2/4/15 19:09 Failure of a ritonavir plus saquinavir-based rescue regimen... : AIDS Página 1 de 2 http://journals.lww.com/aidsonline/Fulltext/2000/03100/Failure_of_a_ritonavir_plus_saquinavir_based.25.aspx Author Information A high rate of protease inhibitor (PI) failures have been observed in clinical cohorts of HIV-infected patients [1] . In patients failing on indinavir (IDV) therapy, virological failure is frequently associated with cross-resistance to other PI [2] . Dual PI therapy with ritonavir (RTV) plus saquinavir (SQV) has become an attractive therapeutic option taking into account the favourable pharmacokinetic interactions [3] ; and it has been shown to be successful in patients who have failed previous single PI therapy [4,5] . No data exist, however, about the best option for patients in whom the RTV–SQV rescue regimen has failed. In particular, the use of any other PI could be compromised as a result of cross-resistance [6] . In order to clarify this issue, the rate of resistance in patients failing an RTV + SQV rescue regimen and the degree of virological response to a new PI-containing regimen was retrospectively analysed. Patients included in this study met the following criteria: failure after therapy with two nucleoside analogues plus IDV, and detectable HIV load during a rescue regimen with RTV (400 mg twice a day) plus SQV (400 mg twice a day) plus at least one new nucleoside analogue. Each patient was evaluated at baseline (that is, after RTV + SQV failure), at 12 and at 24 weeks. The CD4 cell count was determined by flow cytometry. Plasma viral load determinations were performed using an ultrasensitive branched DNA assay (Chiron Diagnostics, Emeryville, CA, USA). For resistance analysis, 16 patients had plasma samples obtained before initiating salvage therapy (baseline), and stored at 70°C. Genotypic analysis was performed by automated population-based full-sequence analysis (ABI). Results of the genotypic analysis are reported as amino acid changes at positions along the entire protease gene compared with the wild-type (HXB2) reference sequence. Phenotypic analysis was performed using the recombinant virus assay approach as described by Hertogs et al. [7] (Antivirogram, Virco, Mechelen, Belgium). The results of this analysis are expressed as fold- resistance values, reflecting the fold-increase in mean IC 50 (µM) of a particular drug when tested with patient-derived recombinant virus isolates, relative to the mean IC 50 of the same drug obtained when tested with a reference wild-type virus isolate (IIIB/LAI). From July 1997 to March 1999, 20 patients met the inclusion criteria. Mean age was 38 years (24–56 years) and 60% were men. Patients had received triple therapy with IDV for a median time of 313 days (271– 556 days). At the time of failure, median HIV load was 4.6 log 10 copies/ml (2.8–5.7 log 10 copies/ml). Then, a combination containing RTV + SQV was administered during a median time of 207 days, before switching to a new regimen as a result of virological failure. Salvage regimen included stavudine in 90% and stavudine–didanosine in 10% of cases, plus either nevirapine plus nelfinavir (NFV) plus SQV (15 cases), nevirapine plus NFV (three patients) or nevirapine plus RTV plus IDV (two cases). At the time of RTV + SQV failure, median HIV load was 5 log 10 copies/ml (2.53–5.7 log 10 copies/ml) and the CD4 cell count was 214 × 10 6 /l (15–1160 × 10 6 /l). In a genotypic analysis, the median number of mutations in the protease gene was 12 (7–18), and 94% of patients (15 out of 16) showed primary mutations associated with resistance to PI (Table 1), mainly the L90M and V82A mutations (50% each). A substitution at position 46, 48 or 84 was observed in 50, 19 and 31% of viral isolates, respectively. Phenotypic analysis revealed a greater than 10-fold increase in the IC 50 to IDV, RTV and SQV in 70% and to NFV in 80% of cases. Table 1 During the new salvage regimen, HIV load decreased a median 0.26 log 10 copies/ml (range +2.5 to −1.6) after 12 weeks, and a median 0.4 log 10 (range +0.4 to −1.5) after 24 weeks of therapy. A reduction of greater than 0.5 log 10 was obtained in 35% of patients at 12 weeks. Only 12% of patients at the third month and 14% at the sixth month reached plasma viral loads below 50 copies/ml. However, the CD4 cell count continued to increase (72 and 41 × 10 6 /l at 3 and 6 months). Current guidelines recommend considering dual PI therapy for patients who have failed on an IDV-containing regimen. Previous studies with the combination of RTV–SQV as rescue regimen have shown different responses, ranging from 15% to more than 50% of patients reaching undetectable HIV load [4,5,8] . This study showed the high rate of resistance in patients failing on a rescue regimen with RTV + SQV, as well as the lack of virological response to a new regimen based on PI. Nearly 70–80% of viral isolates were resistant to all available PI, although nelfinavir had not been administered previously. The presence of resistance to PI adequately predicted the poor response to the new combination, despite the inclusion of stavudine and nevirapine, to which most patients had susceptible virus as determined by phenotypic analysis (data not shown). Moreover, it was shown that the use of non- nucleoside reverse transcriptase inhibitors in combination with PI in patients failing RTV + SQV can compromise this family of drugs [9] . These patients had received PI (IDV, then RTV + SQV) for more than 1.5 years before switching to a new salvage PI-containing regimen, probably leading to a higher number of mutations. It is unknown whether a shorter time on previous PI therapy could allow the use of new PI in the salvage regimen. This study reinforced the utility of phenotypic resistance testing in the design of rescue regimens in patients failing a PI-containing regimen, and these data are more important according to the number of drugs previously used. Pending further studies with new PI in preclinical and early clinical Jose L. Casadoa Fernando Drondaa Kurt Hertogsb Antonio Antelaa Santiago Morenoa AIDS: 10 March 2000 - Volume 14 - Issue 4 - p 466 Correspondence Failure of a ritonavir plus saquinavir-based rescue regimen precludes the use of protease inhibitors Casado, Jose L. a ; Dronda, Fernando a ; Hertogs, Kurt b ; Antela, Antonio a ; Moreno, Santiago a a Infectious Diseases Service, Ramon y Cajal Hospital, Madrid, Spain; and b Virco, Mechelen, Belgium. Received: 24 November 1999; accepted: 2 December 1999. Presented in part at the 7th European Conference on Clinical Aspects and Treatment of HIV Infection. Lisbon, 23–27 October 1999 [Abstract 531].