People treated with atazanavir had lower risk of stroke and heart attack

People who started HIV treatment with a drug combination containing atazanavir (Reyataz) were significantly less likely to suffer a heart attack or stroke than people starting treatment with other regimens, a large study of US military veterans has found.

The findings are published in advance online in the journal AIDS.

Atazanavir is an HIV protease inhibitor that has been prescribed widely in the United States and Europe as part of first-line antiretroviral treatment since the drug was licensed in 2003. Clinical trials have shown that participants who received atazanavir experienced significantly smaller increases in LDL (`bad`) cholesterol and total cholesterol than those treated with other protease inhibitors or with the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. Lipid levels were lower in people treated with atazanavir regardless of whether it was boosted with ritonavir or not.

Increased lipid levels as a result of HIV infection and its treatment contribute to an increased risk of cardiovascular disease in people living with HIV compared to the general population. Recent US research has led researchers to argue that HIV infection is just as significant a risk factor for heart disease as diabetes and that the long-term impact of HIV on cardiovascular risk is still not fully appreciated.

Although antiretroviral treatment reduces the risk of cardiovascular disease in people living with HIV, some protease inhibitors have been associated with an increased risk of cardiovascular disease compared to other treatment regimens. The D:A:D study of long-term adverse effects of antiretroviral therapy has reported that indinavir, lopinavir/ritonavir (Kaletra) and darunavir/ritonavir are each associated with an increased risk of cardiovascular events (heart attack and/or stroke).

On the other hand, there are biological grounds for thinking that atazanavir may reduce the risk of cardiovascular disease. As well as the lack of lipid elevations observed in clinical trials, atazanavir treatment also results in raised levels of bilirubin which are asymptomatic in the majority of people treated with the drug. In people with Gilbert’s syndrome, characterised by long-term modest increases in bilirubin, the risk of cardiovascular disease is approximately half that seen in the general population. An analysis of over 96,000 people in the Veterans Aging Cohort Study found that elevated bilirubin was associated with a reduced risk of heart failure in people living with HIV, investigators reported at this year’s Conference on Retroviruses and Opportunistic Infections.

To find out whether the early effects of atazanavir on lipid levels and bilirubin translate into a longer-term reduction in cardiovascular risk in people taking HIV treatment, researchers from the University of Utah looked at the long-term outcomes of 9500 people with HIV who started antiretroviral treatment between 2003 and 2015 under the care of the Veteran’s Health Affairs healthcare system in the United States. The study was funded by a grant from Bristol-Myers Squibb, the manufacturer of atazanavir.

Of the 9500 people, 1529 received atazanavir, 2053 another protease inhibitor, 5307 an NNRTI and 611 an integrase inhibitor. The average age of the cohort was 50. The study population had a high prevalence of cardiovascular risk factors: 56% were African American, 28% were smokers, 36% were already receiving medication for high blood pressure, 13% had diabetes and 10% had a history of cardiovascular disease. The prevalence of all cardiovascular risk factors was higher in this study population than in the D:A:D cohort.

All cardiovascular risk factors with the exception of previous heart attack were more common in people treated with integrase inhibitors. This may be explained by a tendency to prescribe integrase inhibitors to people perceived to be at higher risk of cardiovascular disease.

Atazanavir was more likely to be prescribed to people with psychiatric disorders, to African Americans and to people with mildly impaired renal function. People with multiple cardiovascular risk factors were more likely to receive an integrase inhibitor (raltegravir, elvitegravir or dolutegravir) than atazanavir.

Although follow-up time was relatively short – a mean of 13 months – the study found a higher rate of cardiovascular events than previous studies, and found a significantly lower risk of cardiovascular events (stroke or heart attack) in people treated with atazanavir or atazanavir/ritonavir. Compared to people receiving other regimens, people treated with atazanavir were approximately 40% less likely to experience a heart attack (adjusted hazard ratio 0.59, 95% CI 0.41-0.84) or a stroke (AHR 0.64, 0.50-0.81).

Seventy-five per cent of people taking other regimens were taking agents recommended in the 2016 US Department of Health and Human Services guidelines, which prefer an integrase inhibitor, darunavir/ritonavir, atazanavir/ritonavir, efavirenz or rilpivirine as the third agent in first-line treatment, so the analysis is highly relevant to current prescribing.

The effect appeared strongest when atazanavir was compared only to protease inhibitors but was also significant when atazanavir was compared to NNRTIs. Sensitivity analyses which included adjustments for guideline changes and year of treatment initiation showed that the association persisted for stroke, and for heart attack when atazanavir was compared to non-atazanavir treatment or to other protease inhibitor treatment but ceased to show a significant difference in the risk of heart attack when atazanavir was compared to NNRTIs.

The researchers say that theirs is the first study to find a reduced risk of cardiovascular events in people taking atazanavir and they urge more research to understand the mechanisms leading to the lowered risk.