Large French study examines neuropsychiatric side effects with integrase inhibitors

Integrase inhibitors are a class of anti-HIV drugs widely used as part of HIV combination therapy (ART) in Canada and other high-income countries. Integrase inhibitors are used because of at least the following reasons:

• the amount of HIV in the blood usually falls relatively quickly with their use
• they are generally well tolerated
• they tend to have few drug interactions

The leading integrase inhibitor is the drug dolutegravir, sold under the following brand names:

• Tivicay – dolutegravir
• Juluca – dolutegravir + rilpivirine
• Triumeq – dolutegravir + abacavir + 3TC

Dolutegravir was first approved in high-income countries around 2013. Starting in 2016, reports emerged of dolutegravir-associated side effects, including the following:

• sleeping problems
• anxiety
• depression
• problems with concentration

This cluster of problems is generally referred to as “neuropsychiatric” side effects by researchers and doctors. In the initial reports about these problems with dolutegravir, the neuropsychiatric side effects seemed relatively common and, in some cases, seemed to particularly affect women. However, the reports largely came from datasets that may have had unmeasured factors that caused inadvertent bias when drawing conclusions. Nonetheless, it should not be surprising that dolutegravir can cause such side effects in a minority of people, as similar side effects have been reported with other integrase inhibitors.

In France

A team of scientists in France has conducted the largest prospective study to date about the use of integrase inhibitors and their potential for being associated with neuropsychiatric side effects. The scientists scoured data from more than 21,000 HIV-positive people from 18 major clinics in France. The team focused on people who were using integrase-inhibitor-containing regimens for the first time. These regimens were initiated between 2006—when the first integrase inhibitor (raltegravir; Isentress) became available—and the end of 2016.

The distribution of integrase inhibitors among study participants was as follows:

• dolutegravir – 6,274 people
• elvitegravir (in Genvoya and Stribild; the vast majority of people who used elvitegravir would have used the formulation called Genvoya) – 3,421 people
• raltegravir – 11,520 people

The average profile of participants upon entering the study was as follow:

• age – 49 years
• 72% men, 28% women
• CD4+ cell count – 500 cells/mm³
• viral load – less than 40 copies/mL

Most participants who took dolutegravir (66%) also took abacavir + 3TC, as these drugs are co-formulated with dolutegravir in one pill (Triumeq). People who took other integrase inhibitors used them mostly with the combination of tenofovir DF + FTC (sold as Truvada and available in generic formulations).

Results

The French scientists found that the following proportions of participants who were currently taking the following integrase inhibitors had experienced neuropsychiatric issues prior to using integrase inhibitors:

• dolutegravir – 5%
• elvitegravir – 3%
• raltegravir – 10%

As the study was large, all differences reported below were statistically significantly; that is, not likely due to chance alone.

Overall, about 35% of all participants discontinued taking an integrase inhibitor. The proportions of people who discontinued each regimen is as follows:

• dolutegravir – 13%
• elvitegravir – 20%
• raltegravir – 51%

It is important to bear in mind that raltegravir is generally well tolerated. In the present study, many raltegravir users discontinued their use of this drug for single-tablet regimens (Genvoya, Stribild or Triumeq), as raltegravir was not co-formulated with other drugs.

Here are the proportions of people who discontinued each regimen because of neuropsychiatric effects:

• dolutegravir – 2.7%
• elvitegravir – 1.3%
• raltegravir – 1.7%

Unlike smaller studies done in the past, the present French study found no increased risk of experiencing neuropsychiatric effects because of the following factors:

• age
• gender
• use of abacavir + 3TC

An unexpected result

The researchers found that the lower a person’s CD4+ cell count prior to initiating ART, the greater the risk of them experiencing neuropsychiatric side effects. Although this association was statistically robust in their analysis, the researchers cannot explain why it occurred.

Bear in mind

The French study was not a randomized clinical trial; such a trial with more than 21,000 people would have been expensive and not feasible. Randomization is an important way to help reduce the risk of drawing biased conclusions when interpreting the results from a study. This lack of randomization led the French researchers to underscore that people who were prescribed dolutegravir in this study (vs. elvitegravir) were more likely to:

• be older
• have been HIV positive for longer
• have a long history of using ART
• have previously experienced neuropsychiatric side effects from other medicines prior to the use of dolutegravir

Key points

• This prospective French study with more than 21,000 participants using integrase inhibitors will likely become the landmark study about the overall rate of neuropsychiatric side effects with this class of medicines over the next several years.
• The proportion of participants who stopped taking integrase inhibitors due to neuropsychiatric side effects was generally very low, between 1% and 3%. When it comes to the safety of integrase inhibitors, these figures are reassuring for doctors, nurses, pharmacists and patients.
• It is important to note that the French study’s design cannot prove that specific integrase inhibitors mentioned in the study caused neuropsychiatric side effects.
• The scientists stated that, overall, “discontinuation for side effects was less frequent with dolutegravir than with elvitegravir.” However, they noted that “discontinuation for neuropsychiatric side effects, although rare (2.7%), was more frequent with dolutegravir.”
• An important point to note is that prior to initiating treatment with an integrase-inhibitor-containing regimen, between 3% and 10% of participants had previously experienced neuropsychiatric side effects.

—Sean R. Hosein

REFERENCES:

Cuzin L, Pugliese P, Katlama C, et al. Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort. Journal of Antimicrobial Chemotherapy. 2019 Mar 1;74(3):754-760.