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Changes in Darunavir/r Resistance Score After Previous Failure to Tipranavir/r in HIV-1-Infected Multidrug-Resistant Patients

Spagnuolo, Vincenzo MD*; Gianotti, Nicola MD*; Seminari, Elena MD*; Galli, Laura MSc*; Fusetti, Giuliana SC*; Salpietro, Stefania MSc*; Lazzarin, Adriano MD*†; Castagna, Antonella MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: February 2009 - Volume 50 - Issue 2 - p 192-195
doi: 10.1097/QAI.0b013e31819367fc
Brief Report: Clinical Science
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Objectives: To evaluate changes in resistance to tipranavir/r (TPV/r) and darunavir/r (DRV/r) in patients who had failed a TPV/r-including regimen.

Methods: HIV genotypes obtained both at baseline and at tipranavir/r failure (TPVF) were analyzed in 47 HIV-infected patients failing a TPV/r-including regimen. Genotypes were evaluated through the Stanford mutation score: patients were ranked for TPV/r and DRV/r resistance as susceptible (class 1), potential low-level (class 2), low-level (class 3), intermediate-level (class 4), and high-level resistance (class 5). Values are expressed as median (interquartile range) or as frequency (%).

Results: Forty-seven patients were eligible. At baseline (tipranavir initiation), the scoring for TPV/r was: class 3 = 4 (8.5%); class 4 = 31 (66%); and class 5 = 12 (25.5%). Corresponding scores for DRV/r were: class 2 = 1 (2%), class 3 = 12 (25.5%), class 4 = 32 (68%), and class 5 = 2 (4.5%). At TPVF, a shift toward a higher TPV/r scoring class was seen in 16 (34.1%) patients (P = 0.001), whereas a shift toward a higher DRV/r scoring class was observed in 9 (19.2%) patients (P = 0.2381). After TPVF, 25/47 patients (53%) were treated with a DRV/r-containing regimen. After 24 weeks (on-treatment analysis), the median HIV RNA decrease was 3.04 (2.13-3.45) log10 copies per milliliter in DRV/r group versus −0.04 (−0.44; 0.50) log10 copies per milliliter in patients not treated with a DRV/r-containing regimen (P < 0.0001); CD4+ increase was 126 (70-169) cells per cubic millimeter in DRV/r group versus −42 (−121; 42) (P < 0.0001).

Discussion: Treatment with TPV/r did not significantly increase the resistance score to DRV/r and did not preclude the efficacy of subsequent treatment with DRV/r.

From the *Department of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy; and †Università Vita-Salute San Raffaele, Milan, Italy.

Received for publication April 1, 2008; accepted September 19, 2008.

A.C., N.G., A.L., and E.S. are recipients of financial support for research and educational programs from Glaxo Smith Kline, Bristol Myers Squibb, Abbott, Gilead Sciences, Roche, Boehringer-Ingelheim, Pfizer, and Virco (Johnson & Johnson).

Presented in part at XI Conference of European AIDS Clinical Society, October 24-27, 2007, Madrid, Spain. Poster P 7.4/05.

G.F, L.G., S.S., and V.S. have no potential conflict of interest to declare.

Correspondence to: Vincenzo Spagnuolo, MD, Division of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy (e-mail: spagnuolo.vincenzo@hsr.it).

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INTRODUCTION

Darunavir (DRV) and tipranavir (TPV) are the 2 most recent protease inhibitors showing activity against multiresistant-viral strains,1,2 but their optimal sequencing has not yet been defined in the context of salvage regimens.

The aim of this study was to evaluate changes in resistance to darunavir/r (DRV/r) in patients who had failed a tipranavir/r (TPV/r)-including regimen and the virological response to DRV/r-including regimens after failure to TPV/r.

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METHODS

Patients who had failed a TPV/r-including regimen and naive to DRV/r were considered eligible for this study. Failure to TPV/r was defined by the presence of HIV RNA >400 copies per milliliter after at least 6 months of treatment.

Genotypes were performed both at baseline and at tipranavir/r failure (TPVF) from all patients. The HIV-1 pol gene was sequenced by means of Megabace 1000 (Pharmacia-Amersham, Freiburg, Germany), and the sequences were analyzed by the HIVdb, HIV reverse transcriptase (RT) and protease sequence database (http://hivdb.stanford.edu/). According to the Stanford genotypic score, patients were ranked for TPV/r and DRV/r resistance as susceptible (class 1), potential low-level (class 2), low-level (class 3), intermediate-level (class 4), and high-level resistance (class 5).

Furthermore, using genotypes at TPV/r baseline, we have calculated cumulative genotypic sensitivity score (GSS) for each patient in accordance with Stanford genotypic score. We have attributed a score of 1 for every drug (used during TPV/r or at subsequent DRV/r treatment) scored as susceptible or with a potential low-level resistance.

All values used for statistical analysis are expressed as median (interquartile range) or as frequency (%). Proportions were compared using the Fisher exact test or the McNemar test, as appropriate. Wilcoxon rank sum test was used to compare values of independent distributions of continuous variables. The multivariable logistic regression was applied to find out the independent predictors of the DRV/r score increase. All of the statistical tests were 2 sided at the 5% level and performed using SAS Software, release 8.2.

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RESULTS

Inclusion criteria were fulfilled by 47 patients (36 males and 11 females). At baseline, they were aged 44.1 (42.51-49.27) years and had 10.1 (8.2-12.3) years of treatment with antiretrovirals, 86 (39-222) CD4+ T lymphocytes per micoliter [with nadir counts of 32 (7-73) cells/μL], 4.9 (4.17-5.31) log10 copies per milliliter HIV RNA, 10 (7-12) mutations associated with resistance to nucleoside/nucleotide analogues, and 9 (8-10) mutations associated with resistance to protease inhibitors. In 13 patients (27.5%), enfuvirtide was coadministered with TPV. The duration of the treatment with TPV/r was 408 (252-556) days.

The ranking for TPV/r and DRV/r resistance, at baseline and at TPVF, is reported in Table 1, whereas the proportion of patients with protease inhibitor mutations (at baseline and at TPVF) is reported in Figure 1.

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

At baseline, GSS was 0 in 28 of 47 patients (59.6%), 1 in 16 of 47 patients (34%), 2 in 2 of 47 subjects (4.3%), and 3 in 1 of 47 patients (2.1%).

From TPV/r baseline to TPVF, a shift toward a higher TPV/r scoring class was seen in 16 (34.1%) patients (P = 0.001).

At TPVF, a shift toward a higher DRV/r scoring class was detected in 9 (19.2%) patients (P = 0.2381).

Based on the univariate analysis, no baseline protease mutations were significantly associated with an increase in the DRV/r resistance score upon TPVF. A stable or decreased DRV/r score during treatment with TPV/r was observed in 21 of 30 patients (70%) with the L10I mutation at baseline versus 4 of 17 patients (23.5%) without it (P = 0.0029); in 19 of 29 patients (65.5%) with the M36I mutation at baseline versus 6 of 18 patients (33.3%) without it (P = 0.0402); and in 14 of 19 patients (73.7%) with the V82A mutation at baseline versus 11 of 28 patients (39.3%) without it (P = 0.0362). Two baseline RT mutations (Q151M and K219Q) were associated with an increased DRV/r score at TPVF: 6 of 7 patients (85.7%) with the Q151M mutation versus 16 of 40 patients (40%) without it showed an increase in DRV/r score (P = 0.04), and the same occurred in 11 of 15 patients (73.3%) with the 219Q mutation versus 11 of 32 patients (34%) without it (P = 0.0264).

After adjusting for nadir CD4+ cell counts, duration of TPV/r treatment, baseline CD4+ cell counts, CD4+ percentage, log10 HIV RNA, cumulative GSS for each patient, total number of mutations, and the presence of the Q151M, K219Q, M36I, L10I, and V82A mutation at baseline, the Q151M mutation independently predicted an increase in DRV/r score (p = 0.0159), whereas the L10I mutation independently predicted no further increase in the DRV/r score (P = 0.0360).

After TPVF, 25 of 47 patients (53.2%) were treated by their physician with a DRV/r-containing regimen. At DRV/r baseline, the HIV RNA was 5.07 (4.88-5.64) log10 copies per milliliter, CD4+ were 53 (21-106) cells per microliter, and the CD4+ percentage was 4.7 (1.7-8.3). In 13 of 25 patients (52%), enfuvirtide was coadministrated with DRV/r, and in 3 of 25 patients (12%), etravirine was included in the concomitant highly active antiretroviral therapy.

In contrast, 21 of 47 patients (44.7%) were treated with regimens that did not include DRV/r [alternative regimen group (ARG)]. One of 47 patients (2.1%) has been lost to follow-up immediately after TPVF.

In 3 of 21 patients (14.3%), enfuvirtide was included in the treatment, and in 1 of 21 patients (4.8%), concomitant highly active antiretroviral therapy was completed by raltegravir and etravirine, respectively. Two of 21 patients (9.5%) were treated with a maraviroc-including regimen. The majority of patients were treated with 2 nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor (excluded DRV/r and TPV/r).

At the ARG baseline, the HIV RNA was 4.44 (4.11-4.91) log10 copies per milliliter, CD4+ was 224 (68-322) cells per microliter, and the CD4+ percentage was 12.7 (6.4-21.9).

After 24 weeks (on-treatment analysis), median HIV RNA decrease was 3.04 (2.13-3.45) log10 copies per milliliter in DRV/r group versus −0.04 (−0.44; 0.50) log10 copies per milliliter in patients not treated with a DRV/r-containing regimen (P < 0.0001); CD4+ increase was 126 (70-169) cells per cubic millimeter in DRV/r group versus −42 (−121; 42) in ARG group (P < 0.0001); CD4+ percentage increase was 5% (1.6-6.6) in DRV/r group versus −0.9% (−3; 0.8) in ARG group (P = 0.0001).

Fourteen of 25 patients (56%) in DRV/r group attained a viral load below 50 copies per milliliter (Table 2).

TABLE 2

TABLE 2

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DISCUSSION

The RT mutation Q151M complex confers high-level resistance to all nucleoside analogues3-5 and a study showed that patients harboring the Q151M mutation had reduced response to rescue treatments.6 In our study, none of the patients presenting with Q151M at baseline reached viral loads below 50 copies per milliliter while on TPV/r regimens; all patients increased their TPV/r score and 6 of 7 patients (85.7%) worsened their DRV/r score. The absence of an optimal backbone seems to be the main reason for the poor virological response and the consequent accumulation of new protease mutation in these patients.

An in vitro study showed that 28% of the viruses resistant to TPV retain susceptibility to DRV.7 Our results are consistent with those from the POWER study, in which 44% of those patients failing a TPV/r-based regimen attained undetectable viral loads when treated with DRV/r.8

The overlap between mutations conferring reduced response to DRV/r and those impairing response to TPV/r is limited. Twenty-one mutations at 16 protease positions have been associated with reduced response to regimens including TPV/r in the RESIST trials: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V.9 After joining the results of the POWER and DUET studies, 12 mutations at 11 codons have been associated with reduced response to DRV/r including 11I, 32I, 33F, 47V, 50V, 54L/M, 74P, 76V, 84V, and 89V.10 Thus, only the mutations 33F, 47V, 54M, and 84V are shared by both patterns of resistance. Furthermore, it has been shown that the mutations 50V, 54L, and 76V (which are able to blunt the virological response to DRV/r) are associated with a better virological outcome in patients treated with TPV/r-including regimens.11 We hypothesize that the limited overlap between the 2 patterns of resistance explains both the negligible increase in DRV resistance and the rate of response to a DRV/r-containing regimen after failure to TPV/r in our patients.

In conclusion, the only independent predictor of an increase in DRV/r resistance score after failure to TPV/r-containing regimens was the presence of the Q151M mutation at baseline. Fifty-six percent of the 24 patients treated with DRV/r after TPVF showed a 24-week virological response.

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REFERENCES

1. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. 2006;368:466-475.
2. Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007;369:1169-1178.
3. Shirasaka T, Kavlick MF, Ueno T, et al. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc Natl Acad Sci U S A. 1995;92:2398-2402.
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7. Picchio G, Staes M, Van Craenenbroeck, et al. HIV-1 susceptibility to TMC114 among routine clinical samples with different levels of protease inhibitor susceptibility using linear regression model-based fold change predictions. In: Programme and Abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 27-30, 2006. Abstract H-999.
8. Lefebvre E, de Bethune M, De Meyer, et al. Impact of use of TPV, LPV, and, (f)APV at screening on TMC114/r virologic response in treatment-experienced patients in POWER 1, 2, and 3. In: Programme and Abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 27-30, 2006. Abstract H-1387.
9. Baxter JD, Schapiro JM, Boucher CA, et al. Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir. J Virol. 2006;80:10794-10801.
10. De Meyer S, Dierynck I, Lathouwers E, et al. Identification of mutations predictive of a diminished response to darunavir/ritonavir: analysis of data from treatment-experienced patients in POWER 1, 2, 3 and DUET-1 and 2. Presented at: Program and abstracts of the 6th European HIV Drug Resistance Workshop; March 26-28, 2008; Budapest, Hungary. Abstract 54.
11. Scherer J, Boucher CA, Baxter JD, et al. Improving the prediction of virological response to tipranavir: the development of a tipranavir weighted score. Presented at: 11th European AIDS Conference; October 24-27, 2007; Madrid, Spain. Poster P3.4/07.
Keywords:

darunavir/r; resistance; Stanford mutation score; sequencing; tipranavir/r

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