HBEAG NEGATIVE PATIENTS WITH CHRONIC HEPATITIS B ARE LESS LIKELY TO HAVE A BIOCHEMICAL BREAKTHROUGH DURING LAMIVUDINE TREATMENT

U.S. Akarca1, F. Gunsar1, G. Ersoz1, T. Ozacar2, S. Erensoy2, M. Akyildiz1, E. Kasap1, S. Akay1, F. Tekin1, Z. Karasu1, Y. Batur1, T. İlter1  

1Department of Gastroenterology, Ege University Medical School, Izmir, Turkey  2Department of Microbiology, Ege University Medical School, Izmir, Turkey 

 

Introducion

Resistance to lamivudine is a major drawback of treatment of chronic hepatitis B (CHB). Most of the studies have shown an equal rate of resistance to lamivudine in HBeAg positive and HBeAg negative patients. However, our previous reports implied that HBeAg negative patients had a lower rate of lamivudine resistance which was attributed to the lower replicative capacity of the HBeAg minus virus.

 

Aim

In this study we analyzed the cumulative probability of biochemical breakthrough of lamivudine-treated patients by considering their age, gender, HBeAg status, baseline ALT and HBV DNA levels.

 

Methods

We reviewed data on 498 patients with compensated chronic hepatitis B who received lamivudine for up to 6 years in a single center. Biochemical breakthrough was defined as the presence of two consecutive ALT values more than the upper limit of normal, at least 1 month apart, after ALT normalization. Primary resistance was defined as the persistent ALT elevation during lamivudine treatment. To investigate the parameters which were related to breakthrough, Kaplan-Meier analysis and log-rank test were performed after categorization of the above parameters. Variables reaching a statistical significance were introduced into Cox’s multiple regression analysis.

 

Results

Of 498 lamivudine-treated patients (346M, 152F, median age: 41), 322 (64.7%) were HBeAg negative, 176 (35.3%) HBeAg positive. Median ALT was 113 IU/L, HBV DNA was 312 pg/ml. Biochemical breakthrough rate at 1, 2, 3, 4, and 5 years were 9%, 21%, 36%, 49%, and 59% respectively. These values for HBeAg positives were 13, 33, 59, 74 and 88%, for HBeAg negatives were 7, 15, 25, 35, and 41% (p<0.00001). Univariate analysis showed that baseline ALT (p=0.036), age (p=0.0019), HBV DNA (p<0.0001) were related to breakthrough, as well. Multivariate analysis indicated that HBeAg status, HBV DNA and categorized ALT (<2xULN, 2-5xULN, >5xULN) were independently related to cumulative biochemical breakthrough rate.

 

Conclusions

HBeAg negative patients have a lower rate of biochemical breakthrough during lamivudine therapy comparing to HBeAg positive patients independent of baseline HBV DNA and ALT values.

 

 

OCCULT HBV INFECTION IN PATIENTS WITH CHRONIC HEPATITIS C AND IN HCV/HIV COINFECTED PATIENTS

P. Fabris1, M.R. Biasin2, M.T. Giordani1, L. Berardo2, D. Infantolino2, V. Menin2, E. Conti1, C. Stecca1, F. de Lalla1  

1Department of Infectious Diseases and Tropical Medicine, S. Bortolo Hospital, Vicenza, Italy  2Department of Pathology, Hospital of Castelfranco Veneto, Treviso, Italy 

 

Background

The frequency and the impact of occult HBV infection in patients with chronic hepatitis C are  still under discussion.

 

Aims

To evaluate the prevalence of  occult  HBV infection and to assess  its impact on HCV viral titre, and  liver histology in patients with chronic hepatitis C and in HIV/HCV coinfected patients..

 

Methods

One-hundred and sixty-one  frozen liver biopsies from patients (74% IVDUs) with chronic hepatitis C (Group A), 26 liver biopsies from HIV/HCV coinfected patients (Group B) and 32 biopsies from a control group (25 HBsAg+, 4 autoimmune hepatitis and 3 cryptogenic chronic hepatitis) were studied. DNA was extracted with QIAGEN kit method and amplified with nested PCR by using  primers for S, Core and X genes. Liver histology was evaluated  using the Ishak’ s modified HAI.

 

Results

The overall HBV-DNA frequency was  14.2% (23/161) in specimens from Group A, and  in 11.5%  (3/26) specimens from Group B (p=ns). In both groups, HBV-DNA positivity was unrelated to HCV genotype, while a significant (p<0.01) association with  serological markers of previous exposure to HBV infection was found. In Group A, HCV viral titre was lower in HBV-DNA positive than in HBV-DNA negative patients    (0.4 x 106 UI/ml vs 1.4 x 106, p=0.06).Furthermore, grading (but not staging) was significantly higher in HBV-DNA positive than in HBV-DNA negative patients (mean score 7.0 vs 5.2, p=0.03). Among HCV mono-infected, 5 samples were positive for S gene, 11 for Core gene, 5 for both S gene and Core gene, and 2 for X gene. Similar figure was observed in liver tissue from  HCV/HIV co-infected patients. 

 

Conclusions

In our study the prevalence of occult HBV infection appears to be lower than previously reported, with a  similar  figure   in HCV mono-infected and in HCV/HIV co-infected patients. The inverse correlation between the HBV-DNA positivity in liver tissue and HCV viral titre seems to support an  interference of occult HBV infection on HCV replication. Although HBV-DNA positivity  appears associated with more severe liver inflammation, prospective studies should be designed to evaluate the impact of occult HBV infection on liver disease progression.

 

 

WHAT DOES THE HEPATITIS B VIRUS DNA LEVEL TELL US IN HBEAG-NEGATIVE PATIENTS INFECTED WITH HBV GENOTYPE D ?

G. Germanidis1, S. Chevaliez2, F. Roudot-Thoraval2, M. Bouvier-Alias2, F. Guerre2, A. Miladi2, I. Makri3, S. Manolakopoulos4, E. Pagkalos1, A. Avgerinos4, G. Dalekos3, J.M. Pawlotsky2  

 

1Department of Internal Medicine, Papageorgiou General Hospital, Thessaloniki, Greece  2Department of Virology, INSERM U635, Hôpital Henri Mondor, Université Paris 12, Créteil, France  3University of Larissa, Larissa, Greece  4Evangelismos Hospital, Athens, Greece 

 

Introduction

The diagnostic and prognostic value of single HBV DNA level measurements in individual patients is unknown, and no clinically relevant thresholds have been established to make accurate clinical or therapeutical decisions.

 

Objective

To determine the clinical information provided by HBV DNA levels and identify clinically relevant HBV DNA thresholds in HBeAg-negative, HBV genotype D-infected patients.

 

Methods

HBV DNA was quantified in 808 Greek patients with chronic hepatitis B (695 HBeAg-negative, 113 HBeAg-positive as a control group). HBV DNA levels were compared with the clinical, biochemical and histological characteristics of infection. The HBV genotype and precore and core promoter mutations were determined.

 

Results

Preliminary results are available for 241 patients (154 M, 87 F, mean age 50±14) with HBeAg-negative chronic hepatitis B, 19.5% having cirrhosis. All but 3 were infected with HBV genotype D. The HBV DNA level varied according to the predominant precore nucleotide at position 1896: (wild-type: 5.9±2.1 vs precore mutant: 4.8±1.5 log IU/ml), but was unrelated to core promoter mutations. The HBV DNA load was significantly higher in the patients with cirrhosis (5.5±1.3 vs 4.7±1.6, p=0.006). Among 102 patients with a Metavir score, HBV DNA load was associated with the activity grade (p=0.0005), together with the age and serum ALT and AST levels. An HBV DNA load of 600,000 IU/ml (5.8 log IU/ml) was the best predictor of chronic active hepatitis, ie A2 or A3 (PPV=64.2%, NPV=75.5%). When combining the activity grade and fibrosis score, the HBV DNA load was significantly associated with the severity of HBV-induced liver disease (p=0.04), together with an older age and higher AST levels.

 

Conclusion

In genotype D-infected, HBeAg-negative patients with chronic hepatitis B, the HBV DNA load is significantly related to the type of precore mutation, and increases with the severity of HBV-induced liver disease. Combining HBV DNA load, aminotransferase levels and the patient?s age may allow to discriminate among the patients who need and those who do not need antiviral therapy. The final results on the full series of 808 patients will be presented. They will help deriving a treatment decision algorithm for HBeAg-negative, HBV genotype D-infected patients.

 

 

OCCULT HEPATITIS B VIRUS INFECTION IN A COHORT OF HIV POSITIVE PATIENTS

N. Marino1, S. Lo Caputo1, P. Pierotti1, C. Blé1, M.P. Riccardi2, M. Trezzi2, M. Toti2, M. De Gennaro3, A. Scasso3, A. Vivarelli4, D. Dionisio4  

1Division of Infectious Diseases,S.M.Annunziata Hospital, Florence, Italy  2Division of Infectious Diseases, Misericordia Hospital, Grosseto, Italy  3Division of Infectious Diseases, Campo Di Marte Hospital, Lucca, Italy  4Division of Infectious Diseases, Del Ceppo Hospital, Pistoia, Italy 

 

Background

70–90% of HIV-infected patients have evidence of infection with Hepatitis B virus. Most individuals develop anti-HBs and anti-HBc; 10-18% develop anti-HBc in absence of detectable anti-HBs and may reflect latent HBV infection.

 

Methods

HIV+ consecutive patients in the year 2003 were chequed in 4 Infectious Disease Units in Tuscany (Italy) in order to assess parameters HIV-related (CD4 count, HIV-RNA), serological markers for HBV (HBsAg, anti-HBs, anti-HBc , HBeAg, anti-HBe) and HCV (anti-HCV, HCV-RNA ). Polymerase chain reaction (PCR) for HBV-DNA (Cobas Amplicor HBV Monitor ) was performed in patients who showed only anti-HBc reactivity. Clinical and therapeutical data were collected. T.Student test was employed.

 

Results

955 HIV+ patients ( 71,3% males, median age 42,3 years, eterosexual transmission 26,7%, omosexual 30,2%, IVD 59,4%) were evaluated for HBV infection. 581 patients (60,8%) were anti-HBc+, 64 (6,7%) were HbsAg+, 361 (37,8%) were anti-HBs+, 190 (19,9%) were anti-HBc+ alone. 402 patients (42,1%) were coinfected with HCV. Isolated antiHBc+ was not related to sex, age, immunological status and HIV-viremia. Patients with isolated anti-HBc were more likely than patients anti-HBc - to be HCV seropositive ( 71% vs 17,3% p<0,0001) . Patients HCV+ were more likely to have isolated anti-HBc than were subjects with HIV alone ( 33,6% vs. 9,9% p<0,0001). HBV-DNA was positive in 6,9% of anti-HBc + patients. with low level of replication ( from 102 to 103 copies/mL). Patients HBV-DNA positive didn’t show either clinical or laboratory abnormalities, no evidence of relation with CD4 count, HIV-RNA, HAART, or HCV coinfection. Data on the follow-up of the HBV viraemic patients report that viraemia in occult Hepatitis B is not persistent. Liver cirrhosis was observed only in HCV+ patients and does not relate to HBV-DNA; prevalence was higher in anti-HBc+ 15,8% vs. anti-HBc- 1,5% (p<0,0001).

 

Conclusions

These findings suggest that occult HBV infection is frequent in patients HIV+, occurs more frequently in patients with chronic hepatitis C and enhances the severity of liver disease. HBV-DNA positive in 6,9% was not related to clinical or laboratoriy. Longitudinal evaluation of HBV-DNA is necessary for correct etiologic diagnosis of occult HBV infection.

 

 

IS TENOFOVIR PLUS LAMIVUDINE SUPERIOR TO TENOFOVIR MONOTHERAPY IN PATIENTS WITH HBV/HIV COINFECTION?

S. Mauss1, T. Lutz2, F. van Boemmel3, F. Berger1, T. Berg3, A. Stoehr4, A. Carlebach2, G. Schmutz1  

 

1Center for HIV and Hepatogastroenterology, Duesseldorf, Germany  2HIV-Cohort, Frankfurt, Germany  3Medical Clinic Charite, Berlin, Germany  4Institute for Interdisciplinary Infectiology and Immunology, Hamburg, Germany 

 

Objective

Sequential monotherapy is the standard of care in the treatment of chronic hepatitis B. In contrast in HIV- or HCV-infection antiviral combination therapy has been proven to be superior to monotherapy.

 

Methods

Patients with HBV/HIV-coinfection never pretreated with tenofovir (TDF) and lamivudine (3TC) starting antiretroviral therapy on TDF in combination with 3TC were compared to patients who had highly replicative hepatitis B under treatment with 3TC and were switched to TDF as the only active HBV-polymerase inhibitor. All patients were HBe-antigen positive. All patients who switched to TDF as monotherapy for HBV had highly replicative chronic hepatitis B despite 3TC therapy defined as >500.000 copies/mL indicating 3TC resistance. The lower limit of detection of HBV-DNA was <1000 copies/mL. Results: At baseline patients on TDF + 3TC (n=8) had a median HBV-DNA of 49.000.000 copies/mL compared to 187.000.000 copies/mL on TDF (n=24). After 3 months on treatment median HBV-DNA decreased to 140.000 copies/mL on TDF + 3TC compared to 30.000 copies/mL on TDF. After 12 months on therapy median HBV-DNA was 2200 copies/mL in patients on TDF + 3TC and <1000 copies/mL on TDF. A sustained undetectable HBV-DNA <1000 copies/mL was achieved in 6/8 (75%) patients on 3TC + TDF and in 19/24 (79%) patients on TDF. Viral rebound was observed in 0/8 and 2/24 patients, respectively. ALT normalised in 5/8 (63%) and 16/24 (67%) patients. ALT >2x upper limit of normal was observed in 0/8 and 2/24 patients. A loss of HBe-antigen was observed in 1/8 patients on TDF + 3TC and in 6/24 patients on TDF. HBs-antigen loss was found in 0/8 and 2/24 patients.

 

Conclusion

In this cohort of HBe-antigen positive HBV/HIV-coinfected individuals full virologic suppression of HBV-DNA was achieved in the majority of patients independent of treatment allocation. HBe-antigen loss and ALT normalisation were not in favour of the combination therapy. From these preliminary data monotherapy with TDF seems as effective as TDF + 3TC in coinfected patients with highly replicative hepatitis B.

 

 

IFN IMPACT ON LIVER DISEASE PROGRESSION IN HBEAG NEGATIVE CHRONIC HEPATITIS B (CHB): A LONG TERM ITALIAN  MULTICENTER AISF STUDY

F. Oliveri1, M. Puoti2, T. Santantonio3, P. Lampertico4, G. Colloredo5, G. Niro6, G. Fattovich7, F. Morisco8, A. Marrone9, P. Costa10, M. Felder11, P. Cacciatore12, A. Smedile13, M.R. Brunetto1  

 

1U.O. Gastroenterologia ed Epatologia, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy  2Clinica Malattie Infettive e Tropicali, AO Spedali Civili, Brescia, Italy  3Clinica Malattie Infettive, Azienda Ospedaliera Policlinico Consorziale, Bari, Italy  4Divisione di Epatologia, IRCCS Ospedale Maggiore Policlinico, Milano, Italy  5Divisione Medicina, Policlinico San Pietro, Ponte San Pietro, Italy  6Gastroenterologia Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy  7Dipartimento di Gastroenterologia, Università di Verona, Verona, Italy  8Cattedra Di Gastroenterologia, Dipartimento di Scienza Degli Alimenti, Università di Napoli 'Federico II', Napoli, Italy  9Divisione di Medicina Interna ed Epatologia, Seconda Università di Napoli, Napoli, Italy  10Divisione Malattie Infettive Ospedale 'C. Poma' – Mantova 11Divisione di Gastroenterologia, Ospedale Centrale Bolzano 12Clinica Malattie Infettive, Università Di Chieti 13UO Gastroenterologia Ospedaliera, Ospedale S. Giovanni Battista 'Molinette', Torino, Italy, Italy

Introduction

HBeAg negative CHB is a progressive disease with low spontaneous and drug induced resolution rates. We evaluated sustained response (SR) to IFN and factors influencing  treatment and disease outcome in a large series of patients.

 

Patients and Methods

We followed up prospectively 558 anti-HBe positive CHB patients (451 males, 107 females; mean age 41, range 12-66 y) from 13 Italian Centers. Patients received at least 3 months (m) of alpha-IFN from 1985 to 2001: 437 (78%) experienced single courses whereas 121 (22%) 2 or more courses.  Mean follow up after end of treatment (EOT) 54 m (1-205 m). SR=normal ALT, HBV-DNA<10 pg/ml, IgM anti-HBc<0.2 IMx index for at least 12 m after EOT.

 

Results

At baseline 150 (27%) patients had cirrhosis, 49 (9%) moderate-severe steatosis. At first IFN treatment 319 (57,2%) patients achieved EOT response, 96 (17,2%) were SR; after relapse 14 (2,5%) developed persistently normal ALT and undetectable HBV-DNA  (PRR=Persistent Remission after Relapse). Long Term Response (LTR=SR+PRR) rate in naives (19,7%) was the same of that in retreated (19,8%). At multivariate analysis (MVA) age younger than 40 y (p=0,011) and treatment duration (p<0,000001) were independently associated with SR, observed in 6,8%, 15.9% and 30.7% of patients treated 3-6 m, 7-12 m and more than 1 y (mean 19 m) respectively. HBsAg clearance was observed in 47 (35%) of 134 LTR (anti-HBs seroconversion in 32). During follow up 43 (7,7%) patients developed End Stage Complications (ESC) (jaundice, ascites, var.bleeding, encephalopathy) and/or Hepatocellular Carcinoma (HCC in 27, 4,8%). Four patients were transplanted because of HCC and 1 for terminal cirrhosis (t.c.); 14 (2,5%) died 15-100 m after EOT because of HCC (10), t.c.(3) and extraepatic tumor (1). Among 43 ESC patients  31 had baseline cirrhosis, only 1 was female. At MVA female sex, younger age, absent-mild steatosis, absence of cirrhosis and LTR to IFN were independently associated with a better outcome. In cirrhotics LTR was independently associated with the absence of ESC except HCC.

 

Conclusions

In HBeAg negative CHB standard IFN warrants a  20% LTR associated with a better clinical outcome. In cirrhotics IFN may avoid clinical decompensation, but not HCC.

 

 

FACTORS ASSOCIATED WITH THE SEVERITY OF HBV-RELATED CHRONIC HEPATITIS IN HIV-INFECTED PATIENTS

J.B. Trabut1, B. Nalpas1, M.L. Chaix2, V. Verkarre3, J. Serpaggi1, H. Fontaine1, S. Pol1  

1Unité D'Hépatologie-INSERM U 370, CHU Necker Enfants-Malades, Paris, France  2Laboratoire De Virologie-EA 3620, Université René Descartes- CHU Necker Enfants-Malades, Paris, France  3Laboratoire D'Anatomo-Pathologie, CHU Necker Enfants-Malades, Paris, France 

Background

HBV infection is a frequent cause of morbidity and mortality in HIV-infected patients.

 

Aim

The aim of our study was to analyse the factors associated with the severity of their liver disease.

 

Patients and methods

A cohort of 110 patients HBV/HIV co-infected (110 sexual contaminations and 10 unknown). Analysis of : 1. parameters significantly associated with fibrosis score and mortality ; 2. the impact of’interferon and lamivudine therapies.

 

Results

Cirrhosis was present in 25.5% of the patients. Among the 85 patients without any anti-HBV therapies, fibrosis with the Metavir scoring system (F3-4 vs. F0-2) was significantly more severe in the older patients (p= 0.004), in those with the longer duration of HBV infection (p=0.006), with a CD4+ lymphocytes count < 250/mm3 (p=0.03) and those with antiretroviral therapy (53 vs 28%, p=0.02). Necro-inflammation correlated with severity of fibrosis (p=0.002). In multivariate analysis, antiretroviral therapy  and the necro-inflammatory activity were significantly associated with fibrosis (p=0.04, RR=3.1 and 0.001, respectively). Eight patients (8.7%) died (5 F4, 2 F3 and one F1) during the follow-up, including 5 liver-related deaths ; yearly mortality was 1.7% and was significantly higher in cirrhotics (20% vs 5%, p=0.039) and in patients with with a CD4+< 250/mm3 (26.3 vs 4.5%, p=0.004). Mortality was reduced in patients under antiretroviral therapy including lamivudine (p=0.04). Standard Interferon efficacy (HBV DNA<700.000 copies/ml) was poor since only 10.5% of treated patients had sustained virosuppression (> 6 months) and only one (2.8%) had HBe/antiHBe seroconversion. Lamivudine, given to 51 patients, resulted in HBeAg loss in 44.8% and a primary control of HBV replication in 95% of patients ; 52.6% developped resistance after a mean of 23 months. Lamivudine therapy was associated with less severe liver lesions, reduction of fibrosis progression and a lower mortality.

 

Conclusion

Our study establishes that in HBV/HIV co-infection :1. cirrhosis is frequent (25%) and severe  (20% of deaths) ; 2. antiretroviral therapies (and CD4<250/mm3) enhance liver lesions; 3. lamivudine provides a benefit in reducing liver-related morbidity and mortality.

 

 

SUCCESSFUL THERAPY OF CHRONIC HEPATITIS B WITH TENOFOVIR IN HBV-MONOINFECTED AND IN HIV-COINFECTED PATIENTS FAILING PREVIOUS ADEFOVIR AND LAMIVUDINE TREATMENT

O. Schildgen1, U.C. Wend7, C.K. Schewe4, M. Vogel2, M. Daeumer3, R. Kaiser3, L. Weitner4, M. Helm5, H. Hartmann6, B. Matz1, J.K. Rockstroh2, W. Gerlich7  

1University of Bonn, Institute for Medical Microbiology and Immunology, Bonn, Germany  2University of Bonn, Medizinische Klinik und Poliklinik 1, Bonn, Germany  3University of Cologne, Institute for Virology, Cologne, Germany  4Praxis St. Georg, Hamburg, Germany  5Praxis Abelein & Helm, Nuernberg, Germany  6Innere Medizin, Hepatologie, Krankenhaus Duderstadt, Duderstadt, Germany  7University of Giessen, Institut fuer Medizinische Virologie, Giessen, Germany 

 

Introduction

Within the adefovir early access program (EAP) for treatment of chronic hepatitis B three HBV/HIV coinfected patients were observed which did not respond to adefovir therapy virologically within the first 6 months of treatment with respect to HBV load (Schildgen et al., AIDS, in press). Three additional HBV-monoinfected patients infected with lamivudine resistant HBV strains displayed no virologic reaction on adefovir; a therapy switch to tenofovir was succesful also in these patients. After changing the treatment to tenofovir all patients recieving tenofovir responded with a significant drop of viral load. 

 

Methods

HBV-DNA was isolated and the DNA-polymerase gene was amplified by PCR for sequencing. Sequencing was carried out using the BigDye terminator reaction (Applied Biosystems). Genotyping and lamivudine-resistance testing were carried out with the INNO-LiPA assay (Innogenetics) or by sequencing of PCR products (Schildgen et al., AIDS, in press). 

 

Results

Adefovir was useless in all six patients. Sequencing analysis of all HBV strains analysed from the six patients revealed no amino acid exchange at the aa position rt236 nor at position rt181, the positions described to mediate resistance to Adefovir. All 3 HIV infected patients were infected with HBV genotype A accompanied by identical lamivudine resistance pattern (rtL180M/rtYVDD) at baseline, but were epidemiologically not related. In case of the HIV infected patients we identified mutations in a nonconserved HBV polymerase-region (aa rt217) that might mediate Adefovir resistance. In contrast, the HBV monoinfected patients were infected with HBV genotype D, accompanied by the unusual pattern yw4, and displayed a unique mutation. 

 

Conclusion

Based on our data we draw the conclusions, that (a) the polymerase/reverse-transcriptase domain aa 215 to aa 236 might mediate adefovir resistance, (b) the combination of the lamivudine resistance plus HBV genotypes A or D predestinates resistance to Adefovir, and (c) a therapy change to tenofovir should be considered in the case of adefovir non-responders.  Literature: Schildgen O, Schewe CK, Vogel M, Däumer M, Kaiser R, Weitner L, Matz B and Rockstroh JK (2004): Successful therapy of hepatitis B with tenofovir in HIV-infected patients failing previous adefovir and lamivudine treatment; AIDS, in press

 

 

CHARACTERISTICS OF HEPATITIS B VIRUS (HBV) INFECTED PATIENTS IN FRANCE: A CROSS-SECTIONAL MULTICENTER STUDY OF 406 PATIENTS

D. Sène1, S. Pol2, L. Piroth3, C. Goujard4, P. Dellamonica5, J. Moussali1, D. Rey6, V. Loustaud-Ratti7, L. Alric8, F. Borsa-Lebas9, D. Séréni10, P. Cacoub1  

 

1CHU Pitié-Salpétrière, Paris, France  2CHU Necker, France, France  3CHU Dijon, Dijon, France  4CHU Kremlin-Bicêtre, Kremlin-Bicêtre, France  5CHU Nice, Nice, France  6Hop. Civils Strasbourg, Civils Strasbourg, France  7CHU Limoges, Limoges, France  8CHU Toulouse, Toulouse, France  9CHU Rouen, Rouen, France  10CHU St Louis, Paris, France

 

Objective

To appraise main epidemiological, clinical, virological, liver histological and therapeutic features of HBV-infected patients in France.

 

Methods

A questionnaire itemizing the epidemiological, virological, histological and therapeutic characteristics of HBV infection was sent to the French Departments of Internal Medicine, Infectious Diseases and Hepatogastroenterology. All patients chronically HBV-infected (AgHBs+) seen during a 4 week-interval (September-October, 2003) were candidate for inclusion.

 

Results

1-Epidemilogical features: 406 HBV-infected patients were included from 38 departments (76% males; mean age 41+/-12 years), native of Europe (49%) and Africa (35%), infected through sexual transmission (65%), intravenous drugs addiction (18%), vertical transmission (18%) and blood transfusion (6%). Clinical manifestations included: asthenia in 20% of patients, cirrhosis 12%, acute hepatitis 1.7%, hepatocarcinoma 0.2% and auto-immune disease 1.9%. A HIV-HBV co-infection was reported in 53% of patients, HCV-HBV in 12% and HDV-HBV in 10%. 2-Liver histological features: A liver biopsy was performed in 169 patients (42%), more frequently in patients without than those with HIV-HBV co-infection (51% versus 32%, p=0.0002). An extensive fibrosis (Metavir F3-F4) was found in 37% of patients and a cirrhosis (F4) in 22%. In multivariate analysis, the presence of clinical or histological cirrhosis (14.5%) was associated with the presence of co-infection with HCV (OR=8.5; p=0.03) and HDV (OR=5.2; p=0.003), but not HIV (OR=0.77). 3-Virological features: Serum HBV DNA was detectable in 58.5% of patients; HBeAg positive 39.7% and anti-HBe antibodies 59%. Among patients that did never receive anti-HBV treatment, a serological profile for a precore mutant infection (negative HBeAg, positive anti-HBe antibodies, positive HBV DNA) was highlighted in 32% and was found negatively associated with HIV-infection (OR=0.29; p=0.02). 4-Therapeutic features: 248 patients (61%) received anti-HBV therapy with 223 patients still under treatment at the time of the study, including lamivudine (79%), adefovir (26%), tenofovir (25%), pegylated interferon (5%) and standard interferon alpha (2%).

 

Conclusion

Main characteristics of HBV-infected patients in France are: male sex, native of European or African countries, one half with HIV-HBV co-infection and more than one third with extensive liver fibrosis. Even scarce, HBV-HCV and HBV-HDV co-infections were tightly associated with cirrhosis, justifying a systematic appraisal of viral co-infections among HBV-infected patients.

 

 

FREQUENCY OF HBEAG LOSS AND LONG-TERM ANTIVIRAL SUPPRESSION UNDER NUCLEOS(T)IDE TREATMENT IN HBEAG POSITIVE CHRONIC HEPATITIS B

F. van Bömmel1, S. Mauss2, T. Wünsche3, D. Schürmann3, B. Wiedenmann1, A. Bergk1, V. Weich1, T. Berg1  

1Medizinische Klinik Mit Schwerpunkt Hepatologie und Gastroenterologie, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany  2Zentrum für HIV Und Hepatogastroenterologie, Düsseldorf, Germany  3Medizinische Klinik M. S. Infektiologie Und Asthma-Poliklinik Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany 

 

Background

Tenofovir disoproxil fumarate and adefovir dipivoxil were shown to be effective in the therapy of lamivudine resistant chronic hepatitis B.

 

Aim

Aim of t \his study was to document the long-term effectiveness and safety of tenofovir in patients suffering from chronic lamivudine-resistant HBV-infection. Moreover, we compared the long-term effectiveness of tenofovir and adefovir to lamivudine by virological and immunological parameters.

 

Methods

182 HBV infected patients (m/f 112/26, mean age 47 years [18-93]) with chronic hepatitis B were treated either with tenofovir 245mg (n=38, 34 HBe-Ag positive, 24 HBV/HIV co-infected), adefovir 10mg (n=28, 24 HBe-Ag positive) or lamivudine 100mg (n=116, 58 HBe-Ag positive) for a mean duration of 26±7.5,19±4.4 and 26±13 months (range 12-39, 12-26 and 12-66 months) and retrospectively analyzed. All patients had HBV viremia > 20 x 105 copies/ml (HBV-Monitor, Roche) at baseline and elevated ALT. Patients treated with tenofovir and adefovir had phenotypic and genotypic resistance to lamivudine (INNO-LIPA HBV DR, Innogenetics, Belgium). Results: During treatment with tenofovir, adefovir and lamivudine, reduction of HBV DNA below limit of detection was found in 92%, 43% and 56% at month 12 and in 100%, 64% and 66% of the patients at month 24. HBV DNA suppression below 105copies/mL was found in 100%, 54% and 83% at month 12 and in 100%, 73% and 86% at month 24. HBe-Ag loss was found in 41%, 17% and 33% after a mean duration of treatment 12±5.6 [3-24], 13±3.6 [10-17] and 14±6 [2-38] months. HBs-Ag loss was found in 8%, 3.6% and 3% after a mean duration of treatment 15±8.5 [9-25], 17 and20±15[6-36] months. No significant side effects were noted in all three treatment groups and creatinine levels remained within normal ranges.

 

Conclusion

The results of this retrospective analysis demonstrate the high long-term efficacy and the high safety profile of tenofovir. In the treatment of chronic hepatitis B with nucleos(t)ide analogues, virological and immunological response are important conditions for long-term response and avoidance of drug resistance. Tenofovir exhibits a higher rate of HBe-Ag and HBs-Ag loss compared to adefovir and lamivudine making trials for tenofovir as first line therapy desirable.