Two new analyses add to abacavir cardiovascular risk debate

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Two studies presented on Monday at the Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Cape Town, South Africa, found no association between abacavir (Ziagen, also in the Kivexa combination pill) and increased risk of heart attack or stroke, and underlined the importance of confounding risk factors.

At the 2008 Conference on Retroviruses and Opportunistic Infections, researchers first reported that participants in the large D:A:D study who used abacavir had more heart attacks than people who took other nucleoside reverse transcriptase inhibitors (NRTIs). Several subsequent studies examining this link, however, have produced conflicting results.

Role of kidney disease

In the first study presented this week, investigators searched the US Veterans Administration’s Clinical Case Registry to identify patients who had experienced heart attacks or cerebrovascular events such as strokes.

Patients were allocated to one of four categories according to the type of antiretroviral therapy they received between 1996 and 2004:

Glossary

biomarker

Genes, proteins or chemicals that can act as signals for certain diseases.

cardiovascular

Relating to the heart and blood vessels.

stroke

An interruption of blood flow to the brain, caused by a broken or blocked blood vessel. A stroke results in sudden loss of brain function, such as loss of consciousness, paralysis, or changes in speech. Stroke is a medical emergency and can be life-threatening.

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

confounding

Confounding exists if the true association between one factor (Factor A) and an outcome is obscured because there is a second factor (Factor B) which is associated with both Factor A and the outcome. Confounding is often a problem in observational studies when the characteristics of people in one group differ from the characteristics of people in another group. When confounding factors are known they can be measured and controlled for (see ‘multivariable analysis’), but some confounding factors are likely to be unknown or unmeasured. This can lead to biased results. Confounding is not usually a problem in randomised controlled trials. 

  • Combination antiretroviral therapy including abacavir.
  • Combination antiretroviral therapy including other NRTIs but not abacavir.
  • Antiretroviral treatment that does not meet the definition of a highly active antiretroviral therapy (HAART) regimen.
  • No antiretroviral therapy.

The researchers performed a statistical analysis to determine the link between these different treatment strategies and heart attacks or strokes, and how this was influenced by other risk factors, including demographic characteristics (sex, age), traditional cardiovascular risk factors (elevated blood lipid levels, smoking), and co-existing medical conditions including high blood pressure, diabetes, hepatitis C and kidney disease.

The researchers recently reported that hepatitis C was associated with a higher rate of heart attacks in both HIV-positive and HIV-negative people. The present analysis focused on kidney disease.

Kidney disease is a recognised risk factor for heart disease in the general population. Patients with kidney problems are more likely to be prescribed abacavir because another drug often used instead, tenofovir (Viread, also in the Truvada and Atripla combination pills) can cause kidney dysfunction in a small proportion of susceptible people.

A total of 19,424 patients were followed for an average of about four years, representing 76,376 person years of follow-up. The median duration of follow-up was a little under four years. During this time, a total of 278 heart attacks and 868 strokes were diagnosed. People who had heart attacks were significantly more likely to have traditional risk factors as well as hepatitis C and kidney disease.

The overall heart-attack rate was 3.69 per 1000 person years, while the overall stroke rate was 11.68 per 1000 person years. An unadjusted statistical analysis showed that use of abacavir was associated with an increased risk of heart attack that was of borderline significance (hazard ratio [HR] 1.27, or 27% increased risk). Abacavir was also linked to a slight increase in the risk of stroke (HR 1.17).

However, when the investigators repeated their analysis after controlling for recognised heart disease risk factors and co-existing conditions, the associations between abacavir and heart attack or stroke were weak and no longer close to being statistically significant.

In particular, the researchers noted that people with kidney disease were significantly more likely to have heart attacks and also significantly more likely to be prescribed abacavir, indicating that kidney dysfunction may be an important confounding factor. In fact, kidney disease was associated with a significantly higher risk of heart attacks and strokes even when no other risk factors were considered.

BICOMBO

The second study was a retrospective analysis of data from the Spanish BICOMBO study, a randomised comparison of abacavir plus 3TC (Epivir) versus tenofovir plus FTC (Emtriva).

The original study included more than 300 patients with suppressed viral load who were randomly assigned to switch to the abacavir or tenofovir combination pill. This analysis included a subset of 80 patients. Of these, 46 were taking abacavir/3TC; the rest were being treated with tenofovir/FTC. Participants had been on antiretroviral therapy for an average of nearly four years.

The investigators measured several blood biomarkers associated with an increased risk of cardiovascular disease. These included C-reactive protein, monocyte chemottractant protein-1, osteoprotegrin, adiponectin, IL-6, IL-10, tumour necrosis factor-alpha, ICAM-1, VCAM-1, selectin E and P, D-dimer, and insulin.

There were no significant differences in baseline biomarker levels between the abacavir-treated patients and those taking tenofovir. After a year of treatment, changes in all biomarker levels were relatively minor and were comparable for patients taking abacavir and those taking tenofovir.

The researchers concluded that among otherwise healthy HIV patients with suppressed viral load, starting abacavir did not lead to significant changes in biomarkers of inflammation, coagulation, blood vessel dysfunction, or insulin resistance. These results, they said, "argue against the involvement of abacavir in any of these mechanisms" and do not explain the higher risk of heart attack seen in some recent cohort studies.

In another presentation at the same session, the lead investigator with a French study (ANRS CO4) presented earlier this year that showed a link between abacavir and heart attacks risk reported that use of cocaine and injecting drug use were strong cardiovascular risk factors that must be taken into account.

These studies do not put to rest the debate about whether abacavir is a risk factor for cardiovascular events, but do emphasise the importance of looking carefully at potentially confounding factors.

Further information

Powerpoint presentations by Roger Bedimo and Esteban Martinez, and a webcast of the conference session in which they were presented are available on the IAS 2009 website.

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