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CROI 2014: Raltegravir Has Edge Over 2 HIV Protease inhibitors in 3-Drug Comparison

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In a head-to-head comparison of 3 drugs presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) last week in Boston, the integrase inhibitor raltegravir (Isentress) proved to be superior, in terms of the overall likelihood of treatment failure, when compared to 2 ritonavir-boosted protease inhibitors, atazanavir (Reyataz) and darunavir (Prezista).

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All 3 drugs being compared were taken with tenofovir and emtricitabine (coformulated in Truvada). The superiority of raltegravir was not due to the likelihood of virological failure -- which was not very different for the 3 drugs -- but rather to more discontinuations of the protease inhibitors, mainly due to gastrointestinal symptoms (with both drugs) and jaundice related to atazanavir. When virological failure and discontinuations were taken together as an overall measure of treatment failure, darunavir was also superior to atazanavir.

The Study

In the ACTG A5257 study, 1809 people living with HIV, who had not taken HIV treatment before, were randomized into 3 groups that received Truvada plus ether raltegravir, atazanavir boosted with ritonavir, or darunavir boosted with ritonavir; their progress was monitored for 96 weeks.

The mean age was 37, a quarter were women, 34% were non-Hispanic whites, 42% non-Hispanic blacks, and 22% Hispanic. The mean viral load was 40,000 copies/mL before treatment -- though 31% had a viral load over 100,000 copies/mL -- and the average CD4 T-cell count at baseline was 308 cells/mm3.

Most participants (92%) completed the study, with similar numbers in the 3 groups, although it should be noted that switching to one of the other drugs in the study for reasons of toxicity was allowed and not counted as failures.

Results

At 96 weeks, viral load was below 50 copies/mL in 88% of participants who had started treatment with atazanavir, 94% for those who had started with raltegravir, and 89% for those who had started with darunavir. These rates were not statistically different within the study's pre-determined definition of superiority, although an audience member pointed out that the proportion with a viral load over 50 copies/mL in the raltegravir arm was half the proportion among participants taking the other 2 drugs.

"Virological failure" was defined as 2 viral load results over 1000 copies/mL during the first 6 months, or over 200 copies/mL during the rest of the study. By this measure, raltegravir came out slightly better than darunavir, with a 5.6% absolute difference in the rate of virological failure, and this was statistically significant.

However, in terms of discontinuations due to toxicity, atazanavir had a clear disadvantage compared to the other 2 drugs. Its rate of discontinuation due to toxicity (16% at week 96) was 13% worse than raltegravir and 9.2% worse than darunavir. Darunavir was 3.6% worse than raltegravir. All these differences were statistically significant. Only 1% of participants taking raltegravir (8 people) discontinued due to toxicity.

The main reason for the atazanavir results being worse for toxicity was that 47 participants discontinued due to the jaundice that is a common side effect of the drug. This yellowing of the skin and eyes caused by a build-up of the waste compound bilirubin in the body is normally considered harmless, but can cause distress about appearance. In addition, there were 25 discontinuations due to gastrointestinal side effects among people taking atazanavir and 14 among people taking darunavir, compared to only 2 among people taking raltegravir.

When the 2 measures -- virological failure and toxicity failure -- were combined into an overall definition of treatment failure, raltegravir was shown to be 15% better than atazanavir and 7.5% better than darunavir, and darunavir was shown to be 7.5% better than atazanavir. If switching drugs due to toxicity was included in the definition of treatment failure, then the overall efficacy of the drugs at 96 weeks was 80% for raltegravir, 73% for darunavir/ritonavir, and 63% for atazanavir/ritonavir. These differences were all significant within the study's predetermined definition of superiority.

The only area where raltegravir was at a slight disadvantage was that 18 (3%) of participants taking it acquired drug resistance compared to 1.5% of people taking atazanavir and 0.8% taking darunavir. 11 people had resistance specifically to raltegravir compared to 3 to atazanavir and none to darunavir.

Participants taking darunavir had slightly lower CD4 cell rises compared to the other 2 drugs (256 cells/mm3 compared to 284 on atazanavir and 288 on raltegravir), though this was probably of no clinical significance.

As expected, participants taking the 2 protease inhibitors had greater increases in their cholesterol and triglyceride levels compared to people taking raltegravir, but there was no change in their HDL-to-LDL ratio (their "good" versus "bad" cholesterol). Analyses of other side effects are ongoing.

Implications for Guidelines

This study is important because it may lead to changes in recommendations for first-and second-line drugs in treatment guidelines.

At present, in the U.S. treatment guidelines, the 3 drugs are equally recommended for use as the third drug alongside Truvada as drugs of first choice. The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva) is also recommended (and is coformulated with Truvada in the combination pill Atripla). However in one study, over a long time period (5 years), raltegravir has already proven to perform significantly better than efavirenz in terms of its ability to maintain continued viral suppression. The British HIV Association (BHIVA) guidelines have the same recommendations for first-line drugs, except that they add the 4-drug combination pill Stribild (Truvada plus elvitegravir/cobicistat).

In short, raltegravir was shown to be superior to both atazanavir/ritonavir and darunavir/ritonavir -- and darunavir to atazanavir -- when considering virological failure and toxicity failure together in this study, and this finding is likely to be taken into account the next time treatment guidelines are revised.

3/14/14

Reference

RJ Landovitz, HJ Ribaudo, I Ofotokun, et al. Efficacy and Tolerability of Atazanavir, Raltegravir, or Darunavir With FTC/Tenofovir: ACTG 5257. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 85.

Other Source

Merck. New 96-Week ACTG Study Results Presented at CROI 2014; First Large Study Comparing Isentress (raltegravir) Regimen to Two Protease Inhibitor Regimens in Previously Untreated Adults with HIV-1. Press release. March 5, 2014.