Plusieurs laboratoires de virologie français viennent de publier dans le journal JAIDS les résultats d’une étude sur la fréquence des résistances pour le VIH-1 chez les patients français. L’étude conclut que cette fréquence n’est pas significativement plus élevée en 2001/02 que dans les études précédentes. Nous parlons ici des patients naïfs de tout traitement antirétroviral (non traités). Par ailleurs, la prévalence du sous-type non-B est en augmentation comme indiqué dans la surveillance virologique de la DO-VIH.

Par ailleurs, l’étude s’est penchée sur l’évolution de la prévalence des différentes souches VIH. Le pourcentage de personnes porteuses du sous-type non-B est en augmentation dans la cohorte primo-infection, ce qui implique une augmentation de l’exposition de la population d’origine européenne à cette souche. (17% en 2002 contre 14% en 99/2000).

L’étude a été menée sur les cohortes Primo et Odyssee. La fréquence de résistance pour le VIH-1 à au moins 1 antirétroviral est de 12% chez les patients en primo-infection (cohorte Primo) et 1,7% chez ceux non traités (cohorte Odyssee).

Pour les cas de primo infection, la résistance n’apparaît pas en plus grand nombre entre 1996 (10%) et 2002 (12%). Pour les patients non traités, elle tombe de 5,6% à 1,7 % entre 1998 et 2001. Cette différence, d’après les auteurs de l’étude, peut s’expliquer du fait d’une durée plus courte de connaissance de la séropositivité dans l’étude actuelle par rapport à la précédente.

Les auteurs font observer qu’en France, la proportion de personnes infectées avec des souches VIH-1 résistantes n’a pas augmenté ces dernières années.

L’étude complète est disponible ci-dessous.

 

HIV Drug Resistance in France

“French National Sentinel Survey of Antiretroviral Drug Resistance in Patients With HIV-1 Primary Infection and in Antiretroviral-Naive Chronically Infected Patients in 2001-2002”

JAIDS Journal of Acquired Immune Deficiency Syndromes : Volume 38(5) 15 April 2005. Author list at end of article.

Author discussion : The frequency of HIV-1 resistance to at least 1 antiretroviral drug, based on the French ANRS resistance algorithm, was 12% in patients with primary infection and 1.7% in treatment-naive, chronically infected patients (the Primo and Odyssee study populations, respectively). The frequency of such resistance in patients with primary infection did not change significantly from 1996 to 2002 (10 to 12%),9 while in chronically infected patients it fell from 5.6 to 1.7% between 1998 and 2001 (P = 0.004).14 This latter difference may be explained by the much shorter duration of known seropositivity in this study than in the previous study.14 Indeed, in 1998 we excluded patients with known duration of seropositivity of <6 months, while in 2001 we excluded only patients who met the definition of primary infection used in the Primo study. Our results are in keeping with those of the large European CATCH study (12.5% in primary infection, 8.8% in chronic infection).32 In France, the proportion of patients infected with resistant strains has not increased in recent years, a finding in line with the fall in the proportion of patients with a detectable viral load (>500 copies/mL) between 1999 (48%) and 2002 (31%).33 Most previous studies of drug resistance in treatment-naive patients were relatively small and limited to a single center or to a few cities or single countries ; in addition, the definition of resistance and the duration of known seropositivity varied widely. The distribution of the patients included in our 2 studies closely matches with the geographic distribution of AIDS cases in France. Moreover, in the Odyssee study, weighted statistical analyses were used to derive representative estimates of the percentage of patients with resistance mutations.

Abstract 
Objective : To survey the frequency of genotypic antiretroviral resistance and the spread of non-B subtypes in patients with primary HIV-1 infection (2001-2002) and in treatment-naive chronically HIV-1-infected patients (2001).

Methods : Plasma samples from 303 patients with acute HIV-1 infection (Primo study) and 363 treatment-naive patients with chronic HIV-1 infection (Odyssee study) were tested for genotypic resistance. Resistance mutations were identified from the International AIDS Society Resistance Testing-USA panel and resistant viruses were defined according to the French Agence Nationale de Recherches sur le SIDA (ANRS) resistance algorithm.

Results : In the Primo study, 14% of the patients had viruses with resistance mutations and 12% of patients had viruses with mutations conferring resistance to least 1 antiretroviral drug. Thirty patients had viruses with mutations to at least 1 antiretroviral drug in a single pharmacologic class. Six patients were infected by viruses resistant to 2 or 3 classes of drugs. In the Odyssee study, the prevalence of reverse transcript (RT) associated and major protease inhibitor-associated mutations was 6.1% (95% CI : 3.6-8.6). Six patients had viruses resistant to at least 1 antiretroviral drug and 3 patients had viruses resistant to 2 classes of antiretroviral drugs. Twenty-four percent of acutely infected patients harbored non-B subtype strains (19% in 1999-2000) and 33.2% of chronically infected patients (10% in 1998 ; P < 0.0001).

Conclusion : In France, the frequency of HIV-1 resistance in untreated patients was not significantly higher in 2001-2002 than in previous surveys while the prevalence of non-B subtypes is increasing.

Genotypic Drug Resistance 
In the Primo study, the RT gene was not amplified in 2 cases and the protease gene was not amplified in another 2 cases. According to the IAS list, 14% (42/299) of the patients had viruses with resistance mutations. The prevalences of mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) were 10.3% (31/301), 3.3% (10/301), and 4.3% (13/301), respectively. The classic amino acid substitution at codon 215 (T215Y) was present in 9 patients. Atypical mutated profiles at this position (T215C/D/E/H) were identified in 12 patients. According to the French ANRS resistance algorithm, 12% of patients (36/299) had viruses with mutations associated with resistance to at least 1 antiretroviral drug. Thirty patients had viruses with mutations conferring resistance to at least 1 antiretroviral drug belonging to a single pharmacologic class (NRTI in 18 cases, NNRTI in 5 cases, and PI in 7 cases). Six patients harbored viruses resistant to 2 or 3 classes of antiretroviral drugs. Eight percent (24/301) had viruses resistant to NRTIs, 2.6% (8/301) to NNRTIs, and 4.3% (14/301) to PIs. Median plasma viral load was lower in patients with viruses with at least 1 resistance mutation than in patients with viruses without mutations (4.86 vs. 5.39 log copies/mL, P = 0.035), and CD4 cell counts were significantly higher (676 vs. 489 cells/mm3, P = 0.048).

In the Odyssee study, according to the IAS expert panel list of mutations, the global weighted prevalence of RT- and major PI-associated mutations was 6.1% (95% CI : 3.6-8.6). The weighted prevalence of NRTI and NNRTI resistance-associated mutations was 4.3% (95% CI : 2.2-6.4) and 0.8% (95% CI : 0.0-1.8), respectively. The duration of known seropositivity had no significant impact on the prevalence rate. The prevalence of major PI resistance-associated mutations was 1% (95% CI : 0.0-2.0), again with no significant influence of the duration of known seropositivity. Patients harboring mutations (unweighted results) are described in Table 3. The classic amino acid substitution at codon 215 (T215Y) was present in 1 patient. Atypical mutation profiles at this position (T215C/D/H/N) were observed in 4 patients. The weighted prevalence of these atypical substitutions at codon 215 was 1% (95% CI : 0-2). According to the French ANRS resistance algorithm, 6 patients (1.7%) had viruses resistant to at least 1 antiretroviral drug. Four patients (1.1%) had viruses resistant to NRTIs, 1 was resistant to NNRTIs (0.4%), and 4 to PIs (1.1%). Three patients had viruses resistant to 2 classes of antiretroviral drugs. No difference in median plasma viral load or the CD4 cell count was observed between patients with and patients without mutant viruses.

More Author Discussion
The definition of resistance varies among studies, and algorithms of interpretation evolve over time. We used 2 definitions of resistance, ie, the IAS-USA list of mutations (used in many published studies) and the ANRS resistance algorithm (used routinely in France). The IAS list is not a resistance algorithm (although some use it as such), but simply a list of mutations associated with some degree of resistance. In the Primo study the prevalence of resistance was similar whether the IAS list or the ANRS algorithm was used. In contrast, the 2 definitions gave different results in the Odyssee study. This might be explained by the fact that isolated thymidine analogue resistance-associated mutations observed in the Odyssee study (eg, at positions 41, 70, 210, and 219 of the RT gene) do not alone confer antiretroviral resistance.

Patients with recent infection were more likely to harbor resistant HIV variants than were treatment-naive patients with chronic infection. This might be explained by a lower risk of initial infection by a resistant virus in past years. It is also noteworthy that the proportion of patients infected in sub-Saharan African countries with no access to antiretroviral drugs was higher in the chronic infection cohort than in the primary infection cohort. Finally, when an individual is infected by a quasispecies containing both wild-type and mutant viruses, the wild-type strain may become predominant in the absence of drug pressure.34-36 However, recent evidence suggests that resistant strains may persist in an individual for long periods even without selective drug pressure.37-39 In any case, one might expect that the initial resistant quasispecies would still be present as archived provirus in resting cells of the untreated individuals.

We observed a higher proportion of atypical than classic substitutions at codon 215 of the RT gene. Viruses containing partial revertants at codon 215 are selected because they are fitter than their resistant counterparts.35,40,41 Subsequent treatment with thymidine analogues has been linked to the development of resistance.

In primary infection, we found that the proportion of patients infected by non-B subtypes tended to increase from 1998 to 2002, probably owing to increasing exposure of the European population to such strains. Indeed, 17% of patients of European origin with primary infection harbored a non-B strain in the present survey (2002), while we observed a figure of 14% in 1999-2000, and Couturier et al23 reported a rate of 6% in 1996-1998 among chronically infected patients (17 vs. 6%, P < 0.05). A similar increase was also observed among homosexuals and bisexuals. In the Odyssee study, the prevalence of non-B subtypes increased from 10% in 1998 to 33% in 2001.14 This latter change in subtype distribution was mainly due to a higher proportion of patients originating from sub-Saharan countries (particularly women and patients whose disease was diagnosed at a late stage of infection), as also noted in the French Hospital Database on HIV.33 Initial data generated by mandatory reporting of new diagnoses of HIV infection in France, initiated in 2003, show that 19% of newly diagnosed infections involved non-B subtypes in French patients and 82% in patients from sub-Saharan Africa.42 Our is the first report of resistance among non-B subtypes infecting untreated patients in France. These results confirm the spread of non-B subtypes in France but do not address a potential difference in transmission rates between B and non-B strains.

In conclusion, the frequency of genotypic HIV-1 resistance in untreated patients in France was not higher in 2001-2002 than in previous years. The prevalence of non-B subtypes is on the increase.

RESULTS 
Characteristics of the Population 
The baseline characteristics of the 303 patients included in the Primo study and the 363 patients included in the Odyssee study are shown in Table 1. About half the patients included in the 2 studies lived in the Paris area and the others were distributed in different regions of France including the French West Indies (1 patient).

Phylogenetic Analyses 
In the Primo study, 24% of patients (73/303) harbored non-B subtype viruses, with a predominance of CRF02 strains (11%) (Fig. 1). Four of the 36 resistant viruses were non-B subtypes (1D, 1A, 1 CRF02, 1 CRF11). Table 4 cross-tabulates the subtype distribution by sex, disease stage, race, and transmission group. Among patients infected through homosexual or bisexual contact, 11% were infected by a non-B strain. Finally, 37 (17%) of the 218 European patients were infected by a non-B subtype. Seven of these 37 patients (19%) reported intercourse with a partner originating from sub-Saharan Africa, and 2 (5%) with a partner originating from Asia. The frequency of viral resistance was lower in patients infected by non-B subtypes (5.5%) than in patients infected by subtype B (13.9%) (P = 0.0524).

In the Odyssee study, 33% of the patients were infected by non-B subtype strains (CRF02 in 19.6%). Non-B subtypes infected 53.9% of women and 23.0% of men (P < 0.001). Patients at Centers for Disease Control stage C were more frequently infected by non-B subtypes (45.9 vs. 35.7% at stage B and 29.7% at stage A ; P = 0.033). Patients with a duration of known seropositivity of <6 months were more frequently infected by non-B subtypes (43.2 vs. 23.2%, P < 0.001). The frequency of viral resistance tended to be lower in patients infected by non-B subtypes (3.4%) than in patients infected by subtype B (7.1%) (P = 0.117). On the basis of historical data, the proportion of patients infected by non-B subtypes increased from 1998 to 2002.

PATIENTS AND METHODS 
Study Population

In the Primo study, 303 patients with acute HIV infection (<6 months since infection) were recruited in 2001-2002 as part of a national survey conducted by the French Network on HIV-1 Primary Infection (Primo Cohort study 135 patients, ANRS AC-11 Resistance Group Laboratories 134 patients, INTERPRIM study 32 patients, and Primstop study 2 patients). The inclusion criteria were a negative or indeterminate HIV enzyme-linked immunosorbent assay associated with positive antigenemia or plasma HIV RNA ; a Western blot profile compatible with ongoing seroconversion ; or an initially negative test for HIV antibodies followed, within 6 months, by positive HIV serologic results. Patients were recruited throughout France to make the survey as thorough and as representative as possible. In the Odyssee study, 363 treatment-naive chronically infected patients (20 consecutive patients in each laboratory with complete Western blot profiles) managed in 23 specialized AIDS centers throughout metropolitan France were enrolled from January 2001 to April 2002. All patients gave their written informed consent to the study. Weighted analysis was used (see below) to derive representative estimates.

Genotypic Resistance Analyses
Genotypic resistance studies were performed on plasma viral RNA by using the consensus technique of the ANRS Resistance study group,28 the TruGene HIV-1 genotyping kit (Bayer Healthcare, Eragny, France), or the ViroSeq sequencing-based HIV-1 genotyping kit (Abbott, Rungis, France). Protease and RT mutations were identified from the consensus statement of the International AIDS Society Resistance Testing-USA Panel ( www.iasusa.org ).6 Resistant viruses were defined using the French Agence Nationale de Recherches sur le SIDA (ANRS) resistance algorithm ( http://www.hivfrenchresistance.org ). All 24 laboratories involved in these studies have participated in national quality control studies.

Phylogenetic Analyses 
Phylogenetic analyses were performed by estimating the relationships among pol sequences and reference sequences of HIV-1 genetic subtypes and circulating recombinant forms obtained from the Los Alamos Database ( http://hiv-web.lanl.gov ). Nucleotide sequences were aligned with the CLUSTAL W program version 1.7.29 Phylogenetic reconstruction was performed using a Kimura 2-parameter model and the neighbor-joining method with 500 bootstrapped data sets.

Statistical Analyses 
The ?2 test or the Fisher exact test was used, as appropriate, to compare categorical variables, and the Mann-Whitney U test was used to compare continuous variables. The 95% CIs were computed using a binomial distribution. Links between primary mutations and sex, age, risk factors, clinical stage, duration of known seropositivity, CD4 count, and viral load were tested, together with links between the HIV-1 subtype and the other factors. In the Odyssee study, weighted analyses were used to derive representative estimates of the percentage of patients with resistance mutations.30 The weight of each center was attributed on the basis of the number of patients treated in each center, as stated in the French Hospital Database on HIV infection.31 Statistical analyses were performed using SSPS software (SPSS, Inc., Chicago, IL).

Descamps, Diane MD, PhD* ; Chaix, Marie-Laure MD, PhD ; André, Patrice MD, PhD ; Brodard, Véronique PharmD§ ; Cottalorda, Jacqueline MD ; Deveau, Christiane MD ; Harzic, Martine MD# ; Ingrand, Didier MD** ; Izopet, Jacques MD, PhD ; Kohli, Evelyne MD ; Masquelier, Bernard PharmD, PhD§§ ; Mouajjah, Said MD ; Palmer, Pierre MD ; Pellegrin, Isabelle MD, PhD§§ ; Plantier, Jean-Christophe PharmD, PhD## ; Poggi, Cécile MD*** ; Rogez, Sylvie PharmD, PhD ; Ruffault, Annick PharmD ; Schneider, Véronique MD§§§ ; Signori-Schmück, Anne PharmD, PhD ; Tamalet, Catherine MD, PhD ; Wirden, Marc MD### ; Rouzioux, Christine MD, PhD ; Brun-Vezinet, Françoise MD, PhD* ; Meyer, Laurence MD, PhD ; Costagliola, Dominique PhD

From the *Laboratoire de Virologie, CHU Bichat-Claude Bernard, Paris, France ; Laboratoire de Virologie, CHU Necker-Enfants Malades, Paris, France ; Laboratoire de Virologie, CHU Lyon, France ; §Laboratoire de Virologie, CHU Reims, France ; Laboratoire de Virologie, CHU Nice, France ; INSERM U569, Service d’Epidémiologie, Le Kremlin-Bicêtre, France ; Laboratoire de Virologie, Hôpital de Versailles, Le Chesnay, France ; Laboratoire de Virologie, Hôpital Antoine Beclère, Clamart, France ; Laboratoire de Virologie, CHU Toulouse, France ; Laboratoire de Virologie, CHU Dijon, France ; Laboratoire de Virologie, CHU Bordeaux, France ; INSERM EMI0214, CHU Pitié Salpètrière, Paris, France ; Laboratoire de Virologie, CHU Saint-Louis, Paris, France ; Laboratoire de Virologie, CHU Rouen, France ; Laboratoire de Virologie, Hôpital de Toulon, Toulon, France ; Laboratoire de Virologie, CHU Dupuytren, Limoges, France ; Laboratoire de Virologie, CHU Pontchaillou, Rennes, France ; §§§Laboratoire de Virologie, CHU Tenon, Paris, France ; Laboratoire de Virologie, CHU Michalon, Grenoble, France ; Laboratoire de Virologie, CHU La Timone, Marseille, France ; and Laboratoire de Virologie, CHU Pitié-Salpètrière, Paris, France.

 

REFERENCES
1. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature. 1997 ;387:188-191.

2. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997 ;337:734-739.

3. Yeni PG, Hammer SM, Carpenter CC, et al. Antiretroviral treatment for adult HIV infection in 2002 : updated recommendations of the International AIDS Society-USA Panel. JAMA. 2002 ;288:222-235.

4. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997 ;337:725-733.

5. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998 ;338:853-860.

6. Hirsch MS, Brun-Vezinet F, Clotet B, et al. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1 : 2003 recommendations of an International AIDS Society-USA Panel. Clin Infect Dis. 2003 ;37:113-128.

7. Little SJ, Daar ES, D’Aquila RT, et al. Reduced antiretroviral drug susceptibility among patients with primary HIV infection. JAMA. 1999 ;282:1142-1149.

8. Boden D, Hurley A, Zhang L, et al. HIV-1 drug resistance in newly infected individuals. JAMA. 1999 ;282:1135-1141.

9. Chaix ML, Descamps D, Harzic M, et al. Stable prevalence of genotypic drug resistance mutations but increase in non-B virus among patients with primary HIV-1 infection in France. AIDS. 2003 ;17:2635-2643.

10. Tamalet C, Pasquier C, Yahi N, et al. Prevalence of drug resistant mutants and virological response to combination therapy in patients with primary HIV-1 infection. J Med Virol. 2000 ;61:181-186.

11. Salomon H, Wainberg MA, Brenner B, et al. Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use. Investigators of the Quebec Primary Infection Study. AIDS. 2000 ;14:F17-F23.

12. Yerly S, Kaiser L, Race E, et al. Transmission of antiretroviral-drug-resistant HIV-1 variants. Lancet. 1999 ;354:729-733.

13. Alexander CS, Dong W, Schechter MT, et al. Prevalence of primary HIV drug resistance among seroconverters during an explosive outbreak of HIV infection among injecting drug users. AIDS. 1999 ;13:981-985.

14. Descamps D, Calvez V, Izopet J, et al. Prevalence of resistance mutations in antiretroviral-naive chronically HIV-infected patients in 1998 : a French nationwide study. AIDS. 2001 ;15:1777-1782.

15. Gallego O, Ruiz L, Vallejo A, et al. Changes in the rate of genotypic resistance to antiretroviral drugs in Spain. AIDS. 2001 ;15:1894-1896.

16. Geretti AM, Smith M, Watson C, et al. Primary antiretroviral resistance in newly diagnosed patients with established heterosexually acquired HIV-1. AIDS. 2002 ;16:2358-2360.

17. Puig T, Perez-Olmeda M, Rubio A, et al. Prevalence of genotypic resistance to nucleoside analogues and protease inhibitors in Spain. The ERASE-2 Study Group. AIDS. 2000 ;14:727-732.

18. Wegner SA, Brodine SK, Mascola JR, et al. Prevalence of genotypic and phenotypic resistance to anti-retroviral drugs in a cohort of therapy-naive HIV-1 infected US military personnel. AIDS. 2000 ;14:1009-1015.

19. Wensing AM, Boucher CA. Worldwide transmission of drug-resistant HIV. AIDS Rev. 2003 ;5:140-155.

20. Ristig MB, Arens MQ, Kennedy M, et al. Increasing prevalence of resistance mutations in antiretroviral-naive individuals with established HIV-1 infection from 1996-2001 in St. Louis. HIV Clin Trials. 2002 ;3:155-160.

21. Van Vaerenbergh K, Debaisieux L, De Cabooter N, et al. Prevalence of genotypic resistance among antiretroviral drug-naive HIV-1-infected patients in Belgium. Antivir Ther. 2001 ;6:63-70.

22. Alexander CS, Dong W, Chan K, et al. HIV protease and reverse transcriptase variation and therapy outcome in antiretroviral-naive individuals from a large North American cohort. AIDS. 2001 ;15:601-607.

23. Couturier E, Damond F, Roques P, et al. HIV-1 diversity in France, 1996-1998. The AC 11 laboratory network. AIDS. 2000 ;14:289-296.

24. Vergne L, Peeters M, Mpoudi-Ngole E, et al. Genetic diversity of protease and reverse transcriptase sequences in non-subtype-B human immunodeficiency virus type 1 strains : evidence of many minor drug resistance mutations in treatment-naive patients. J Clin Microbiol. 2000 ;38:3919-3925.

25. Pieniazek D, Rayfield M, Hu DJ, et al. Protease sequences from HIV-1 group M subtypes A-H reveal distinct amino acid mutation patterns associated with protease resistance in protease inhibitor-naive individuals worldwide. HIV Variant Working Group. AIDS. 2000 ;14:1489-1495.

26. Ariyoshi K, Matsuda M, Miura H, et al. Patterns of point mutations associated with antiretroviral drug treatment failure in CRF01_AE (subtype E) infection differ from subtype B infection. J Acquir Immune Defic Syndr. 2003 ;33:336-342.

27. Brenner B, Turner D, Oliveira M, et al. A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS. 2003 ;17:F1-F5.

28. Pasquier C, Millot N, Njouom R, et al. HIV-1 subtyping using phylogenetic analysis of pol gene sequences. J Virol Methods. 2001 ;94:45-54.

29. Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W : improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994 ;22:4673-4680.

30. Warszawski J, Messiah A, Lellouch J, et al. Estimating means and percentages in a complex sampling survey : application to a French national survey on sexual behaviour (ACSF). Analyse des Comportements Sexuels en France. Stat Med. 1997 ;16:397-423.

31. Grabar S, Pradier C, Le Corfec E, et al. Factors associated with clinical and virological failure in patients receiving a triple therapy including a protease inhibitor. AIDS. 2000 ;14:141-149.

32. Wensing AMJ, Van de Vijver DAMC, Asjo B, et al. Prevalence of transmitted drug resistance in Europe is largely influenced by the presence of non-B sequences : analysis of 1400 patients from 16 countries : the CATCH-Study. Paper presented at : XII International HIV Drug Resistance workshop : Basic Principles and Clinical Implications, 2003 ; Los Cabos, Mexico.

33. Delfraissy JF. Prise en charge thérapeutique des personnes infectées par le VIH : recommandations du groupe d’experts. Rapport Sous la Direction du Pr. Delfraissy. Paris, France : Ed. Flammarion, coll. Médecine-Sciences ; 2004.

34. Brenner BG, Routy JP, Petrella M, et al. Persistence and fitness of multidrug-resistant human immunodeficiency virus type 1 acquired in primary infection. J Virol. 2002 ;76:1753-1761.

35. Yerly S, Rakik A, De Loes SK, et al. Switch to unusual amino acids at codon 215 of the human immunodeficiency virus type 1 reverse transcriptase gene in seroconvertors infected with zidovudine-resistant variants. J Virol. 1998 ;72:3520-3523.

36. Devereux HL, Youle M, Johnson MA, et al. Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy. AIDS. 1999 ;13:F123-F127.

37. Brenner B, Routy JP, Quan Y, et al. Persistence of multidrug-resistant HIV-1 in primary infection leading to superinfection. AIDS. 2004 ;18:1653-1660.

38. Delaugerre C, Morand-Joubert L, Chaix ML, et al. Persistence of multidrug-resistant HIV-1 without antiretroviral treatment 2 years after sexual transmission. Antivir Ther. 2004 ;9:415-421.

39. Barbour JD, Hecht FM, Wrin T, et al. Persistence of primary drug resistance among recently HIV-1 infected adults. AIDS. 2004 ;18:1683-1689.

40. de Ronde A, van Dooren M, van Der Hoek L, et al. Establishment of new transmissible and drug-sensitive human immunodeficiency virus type 1 wild types due to transmission of nucleoside analogue-resistant virus. J Virol. 2001 ;75:595-602.

41. Garcia-Lerma JG, Nidtha S, Blumoff K, et al. Increased ability for selection of zidovudine resistance in a distinct class of wild-type HIV-1 from drug-naive persons. Proc Natl Acad Sci USA. 2001 ;98:13907-13912.

42. Institut de Veille Sanitaire. Premiers résultats du nouveau dispositif de surveillance de l’infection à VIH et situation du SIDA au 30 septembre 2003. Bulletin Epidémiologique Hebdomadaire. 2004 ;24-25:102-110.