Meta-analysis reports no significant risk of cardiac, IRIS or suicide with dolutegravir
Polly Clayden, HIV i-Base
Meta-analysis shows no significant effect of dolutegravir on the risk of cardiac, IRIS or suicide-related serious adverse events. There was a higher risk of insomnia with dolutegravir-based ART.
The results were first presented at EACS 2017 and published in the March 2018 edition of Current Opinion in HIV and AIDS. [1, 2, 3] Although slightly expanded in the recent article the safety findings have remained consistent.
In this meta-analysis of 6647 patient-years follow up, the authors found a higher risk of Grade 1–4 insomnia adverse events for dolutegravir compared to other antiretrovirals: 6.1 vs 4.5% respectively, p=0.02.
But they found no significant difference between dolutegravir and other antiretrovirals in the risk of cardiovascular serious adverse events.
The authors note that as there are plans to switch millions of people onto dolutegravir-based treatment in sub-Saharan Africa within the next 18 months, this transition needs to be supported by continued pharmacovigilance with meta-analysis to monitor safety.
As other randomised trials looking at dolutegravir are completed these should be included in further safety evaluations: DAWNING (n=627), SWORD 1 and 2 (n=1024), Gilead trial 1489 (n=629) and Gilead trial 1490 (n=645).
The authors also highlight a recent analysis of the psychiatric disorders reported to the WHO pharmacovigilance database suggesting a higher risk of depression, suicide and self-injury for dolutegravir and raltegravir, compared with elvitegravir.  “Analyses of this type need to be repeated regularly and checked for potential confounding factors” they add.
Many other studies at EACS 2017 found few differences between dolutegravir and other integrase inhibitors. [5-8]
Also, an intensive six-month dolutegravir sleep study in older participants (>60 years), was presented at the PK workshop last year by Marta Boffito and colleagues. This study reported that higher dolutegravir Cmax and AUC were associated with reduced sleep time, but there were no significant changes in sleep scores over the first 28 days after switching to dolutegravir/abacavir/3TC. 
Unlike with sleep disturbance with efavirenz, dolutegravir can be taken in the morning and anecdotally this overcomes difficulties with insomnia in most cases, without causing additional problems during the day.
- Hill A and Mitchell N. Meta-analysis of safety for DTG versus other ARVs in randomised trials: analysis of cardiovascular, CNS and IRIS endpoints. 16th EACS, 2017, Milan. Poster abstract PE12/17.
- Clayden P. Studies on dolutegravir and sleep, cardiovascular and CNS side effects, and risk of IRIS. HTB. 28 November 2017.
- Hill AM et al. Risks of cardiovascular or central nervous system adverse events and immune reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals: meta-analysis of randomised trials. Curr Opin HIV AIDS. 13 (2) March 2018.
- Kheloufi F et al. Neuropsychiatric events and dolutegravir in HIV patients: a worldwide issue involving a class effect. AIDS 2017; 31:1775 –1777.
- Bollen P et al. Discontinuation of dolutegravir- and elvitegravir-containing cART in the Netherlands: incidence rates and risk factors. 16th EACS, 2017, Milan. Poster abstract PE12/10.
- Mondi A et al. Effectiveness and discontinuation rate of dolutegravir (DTG)-based regimens as either first line or switch antiretroviral therapy (ART): data from the Icona Cohort. 16th EACS, 2017, Milan. Poster abstract PE9/83.
- Migliorini D et al. Experience in using dolutegravir in experienced and treatment naïve patients attending two HIV clinics in Northamptonshire UK. 16th EACS, 2017, Milan. Poster abstract PE12/3.
- Lüftenegger D et al. Tolerability and persistence of dolutegravir-based regimens: second interim analysis of the prospective multicenter DOL-ART cohort. 16th EACS, 2017, Milan. Poster abstract PE9/52.
- Elliot E et al. Relationship between dolutegravir plasma exposure, quality of sleep and its functional outcome in patients living with HIV over the age of 60 years. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, 14- 16 June 2017, Chicago. Oral abstract O8.