Top 10 HIV Clinical Developments of 2012

Dolutegravir

A review of:

Sharon Walmsley, et al. Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results -- SINGLE (ING114467). ICAAC 2012; Abstract H-556b.

While the Quad is finding its place in the HIV treatment landscape, the excitement regarding dolutegravir, an integrase inhibitor that is not yet FDA approved, is looming over the horizon. In the final phases of development, the drug made a splash at ICAAC, where the 48-week results of the SINGLE trial were presented.

The SINGLE results showed statistical superiority of dolutegravir paired with abacavir/3TC over efavirenz/TDF/FTC in treatment-naive patients. Tolerability of the drug was excellent -- in fact, it drove the difference in the primary outcome between the study arms, as there were more patients who experienced treatment-limiting toxicities with the efavirenz-based therapy (10%) compared to the dolutegravir-based therapy (2%).

Most impressive was the complete absence of detected integrase or reverse transcriptase (RT) resistance mutations among the few participants experiencing virologic failure while on dolutegravir. In vitro data suggest a relatively high bar to drug resistance for this new integrase inhibitor. However, it should be noted that the study procedures regarding monitoring and responding to increases in viral load may have allowed for virologic failure to be caught early, reducing the time that resistance could be selected for and emerge on testing.

Earlier in the year, 48-week data from the SPRING-2 study, which compared dolutegravir plus two NRTIs to raltegravir plus two NRTIs, were presented. They found no significant difference in rates of viral suppression between the arms. Again, integrase and RT resistance was not seen in those on dolutegravir while 1 of 18 and 4 of 19 participants in the raltegravir arm with paired baseline and failure samples available had integrase and RT mutations detected, respectively.

It is expected that a stand-alone dolutegravir tablet will be approved and available in the first half of 2013, with a fixed-dose combination with abacavir/3TC to follow. A potent, once a day integrase that behaves like a boosted protease inhibitor when it comes to resistance may be too good to be true, but it seems is something that providers are yearning for. It certainly will spice things up for 2013.