LAUSR

With great interest we have read the recent article by Hoffmann et al. [1], in which an almost 6% discontinuation rate for dolutegravir (DGV) because of neuropsychiatric adverse events was described in a large cohort study. To illustrate the importance of these findings, we describe two patients with unexpected DGV-associated severe depression, in conjunction with presenting a concise review of the recent literature on DGV-induced depression. The first patient was a 58-year-old man with an unremarkable medical and psychiatric history and a newly diagnosed HIV infection. He was in good health and did not use comedication. His CD4 T-cell count was 549 cells/lL and his viral load was 165 000 HIV-1 RNA copies/mL. No coinfections were diagnosed. One month after his first visit he was started on abacavir/lamivudine/DGV (Triumeq , Viiv Healthcare, Brentford, UK), which he took before sleeping. One week later he began to feel gloomy, followed shortly by feeling extremely depressed. He developed paranoid ideation and short-tempered behaviour. Laboratory testing was unremarkable. Subsequently, Triumeq was stopped and elvitegravir/cobicistat/emtricitabine/tenofovir was started instead. Within 1 week his symptoms improved. Twenty days after the medication switch, his symptoms had resolved completely. Three months later, he felt emotionally stable without any relapse of his depressive symptoms. The second patient was a 52-year-old man with HIV infection whowas switched to DGV, abacavir and lamivudine (Triumeq ) after complaints of tiredness allegedly caused by efavirenz. He did not have a psychiatric history. His HIV-1 viral load was undetectable, his CD4 T-cell count was 738 cells/lL and serology for hepatitis B and C viruses and syphilis was negative. Twomonths after the switch he began to feel mildly depressed. While remaining uninformed of this, his attending physician continued treatment 4 months after switching cART. His symptoms worsened and he developed distressing suicidal thoughts. Finally, on the verge of committing a serious suicide attempt, he was admitted to the psychiatric unit of our hospital. Laboratory screening did not reveal abnormalities; no other potential causes could be identified. cART was switched the same day to boosted darunavir plus tenofovir and emtricitabine. He was started on benzodiazepines (oxazepam 10 mg three times a day). Five days later he was able to be discharged with a significant reduction of his psychiatric symptoms. Two weeks later, his depressive disorder was almost in remission. Three months later he was active again without any of the psychiatric symptoms that had bothered him before. These cases demonstrate that patients without any preexisting history of psychiatric illness can develop severe depressive symptoms after starting a DGV-containing regimen. In both cases, no other predisposing or precipitating factors were found that could explain the onset of depression. The depressive symptoms improved quickly after the withdrawal of DGV, while at the same time neither patient was treated with antidepressants. This strongly suggests a causal relationship. In addition, Hoffmann et al. [1] reported recurrence of neuropsychiatric symptoms upon re-exposure to DGV after earlier discontinuation in six patients. These observations have been confirmed in a case series and three other cohort studies (Table 1) in which the incidence of depression and other neurocognitive side effects that led to withdrawal of DGV appeared to occur more frequently than reported in the registration studies [1–3]. Data from two of these cohort studies suggest that the threshold for intolerability may be lowered by co-administration of abacavir, but more data are needed to draw stronger conclusions [2]. These relatively high discontinuation rates because of neuropsychiatric symptoms are unexpected and in contrast with the data of preceding clinical trials. A recent meta-analysis of clinical trials reported discontinuing dolutegravir because of adverse events in < 2% of patients [4]. A review of five clinical trials, the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort study and 50 cases spontaneously reported to ViiV Healthcare with suicidality reported discontinuation rates because of psychiatric symptoms in only 0.1 to 0.6% of DGV-treated patients [5]. In these trials, depression occurred within 1 month after starting treatment. It is noteworthy that depressive symptoms Correspondence: Dr Mark G. J. de Boer, Department of Infectious Diseases, Leiden University Medical Center, PO Box 9600, Leiden, The Netherlands. Tel: +31715262613; fax: +3175266758; e-mail: [email protected]