interval 1.09-2.05)), even after controlling for measures of kidney function and changes in kidney function over time.
When different types of cardiovascular event were isolated, abacavir treatment was significantly associated with stroke (2.05, 95% CI 1.00-4.19) but not with other cardiovascular events and duration of exposure or less recent exposure to abacavir were not associated with an increased risk of a cardiovascular event.
Tenofovir treatment was associated with an 82% increase in the risk of heart failure in multivariate analysis (HR = 1.82, 95% CI 1.02 – 3.24, p=0.04) when compared to use of abacavir or other drugs, and the authors report that this association appeared stronger in patients with poorer kidney function (GFR <60 mL/min/1.732 (HR = 3.29, 95% CI 1.39 – 7.76).
Besides the known effect of tenofovir on kidney function, which tends not to be profound in observational studies, the authors ask whether another mechanism might be at work.
They note that tenofovir can cause damage to the lining of the kidney tubules, and so may disrupt both vitamin D activation and correct balance of calcium and phosphate. Renal mineral bone disease, characterised by abnormal metabolism of vitamin D, calcium and phosphate, has been associated with cardiovascular disease, and the authors say that there is an urgent need to determine whether tenofovir treatment might lead to a higher rate of heart failure through this pathway.
The authors caution that their results may not be generalisable to women, who comprised less than 3% of the cohort receiving abacavir or tenofovir.
Choi AI et al. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS 25: advance online publication, 2011. (View free abstract here).