Psychiatric Symptoms Rare With Dolutegravir in Trials and Large Cohort

Psychiatric symptoms including insomnia and depression proved infrequent with the integrase inhibitor dolutegravir (Tivicay, DTG) and similar to rates with other key antiretrovirals in an analysis of five randomized trials, a large cohort and spontaneous reports. In the cohort analysis, the prevalence and incidence of psychiatric symptoms were similar with dolutegravir and three comparator antiretrovirals.

Psychiatric symptoms often affect people with HIV infection and have been linked to antiretroviral therapy, notably with efavirenz (Sustiva, Stocrin). Suicidal ideation troubles about one-quarter of HIV-positive people, according to the results of a 1989-2008 systematic review. The authors of the new study suggest psychiatric symptoms in HIV populations can be traced to multiple factors, including antiretroviral toxicity, immune activation, stigma and habits such as drinking and drug use. To get a better understanding of these problems in people taking contemporary antiretroviral regimens, they conducted this retrospective review.

The analysis focused on four psychiatric symptoms (rather than formal diagnoses) -- insomnia, depression, anxiety and suicidality -- reported in five phase 3 randomized trials (three of them double-blind), the OPERA cohort study of people with HIV and spontaneous reports to ViiV Healthcare, maker of dolutegravir. The trials involved one or more of four comparator drugs: atazanavir (Reyataz), darunavir (Prezista), efavirenz or raltegravir (Isentress). OPERA includes 6,347 HIV-positive people starting a regimen containing dolutegravir, darunavir, efavirenz or raltegravir. Spontaneously reported cases of psychiatric problems were reported to the ViiV Healthcare Global Safety Database through February 2016.

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The five clinical trials involved 1672 adults taking dolutegravir and 1681 taking a comparator antiretroviral. For anxiety, depression and suicidality, the four antiretrovirals assessed did not differ in median time to symptom onset, proportion of drug-related psychiatric events or serious or grade 3 or 4 events. A higher proportion of participants taking efavirenz than one of the other three drugs withdrew because of psychiatric symptom (4% versus <1%). In the SINGLE trial insomnia affected a larger proportion of people taking dolutegravir than efavirenz (17% versus 12%). But insomnia rates were consistently lower with dolutegravir in the other four trials and comparable with rates seen with comparator drugs. Suicidality was rare and considered drug-related in two of 20 people taking dolutegravir and five of 20 taking a comparator antiretroviral.

Median follow-up stood at 15 months in the OPERA cohort and was similar among regimens. History of anxiety, depression and insomnia was highest among cohort members taking dolutegravir and lowest among efavirenz takers. Yet, prevalence of anxiety, depression and insomnia during follow-up was similar among the four antiretrovirals assessed, with three exceptions: anxiety or depression prevalence was higher among raltegravir-treated people, while insomnia prevalence was lower in the darunavir group. Treatment discontinuations for anxiety, depression and insomnia were usually lowest in dolutegravir takers. Among people who did not have anxiety, depression or insomnia when they entered the cohort, incidence of these symptoms was similar across the four antiretrovirals assessed. A lower proportion of people stopped dolutegravir than the other three antiretrovirals for these three symptoms (0.1% versus 0.3%). Prevalence and incidence of suicidality were low and similar for the four drugs.

Spontaneously reported cases of depression, anxiety and suicidality were 0.55 per 1000 or lower with either dolutegravir or dolutegravir/abacavir/lamivudine (Triumeq). Spontaneously reported cases of insomnia were 1.23 per 1000 with dolutegravir and 1.11 per 1000 with dolutegravir/abacavir/lamivudine. Overall, rates of the four symptoms combined were about three per 1000.

The researchers conclude that rates of the four psychiatric symptoms were low among people taking dolutegravir in all three data sources -- trials, the OPERA cohort and spontaneous reports to the manufacturer. Dolutegravir discontinuation rates for these problems were also low, and these symptoms typically resolved or improved as treatment continued. The researchers propose that "the consistency of data from the clinical trials, the OPERA cohort, and spontaneously reported cases supports the reliability of the conclusions."