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Stable frequency of HIV-1 transmitted drug resistance in patients at the time of primary infection over 1996–2006 in France

Chaix, Marie-Laurea; Descamps, Dianeb; Wirden, Marcc; Bocket, Laurenced; Delaugerre, Constancee; Tamalet, Catherinef; Schneider, Veroniqueg; Izopet, Jacquesh; Masquelier, Bernardi; Rouzioux, Christinea; Meyer, Laurencej; Costagliola, Dominiquek,l,mfor the ANRS AC11 Resistance GroupCohort PRIMO ANRS CO 6FHDH ANRS CO4 Study Groups

doi: 10.1097/QAD.0b013e328326ca77
EPIDEMIOLOGY AND SOCIAL
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Background: Transmission of drug-resistant variants is influenced by several factors, including the HIV-1 RNA levels in HIV-1-infected patients. Our study describes the transmitted drug-resistant virus among 1446 French patients diagnosed at the time of primary infection and included from 1996 to 2006 along with the proportion of chronically infected treated patients in the French Hospital Database on HIV (FHDH).

Methods: Genotypic resistance tests were performed at the time of primary infection. The proportion of patients with viral load <500 copies/ml among treated patients, enrolled in the FHDH, was calculated.

Results: Over 1996–2006, the proportion of transmitted resistant viruses to at least one antiretroviral was estimated as 10.9%. When considering class resistance, there was an increase in transmission of nonnucleoside reverse transcriptase inhibitor-resistant virus from 0.6% in 1996–1998 to 4.4% in 1999 (P = 0.034), whereas no change was evidenced for either nucleoside/nucleotide reverse transcriptase inhibitor or protease inhibitor resistance. In the FHDH, the proportion of patients receiving combination antiretroviral therapy (cart) increased from 27.7% in 1996 to 81.4% in 2006 and the proportion of viral load <500 copies/ml in treated patients increased from 17.0% in 1996 to 85.3% in 2006. Phylogenetic analysis revealed that 25.5% of patients harboured HIV-1-non-B virus at the time of primary infection in 2005–2006 compared to 10% in 1996–1998.

Conclusion: In this large study of patients at the time of primary infection, the frequency of acquired resistant virus was stable over time, over 5% for nucleoside/nucleotide reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor. One explanation for this stability may be the increasing number of treated patients in virological success.

aUniversité Paris Descartes EA 3620, AP-HP, Laboratoire de Virologie, CHU Necker-Enfants Malades, Paris, France

bLaboratoire de Virologie, CHU Bichat Claude Bernard, Paris, France

cLaboratoire de Virologie, CHU Pitié Salpètrière, Paris, France

dLaboratoire de Virologie, CHU Lille, Lille, France

eLaboratoire de Virologie, CHU Saint Louis, Paris, France

fLaboratoire de Virologie, CHU La Timone, Marseille, France

gLaboratoire de Virologie, CHU Tenon, Paris, France

hLaboratoire de Virologie, CHU Purpan, Toulouse, France

iLaboratoire de Virologie, CHU Pellegrin, Bordeaux, France

jInserm, U822, Le Kremlin-Bicêtre, Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, AP-HP, Hopital Bicêtre, Epidemiology and Public Health Service, France

kINSERM, U 720, Paris, France

lUPMC Univ Paris 06, UMR S 720, France

mAP-HP, Groupe hospitalier Pitié Salpétrière, Service de Maladies Infectieuses et Tropicales, Paris, France.

*www.hivfrenchresistance.org

http://u822.kb.inserm.fr/COHAD/participantsPRIMO.htm

http://www.ccde.fr/

Received 31 October, 2008

Revised 12 December, 2008

Accepted 12 December, 2008

Correspondence to Dr Marie Laure Chaix, Laboratoire de Virologie, CHU Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. Tel: +33 1 44 49 49 62; fax: +33 1 44 49 49 60; e-mail: marie-laure.chaix@nck.aphp.fr

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Introduction

The transmission of drug-resistant HIV-1 occurs with a frequency of between 5 and 25% of patients diagnosed shortly after primary infection (PHI) in Europe and North America [1–8]. The wide variation in rates probably reflects differences in eligibility criteria, study design, definition of PHI and definition of transmitted resistance [9–15]. Recent epidemiological studies showed conflicting trends in the frequency of transmitted variants over time with some studies observing a decline and others an increase in the transmission of HIV drug-resistant virus. In France, through a network of clinicians and virologists, the frequency of transmitted resistant virus is surveyed each year since 1996 in patients at the time of PHI and ranged from 7.7 to 12.2% over 1996–2004 [10,16–18]. Epidemiological surveillance of strains circulating in France is also conducted. Subtype B predominates, like in other European countries and in North America, but the overall prevalence of non-B strains is increasing in patients at the time of PHI overall as well as among French Caucasian individuals [10,17]. In newly diagnosed HIV-1 infections, non-B strains represented 10% of the cases in 1998, 33% in 2001 and 50% in 2005 [19]. In parallel, the French hospital database on HIV infection-Agence Nationale de Recherche sur le Sida et les Hépatites (FHDH-ANRS CO 4) was created in 1992 in order to collect clinical information on HIV-infected patients managed in HIV/AIDS centres. The present study describes the survey of transmitted drug-resistant virus among one of the largest series of patients (1446 French patients) diagnosed at the time of PHI and included over an 11-year period (1996–2006) with emphasis on the years 2005 and 2006 along with estimates of the proportion of chronically infected treated patients with plasma HIV-1 RNA below 500 copies/ml in France.

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Materials and methods

Study population

Between November 1996 and December 2006, the study population comprised 1446 patients presenting with PHI: 156 in 1996–1998, 249 in 1999–2000, 299 in 2001–2002, 327 in 2003–2004 and 415 in 2005–2006 [10,16,17]. All of them were recruited either in the PRIMO Cohort Study (ANRS CO 6) [20] or through the Primo study of the ANRS AC11 Resistance group within the network of French virology laboratories. Enrolment criteria were: a negative or indeterminate HIV ELISA associated with a positive antigenemia or plasma HIV RNA; a western blot profile compatible with ongoing seroconversion (incomplete western blot with absence of antibodies to pol proteins) or an initially negative test for HIV antibody followed within 6 months by a positive HIV serology.

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The French hospital database on HIV (FHDH-ANRS CO 4)

French Hospital Database on HIV is an open, multicentre hospital cohort of patients with HIV-1 or HIV-2 infection, followed between 1 January 1992 and 30 June 2007 in one of 62 participating hospitals, who gave written informed consent, which includes 57% of the patients followed in France. The data collected include transmission group, date of first positive serology, known date of infection, AIDS-defining diseases and other severe non-AIDS diagnoses, viral load and CD4 cell count, and therapeutic information.

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Genotypic resistance analysis

Genotypic resistance tests were performed on sites, on plasma samples collected before initiation of antiretroviral treatment using either commercial assays (Viroseq Vs1, PE Biosystems, France; Viroseq Vs.2, Abbott AG, France; TrueGene HIV-1 genotyping kit, Visible Genetics, France) or using the consensus technique of the AC11 ANRS Resistance group (www.hivfrenchresistance.org). In France, all the laboratories participate in the annual ANRS quality assurance programme and no discrepancy was evidenced according to the different genotypic techniques [21]. Prevalence of HIV-1-transmitted drug resistance was analysed using two definitions: the list of mutations for surveillance of transmitted drug resistance [22] and the French resistance algorithm 2007 v16 (www.hivfrenchresistance.org). The Stanford list of mutations was developed to harmonize the definition of transmitted resistance between the different studies and the French resistance algorithm allows an interpretation of the resistance to each drug.

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Phylogenetic analysis

Phylogenetic relationships of the reverse transcriptase were estimated from sequence comparisons with previously reported representatives of group M subtypes and circulating recombinant forms (CRFs) for which sequences are available in the HIV database. The reverse transcriptase nucleotide sequences were aligned using Clustal W (v1.7) with minor manual adjustments [23]. Phylogenetic trees were constructed with the neighbour-joining method, and reliability of the branching orders was implemented by Clustal W using the bootstrap approach [24]. Neighbour-joining plot was used to draw trees for illustrations.

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Statistical methods

Comparisons between percentages were performed using the chi-squared or the Fisher exact test when appropriate and comparisons between continuous variables were tested using the Mann–Whitney test. The 95% confidence intervals (CIs) were computed using the binomial distribution. Analyses were performed using Stata 10 (StataCorp, College Station, Texas, USA).

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Results

Study population for the period 2005–2006

In 2005–2006, 415 patients presenting with HIV-1 PHI were included in this French national survey (176 patients in 2005 and 239 in 2006). Median viral load and median CD4 cell count at inclusion were 5.30 log10 copies/ml [range 1.79–7.88, interquartile range (IQR) 4.62–5.88] and 490 cells/μl (range 9–1510, IQR 347–646), respectively.

Eighty-nine percent of patients were men. The risk factor for infection was being homosexual or bisexual men for 64.5%, heterosexual for 24% (62 men and 38 women), intravenous drug use for 1.5% and unknown for 10%. About 40% of the patients lived in the Paris area (162/415), the other patients originated from different regions of France, including six patients recruited in the French West Indies (Martinique).

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Prevalence of drug-resistant variants for the period 2005–2006

Overall, 54 patients are described in Table 1: 42 with resistant viruses according to the Stanford list of mutations for surveillance of transmitted drug resistance [22] and the ANRS algorithm, two according to ANRS algorithm only and 10 according to the Stanford list only. Fifty-two out of the 415 patients (12.5%) had resistance mutations according to the Stanford list. The mutation frequency for resistance to nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) mutations was 6.7%: 4.6% for nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations and 2.9% for protease inhibitor mutations. The most frequent mutation was T215Y/F/D/S/E/C (4.3%) for the NRTI followed by the mutation K103N (3.6%) for NNRTI. Q151M was found in one case, K70E in one case and K65R was not observed.

Table 1

Table 1

According to the ANRS resistance interpretation algorithm, 10.6% of patients (44/415) presented with virus mutations associated with resistance to at least one antiretroviral drug (95% CI 7.8–14.0%) (Table 1, patients 1–44). Seven patients (1.7%) presented with virus mutations associated with resistance to two or three classes of antiretroviral drugs. Nine percent (37/415) (95% CI 6.3–12.1%) showed resistance mutation to one or more antiretroviral drugs in one class only. For the resistance to NRTIs, 5.5% of patients (23/415) harboured drug-resistance viruses (95% CI 3.5–8.2%); 4.8% (20/415) presented with virus mutations associated with resistance to NNRTIs (95% CI 3.0–7.3%). Primary resistance mutations to protease inhibitors were detected in 2.2% (9/415) (95% CI 1.0–4.1%).

Concerning NRTI resistance, seven individuals detected by the Stanford criteria had no resistance or possible resistance to any NRTI using the ANRS rule (one patient with D67G, T69N, K219Q, one with M41L, T69N, one with D67N, K219Q, one with D67N, T69N/D, one with isolated M41L, one with isolated D67N and one with isolated K219Q) (Table 1, patients 45–51). In contrast, one individual with isolated L74I was considered to harbour NRTI-resistant viruses by the ANRS algorithm but not by the Stanford list (Table 1, patient 39). For resistance to NNRTIs, we found only one discrepancy, a patient infected with a B subtype virus harbouring a mutation A98S considered as possibly resistant for the ANRS algorithm but not by the Stanford list (Table 1, patient 31). For individuals with protease inhibitor resistance, three individuals were considered with resistant virus by the Stanford list but not by the ANRS algorithm (one with L10I, I13V, L24I, L33F, D60E, I62V, one with L10P, G16E, M36L, F53FL, I62V, L63A and one with isolated L24I) (Table 1, patients 52–54). All these three viruses are subtype B.

The prevalence of drug resistance for individual NRTI was 4.6% to zidovudine (ZDV), 4.8% to stavudine (d4T), 0.7% to lamivudine (3TC), 0.7% to didanosine (ddI), 0.5% to tenofovir (TDF) and 0.2% to abacavir (ABC). Because of the wide cross-resistance between NNRTI, the prevalence of resistance was 4.5% for efavirenz (EFV) and 4.8% for nevirapine (NVP). The virus harbouring the mutation A98S was considered resistant for nevirapine only [25]. None of the viruses was resistant to etravirine (ETV). Resistance to protease inhibitors varied from 0% (darunavir) to 1.9% (indinavir). We found a frequency of resistance of 1.6% to nelfinavir, 0.7% to saquinavir/r and atazanavir/r, 0.5% to fos-amprenavir/r and 0.2% to lopinavir and tipranavir/r.

For patients enrolled in 2005–2006, median baseline HIV-1 RNA level was slightly higher in individuals with resistance to at least one antiretroviral than without (5.52 log versus 5.24 log, P = 0.0738). The median CD4 cell count was 425 cells/μl in patients with resistance to at least one antiretroviral drug compared to 493 cells/μl in patients without mutated virus (P = 0.277).

There was, however, no difference in either plasma HIV-1 RNA or CD4 cell counts, on the 11-year period overall. The median plasma HIV-1 RNA was 5.27 log10 copies/ml (IQR 4.60–5.84) in patients with no transmitted resistance versus 5.30 log10 copies/ml (IQR 4.46–5.87) in patients with transmitted resistance (P = 0.643), and the median CD4 cell counts was 501 cells/μl (IQR 358–670) versus 507 cells/μl (IQR 335–783) (P = 0.443).

In 2005–2006, the frequency of transmitted drug-resistant virus was 16.3% (8/49) for the women and 12.6% (46/366) for the men (P = 0.215). According to risk group, the frequency of transmitted resistant virus was 13.1% (35/268) for the homo-bisexual individuals and 16.0% (16/100) for the heterosexual individuals (P = 0.092).

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Frequency of transmitted resistant virus over time

Table 2 shows the frequency of transmitted drug resistance from 1996 to 2006. No significant change for the proportion of resistant virus to at least one antiretroviral drug (ANRS v16 algorithm) was observed over time: 7.7% in 1996–1998, 10.4% in 1999–2000, 12.0% in 2001–2002, 12.2% in 2003–2004 and 10.6% in 2005–2006 (P = 0.603). The overall proportion of transmitted resistant viruses to at least one antiretroviral drug was estimated as 10.9%. Among resistant viruses, the proportion of those resistant to two or three classes picked in 1999–2000 (46%) has remained stable since (around 19%) (P = 0.046). When considering class resistance, there was an increase in transmission of NNRTI-resistant virus from 0.6% in 1996–1998 to 4.4% from 1999 following the introduction of the NNRTI in France (P = 0.034), whereas no change was evidenced for either NRTI or protease inhibitor resistance.

Table 2

Table 2

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Evolution of the virological parameters of patients treated between 1996 and 2006 in the FHDH ANRS CO4

The number of patients enrolled in FHDH increased each year, with an estimated coverage of 57% of the patients followed in France [26]. Figure 1a shows the percentage of patients receiving cART per year of follow-up; this percentage increased from 28% in 1996 to 81% in 2006. Among the cART-receiving patients, most of them were treated with a protease inhibitor regimen: 90.2% in 1998, 62.8% in 2000, 54.2% in 2002, 56.9% in 2004 and 62.3% in 2006. The frequency NNRTI regimen ranged from 1.8% in 1996, 24.6% in 1998, 50.6% in 2000, 44.4% in 2002, 41.9% in 2004 and 38.0% in 2006. Among patients under cART for at least 6 months, the percentage of those with a viral load <500 copies/ml was increasing from 17% in 1996 to 63% in 2000, 78% in 2004 and 85% in 2006 (Fig. 1b). In 2006, the percentage of patients treated for at least 6 months with a viral load <50 copies/ml reached 74.1%.

Fig. 1

Fig. 1

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Phylogenetic analysis

In 2005–2006, the phylogenetic tree based on the 415 reverse transcriptase sequences revealed that 25.5% of the PHI patients harboured non-B subtype strains (106 out of 415). We described a wide diversity with two subtypes A, 5 C, 1 D, 3 F, 5 G, 1 J, 5 CRF01_AE, 66 CRF02_AG, 1 CRF05, 5 CRF06, 1 CRF09, 1 CRF11, 1 CRF13, 1 CRF18, 1 CRF27 [27], 5 URF_BC [28] and two undetermined strains as they did not cluster with any known subtype or CRFs. In 2005–2006, 268 patients were infected through homosexual or bisexual contact and 15.7% were infected with a non-B virus; 100 patients were infected through heterosexual contact, 51% were infected with a non-B virus (35 men, 16 women) and 49% with a B virus (26 men, 23 women) (Fig. 2).

Fig. 2

Fig. 2

In 2005–2006, the frequency of viral resistance was slightly smaller in patients infected by non-B subtypes, 7.5% had a resistant virus (8/106, 6 CRF02_AG, 1 CRF05 and 1F) compared to 14.9% (46/309) for patients infected with a B strain (P = 0.059).

The analysis of the frequency of non-B viruses by calendar year since 1996 revealed an increase in the frequency of non-B strains at the time of PHI. Indeed, 10.3% (16/156) of patients harboured HIV-1 non-B virus in 1996–1998 compared to 18.8% (45/240) in 1999–2000, to 24.4% (73/299) in 2001–2002, to 27.6% in 2003–2004 (88/319) and to 25.5% (106/415) in 2005–2006 (P < 0.001). The same trend was observed in patients infected through homosexual or bisexual contact, 4.5% (3/67) were infected with a non-B virus in 1996–1998 compared to 6.4% (9/140) in 1999–2000 to 10.9% (19/174) in 2001–2002, to 11.9% (24/201) in 2003–2004 and to 15.7% (42/268) in 2005–2006 (P = 0.020) The proportion of resistant viruses did not significantly change over time in non-B subtype, being 6.2% in 1996–1998 (1/16), 0% in 1999–2000 (0/45), 5.5% in 2001–2002 (4/73), 9.1% in 2003–2004 (8/88) and 7.5% in 2005–2006 (8/106) (P = 0.279).

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Discussion

The present study describes the survey of transmitted drug-resistant virus among one of the largest series of patients (1446 French patients) diagnosed at the time of PHI and included over an 11-year period (1996–2006). We emphasized the period 2005–2006 (415 patients) with the description of the evolution of transmitted virus over time since 1996. We used genotypic resistance tests rather than phenotyping as it is recommended by the French guidelines at the time of PHI both for the epidemiological survey of transmitted resistant virus and to allow a rapid modification of treatment in case of infection with a resistant virus [26]. Genotyping is less expensive than phenotyping and easier to implement in virological laboratories all over France. The definition of transmitted drug resistance is still a matter of debate because of the potential impact of natural polymorphisms. We, therefore, used two definitions of drug resistance: the list of mutations for surveillance of transmitted drug resistance [22] and the 2007 French ANRS algorithm. Both methods led to almost identical prevalence of resistance with minor discrepancies. According to the Stanford list, the frequency of resistant virus was 12.5% in 2005–2006. In France from 1996 to 2006, we observed a stable prevalence of transmitted virus with at least one drug resistance: 7.7% in 1996–1998, 10.4% in 1999–2000, 12% in 2001–2002, 12.2% in 2003–2004 and 10.6% in 2005–2006, showing no significant evolution during these periods of time [10,17,18]. The overall proportion of transmitted resistant viruses to at least one antiretroviral drug was estimated as 10.9%. Moreover, according to drug class, a stable frequency of transmitted virus was observed over time, except for an increase in the NNRTI-resistant virus between 1996–1998 and 1999–2000. This frequency has been stable around 4.4% since 1999.

Most of the individuals diagnosed at the time of PHI harboured strains resistant to one class only; multidrug resistance was rare (<2%). This frequency is similar to those reported from other large databases in Europe [9,29] but lower than frequencies reported from the UK or the USA [3,4]. More recently, Yerly et al.[30] reported a frequency of transmitted resistant virus of 10% in 2005 in the Swiss Cohort. In London, 140 patients with PHI were included between January 2005 and January 2006 and the frequency of transmitted virus was 6% [31]. From 1996 to 2001, San Francisco researchers found a significant increase in the prevalence of mutations that were associated with resistance to NNRTIs, from 6% of isolates in 1998–1999 to 13% of isolates in 2000–2001, although resistance to all available classes of antiretroviral therapy remained rare (0.4%) [7]. In New York, Simon et al.[14] described a frequency of resistance associated mutations in protease and reverse transcriptase genes which increased from 13.2% (1995–1998) to 19.7% (1999–2001). In contrast to the USA studies, it appears that drug resistance in Western Europe is not rapidly increasing at least in Switzerland and France.

One explanation for the stability of transmitted drug-resistant HIV, over 5% for NRTI and 4% for NNRTI, may be the increasing number of treated patients in virological success who have a low risk of transmission. In France, where health expenses are covered 100% for patients with HIV infection, 81% of patients in care were under cART in 2006. Treatment was virologically effective (viral load <500 copies/ml) in 85% of treated patients, and even in 74% using a stricter definition (viral load <50 copies/ml). Plasma viral load is likely the main predictor for the transmission of drug-resistant virus, as it is for transmission [32]. Transmission of drug-resistant variants probably originates in a population of individuals who continue to be viremic despite cART and harboured resistant viruses. As we showed that this group of patients decreased over time since 1996, this likely explains the stable frequency of transmitted virus in France.

In Switzerland, Yerly et al.[2] postulated that the decreasing rates of resistance since 1997 may be due to several factors, including the efficacy of antiretroviral agents in decreasing transmission, an aggressive HIV prevention programme and the increase of nonclade B transmission from migrant populations from countries where antiretroviral therapy has not yet been implemented (predominantly African). In the United Kingdom, a decline in transmitted drug-resistant HIV-1 was described in patients with recent infection. In 2004, the rate of resistant virus was 4% compared to 10.5% in 1996–1997 [33]. In the same way, Routy et al.[13] reported a decrease in the transmitted resistant virus in PHI patients from 13% in 1997–2000 to 4% in 2001–2003 in Montreal (P = 0.04). In the Quebec study, the decrease in transmission since 2000 coincides with the drop in mean viral load observed in chronically infected treated patients. Factors that contribute to the decrease in viral load include routine access to genotyping and availability of more potent antiretroviral drugs. Our analysis over the period since 1996, in French patients at the time of PHI and in chronically treated patients, reinforces this hypothesis.

About 89% of the patients at the time of PHI were infected with a wild-type virus. It has been suspected that individuals with PHI are more likely to transmit infection, owing to high viremia and unawareness of their infection status. In a study conducted in Quebec, Brenner et al.[34] reported that PHI could account for a high (50%) proportion of HIV transmissions. In France, 28.5% of PHI forms phylogenetic clusters, indicating that these individuals may contribute to HIV transmission [35]. On the contrary, a significant proportion of PHI can be caused by chronically infected patients ignoring their HIV status or untreated. Concerning the surveillance of HIV-1 strains, we showed that, although HIV-1 B subtype is still predominant, non-B subtypes are now present in 25% of patients with PHI compared to 10% in 1996–1998. A similar increase in the frequency of non-B strain was observed in homo-bisexual patients, 15.7% in 2005–2006 compared to 6.4% in 1999–2000 [10]. The distribution of HIV-1 strains circulating in France, particularly for CRF02_AG strains, is influenced by successive migratory flows mainly from French-speaking African countries, which have led to an exceptional viral diversity, higher than in other European countries, where subtype B epidemic is predominant [36,37]. In 2005–2006, we described the introduction of several subtypes or CRFs, the appearance of the new CRF27 strain [27] and the rapid spread in the homo-bisexual population of a URF_BC [28] as five homo-bisexual individuals were infected in 2006 suggesting a rapid spread of this strain in this population.

Even if the proportion of non-B viruses increased over time, the proportion of resistant viruses did not significantly change over time in non-B subtype and in 2005–2006, the frequency of viral resistance was only slightly smaller in patients infected by non-B subtypes compared to patients infected with a B strain.

The large epidemiological survey including 1446 patients at the time of PHI reveals a stable frequency of transmitted resistant virus over time, over 5% for NRTI and 4% NNRTI. One explanation for this stability may be the increasing number of treated patients in virological success. We clearly confirm the increase of non-B strains in France with no significant increase of non-B resistant virus. Our results strengthen the French guidelines which recommend performing genotypic resistance tests at the time of PHI or prior to treatment initiation. The surveillance of the frequency of resistant strains, as well as the molecular surveillance of the HIV-1 diversity could therefore be continued.

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Acknowledgements

The authors are indebted to the patients enrolled in the different studies without which none of these studies would have been possible. The full list of investigators for the French Primo Study group can be found at: http://u822.kb.inserm.fr/COHAD/participantsPRIMO.htm and for the AC11 resistance group at www.hivfrenchresistance.org and for the FHDH at http://www.ccde.fr.

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Keywords:

drug resistance; epidemiology; France; HIV-1 primary infection; subtype

© 2009 Lippincott Williams & Wilkins, Inc.