Only a few people starting an integrase inhibitor discontinue the treatment during the first year of therapy due to drug-related toxicities, investigators from Switzerland report in an advance online publication in the journal AIDS. The prospective study monitored over 4000 HIV-positive people who started treatment with raltegravir or dolutegravir between 2006 and 2015. Side-effects leading to the discontinuation of therapy occurred in 5% of people and less than 2% of individuals switched from an integrase inhibitor because of neuropsychiatric toxicity.
“Raltegravir or dolutegravir drug toxicity is an infrequent reason for treatment modification,” comment the authors.
The HIV integrase inhibitors raltegravir and dolutegravir are preferred options in the antiretroviral treatment guidelines of the International AIDS Society and European AIDS Clinical Society. The drugs have a powerful anti-HIV effect, a low risk of resistance, a convenient dosing schedule, few known interactions and – according to the results of clinical trials – are safe and well tolerated.
However, there have been reports from “real world” practice of higher than expected rates of dolutegravir treatment discontinuation due to drug-related toxicities, especially neuropsychiatric side-effects.
Investigators from the Swiss HIV Cohort Study designed a prospective study to compare the frequency and risk factors of discontinuation in the first year of treatment with raltegravir or dolutegravir.
Adults who started treatment with either drug between 2006 and 2015 and who had at least 12 months of follow-up were eligible for inclusion.
The study population comprised 4041 people, 2091 of whom initiated therapy with raltegravir and 1950 with dolutegravir.
During the first year of therapy, 568 (14%) people changed treatment for any reason, corresponding to a discontinuation rate of 15.5 per 100 patient-years. A total of 364 (17%) people starting raltegravir changed therapy compared to 204 (11%) individuals initiating dolutegravir.
The main reason for changing treatment was convenience (n = 302) but 181 people stopped taking an integrase inhibitor because of intolerance or toxicity. Only ten people taking raltegravir and two taking dolutegravir experienced virological failure.
Risk factors for changing therapy were female gender (HR = 1.28; 95% CI, 1.06-1.53, p = 0.009), younger age (HR = 0.90; 95% CI, 0.83-0.98 per ten years older, p = 0.011), baseline viral load above 100,000 copies/ml (HR = 1.49; 95% CI, 1.09-2.02, p = 0.011) and starting a raltegravir-containing regimen (HR = 1.71; 95% CI, 1.38-2.08, p < 0.001).
Side-effects leading to a treatment occurred in 5% of people, a discontinuation rate of 4.4 per 100 patient-years for dolutegravir and 5.7 per 100 patient-years for raltegravir, a non-significant difference.
The only risk factor for a toxicity-driven treatment change was female gender (HR = 1.98; 95% CI, 1.45-2.71, p < 0.002).
Neuropsychiatric complaints were the most commonly reported toxicity but occurred in less than 2% of people. The discontinuation rate for this side-effect was higher for dolutegravir (1.83 per 100 patient-years) than raltegravir (0.70 per 100 patient-years). Analysis of the individuals reporting neuropsychiatric toxicity showed a significantly lower risk of treatment discontinuation for raltegravir compared to dolutegravir (HR = 0.46; 95% CI, 0.22-0.96, p = 0.037).
Gastrointestinal side-effects were the second most common reason for changing therapy and were reported by 19 dolutegravir-treated people and six people taking raltegravir. Immune reconstitution inflammatory syndrome was observed in seven people, six of whom were taking raltegravir. Allergies and lipid elevations occurred more frequently with raltegravir (16 and 12, respectively) than dolutegravir (4 and 1, respectively).
Overall, the authors were encouraged by these findings. Nevertheless, they recommend that people taking dolutegravir should be monitored for neuropsychiatric side-effects.
In a separate letter to the journal, investigators from the Marseille regional centre for pharmacovigilance say that neuropsychiatric adverse reactions to integrase inhibitors are probably under-reported to national health authorities and that greater vigilance is needed. They point out that as integrase inhibitors become more widely used in the treatment of HIV worldwide, a better understanding of the risk of severe neuropsychiatric adverse effects such as depression, anxiety disorders and suicidal behaviour is needed.
Elzi L et al. Adverse events of raltegravir and dolutegravir: a prospective analysis of 4,041 HIV-infected individuals from the Swiss HIV Cohort Study. AIDS, online edition. DOI: 10.1097/QAD.0000000000001590, 2017.
Kheloufi et al. Neuropsychiatric events and dolutegravir in HIV patients: a worldwide issue involving a class effect. AIDS, online edition, 2017.