Further reports of CNS-related side effects with dolutegravir
Simon Collins, HIV i-Base
Several studies at Glasgow 2016 provided additional information about real world experience with the integrase inhibitor dolutegravir.
Although registrational studies showed that dolutegravir has higher efficacy and fewer side effects compared to many other drugs, post marketing experience has included higher reports of CNS-related side effects in a minority of patients.
These CNS symptoms include dizziness, nervousness, depression, headache, reduced concentration, insomnia and other sleep problems and other unexplained pain.
Four studies reported on retrospective analyses from clinical cohorts – two in Germany, one in Spain and one in the UK. Two other UK studies reported on generally good results from switching from efavirenz to dolutegravir. And an analysis from the manufacturer ViiV included evidence supporting this being an issue, but tried to minimise the results by suggesting this was only seen in an “outlier” study.
The largest cohort report was presented by Michael Sabranski from the Infectious Diseases Centre in Hamburg and colleagues. This was a retrospective analysis from all treatment naive patients who started on an integrase inhibitor based combination at two large German out-patient clinics from 2007 to 2016 (but which excluded patients in clinical studies). 
The analysis included 1704 patients who used 1950 integrase-based combinations.
Rates of discontinuations linked to any side effect vs neuropsychiatric side effects were 7.6% vs 5.6% for dolutegravir (n=985), 7.6% vs 0.7% for elvitegravir (n=287) and 3.3% vs 1.9% for raltegravir (n=678), see Table 1.
The difference between dolutegravir and other two integrase inhibitors for neuropsychiatric side effects was significant (p<0.0001).
In multivariate analysis, neuropsychiatric side effects that led to dolutegravir discontinuation were observed significantly more frequently in women (hazard ratio [HR] 2.64; 95%CI: 1.23 to 5.65, p 0.012), patients older than 60 years (HR 2.86; 95%CI: 1.42 to 5.77, p 0.003) and HLA-B*57:01-negative patients who started abacavir at the same time (HR 2.42; 95%CI: 1.38 to 4.24, p 0.002).
These findings did not change when excluding patients who started in 2016 (following greater awareness of these side effects), although starting in 2016 (compared to 2014/2015) had a HR 11.36 95%CI 4.31 to 29.41, p<0.0001.
Symptoms generally resolved quickly after discontinuation (although they returned in six people who were later re-challenged with dolutegravir). Also importantly, no association was found in people with previous intolerance to efavirenz.
A second German study reported on 411 patients who were enrolled between March and May 2016 into the prospective non-interventional DOL-ART cohort to look at responses to dolutegravir outside a clinical study. This was a largely treatment experienced group with only one quarter being treatment-naive. During the first year 10.7% of patients experienced side effects with 4.4% discontinuing dolutegravir for this (including 1.2% for depression).
The Spanish study was a retrospective analysis of dolutegravir-related discontinuations from Hospital Ramon y Cajal in Madrid, presented by Maria Vivancos-Gallego and colleagues. 
From September 2014 to May 2016, 827/2470 patients (33.5%) using dolutegravir (naive and experienced, with 70% using single tablet combination with abacavir/3TC), 104/827 (12.6%) later discontinued dolutegravir for any reason. Side effects were the primary reason in 36/104 cases (34% of discontinuations and 4.3% of people using dolutegravir overall).
Most frequent toxicities leading to drug interruption included headache (n=9), high cholesterol (n=8), insomnia (n=7) and dizziness (n=6). One case was reported of serious mood disorders which recovered soon after discontinuation.
A similar retrospective analysis compiled from 178 patients using dolutegravir at the Royal Liverpool Hospital in Liverpool from June 2013 to June 2016 was presented as a poster. 
Approximately 29% were treatment-naive (52/178) and 71% were treatment experienced (126/178). Baseline demographics included: 72% men and 28% women; 78% Caucasian, 20% African/Caribbean and 2% Asian/other; and with median age 40 years (range 18 to 76).
Overall, side effects were recorded for 59/178 (33%) of this group with 20% of people (35/178) reporting CNS side effects. Other side effects included gastrointestinal (10%), neurological (7%), musculoskeletal (3%), lethargy (3%), skin related (2%) and urological (1%).
Two UK studies, presented results from people switching to dolutegravir because of neuropsychiatric side effects on efavirenz-based combinations.
An open label study randomised 40 patients with CNS side effects on efavirenz-based combinations to either immediately switch to dolutegravir or to switch following a four-week delay. The primary endpoint was rate of CNS toxicity measured by patient questionnaire at 4 weeks with numerous tolerability-related secondary endpoints. 
This group was largely male (38/40) with mean age 48 years (range 28 to 67).
CNS scores were significantly improved at 4 weeks post-switch and maintained at 12 weeks (p<0.001 at both time points). Statistically significant reductions were also reported for abnormal dreams (p<0.001), dizziness and depression (p=0.008) and improved for anxiety and depression scores, quality of life and quality of sleep.
In a related study, Michael Keegan from the Chelsea and Westminster Hospital in London reported on markers that might be related to the (currently unknown) pathogenesis of CNS complications associated to efavirenz.  Both indoleamine 2,3-dioxygenase-1 activity (IDO-1) and kynurenine/tryptophan ratios (KYN/TRP) improved following a switch from efavirenz to dolutegravir and these results also correlated with self-reported improvement of symptoms. Severe CNS side effects that included suicidal ideation was only reported in one case. Discontinuation rates were low however, with only 10/178 people stopping treatment (6%) with 8/10 (4%) being due to side effects.
Finally, ViiV Healthcare, the manufacturer of dolutegravir, presented an analysis in a poster on psychiatric side effects in four randomised, blinded, placebo-controlled treatment-naive phase 3 studies. 
This included 2634 participants, half of whom received dolutegravir. Of the four studies presented (SPRING-2, SINGLE, FLAMINGO and ARIA), only one reported psychiatric side effects at higher than 5%. When Romina Quercia from ViiV presented a summary of this poster in an oral discussion, the results were controversially down-played as this study being an outlier due to lack of investigator assignment of the side effects being linked to the investigational drugs.
In practice, however, the outlier (SINGLE) was the only study where researchers would have been actively looking for CNS-related side effects. It was the only study with efavirenz in the comparator arm and it also included a questionnaire on CNS events. In SINGLE, anxiety was reported by 7% vs 7%, depression by 8% vs 10%, insomnia by 17% vs 11% and sleep problems by 10% vs 21%, all in the dolutegravir vs efavirenz groups respectively.
Most of these were low grade reports and the number of people discontinuing treatment were low, in SINGLE these occurred less often for the dolutegravir vs efavirenz group respectively (anxiety 0 vs 4, depression 1 vs 7, insomnia 1 vs 3 and sleep problems by 2 vs 7).
While ViiV tried to explained the results from SINGLE as at least partially due to a design bias that involved more careful receding of CNS-related side effects because efavirenz was the comparator, the double-blind study design actually makes this the study that would have been most likely to report unbiased results.
These real-world reports of CNS-related side effects with dolutegravir are similar to those from other research groups that we reported in the previous issue of HTB. [8, 9, 10]
The results do not detract from the importance of dolutegravir as an essential new HIV drug. Instead they highlight an area where greater care is needed when using doiutegravir.
It is also reassuring that previous CNS problems with efavirenz are not predictive of similar risk with dolutegravir – indicating a likely different mechanism. However, the increased associations reported by Sabranski et al, with sex, age and abacavir use deserve further attention.
In discussions at the conference, few doctors were surprised by the results, with most reporting similar experiences when they have switched small but noticeable numbers of patients to alternative durgs because of CNS-related side effects.
The revised version of the EACS guidelines (October 2016) now includes a stronger reference to CNS side effects with dolutegravir. 
Unless stated otherwise, all references are to the Programme and Abstracts of the Glasgow Congress on HIV Therapy, 23-26 October 2016 (Glasgow 2016). Abstracts are published as a supplement to the Journal of the IAS.
- Sabranski M et al. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. Glasgow 2016. Oral abstract O124. Webcast:
- Postel N et al. The DOL-ART cohort: providing evidence from real-world data use of dolutegravir-based regimens in routine clinical care in Germany. Glasgow 2016. Poster abstract P133.
- Vivancos-Gallego MJ et al. Discontinuation of dolutegravir (DTG)-based regimens in clinical practice. Glasgow 2016. Poster abstract P116.
- Fernandez C et al. Adverse events and discontinuation of dolutegravir-based therapy in niaive and experienced HIV patients: tertiary HIV centre experience. Glasgow 2016. Poster abstract P212.
- Bracchi M et al. Multicentre open-label pilot study of switching from efavirenz to dolutegravir for central nervous system (CNS) toxicity. Glasgow 2016. Poster abstract P209.
- Keegan M et al. Tryptophan metabolism and its relationship with central nervous system toxicity in subjects switching from efavirenz to dolutegravir. Poster discussion abstract P208. Webcast:
- Quercia R et al. Psychiatric adverse events from the DTG ART-naıive phase 3 clinical trials. Glasgow 2016. Poster discussion abstract P210. Webcast:
- Padilla M et al. Tolerability of integrase inhibitors in clinical practice. 18th International Workshop on Comorbidities and Adverse Drug Reactions in HIV, 12-13 September 2016. New York. Oral abstract O25.
- Lepik KJ et al. Adverse drug reactions associated with integrase strand transfer inhibitors in clinical practice: post-marketing experience with raltegravir, elvitegravir-cobicistat and dolutegravir. IAS 2015, Toronto. Poster abstract TuPEB258.
- de Boer M et al. Intolerance of dolutegravir containing cART regimens in real life clinical practice. AIDS 2016. Published online: 24 September 2016. dos: 10.1097/QAD.0000000000001279.
- EACS. European Guidelines for treatment of HIV-positive adults in Europe, version 8.1 (October 2016).