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:
The safety of both dolutegravir- and raltegravir-containing regimens was good, with generally similar rates of reported adverse events (side effects and complications). Most side effects occurred during the first year of the study.
No participant taking dolutegravir in the second year of the study left prematurely because of side effects. However, three participants who were taking raltegravir had to stop due to side effects.
Side effects reported in the second year of the study were usually of mild or moderate intensity. Adverse events reported at week 96 were distributed as follows:
Stuffy nose and/or sore throat
No deaths related to the study medicines occurred.
Researchers did not find any clinically meaningful changes in levels of cholesterol in the blood of participants during the study.
Dolutegravir users had small increases in their level of creatinine (a waste product formed from the breakdown of muscle) in their blood as follows:
These small but sustained changes in creatinine occurred because dolutegravir interferes with the kidneys' ability to remove creatinine from the blood. The change appears to be harmless. For instance, researchers conducted additional and more direct tests of kidney health -- focusing on the ratio of the protein albumin to creatinine in the blood -- and did not find any significant differences in this ratio between dolutegravir and raltegravir users.
The small interference with creatinine release into the urine is also seen with other drugs, such as in these cases:
In such cases, the small increase in creatinine that occurs when these drugs are used does not appear to cause harm.
Overall, the researchers did not find any differences in changes in heart beat or abnormal heart rhythms in participants. However, one participant taking dolutegravir had a slightly abnormal heart rhythm.
As with all the clinical trials of dolutegravir, there have not been any reports of increased risk of heart attacks in participants in general and in users of abacavir in particular. This latter finding is consistent with an analysis of abacavir done by the U.S. Food and Drug Administration (FDA), which reviewed many randomized clinical trials and found no increased risk of cardiovascular complications in people who had used the drug.
In analysing the two-year data on dolutegravir-based regimens, researchers have found that this drug, when taken in a dose of 50 mg once daily, was as effective and safe as twice-daily raltegravir-based regimens. Results with dolutegravir were similar regardless of initial viral load or the additional nukes used in regimens -- abacavir + 3TC or tenofovir + FTC.
Dolutegravir and raltegravir caused a relatively low rate of side effects; when they did occur, such side effects were generally of mild-to-moderate intensity. This is similar to what has been seen in other trials of dolutegravir.
Other trials with dolutegravir are ongoing, including a clinical trial in women called Aria.