Five antiretroviral combinations associated with increased risk of a cardiovascular event

Treatment with four individual and five combinations of anti-HIV drugs is associated with an increased risk of a cardiovascular event, investigators from the United States report in the online edition of Clinical Infectious Diseases.

But the authors emphasise that the absolute risk of an event was low and suggest “the primary consideration in choice of ART [antiretroviral therapy] regimen should be its efficacy for HIV and tolerability. In situations in which equally effective regimens are available, clinicians may want to consider the potential elevation in risk of cardiovascular events, particularly in patients who are older or who have cardiovascular risk factors.”

The life expectancy of many people with HIV is now normal. However, cardiovascular disease is an important cause of serious illness and death in people with HIV. The reasons for this are not yet fully understood. Traditional risk factors are thought to have an important role, so too the inflammatory effects of HIV infection. But individual anti-HIV drugs, especially abacavir and protease inhibitors, have been associated with an increased risk of a cardiovascular event in some studies.

Glossary

cardiovascular

Relating to the heart and blood vessels.

absolute risk

The chance that a person will experience a specific event during a period of time. It is always between 0 and 1 (when expressed as a probability), or between 0 and 100 (when expressed as a percentage).

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.

diabetes

A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body fails to produce insulin, which is a hormone that regulates blood sugar. Type 2 diabetes occurs when the body either does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, unusual thirst and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.

integrase

HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected.

HIV therapy consists of treatment with a combination of at least three antiretroviral drugs. It is therefore important to know if specific drug combinations can increase the risk of cardiovascular events.

To answer this question, investigators designed a study involving 24,510 people with HIV enrolled in the Veterans Health Administration Case Registry, who received antiretroviral therapy between 1996 and 2009.

“We chose to evaluate combinations of ART drugs because the drugs are always used in combination,” explain the authors. “It is possible that combinations of drugs may elevate cardiovascular risk in a way that would not be discoverable by assessing only individual drugs, or by assessing classes of drugs, as prior studies have done.”

Fifteen individual drugs and 23 combinations were considered in the investigators’ analyses. Integrase inhibitors and newer non-nucleoside reverse transcriptase inhibitors (NNRTIs) were not included, but older drugs such as indinavir, nelfinavir and full-dose ritonavir were included.

The study participants had an average baseline age of 47 years. Almost half (47%) had a history of smoking and 12% had evidence of diabetes. Although fewer than 1% of individuals had experienced a cardiovascular event at baseline, some 18% had been taking statins for a year or more. The authors believe that the high prevalence of cardiovascular risk factors made this an especially appropriate population in which to examine the association between individual antiretroviral drugs and combinations and the risk of cardiovascular events – heart attack, stroke, percutaneous coronary intervention (angioplasty) and bypass surgery.

During over 164,000 years of follow-up, 934 people experienced a cardiovascular event.

The study looked at the relationship between current exposure to drug combinations at the time of an event rather than cumulative exposure.

Current treatment with four individual drugs was associated with this outcome:

  • Lamivudine (OR = 1.53; 95% CI, 1.34-1.75)
  • Abacavir (OR = 1.50; 95% CI, 1.26-1.79)
  • Efavirenz (OR = 1.40; 95% CI, 1.19-1.66)
  • Zidovudine (OR = 1.41; 95% CI, 1.22-1-63)

Current therapy with five regimens was also associated with increased risk of a cardiovascular event:

  • Abacavir/lamivudine/atazanavir (OR = 2.08; 95% CI, 1.41-3.06)
  • Zidovudine/lamivudine/atazanavir (OR = 2.04; 95% CI, 1.37-3.02)
  • Abacavir/lamivudine/efavirenz (OR = 1.94; 95% CI, 1.34-2.79)
  • Zidovudine/lamivudine/efavirenz (OR = 1.60; 95% CI, 1.25-2.04)
  • Zidovudine/abacavir/lamivudine (OR = 1.60; 95% CI, 1.21-2.11).

The authors emphasise that their analyses were designed to take into account competing risk factors. Results were similar results in a secondary analysis, which implicated four drugs and two combinations.

“Ours is the first study to evaluate the association between combinations of antiretroviral medications and risk of cardiovascular events,” comment the researchers. “Five combinations were implicated by our primary analysis.”

But the investigators urge caution in the interpretation of their results. “To provide some context for our findings, we note that the absolute risk of cardiovascular events for our cohort is twice that of a population with similar cardiovascular risk factors (approximately 4% versus 1.8%. The absolute risk, however, is still low. We suggest clinicians interpret our findings in light of the relatively low absolute risk of cardiovascular events.”

References

Desai M et al. Risk of cardiovascular events associated with current exposure to HIV antiretroviral therapies in a US veteran population. Clin Infect Dis, online edition, 2015.