Dolutegravir and the Central Nervous System: A Top HIV Clinical Development of 2016

Top 10 Clinical Developments of 2016
1. Donald Trump6. Return of the Antibodies
2. Switch Frenzy7. Is an Unexpected Low HIV RNA Level Real?
3. 2-Drug ART8. Dolutegravir and the Central Nervous System
4. Is HIV PrEP at a Tipping Point?9. TAF in Hepatitis B
5. Start ART Now10. New HIV infections in U.S. Are Down -- a Bit

As described above, the integrase inhibitor dolutegravir (Tivicay, DTG) has proved to be a potent and durable antiretroviral agent. Initial reports of a high barrier to resistance, well beyond that seen with raltegravir (Isentress) and elvitegravir (Vitekta), have allowed it to be used where before only a boosted protease inhibitor would do. This year, however, there were rumblings, especially in Europe, that dolutegravir might also stand out by having some unsavory neuropsychiatric effects.

  • Germany: The rates of integrase inhibitor discontinuations due to adverse effects among over 1,700 patients treated with this class of antiretrovirals at two large medical centers were 9.4% for elvitegravir, 6.8% for dolutegravir and 4.1% for raltegravir. Discontinuations due to neuropsychiatric events were highest for dolutegravir: 5.6% for dolutegravir, 0.7% for elvitegravir and 1.9% for raltegravir (n=678). Being female, older than 60 years of age and co-administration with abacavir (Ziagen), were each associated with dolutegravir neuropsychiatric adverse events. In a handful of patients rechallenged with dolutegravir, central nervous system (CNS) symptoms returned.
  • Spain: In 1,091 patients at a Barcelona clinic initiating or switching to antiretroviral therapy that included an integrase inhibitor, discontinuations over the next year were not statistically significantly different among the three agents of this class: raltegravir, elvitegravir and dolutegravir. However, fewer patients discontinued raltegravir due to adverse events (28%) compared with patients on elvitegravir (62%) or dolutegravir (31%) (P = .0083). Yet, when looking at CNS problems specifically, significantly more patients receiving dolutegravir (88%) than raltegravir (35%) or elvitegravir (19%) discontinued their treatment for these CNS adverse effects (P = .0046). Interestingly, older age was again found to be an independent predictor of early discontinuation of integrase inhibitor therapy.
  • Netherlands: Among 556 dolutegravir treated patients, 15% stopped treatment (14% of the 556 for adverse effects). A host of neuropsychiatric adverse effects, including insomnia and other sleep disturbances, depression, anxiety and psychosis, led the reasons for dolutegravir discontinuations and, as in the German study, the risk seemed to be greater when abacavir was also part of the regimen.

Retrospective cohort studies have their flaws and should be interpreted with caution. Reporting and channeling bias can over-call events, and the lack of standardization in the collection of data can miss important findings. In an initial response to concerns of CNS effects, the makers of dolutegravir conducted an analysis using adverse event reporting received during four industry-sponsored clinical trials that enrolled patients who were treatment-naïve and could be randomized to dolutegravir (SPRING-2, FLAMINGO, SINGLE, ARIA). Specifically, rates of psychiatric events including insomnia, nightmares/abnormal dreams, anxiety, depression and suicidality among those receiving this integrase inhibitor were compared across the various study arms. Together, these studies enrolled 2,634 participants, 1,315 of whom received dolutegravir. In general, the rates of each symptom were similar among those treated with dolutegravir and the comparator regimens. Interestingly, in the double-blind SINGLE trial, where the control arm included efavirenz (Sustiva, Stocrin), rates of most the psychiatric events (except for suicidality, which was very low in both arms), were much higher than those reported in the other studies included in the analysis. The investigators surmised that the inclusion of efavirenz and the double-blind design of SINGLE might explain this difference. However, it is also very plausible that the more careful assessments for neuropsychiatric events in this trial could also have revealed an issue that would be missed otherwise.

The Bottom Line

Dolutegravir is an important and useful antiretroviral that is generally well tolerated. The recent reports of neuropsychiatric adverse events with integrase inhibitors, and dolutegravir in particular, may be a signal of an off-target effect of these medications. Given their key role in modern-day HIV therapy, this potential problem needs to be addressed head-on. Additional research to better understand if this is real and, if it is, why it happens and who is at greatest risk is necessary, particularly as we increasingly use this and other drugs of this class in older patients, who these preliminary studies indicate may be at heightened risk.

What are some other top clinical developments of 2016? Read more of Dr. Wohl's picks.

David Alain Wohl, M.D., is a professor in the Division of Infectious Diseases at the University of North Carolina at Chapel Hill, director of the North Carolina AIDS Training and Education Center and site leader of the University of North Carolina Chapel Hill AIDS Clinical Research Site.