This article discusses a significant study presented at the 19th European AIDS Conference (EACS 2023), held in Warsaw, Poland, from October 18-20, 2023. Professor Bernard Surial from the University of Bern in Switzerland shared the results of an international cohort study, which revealed that the use of integrase strand transfer inhibitors (INSTIs) in the treatment of HIV does not increase the risk of cardiovascular events.
Study Overview:
The study included clinical data from 12 international cohorts in Europe and North America, collected from January 2013 to January 2023. It focused on cardiovascular events, BMI, and blood pressure in HIV-infected cohorts. For treatment-naïve HIV patients, inclusion criteria were being over 18 years old, having HIV RNA levels above 50 copies/mL, and no history of cardiovascular events or cancer. For patients previously treated with non-INSTI-based ART, criteria included being over 18, having been treated with at least one non-INSTI-based ART regimen, viral suppression (HIV RNA ≤ 50 copies/mL), and no prior history of cardiovascular events or cancer.
Researchers used a time-adjusted and baseline covariate-adjusted summary logistic regression model to estimate standardized 4-year cardiovascular event risks. The results showed similar risk levels between INSTI-treated and non-INSTI-treated groups in both treatment-naïve and experienced patients, indicating that INSTI use does not lead to a clinically significant increase in cardiovascular event risk.
Q: Could you explain what the Swiss Cohort study is and share some of its key findings, particularly those related to integrase inhibitors and CVD events in people with HIV starting art?
Dr. Surial: Yes, so the Swiss HIV Cohort Study is a nationally representative cohort of all people with HIV in Switzerland. It collects data on 70 to 80% of all people who receive ART in Switzerland. And it’s a really nice platform to study a lot of clinical questions that could be related to cardiometric conditions but also to a lot of basic science research questions for which the cohort is also very active.
And so regarding integrase inhibitors, we have just published a paper this year where we found that the use of integrase inhibitors, at least in people with HIV who start them, was not associated with an increased risk of cardiovascular disease. This was quite reassuring for us because patients were really concerned about their cardiovascular disease risk.
Q: Thank you. And could you elaborate on the methodology used in this study, particularly the target trial framework and the use of inverse probability treatment and censoring of ways?
Dr. Surial: Yes, so the target trial framework is a very important tool. The target trial framework is actually, it’s a method where you define a protocol from a hypothetical trial where you clearly try to define the patient population, the intervention and the outcome, similar to a randomized trial. So that means that the intervention needs to be clearly defined and the population needs to be clearly defined, similar to a randomized trial. For example, it’s very difficult to imagine a randomized trial conducted among treatment naive and treatment experienced patients. That was actually, what we did. It what was very important to restrict the analysis to people who were treatment naive and I have to acknowledge that we still need a similar study in treatment experienced individuals.
Regarding the inverse probability weighting and censoring weights. After baseline there are things that happened, for example individuals were switching from non –INSTI ART to INSTI ART, which can introduce selection bias. So you have to adjust for that using censoring weights which is done with inverse probability weighting. And in the study there is no significant difference in short or long term risk for CVD events between treatment-naïve people with HIV who started INSTI based art and those are other art once we accounted for this fact.
Q: Can you discuss the implication of these findings for treatment for HIV patients?
Dr. Surial: Yeah, I think it’s a very important question because worldwide now the primary antiretroviral therapy regimen that people are receiving are Integrase-inhibitor based. And so it is very reassuring to know that at least when you start the drug in those patients it does not lead to an increased risk. So from that point of view I think it has a big implication also for international guidelines.
Q: So would you like to comment on the use of INSTI in the treatment of HIV particularly in relation to findings of Swiss cohort study?
Dr. Surial: Yeah, I think it goes again to what I just said that integrase inhibitors are really a key component of antiretroviral therapy because of their really high barrier to resistance, they’re really well tolerated and they’re also very effective, actually even more effective than most other drugs and so I think they will keep their place in the guidelines as first line for a long time. Also, I’m quite happy to see that at least for treatment naive individuals this does not translate into an increased cardiovascular disease.
What’s interesting or important to say is that we’ve seen that integrase inhibitors can lead to an increase in obesity, there are also studies that showed that integrase inhibitors can lead to an increased rate of hypertension and whether this will translate in long term into an increased risk of cardiovascular disease. say maybe 10, 20 years, this is still unclear. We don’t have data on that.
Q: What are the next steps in your research following the finding from this risk cohort study? And are there any specific areas where further research is needed?
Dr. Surial: Yeah, so I think the next step, what we will do is we will repeat the analysis in treatment experienced individuals. This is a bit more difficult to do and not as straightforward as in treatment naive individuals. So this will be very important. And then of course also, we need to understand better why these, why ART components lead to those cardiovascular comorbidities.
References:
1. Rein SM, Lodi S, Logan RW, Touloumi G, Antoniadou A, Wittkop L, Bonnet F, van Sighem A, van der Valk M, Reiss P, Klein MB, Young J, Jarrin I, d’Arminio Monforte A, Tavelli A, Meyer L, Tran L, Gill MJ, Lang R, Surial B, Haas AD, Justice AC, Rentsch CT, Phillips A, Sabin CA, Miro JM, Trickey A, Ingle SM, Sterne JAC, Hernán MA; Antiretroviral Therapy Cohort Collaboration and the HIV-CAUSAL Collaboration. Integrase strand-transfer inhibitor use and cardiovascular events in adults with HIV: an emulation of target trials in the HIV-CAUSAL Collaboration and the Antiretroviral Therapy Cohort Collaboration. Lancet HIV. 2023 Nov;10(11):e723-e732.
2. Surial B, Chammartin F, Damas J, Calmy A, Haerry D, Stöckle M, Schmid P, Bernasconi E, Fux CA, Tarr PE, Günthard HF, Wandeler G, Rauch A; Swiss HIV Cohort Study. Impact of Integrase Inhibitors on Cardiovascular Disease Events in People With Human Immunodeficiency Virus Starting Antiretroviral Therapy. Clin Infect Dis. 2023 Sep 11;77(5):729-737.
