If the characters on Mad Men had won the dolutegravir (Tivicay, DTG) account, they might have pitched something along the lines of, "Dolutegravir: the tolerability of an integrase but, the barrier to resistance of a boosted protease inhibitor." Or maybe something catchier, but you get the idea. This hook, though, is what many providers are thinking about when considering this newest integrase inhibitor, and as a test of faith, several investigators have looked at dolutegravir scantily clad or completely naked.
In the exciting and chutzpahdik PADDLE study, 20 treatment-naive patients in Argentina with screening HIV RNA levels below 100,000 copies/mL and CD4+ cell counts above 200 cells/mm3 were treated with dolutegravir and lamivudine (3TC, Epivir) alone. All patients achieved HIV RNA levels below 50 copies/mL by week eight, including four whose viral loads had crept from screening to baseline to above the 100,000-copies/mL mark. Viral suppression was maintained out to 24 weeks and follow-up continues. As expected, treatment was well tolerated.
In a separate study conducted in Spain, 33 patients with no known integrase resistance, suppressed HIV RNA levels and a non-virologic reason to change antiretroviral therapy (ART) were switched to dolutegravir 50 mg daily as monotherapy. Interestingly, in 22 of the 33, the pre-switch regimen consisted of boosted protease inhibitor (PI) monotherapy -- a testament to the appetite, especially in Europe, for nuke sparing. At 24 weeks, all but one patient had maintained viral suppression. The lone case of virologic failure was a man with extensive ART exposures, including virologic failure of a raltegravir (Isentress)-containing regimen, who had persistent low-level viremia around 155 copies/mL out to 24 weeks. HIV DNA genotypic testing revealed 118R mutation in 7% of integrated DNA at week 24.
Another presentation of dolutegravir monotherapy as maintenance of viral suppression from France provided a tale that was more cautionary. Billed as an observational cohort study, the "study" turned out to not really be a study in the traditional "get Institutional Review Board approval and informed consent" sense of the term. The cohort consisted of 28 patients whose clinicians had decided that dolutegravir monotherapy, although clearly experimental and risky, was a fine choice for them (oy vey!). For three patients who experienced viral rebound this proved to be a less-than-great idea. Each had prior integrase exposure and, after the failure following their switch to dolutegravir alone, integrase resistance was newly detected.
The Bottom Line
Dolutegravir challenges our thinking that a high barrier to drug resistance alone is the province of boosted PIs. In vitro and accumulating clinical data support this integrase as being exceptionally hardy when it comes to resistance.
As such, this well-tolerated agent has become the darling of the "no nukes" movement that seeks to rid the world of what they perceive to be "dangerous" nucleoside reverse transcriptase inhibitors (NRTIs). These are the people who are way too into boosted-PI monotherapy. For them, dolutegravir is manna from heaven and replaces raltegravir with its pesky twice-daily dosing and middling resistance barrier.
These small studies serve as stress tests for this integrase. The ability of dolutegravir in combination with lamivudine to suppress viral replication in PADDLE and alone as a switch option to maintain suppression in the Spanish study is impressive. That monotherapy cracked in the French study when not used more prudently is not wholly unexpected and should temper aggressive use of the drug outside of carefully conducted research studies. Only such studies will determine if dolutegravir can serve as Spartan ART and replace potent multidrug single-pill regimens -- reducing cost and potential side-effect risks.
What are some other top clinical developments of 2015? Read more of Dr. Wohl's picks.
David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.