November 30, 2016
|Top 10 Clinical Developments of 2016|
|1. Donald Trump||6. Return of the Antibodies|
|2. Switch Frenzy||7. Is an Unexpected Low HIV RNA Level Real?|
|3. 2-Drug ART||8. Dolutegravir and the Central Nervous System|
|4. Is HIV PrEP at a Tipping Point?||9. TAF in Hepatitis B|
|5. Start ART Now||10. 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.
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.
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.
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