AIDS 2010: Studies Explore NRTI-sparing Antiretroviral Regimens Using New Drug Classes

Novel antiretroviral therapy (ART) regimens that combine boosted protease inhibitors with a new integrase inhibitor or CCR5 antagonist, while omitting nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), demonstrated good efficacy and tolerability in treatment-naive patients, researchers reported at the XVIII International AIDS Conference last week in Vienna. A regimen containing unboosted atazanavir plus raltegravir, however, raised concerns about side effects and drug resistance.

Highly active antiretroviral therapy, or HAART, regimens traditionally include a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus a "backbone" of at least 2 NRTIs. But the recent development of 2 novel drug classes -- CCR5 antagonist entry inhibitors and integrase inhibitors, which prevent HIV from inserting its genetic material into a host cell -- offers flexibility to construct potent combinations that target different steps of the viral lifecycle while leaving out, or "sparing," potentially problematic drug types.

PROGRESS

The PROGRESS study was a head-to-head comparison of a traditional 3-drug HAART regimen versus a 2-drug NRTI-sparing regimen. In this open-label Phase 3 trial, 206 treatment-naive participants were randomly assigned to receive 400/100 mgtwice-daily lopinavir/ritonavir (Kaletra) in combination with either the integrase inhibitor raltegravir (Isentress) at 400 mg twice-daily, or the once-daily tenofovir/emtricitabine (Truvada) NRTI coformulation.

The 2 study arms were similar at baseline. Most (about 85%) were men, the average age was 49 years, and three-quarters were white. All had HIV viral load > 1000 copies/mL (mean about 20,000 copies/mL) and the average CD4 count was about 300 cells/mm3.

Jacques Reynes from University Hospital Center of Montpellierreported 48-week results; follow-up is scheduled to continue through week 96.

Results

• In an intent-to-treat analysis at 48 weeks, 83% in the raltegravir group and 85% in the tenofovir/emtricitabine group achieved undetectable viral load < 40 copies/mL.
• The minimal difference between the arms indicated that the NRTI-sparing regimen was non-inferior to the traditional HAART regimen.
• CD4 cell gains were slightly smaller in the raltegravir group, 215 vs 245 cells/mm3, but the difference was not statistically significant.
• About 9% of study participants dropped out for various reasons, distributed similarly between the 2 arms.
• 2 participants in each group stopped early due to adverse events; 1 in the raltegravir group and 2 in the tenofovir/emtricitabine group did so due to virological treatment failure.
• Both study regimens were generally well-tolerated.
• However, lipid elevations occurred somewhat more often in the raltegravir arm.
• 1 person in each arm showed evidence of drug-resistance mutations.

Based on these findings, the investigators concluded that through 48 weeks, lopinavir/ritonavir plus raltegravir and lopinavir/ritonavir plus tenofovir/emtricitabine "had similar efficacy in treatment-naive subjects."

"Both regimens were generally well tolerates with few study drug-related discontinuations," they added. "No new protease mutations associated with lopinavir resistance developed on study in either treatment arm."

"The 48-week PROGRESS study results, while not definitive, suggest that the nucleoside-sparing HIV regimen of Kaletra and Isentress may be an alternative treatment option for patients new to HIV therapy, when compared to a standard HIV regimen." Reynes said in a press release issued by study sponsor Abbott, which makes lopinavir/ritonavir.

Study A4001078

Study A4001078 was an open-label pilot study evaluating a NRTI-sparing regimen of ritonavir-boosted atazanavir (Reyataz) plus the CCR5 antagonist maraviroc (Selzentry).

This trial included 121 treatment-naive participants randomly assigned (1:1) to receive 300/100 mg atazanavir/ritonavir plus either 150 mg maraviroc or tenofovir/emtricitabine, with all components taken once-daily.

Participants had confirmed CCR5-tropic HIV and no evidence of resistance to the study drugs. About 90% were men, the average age was about 36 years, 75% were white, and about 20% were black. The median CD4 cell count was about 250 cells/mm3 and approximately 33% had baseline viral load > 100,000 copies/mL.

Anthony Mills from Beth Israel Medical Center presented data from a planned 24-week analysis. He explained that the study was not powered to compare efficacy, so statistical significance was not reported. The study was originally designed to last 48 weeks, but has been extended to 96 weeks.

Results

• At week 24, 80% of participants taking atazanavir/maraviroc and 89% taking the 3-drug regimen achieved viral suppression < 50 copies/mL.
• 93% and 90%, respectively, had viral load below 400 copies/mL.
• Virological response was described as comparable in both arms when stratified by viral load, but the difference was greater in the higher HIV RNA arm:
  • High (³100,000 copies/mL): 80% vs 95%, respectively;
  • Low (< 100,000 copies/mL): 81% vs 77%, respectively.
• CD4 cell gains were somewhat faster and larger in the atazanavir/maraviroc arm, 195 vs 173 cells/mm3, by week 24.
• 5 participants in the atazanavir/maraviroc arm and 4 in the 3-drug arm discontinued therapy prematurely.
• Participants taking atazanavir/maraviroc were more likely to develop elevated bilirubin levels; 26% vs 13%, respectively, had grade 3 or 4 adverse events related to hyperbiliubinemia.
• 5 patients in the atazanavir/maraviroc arm switched from atazanavir to darunavir (Prezista) due to jaundice or yellowing eyes, while 1 switched in the 3-drug arm.
• Among 5 evaluable participants (3 in the atazanavir/maraviroc arm, 2 in the triple combination arm), no new genotypic resistance mutations and no phenotypic changes in drug susceptibility were observed through week 24.
• No changes in viral tropism (switch from CCR5 to CXCR4) were seen among maraviroc recipients.

The researchers concluded that, "Interim results of this pilot analysis support the antiviral activity of this once-daily, 2-drug combination." They added that a Phase 3 study of atazanavir/maraviroc is planned.

SPARTAN

In a third non-traditional regimen study, elevated bilirubin and emergent resistance were cause for greater concern, however.

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. It is usually not dangerous but can cause jaundice, or yellowing of the skin and eyes.

Michael Kozal from Yale University School of Medicine presented findings from the SPARTAN study, an open-label pilot study evaluating the safety and effectiveness of unboosted atazanavir plus raltegravir without NRTIs in treatment-naive patients. Since raltegravir raises atazanavir levels somewhat, it may be able to substitute for ritonavir as a booster.

This study enrolled 94 participants who were randomly assigned (2:1) to receive either 300 mg unboosted atazanavir plus 400 mg raltegravir twice-daily, or else 300/100 mg atazanavir/ritonavir plus tenofovir/emtricitabine once-daily.

Here too, most participants (about 90%) were men, the median age was 40 years, and about 80% were white. The average baseline CD4 cell count was about 260 cells/mm3; high viral load (³100,000 copies/mL) was somewhat more common in the atazanavir/raltegravir arm.

Again, this study was not adequately powered to compare efficacy of the regimens and statistical significance was not reported.

Results

• In a modified intent-to-treat analysis at 24 weeks, 75% of participants taking atazanavir/raltegravir and 63% taking the boosted atazanavir regimen achieved confirmed virological response (undetectable viral load on 2 consecutive tests or re-suppression after viral rebound).
• In a 24-week as-treated analysis that excluded participants who dropped out, the corresponding response rates were 81% and 70%, respectively.
• 17% of atazanavir/raltegravir recipients and 26% in the 3-drug arm experienced virological failure (HIV rebound > 50 copies/mL).
• CD4 cell gains averaged 166 and 127 cells/mm3, respectively.
• About 10% of participants in both arms stopped treatment before week 24.
• Overall treatment-related adverse events (30% vs 33%, respectively) occurred at similar frequencies in both arms.
• Bilirubin increases were seen in both arms (19% vs 17%, respectively), but grade 4 (severe) elevations were only seen in the atazanavir/raltegravir group (20% vs 0%).
• Atazanavir/raltegravir recipients were more likely to drop out due to side effects (6% vs 0%).
• Changes in cholesterol and triglycerides were similar in both arms.
• Atazanavir concentrations were higher in the atazanavir/raltegravir arm than in the boosted atazanavir arm.
• 6 people in the atazanavir/raltegravir arm and 1 in the 3-drug arm were eligible for resistance testing due to viral load ³400 copies/mL; 4 raltegravir recipients developed integrase resistance mutations, but none in either arm showed atazanavir resistance.

Based on these findings, the researchers concluded, "Response rates (HIV < 50 copies/mL) for atazanavir + raltegravir at the primary endpoint (week 24) were consistent with current standard of care."

Although the investigators reported "no new or unexpected safety signals" for either dose of atazanavir, the study -- which had planned to monitor safety and CD4 cell recovery through week 96 -- was halted ahead of schedule due to concerns about elevated bilirubin and drug resistance, as well as the need for twice-daily dosing.

Investigator affiliations:

MOAB0101: Hôpital Gui de Chauliac, University Hospital Center of Montpellier, Montpellier, France; Abbott, Abbott Park, IL; Hospital 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain; Innovative Care PSC, Bayamon, Puerto Rico; Therapeutic Concepts, Houston, TX.

THLBB203: Beth Israel Medical Center Division of Infectious Diseases, New York, NY; HIV Unit, Infectious Disease Service, Hospital Unversitari de Bellvitge, Barcelona, Spain; Universitaet Koeln, Koeln, Germany; Laboratory of Immunovirology, Biomedicine Institute of Seville (IBIS), Infectious Diseases Service, Virgen del Rocio University Hospital, Sevilla, Spain; Pfizer Inc, New York, NY; Pfizer Global Research and Development, Sandwich, UK.

THLBB204: Yale University School of Medicine and VA CT Healthcare System, New Haven, CT; Instittuto CAICI, Rosario, Argentina; Orlando Immunology Center, Orlando, FL; Department of Infectious Diseases, Saint-Louis Hospital and University of Paris Diderot Paris 7, Paris, France; Tarrant County Infectious Association, Fort Worth, TX; University Hospital, Nantes, France; FUNDAI and University of Buenos Aires, Buenos Aires, Argentina; Bristol-Myers Squibb, Global Development and Medical Affairs, Wallingford, CT; Merck Research Laboratories, North Wales, PA.

7/30/10

References

J Reynes, A Lawal, F Pulido,and others. Lopinavir/ritonavir combined with raltegravir demonstrated similar antiviral efficacy and safety as lopinavir/ritonavir combined with tenofovir disoproxil fumarate/emtricitabine in treatment-naive HIV-1 infected subjects.XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract MOAB0101.

A Mills, D Mildvan, D Podzamczer, and others. 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.XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract THLBB203.

M Kozal, S Lupo, E DeJesus,and others (SPARTAN Study Team). 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.XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract THLBB204.

Other Source

Abbott. Abbott's PROGRESS Study of Kaletra and Isentress Compared with a Standard HIV Regimen Meets the Pre-Specified Primary Efficacy Endpoint. Press Release. July 19, 2010.