Psychiatric Symptoms in Patients Receiving Dolutegravir

Anna Fettiplace, PhD, MBChB; Chris Stainsby, BSc Hons; Alan Winston, MD; Naomi Givens, MSc; Sarah Puccini, BSc Hons; Vani Vannappagari, PhD; Ricky Hsu, MD; Jennifer Fusco, BS; Romina Quercia, MD, PhD; Michael Aboud, MBChB, MRCP; Lloyd Curtis, MA, MRCP


J Acquir Immune Defic Syndr. 2017;74(4):423-431. 

In This Article

Abstract and Introduction


Introduction: Psychiatric symptoms (PSs) are reported to occur frequently in people living with HIV and may be associated with specific antiretrovirals. We analyzed PSs observed with dolutegravir (DTG) and other frequently prescribed anchor drugs.

Methods: Selected PSs (insomnia, anxiety, depression, and suicidality) occurring in HIV-positive patients during DTG treatment across 5 randomized clinical trials (3 double-blind), in the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, and among cases spontaneously reported to ViiV Healthcare were analyzed.

Results: In clinical trials, PSs were reported at low and similar rates in patients receiving DTG or comparators [atazanavir, darunavir, efavirenz, or raltegravir (RAL)]. Insomnia was most commonly reported. The highest rates were observed in SINGLE (DTG 17%, efavirenz 12%), with consistently lower rates in the other trials (DTG: 3%–8% versus comparator: 3%–7%). More efavirenz-treated patients withdrew because of PSs than patients treated with other anchor drugs. In OPERA, history of PSs at baseline was lowest in efavirenz-treated patients compared with patients treated with DTG, RAL, or darunavir. Despite baseline differences, prevalence and incidence during treatment were similar across the 4 anchor drugs. Withdrawal rates for PSs were lowest for DTG (0%–0.6%) and highest for RAL (0%–2.5%). Spontaneously reported events were similar in nature to clinical trial data.

Conclusions: Analysis of 3 different data sources shows that, similar to other frequently prescribed anchor drugs to treat HIV infection, PSs are also reported in DTG-treated patients. These events are reported with low frequency and rarely necessitate DTG discontinuation.


The integrase strand transfer inhibitor (INSTI) class of antiretroviral drugs used to treat HIV-1 infection includes raltegravir (RAL), elvitegravir, and dolutegravir (DTG). Clinical studies using INSTIs have demonstrated 80%–90% efficacy in HIV-positive, antiretroviral therapy (ART)-naive patients.[1] The INSTIs have also demonstrated favorable safety and tolerability,[2] are recommended options for patients initiating ART,[3–6] and are often used in switch strategies for patients with tolerability issues.[2,7] They show similar rates of adverse events (AEs), with nausea, diarrhea, and headache reported most commonly.[7–9] These AEs have been shown to be mild to moderate in severity and are not typically associated with treatment discontinuation. Psychiatric symptoms (PSs) have been reported in patients treated with INSTI class drugs but typically occur less frequently than in patients treated with efavirenz.[9,10]

PSs are substantially more frequent among persons living with HIV (PLWH; anxiety 28%, depression up to 48%, insomnia 29%–73%)[11–15] compared with the general population (anxiety 7.3%, depression 5%–10%, and insomnia 3.6%–18%).[11,12,15–17] The rate of suicide for PLWH has been reported to be up to 8 times higher than that of the general population.[18,19] A systematic review of studies published between 1989 and 2008 showed a prevalence of 27% (range 4%–78%) for suicidal ideation among PLWH.[20] Although the underlying pathogenesis of PS in PLWH remains elusive, several factors have been proposed. The etiology is likely multifactorial, including immune activation due to HIV disease, antiretroviral toxicities, stigma from living with HIV, and lifestyle factors, such as drug and alcohol use, which may be higher in PLWH compared with control populations.[15,21–23] Although antiretroviral therapy improves survival and reduces morbidity in PLWH, PSs may be associated with certain antiretroviral agents.[10,24]

High background rates of psychiatric conditions among PLWH and the likely multifactorial pathogenesis make it challenging to assess the relationship between PSs and specific antiretroviral therapies. The objectives of this analysis are to provide insight into the frequency and characteristics of PSs that have been reported in patients treated with DTG-based regimens using new data sources, including aggregated data from ViiV Healthcare clinical trials, the Observational Pharmaco-Epidemiology Research & Analysis (OPERA)[25] cohort, and cases spontaneously reported to ViiV Healthcare; and put these findings in the context of results for other anchor drugs.