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Q151M-Mediated Multinucleoside Resistance: Prevalence, Risk Factors, and Response to Salvage Therapy
 
 
  Clinical Infectious Diseases 2004;38:433-437
 
Mauro Zaccarelli,a Carlo Federico Perno,a Federica Forbici, Fabio Soldani, Sandro Bonfigli, Caterina Gori, Maria Paola Trotta, Maria Concetta Bellocchi, Giuseppina Liuzzi, Roberta D'Arrigo, Patrizio De Longis, Evangelo Boumis, Rita Bellagamba, Valerio Tozzi, Pasquale Narciso, and Andrea Antinori
 
Istituto Nazionale per le Malattie Infettive "Lazzaro Spallanzani," Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
 
BACKGROUND
 
Cross-resistance among nucleoside reverse-transcriptase inhibitors (NRTIs) of HIV replication has been associated with the selection and appearance of a complex of mutations, including A62V/V75I/F77L/F116Y/Q151M. This complex, located around the catalytic site of the enzyme, is commonly referred to as "Q151M-mediated multinucleoside resistance" (Q151M-MNR). The substitution of glutamine by methionine at the amino acid 151 (Q151M) represents the primary mutation of this complex; this mutation leads to various levels of reverse-transcriptase resistance toward all nucleoside analogues currently in clinical use. The first reported in vivo occurrences of Q151M-MNR were in patients treated with long-term combination therapy with 2 NRTIs who had undergone genotypic resistance testing (GRT) after virological failure. Its appearance is, indeed, reported to be associated with long-term antiretroviral treatment; by contrast, it is thought to be nonexistent in NRTI-naive patients, with the exception of a single patient with a case of primary infection.
 
Several European studies have evaluated the prevalence of the Q151M mutation in patients for whom an NRTI-containing therapy has failed and have reported a prevalence of 1.6%-3.5%, but risk factors related to the appearance of the Q151M mutation have not been defined. The characterization of such risk factors may help in selecting therapeutic approaches that are able to decrease the frequency of its appearance and, therefore, potentially influence the rate of therapeutic failure. For this reason, we analyzed a database of 470 patients undergoing GRT after experiencing failure of HAART who were attending a reference center for HIV treatment in Rome. We also evaluated the dynamics of the appearance and/or disappearance of the Q151M mutation in response to treatment changes.
 
ABSTRACT/SUMMARY
 
Among 470 patients with acquired immune deficiency syndrome and/or human immunodeficiency virus infection (HIV/AIDS) who underwent genotype resistance testing (GRT) after the failure of therapy, 17 (3.6%) harbored the Q151M mutation.
 
The Q151M mutation was associated with younger age, lower CD4+ lymphocyte count, higher HIV RNA level, and treatment with >2 pre-GRT regimens. By contrast, the Q151M mutation was inversely associated with lamivudine administration.
 
A full reversion of the Q151M mutation was observed in 5 of 5 patients who underwent treatment interruption after GRT. The reversion was followed by a response to salvage therapy in 4 (80%) of 5 patients.
 
RESULTS
 
The detection of the Q151M mutation increased with the overall duration of NRTI therapy; indeed, no Q151M mutation was found among patients treated with NRTIs for <6 months. Among those treated with NRTIs for 612 months, 2.6% had the mutation; among those treated for 12 years, 3.7% had the mutation; and among those treated for 23 years, 4.1% had the mutation. The prevalence of the Q151M mutation remained steady at 3.5% of patients among those receiving >3 years of NRTI treatment.
 
The presence of the Q151M mutation was significantly associated with lower CD4+ lymphocyte count (significant in patients with a CD4+ lymphocyte count of <150 lymphocytes/L at the time of GRT), higher HIV RNA level (i.e., >70,000 copies/mL), and receipt of >2 treatment regimens before GRT. In contrast, presence of the Q151M mutation was inversely associated with older age and longer treatment with lamivudine before GRT. Only 3 (1.3%) of 235 patients receiving therapy with lamivudine developed the Q151M mutation, compared with 14 (6%) of 235 patients not receiving lamivudine at the time of GRT (P = .01). No association with duration of treatment was found for any other single NRTI. Moreover, no association was found between the presence of the Q151M mutation and receipt of any NRTI at the time of GRT (data not shown).
 
Single NRTI-associated mutations (other than the Q151M-MNR complex) that were significantly associated with the detection of the Q151M mutation were K65R (OR, 32.1; 95% CI, 6.0173.6; P < .001) and K219E (OR, 14.3; 95% CI, 2.198.3; P = .007). By contrast, NRTI mutations inversely associated with the detection of the Q151M mutation were M41L (OR, 0.02; 95% CI, 0.0040.09; P < .001), K70R (OR, 0.1; 95% CI, 0.030.3; P < .001), and M184V (OR, 0.03; 95% CI, 0.010.1; P < .001).
 
After GRT, the decision was made to interrupt treatment for 5 patients for whom a valid treatment option could not be found. GRT was repeated for these patients after a median of 6 months of interruption (range, 411 months). A full reversion of Q151M-MMR was observed in all 5 patients.
 
All 17 patients carrying the Q151M-MMR complex (including those undergoing treatment interruption) were treated with GRT-based therapy. Seven patients (38.9%) achieved undetectable HIV RNA levels (i.e., <500 copies/mL); 6 patients responded to a 2-class regimen (2 NRTIs plus a protease inhibitor), and 1 patient responded to a 3-class regimen.
 
It is remarkable that 4 (80%) of 5 patients undergoing treatment interruption and reversion of the Q151M mutation achieved undetectable HIV RNA levels. Only 3 (25.0%) of 12 patients who were immediately treated with a salvage regimen without interruption achieved undetectable RNA levels.
 
Discussion
 
The prevalence found in our group of patients was similar to that found in previous cohorts of Italian patients. It is of interest that, on multivariate analysis, the Q151M mutation was shown to have a relationship with many different factors, suggesting that the emergence of the Q151M mutation is attributable to multiple factors. Thus, the differences in the prevalence of the Q151M mutation found in different studies can be easily related to differences in the sample of patients studied, particularly differences in the duration of treatment the patients received before GRT was performed and in the status of their HIV infection.
 
An overview of the main studies available also shows that the Q151M mutation was found in patients treated with all NRTIs, whether administered alone or in double-combination. All of the most widely used NRTIs, such as zidovudine, stavudine, didanosine, and zalcitabine, were found to be associated with the Q151M mutation in studies involving dual therapies, but very few data are actually available on HAART failure. Our group was the first to analyze a large cohort of patients experiencing HAART failure, and our data showed no evidence of a clear effect of HAART failure on the onset of the Q151M mutation, taking into account both the duration of treatment with each NRTI and those NRTIs received as part of the treatment current at the time of GRT.
 
More recently, it was hypothesized that stavudine and didanosine play a major role in the emergence of the Q151M mutation. Our data showed only univariate association between the Q151M mutation and protracted didanosine treatment, an association that was not confirmed by multivariate analysis, and our data showed no association with exposure to stavudine. Our data also confirm and extend a previous observation showing that treatment with lamivudine could be significantly associated with a lower rate of detection of the Q151M mutation. This result is strengthened by observations of inverse association between the Q151M and M184V mutations. The M184V mutation was already found to be associated with a low incidence of thymidine analogue mutations, consistent with a low phenotypic resistance to zidovudine and stavudine and associated with a low cross-resistance to NRTIs. In a recent article from our group, among patients who experienced treatment failure with regimens containing lamivudine, those who harbored the M184V mutation had higher CD4+ lymphocyte counts and lower HIV RNA levels than did those without the M184V mutation. The results from the present study extend this observation by showing the protective effect of the M184V mutation versus Q151M-associated multidrug-resistance.
 
As a final point, our data suggest that the presence of the Q151M mutation is not detrimental to future treatment attempts, because 40% of patients with the Q151M mutation responded to salvage therapies involving treatment with 3 or 4 drugs; in this context, the response to treatment of patients harboring the Q151M mutation seems to be strongly related to complete drug interruption.
 
Two conclusions can be drawn from these results: first, that resistance to the Q151M complex is not absolute and can be overcome without resorting to drug therapies involving >4 agents; second, that the 2-base mutation required to achieve the Q151M mutation is not stable, conceivably because of the limited fitness that it induces. Indeed, in our sample, we observed a 10% reversion of the Q151M mutation after treatment interruption, followed by an 80% response to post-GRT treatment. Additional studies are also necessary to assess the real utility of treatment interruption in patients infected with drug-resistant viruses. This subject is obviously now quite controversial, and this important point must be better defined in the future.
 
In conclusion, our results suggest that the evaluation of the dynamics of the appearance and disappearance of key mutations (such as Q151M) may help in understanding when and how to recycle drugs successfully, particularly in heavily pretreated patients for whom the choice of an effective regimen is limited. Our data also suggest that an effective salvage regimen can be achieved in the presence of the Q151M mutation, even with limited drug options.
 
 
 
 
 
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