AIDS 2012: Once-daily Maraviroc + Boosted Atazanavir Looks Promising at 96 Weeks

A NRTI-sparing regimen of maraviroc (Selzentry) plus ritonavir-boosted atazanavir (Reyataz) produced good virological suppression and was generally well tolerated through 96 weeks, according to a study presented Tuesday at the XIX International AIDS Conference (AIDS 2012) in Washington, DC.

[Editor's note: This article has been corrected since publication: The dose of maraviroc used in the study was 150 mg (not 50 mg as originally stated); in bullet 8, the higher rate of jaundice in the maraviroc arm was attributed to a drug-drug interaction with tenofovir that leads to lower atazanavir levels.]

Standard combination antiretroviral regimens consisting of 2 nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) plus a third drug from another class are effective at suppressing HIV, but can cause side effects including mitochondrial toxicity. This has led researchers to explore NRTI-sparing regimens containing 2 -- or potentially more -- drugs from other classes.

Anthony Mills reported the latest findings from Study A4001078, an exploratory pilot study evaluating a once-daily, NRTI-sparing, dual regimen containing the CCR5 blocker maraviroc plus atazanavir/ritonavir for previously untreated individuals.

This Phase 2b open-label trial included 121 treatment-naive participants with CCR5-tropic HIV (virus that uses the most common co-receptor to enter human cells). About 90% were men, three-quarters were white, and the median CD4 T-cell count was approximately 350 cells/mm³. At study entry they had no evidence of resistance to study drugs.

Participants were randomly assigned to receive either 150 mg once-daily maraviroc or coformulated tenofovir/emtricitabine (Truvada), both with 300 mg atazanavir boosted with 100 mg ritonavir.

The study's primary analysis was done at 48 weeks, and the trial was extended to 96 weeks. It was not powered to show statistically significant differences between the treatment regimens, meaning observed differences in this small study might be due to chance.

Results

• At 96 weeks, 67.8% of maraviroc recipients and 82.0% of tenofovir/emtricitabine recipients had viral suppression below 50 copies/mL at 96 weeks (P value not calculated).
• Using a less sensitive test, 78.0% and 83.6%, respectively, had viral load below 400 copies/mL.
• Most participants with HIV RNA above 50 copies/mL had transient low-level viral load episodes that fell below 400 copies/mL.
• People with viremia at 96 weeks typically also had detectable HIV RNA sometime earlier in the follow-up period, often due to suboptimal adherence.
• 3 people taking maraviroc and 2 individuals taking tenofovir/emtricitabine experienced protocol-defined treatment failure (either failure to achieve viral suppression or confirmed rebound after suppression).
• Median CD4 cell increases were similar in the 2 arms, at 264 vs 240 cells/mm³, respectively, at 96 weeks (although earlier data suggested maraviroc appeared to produce larger CD4 cell gains soon after starting treatment).
• There were more serious adverse events (22% vs 18%, respectively) and study discontinuations due to adverse events (2 vs 1 patients) in the maraviroc arm than in the tenofovir/emtricitabine arm.
• The maraviroc group was more likely to develop jaundice due to elevated bilirubin, a known side-effect of atazanavir (17% vs 10%); Mills suggested this might be due to a drug-drug interaction with tenofovir that leads to lower atazanavir concentrations.
• People taking maraviroc showed less decrease in creatinine clearance, a potential indicator of impaired kidney function (5.5 vs 18.0 mL/min, respectively).
• An ad hoc analysis showed that participants receiving maraviroc had less change in bone formation markers compared with tenofovir/emtricitabine recipients; bone analysis was not done at baseline, however, so it was not possible to compare changes over time.
• Among the 7 participants in the maraviroc arm and 4 in the tenofovir/emtricitabine arm who underwent viral genetic analysis, none had evidence of genotypic or phenotypic drug resistance or changes in HIV tropism (switching to use the CXCR4 instead of CCR5 co-receptor).
• Participants taking maraviroc showed a larger reduction in immune activation on CD4 cells at 48 weeks, consistent with earlier research suggesting maraviroc might reduce inflammation, but the clinical significance of this finding is unknown.

"Durable virologic activity of [150 mg once-daily maraviroc] plus atazanavir/ritonavir was demonstrated through 96 weeks, with no differences between the arms in the rates of virologic failure, no resistance or change in tropism seen, and with most of the treatment difference due to low-level transient viremia," the researchers concluded.

Mills noted that even people with viral loads up to 400 copies/mL did not develop resistance, suggesting that it may not be necessary to keep HIV RNA below 50 copies/mL to prevent emergence of resistance mutations.

The researchers said that the observed differences in immune activation and bone markers between the 2 regimens require further investigation in larger and longer trials.

A Phase 3 trial (study A4001095) is now underway testing maraviroc with a different protease inhibitor, darunavir (Prezista), in about 800 people, which will be powered to allow comparison between regimens.

7/25/12

Reference

A Mills, D Mildvan, D Podzamczer, et al. Once-daily maraviroc in combination with ritonavir-boosted atazanavir in treatment-naive patients infected with CCR5‑tropic HIV-1 (study A4001078): 96‑week results. XIX International AIDS Conference (AIDS 2012).  Washington, DC, July 22-27, 2012. Abstract TUAB0102.