Comparison of viro-immunological marker changes between HIV-1 and HIV-2-infected patients in France
Drylewicz, Juliaa,b; Matheron, Sophiec; Lazaro, Estibalizd; Damond, Florencec; Bonnet, Fabriced; Simon, Françoise; Dabis, Françoisa,b; Brun-Vezinet, Françoisec; Chêne, Genevièvea,b; Thiébaut, Rodolphea,b
From the aINSERM, U875 “Epidemiology and Biostatistics”, Bordeaux F-33076, France
bBordeaux 2 University, ISPED, Bordeaux F-33076, France
cBichat Claude Bernard Hospital, Assistance Publique des Hôpitaux de Paris, Paris F-75018, France
dBordeaux University Hospital, Bordeaux F-33000, France
eCharles Nicolle Hospital, Rouen F-76000, France.
Received 1 August, 2007
Revised 16 October, 2007
Accepted 26 November, 2007
Correspondence to Rodolphe Thiébaut, INSERM U897, ISPED – Université Bordeaux 2, 146 Rue Léo Saignat, 33076 Bordeaux, France. Tel: +33 5 57 57 45 21; fax: +33 5 56 24 00 81; e-mail: firstname.lastname@example.org
Background: HIV-2 is known to be less pathogenic than HIV-1, although the underlying mechanisms are still debated. We compared the changes over time in viro-immunological markers in HIV-1 and HIV-2-infected patients living in France during natural history and after initiation of the first combination antiretroviral therapy (CART).
Method: Patients were included in the ANRS CO3 HIV-1 cohort (N = 6707) or the ANRS CO5 HIV-2 cohort (N = 572). HIV-1-infected patients were matched to HIV-2 patients according to sex, age, HIV transmission group and period of treatment initiation. Changes in markers were estimated using linear mixed models.
Results: Analyses were performed for three groups of patients: those with estimated date of contamination (98 HIV-1 and 49 HIV-2-seroincident patients); untreated seroprevalent patients (320 HIV-1 and 160 HIV-2); and those initiating a first CART (59 HIV-1 and 63 HIV-2). In group 1, CD4 T-cell counts decreased less rapidly in HIV-2 than HIV-1 patients (−9 versus −49 cells/μl per year, P < 10−4). Results were similar in group 2. Baseline CD4 cell count at CART initiation was not different according to the type of infection. During the first 2 months of treatment, the CD4 cell count increased by +59 cells/μl per month (CI 34; 84) for HIV-1 and +24 (CI 6; 42) for HIV-2. The plasma viral load drop was threefold more important in HIV-1 patients: −1.56 log10/ml per month versus −0.62 among HIV-2 patients (P < 10−4).
Conclusion: Differences between the two infections during natural history are similar to those previously described in Africa. Once treatment is started, response is poorer in HIV-2 than in HIV-1 patients.
HIV-2 is endemic in West Africa and sporadic in the rest of the world [1–4]. Compared with individuals infected by HIV-1, those infected by HIV-2 have a slower clinical progression , a lower mortality rate for patients with high CD4 T lymphocyte counts [6–7] and lower rates of transmission [8–11]. In west African countries, comparisons have shown a slower CD4 cell depletion [11–13] and a lower plasma viral load in HIV-2-infected patients [13–20]. At the AIDS stage, HIV-2-infected patients tend to have higher CD4 cell count  and clinical manifestations may differ between the two infections [16,17]. Several hypotheses have been suggested to explain the differences between the two infections: lower virulence of HIV-2 [21,22], lower replication capacity of HIV-2 [23–27], better immune control [28–33] and lower activation of the immune system during HIV-2 infection [12,23,28,34]. These factors might be associated as cell activation is linked to viral load . Cell responsiveness to activation might also vary [5,35].
All reported differences in the rate of disease progression between the two infections are from cohort studies performed in sub-Saharan Africa. No direct comparison has been made in Europe or the United States during the course of the infection, although the environment may play a role in the difference of pathogenicity between the two infections. For example, the level of lymphocyte activation is higher in Africa than in Europe , consequently the role of activation in the difference between the two infections may be weaker or even reinforced because of different background rates. Therefore, we hypothesized that the differences in viro-immunological marker levels and evolution could be different in Europe compared with sub-Saharan Africa.
Here, we report the changes in plasma HIV RNA, CD4 and CD8 cell counts over time in the French national cohort of HIV-2-infected adult patients compared with individually matched HIV-1-infected patients from the French Aquitaine Cohort.
Data are taken from the ANRS CO5 HIV-2 cohort  and the ANRS CO3 Aquitaine cohort . The ANRS CO5 HIV-2 cohort is an ongoing national prospective study initiated in 1994 in 111 clinical centres in France. Inclusion criteria to the cohort are HIV-2 infection only, age 18 years or greater, residence in France planned for at least one year and informed consent available. The ANRS CO3 Aquitaine cohort is an ongoing prospective study initiated in 1987. Inclusion criteria are HIV-1 infection in patients aged over 18 years, and informed consent available. In the two cohorts, clinical, epidemiological and therapeutic data are collected by standardized questionnaires at each visit to the hospital (every 3–6 months according to clinical, immunovirological and therapeutic status).
CD4 cell count was performed by flow cytometry in the two cohorts. Plasma HIV-1 RNA was quantified mainly by branched DNA assays (Chiron Quantiplex RNA HIV-1, Emeryville, California, USA) with detection limits of 2.7 log10 copies/ml (500 copies/ml) or 1.7 log10 copies/ml (50 copies/ml). Although there is one commercial kit designed for HIV-1, which can also quantify only HIV-2 subtype A RNA, there is no commercial assay specifically designed for HIV-2 viral load . Plasma HIV-2 RNA quantification was performed using HIV-2 strain NIHZ as a standard (Advanced Biotechnologies Inc., Columbia, Maryland, USA) with lower detection limits of either 2.4 log10 copies/ml (250 copies/ml)  or 2.0 log10 copies/ml (100 copies/ml) .
We defined three study populations in each cohort: (i) seroincident patients; (ii) seroprevalent patients; and (iii) naive patients starting combination antiretroviral therapy (CART; combination of two nucleoside inhibitors and one protease inhibitor or three nucleoside inhibitors). The seroincident group included all seropositive patients whose date of seroconversion was known or well estimated, based on the period between the last negative and the first positive antibody test of less than 3 years. This population was defined retrospectively according to the availability of negative serology in the patients already included in each cohort. Data were collected from date of seroconversion and censored after 3 years of follow-up to avoid any informative dropout . In this group, no patient started antiretroviral treatment or died before the censoring date. The seroprevalent group included all seropositive untreated patients, and without documented date of HIV infection. Data were collected from inclusion and were censored if the patient started antiretroviral treatment or died. The last group included all HIV antiretroviral-naive patients who started antiretroviral therapy consisting of at least three antiretroviral drugs. Data were collected from the date of the first CART regimen initiation and were censored if the antiretroviral treatment was modified or if the patient died. An intent-to-continue analysis was also performed and results were similar (data not shown).
HIV-1-infected patients were individually matched to HIV-2-infected patients according to factors known to be associated with HIV-1 disease progression [38,42–44]. We considered: sex, HIV transmission group (in four categories: heterosexual, homosexual, blood recipients and other), period of treatment initiation (in two categories: 1996–2000 and 2001–2005 according to the generation of available treatment) and age (in four categories: ≤ 30, 31–40, 41–50 and > 50 years) at seroconversion (for group 1), at cohort inclusion (for group 2) and at first CART regimen initiation (for group 3). For each HIV-2-infected patient, one (for group 3) to two (for groups 1 and 2) HIV-1-infected patients were randomly selected for matching among eligible candidates. We selected only one HIV-1 patient for each HIV-2 patient in group 3 because of the restricted number of available patients. All HIV-1-infected patients who were prescribed a non-nucleoside inhibitor in their CART regimen were excluded, this class of antiretroviral drugs not being active against HIV-2 infection .
We carried out two subanalyses to account for additional factors. For group 2, in addition to sex, age and HIV transmission group, we constituted a new study population by matching for country of birth (west Africa, Europe and others). This subanalysis was not feasible in groups 1 and 3 because of the restricted number of available patients. In group 3, we performed an additional match according to the baseline plasma viral load at treatment initiation (> 3.5 versus ≤ 3.5 log10 copies/ml).
Changes in biological markers were studied using piecewise linear mixed models. The baseline (t = 0) was the date of seroconversion for group 1, the date of inclusion for group 2 and the date of first CART regimen initiation for group 3. Trends in the evolution of markers were fitted using one slope (in unit/year) for the first two groups. For the last group of treated patients, two slopes were considered: one for the early change (in unit/month) and a second for the long-term trend (in unit/year). The time taken for the slope to change (t = 2 months) was determined for all patients by a likelihood profile. The correlation between individual baseline value(s) and the subsequent slope(s) was handled through the unstructured covariance matrix of random effects. The left-censoring of plasma viral load as a result of undetectable values was taken into account using a maximum likelihood method as previously described . Adjustment for the type of assay used to quantify viral load did not modify the estimates of the slopes (data not shown). Data analyses were conducted using SAS 8.1 (SAS Institute, Cary, North Carolina, USA).
In January 2006, the ANRS CO5 HIV-2 cohort had recruited 572 patients. Of these, 89 were seroincident patients, of whom 49 were antiretroviral naive at inclusion in the cohort (group 1). Among the 483 seroprevalent patients, 160 had no history of any antiretroviral treatment (group 2). Of the 572 patients, 105 started an antiretroviral regimen, of whom 63 received CART (group 3). By January 2006, 6707 HIV-1-infected patients had been recruited into the ANRS CO3 Aquitaine cohort. The date of seroconversion was well estimated for 1464 patients including 962 who were antiretroviral naive. Among the entire cohort, 1036 patients started the CART regimen without any previous exposure to antiretroviral agents. A total of 98 HIV-1 and 49 HIV-2-seroincident patients, 320 HIV-1 and 160 HIV-2-seroprevalent patients and 59 HIV-1 and 63 HIV-2 CART-treated patients were included (Fig. 1). Study populations are described in Table 1.
The median delay between seroconversion and the first available laboratory measure was significantly shorter for HIV-1-infected patients than for HIV-2 (Table 2): 4.1 years versus 6.8 years (P < 10−4). Without administrative censoring, the median follow-up was 36 and 81 months for HIV-1 and HIV-2, respectively. During the first 3 years of follow-up, a median of four biological measurements per patient were available among HIV-1 and HIV-2 patients. The proportion of undetectable viral load measures were 14 and 85% in HIV-1 and HIV-2-infected patients, respectively. At enrolment in the cohort, the median viral load was 4.11 log10 copies/ml for HIV-1 and 2.09 log10 copies/ml for HIV-2 and the median CD4 cell counts were 399 and 585 cells/μl for HIV-1 and HIV-2, respectively.
The mean slopes estimated using linear mixed models were as shown in Table 3. The CD4 cell count and CD4 cell percentage decreased significantly in the HIV-1 group (−49 cells/μl per year and −1.01%/year) but was quite stable in the HIV-2 group (−9 cells/μl per year and −0.04%/year). On average, the plasma viral load was quite stable over time in the HIV-1 group and in HIV-2 (−0.02 and +0.06 log10 copies/ml per year, respectively). The CD8 cell count did not change significantly in either group (Table 2). Therefore, the CD4: CD8 cell ratio decreased significantly in the HIV-1 group (−0.06/year), whereas it did not change in the HIV-2 group (0.02/year, P < 10−4).
The median delay between inclusion in the study and the first measurement of the CD4 cell count was 2 months for HIV-1 and 6 months for HIV-2. During the follow-up (median of 4.9 years for HIV-1 and 2.9 for HIV-2), a median of four measurements were available for HIV-1 and seven for HIV-2. At inclusion in the study, the proportion of patients with undetectable plasma viral loads was 9 and 39% for HIV-1 and HIV-2, respectively.
At enrolment into the cohorts, the median CD4 cell count was significantly lower in HIV-2 than in HIV-1 patients: 260 cells/μl versus 324 (P = 0.007), probably reflecting the later enrolment of HIV-2 patients compared with HIV-1 patients. The median plasma viral load was, however, still significantly lower in HIV-2 (2.62 versus 4.39 log10 copies/ml, P < 10−4) as well as the median CD8 cell count (P = 0.0005).
The estimated average decrease in CD4 cell count was 4.5-fold more pronounced in HIV-1: −49 cells/μl per year than HIV-2: −11 (P = 0.003, Table 3). The CD4 cell percentage decrease was not significantly different between the two groups (P = 0.70). There was a small insubstantial increase in plasma viral load in the two groups: +0.20 log10 copies/ml per year for HIV-1 and +0.14 for HIV-2. Therefore, the plasma viral load was still very different in the two populations after one year of follow-up (difference of 1 log10 copies/ml, P = 0.005). The increase in the CD8 cell count did not differ between the two groups (P = 0.44). The CD4: CD8 cell ratio decreased over time in the two groups, but was more pronounced in the HIV-1 group: −0.06/year versus −0.02 (P = 10−4). We performed a second match including country of birth as a matching variable and the results were similar. In addition, we looked at any modification of the effect of the type of infection (HIV-1 or HIV-2) on the slopes of each marker according to the country of birth, and none were significant.
Patients starting combined antiretroviral treatment regimen
At the initiation of CART, the observed median CD4 cell count was not significantly different in the two groups (Table 2, P = 0.06), as well as the CD4 cell percentage (P = 0.70). The plasma viral load was significantly higher in the HIV-1 group (P < 10−4). During the first 2 months of CART, the decline in plasma viral load was threefold steeper in the HIV-1 group (−1.56 versus −0.62 log10 copies/ml per month, P < 10−4). The increases in CD4 cell count and CD4 cell percentage were more pronounced in the HIV-1 group (+59 cells/μl per month versus +24 for HIV-2, Table 3). The CD8 cell count was stable and did not differ significantly between the two groups (P = 0.26). The CD4: CD8 cell ratio increased significantly in the two groups: +0.11/month for HIV-1 versus +0.06 for HIV-2.
After the first 2 months of CART, in HIV-1-infected patients, the CD4 cell count and CD4 cell percentage continued to increase:+46 cells/μl per year and +3.3%/year, respectively. Plasma HIV RNA: −1.13 log10 copies/ml per year and CD8 cell count: −100 cells/μl per year decreased slightly. Therefore, the CD4: CD8 cell ratio increased significantly: +0.16/year. In HIV-2-infected patients, all these markers were stable (Table 4). There was no further increase in the CD4 cell count (−2.88 cells/μl per year). Among the 24 patients (60%) who reached a viral load below 2.7 log10 copies/ml without rebound during the first 6 months of follow-up, the slope of CD4 cell count was also stable (+18 cells/μl per year, P = 0.50). In the 34 HIV-1-infected patients (77%) who achieved the same viral load target, the CD4 cell increase was still greater (+59 cells/μl per year, P < 0.0001).
Changes in markers were not modified according to the treatment type, i.e. with or without protease inhibitor (data not shown). In a secondary analysis, we matched patients according to a plasma viral load greater than 3.5 log10 copies/ml (54% of HIV-1 and 24% of HIV-2 patients) and the results were similar.
We compared the changes in viro-immunological markers between individuals infected with HIV-2 and individuals infected with HIV-1, all being followed in France. During the natural history of infection, the estimated rates of CD4 cell decrease were much more pronounced in HIV-1-infected patients compared with HIV-2-infected patients. Furthermore, the estimated slopes were noticeably similar in seroprevalent and seroincident patients (−49 cells/μl per year for HIV-1 and −9 for HIV-2, Fig. 2). The plasma viral load always remained higher in HIV-1 patients compared with HIV-2 patients with the difference varying from 1.1 log10 copies/ml in seroincident patients to 2.2 log10 copies/ml in the patients initiating CART. Differences in the CD8 cell count mirrored the differences in the plasma viral load. Although a formal comparison with studies performed in Africa is difficult because of the great variability in the dates of enrolment since the onset of infection, reported differences in the present study look similar to those performed in Africa [12,13,18–20,23,24,26,33,47,48]. In seroprevalent cohorts of patients not treated with antiretroviral drugs, the reported differences in HIV RNA varied between 1.5 log10 and 3.3 log10, and between 50 and 400 cells/μl for the CD4 cell count [23,24,47,48]. The average difference of each marker between the seroincident HIV-1 and HIV-2 groups in the present study were also similar to those reported in a seroincident cohort of female sex workers in Senegal .
A novel aspect of this study is the estimation of slopes for each marker. Here again, these estimations were similar to those reported in Senegal , with a decline of 13% in the T-cell count in HIV-1-infected patients (16% in Senegal ) and 3.7% in HIV-2-infected patients (4.1% in Senegal ). Gottlieb et al. , however, reported similar slopes in both infections when controlling for plasma viral load levels. In our study, however, neither the baseline plasma viral load (according to the following categories: < 2.7, 2.7–3.7, > 3.7, P = 0.44) nor the baseline CD4 cell count (< 200, 200–500, > 500, P = 0.17) influenced the effect of either HIV-1 or HIV-2 on CD4 cell slopes in seroprevalent patients. In other words, the differences in CD4 cell count decline between the two infections were similar whatever the viral load or CD4 cell count at the time of enrolment into the cohort.
The difference in pathogenicity between the two types of virus may be independent of environment because, in this study, the differences between the natural history of HIV-1 and HIV-2 infection were similar for patients from the same geographical area. This study did not, however, explore the respective roles of the host and the virus in determining the differences between the two infections. Whether differences in pathogenicity are mainly caused by viral replication, viral infectivity, cell susceptibility to activation, or cytotoxic T-lymphocyte response remains unknown.
The virological response to CART was weaker in HIV-2 patients whatever the initial HIV-RNA level. This result has previously been reported in Africa, Europe and the United States [49–54]. In Abidjan (Côte d'Ivoire), Adjé-Touré et al.  reported a median viral load decrease of −0.6 log10 copies/ml and an increase of +80 cells/μl for CD4 cell count, 2 months after the beginning of therapy in HIV-2-treated patients. The cause of this poor immunological response to treatment is a matter of debate , the first hypothesis being the limited impact of antiretroviral drugs on in-vivo HIV-2 replication. It is difficult to distinguish whether the poorer in-vivo response in HIV-2 patients might be linked to the potency of antiretroviral drugs [51,53,55] or to pathogenic features of HIV-2 infection such as the low replicative capacity [27,56]. The 50% divergence in protease gene nucleotides between the two types of infection could explain the reduced susceptibility of HIV-2 to the protease inhibitors developed for HIV-1-infected patients [49,56]. It is also clear that the potency against HIV-2 differs for each individual protease inhibitor [55,57] and that resistance may occur [51,58–61]. Some of these resistances are similar to those observed in HIV-1 infection [54,62] but others differ (e.g. Q151M), leading to the hypothesis that the preferred pathway for resistance development may be different between the two viruses . It could be expected that a more potent regimen leading to better virological control would improve the global response to treatment. The CD4 cell count did not, however, increase in response to treatment in HIV-2 patients with controlled viral load during the first 6 months. It should also be noted that HIV-2 patients started an antiretroviral treatment at the same CD4 cell count as HIV-1 patients, so they started therapy after a longer duration of infection. This late initiation of antiretroviral therapy in HIV-2 infection might contribute to the poorer response to treatment in particular in the CD4 cell increase. Therefore, the findings of the present study are in favour of an earlier initiation of HAART treatment in HIV-2-infected patients.
Several limits of this study should be recognized. First, the individual matching was limited to a restricted number of potential confounding factors. We were not able to match for country of birth in all analyses because of the restricted number of patients from west Africa in the Aquitaine cohort. We could, however, perform such matching for the seroprevalent group and the results were similar. Another limitation was the censoring of follow-up because of a change in treatment or death. This may lead to biased estimates of the change in viro-immunological markers. The consistency in the estimates of the slopes for each marker between the seroprevalent and seroincident groups, although the censoring was only administrative for this latter group (3 years of follow-up), argues in favour of the validity of estimates. Finally, the large number of HIV-2-infected patients with undetectable viral loads yielded insufficient information to estimate the slopes reliably. Therefore, blunted variations in HIV-RNA viral load (lower than the usual measurement of 0.5 log10 copies/ml) need to be explored with more sensitive assays.
In conclusion, this study, the first comparing the evolution of markers between HIV-1 and HIV-2-infected patients outside of Africa, found similar differences between the two infections in Europe and in sub-Saharan Africa. Although the difference in viral load is consistent across all analyses, the biological mechanism is still a matter of debate. The reduced response to CART in HIV-2-infected patients raises the question of optimal antiretroviral drug regimens and the right time to initiate treatment in HIV-2 infection. A better understanding of the differences in pathogenicity between the two infections may lead to improvements in treating both of them.
The authors gratefully thank Delali Sefe for editing the English in this paper.
Composition of the ANRS CO3 Aquitaine cohort
Scientific committee: R. Salamon (chair), J. Beylot, M. Dupon, M. Longy-Boursier, J.L. Pellegrin, J.M. Ragnaud
Coordinator: F. Dabis
Epidemiology: G. Chêne, F. Dabis, S. Lawson-Ayayi, C. Lewden, R. Thiébaut, M. Winnock
Medical coordinator: Dr M. Bonareck (Bordeaux), Dr F. Bonnal (Bordeaux), Dr F. Bonnet (Bordeaux), Dr N. Bernard (Bordeaux), Dr O. Caubet (Bordeaux), Dr L. Caunègre (Dax), Dr J. Ceccaldi (Libourne), Pr P. Couzigou (Bordeaux), Dr C. De La Taille (Bordeaux), Dr S. De Witte (Mont de Marsan), Pr M. Dupon (Bordeaux), Dr H. Dutronc (Bordeaux), Dr S. Farbos (Bayonne), Dr T. Galpérine (Bordeaux), Dr K. Lacombe (Bordeaux), Dr D. Lacoste (Bordeaux), Dr S. Lafarie (Bordeaux), Dr P. Loste (Dax), Pr D. Malvy (Bordeaux), Pr P. Mercié (Bordeaux), Pr P. Morlat (Bordeaux), Pr D. Neau (Bordeaux), Dr A. Ochoa (Bordeaux), Pr J.L. Pellegrin (Bordeaux), Pr J.M. Ragnaud (Bordeaux), Dr S. Tchamgoué (Libourne), Pr J.F. Viallard (Bordeaux)
Virological coordinator: Pr H. Fleury (Bordeaux), Pr M.E. Lafon (Bordeaux), Dr B. Masquelier (Bordeaux), Dr I. Pellegrin (Bordeaux)
Clinical pharmacology: Pr D. Breilh (Bordeaux)
Pharmacovigilance: Dr G. Miremont-Salamé (Bordeaux)
Immunology: Dr P. Blanco (Bordeaux), Pr J.F. Moreau (Bordeaux)
Data management and statistical analysis: E. Balestre, M.J. Blaizeau, M. Decoin, S. Delveaux, L. Dequae-Merchadou, C. Hannapier, S. Geffard, S. Labarrère, V. Lavignolle-Aurillac, B. Uwamaliya-Nziyumvira
Technical team: J. Lemonnier, D. Touchard, H. Zouari, B. Boulant, N. Boulant, D. Dutoit, L. Houinou
Composition of the ANRS CO5 HIV-2 cohort
Investigator coordinator: S. Matheron (Hôpital Bichat Claude Bernard, Paris)
Virological coordinators: F. Brun-Vezinet, F. Damond (Hôpital Bichat Claude Bernard, Paris)
Methodological coordinator: G. Chêne, A. Bénard (INSERM U897, Bordeaux)
Clinical investigators: M. Beaufils, I. Lecomte, (Tenon, Paris); C. Boitard, L. Roudière, J.P. Viard (Necker, Paris); P.M. Girard, M.C. Meyohas, D. Bollens, D. Berriot, F. Besse, P. Tangre, M. Kirsteter (St Antoine, Paris); J.B. Dubuisson, A. Compagnucci, L. Finkielsztejn (Port Royal, Paris); D. Sicard, C. Bernasconi, O. Zak dit Zbar (Cochin, Paris); W. Rozenbaum, C. Lascoux-Combe, I. Donadieu, A. Coridian, S. Thevenet, S. Courtial-Destembert (Tenon, Paris); J. Gilquin (St Joseph, Paris); J.L. Vildé, P. Longuet, W. Nouioua, G. Breton, C. Charlois (Bichat, Paris); J.P. Coulaud, S. Matheron, A. Leprêtre, S. Mas, G. Moreau, P. Campa, E. Bouvet, S. Fegueux, V. Joly, S. Lariven, P.H. Consigny, I. Fournier, R. Landman, C. Voyer, G. Benabdelmoumen, C. Gaudebout, P. Yéni (Bichat, Paris); F. Bricaire, R. Tubiana, V. Zeller, M. Pauchard (Pitié Salpêtrière, Paris); F. Meier, E. Mortier, C. Chandemerle (L. Mourier, Colombes); C. Perronne, J.C. Melchior, P. de Truchis (R. Poincaré, Garches); D. Mechali, M.A. Khuong-Josse, T. Labergère, B. Taverne (Delafontaine, Saint Denis); A. Krivitzky, M. Bentata, J.P. Pathé, F. Rouges, A. Mosnier, P. Honoré-Berlureau (Avicenne, Bobigny); P. Morel, F.J. Timsit, E. Spindler (St Louis, Paris); M. Thomas, H. Mouas, V. Jeantils (J. Verdier, Bondy); O. Patey, C. Semaille, L. Richier(Villeneuve St Georges); J.F. Delfraissy, C.Goujard, C. Rousseau, Y. Quertainmont, T. Rannou (Bicêtre, Le Kremlin Bicêtre); J.P. Clauvel, L. Oksenhendler, L. Gérard (St Louis, Paris); M. Beumont-Mauriel, G. Cessot (Institut A. Fournier, Paris); P. Vinceneux, M. Bloch, E. Lafon, A.M. SimonPoli (L. Mourier, Colombes); P. Lagarde, F. David-Ouaknine, E. Froguel, P. Simon (Lagny sur Marne); P. Mornet, Y. Welker (St Germain en Laye); M. Ruel, K. Chemlal (M. Fourestier, Nanterre); F. Lionnet, P. Genet (V. Dupouy, Argenteuil); P. Polomeni, A. Leprêtre (E. Roux, Eaubonne); T. Papo (Bichat, Paris); J.M. Decazes, D. Ponscarme, F. Bani-Sadr, N. Colin Deverdière (St Louis, Paris); O. Blétry, D. Zucman, C. Majerholc (Foch, Suresnes); D. Champetier de Ribes, G. Force (Perpétuel Secours, Levallois); S. Herson, N. Amirate, A. Coutelier, M. Brançon (Pitié Salpêtrière, Paris); P.Y. Redelsperger, B. Ponge (M. Jacquet, Melun); J.P. Escande, N. Dupin (Tarnier, Paris); M. Kazatchkine, M. Karmochkine, L. Weiss, D. Batisse, C. Picketty, S. Marinier-Roger, D. Tisne-Dessus (HEGP, Paris); M. Chousterman, V. Garrait, L. Richier (Intercommunal, Créteil); D. Hillion, H. Masson (Poissy); O. Danne, L. Blum, M. Eouzan (Pontoise); A. Sobel, Y. Lévy, P. Lesprit, F. Bourdillon, C. Jung (H. Mondor, Créteil); G. Guermonprez, A. Dulioust, P. Chardon (CMC de Bligny, Briis sous Forges); G. Raguin, M. Karmochkine (La Croix St Simon, Paris); F. Bournerias (St Cloud); F. Granier, V. Perronne (F. Quesnay, Mantes la Jolie); C. Lejeune, P. Bellaiche (HEGP, Paris) M. Janowski, C. Winter (Intercommunal, Montreuil); C. Vilain, I. La Torre (Montargis); G. Naudin (Diaconnesses, Paris); G. Tobelem, J. Cervoni, J.M. Zini (Lariboisière, Paris); D. Sereni, C. Lascoux-Combe, F. Prévoteau du Clary, C. Pintado (St Louis, Paris); J. Molina, D. Ponscarme, M. Lafaurie (St Louis, Paris); P. Brunet (Arpajon); B. Godeau, A. Schaeffer (H. Mondor, Créteil); G. Charpentier, A. Devidas, P. Chevojon, P. Kousignian, C. Petitdidier, Y. Lemercier, I. Turpault (Corbeil); E. Rouveix, S. Daum-Morelon (A. Paré, Boulogne); P. At Khen, I. Bouchard (Etablissement public de santé national, Fresnes); R. Stein Metzer, S. Kernbaum (Hôpital Américain, Neuilly); B. Gachot (Institut Pasteur, Paris); P. Bourdon, J.L. Delassus (R. Balanger, Aulnay); M. Gayraud, L. Bodard, L. Raffenne (Institut Mutualiste Montsouris, Paris); H. Sors, D. Israël-Biet (HEGP, Paris); R. Roué, P. Imbert (Bégin, St Mandé); P. Galanaud, F. Boué, D. Emilie, A.M. Delavalle (A. Béclère, Clamard); L. Guillevin, O. Launay, L. Belarbi (Avicenne, Bobigny); G. Beck-Wirth, C. Beck (Mulhouse); J. Barrier, F. Raffi, E. Billau (Hotel Dieu, Nantes); J.F. Stalder, B. Milpied (Hotel Dieu, Nantes); R. Laurent, C. Drobacheff, D. Bourezane (St Jacques, Besançon); C. Trépo, L. Cotte, C. Brochier (Hotel Dieu, Lyon); A.P. Blanc, T. Allègre (Aix en Provence); J.A. Gastaud, M.P. Drogoul, M. Fabre (Régional, Marseille); G. Dien, C. Daniel, A. Hascouet (Saint Brieuc); P. Granier (Fleyriat, Bourg en Bresse); P. Choutet, J.M. Bestnier, D. Vautier (Bretonneau, Tours); F. Caron, F. Borsa Lebas, Y. Debab (C. Nicolle, Rouen); C. Brambilla, P. Leclerc (Michalon, Grenoble); M. Mornet, G. Adam (J. Coeur, Bourges); J.P. Delmont, J. Moreau, P. Brouqui (Nord, Marseille); T. Cartier, F. Andrieux, C. Bouvier (Pontchaillou, Rennes); M.H. Delangle, B. Héry (St Nazaire); B. Becq-Giaudon, J.P. Breux (J. Bernard, Poitiers); P. Arsac (Régional, Orléans); A. Lafeuillade (Chalucet, Toulon); J.M. Ragnaud (Pellegrin Tripode, Bordeaux); M.J. Chantereau, S. Durupatient (W. Morey, Chalon sur Saône); P. Perré (La Roche sur Yon); M. Langlois (Villefranche de Rouergue); M. Dupon, H. Dutronc (Pellegrin Tripode, Bordeaux); J.L. Pellegrin, P. Mercié (Haut Lévêque, Bordeaux Pessac); P. Simonet, B. Vialatte (Cannes); T. May, L. Boyer (Nancy Brabois, Vandoeuvre les Nancy); B. Manoury, M. Daumal (St Quentin); F. Janbon, J. Reynes, M. Vidal (Montpellier); J.L. Schmit, A. Smail (Amiens Nord, Amiens); H. Jardel, Y. Poinsignon, D. Le Pichon (P. Chubert, Vannes); J. Beytout, C. Jacomet, F. Gourdon (Hotel Dieu, Clermont Ferrand); H. Portier, M. Buisson, M. Greusard (Bocage, Dijon); Y. Mouton, F. Ajana, V. Baclet (Dron, Tourcoing); L. Yver, Y. Turpin (Angoulême); M. Uzan, D. Garipuy (J. Ducuing, Toulouse); M. Bonnefoy, A. Riché (Angoulême).
Virological investigators: F. Brun-Vézinet, F. Damond (Bichat, Paris); F. Ferchal, P. Palmer (St Louis, Paris); L. Morand-Joubert (St Antoine, Paris); D. Cottalorda (F. de médecine, Nice); M.P. Schmitt (F. de médecine, Strasbourg); P. Billaudel, V. Ferre (Institut de Biologie, Nantes); P. Lab, A. Bassignot (Besançon); P. Barin (Bretonneau, Tours); P. Boulanger, D. Tardy (Université, Lyon); D. Raoult, C. Tamalet (La Timone, Marseille); P. Avril, M. Kerriguy (Pontchaillou, Rennes); J. Puel, A. Jaafar (Purpan, Toulouse); P. Buffet-Janvresse (C. Nicolle, Rouen); P. Seigneurin, D. Morand (Grenoble); P. Agius, M. Bourgoin (J. Bourgoin, Poitiers); P. Fleury, B. Masquelier (Pellegrin Tripode, Bordeaux); D. Duverlie, M. Roussel (Amiens); H. La Feuille, D. Henquell (F. de médecine, Clermond Ferrand); A. Chiacha (St Michel, Angoulême); D. Trevoux, D. Delarbre (Mulhouse); C. Brehant, M. Marty (La Rochelle); P. Watry, D. Bocket (Lille); B. Montes (St Eloi, Montpellier).
Data management and statistical analysis: P. Campa, A. Kissila, V. El Fouikar, A. Taieb
Conflicts of interest: None.
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