Back HIV-Related Conditions Cardiovascular Current HIV Protease Inhibitor Use Not Linked to Sudden Death or Stroke, but Cumulative Exposure Ups Risk

Current HIV Protease Inhibitor Use Not Linked to Sudden Death or Stroke, but Cumulative Exposure Ups Risk


Current or recent use of HIV protease inhibitors was not associated with a significantly increased likelihood of sudden death or a first ischemic stroke among participants in the D:A:D cohort, according to a report in the February 2012 Journal of Infectious Diseases. Longer total cumulative use, however, did appear to raise the risk.

A number of observational studies over the years have indicated that people using antiretroviral therapy (ART) have a higher risk of cardiovascular events such as heart attacks and strokes. Certain antiretroviral drugs have been linked to blood lipid abnormalities and changes in normal heart rhythm (arrhythmias).

Elevated "bad" cholesterol and triglycerides can contribute to artery blockage (atherosclerosis) that can deprive the heart of oxygen, leading to muscle damage or death (myocardial infarction). Bits of plaque or clots from arteries can break off and lodge in blood vessels in the brain, leading to oxygen-deprivation or ischemic stroke (another type of stroke, known as hemorrhagic, is due to uncontrolled bleeding in the brain). Furthermore, some HIV protease inhibitors (PIs) may interfere with cardiac electrical conductivity, leading to arrhythmias that could result in a heart attack.

However, HIV infection itself is associated with atherosclerosis, and studies such as SMART indicate that ART interruption and delayed treatment can worsen cardiovascular health. Such conflicting findings have proven frustrating for both patients and clinicians.

The latest set of data comes from the large D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) study, a long-running prospective analysis of multiple HIV patient cohorts in the U.S., Europe, and Australia.

The D:A:D researchers hypothesized that sudden death and non-hemorrhagic stroke could be rare end-stage outcomes of heart rhythm abnormalities such as prolonged QT or PR intervals on an electrocardiogram (ECG). If PI exposure directly causes such abnormalities, PI users might be expected to have excess risk of sudden death and stroke.

The investigators followed 49,737 people with HIV for a total of 234,818 person-years, collecting data about all incident (new) cases of myocardial infarction, new non-hemorrhagic strokes, and all deaths due to any cause. Within this group, 31,876 (64%) had used PIs, for a median of 1.5 years (range 0 to 5 years). Recent use was classified as use during the past year.


  • During the study period there were 78 reported sudden deaths (0.33 per 1000 person-years) and 172 first non-hemorrhagic strokes (0.73 per 1000 person-years).
  • Looking at sudden death and stroke combined, the rate was 1.3 per 1000 person-years among current and recent PI users, compared with 0.9 per 1000 person-years for those without recent PI exposure.
  • In an unadjusted analysis, current or recent PI exposure was associated with a 42% greater risk of sudden death or stroke (unadjusted rate ratio 1.42; P = 0.005).
  • Several known cardiovascular risk factors -- male sex, older age, smoking, low body weight, diabetes, high blood pressure, history of prior heart disease -- were also independently associated with greater likelihood of sudden death or stroke combined.
  • After adjusting for confounding factors, there was no significant association between current or recent PI exposure and sudden death or non-hemorrhagic stroke (adjusted rate ratio 1.22; P = 0.12).
  • In a secondary analysis, however, cumulative PI exposure was associated with a small but significant 6% annual risk increase (adjusted rate ratio 1.06 per additional year of exposure).

"We did not observe an independent association between current or recent use of PIs (as a class) and the risk of sudden death or non-hemorrhagic stroke," the study authors concluded.

"Although our primary hypothesis was that any association with PI exposure would be relatively short lived, we did find that the risk of an event increased as cumulative exposure increased," they continued. "[T]his association remained significant after adjustment for potential confounders and is more consistent with our previously reported results indicating that PI exposure may lead to the development of ischemic coronary disease, which, in turn, may result in sudden death."

Given that sudden death due to abnormal heart rhythms does not appear to be more common among current PI users, the investigators suggested that it would be premature to recommend routine electrocardiograms for all patients using these drugs, but further research is needed.

Investigator affiliations: Copenhagen HIV Programme, University of Copenhagen, Denmark; Research Department of Infection and Population Health, University College London, London, UK; Academic Medical Center, Amsterdam, Netherlands; CHU Nice Hopital de l'Archet, Nice, France; Department of Infectious Diseases, CHU Saint-Pierre Hospital, Bruxelles, Belgium; Columbia University/Harlem Hospital, New York, NY; Hospital San Paolo, University of Milan, Italy; Kirby Institute, Sydney, Australia; University Victor Segalen ISPED Bordeaux, France; University Hospital, Zurich, Switzerland; Research Department of Infection and Population Health, University College London, London, United Kingdom; Copenhagen HIV Programme, University of Copenhagen, Denmark.



SW Worm, DA Kamara, P Reiss, et al (D:A:D Study Group). Evaluationof HIV Protease Inhibitor Use and the Risk of Sudden Death or Nonhemorrhagic Stroke. Journal of infectious Diseases 205(4):535-539. February 2012.