Abacavir and cardiovascular risk: contradictory findings continue to emerge, mechanisms still unclear

Yet more studies looking at the potential cardiovascular risks associated with the use of the antiretroviral drug abacavir report apparently contradictory findings this month.

A large study of everyone receiving antiretroviral therapy in Denmark found an increased risk of stroke and other cerebrovascular events in patients treated with abacavir.

However another large study, of American patients receiving care through the US Veterans Administration hospitals for current and former military personnel, found no increased risk of stroke or of other forms of cardiovascular disease in abacavir-treated patients.

These studies add to the contradictory evidence regarding the potential cardiovascular risks attached to treatment with abacavir.

Concerns emerged about a possible link between abacavir and heart attack after a large international study of HIV-positive people found an approximate doubling of the risk of heart attack in those who were taking abacavir.

This doubling of risk would be most likely to pose a serious risk to people who already have a high risk of heart attack, as measured by well-known risk factors such as family history of heart disease, high cholesterol and low HDL cholesterol, smoking and advanced age.

While a number of studies have subsequently come to the same conclusion, other cohort studies have been unable to detect a strong association between abacavir and heart attck.

The Danish study population comprised 5031 individuals who received HIV care in Denmark after 1995. Injecting drug users, who have a high risk of cerebrovascular illness, comprised 11% of the HIV population. The HIV-infected individuals were matched with 45,279 HIV-negative controls of the same gender and age.

“A main strength of our study is its nationwide population-based design with long and complete follow-up,” noted the investigators.

Overall, a cerebrovascular event was diagnosed in 2.7% of HIV-positive individuals who did not inject drugs, and 3.2% of HIV-infected injecting drug users.

Analysis of the control population showed that 1.7% of HIV-negative non-injecting drug users had an event, as did 2.5% of individuals who injected drugs.

Traditional risk factors for stroke and similar diseases were present in 56% of HIV-positive non-injecting drug users who had an event, and 59% of HIV-infected drug users.

Comparison between the patients and controls showed that HIV-positive non-injecting drug users had a significantly increased risk of an event (adjusted risk ratio, 1.60, 95% CI: 1.30-1.95). The risk was even higher for HIV-positive people who injected drugs (adjusted risk ratio, 3.95, 95% CI: 2.16-7.16).

Immune deficiency was identified as an important risk factor. HIV-positive non-injecting drug users who were not taking HIV therapy and had a CD4 cell count below 200 cells/mm³ also had an increased risk of cerebrovascular disease (adjusted risk ratio, 2.26, 95% CI: 1.05-4.86).

“Whether this association is due to immunodeficiency per se, an association with increased risk of cerebral opportunistic diseases or a general deteriorated condition in these patients has to be established,” comment the authors.

Treatment with abacavir (Ziagen, also in Kivexa and Trizivir) was also a significant risk factor (adjusted risk ratio, 1.66; 95% CI: 1.03-2.68). The risk was only slightly reduced by stopping treatment with the drug.

“Abacavir has been associated with an increased risk of myocardial infarction,” note the investigators, “we observed a higher risk of cerebrovascular events in HIV-infected individuals on abacavir…we presume that the mechanisms for this phenomenon are equivalent to that seen for myocardial infarction.” However, they also acknowledge that the finding could be a consequence of "channelling," whereby patients deemed to be at a higher risk of cardiovascular illnesses were placed on abacavir because of the drug's perceived safety.

The investigators conclude, “HIV infection is associated with an increased risk of cerebrovascular events with and without proven risk factors. The risk is associated with injecting drug use, low CD4 cell count, and treatment with abacavir, but not HAART in general.”

But US investigators reporting in the July 1^st edition of Clinical Infectious Diseases, found no association between abacavir and heart attack.

Although they initially found a modest association between therapy with the drug and heart attack, this disappeared after taking into account traditional risk factors for heart disease, especially kidney dysfunction.

“We observed no association between cumulative or current abacavir use and use and acute myocardial infarction or cerebrovasular events”, comment the authors.

Patients who were not taking potent HIV therapy had an increased risk of heart disease and stroke, and patients taking current tenofovir treatment had the lowest risk of such diseases.

The investigators note that unlike some other research finding a relationship between abacavir and heart attack, theirs controlled for chronic kidney disease – an established risk-factor for heart attack.

In an accompanying editorial, Dr Samuel Bozzette suggests that “mechanistic studies” examining the causes of cardiovascular disease in patients with HIV “are now probably the highest research priority.”

There is currently extremely limited evidence that abacavir’s main competitor in first-line HIV treament, tenofovir (Viread, also in Truvada and Atripla) has any association with heart disease. However, this drug can cause disturbances in kidney function, an established risk factor for cardiovascular disease.

Investigators from the US Department of Veterans Affairs hypothesised that the apparent association between abacavir and heart attack could be because patients with established kidney disease were being channelled onto the drug.

Taking this and other traditional risk factors into account, they analysed the records of over 19,000 patients who received HIV care between 1996 and 2004 to see if kidney disease or antiretroviral therapy increased the risk of heart attack or stroke.

A total of 76,376 person-years of follow-up were available for analysis (median duration per patient, 3.93 years).

During this time, a total of 278 heart attacks and 868 cerebrovascular events were diagnosed. The incidence of heart attack was 3.69 events every 1000 person-years, and incidence of stroke was 11.68 events per 1000 per person-years.

Approximately 75% of patients received antiretroviral drugs.

Unadjusted analysis found an association just short of significance between treatment with abacavir and heart attack (hazard ratio [HR] = 1.27; 95% CI, 0.99-1.62; p = 0.056).

There was no evidence of a significant relationship between heart attack and other antiretroviral drugs. However, patients who received monotherapy or dual therapy HIV treatment regimens were significantly more likely to have a heart attack (p = 0.001).

A significant relationship was also identified between poorer kidney function and an increased risk of heart attack.

Analysis controlling for kidney disease showed that abacavir did not increase the risk of heart attack. Nor was there any evidence that any other anti-HIV drug increased the risk. However, the association with mono- and dual-therapy remained significant (p = 0.001).

Adjustment for other established risk factors for cardiovascular disease produced similar results, with the only type of HIV treatment associated with heart attack risk being dual- and monotherapy (p = 0.002).

Other risk factors for heart attack were older age (HR 1.79 for each ten year increase, 95% CI, 1.60-2.01; p = 0.001), hypertension (HR = 2.05; 95% CI, 1.57-2.67; p = 0.001), and cumulative exposure to HIV therapy (HR 1.12 for each year of treatment, 95% CI, 1.01-1.24; p = 0.041).

Results for cerebrovascular disease were broadly similar.

The impact of current therapy on the risk of cardiovascular events was then analysed.

As the investigators hypothesised, a higher proportion of patients taking abacavir than tenofovir had prior kidney disease (12 vs 15%).

Baseline kidney dysfunction was associated with a significant increase in the risk of heart attack (HR = 2.41; 95% CI, 1.73-3.36) and cerebrovascular events (HR = 1.80; 95% CI, 1.44-2.24).

Cumulative rates of heart attack and stroke per 1000 person-years were 4.41 for patients taking no or sub-optimal HIV therapy; 3.20 for individuals taking abacavir; 1.10 for those treated with both tenofovir and abacavir; and 0.72 for individuals receiving tenofovir.

Adjustment for chronic kidney disease showed that there was no relationship between current abacavir therapy and heart attack.

Indeed, compared to individuals treated with neither abacavir nor tenofovir, abacavir therapy reduced the risk of a cardiovascular event by a significant 40% (p = 0.001).

Nevertheless, an even greater reduction in risk was associated with current tenofovir  therapy (88%; p = 0.001).

“We could not confirm the association of abacavir therapy and cardiovascular events,” comment the investigators, adding, “the use of HAART has a protective effect on cardiovascular events.”

They suggest that the low risk seen with tenofovir could be because of “its lipid lowering qualities”.