Once-daily maraviroc plus boosted atazanavir promising at 96 weeks

A NRTI-sparing regimen of maraviroc (Celsentri or 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 19^th International AIDS Conference (AIDS 2012) in Washington DC.

Standard combination antiretroviral regimens consisting of two 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 two – 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 IIb 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 150mg once-daily maraviroc or coformulated tenofovir/emtricitabine (Truvada), both with 300mg atazanavir boosted with 100mg 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.

At 96 weeks, 67.8% of maraviroc recipients and 82.0% of tenofovir/emtricitabine recipients suppressed HIV RNA 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.

Dr Mills noted that most participants with HIV RNA above 50 copies/mL had transient low-level viral load that fell below 400 copies/mL. People with viraemia at 96 weeks typically also had detectable HIV RNA at some time point earlier in the follow-up period, often due to suboptimal adherence.

Three people taking maraviroc and two 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 maraviroc and tenofovir/emtricitabine arms, at 264 vs 240 cells/mm³, respectively. Earlier studies suggested maraviroc appeared to produce larger CD4 cell gains soon after starting treatment, but here increases were similar by 96 weeks.

Turning to side-effects, there were more serious adverse events (22% vs 18%, respectively) and study discontinuations due to adverse events (two people vs none) in the maraviroc arm than in thetenofovir/emtricitabine arm.

The maraviroc group was more likely (17 vs 10%) to develop jaundice due to elevated bilirubin, a known side-effect of atazanavir. Mills suggested this may happen because a drug-drug interaction between tenofovir and atazanavir leads to lower atazanavir concentrations that are less likely to raise bilirubin.

People taking maraviroc showed less decrease in creatinine clearance, an indicator of impaired kidney function (5.5 vs 18.0 mL/min, respectively). Tenofovir is known to cause kidney problems in a small proportion of susceptible individuals.

An ad hoc analysis showed that participants receiving the maraviroc regimen appeared to have more normal levels of bone formation markers, consistent with previous reports showing that tenofovir is associated with bone loss. However, bone analysis was not done at baseline in the study, so it was not possible to compare changes over time.

Among the seven participants in the maraviroc arm and four 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 co-receptor instead of CCR5).

Earlier research suggested maraviroc might have a beneficial effect on inflammation. In this study, participants taking maraviroc showed a larger reduction in immune activation on CD4 cells at 48 weeks, but the clinical significance of this findings is unknown.

"Durable virologic activity of [150mg 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 viraemia," 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 recommended that the observed differences in immune activation and bone markers between the two regimens require further investigation in larger and longer trials.

A Phase III 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.

Mills A 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. 19^th International AIDS Conference, abstract TUAB0102, Washington, DC, 2012.

View the abstract on the conference website.

View the webcast on the conference website.