Integrase inhibitors do not raise cardiovascular risk in people starting HIV treatment

Starting treatment with an integrase inhibitor did not lead to an increased risk of heart attack, stroke or heart surgery in people with HIV in Switzerland, Dr Bernard Surial from the Swiss HIV Cohort study reported on Tuesday at the 30th Conference on Retroviruses and Opportunistic Infections (CROI 2023) in Seattle.

The question of whether integrase inhibitors affect cardiovascular risk has been uncertain. As with any new type of medication, large-scale study of their effects on heart disease takes time. Although integrase inhibitors are less likely to cause increases in cholesterol, people with HIV taking integrase inhibitors tend to gain more weight after starting treatment than others. Substantial weight gain might raise the risk of cardiovascular disease.

Studies of the question have produced contradictory findings.

One study of more than 20,000 people with HIV who started treatment in the United States found that people who started treatment with an integrase inhibitor had a lower risk of a serious cardiovascular event.

But the RESPOND cohort consortium, analysing data from people with HIV in Europe, Argentina and Australia, found that taking an integrase inhibitor raised the risk of a cardiovascular event during the first two years of treatment. Yet, after two years on treatment, the increased risk disappeared, leaving researchers struggling to explain how medication-related risk could disappear after two years of exposure to a drug.

For the new study, researchers assessed the risk of a serious cardiovascular event (stroke, heart attack or an invasive procedure such as angioplasty or stenting) in people with HIV who started treatment in Switzerland after May 2008. 

During the study period, 5362 people started treatment, 1837 with an integrase inhibitor-based regimen and 3525 with another type of regimen. Prescriptions for integrase inhibitors began to increase after they were recommended for first-line treatment in 2012 and formed the majority of prescriptions for first-line treatment from 2014 onwards. In 2021, 96% of people in the Swiss HIV Cohort started treatment with an integrase inhibitor.

More than half of people who started an integrase inhibitor received dolutegravir (53%). The rest received bictegravir (18%), elvitegravir (16%) or raltegravir (13%).

Of those who started treatment with a different regimen, 52% received a boosted protease inhibitor, 43% a non-nucleoside reverse transcriptase inhibitor and 5% another type of regimen.

Study participants who started with an integrase inhibitor or another drug class were evenly matched in most respects. The average age at which people started treatment was 39 years, approximately half of participants smoked, 10% had high blood pressure and 1.5% had a previous history of cardiovascular disease.

A higher proportion of those who started treatment with a non-integrase inhibitor regimen were women (24% vs 11% of integrase inhibitor recipients) and African (18% vs 11% of integrase inhibitor recipients).

Approximately one in four people who started an integrase inhibitor-based regimen also received abacavir, compared to one in eight of those who started a non-integrase inhibitor regimen. Tenofovir alafenamide was taken by 40% of people starting an integrase inhibitor but only 1% of those taking a non-integrase inhibitor regimen.

During a median follow-up period of 4.9 years, 116 cardiovascular events occurred. After adjusting for demographic and HIV-related factors as well as cardiovascular risk factors, NRTI backbone and use of lipid-lowering medication, the investigators found no significant difference in the risk of cardiovascular events at any time-point in follow-up (-0.2% risk difference at two years and -0.6% risk difference at five years).

Presenting the results, Dr Surial said that larger international cohort collaborations should replicate this analysis and should also look separately at treatment-experienced people who have switched to an integrase inhibitor.

He drew attention to potential biases that could exist in studies of cardiovascular risk and integrase inhibitor treatment, including switching of people with comorbidities onto integrase inhibitors to reduce the risk of drug-drug interactions. If more people at higher risk of cardiovascular disease are channelled onto a specific drug, that will affect its cardiovascular risk profile, so it is important to control carefully for these factors when assessing risks. He also pointed out that women – who have a lower risk of cardiovascular disease than men – may not have received integrase inhibitor treatment due to concerns about neural tube defects if they were exposed to dolutegravir around the time of conception.