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Low prevalence of primary mutations associated with drug resistance in antiviral-naive patients at therapy initiation

Perno, Carlo Federicoa,b; Cozzi-Lepri, Alessandroc; Balotta, Claudiad; Bertoli, Adaa; Violin, Michelad; Monno, Laurae; Zauli, Tizianof; Montroni, Mariag; Ippolito, Giuseppea; d'Arminio-Monforte, Antonella*; for the I.CO.N.A Study Group

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From the aIRCCS L Spallanzani, Rome, the bDepartment Experimental Medicine, University Tor Vergata, Rome, Italy, the cRoyal Free and University College Medical School, London, UK, the dInstitute of Infectious and Tropical Diseases, University of Milan, L Sacco Hospital, Milan, the eClinic of Infectious Diseases, University of Bari, the fDepartment of Infectious Diseases, S. Maria delle Croci Hospital, Ravenna and the gChair of Allergology and Clinical Immunology, University of Ancona, Italy. *See Appendix.

Correspondence to Carlo-Federico Perno MD, PhD, IRCCS L. Spallanzani Hospital, Via Portuense 292, 00149 Rome, Italy. Tel: +39 06 55170915; fax: +39 06 72596552; e-mail: cf.perno@uniroma2.it

Received: 12 September 2000;

revised: 24 July 2001; accepted: 19 October 2001.

Sponsorship: Funding for this study was provided through grants from the Italian National Institute of Health, the Ministry of University and Scientific Research, and Current and Finalized Research of the Italian Ministry of Health. The I.CO.N.A. network is supported by unrestricted educational grants from Glaxo-Wellcome, Italy.

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Abstract

Objective: To assess the prevalence of mutations in the reverse-transcriptase (RT) and protease (PR) region in a cohort of chronically-infected HIV-positive patients requiring highly active antiretroviral therapy (HAART).

Methods: The study included 347 patients enrolled in the Italian Cohort of Antiretroviral Naive patients (I.CO.NA) who had to initiate HAART. The whole PR-region, and aminoacids 1-320 of RT-region were sequenced from plasma samples at baseline.

Results: Median CD4-lymphocytes and HIV-RNA at baseline were 231 × 106 cells/l and 4.89 log10 copies/ml; 307 of 347 (88.5%) patients carried no mutations in the RT region, whereas 40 (11.5%) carried one or more mutations associated with resistance to nucleoside-RT inhibitor (NRTI) (7.8%), or non-nucleoside-RTI (NNRTI) (4.9%), with four patients carrying mutations to both classes. Among mutations associated with high-level resistance to RTI, T215Y was found in only two patients, M184V in two cases, T69D and T215C in other two cases (one each), and K103N in only one patient, for a total of six patients (one carrying both T215Y and M184V) (1.7%). Seventy-six patients (21.9%) carried no mutations in the PR region, whereas 271 (78.1%) had one or more mutations. Primary mutations associated with substantial resistance to protease inhibitors were found in only five of 347 patients (1.4%) (M46V/L, I54V, V82A/I); all the other patients carried only secondary mutations (L10F/I/V, M36I, L63P, A71T/V, V77I).

Conclusions: Prevalence of mutations associated with high-level resistance to antiretroviral drugs is low in HIV-infected patients with long-term infection. This suggests no preclusion in principle to any antiretroviral drug at the time of decision of the first therapeutic regimen.

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Introduction

The appearance and selection of strains of human immunodeficiency virus (HIV) mutated in their genome, which show resistance to antiretrovirals, is considered a major cause of therapeutic failure [1]. For this reason, international guidelines for antiretroviral therapy recommend resistance testing to help guide the choice of new therapeutic regimens after failure [2,3]. At the same time, they suggest the consideration, but not recommendation, of resistance testing in drug-naive patients with long-term, established infection who need to begin antiretroviral therapy [2,3]. This indication is mainly based upon the unavailability of consistent data in large cohorts of chronically-infected drug-naive patients, providing evidence about the prevalence of virus mutations related to resistance to antiretroviral drugs, and their correlation with clinical outcome.

Recent data show that a substantial rate of patients with acute infection carry mutations associated with resistance to antiretroviral drugs [4–7]. Nevertheless, estimates cannot be directly compared to naive patients with long-term infection, because of the rapid viral turnover that may favour the disappearance from plasma of mutated strains (normally characterized by low fitness) in favour of other strains, such as those with wild-type phenotype, which is highly fitting in the drug-deprived environment that is typical of drug-naive patients. As a consequence, estimations of the prevalence of mutations in the HIV genome in large populations of naive patients with established (long-term) HIV infection are urgently required.

For these reasons, we studied a large cohort of antiretroviral-naive patients with established HIV infection at the time of HAART initiation, to evaluate the prevalence of mutations in the reverse transcriptase and protease regions of HIV strains that are present in plasma.

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Patients and methods

All individuals included in the study belong to I.CO.NA, an Italian cohort of antiretroviral-naive HIV-positive patients, described in details elsewhere [8]. Among them, we identified 415 consecutive patients who began the first highly active antiretroviral therapy (HAART) regimen with more than drugs simultaneously including two nucleoside-reverse transcriptase inhibitors (NRTI) plus at least one protease inhibitor (PI) or one non-nucleoside reverse transcriptase inhibitor (NNRTI), and for whom a baseline pre-HAART plasma sample was available. Of these patients, 68 were excluded because of a documented seroconversion in the preceding 12 months. Therefore, the study included 347 chronically-infected, HIV-positive patients.

Genotypic analysis was performed using the pre-therapy stored plasma sample, by a commercially available genotyping test (ABI;, Applied Biosystems, Foster City, California, USA). The whole protease (PR) region and aminoacids 1–320 of reverse transcriptase (RT) were sequenced. The mutations considered in the analysis were those reported to be associated with resistance to antiretrovirals available for clinical use [2,9].

The frequency of patients with mutations in the RT and PR gene were calculated. Differences in the proportion of patients carrying a certain mutation or a certain group of mutations between groups were tested using the χ2 test.

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Results

Baseline characteristics of patients enrolled in this study are shown in Table 1: the median CD4-cell count of the whole cohort was 231 × 106 cells/l [interquartile range (IQR), 77–446 × 106 cells/l), and median viral load was 4.89 log10 copies/ml (IQR 4.41–5.36 log10 copies/ml); 20.7% of patients were in CDC stage C. Therefore, a quite advanced HIV disease characterized this cohort of patients who required therapy initiation.

Table 1
Table 1
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A total of 71 of 347 patients (20.5%) carried no mutations in either the RT or PR region; 239 (68.9%) had mutations to one class of antiretroviral drugs (either NRTI, NNRTI or PI), 35 (10.1%) to two classes and two (0.6%) to three classes. Patients carrying mutations in the RT and PR region were distributed in Italy (where the study was performed), without evident clusters of prevalence in specific geographic areas, with a slightly greater prevalence of mutations in patients located in large urban areas (difference significant only in case of NRTI-related mutations, P = 0.05 compared to patients living in areas outside the cities).

Mutations in the RT region associated with resistance to RT-inhibitors (RTI) were present in 40 out of 347 patients (11.4%). Thirty patients (8.6%) carried one mutation, and 10 (2.8%) had two to four mutations, for a total of 53 aminoacid changes. Mutations associated with resistance to NRTI were found in a total in 27 patients (7.8%), for a total of 36 aminoacid changes (Table 2): six patients had two and one patient had four mutations. Seventeen patients (4.9%) carried mutations associated with resistance to NNRTI (each carrying one single mutation). Of note, four of these patients (1.2%) had mutations associated with resistance both to NRTI and NNRTI.

Table 2
Table 2
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Thirteen of 347 patients (3.7%) carried mutations (at position 41, 67, 70, 210, 215, and/or 219) related to resistance to zidovudine (Table 2). Nevertheless, substantial resistance to zidovudine could be predicted in only two patients carrying the mutation T215Y (accompanied in both cases by mutation M41L). Two out of 347 patients (0.6%) carried the mutation M184V conferring full resistance to lamivudine. Another two patients in total (0.6%) carried mutations (T69D and T215C) associated with resistance to zalcitabine. Finally, one patient carried mutation K103N conferring high-level full resistance to all NNRTI. Overall, primary mutations conferring high-level resistance to RTI were thus found in only six out of 347 (1.7%) patients (one patient carrying both T215Y and M184V).

A low prevalence of other mutations associated with limited degrees of resistance to RTIs was also reported (Table 2), including two patients carrying only the mutation M41L (two others had it associated with the key T215Y). Of note, 12 patients (3.5%) carried mutation V118I (11 patients) or E44D (one patient) which has recently been reported to confer a moderate degree of resistance to lamivudine [2,10]. V118I was the most represented RT-mutation in this cohort of drug-naïve patients (3.2%).

With regard to the protease, 76 patients (21.9%) carried no mutations in this region; 153 (44.1%) had one mutation, 97 (27.9%) had two, 16 (4.6%) had three, four (1.2%) had four mutations, and one (0.3%) had five, for a total of 419 mutations. All these patients carried only secondary mutations, with the exception of one patient carrying primary mutations V82A +I54V, another carrying V82I, and finally three patients carrying mutations at position 46 (M to either V or L) (Table 3). Thus, a total of five out of 347 patients (1.4%) carried mutations conferring substantial levels of resistance to protease inhibitors. Regarding secondary mutations, other than L63P (a common polymorphism found in 182 patients, 53.3%) the most frequent was V77I (79 patients, 22.8%), followed by M36I (72 patients, 20.7%), L10F/I/V (39 patients, 11.2%) and A71T/V (26 patients, 7.5%). Each of the other secondary mutations in the PR region were found in less than 5% of these patients.

Table 3
Table 3
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Discussion

Data reported in the literature about the prevalence of overall mutations in naive patients are often conflicting, with figures ranging from 0 to 26% [4–7,11–20], and obtained mainly from patients tested within 1 year from seroconversion; these latter cannot in principle be extrapolated to naive patients with long-term infection (and relatively advanced disease, as those of our cohort). A number of factors, including a high daily production of virus particles, high rate of mutation induced by the error-prone reverse transcriptase, and long-term absence of a selective pressure induced by drugs, may over the years favor the appearance of virus strains, such as the wild-type, characterized by a replicative fitness that is usually greater than that of mutated strains selected by antiviral pressure [21–28]. Confirmatory to this hypothesis, data about a group of recently seroconverted patients belonging to the same I.CO.NA cohort show a prevalence of 11.4 and 5.7% of primary mutations conferring resistance to NRTI and PI respectively [18], again far greater than that found in patients with long-term infection. Among recently infected patients of this cohort, 10 and 2.8% carried primary mutations conferring resistance to zidovudine and lamivudine, respectively. This further suggests that mutations acquired at the time of infection may revert over time to a wild-type (and usually more fit) virus. The presence in our cohort of a patient carrying in RT a single-base mutation T215C, known to confer resistance to zalcitabine, but reported also as an intermediate to (and from) a 2-base mutation T215Y (conferring high-level resistance to zidovudine) [28], further supports this hypothesis.

Published papers regarding the prevalence of mutations in naive patients with long-term infection are few, the overall number of patients is limited, and/or genotype often assessed by methods able to detect just some primary mutations; the exception is a recent paper showing the prevalence of mutations in a large cohort of North-American subjects [29]. Even under these limiting circumstances, the overall prevalence of the mutations conferring a high level of resistance to either class of antiretrovirals is below 5% (about 3.5% in the above-mentioned American cohort) [5,12,15,19,20,29]. Our data, obtained in a large European cohort of HIV-patients with advanced infection, bring the overall prevalence of primary mutations to an even lower figure.

In the evaluation of clinical implications of these results, two factors should be borne in mind. First, the prevalent strain circulating in the blood may not be representative of resistant strains eventually acquired at the time of infection, but hidden as proviral DNA within cellular genomes at the time of therapy initiation; this virus may quickly reappear upon pressure imposed by antiviral drugs. In this regard, a recent paper shows two cases of mutated, resistant virus in the DNA in the presence of the wild-type virus in plasma [20]. Second, the role of secondary mutations in the development of resistance to antiretrovirals still needs to be elucidated, particularly in view of their presence as a natural polymorphism before the appearance of primary mutations, as demonstrated by this and other papers [4,5,29]. This situation seems particularly true for polymorphic mutations at positions 10, 36, 63, 71, and 77 in the protease, occurring in more than 7% of drug-naive patients enrolled in our study. Recent data suggest that some of them can be associated with therapeutic failure in naive or therapy-experienced patients [30,31]. In the case of RT mutations, however, phenotyping testing showing four- to 10-fold resistance to NNRTI was not associated with virological outcome of therapeutic regimens containing NNRTI [32]. Therefore, further studies in large cohorts are required to clarify this important point; also in view of the variable prevalence of some of these polymorphisms in different HIV clades, such as M36I in the protease, reported to be present in more than 80% of non-B subtypes [33–35].

Based upon these observations, no straightforward conclusions should be drawn from our data regarding the usefulness of resistance testing in predicting the efficacy of antiviral drugs in naive patients. Nevertheless, the low prevalence of primary mutations conferring high levels of resistance to antiretrovirals (less than 2% both for RT- and PR-inhibitors) found in our cohort of advanced patients suggests that there are no firm reasons to preclude in principle any drug or drug class in the choice of the first therapeutic regimen. The role of phenotyping tests, and/or of genotyping testing in being able to provide a complete sequence of protease and reverse transcriptase, in the setting of drug-naive patients requiring therapy initiation, needs to be further assessed in large prospective trials specifically aimed at this purpose.

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Acknowledgements

Other members of the I.CO.N.A study group that contributed to this work are: Federica Forbici and Maria R. Capobianchi (IRCCS L Spallanzani, Rome, Italy); Guido Facchi and Mauro Moroni (University of Milan, L Sacco Hospital, Milan, Italy); G. Angarano (University of Foggia, Italy); Patrizio Pezzotti (Italian Institute of Health, Rome, Italy); Paolo E Manconi (University of Cagliari, Cagliari, Italy); Francesco Mazzotta (Department of Infectious Diseases, Bagno a Ripoli, Florence, Italy); Fanny Del Fanti (Ateneo Vita-Salute, Milano); Luigina Tacconi (Centro Riferimento AIDS, Latina, Italy); Lucio Bonazzi (S. Maria Nuova Hospital, Reggio Emilia, Italy).

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Appendix
I.CO.N.A study group

Italy: Ancona: M. Montroni, G. Scalise, A. Costantini, M.S. Del Prete. Aviano (PN): U. Tirelli, G. Nasti. Bari: G. Pastore, N. Ladisa, L.M. Perulli. Bergamo: F. Suter, C. Arici. Bologna: F. Chiodo, F.M. Gritti, V. Colangeli, C. Fiorini, L. Guerra. Brescia: G. Carosi, G.P. Cadeo, F. Castelli, C. Minardi, D. Vangi. Busto Arsizio: G. Rizzardini, G. Migliorino. Cagliari: P.E. Manconi, P. Piano. Catanzaro: T. Ferraro, A. Scerbo. Chieti: E. Pizzigallo, F. Ricci. Como: E. Rinaldi, L. Pusterla. Cremona: G. Carnevale, D. Galloni. Cuggiono: P. Viganò, M. Mena. Ferrara: F. Ghinelli, L. Sighinolfi. Firenze: F. Leoncini, F. Mazzotta, S. Ambu, S. Lo Caputo. Foggia: G. Angarano, B. Grisorio, S. Ferrara. Galatina (LE): P. Grima, P. Tundo. Genova: G. Pagano, N. Piersantelli, A. Alessandrini, R. Piscopo. Grosseto: M. Toti, S. Chigiotti. Latina: F. Soscia, L. Tacconi. Lecco: A. Orani, G. Castaldo. Lucca: A. Scasso, A. Vincenti. Mantova: A. Scalzini, F. Alessi. Milano: M. Moroni, A. Lazzarin, A. Cargnel, G.M. Vigevani, L. Caggese, A. d'Arminio Monforte, M. Bongiovanni, R. Novati, F. Delfanti, S. Merli, C. Pastecchia, C. Moioli. Modena: R. Esposito, C. Mussini. Napoli: N. Abrescia, A. Chirianni, C. Izzo, M. Piazza, M. De Marco, V. Montesarchio, E. Manzillo, S. Nappa. Palermo: A. Colomba, V. Abbadessa, T. Prestileo, S. Mancuso. Pavia: G. Filice, L. Minoli, R. Bruno, R. Maserati. Perugia: S. Pauluzzi, A. Tosti. Piacenza: F. Alberici, M. Sisti. Pisa: F. Menichetti, A. Smorfa. Potenza: C. De Stefano, A. La Gala. Ravenna: T. Zauli, G. Ballardini. Reggio Emilia: L. Bonazzi, M.A. Ursitti. Rimini: R. Ciammarughi, P. Ortolani. Roma: L. Ortona, F. Dianzani, A. Antinori, G. Antonucci, S. D'Elia, G. Ippolito, P. Narciso, N. Petrosillo, G. Rezza, V. Vullo, A. De Luca, A. Del Forno, M.R. Capobianchi, M. Zaccarelli, P. De Longis, M. Ciardi, E. Girardi, G. D'Offizi, P. Noto, P. Pezzotti, R. Bugarini, M. Lichter. Sassari: M.S. Mura, M. Mannazzu. Torino: P. Caramello, A. Sinicco, M.L. Soranzo, L. Gennero, M. Sciandra, B. Salassa. Varese: P.A. Grossi, C. Basilico. Verbania: A. Poggio, G. Bottari. Venezia: E. Raise, S. Pasquinucci. Vicenza: F. De Lalla, G. Tositti. Taranto: F. Resta, A. Chimienti. UK: London: A. Cozzi-Lepri. Cited Here...

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Microbiology and Immunology, 47(7): 499-505.

Journal of Medical Virology
Subtype analysis and mutations to antiviral drugs in HIV-1-infected patients from Mozambique before initiation of antiretroviral therapy: Results from the DREAM programme
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AIDS Research and Human Retroviruses
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Daar, ES; Richman, DD
AIDS Research and Human Retroviruses, 21(5): 343-357.

Deutsche Medizinische Wochenschrift
Epidemiology of primary drug resistance in chronically HIV-infected patients in Nordrhein-Westfalen, Germany, 2001-2005
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Antiviral Research
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Microbiologica
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Journal of Infectious Diseases
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AIDS
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Journal of Infectious Diseases
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AIDS
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AIDS Research and Human Retroviruses
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Biochemistry
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Plos One
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AIDS
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Menzo, S; Monachetti, A; Balotta, C; Corvasce, S; Rusconi, S; Paolucci, S; Baldanti, F; Bagnarelli, P; Clementi, M
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JAIDS Journal of Acquired Immune Deficiency Syndromes
Long-Term Persistence of Primary Genotypic Resistance After HIV-1 Seroconversion
Pao, D; Andrady, U; Clarke, J; Dean, G; Drake, S; Fisher, M; Underhill, G; Pillay, D; Cane, P; Green, T; Kumar, S; Murphy, M; Tang, A; Taylor, S; White, D
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Keywords:

HIV; mutations; resistance; antiretroviral drugs; naive patients; genotype

© 2002 Lippincott Williams & Wilkins, Inc.

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