More evidence that integrase inhibitors don’t raise heart disease risk

Mareike Günsche |

Integrase inhibitors do not increase the risk of major cardiovascular events such as a heart attack or stroke compared to other types of antiretroviral drug over four years of follow-up, a large multinational study reports in Lancet HIV.

The study confirms research from the Swiss HIV Cohort, which used a similar method of calculating the risk, and contradicts the findings of a study of people with HIV in Europe and Australia which found a raised risk during the first two years on treatment.

Integrase inhibitors are the most commonly prescribed anchor drug in an antiretroviral combination, usually combined with one or two other drugs. Globally, dolutegravir (in Triumeq or Dovato as well as numerous generic combinations) is taken by almost 20 million people and bictegravir (in Biktarvy) is widely prescribed in Europe and North America.


integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.


Relating to the heart and blood vessels.

cardiovascular disease

Disease of the heart or blood vessels, such as heart attack (myocardial infarction) and stroke.


The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.


Confounding exists if the true association between one factor (Factor A) and an outcome is obscured because there is a second factor (Factor B) which is associated with both Factor A and the outcome. Confounding is often a problem in observational studies when the characteristics of people in one group differ from the characteristics of people in another group. When confounding factors are known they can be measured and controlled for (see ‘multivariable analysis’), but some confounding factors are likely to be unknown or unmeasured. This can lead to biased results. Confounding is not usually a problem in randomised controlled trials. 

Concerns about the potential cardiovascular risks associated with the integrase inhibitor class of drug have arisen because of weight and metabolic changes occurring in people who take them.

People taking integrase inhibitors are more likely to gain weight than people taking other regimens and some studies have shown an increased risk of diabetes and other metabolic complications in people taking integrase inhibitors. These factors increase the risk of cardiovascular disease. Studies in Africa, Europe and Australia have found an increased risk of high blood pressure, another risk factor for cardiovascular disease, in people taking integrase inhibitors.

Studies looking at the risk of cardiovascular disease in people with HIV have produced contradictory results. A large North American study found the risk of cardiovascular disease was lower in people taking integrase inhibitors compared to other antiretrovirals, a Swiss study found the risk was the same and a European and Australian study found the risk was higher.

But all these findings come from observational studies. Although researchers can use statistical methods to adjust for biases, these methods do not have the same rigour as a randomised clinical trial, in which confounding factors tend to be equally distributed between groups by random assignment of participants to a treatment.

One example of a confounding factor is use of antiretroviral drugs which are known to raise cardiovascular risk. Abacavir and darunavir are known to increase cardiovascular risk, so it is possible that people with higher baseline risk will be channelled away from these drugs.

To overcome the lack of data on integrase inhibitors and cardiovascular disease from large clinical trials comparing drug classes, researchers from the Antiretroviral Therapy Cohort Collaboration and HIV-CAUSAL collaboration designed a 'target trial emulation' using data from 12 cohorts of people with HIV in Europe and North America.

A target trial emulation imitates a clinical trial protocol in terms of who is selected, how long they are followed and having a predefined outcome of interest, but uses the observational data from a cohort to provide the follow-up data for ‘participants’. Participants are selected from a cohort database if their treatment matches one of the two assigned treatment regimens. Then the risk factors for heart disease in the trial population needs to be characterised as fully as possible so that potential confounding factors can be adjusted for in the analysis, in order to ensure that the two groups are balanced. The Swiss study cited above employed this kind of approach too.

At CROI 2023, Dr Bernard Surial from the University of Bern spoke to NAM's Roger Pebody about a previous study on integrase inhibitors and cardiovascular disease.

The study looked for major cardiovascular events: stroke, heart attack, clinical intervention for a cardiac problem or undefined major events. It compared 10,767 previously untreated people who started treatment with an integrase inhibitor and 8292 people who started another type of antiretroviral regimen between 2013 and 2023. The analysis excluded people with a previous diagnosis of cancer.

The median age of previously untreated participants was 39, just over 85% were male and the median CD4 count upon starting treatment was approximately 350.

Previously untreated people taking integrase inhibitors or other treatment did not differ except for hepatitis B coinfection and hypertension, both of which were slightly more common in people treated with non-integrase regimens. People starting integrase inhibitors had significantly higher baseline viral load than people starting other regimens (78,000 vs 66,000 copies/ml) but the difference is not clinically significant. They were also slightly more likely to have diabetes. Twenty percent of integrase inhibitor recipients and 6% of non-integrase inhibitor recipients took abacavir during their first six months on treatment (abacavir increases cardiovascular risk). These factors were all adjusted for in the analysis.

In the intent-to-treat analysis, which assessed everyone according to their initial therapy and followed them for four years, there were 43 cardiovascular events in the integrase treatment group and 52 in the non-integrase group. After adjusting for demographic and HIV-related factors, smoking, body mass and metabolic factors, the 4-year risk was 0.76% in people taking an integrase inhibitor and 0.75% in people taking another type of antiretroviral. When the analysis was restricted to people who stayed on their initial class of antiretroviral (per-protocol) throughout follow-up, the adjusted risk was 0.6% in the integrase inhibitor group and 0.88% in the non-integrase inhibitor group.

A separate analysis in treatment-experienced people compared cardiovascular risk in 7875 virologically suppressed people who switched to an integrase inhibitor and 67,411 virologically suppressed people who switched to a non-integrase-containing regimen between 2013 and 2023.

Treatment-experienced people were older than previously untreated people (median age 50) and had been taking antiretroviral therapy for a median of six years. The median CD4 count in this group was approximately 620. People taking integrase inhibitors were significantly more likely to have diabetes, raised cholesterol or hepatitis C and less likely to have a previous AIDS diagnosis, but the absolute differences were small. Abacavir use in the preceding six months was more common in the integrase inhibitor group. Again, these factors were adjusted for in the analysis.

In the intent-to-treat analysis, there were 56 cardiovascular events in people taking integrase inhibitors and 808 events in people taking other regimens, an adjusted 4-year risk of 1.41% in the integrase inhibitor group and 1.48% in the non-integrase group. In the per-protocol analysis the respective 4-year risks were 1.2% and 1.34%.

Although the study was not designed to look at specific integrase inhibitors, they say that sensitivity analyses which looked at people who started treatment with either dolutegravir or bictegravir found no differences from the overall study result. Equally, sensitivity analyses which focused on the three most commonly prescribed integrase inhibitor-containing regimens – thereby taking account of the drugs integrase inhibitors were prescribed with – found no differences from the overall study result.

The researchers say their study shows no increased risk of cardiovascular events in people taking integrase inhibitors and that the incidence of events in the cohorts they studied is consistent with other studies on this question.