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Phenotypic resistance to protease inhibitors in patients who fail on highly active antiretroviral therapy predicts the outcome at 48 weeks of a five-drug combination including ritonavir, saquinavir and efavirenz

Piketty, Christophea; Race, Estherb; Castiel, Philippea; Belec, Laurentc; Peytavin, Gillesd; Si-Mohamed, Alic; Gonzalez-Canali, Gustavoe; Weiss, Laurencea; Clavel, Françoisb; Kazatchkine, Michel D.a

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aUnité d'Immunologie, Hôpital Broussais and Université Pierre et Marie Curie, Paris, France; bLaboratoire de Virologie, Hôpital Bichat-Claude Bernard, Paris, France; cLaboratoire de Virologie, Hôpital Broussais, Paris, France; dLaboratoire de Pharmacologie, Hôpital Bichat-Claude Bernard, Paris, France; and eCIRBS, Hôpital Saint Joseph, Paris, France.

Sponsorship: This work was supported by ROCHE and by the Agence Nationale de Recherches sur le SIDA, France.

Received: 17 December 1999; accepted: 22 December 1999.

We recently demonstrated the efficacy at 24 weeks of a salvage therapy regimen including ritonavir (RTV), saquinavir (SQV) and efavirenz in patients who failed on a first-line conventional protease inhibitor-containing triple combination treatment [1]. The baseline resistance phenotype to SQV was found to be a better predictor of the virological response than the protease genotype. In this paper we report that at 48 weeks after the switch, 61% of patients who had failed on an indinavir- or RTV-containing triple-drug regimen (19/31), exhibited plasma HIV-RNA levels below 500 copies/ml. The phenotypic resistance to SQV, but not the genotypic mutation resistance pattern for the protease gene, remained predictive of the failure of salvage therapy at week 48.

The study was an open trial of the safety and efficacy of a five-drug combination therapy including RTV/SQV and efavirenz and two recycled nucleoside reverse transcriptase inhibitors (NRTI) in 32 adult patients with advanced HIV disease who had failed on a first-line triple drug regimen, as defined by levels of plasma HIV RNA above 5000 copies/ml [1]. Exclusion criteria were previous exposure to SQV and to non-nucleoside reverse transcriptase inhibitors. RTV and SQV in hard gelatin capsule formulation were given at 100 mg twice a day and 1000 mg twice a day, respectively. Efavirenz was given at 600 mg a day.

Phenotypic sensitivity and genotypic mutation to protease inhibitors were assessed as described [1] in all patients at the time of switch and at week 48 in patients who exhibited a virological failure to therapy.

Thirty-one of the 32 patients completed the 48 week trial. One patient was lost to follow-up at week 4. The treatment was well tolerated. Side-effects included: dizziness in eight patients, headache (three), skin rash (one) and insomnia (one). One case of non-Hodgkin's lymphoma was diagnosed in a patient at week 48. Results were analysed on an intention-to-treat basis. Changes in CD4 cell counts and plasma HIV-RNA levels throughout the 48 weeks of the study are presented in Table 1.

Table 1
Table 1
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The lack of SQV phenotypic resistance at baseline was associated with a significant increase in the number of patients having achieved a plasma viral load below 500 copies/ml at week 48 (79 versus 33%, P  = 0.02). The lack of SQV phenotypic resistance at baseline was also associated with a significant increase in the number of patients having achieved a plasma viral load below 50 copies/ml at week 48 (74 versus 33%, P  = 0.05). At week 48 of treatment, the mean decrease in plasma viral load in patients exhibiting and those who did not exhibit phenotypic resistance to SQV were 0.79 log10 copies/ml and 1.47 log10 copies/ml, respectively (P  = 0.007). At week 48 of therapy, using the cut-off of 50 copies/ml, the median decrease in plasma viral load in patients exhibiting and those who did not exhibit phenotypic resistance to SQV were 1.13 log10 copies/ml and 2.23 log10 copies/ml, respectively (P  = 0.004).

At week 48 of therapy, the mean decrease in plasma viral load in patients exhibiting and those who did not exhibit the L90M and G48V mutations were 1.09 log10 copies/ml and 1.29 log10 copies/ml, respectively (p = 0.5). The lack of L90M and G48V mutations at baseline was not associated with a significant increase in the proportion of patients exhibiting a plasma viral load below 500 copies/ml at week 48 (74 versus 45%, P  = 0.2). The lack of L90M and G48V mutations at baseline was also not associated with a significant increase in the proportion of patients exhibiting a plasma viral load below 50 copies/ml at week 48 (68 versus 45%, P  = 0.4). No correlation was observed between the number of primary and secondary protease inhibitor-resistance mutations at baseline and the virological response at week 48. Phenotypic resistance to SQV and efavirenz were observed in seven out of 11 patients and eight out of 10 patients exhibiting virological failure at week 48, respectively.

The present study demonstrates the virological and immunological efficacy of a salvage therapy regimen including RTV, SQV and efavirenz in patients who failed on a conventional protease inhibitor-containing triple combination treatment.

Several groups have reported on the lack of virological efficacy of RTV and SQV in protease inhibitor-experienced patients [2–7]. One may thus suggest that the significant activity of the salvage regimen in our study was dependent on the addition of efavirenz, to which all patients were naive. Because baseline plasma HIV-RNA levels in our trial were lower than those in previous studies, the results suggest that patients may experience a greater benefit if rapidly switched to an alternative antiretroviral regimen.

Our results indicate that protease resistance phenotype may be a better predictor of virological response than protease genotype in patients failing indinavir or RTV who switch to the RTV/SQV combination. The results of trials prospectively evaluating the impact of phenotype or of genotype resistance testing on response to HIV therapeutic switches are awaited to determine the respective value of these two techniques.

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Acknowledgements

The authors are indebted to Drs Julien Vrtovsnik, Didier Laureillard, Dominique Batisse, Marina Karmochkine, Martin Buisson and Didier Jayle for their participation in the trial.

Christophe Pikettya

Esther Raceb

Philippe Castiela

Laurent Belecc

Gilles Peytavind

Ali Si-Mohamedc

Gustavo Gonzalez-Canalie

Laurence Weissa

François Clavelb

Michel D. Kazatchkinea

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References

1. Piketty C, Race E, Castiel P. et al. Efficacy of a five-drug combination including ritonavir, saquinavir and efavirenz in patients who failed on a conventional triple drug regimen: phenotypic resistance to protease inhibitors predicts outcome of therapy. AIDS 1999, 13: F71 –F77.

2. Lorenzi P, Yerly S, Abderrakim K. et al. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir. :Swiss HIV Cohort Study. AIDS 1997, 11: F95 –F99.

3. Deeks SG, Grant RM, Beatty GW, Horton C, Detmer J, Eastman S. Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure. AIDS 1998, 12: F97 –F102.

4. Kaufmann GR, Duncombe C, Cunningham P. et al. Treatment response and durability of a double protease inhibitor therapy with saquinavir and ritonavir in an observational cohort of HIV-1-infected individuals. AIDS 1998, 12: 1625 –1630.

5. Rhone SA, Hogg RS, Yip B. et al. The antiviral effect of ritonavir and saquinavir in combination amongst HIV-infected adults: results from a community-based study. AIDS 1998, 12: 619 –624.

6. Hall CS, Raines CP, Barnett SH. et al. Efficacy of salvage therapy containing ritonavir and saquinavir after failure of single protease inhibitor-containing regimens. AIDS 1999, 13: 1207 –1212.

7. Tebas P, Patrick AK, Kane EM. et al. Virologic responses to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelvinavir. AIDS 1999, 13: F95 –F28.

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