People taking a protease inhibitor who have heart failure have an increased mortality risk, study claims

HIV-positive people who are taking antiretroviral therapy (ART) and are hospitalised due to heart failure are more likely to die because of cardiovascular disease if they are taking a regimen containing a protease inhibitor, according to research conducted in the United States and published in the Journal of the American College of Cardiology.

Mortality and hospital readmission rates were twice as high among people taking a protease inhibitor (PI) compared to a non-protease inhibitor (NPI) regimen. The relationship between PI therapy and these adverse outcomes remained significant after controlling for other risk factors.

“To our knowledge, these findings are the first data linking PI-based ART to adverse structural changes and outcomes among PWHIV [people with HIV] with HF [heart failure],” comment the researchers.

Glossary

protease inhibitor (PI)

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

cardiovascular

Relating to the heart and blood vessels.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

retrospective study

A type of longitudinal study in which information is collected on what has previously happened to people - for example, by reviewing their medical notes or by interviewing them about past events. 

inflammation

The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

But the authors of an accompanying editorial are not convinced. They note that many of the patients had ongoing HIV replication despite taking antiretrovirals, and they suggest this could have been a cause of cardiovascular death.

Thanks to ART, most HIV-positive people have an excellent life expectancy. The diseases of ageing, including cardiovascular disease, are now an important cause of serious illness and death among HIV-positive people.

Heart failure occurs when the heart is unable to pump blood, because of damage to valves or muscles in the heart, or prolonged high blood pressure, or because of congestion in the arteries that supply the heart. The condition is progressive without treatment.

Treatment with PIs has been associated with adverse changes in cardiac structure and an increased risk of cardiovascular events. Investigators at the Mount Sinai Hospital in the Bronx wanted to see if PI treatment was associated with adverse cardiovascular outcomes among HIV-positive people hospitalised because of heart failure.

They therefore designed a retrospective study involving all antiretroviral-treated people admitted to their hospital with heart failure in 2011. The patients were stratified according to use of PI-containing and non-PI-containing regimens. Data were collected on the baseline prevalence of cardiovascular risk factors. The investigators compared cardiovascular mortality, and readmission due to heart failure within 30 days according to use of PI and non-PI regimens.

The study population consisted of 394 people. The median duration of ART was 8.5 years. Mean CD4 cell count was 295 cells/mm3 and median viral load was 274 copies/ml. Almost half (48%) of people had a detectable viral load (above 200 copies/ml). The mean age was 60 years and 47% of the sample were female.

Just over a third (37%) were taking a PI-containing regimen and 67% were taking a non-PI combination. All the PI regimens were ritonavir boosted.

People taking PIs had a higher prevalence of several cardiovascular risk factors than individuals treated with alternative regimens, including hyperlipidemia (52% vs 35%, p < 0.001), diabetes mellitus (44% vs 31%, p = 0.012), coronary artery disease (52% vs 33%, p < 0.001), higher pulmonary artery pressure (PASP) (p < 0.001) and lower left ventricular ejection fraction (LVEF) (p = 0.003).

During two years of follow-up, 23% of people died because of a cardiovascular cause. Cardiovascular mortality was 35% among people who were taking a PI at the time of their hospital admission with heart failure and 17% among people taking a non-PI regimen at the time of their admission. This difference was highly significant (p < 0.001).

Rates of hospital readmission due to heart failure within 30 days were also significantly higher among PI-treated people than non-PI-treated people (68% vs 34%, p < 0.001).

After controlling for other risk factors, PI therapy was associated with an almost twofold increase in the risk of cardiovascular mortality (HR = 1.797; 95% CI, 1.257-2.567, p = 0.001). A low CD4 cell count, abnormal cardiovascular structure and history of coronary artery disease were also risk factors.

“Further research is needed to determine whether PI-based regimens, either individual regimens or as a class effect, contribute pathophysiologically to processes leading to worse outcomes in HF…and whether these findings can be replicated in prospective cohorts,” conclude the investigators.

However, the authors of an accompanying editorial believe the study’s findings are far from definitive.

They believe the results are “intriguing” but also note that a very high proportion of people had ongoing HIV replication and that the investigators did not present data on medication adherence, one of many limitations they highlight in the study design.

“We suggest that immune dysregulation and inflammation are also plausible mechanisms for the higher mortality seen in PHIV,” they write. “Data on medication adherence and viral suppression should be carefully collected because not only is medication adherence an important predictor of health outcomes among PHIV, but also differences by drug class may serve as important confounders for cardiovascular endpoints.”

References

Alvi RM et al. Protease inhibitors and cardiovascular outcomes in patients with HIV and heart failure. JACC, online edition, DOI: 10.1016/j.jacc.2018.04.083

Rosenson RS et al. Cardiovascular outcomes in persons with HIV and heart failure: medication class or suboptimal viral suppression? JACC, online edition, DOI: 10.1016/j.jacc.2018.05.031

Related topics