Integrase inhibitors more likely to be linked to depression and suicidality than other HIV drugs

Cases of new-onset depression and suicidal behaviour are each more likely to be reported for integrase inhibitors than any other type of antiretroviral drug, a review of the World Health Organization’s side-effects reporting database has found.

Healthcare workers need to be alert for these rare adverse events during the early months of integrase inhibitor treatment and more research is needed to understand the causes, say French researchers who carried out a review of more than 124,000 reports of adverse reactions to antiretroviral drugs.

Depression is common among people with HIV and there is some evidence that suicide rates are higher in people with HIV. UK research found that the suicide rate in men with HIV, but not women, was twice as high as the general population. The risk was highest in the first year after HIV diagnosis.

Both depression and suicidal thoughts or behaviour have been identified as potential side effects of integrase inhibitors in clinical trials and post-marketing surveillance. However, it’s unclear to what extent this class of antiretroviral might increase the risk of suicidal behaviour or depression and whether there are any differences between integrase inhibitors.

Integrase inhibitors include dolutegravir (Tivicay, also included in Triumeq, Juluca and Dovato), bictegravir (in Biktarvy), cabotegravir (Vocabria or Cabuneva), elvitegravir (in Stribild and Genvoya) and raltegravir (Isentress).

As integrase inhibitors are the most widely prescribed anchor drug in antiretroviral regimens throughout the world, it is important to know more about the potential risk of suicidality or depression. To answer this question, researchers from the Centre Régional de Pharmacovigilance, Université Paris Cité, needed to assess whether these adverse drug effects were reported in disproportionate numbers in people taking integrase inhibitors compared to other types of antiretrovirals.

The French research group analysed case safety reports submitted to VigiBase, the World Health Organization pharmacovigilance database, to identify case reports classified as depression or “suicide/self-injury” in people taking an antiretroviral drug between 2008 and 2020. The researchers were looking for ‘new onset’ events that emerged after starting a drug and which were identified in the case report as a potential adverse drug reaction.

Vigibase compiles all the adverse drug reaction case reports sent to national pharmacovigilance schemes by doctors, pharmacists and patients. These case reports are reviewed at the national level before being added to the WHO database.

A total of 19.99 million reports were submitted to VigiBase during this period, including 124,184 in people exposed to an antiretroviral drug. Of those taking an antiretroviral, 22,661 were taking an integrase inhibitor (18.2%).

The researchers identified 1404 cases of depression and 777 cases of suicidality linked to an antiretroviral drug. Of these, 547 cases of depression and 357 cases of suicidality were in people treated with an integrase inhibitor. Reports came most often from the United States, France and Spain.

They carried out a disproportionality analysis to determine whether the prevalence of depression or suicidal behaviours was higher in case reports concerning people taking integrase inhibitors than other drugs.

" In people with a previous psychiatric history, a treatment switch should be considered if neuropsychiatric side effects emerge."

The disproportionality analysis showed that reporting of depression or suicidality was three to four times higher for integrase inhibitors compared to other antiretrovirals.

Compared to other antiretroviral agents, integrase inhibitors were 3.6 times more likely to be associated with case reports of depression. All integrase inhibitors were associated with a higher likelihood of reporting depression. Bictegravir and dolutegravir were significantly more likely to be associated with depression than elvitegravir or raltegravir.

Compared to other antiretroviral agents, integrase inhibitors were 4.7 times more likely to be associated with case reports of suicidality. All integrase inhibitors were associated with a higher likelihood of reporting suicidality. Dolutegravir was significantly more likely to be associated with suicidality than other integrase inhibitors.

Depression developed an average of 90 days after starting an integrase inhibitor, although the onset was sooner in people taking bictegravir (30 days).

Although the average time between starting treatment and a suicide attempt was 90 days, there was large variation between drugs, ranging from an average of six days in people taking bictegravir to 90 days in people taking dolutegravir, 120 days in people taking raltegravir and 150 days in people taking cabotegravir.

The reasons for the higher rates of depression and suicidality in people taking integrase inhibitors are uncertain. As the case reports did not contain standardised information about medical history, CD4 count or time since HIV diagnosis, it was impossible to analyse the contribution of these factors. It’s unclear if people who attempted or committed suicide had a history of depression or suffered an exacerbation of an existing mental health condition as a result of starting an integrase inhibitor.

In people with a previous psychiatric history, a switch away from an integrase inhibitor should be considered if neuropsychiatric side effects emerge, say the researchers.

If you've been affected by some of the issues in this article, Samaritans can be contacted in the UK on 116 123, and in the US, the National Suicide Prevention Lifeline is 1-800-273-8255. Other international helplines can be found at www.befrienders.org or via this Wikipedia page.