• Salvage Therapy With Lopinavir/Ritonavir (LPV/r), Amprenavir (APV) ± an Additional Boost With Ritonavir in HIV Infected Patients (pts) With Multiple Treatment Failure: Final 26-Week Results of Puzzle 1-ANRS104 Study (Abstract H-1078)
  Authored by G. Raguin, G. Chene, L. Morand-Joubert, A. Taburet, C. Droz, C. Le Tiec, F. Clavel, P. Girard
  Slide Presentation: View the original abstract

Dr. Raguin presented the final analysis data from the French ANRS 104 study (Puzzle-1 study). This was a study in heavily pre-treated patients, which attempted to determine whether a double protease inhibitor (PI) regimen alone or with additional low-dose ritonavir (RTV, Norvir) would reduce viral load more. It is well known that ritonavir can boost blood levels of several other PIs, which in turn has resulted in improved potency of these PIs. This was the basis for combining lopinavir (LPV) and low-dose ritonavir as Kaletra (LPV/r). There are also additional data that suggest that two PIs in therapeutic doses can have additive potency, and that perhaps with the addition of small doses of ritonavir, even greater potency of a dual PI regimen might be realized. The ANRS 104 study had two arms: lopinavir/ritonavir (200 mg/day) + amprenavir (APV, Agenerase, 600 mg) versus those two drugs plus an additional 200 mg of ritonavir/day (total 400 mg/day).

This was a randomized, open label, multicenter study. Patients had to have a CD4 count of less than 500/mm³, a HIV viral load of greater than 10,000 copies/ml, have experienced two PIs and at least one non-nucleoside reverse transcriptase inhibitor (NNRTI), have had no change in regimen for at least three months, and have not received either lopinavir/ritonavir or amprenavir before. Thirty-seven patients were randomized and started treatment, 19 in the 200 mg ritonavir arm and 18 in the 400 mg ritonavir arm. Baseline inclusion criteria included a mean age of 42, CD4 count of 207/mm³, viral load of 4.7 log (50,000 copies/ml), median number of prior antiretroviral agents used was 7.8 with 53 and 28 months of PI and NNRTI exposure respectively, and 7 and 22 mutations in the protease and reverse transcriptase genes respectively.

Results showed that with a standard small dose of ritonavir (200 mg, only the lopinavir/ritonavir dose), viral load was reduced by 1.4 log vs. 2.5 log copies/ml in the 400 mg ritonavir arm after 26 weeks. In addition, only six of 19 patients (32 percent) receiving 200 mg of ritonavir compared to 11 of 18 patients (62 percent) who received 400 mg of ritonavir were able to achieve an undetectable viral load (less than 50 copies/ml). Each arm was able to achieve a CD4 increase of 120 CD4 cells/mm³. Thus, there was no significant difference in CD4 increases between arms.

Four subjects in each arm stopped treatment, and there were six serious adverse events in each group (mostly related to gastrointestinal disturbances). In a multivariate analysis, the only significant correlate of a significant virologic response was the number of PI mutations in the protease gene. In other words, the fewer mutations you had, the greater your response to the regimen.

This study indicates that in heavily pretreated patients with multidrug resistant virus, one can still achieve a significant viral load reduction with a ritonavir boosted, dual PI regimen. However, the potency of such a strategy might be enhanced with additional low-dose ritonavir added to this regimen. This study was quite small and several patients had significant side effects requiring discontinuation of the regimen. Therefore, one should be cautious about using this regimen as the side effects and potential drug interactions may be significant.