In my practice, 5% to 15% of the patients I start on dolutegravir (DTG) experience intolerable headaches or insomnia that necessitate a switch to another agent. This level of intolerance is higher than reported from clinical trials. I always wonder whether the patients of other clinicians have had the same "real-world" experience with DTG side effects and now several recent studies shed light on this issue. 

In one study, researchers from the Netherlands (de Boer, et al. PMID: 27824625) reported on the tolerability of DTG among 556 patients initiated on DTG between August 2014 and March 2016. DTG was stopped in 76 patients (13.7%) due to adverse drug reactions after a median of 73 days (range 5-327). The combination of DTG with abacavir (ABC) led to a higher overall discontinuation rate (16.3%). The majority of side effects were neuropsychological or psychiatric (insomnia, headaches, mood alterations, and malaise) and gastrointestinal. Discontinuation for neuropsychiatric side effects was 2.3 times more likely among patients taking DTG plus ABC.

Other researchers have also reported neuropsychiatric side effects with DTG. Researchers in Germany (Hoffmann, et al. PMID: 27860104) evaluated a cohort of 1,704 patients who initiated an ART regimen containing an integrase strand transfer inhibitor (ISTI) between January 2007 and April 2016. The rates of adverse events leading to discontinuation within 12 months were 7.6% for elvitegravir (EVG), 7.6% for DTG, and 3.3% for raltegravir (RAL). Renal side effects were the leading cause of EVG discontinuation (3.5%); neuropsychiatric side effects were most commonly reported with DTG (5.0%). The most common neuropsychiatric symptoms among the 49 patients who discontinued DTG were insomnia and other sleep disturbances, dizziness, headache, poor concentration or slowed thinking, depression, and painful paresthesia.

An older (2015) case series from France that includes four patients (Kheloufi, et al. PMID: 26372287) described the following symptoms post-DTG-initiation: fatigue and "drunk feeling" in patient 1, headaches and depression in patient 2, worsening psychiatric symptoms in patient 3, and intense headaches (which spontaneously resolved) followed by suicidal ideation in patient 4. 

DTG is a highly potent agent with a high barrier to resistance and unparalleled outcomes in randomized trials (Cahn, et al. PMID: 23830355; Clotet, et al. PMID: 24698485; Walmsley, et al. PMID: 24195548), and it appears to be very well tolerated in most patients who do not experience side effects. For these reasons, it has an important role in current antiretroviral therapy (ART). However, assessing for side effects and correctly identifying DTG as a potential cause of new and unexpected symptoms in the days to weeks after initiating this drug is essential to optimal care. My experience with the side effects with DTG has taken a little of the shine off this potent agent and has led me to consider the potential for DTG-associated side effects when selecting a regimen for an ART-naïve patient or planning a switch for failure or convenience.    

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