Canadians find some ARVs increase risk of heart attack, but urge caution and stress need for context

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The anti-HIV drugs abacavir, efavirenz, lopinavir, and ritonavir are all associated with an increased risk of heart attack in a Canadian study published in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

The research also showed that patients with HIV had twice the risk of heart attack compared to matched HIV-negative controls.

However, the investigators are cautious about their findings, writing: “Concerns remain about the presence of confounders that could not be captured, in particular smoking, family history of cardiovascular disease, creatinine, viral load and CD4 levels.”

Glossary

matched

In a case-control study, a process to make the cases and the controls comparable with respect to extraneous factors. For example, each case is matched individually with a control subject on variables such as age, sex and HIV status. 

observational study

A study design in which patients receive routine clinical care and researchers record the outcome. Observational studies can provide useful information but are considered less reliable than experimental studies such as randomised controlled trials. Some examples of observational studies are cohort studies and case-control studies.

cardiovascular

Relating to the heart and blood vessels.

meta-analysis

When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.

traditional risk factors

Risk factors for a disease which are well established from studies in the general population. For example, traditional risk factors for heart disease include older age, smoking, high blood pressure, cholesterol and diabetes. ‘Traditional’ risk factors may be contrasted with novel or HIV-related risk factors.

Moreover, a recent meta-analysis of randomised studies showed that therapy with one of these drug -  abacavir (Ziagen, also in the combination pills Kivexa and Trizivir) -  did not increase the risk of heart attack.

Nevertheless, the results of this latest study are of note in light of the recent decision on cost grounds that most patients starting HIV therapy in London should take an abacavir-based regimen.

A number of studies have now shown that patients with HIV have an increased risk of cardiovascular disease. There has been debate about the reasons for this. Untreated HIV infection may be a risk factor, but therapy with some antiretroviral drugs has also been implicated.

In some observational research, both the nucleoside reverse transcriptase inhibitor (NRTI) abacavir and the protease inhibitor Kaletra (lopinavir/ritonavir) have been associated with a significant increase in the relative risk of heart attack.

Investigators in Montreal wished to clarify the impact of HIV and antiretroviral therapy on the risk of heart attack.

They designed an observational study involving 7,053 HIV-positive patients who received care between 1985 and 2007. Each of these patients was matched with up to five HIV-negative controls of the same sex and similar age.

In addition, each HIV-positive patient who had a heart attack was matched with to up to ten HIV-positive controls of the same sex and age and who entered care at the same time.

Most of the patients were men (78%) and their median age was 37 years.

There were 139 heart attacks among the HIV-positive patients, providing an incidence of 3.88 per 1000 person-years of follow-up. This compared to a total of 226 heart attacks among the HIV-negative controls, an incidence of 2.21 per 1000 person-years.

The investigators calculated that HIV infection doubled the relative risk of heart attack (adjusted hazard ratio, 2.11; 95% CI, 1.69-2.63).

Incidence of heart attack was steady in the control population, but increased by approximately 8% per year among the patients with HIV. However, after adjusting for age and other confounding factors this temporal trend ceased to be significant.

The125 HIV-positive heart attack patients were matched with 1084 HIV-positive controls who did not have a heart attack. The first heart attack was recorded in 1989, and 92% of events occurred between 1997 and 2007.

Any exposure to abacavir (p =0,008), lopinavir (p = 0.004), ritonavir (p < 0.01) and efavirenz (p = 0.004) was associated with an increased risk of heart attack.

Recent therapy (within the previous six months) with abacavir (p = 0.02), lopinavir (p = 0.02) and ritonavir (p = 0.003) was also associated with an elevated risk of heart attack.

However, the investigators were eager to place these findings into context.  They emphasised that the level of increased risk associated with each of these drugs “is minimal compared to traditional risk factors such as smoking, family history, hypertension, diabetes, and dyslipidaemia.”

The researchers were surprised by the association with efavirenz, and comment: “Although efavirenz is known to have a small lipid effect, no other biological mechanism can be offered at this time to explain this finding.”

However, they suggest that the finding could be because patients who were perceived to have an increased risk of cardiovascular disease were treated with efavirenz rather than the protease inhibitor.

“Our study found an increased risk of AMI [acute myocardial infarction] in HIV+ compared to HIV- individuals…we also found that any and recent exposure to some antiretrovirals as associated with increased AMI risk,” conclude the investigators.

But,they add: “Given limitation about data on confounders, these data should be interpreted with caution and in the light of other data existing on this subject. Meta-analysis of existing observational data, as well as long term randomized-controlled trials that focus on cardiovascular morbidity and mortality in HIV infected patients are needed to guide therapeutic choices.”

References

Durand M et al. Association between HIV infection, antiretroviral therapy and risk of acute myocardial infarction: a cohort and nest case-control study using Quebec’s public health insurance database (RAMQ). J Acquir Immune Defic Synr, online edition: doi: 10.1097/QAI.0b013e31821d33a5, 2011 (click here for the free abstract).