Update on Adverse Reactions of HIV Integrase Inhibitors

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Integrase strand transfer inhibitors (INSTIs) are a generally well-tolerated class of antiretrovirals that have a higher antiviral potency compared with other classes of ART.

Integrase strand transfer inhibitors (INSTIs) are a generally well-tolerated class of antiretrovirals and have a higher antiviral potency compared with other classes of antiretroviral therapy (ART), according to results of a review published in Current Treatment Options in Infectious Diseases.  INSTIs recently became the class of choice and pharmacogenetics is a promising way to explore their adversereactions.

The purpose of this review was to seek answers regarding neuropsychiatric adverse reactions, as well as weight gain, because these are the 2 most common categories of adverse reactions established in preivous studies. Dolutegravir is related to the heaviest burden in terms of neuropsychiatric side effects. Weight gain was reported with all INSTIs, but methodologic caveats in the analysis exist and therefore caution in interpreting this finding is needed.

According to the investigators’ results, INSTIs are well tolerated and effective, but clinicians and patients need to be aware of some red flags when starting treatment and monitoring patients taking INSTIs. Mild increases in creatinine levels are possible with all INSTIs, usually without clinical significance, but caution is needed in patients with a low estimated glomerular filtration rate (<30ml/min), when using other nephrotoxic drugs such as tenofovir disoproxil.

Neuropsychiatric effects should be monitored with all INSTIs, most notably dolutegravir; however, reports are at times contradictory. Therefore, clinicians may wish to avoid dolutegravir in patients with a history of severe neuropsychiatric symptoms until further clarity is provided. Weight gain was also reported with all INSTIs, but was also more notable with dolutegravir. There are possible differential effects according to sex and ethnicity, with female and non-white patients being at increased risk. This finding was concerning because patients of African descent are at higher risk for cardiovascular events and increased body mass index can cause further increased metabolic risk. Furthermore, there is a possibility of an additional effect of tenofovir alafenamide on weight increases.

Investigators found discrepancies between clinical trials, which had low rates of adverse events, and reports from real-life settings. This may be due partly to under-representation of some groups of patients, along with the short duration of follow-up, as some adverse reactionsonly occur after prolonged exposure. There is reassuring data on the safety of bictegravir from both clinical trials and in non-trial settings, which seems to show lower rates of adverse events compared with dolutegravir.

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Caution is required for elvitegravir/cobicistat in patients with other comorbidities due to the potential for polypharmacy, as in the case of aging patients, because of the high potential of drug-drug interactions due to the effects of the cobicistat booster. Finally, the investigators report that cabotegravir could represent a good option for patients struggling with medication adherence despite injection site reactions, but they are awaiting the release of this medication.

The review concluded that the literature affirms, “that all INSTIs are generally well tolerated, although side-effect profiles differ between drugs.” The investigators also suggested that persons experiencing adverse reactions with one INSTIs may tolerate another drug in the class, but caution that switching may result in new side effects.


Kolakowska A, Maresca A.F, Collins IJ, Cailhol J. Update on adverse effects of HIV integrase inhibitors. Curr Treat Options Infect Dis. 2019;11:372.