Data from a study called BMS 045 was first presented in July 2003 at the International AIDS Society (IAS) meeting in Paris. This study involved 358 participants who had triple-class experience and resistance, and were randomized to receive a combination of either standard dose lopinavir/ritonavir (LPV/r, Kaletra), atazanavir (ATV, Reyataz) 300 mg/ritonavir (RTV, Norvir) 100 mg, or unboosted atazanavir with saquinavir (SQV, Invirase, Fortovase) at 1,200 mg once daily. All participants were on one of these protease inhibitor (PI) regimens in combination with tenofovir (TDF, Viread) plus a third NRTI selected by the investigator. This presentation further defines the longer-term outcome of this study, presenting results from week 48.
At study entry, the baseline RNA was about 4.4 logs, and CD4 counts were about 300 cells/mm3. Most patients (about 60%) were on an NNRTI regimen at study entry, limiting the power of this study to define specific baseline PI mutations and their impact on each of the arms of this study. Nonetheless, the overall results give a general idea of the relative potency of each of these approaches. Similar to the week 24 results, both boosted atazanavir and lopinavir/ritonavir provided a 1.9 log drop sustained to week 48, while the unboosted dual-PI regimen had a 1.55 log drop.
The two boosted regimens can be considered equivalent, with statistics demonstrating that these two regimens differ by no more than 0.4 log (97.5% confidence interval). When looking at the more standard percent below cutoff, and using the 400-copy cutoff, both boosted regimens had about 53% below 400, while the dual unboosted arm showed only 37% suppression. With the 50-copy cutoff, there was an 8% difference favoring lopinavir/ritonavir. Lopinavir/ritonavir showed 46% suppression, atazanavir/ritonavir had 38%, while the dual-unboosted arm was only 26% successful, demonstrating some evidence that lopinavir may retain more activity than atazanavir, especially when dealing with highly PI-resistant virus. The CD4 counts were similar in the two boosted-PI arms, showing about 115 cell increases at one year, while the non-boosted arm showed a 72-cell increase.
As with the 24-week analysis, there were differences in the lipid fractions over time. Overall, the two atazanavir arms show less changes to these lipid fractions, with the biggest difference seen in the mean percent change in triglycerides, showing a 30% increase in those on lopinavir/ritonavir, and a fall in those starting on either atazanavir arm.
Similarly, the total cholesterol falls a small amount in both atazanavir arms, with a small 6% increase in the lopinavir/ritonavir arm. Accordingly, fewer patients on the atazanavir arms were started on lipid lowering therapy during the trial. Adverse events continued overall to be low in all three arms, although 11% did report grade 2 or greater diarrhea on lopinavir/ritonavir, while only 3% noted this adverse effect on boosted atazanavir/ritonavir. Supporting this is the observation that 24% required antidiarrheal treatment on the lopinavir regimen, and only 6% did so while on the boosted atazanavir. As expected, 6% did have jaundice on the boosted atazanavir arm, with none on the lopinavir/ritonavir arm.
Overall, these results are similar to what was seen at week 24. The overall potency is similar in the two boosted regimens, while the unboosted dual-PI approach is clearly less successful than either one. The percent with suppression using a 400-copy cutoff confirms the similar response in these two regimens, although there is a small difference noted in the 50-copy cutoff, consistent with earlier reports that in highly PI-resistant virus, there may be some advantage to lopinavir/ritonavir over atazanavir/ritonavir.
The safety and tolerability profile also confirm earlier findings showing less gastrointestinal toxicity in terms of diarrhea on atazanavir/ritonavir versus lopinavir/ritonavir. In addition, there were fewer lipid disturbances on boosted atazanavir. These data continue to provide support to patients and clinicians facing choices about treatment options after prior regimen failure, and allow continued insights about the role of boosted atazanavir as an alternative to the current "gold standard" lopinavir/ritonavir.
Abstract: Efficacy and Safety of Atazanavir With Ritonavir or Saquinavir vs. Lopinavir/Ritonavir in Patients Who Have Experienced Virologic Failure on Multiple HAART Regimens: 48-Week Results From BMS A1424-045 (Poster 547)
Authored by: E. DeJesus, B. Grinsztejn, C. Rodriguez, L. Nieto-Cisneros, J. Coco, A. Lazzarin, K. Lichtenstein, M. Johnson, A. Rightmire, S. Sankoh, R. Wilber
Affiliations: IDC Res. Initiative, Altamonte Springs, FL; Inst. de Pesquisa Clin. Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil; Hosp. Argerich, Buenos Aires, Argentina; Hosp. Gabriel Mancera, IMSS Mexico, D.F., Mexico; Pendleton Memorial Methodist Hosp., New Orleans, LA; S. Raffaele Hosp., Milan, Italy; Univ. of Colorado Hlth. Sci. Ctr., Denver, CO; Royal Free Hosp., London, UK; Bristol-Myers Squibb Co., Hopewell, NJ; Bristol-Myers Squibb Co., Wallingford, CT