Dolutegravir in the real world – more intolerance than first thought?

Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice.

de Boer MG, van den Berk GE, van Holten N, Oryszcyn JE, Dorama W, Moha DA, Brinkman K. AIDS. 2016 Nov 28;30(18):2831-2834.

Objective: Dolutegravir (DGV) is one of the preferred antiretroviral agents in first-line combination antiretroviral therapy (cART). Though considered to be a well tolerated drug, we aimed to determine the actual rate, timing and detailed motivation of stopping DGV in a real-life clinical setting.

Design: A cohort study including all patients who started DGV in two HIV treatment centers in The Netherlands.

Methods: All cART-naive and cART-experienced patients who had started DGV were identified from the institutional HIV databases. Clinical data, including motivation and timing of discontinuation of DGV, were extracted from the patient files. Factors that potentially influenced discontinuation of DGV were compared between patients who stopped or continued DGV by multivariate and Kaplan-Meier analyses.

Results: In total, 556 patients were included, of whom 102 (18.4%) were cART-naive at initiation of DGV. Median follow-up time was 225 days. Overall, in 85 patients (15.3%), DGV was stopped. In 76 patients (13.7%), this was due to intolerability. Insomnia and sleep disturbance (5.6%), gastrointestinal complaints (4.3%) and neuropsychiatric symptoms such as anxiety, psychosis and depression (4.3%) were the predominant reasons for switching DGV. In regimens that included abacavir, DGV was switched more frequently (adjusted relative risk 1.92, 95% confidence interval 1.09-3.38, P log-rank 0.01). No virologic failures were observed.

Conclusion: A relatively high rate of preliminary discontinuation of DGV due to intolerability was detected in our patient population. In particular, DGV was stopped more frequently if the regimen included abacavir. Multiple factors may explain these unexpected postmarketing observations, which warrant further investigation.

Abstract access  

Editor’s notes: The integrase inhibitor dolutegravir has been billed as a very important milestone in the treatment of HIV. Randomized controlled trials reported that not only was it a highly effective antiviral agent, but it also had a high barrier to resistance. Trial data also suggested an excellent safety profile. Trial participants experienced fewer side effects with dolutegravir use compared to many other drugs. For these reasons, dolutegravir is recommended as one of the preferred options for first-line treatment in European and United States treatment guidelines. In addition, it is increasingly becoming a key component in global efforts to expand access to HIV-positive people in low-income countries.

However, with increased use of dolutegravir beyond clinical trials, evidence is growing to suggest that the incidence of side effects is greater than trial data would predict. This study describes the two-year experience of a cohort spanning two medical centres in the Netherlands. It explores the rate and cause of discontinuation of dolutegravir-containing regimes in both antiretroviral therapy naïve and experienced individuals. Of 556 receiving a dolutegravir-containing regimen, just over 15% stopped its use over two years. Adverse effects were cited as the cause in a sizeable 13%. These rates of discontinuation are over five times higher than was reported from clinical trials. The predominant side effects were sleep disturbance and insomnia. Other reactions included gastrointestinal disturbances, anxiety, depression and general malaise. In terms of factors associated with increased risk of discontinuation, only the concomitant use of abacavir was identified.

These results do not detract from the importance of dolutegravir as an antiretroviral agent. Indeed, it is reassuring that in this cohort no virologic failure occurred as result of its discontinuation. The results instead highlight the need for caution concerning recommendations for dolutegravir as a universal first line agent until further data are accrued from real-world experience.

Europe
Netherlands
  • share