Protease inhibitors and heart disease - more evidence of risk

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Concerns that the metabolic disorders associated with anti-HIV therapies may lead to an increased risk of angina and heart attack were boosted today at the International AIDS Conference in Barcelona, Spain.

Dr Giuseppe Barbero reported a randomised study looking at the risk of coronary artery disease among 1,551 HIV-infected people taking highly active antiretroviral therapy (HAART). Comparing two key drug classes – the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) − Dr Barbero found that people taking protease inhibitors had a significantly increased risk of coronary artery disease.

Twenty-three cases of coronary artery disease occurred among 587 people who took PIs for 42 months. In contrast, only two cases of coronary artery disease developed among 621 NNRTI recipients. This translates into a cumulative annual incidence rate of 9.8 cases per 1000 patient-years among those taking PIs compared to 0.8 cases per 1000 patient-years among those taking NNRTIs.

Glossary

coronary artery disease (CAD)

Occurs when the walls of the coronary arteries become narrowed by a gradual fatty build-up. It may lead to angina or heart attack.

metabolism

The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.

nucleoside

A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 

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. 

The incidence of myocardial infarction or heart attack was 5.1 per 1,000 patient years for those taking PIs.

In line with these findings, metabolic disorders and lipodystrophy were significantly more common in the PI group.

Commenting on the findings, Dr Jens Lundgren warned that the low number of coronary events means that the incidence figures are not highly reliable. He also cautioned that nearly half of the original participants did not complete follow-up, raising some doubts about the reliability of the figures.

The general relevance of these findings to other populations is also confounded by the high rate of smoking among study participants. Smoking, defined as more than 15 cigarettes per day, was reported by 87% of participants.

Nevertheless, Dr Lundgren described the study as “very important”. He said the results provided “the strongest evidence I have seen” of a causal link between heart disease and protease inhibitors. He also commented that there appears to be a “lagtime” of about 20 months between the development of metabolic markers which put people at risk of heart disease and actual events such as heart attack or angina.

References

Barbero G et al. Incidence of coronary artery disease in HIV-infected patients receiving or not protease inhibitors: a randomized, multicenter study. Fourteenth International AIDS Conference, Barcelona, WeOr1307, 2002.

Lundgren JD. Perspective of HIV-associated coronary heart disease. Fourteenth International AIDS Conference, Barcelona, WeOr203, 2002.