- A class of anti-HIV drugs called integrase inhibitors is generally safe and highly effective
- One study observed greater cardiovascular disease risk with integrase inhibitors
- Only about 2.5% of people in the study were affected; other studies need to confirm the link
A class of anti-HIV drugs called integrase inhibitors plays a vital role in HIV treatment regimens today. Clinical trials over the past 17 years have found integrase inhibitor–based therapy to be generally safe and highly effective. Another factor that favours integrase inhibitors is that they tend to have far fewer interactions with other medicines compared to earlier classes of HIV treatment.
The first integrase inhibitor, raltegravir (Isentress), became available around 2007 and subsequently others were developed, such as elvitegravir. This drug is co-formulated with other anti-HIV drugs and sold in pills called Stribild and Genvoya.
However, leading clinical guidelines no longer recommend raltegravir or elvitegravir. Instead, they recommend the following integrase inhibitors, which are widely used today:
- bictegravir – co-formulated with other anti-HIV drugs and sold in a pill called Biktarvy
- dolutegravir – sold by itself in a pill called Tivicay and also co-formulated with other anti-HIV drugs and sold in pills called Dovato, Juluca and Triumeq
The Respond cohort
A large database called Respond is populated mostly with patients from Europe and also some from Argentina, Australia and the UK. Respond is headquartered in Copenhagen and has about 30,000 participants, all of whom have HIV. From time to time, researchers associated with Respond analyse the data and produce reports.
An analysis from Respond
In their latest report (in press in the journal Lancet HIV), researchers with Respond analysed data from 29,340 people. They found an unusual association: a very small proportion (2.5%) of participants developed cardiovascular disease after initiating a regimen anchored by an integrase inhibitor. The people who used integrase inhibitors were about twice as likely to develop cardiovascular events (heart attack, stroke, the need for cardiovascular surgery) than people who did not use this class of drugs.
This finding alone would be unusual, as it has previously not been reported and integrase inhibitors have been in use for a long time. But there is more: the risk for cardiovascular events was greatest during the first six months of using integrase inhibitors. After this time, the risk for cardiovascular events fell, and 24 months after participants started using integrase inhibitors the risk reached the same level seen with regimens that do not contain this class of anti-HIV drug. This increase and then decrease in risk occurred while participants stayed on integrase inhibitor–based regimens.
These findings from Respond are deeply puzzling and much work lies ahead to explain and understand the up-and-down risk for cardiovascular events while people remained on integrase-based regimens.
The average profile of participants in the study was as follows:
- 74% men, 26% women; there were 44 transgender people, none of whom developed cardiovascular events
- age: 44 years
- major ethno-racial groups: White – 70%; Black – 10%
- key populations: gay and bisexual men – 45%; heterosexuals – 35%; people who use drugs – 14%
- CD4+ cell count: 524 cells/mm3; 41% had a CD4+ count below the 200 cell/mm3 mark at some point in the past, indicating severe immune deficiency
- smoking status: never smoked – 28%; current smoker – 28%; former smoker – 8%; unknown – 36%
- length of time in the study: six years; the analysis began in January 2012 and ended in January 2019
The distribution of cardiovascular disease events was as follows:
- heart attack – 40%
- stroke – 30%
- invasive cardiovascular procedures – 30%
When researchers considered many factors—including CD4+ cell count, gender, body mass index (BMI), high blood pressure, abnormal cholesterol levels, diabetes, and so on—they found that the association between integrase inhibitors and cardiovascular disease events was similar whether people were at high or low estimated risk for cardiovascular disease. A similar finding occurred with age; that is, people who used integrase inhibitors were at increased risk for cardiovascular disease events whether they were older or younger. However, as mentioned previously, after six months, the increased risk for cardiovascular disease then fell relatively quickly.
The researchers were not able to isolate a specific integrase inhibitor with the temporarily increased risk for cardiovascular disease. For instance, in January 2014 dolutegravir was approved in the European Union, but the signal of risk existed prior to this time and continued afterward (personal communication, Bastian Neesgaard, MD, PhD).
Likewise, bictegravir (in Biktarvy) was approved in June 2018 in the European Union, but the signal of risk existed prior to this time and continued afterward.
Points to consider
Although the news from Respond sounds scary, note that a relatively small proportion of people—2.5%—was affected. Furthermore, the period of greatest risk was in the first six months of use of integrase inhibitors and the risk fell thereafter, eventually becoming similar to that seen in people with HIV on other regimens.
Clues from another study with elvitegravir
The findings from Respond are largely unexpected, as up until now no large study of integrase inhibitors has found an association with increased cardiovascular disease risk. However, a small (36-person) Spanish study found that for the first six months of use, the older integrase inhibitor elvitegravir (found in Stribild and Genvoya) was associated with increased measures of inflammation. As heightened inflammation is associated with an increased risk for cardiovascular disease, it is perhaps plausible that the use of elvitegravir could have raised the risk for cardiovascular disease in susceptible people in Respond.
However, in the Respond analysis, the researchers are not yet able to unpack the effect of different integrase inhibitors and their potential link to cardiovascular disease. Adding to the complexity of future investigations, HIV infection itself is well known to incite and accelerate cardiovascular disease, likely through its effects on inflammation.
The Respond researchers acknowledge that it is possible that some people who were prescribed integrase inhibitors had risk factors for cardiovascular disease that were not measured by the study team.
It is important to note that the design of Respond, which is an observational study, is an issue that itself requires consideration. Observational studies cannot prove that the use of integrase inhibitors caused the serious cardiovascular issues in some participants. As the cardiovascular events were relatively uncommon, a massive and long-term randomized clinical trial would be needed to conclusively answer the issues raised in the Respond analysis. However, such a trial would take years to reach completion and would be expensive.
Advice from scientists outside of Respond
The participants in Respond are from major HIV clinics in Europe and elsewhere. The findings are real in the sense that the cardiovascular events analysed did occur. The question is why? A team of scientists from the University of the Witwatersrand in Johannesburg, South Africa, has reviewed the findings from Respond and placed them in context for clinicians and patients. They stated: “Thankfully, data before [the latest Respond analysis] suggest high levels of safety and efficacy for [dolutegravir and bictegravir], so cautious watchfulness is appropriate for now. But the need to confirm or refute [Respond’s findings] with further studies is now pressing.”
Aware of these issues, the Respond team has called for “analyses in other large studies to verify our findings, and for the potential underlying mechanisms to be explored.”
—Sean R. Hosein
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