- Category: HIV Treatment
- Published on Friday, 30 November 2012 00:00
- Written by Gus Cairns
An analysis of 2 studies of the new HIV integrase inhibitor dolutegravir presented at the 11th International Congress on Drug Therapy in HIV Infection this month in Glasgow had the incidental effect of bringing into question evidence from a previous study suggesting that the nucleoside reverse transcriptase inhibitor abacavir (Ziagen, also in the Epzicom or Kivexa coformulation) was less potent in people starting HIV therapy with high viral loads than another NRTI drug, tenofovir (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations).
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Background -- Why This May Be Important
This new evidence may have considerable importance because it could cause the compilers of treatment guidelines to revise their views on whether abacavir-containing regimens in antiretroviral combination therapy should be rated as equal to tenofovir-based ones, with a number of implications for patient choice and cost.
This year’s HIV treatment guidelines issued by the British HIV Association (BHIVA) recommended that the best NRTI choice for first-line regimens was tenofovir plus emtricitabine (the drugs in Truvada or, with efavirenz, in Atripla). They recommended abacavir plus lamivudine (the drugs in Epzicom) as an alternative choice, but only for people starting treatment with viral loads below 100,000 copies/mL. Current U.S. DHHS treatment guidelines also favor tenofovir plus emtricitabine.
The BHIVA authors did this after weighing up the evidence from a number of trials, but due to its size the findings from one trial predominated. In this trial, ACTG 5202, the time to treatment failure in people taking abacavir/lamivudine who started with high viral loads was significantly shorter than the time in people taking tenofovir/emtricitabine. (ACTG 5202 also compared boosted atazanavir versus efavirenz, but found no difference in their efficacy.)
This recommendation in turn gave the appearance of clashing with the prescribing recommendations of the London Specialised Commissioning Group, which issued a strong recommendation to London HIV clinics in April 2011 that they should start a higher proportion of patients on Epzicom-based regimens for cost reasons (this shift was achieved and the required savings made, but in fact the majority of London patients still start on Truvada).
What the New Studies Say
Findings that abacavir is as potent as tenofovir, at least in some regimens, may therefore be of some importance.
At the Glasgow conference, Joseph Eron of the University of North Carolina compared viral suppression results at 48 weeks in 2 trials of the new integrase inhibitor dolutegravir. In a trial called SPRING-2, presented at the International AIDS Conference in Washington, DC, this summer, dolutegravir was as potent as the first-generation integrase inhibitor raltegravir (Isentress), while in another study called SINGLE, presented at the ICAAC conference in September, it proved superior to the standard-of-care drug efavirenz, producing a viral load of under 50 copies/mL in 88% of patients at 48 weeks, compared with 81% on efavirenz.
In SPRING-2, doctors chose whether to accompany the integrase inhibitors with either Epzicom or Truvada, while in the SINGLE study, participants were randomized either to dolutegravir plus Epzicom or to Atripla.
In SINGLE, the 7% superiority of dolutegravir/Epzicom over Atripla appeared to be independent of trial subjects’ initial viral loads. In people with baseline viral loads under 100,000 copies/mL, the respective proportions with viral loads below 50 copies/mL at 48 weeks were 90% on dolutegravir/Epzicom and 83% on Atripla. Viral load suppression rates were lower in people starting treatment with viral loads over 100,000 copies/mL, but the 7% superiority margin was unchanged: 83% on dolutegravir/Epzicomversus 76% on Atripla were virologically suppressed.
The point here is that if abacavir is less potent than tenofovir in people with higher viral loads, one would expect the dolutegravir superiority margin to be smaller in those patients, and it wasn’t.
In SPRING-2, it was possible to make a more direct comparison of Epzicom and Truvada in people with high and low viral loads. In people with viral loads under 100,000 copies/mL who took Epzicom, 87% and 88%, respectively, on dolutegravir and raltegravir achieved undetectable viral loads, and in people who took Truvada 92% and 91% did so, respectively.
In people starting with viral loads over 100,000 copies/mL who took Epzicom, 81% and 82%, respectively, on dolutegravir and raltegravir achieved undetectable viral loads, and in people who took Truvada, 83% and 71% did so, respectively. None of these differences were statistically significant.
Neither of these studies were set up specifically to compare tenofovir-based versus abacavir-based regimens. However, with 1655 study participants, of whom 495 (30%) had an initial viral load over 100,000 copies/mL, they may be large enough to make HIV specialists re-evaluate the relative potency of abacavir versus tenofovir.
With another meta-analysis published recently that found no raised rates of heart attack in people taking abacavir in randomized controlled trials, in contrast to findings in cohort studies, this could also swing the balance of favor back towards the equal recommendation of abacavir and tenofovir in treatment guidelines.
J Eron, J Rockstroh, A Pozniak, et al. Dolutegravir treatment response by baseline viral load and NRTI backbone in treatment-naive HIV-infected individuals. 11th International Congress on Drug Therapy in HIV Infection (HIV11). Glasgow, November 11-15, 2012. Abstract P204.