In a study called Spring-2, researchers in Canada, Australia, Europe and the U.S. recruited just over 800 HIV-positive volunteers to compare the effectiveness of a dolutegravir-based regimen to one based on the integrase inhibitor raltegravir (Isentress). Researchers found that after two years both integrase inhibitors were generally safe, well tolerated and effective. Side effects during the latter half of the study (weeks 48 to 96) were not common.
Research teams enrolled 822 volunteers who had never previously been exposed to anti-HIV drugs and randomly assigned them to receive one of the following regimens:
The nukes used in the study were as follows:
The average profile of participants at the start of the study was as follows:
As previously reported in TreatmentUpdate 194, at the 48th week of the study researchers found that both regimens were roughly equal in effectiveness (the technical term for this is statistically "non-inferior") against HIV.
The proportions of participants at week 96 whose viral loads were less than 50 copies/ml were as follows:
According to the researchers, the main reason for this difference was that more participants taking raltegravir left the study prematurely. Most of these participants left for reasons unrelated to adverse effects. One explanation for participants leaving the study prematurely was what the researchers called "virological failure." They used this term to capture a number of situations, including the inability to suppress viral load below the 50-copies/ml mark and, in cases where it was suppressed, the inability to keep it below 50 copies/ml. The distribution of virological failure was as follows:
All participants who were taking dolutegravir-based regimens and who developed virological failure had viral loads less than 1,000 copies/ml. Indeed, most (77%) had a viral load more than 50 copies/ml but less than 200 copies/ml. None of these participants developed detectable resistance to any class of anti-HIV therapy.
Among participants taking raltegravir-based regimens who developed virological failure, while most (76%) had a viral load between 50 and 200 copies/ml, three had viral loads greater than 10,000 copies/ml. However, one participant had HIV that had mutated and developed resistance to integrase inhibitors and four other participants had HIV that had become resistant to nukes. This all occurred during the first year of the study.
In the second year of the study, development of detectable resistance mutations to any anti-HIV drug was comparatively uncommon.
The research team stated that "the robustness of dolutegravir in the prevention of virological resistance is unique to the integrase inhibitor class and confers a specific advantage to this molecule."
Many factors could play a role in the response to HIV therapy and researchers involved with this study assessed the findings based on such factors as initial CD4+, initial viral load, and choice of nukes used.
The proportion of participants who responded well to dolutegravir-based regimens was generally good regardless of their initial (baseline) CD4+ cell count. However, participants with a low CD4+ cell count had poorer responses to both dolutegravir and raltegravir. This is likely because of their weaker overall health.
Here are the virological responses distributed by initial CD4+ count:
Baseline CD4+ count less than 350 cells:
Baseline CD4+ count less than 200 cells:
Among participants who had an initial viral load of 100,000 copies/ml or less, here are the proportions that subsequently achieved a viral load less than 50 copies/ml:
Among participants whose initial viral load was greater than 100,000 copies/ml, here are the proportions that subsequently achieved a viral load less than 50 copies/ml:
Among participants who used Kivexa (abacavir + 3TC), here are the proportions that subsequently achieved a viral load less than 50 copies/ml:
Among participants who used Truvada (tenofovir + FTC) here are the proportions that subsequently achieved a viral load less than 50 copies/ml: