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Antimicrobial Agents and Chemotherapy, February 2002, p. 570-574, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.570-574.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Amprenavir Inhibitory Quotient and Virological Response in Human Immunodeficiency Virus-Infected Patients on an Amprenavir-Containing Salvage Regimen without or with Ritonavir

Xavier Duval,1* Claire Lamotte,2 Ester Race,3 Diane Descamps,4 Florence Damond,4 François Clavel,3 Catherine Leport,1 Gilles Peytavin,2 and Jean-Louis Vilde1

Service des Maladies Infectieuses et Tropicales,1 Service de Pharmacie Clinique,2 Laboratoire Viralliance, Hôpital Bichat Claude Bernard, Paris, France,3 Service de Virologie4

Received 30 May 2001/ Returned for modification 30 August 2001/ Accepted 1 November 2001


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ABSTRACT
 
The efficacy of an amprenavir (APV)-containing therapy without (group A) or with (group B) ritonavir was assessed in patients with failure of previous protease inhibitor therapy for human immunodeficiency virus (HIV) infection. The mean minimal plasma APV concentrations in groups A and B were 58 and 1,320 ng/ml, respectively, corresponding to APV inhibitory quotients of 0.2 (range, 0.03 to 0.70) and 7.0 (range, 1.4 to 145), respectively. At week 24, 2 of 8 and 13 of 14 patients in groups A and B, respectively, had <200 HIV RNA copies/ml of plasma, including 4 of 5 patients infected with APV-resistant viruses.


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TEXT
 
In the context of the increasing prevalence of resistance to multiple drugs among human immunodeficiency virus (HIV) isolates, optimization of salvage therapy with all available tools, plasma drug concentration monitoring, and phenotypic and genotypic assessments are of crucial importance. However, the relationship between the predicted levels of viral drug resistance determined by in vitro phenotypic assays and the therapeutic response is unclear. Poor adherence, poor bioavailability, interindividual variabilities in pharmacokinetics, extensive serum protein binding, and drug-drug interactions may lead to underexposures to antiviral drugs and unfavorable outcomes (1–5). Recent in vitro studies have shown that amprenavir (APV) could conserve antiviral efficacy against HIV strains derived from patients experiencing failure of highly active antiretroviral therapy (HAART) by regimens that contain indinavir, ritonavir, nelfinavir, or saquinavir (9, 11). The 90% inhibitory concentration (IC90) of APV corrected for protein binding (IC90c) is approximately 140 to 280 ng/ml for wild-type viruses, whereas the expected minimal concentration of APV (administered at 1,200 mg twice daily [b.i.d.]) in plasma (Cmin) is 280 ng/ml without the coadministration of a nonnucleoside reverse transcriptase inhibitor (NNRTI) (1, 3–5, 9). Condra et al. (1) suggested that improving the level of exposure to APV by increasing plasma APV levels may improve the response to therapy. The APV Cmin is dramatically increased by the coadministration of low doses of ritonavir, even with reduced APV doses, leading to levels in plasma that are theoretically higher than the IC90cs for some resistant HIV strains (1, 2, 10).

(This study was presented in part at the 38th Annual Meeting of the Infectious Diseases Society of America, 7 to 10 September 2000, New Orleans, La. [X. Duval et al., Abstr. 38th Annu. Meet. Infect. Dis. Soc. Am., abstr. 330, 2000].)

To understand the relationship between APV susceptibility, APV Cmin, and the virological response, we determined these parameters in patients who were naive for APV treatment, who had failed previous HAART, and in whom APV-containing salvage therapy was initiated. The first group (group A) consisted of patients starting APV at 1,200 mg b.i.d. in combination with efavirenz or nevirapine and one or two nucleoside reverse transcriptase inhibitors (NRTIs). Patients for whom the APV Cmin was lower than 100 ng/ml at two consecutive determinations were offered ritonavir at 100 mg b.i.d. to increase plasma APV levels, with concomitant reduction of the APV dosage from 900 to 450 mg b.i.d. Due to the low APV Cmin observed in patients in group A, additional patients starting on APV received APV at a dosage of 450 mg b.i.d. combined with ritonavir at 100 mg b.i.d.; this constituted the second group (group B).

Genotyping of the HIV type 1 (HIV-1) protease and reverse transcriptase genes was carried out at the baseline and at month 2 or 3 or at month 6 in patients with detectable viral loads at month 6 (6, 7). According to the recommendations in a European summary of product characteristics based on the results of studies with APV (at 1,200 mg b.i.d.) in APV-naive patients not treated with ritonavir (Amprenavir, European Summary of Product Characteristics, Glaxo-Wellcome, 2000), viruses were considered resistant to APV when at least three mutations at different codons among the M46I, M46L, I54L, I54M, I54V, V82A, V82F, V82I, V82T, I84V, and L90M mutations were detected (12).

Phenotyping was carried out at the baseline by recombinant virus assay (RVA) as described previously (8) and at month 6 in patients with detectable viral loads. The APV IC90c was calculated by multiplying the raw IC90 by 7, the published fold attenuation of APV by 50% human serum in vitro (1, 4, 5). The IC90c of APV for the RVA reference strain, strain NL4-3, was 120 ng/ml. Viruses for which the IC90cs were higher than 480 ng/ml were considered resistant.

The Cmin of APV was measured weekly during the first month and monthly up to month 6 by a validated high-performance liquid chromatography assay. For each patient, the mean APV Cmin during the first month was determined by using the steady-state values (those on days 14, 21, and 30). For the patients in group A, only the levels in plasma determined before the addition of ritonavir were analyzed. For each patient, the APV inhibitory quotient was determined by calculation of the ratio of the mean APV Cmin as defined above and the baseline IC90c.

Group A consisted of 8 patients, and group B consisted of 14 patients. The characteristics of the patients are presented in Table 1. Four patients were NNRTI experienced and carried viruses with NNRTI resistance-associated mutations. Treatment with ritonavir was initiated in five patients in group A on days 14 (patients 2, 6, and 8), 21 (patient 3), and 30 (patient 1).


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  		TABLE 1. Baseline and follow-up characteristics of 22 patients receiving APV without (group A) or with (group B) ritonavir containing salvage HAART

Three or more APV resistance mutations were detected in four patients from each group (Table 2). The median baseline APV IC90c was higher for group A (350 ng/ml) than for group B (175 ng/ml). However, 2 of 8 patients in group A and 5 of 14 patients in group B carried phenotypically resistant viruses (Table 2). The median APV Cmins within the first month were 58 and 1,320 ng/ml for patients in groups A and B, respectively, and the median APV Cmin between months 2 and 6 was 1,310 ng/ml for patients in group B. The median APV inhibitory quotient was 0.2 for patients in group A and 7 for patients in group B (Tables 1 and 2).


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  		TABLE 2. APV genotypic and phenotypic resistance profiles before initiation, Cmins, and inhibitory quotients after initiation of APV-containing salvage therapy in patients previously treated with a protease inhibitor

Viral loads below 200 copies/ml were achieved at week 24 in 2 of 8 patients in group A, despite low APV Cmins, and in 13 of 14 patients in group B. One of the two patients in group A (patient 7) was prematurely switched from APV to another HAART containing dual protease inhibitors because he refused to receive ritonavir-APV on a delayed basis, and the other patient (patient 6) received ritonavir at day 14, which increased the inhibitory quotient from 0.08 to 3.8. Among the 13 patients in group B with virological responses, 3 carried virus predicted to be resistant according to their genotypes and 4 carried virus predicted to be resistant according to their phenotypes (Table 2). The 14th patient (patient 9) in group B, who was 1 of 5 patients infected with virus predicted to be resistant according to its phenotype, had a partial virological response (Table 2).

Seven patients had detectable viral loads at month 6. By month 3, three of four patients in group A and one patient (patient 9) in group B carried viruses which had acquired NNRTI resistance-associated mutation K103N, despite high plasma NNRTI levels. By month 6, four of four patients in group A carried viruses which had acquired NNRTI resistance-associated mutation K103N, despite high plasma NNRTI levels. Viruses from six of seven patients developed new mutations in the protease-encoding region (Table 3). The APV IC90c increased by a mean of 8-fold (range, 2- to >20-fold) for viruses from all four patients whose viruses were phenotypically susceptible to APV at the baseline (Table 3). Virus strains from the three patients that were already resistant to APV at the baseline remained phenotypically resistant to APV. Patient 9 was the only patient whose virus did not develop any new mutation in the protease-encoding region and for which there was no increase in the IC90c from the baseline value. His virus carried the S69S insertion in the reverse transcriptase-encoding region at the baseline. His viral load at month 6 was 1.3 logs below the baseline value; this was probably solely due to the continuing activity of APV-boosted ritonavir.


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  		TABLE 3. Genotypic and phenotypic APV resistance profiles at week 24 and genotypic NNRTI resistance profile at week 8, 12, or 24 after initiation of APV-containing HAART in seven patients experiencing virological failure compared to the profiles at the baseline

The significant decrease in the APV Cmin induced by the coadministration of NNRTI led, in the patients in group A, to APV levels lower than the IC90c (inhibitory quotient less than 1), the early acquisition of major NNRTI resistance-associated mutations, and virological failure, despite the addition of ritonavir within 1 month. Therefore, four patients carried viruses defined as being sensitive to APV but did not benefit from APV therapy. The APV underexposure during the first days of therapy, followed by what was functionally APV monotherapy during the months following the early acquisition of an NNRTI resistance-conferring mutation, led to the selection of new mutations in the protease-encoding region and an increase in the APV IC90c to levels for resistance, which dramatically reduced the remaining therapeutic options for these patients.

Conversely, the concomitant administration of ritonavir to the APV regimen led to inhibitory quotients greater than 1 in all patients in group B, even those infected with viruses defined as genotypically and/or phenotypically resistant. Thus, even if some level of resistance to APV was manifest in viruses from some patients, it was possible to overcome that resistance by providing higher levels of exposure to APV. It is important to appreciate the fact that resistance to antivirals is not absolute but is measured as a continuous scale of a reduction of drug susceptibility. As such, any clinically relevant interpretation of genotypic or phenotypic data generated in vitro must consider the concentrations achievable in plasma in vivo.

In the present evaluation, determination of the relative efficacy of each component of the antiretroviral combination was not performed. At the initiation of therapy, viruses from four patients in group B had an S69S insertion and/or mutations that conferred resistance to NNRTIs. In these patients, the APV-associated reverse transcriptase inhibitors probably had low levels of antiviral efficacy. Nevertheless, favorable virological responses were observed in three of these four patients, which may be explained by the high APV inhibitory quotient. Determination of the optimal inhibitory quotient required to reduce the viral load to undetectable levels should consider the efficacy of each molecule included in the combination. Moreover, knowledge and/or prediction of inhibitory quotients for all antiviral drugs could aid in the selection of the optimal combination therapy, not only in terms of the antivirals selected but also in terms of the determination of the optimal dose of each component required to achieve maximum antiviral efficacy without compromising tolerance.


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FOOTNOTES
 
* Corresponding author. Mailing address: Service des Maladies Infectieuses et Tropicales, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, 75877 Paris, Cedex 18, France. Phone: 33 1 40 25 78 03. Fax: 33 1 40 25 88 60. E-mail: xavier.duval{at}bch.ap-hop-paris.fr. Back


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REFERENCES
 
    1
  1. Condra, J. H., C. J. Petropoulos, R. Ziermann, W. A. Scheil, M. Shivaprakash, and E. A. Emini 2000. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. J. Infect. Dis. 182:758–765.[CrossRef][Medline]
    2. 2
  2. Duval, X., V. Le Moing, P. Longuet, C. Leport, J. L. Vildé, C. Lamotte, G. Peytavin, and R. Farinotti. 2000. Efavirenz-induced decrease in plasma amprenavir levels in human immunodeficiency virus-infected patients and correction by ritonavir. Antimicrob. Agents Chemother. 44:2593.[Free Full Text]
    3. 3
  3. Falloon, J., S. Piscitelli, S. Vogel, B. Sadler, H. Mitsuya, M. F. Kavlick, K. Yoshimura, M. Rogers, S. LaFon, D. J. Manion, H. C. Lane, and H. Masur. 2000. Combination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV)-infected patients failing a protease-inhibitor regimen: pharmacokinetic drug interactions and antiviral activity. Clin. Infect. Dis. 30:313–318.[CrossRef][Medline]
    4. 4
  4. Livingston, D. J., S. Pazhanisamy, D. J. T. Porter, J. A. Partaledis, R. D. Tung, and G. Painter. 1995. Weak binding of VX-478 to human plasma proteins and implications for anti-human immunodeficiency virus therapy. J. Infect. Dis. 172:1238–1245.[Medline]
    5. 5
  5. Molla, A., S. Vasavanonda, G. Kumar, H. L. Sham, M. Johnson, B. Grabowski, J. F. Denissen, W. Kohlbrenner, J. J. Plattner, J. M. Leonard, D. W. Norbeck, and D. J. Kempf. 1998. Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. Virology 250:255–262.[CrossRef][Medline]
    6. 6
  6. Nijhuis, M., C. A. Boucher, P. Schipper, T. Leitner, R. Schuurman, and J. Albert. 1998. Stochastic processes strongly influence HIV-1 evolution during suboptimal protease inhibitor therapy. Proc. Natl. Acad. Sci. USA 95:14441–14446.[Abstract/Free Full Text]
    7. 7
  7. Nijhuis, M., C. A. Boucher, and R. Schuurman. 1995. Sensitive procedure for the amplification of HIV-1 RNA using a combined reverse transcription and amplification reaction. BioTechniques 19:178–180.[Medline]
    8. 8
  8. Race, E., E. Dam, V. Obry, S. Paulos, and F. Clavel. 1999. Analysis of HIV-cross resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. AIDS 13:2061–2068.[CrossRef][Medline]
    9. 9
  9. Sadler, B. M., C. Gillotin, Y. Lou, and D. S. Stein. 2001. Pharmakokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing. Antimicrob. Agents Chemother. 45:30–37.[Abstract/Free Full Text]
    10. 10
  10. Sadler, B. M., P. J. Piliero, S. L. Preston, P. P. Lloyd, Y. Lou, and D. S. Stein. 2001. Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, coadministration to healthy volunteers. AIDS 15:1009–1018.[CrossRef][Medline]
    11. 11
  11. Schmidt, B., K. Korn, B. Moschik, C. Paatz, K. Uberla, and H. Walter. 2000. Low level of cross-resistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors. Antimicrob. Agents Chemother. 44:3213–3216.[Abstract/Free Full Text]
    12. 12
  12. Tisdale, M., R. Myers, S. Randall, M. Maguire, M. Ait-Khaled, R. Elston, and W. Snowden. 2000. Resistance to the HIV protease inhibitor amprenavir in vitro and in clinical studies; a review. Clin. Drug Investig. 20:267–285.[CrossRef]

Antimicrobial Agents and Chemotherapy, February 2002, p. 570-574, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.570-574.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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