Good results seen with NRTI-sparing regimens of atazanavir plus newer drug classes

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Combination antiretroviral regimens containing atazanavir (Reyataz) plus drugs from two newer classes – the integrase inhibitor raltegravir (Isentress) and the CCR5 antagonist maraviroc (Celsentri) – demonstrated promising anti-HIV activity, but presented some concerns related to side-effects and drug resistance, according to two studies reported at a late-breaker session at the Eighteenth International AIDS Conference last week in Vienna.

Highly active antiretroviral therapy, or HAART, traditionally includes a protease inhibitor or non-nucleoside reverse transcriptase inhibitors (NNRTI) plus a 'backbone' of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). But the recent development of two new anti-HIV drug classes allows more flexibility to construct different types of regimens.

SPARTAN

Michael Kozal from Yale University School of Medicine presented findings from SPARTAN, an open-label pilot study evaluating the safety and effectiveness of unboosted atazanavir plus raltegravir without NRTIs in previously untreated people.

NRTIs and ritonavir (Norvir) used as a protease inhibitor booster can cause short-term side-effects and long-term toxicities. By omitting these drugs, the experimental regimen may be better tolerated by some patients. Raltegravir raises atazanavir levels somewhat, so may be able to substitute for ritonavir as a booster.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

bilirubin

A substance produced during the normal breakdown of red blood cells. Bilirubin passes through the liver and is excreted in faeces. Elevated levels of bilirubin (jaundice) may indicate liver damage or disease.

pilot study

Small-scale, preliminary study, conducted to evaluate feasibility, time, cost, adverse events, and improve upon the design of a future full-scale research project.

 

CCR5

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

powered

A study has adequate statistical power if it can reliably detect a clinically important difference (i.e. between two treatments) if a difference actually exists. If a study is under-powered, there are not enough people taking part and the study may not tell us whether one treatment is better than the other.

SPARTAN enrolled 94 participants who were randomly assigned on a two-to-one basis to take either a twice-daily regimen of 300mg unboosted atazanavir plus 400mg raltegravir, or else a once-daily regimen of 300mg atazanavir plus 100mg ritonavir booster plus tenofovir/emtricitabine (Truvada).

Most participants (about 90%) were men, approximately 80% were white, and the median age was 40 years. The average baseline CD4 cell count was about 260 cells/mm3 and participants overall were roughly evenly divided between those with high and low viral load (above or below 100,000 copies/ml), though high viral load was more common in the atazanavir/raltegravir arm.

The primary endpoint of the study was viral suppression below 50 copies/ml after 24 weeks on treatment. Similar proportions of patients in the two study arms (about 10%) stopped treatment before week 24.

Kozal pointed out that this Phase 2b study was not adequately powered to compare the efficacy of the two regimens, so statistical comparisons were not reported.

In a modified intent-to-treat analysis at 24 weeks, 75% of participants taking atazanavir/raltegravir and 63% taking the traditional boosted atazanavir regimen achieved confirmed virological response, defined as either undetectable viral load on two consecutive tests or re-suppression after viral rebound. Amongst a subset of participants followed for 48 weeks, response rates rose in both groups, to 82 vs 76%.

In a 24-week analysis that excluded participants who dropped out, the corresponding confirmed virological response rates were 81% and 70%, respectively. Average CD4 cell gains were 166 cells/mm3 in the atazanavir/raltegravir arm and 127 cells/mm3 in the boosted atazanavir arm.

Although the atazanavir/raltegravir regimen appeared slightly more potent, it also caused more severe side-effects, in particular elevated bilirubin.

Bilirubin is a pigment released when red blood cells are broken down. Elevated bilirubin can be a sign of liver dysfunction, but in people taking atazanavir it is related to impaired bilirubin processing and is generally not dangerous. But it can cause jaundice, or yellowing of the skin and eyes.

While overall treatment-related adverse events (30 vs 33%, respectively) and bilirubin increases (19% vs 17%) were seen in both the atazanavir/raltegravir and boosted atazanavir arms, grade 4 or severe elevations were only seen with the atazanavir/raltegravir regimen (20 vs 0%), and atazanavir/raltegravir recipients were more likely to drop out due to side-effects (6 vs 0%). Bilirubin levels tended to stabilise over time, however.

In attempting to explain these findings, the researchers found that atazanavir concentrations were higher in the atazanavir/raltegravir arm than in the boosted atazanavir arm.

Although use of ritonavir can cause elevated blood fat levels whilst atazanavir is generally 'lipid friendly', changes in cholesterol and triglyceride levels were similar in both arms of this study.

Amongst participants with virological failure who qualified for resistance testing, those taking atazanavir/raltegravir developed more raltegravir resistance mutations – four patients (6%) compared with none on the boosted atazanavir regimen – though no one in either arm developed atazanavir resistance mutations.

The study had planned to monitor safety and CD4 cell recovery through 96 weeks, but it was stopped ahead of schedule due to concerns about elevated bilirubin and resistance.

Study A4001078

A second open-label pilot study looked at another NRTI-sparing atazanavir regimen in treatment-naive people, this one consisting of boosted atazanavir plus maraviroc.

This trial included 121 participants randomly assigned in a one-to-one ratio to receive either 300/100mg atazanavir/ritonavir plus 150mg maraviroc once daily, or else 300/100mg atazanavir/ritonavir plus tenofovir/emtricitabine once daily (the same control regimen as SPARTAN).

Participants had confirmed CCR5-tropic HIV and no evidence of resistance to the study drugs. Again, about 90% were men, 75% were white and the average age was about 36 years. The median CD4 cell count was about 250 cells/mm3 and about one-third had baseline viral load above 100,000 copies/ml.

The study was designed to last 48 weeks, but was extended to 96 weeks; Anthony Mills presented data from a planned analysis at 24 weeks. Here too, the study was not powered to formally compare efficacy so statistical significance was not reported.

At week 24, 80% of participants taking the atazanavir/maraviroc regimen achieved viral suppression below 50 copies/ml, compared with 89% taking the traditional HAART regimen; 93% and 90%, respectively, had viral load below 400 copies/ml. Virological response was also similar in both arms when looking at subsets of patients with high and low viral load.

CD4 cell gains were somewhat faster and larger in the atazanavir/maraviroc arm, Mills said, reaching 195 and 173 cells/mm3, respectively, by week 24.

As in the SPARTAN study, people taking the atazanavir/maraviroc regimen were more likely to develop high bilirubin levels compared with those on the atazanavir/NRTI combination; 26 vs 13%, respectively, experienced grade 3 or 4 adverse events related to elevated bilirubin.

Two participants in the atazanavir/maraviroc armed discontinued the study due to adverse events, but five switched from atazanavir to darunavir (Prezista) due to jaundice or yellowing eyes. In the other arm, none discontinued due to side-effects and one switched to darunavir.

Amongst participants with continued viral replication, no resistance was observed through week 24, there were no changes in drug susceptibility and no changes in viral tropism (switch from using CCR5 to CXCR4 co-receptors).

The researchers concluded that this interim analysis supports the antiviral activity of the experimental once-daily, two-drug combination and a Phase 3 study is planned.

Further information

View abstract and slides from this session on the official conference website

References

Kozal M et al. The SPARTAN study: a pilot study to assess the safety and efficacy of an investigational NRTI- and RTV-sparing regimen of atazanavir (ATV) experimental dose of 300mg BID plus raltegravir (RAL) 400mg BID (ATV+RAL) in treatment-naive HIV-infected subjects. Eighteenth International AIDS Conference, Vienna, abstract THLBB204, 2010.

Mills A et al. Safety and immunovirological activity of once daily maraviroc (MVC) in combination with ritonavir-boosted atazanavir (ATV/r) compared to emtricitabine 200mg/tenofovir 300mg QD (TDF/FTC) + ATV/r in trseatment-naive patients infected with CCR5-tropic HIV-1 (Study A4001078): A week 24 planned interim analysis. Eighteenth International AIDS Conference, Vienna, abstract THLBB203, 2010.