Epidemiology and Social
Epidemiology, diagnosis and treatment of chronic hepatitis B in HIV-infected patients (EPIB 2005 STUDY)
Piroth, Lionela; Sène, Damienb,c; Pol, Stanislasd; Goderel, Isabellee; Lacombe, Karinef; Martha, Benoita; Rey, Davidg; Loustau-Ratti, Véroniqueh; Bergmann, Jean-Françoisj; Pialoux, Gillesk; Gervais, Annel; Lascoux-Combe, Carolinem; Carrat, Fabricee; Cacoub, Patriceb,c; for the GERMIVIC Study Group
From the aCHU, Dijon, Paris
bUniversité Pierre et Marie Curie-Paris 6, CNRS, UMR 7087, Paris
cAP-HP, Hôpital Pitié-Salpêtrière, Service de Médecine Interne, Paris
dCHU Cochin, Paris
eInserm U707, Paris
fCHU Saint-Antoine, Paris
jCHU Lariboisière, Paris
kCHU Tenon, Paris
lCHU Bichat, Paris
mCHU Saint-Louis, Paris, France.
Received 13 November, 2006
Revised 30 January, 2007
Accepted 2 February, 2007
Correspondence to Professor Lionel Piroth, MD, PhD, Service de Maladies Infectieuses et Tropicales, CHU Dijon, 10 boulevard du Maréchal de Lattre de Tassigny, 21079 Dijon Cedex, France. E-mail: firstname.lastname@example.org
*See list preceding References.
Preliminary data of the present article were presented as a poster (number 1318) at the 57th AASLD meeting, 27–31 October 2006, Boston, Massachusetts, USA.
Objective: To describe the characteristics of hepatitis B (HBV) infection in HIV-infected patients and the impact of anti-HBV treatments.
Patients and methods: All the patients with past or present chronic HBV infection seen in October 2005 in 17 French hospitals were included. Data were retrospectively collected from their first visit in a time-dependent manner, through a detailed standardized questionnaire.
Results: Among 477 HBV-infected patients, 261 (55%) were co-infected with HIV. The HBV–HIV co-infected patients underwent fewer serological, virological and histological evaluations. Initial positive HBe antigenemia (HBe Ag) was more frequent in these patients (57.9 versus 28.6%; P < 10−4), as was cirrhosis on the initial liver biopsy (17.9 versus 7.6%; P = 0.05). Throughout the mean 5-year follow-up, HBe Ag loss was less frequent (P = 0.04), as was HBe seroconversion (incidence rate 2.6 versus 10/100 patient-years; P < 10−3). HBe Ag loss was associated with fibrosis improvement (METAVIR score −0.5 ± 0.4 versus +0.2 ± 0.6 if persistent positive HBe Ag, P = 0.01). In co-infected patients on tenofovir, adefovir or interferon, HBe seroconversions were seen in patients on combined HBV treatment, the use of which is increasing (58% in 2005). Nevertheless, no significant difference in virological, immunological or biochemical evolution was observed between these different treatments.
Conclusions: In HBV–HIV co-infected patients, the assessment of HBV infection still needs to be improved, the HBV wild-type remains predominant, and HBe Ag loss is rare and associated with a better histological evolution. There is insufficient evidence of the superiority of combined HBV treatment, and this still needs be demonstrated in long term studies.
From 5 to 10% of patients infected with human immunodeficiency virus (HIV) suffer from an additional co-infection with hepatitis B virus (HBV). As HBV infection was, until recent years, often considered as an epiphenomenon of HIV infection, clinical data were scarce in the field of HIV co-infection. A cross-sectional survey was recently conducted in France to describe the main characteristics of HBV chronic infection in HIV-infected patients in comparison with those who were HIV negative (EPIB2003) . It was observed that the co-infected patients underwent liver biopsy less often, in particular those with severe immunodeficiency. Despite this, they received HBV treatment more often, mainly lamivudine and/or tenofovir. These drugs were used more often primarily to treat HIV infection, and then possibly to suppress HBV replication. This study, however, did not enable us to describe in greater depth the virological and serological characteristics at baseline and their evolution according to the different HBV treatments. This is of utmost interest, since it has been suggested that HBV–HIV co-infected patients have a higher prevalence of persisting HBV DNA and hepatitis B e antigen (HBe Ag) and a higher risk of HBV-related cirrhosis than HBV mono-infected patients . Moreover, liver-related morbidity and mortality (in part related to chronic hepatitis B) were increasing in the first years of the HAART era [3–5]. Despite the widespread use of nucleoside analogues with dual activity against HIV and HBV, the best strategy and the ways to optimize current treatments remain to be established. The few data available are drawn from cohort studies, mostly focusing on the impact of a given antiviral drug with dual activity (i.e. lamivudine, emtricitabine or tenofovir), without a control group of non-HIV-infected patients. There are few data regarding the potential impact of sequential and combination therapies.
We conducted a retrospective study aimed at describing the characteristics of HBV infection in HIV-infected patients, as well as the HBV treatments used and their virological, serological and clinical impact over time.
Patients and methods
Study population and data collection
A data collection form was mailed out in September 2005 to the internal medicine, infectious disease and hepatogastroenterology departments of the French university hospitals and general hospitals that are members of the GERMIVIC group (French Joint Study Group on Viral Hepatitis Infections). The participating centers were asked to provide complete information on each patient, with past or present positive hepatitis B surface antigenemia (HBs Ag), seen during the study period from 26 September to 28 October 2005. The questionnaire contained information regarding the date of diagnosis of the HBV infection; patient characteristics; geographic origin; presumed mode of contamination; daily alcohol consumption (< 40, 40–80, > 80 g); the presence of HBV-associated clinical manifestations; viral co-infections: hepatitis C virus (HCV), HIV, and hepatitis delta virus (HDV).
All the data regarding HBV infection had to be noted in a time-dependent manner. The past history of each patient was divided into periods, each period being defined as an interval of time with the same anti-HBV treatment (i.e. standard interferon-alpha, pegylated interferon-alpha, adefovir, lamivudine, emtricitabine and tenofovir, alone or in combination), whatever the reason for the initiation of this treatment. Adding, withdrawing or modifying a drug with potential anti-HBV activity signaled the end of one period and the beginning of a new one. The presence of the following markers was noted at the beginning, the middle and the end of each period, when available: HBs Ag antibodies to the hepatitis B surface antigen (HBs Ab), hepatitis B e antigen (HBe Ag), antibodies to the hepatitis B e antigen (HBe Ab), markers of HBV replication, YMDD mutations, alanine aminotransferase (ALT) levels, liver histological assessment (liver histology using the METAVIR scoring system for fibrosis stage and activity grade or non-invasive biological surrogate markers). Since different assays were used in the quantification of HBV replication [polymerase chain reaction (PCR), real time PCR, or branched-DNA probe assay], all the results were converted when necessary into IU/ml, on the basis 5.5 copies/ml = 1 IU/ml or 1 pg/ml = 55 000 IU/ml . Among patients who had never received anti-HBV treatment, an infection by a replicative pre-core mutant was defined by the association of a negative HBe Ag, a positive HBe Ab and a serum HBV DNA above 2000 IU/ml.
HIV infection was defined by the presence of HIV antibodies on both enzyme-linked immunosorbent assay (ELISA) and western blot assays. The main features of HIV disease collected were: disease stage according to CDC classification, CD4 cell count, HIV viral load, and antiretroviral treatment. CD4 cell count and HIV viral load were also noted in a time-dependent manner, at the beginning, at the middle and at the end of each period, as previously defined. HCV infection was defined by the presence of HCV antibodies (ELISA third generation) and a positive serum HCV RNA. Previous anti-HCV therapeutic history had to be recorded. HDV co-infection was defined by the presence of positive HDV antibodies.
Categorical variables were compared using Fisher's exact and chi-squared tests, and continuous variables using the Mann–Whitney U test or the Kruskall–Wallis test. All tests were two-sided and a P-value of less than 0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.1 (SAS, Brie Comte Robert, France).
Epidemiological and clinical features of the study population: comparison of HIV-positive versus HIV-negative patients
Seventeen hospital departments participated in the study. Four hundred and seventy-seven patients with past or present positive HBs antigenemia seen during the 4-week study period were included, 261 of them being co-infected with HIV. A comparison of the epidemiological, clinical and liver histological features in HIV–HBV co-infected and HBV mono-infected patients in 2005 are reported in Tables 1 and 2. HIV co-infected patients appeared to be more frequently male with an alcohol intake above 40 g per day. They were more frequently seropositive for HCV, and this correlated with a higher rate of contamination via intravenous drug use. HDV co-infection was rare (5.9%) and no significant difference between the groups was found. However, HDV co-infection was not assessed in 22.6% of HIV-infected patients.
HBV infection characteristics at first visit significantly differed between the two groups. Six HIV-positive patients (2.3%) were HBs Ag negative at first visit, three of them with positive HBs Ab. Although HBe status was not systematically assessed for all patients (especially in HIV-co-infected patients), positive HBe antigenemia at first visit was significantly more frequently encountered in HIV-positive than in HIV-negative patients (103 of 178, 57.9% versus 54 of 189, 28.6%; P < 10−4).
When considering not only the first visit but the first period of follow-up (i.e. without and before any HBV treatment), this difference persisted: positive HBe Ag 140 of 196, 71.4% of HBV–HIV co-infected patients versus 82 of 202, 40.6% HBV mono-infected ones, P < 10−4. In contrast, anti-HBe positive infections were less often observed in HIV-positive than in HIV-negative patients.
HBV DNA levels did not significantly differ between the two groups of patients, 50 to 60% of them with a first HBV DNA above 20 000 IU/ml. Liver histological evaluation was initially less frequently performed in HIV-positive patients. Nevertheless, the proportion of cirrhosis was higher in HBV–HIV co-infected than in HBV mono-infected patients, even when considering only the results from liver biopsies (eight of 39, 17% versus eight of 95, 7.6%; P = 0.05).
Evolution in hepatitis B virus serology and virology over time in the study population: comparison of HIV-positive versus HIV-negative patients
Anti-HBV treatments are summarized in Table 3. HIV-positive patients received HBV treatment more frequently and for a longer period of time, whatever the reason. Among the patients treated for HBV, an HBV combination therapy was used more frequently in HBV–HIV co-infected than in HBV mono-infected patients (145 of /227, 63.9% versus 45 of 94, 47.9%; P < 0.01). This difference persisted when considering the current HBV treatment in October 2005, with only 32 of 74 (43.2%) HBV mono-infected patients on combined HBV treatment versus 124 of 213 (58.2%) HBV–HIV co-infected patients (P < 0.03).
Although drugs with dual activity (mainly lamivudine and tenofovir) were more often used in HBV–HIV co-infected patients, adefovir and interferon (standard or pegylated-interferon) treatments alone or in combination were used in 11.9 and 16.3% of HBV–HIV-co-infected patients, respectively. No significant difference was observed between groups regarding clinical presentation. However, the use of specific anti-HBV drugs significantly decreased over time in HBV–HIV co-infected patients, with 21 of 213 (9.9%) and four of 213 (1.9%) of these on adefovir and interferon, respectively, in October 2005.
HBs Ag loss was observed in nine HIV positive and six HIV negative patients (P = 0.86). HBs seroconversion was present in eight HIV-positive and one HIV-negative patients (P = 0.10, incidence rates of HBs seroconversion 0.7/100 and 0.2/100 patient-years, respectively). In patients with positive HBe Ag during the first period and with subsequent serological reevaluation, HBe Ag loss was observed in 24 of 105 (22.9%) HIV-positive and 17 of 41 (41.5%) HIV-negative patients (P = 0.04). HBe seroconversion was noted in 18 of 105 (17.1%) HIV-positive and 17 of 41 (41.5%) HIV-negative patients (P = 0.0008, the incidence rate of HBe seroconversion 2.6/100 patient-years and 10.0.100 patient-years, respectively).
Liver histology (either via liver biopsy or non-invasive biological surrogate markers) was assessed at least once in only 87 (33%) HIV-positive versus121 (56%) HIV-negative patients (P < 10−4). Liver biopsy was the most frequently used method, more frequently in HIV-positive than HIV-negative patients (86 versus 77%; P = 0.04). In contrast, non-invasive biological surrogate markers were less frequently measured at least once in HIV-positive than HIV-negative patients (16.1 versus 30.6% of those who underwent liver histological assessment, P = 0.02). HBe antigen loss was associated with histological improvement in patients who underwent at least two liver biopsy assessments. Indeed, mean differences in METAVIR scores in HIV-positive patients who had lost HBe antigen in comparison with those who had not were −0.9 ± 1.3 versus −0.1 ± 0.5 for activity (P = 0.02), and −0.5 ± 0.9 versus +0.2 ± 0.6 for fibrosis (P = 0.01, the annual progression rate for fibrosis was −0.1 ± 0.14 versus +0.12 ± 0.26).
Evolution according to hepatitis B virus treatment in Hepatitis V virus–HIV co-infected patients
In HBV–HIV co-infected patients, apart from lamivudine monotherapy, which was very often used as first-line HBV treatment, the most frequent HBV treatments used during the entire medical history were tenofovir in combination (with either lamivudine or emtricitabine, 117 patients, 32 of whom had never been treated for HBV), and tenofovir alone (36 patients, all but two lamivudine-experienced). Adefovir was used in 27 cases (mainly alone or in combination with lamivudine). Standard or pegylated interferon was used alone in 21 cases (in 81% of these as a first-line treatment) or in combination in 26 cases (91% following previous HBV therapy). Interferon monotherapy was used earlier (median year 1996, mainly before any antiretroviral treatment) than combinations with interferon (2001) and tenofovir treatment (2003).
The description of and comparisons between patients on tenofovir, adefovir (both either used as HBV monotherapy or in combination with another analogue, but not with interferon) and interferon (standard or pegylated) combined with analogues are shown in Table 4. Patients in this latter group were on standard (12 cases) or pegylated (14 cases) interferon, associated with analogue bitherapy (mainly lamivudine and tenofovir) in 10 cases or analogue monotherapy (mainly lamivudine) in 16 cases. The baseline characteristics of patients were not significantly different between groups, since most of the patients were antiretroviral (and anti-HBV) treatment experienced. However, the mean ALT level was higher in the adefovir monotherapy group, since two of the 12 patients experienced hepatic flares at the time of adefovir introduction (ALT values > 2000 IU/l). Despite similar baseline HBV DNA levels for the two groups, HBV DNA levels below 2000 IU/ml (although assessed in only 52% of the patients) were reached or maintained in more than 60% on tenofovir or combined interferon, more than that observed with adefovir. Among patients who were HBe Ag positive at the beginning of the period, HBe Ag loss and HBe seroconversion were never observed in patients on monotherapy but only in those on combined HBV therapy. Moreover, two patients seroconverted against HBe on combined pegylated-interferon despite prior standard interferon monotherapy (a few years before). This suggests the potential interest of combinations (since no HBe seroconversions were observed in 11 other patients on interferon monotherapy) of pegylated interferon, as well as the potential impact of immune reconstitution.
When focusing on patients treated with tenofovir bitherapy, those never previously treated against HBV had a lower CD4 cell count (239 ± 162 versus 359 ± 249 cells/μl; P = 0.03), a higher HIV viral load (3.6 ± 2.3 versus 1.6 ± 2.0 log10 copies/ml; P < 10−4), and a higher HBV DNA baseline level (5.1 ± 2.7 versus 3.7 ± 2.7 log10 IU/ml; P < 10−4) than experienced patients. As a result, HBV DNA decrease was greater in naive patients (−5.4 ± 2.6 versus −2.0 ± 2.8 log10 IU/ml, P < 10−4). However, the proportion of patients reaching an HBV DNA level < 2000 IU/ml was similar (66%) in pre-treated patients (supposedly infected with a lamivudine-resistant HBV) and in naive patients (supposedly on true combination therapy), whereas the proportions of patients losing HBe Ag or seroconverting against HBe were not significantly different between groups (two of seven versus four of 30 and two of seven versus one of 30; P = 0.32 and P = 0.15, respectively).
The first main result of our study is the still insufficient assessment of HBV infection in HIV-positive patients. Initially, patients with chronic HBV infection should have HBe antigen, anti-HBe antibodies, HBV DNA levels and HDV status assessed [7,8]. However, initial determination of HBe status is less often performed in HBV–HIV co-infected than in HBV mono-infected patients (67 versus 89%, Table 2), as was the case for determination of HDV status during the follow up (Table 1). Although it could be said that, for 30% of patients, the follow up started before 1995, at a time when hepatitis B was not a major concern in HIV-positive patients and interferon was the only effective treatment against HBV, the difference has decreased but persists in the more recently followed patients. Histological evaluation is also rarely performed, while the use of non-invasive liver fibrosis tests is slowly increasing, despite insufficient validation in HBV-HIV co-infected patients. Recent guidelines may not require histological assessment, but they do recommend on-treatment biochemical, serological and virological re-evaluations, which are too rarely performed at the moment.
Secondly, our study shows that positive HBe antigenemia is more often encountered in HBV-HIV co-infected patients (in almost two-thirds of these patients) associated with a lower frequency of pre-core mutants. The geographical origin of the patients is unlikely to explain this difference. Unfortunately, HBV genotypes were rarely available in this study. A few patients acquired HBV infection while they were already being followed for HIV infection, as already reported . This underlines the need for a wider use of HBV vaccination in HIV-infected patients in addition to other preventive measures. Some patients reactivated HBV infections despite pre-existing HBs Ab, which reinforces the arguments for repetitive serological assessments . The low rate of HBV–HIV co-infected patients with positive HBe Ab and no HBV DNA replication suggests that there is probably a lower rate of spontaneous HBe seroconversion than in mono-infected patients .
Thirdly, in 2005, the clinical status of HIV-positive and HIV-negative patients did not appear to be significantly different. However, the baseline HBV DNA and HIV RNA levels observed in treatment-naive HBV-HIV co-infected patients were lower than generally reported, suggesting that patients with higher HBV DNA and HIV RNA values were under-represented in our study population because of a worse clinical evolution. The proportion of patients with histologically proven cirrhosis was higher in our HBV–HIV-positive patients in comparison with HBV mono-infected patients [1,11]. The 10% per year rate of HBe Ag loss and HBe seroconversion observed in our HBV mono-infected patients remains within the range of those spontaneously observed (5 to 12% per year [12,13]), but it is surprisingly low as nearly half of the patients had been treated or were on treatment. Nevertheless, this rate was nearly four times higher than that observed in HIV-positive patients, despite the higher frequency and duration of HBV treatment in the latter population. Considering the lower rate of HBe seroconversion, but also the trend toward a higher rate of HBs seroconversion in HBV–HIV co-infected patients, it could be speculated that, although the immune control of HBV infection is less frequent due to HIV-related immune impairment, not only anti-HBV but also anti-HIV efficient treatments may lead to such a control. It would be thus more often complete, that is, that HBe seroconversion would more often be followed by HBs seroconversion (albeit rare ), than as naturally occurs in HBV mono-infected patients. This hypothesis needs to be further confirmed.
Fourthly, in HBV mono-infected patients, HBe Ag loss/seroconversion is associated with improved histological findings in the liver . In the present study, for the first time, such benefits were observed in HBV–HIV co-infected patients experiencing HBe Ag loss. Therapeutic approaches should aim to suppress HBV DNA replication and promote HBe Ag loss/seroconversion in positive HBe Ag-HIV co-infected patients .
Finally, the best therapeutic strategy in HIV-infected patients is still to be established, since there is a lack of therapeutic trials in the field of HIV–HBV co-infection. Regarding the use of HBV drugs without antiretroviral activity, adefovir was often used in HIV-infected patients (10% at any time), but surprisingly mainly associated with antiretroviral treatment. Adefovir may be the drug of choice as a first-line treatment in HIV-positive patients who do not need HAART, as it leads to HBV DNA suppression in 25% and HBe seroconversion in 6.9% of cases, and, according to reports published so far, without causing HBV resistance . This contrasts with the results in lamivudine pre-treated HBV mono-infected patients [17–19]. The theoretical risk of triggering HIV K65R mutation  has not been confirmed [16,21]. Entecavir may be of interest, although there is a lack of studies in HBV–HIV co-infected patients. Interferon alpha (now pegylated interferon alpha) may be another choice, even though its efficacy (10% of HBe seroconversion) tended to be lower in HIV-positive than in HIV-negative patients [22–24]. Nevertheless, interferon therapy was also shown to decrease the risk of cirrhosis regardless of the serological response .
Drugs with dual activity against HIV and HBV are very often used in HIV-positive patients. Lamivudine is no longer used alone considering the high risk of HBV resistance . Tenofovir is frequently used and with greater efficacy than adefovir . The mean HBV DNA decrease we observed in naive patients is close to that reported by others, from −3.5 to −4.5 log, as well as the HBe seroconversion rate ranging from 3.7 to 5.3% [27,28].
Combination therapies may be of interest, although their benefits on resistance and efficacy are still to be proved . On the one hand, it seems likely that nucleoside/tide combination therapy reduces the risk of resistance , whereas on the other hand, we failed to observe a superior short/medium term efficacy of nucleoside/tide combinations, as we experienced a lower rate of HBe seroconversion than reported in two previous smaller studies in 20 and six patients [27,31]. There is a risk of relapse following the interruption of nucleoside/tide combination therapy, not described with interferon alpha, which reinforces arguments for long-duration nucleoside/tide treatments [15,32]. In HIV-infected patients, the potential need for HAART modifications linked to the development of HIV resistance, the possibility of HAART interruptions and the development of new strategies without nucleoside/tide backbones underline the potential interest of time-limited HBV treatment strategies. Pegylated interferon therapy seemed to increase the rate of HBe seroconversion in our few pre-treated patients without previous HBe Ag loss, suggesting that additional or sequential pegylated interferon therapy may be of interest, as proposed in HBV mono-infected patients [32,33].
Our study has several strengths. Our results are supported by the large number of HBV–HIV co-infected patients from numerous centers in a real-life setting. All patients seen in the participating centers at the time of the study were included, thus limiting selection biases. A direct comparison of HBV–HIV co-infected with HBV mono-infected patients was performed. The design also allowed a longitudinal study of the biochemical, serological, virological and histological evolution of HBV infection in HIV infected patients, in particular according to therapeutic options. However, several limitations, mostly linked to the retrospective data collection, have to be acknowledged. It is likely that some patients followed in the participating centers a long time ago were not included in this study because of a poor clinical evolution. Comparisons between HBV–HIV co-infected and HBV mono-infected patients according to HBV treatments are limited since tenofovir was very rarely used in HBV mono-infected patients, thus restricting comparisons to the few patients who received adefovir or interferon. Analyses were often limited to subsets of patients, because of missing values, even though these missing values are informative regarding routine practice.
In conclusion, this study shows that in HBV–HIV co-infected patients, the assessment of HBV infection still needs to be improved, the HBV wild-type remains predominant, and HBe Ag loss is rare and associated with a better histological evolution. The use of specific HBV treatment in HIV-positive patients still has to be considered, as pegylated interferon therapy following nucleoside/tide therapy may be of interest. However, no strategy was found to be clearly superior to another, apart from lamivudine monotherapy. Current guidelines have to be more closely applied and their relevance has to be assessed in a prospective way in HBV–HIV co-infected patients.
The authors thank Virginie Danaire and all the study technicians who collected the data, Philip Bastable for his help in reviewing this manuscript and Christine Angenard for her help in the GERMIVIC study group. They are also grateful to the medical teams of Angoulême (Dr A. Riche); Archet – Nice (Dr E. Rosenthal); Avicenne - Bobigny (Dr M. Bentata); Clermont de l'Oise, Paul Brousse-Villejuif, Reims (Dr C. Rouger); and Saint André - Bordeaux, Villeneuve Saint Georges (Dr O. Patey) hospitals who participated in this study. This study was supported in part by unrestricted grants from Gilead and Roche laboratories.
The authors do not have a commercial or other type of association that might pose a conflict of interest.
Members of the GERMIVIC study group
Amiens: B. Pautard-Huchemblé, J.L. Schmit; Angouleme: M. Bonnefoy; Annecy: J.P. Bru, J. Gaillat; Antibes: L. Lerousseau; Arras: D. Dubois; Avignon: A. Azzedine, A. De La Blanchardière, G. Lepeu; Belfort: J.P. Faller; Besancon: P. Balvay, F. Barale, J.M. Estavoyer, D. Vuitton; Bobigny: M. Bentata, P. Cohen, L. Guillevin, B. Jarrousse, B. Padrazzi; Bordeaux: J. Beylot, N. Bernard, J. Constans, I. Loury, F. Moreau, P. Morlat, J.M. Ragnaud, J.F. Viaud, D. Lacoste; Boulogne Billancourt: A. Baglin, M. Dorra, C. Dupont, T. Hanslik, E. Rouveix; Bourg en Bresse: P. Granier; Brest: A. Cénac; Caen: C. Bazin, P. Hazera, R. Verdon; Cebazat: J. Schmidt; Chambery: O. Rogeaux; Charleville: C. Menalba; Clamart: F. Boué, R. Fior, P. Galanaud; Clermont de l'Oise: J.J. Pik; Clermont-Ferrand: J. Beytout, H. Laurichesse, M. Ruivard; Colmar: G. Laplatte, B. Audoy, N. Plaisance, C. Bouterra, G. Laylotte; Colombes: E. Delarocque, P. Vinceneux; Creteil: M. Chousterman, P. Lesprit, A. Schaeffer; Dijon: M. Grappin, L. Piroth, H. Portier; Dolle: J. Guillaumie; Eaubonne: P. Dournovo; Garches: P. De Truchis, C. Perronne; Grenoble: O. Bouchard, M. Micoud, P. Morand; Hyeres: J. Boucher, P. Chambourlier, C. Renou; La Reunion: C. Arvin-Berod, P. Poubeau; La Roche sur Yon: P. Perre; Lille: E. Hachulla, B. Devulder, P.Y. Hatron; Limoges: V. Loustaud-Ratti; Lons le Saunier: J.D. Berthou, D. Baborier; Luneville: E. Constant, E. Dufay; Lyon: D. Peyramond; Mantes la Jolie: F. Trémolières; Marseille: A. Bourgeade, J.M. Durand, J.A. Gastaut, H. Gallais, J. Moreau, J.L. Perret, I. Poizot-Martin, J. Soubeyrand; Mende: P. Meissonnier; Menton: R. Hayek; Metz: C. Constant, J.J. Raabe, A. Wang; Montpellier: J. Astruc, F. Blanc, P. Perney, A. Vandôme; Nantes: D. Bautoille, C. Guerbois, C. Loyau, F. Raffi, D. Villers; Nancy: C. Burty, P. Canton, J.D. de Korwin, G. Thibaut, D. Wahl; Nice: P. Dellamonica, J.P. Cassuto, C. Ceppi, J.G. Fuzibet, M. Poirée, C. Pradier, E. Rosenthal; Nimes: C. Raffanel; Orleans: P. Arsac, G. Calamy, C. Mille; Paris: Z. Amoura, H. Aumaitre, F. Bani-Sadr, J.F. Bergmann, F. Bissuel, A. Boissonnas, E. Bouvet, F. Bricaire, J. Cabane, A. Cabié, P. Cacoub, R. Caquet, C. Carbon, C. Caulin, K. Chemlal, J.P. Coulaud, T. de Beaumont, F. Devars du Mayne, C. Dupont, B. Durand, D. Farge, P. Galanaud, C. Gaudebout, J. Gilquin, C. Goujard, P. Hausfater, C. Katlama, M. Karmochkine, F. Krainik, P. Le Bras, V. Le Moing, C. Leport, J. Modaï, J.M. Molina, J. Moussali, G. Pialoux, J.C. Piette, Y. Poinsignon, S. Pol, Y. Quertainmont, G. Raguin, W. Rozenbaum, D. Sène, D. Sereni, D. Sicard, J. Simon, F. Vachon, A.J. Valleron, J.L. Vildé; Pessac: P. Mercie, J.L. Pellegrin; Poitiers: B. Becq-Giraudon, J.P. Breux, G. Le Moal; Rennes: O. Boucher, C. Michelet, F. Cartier; Reims: I. Beguinot, G. Rémy; Rouen: I. Gueit, F. Borsa-Lebas, G. Humbert; Roubaix: J. Wemeau; St Brieux: C. Hascouet, B. Le Cam; St Denis: M.A. Khuong, D. Mechali, X. Roblin; St. Etienne: C. Defontaine, F. Lucht; St Germain en Laye: S. Fégueux, C. Veyssier-Belot; St Laurent du Var: D. Ouzan; Sete: B. Kitschke; Sens: C. Clément-Bertoldo, G. Gonzales; St Pierre (La Reunion): P. Poubeau; Strasbourg: P. Fischer, J.M. Lang, D. Rey, A. Ruellan, J.L. Schlienger; Suresnes: D. Zucman, O. Blétry; Thonon les Bains: P. Romand; Toulouse: L. Alric, L. Cuzin, M. Duffaut; Tourcoing: F. Ajana, Y. Mouton, Y. Yazdanpanah; Tours: J.C. Borderon, P. Choutet, Y. Guimard; Villeneuve St Georges: O. Patey.
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hepatitis B virus; HIV; co-infection; treatment; evolution
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