422 Gut 1995; 36: 422-426 Adenine arabinoside 5'-monophosphate in patients with chronic hepatitis B: comparison of the efficacy in patients with high and low viral Gut: first published as 10.1136/gut.36.3.422 on 1 March 1995. Downloaded from replication P Marcellin, M Pouteau, M A Loriot, N Boyer, F Degos, P Cales, L Bettan, Y Bacq, H Coppere, J Didier Grange, P H Bernard, C Degott, S Erlinger, J-P Benhamou Abstract Differences in the populations studied could This study compared the response to account for these discrepancies. In a previous adenine arabinoside 5'-monophosphate study, we found that anti-HIV negative homo- (ARA AMP) in 60 patients with chronic sexuals with chronic hepatitis B seemed to Service d'Hepatologie hepatitis B according to the pretreatment respond as frequently as heterosexuals to ARA and INSERM U24, serum hepatitis B virus DNA concentra- AMP treatment.3 In the same study, we found H6pital Beaujon, tion. The level ofhepatitis B virus replica- retrospectively that a low level of hepatitis B Clichy, France P Marcellin tion was defined as low (30 patients) or virus replication, as reflected by low serum M Pouteau high (30 patients) when serum hepatitis B hepatitis B virus DNA concentrations, was a M A Loriot virus DNA concentration was below or factor for predicting response to ARA AMP. N Boyer F Degos above 100 pg/ml, respectively. Patients The aims of this study were to assess, in S Erlinger received a 28 day course ofARA AMP and patients with chronic hepatitis B: (a) the J-P Benhamou a second course of ARA AMP was given response to ARA AMP according to the pre- to with treatment serum Service d'Hepato- six months later patients persis- concentration of hepatitis B Gastroent6rologie, tent hepatitis B virus replication. At the virus DNA, (b) the kinetics of the antiviral Centre Hospitalier end of the first course of ARA AMP, 11 of effect of ARA AMP as assessed by a quantita- Regional, Angers, the patients with low replication tive method, and (c) the efficacy of a second France (37%) P Cales and one of the patients (3%) with high course of ARA AMP given six months after a replication became negative for hepatitis first ineffective course. Service d'Hepato- B virus DNA (p=0.0012); five of the http://gut.bmj.com/ Gastro-Ent6rologie, Centre Hospitalier patients (17%) with low replication and Interconumunal, none of the patients with high replication Methods Vilieneuve Saint had HBe seroconversion (p=0.06). Two of Georges, France L Bettan these five patients lost HBsAg. Kinetics of PATIENTS serum hepatitis B virus DNA during Sixty patients (aged 18-75) with chronic Service des Maladies treatment showed a considerable but hepatitis B were enrolled in this multicentre de l'Appareil Digestif, on September 29, 2021 by guest. Protected copyright. H6pital Trousseau, transient antiviral effect of ARA AMP. trial. Entry criteria were (a) presence ofHBsAg Tours, France Three of 32 retreated patients became in serum for more than one year; (b) presence Y Bacq negative for hepatitis B virus DNA and of HBeAg and absence of antiHBe antibodies; one In Service de patient had HBe seroconversion. (c) increased activities of serum alanine amino- Gastroent6rologie et conclusion, ARA AMP exerts a consider- transferase (ALT) with stable values assessed d'Hepatologie, Centre able but transient antiviral effect on three times within the six months before inclu- Hospitalier Regional hepatitis B virus. Complete and sustained sion (less than 50% change); (d) presence of and Universitaire, Saint Etienne, France inhibition of hepatitis B virus replication serum hepatitis B virus DNA with stable values H Coppere was only obtained in the patients with low assessed three times within the six months hepatitis B virus replication. before inclusion (less than 50% change); (e) Service d'Hepato- Gastro-Enterologie, (Gut 1995; 36: 422-426) absence of antibodies against hepatitis D virus H6pital Tenon, France and HIV; (f) no antiviral treatment in the year J Didier Grange Keywords: hepatitis B virus, purine nucleoside. before entry; (g) absence of any signs of Service des Maladies symptoms of neuropathy (diabetes or chronic de l'Appareil Digestif, alcoholism); (h) histologically confirmed HBpital Saint Andr6, Adenine arabinoside is a synthetic purine chronic active hepatitis. The criteria for exclu- Bordeaux, France P H Bernard nucleoside that has antiviral activity against sion included (a) a course of antiviral or hepatitis B virus. Adenine arabinoside 5'- immunosuppressive treatment with the pre- Service d'Anatomie monophosphate (ARA AMP), the monophos- vious six months or a previous course of inter- and Cytologie ester ofadenine arabinoside, is 400 times of cirrhosis Pathologiques, HBpital phate feron; (b) history decompensated Beaujon, Clichy, more water soluble and is therefore suitable for (ascites, bleeding oesophageal varices, or France intramuscular administration. In three con- hepatic encephalopathy); (c) a platelet count of C Degott trolled trials from Europe, ARA AMP adminis- less than 50 X 109/1, a serum creatinine concen- Correspondence to: tration was followed by sustained interruption tration of more than 150 ,umol/l; (d) patients Dr P Marcellin, Service of B virus in 40 to 550/o of who were unreliable for longterm follow up. d'Hepatologie, H6pital hepatitis replication Beaujon, 100 Bd du General patients.'-3ARA AMP administration did not, Thirty patients with low hepatitis B virus Leclerc, 92118 Clichy however, have a lasting effect on hepatitis B replication and 30 patients with high hepatitis Cedex, France. virus replication in patients of three other B virus replication who fulfilled the criteria Accepted for publication 15 July 1994 controlled trials from the United States.-6 were included in this study. The level of Adenine arabinoside 5 '-monophosphate in patients with chronic hepatitis B 423 TABLE I Clinical and biochemical characteristics ofthe 60 patients with chronic hepatitis ARA AMP administration, and every two B before ARA AMP administration months throughout follow up. Patients Thirty of 60 patients were randomly chosen (15 in each group), and serum hepatitis B virus High HBV replication Low HBV replication Gut: first published as 10.1136/gut.36.3.422 on 1 March 1995. Downloaded from (HBV DNA >100 pg/ml) (HBVDNA s I00 pg/ml) DNA concentrations were retrospectively measured by liquid hybridisation assay Patients (n) 30 30 Age (y) 39 (12) 47 (18) (Genostics, Abbott Laboratories) on frozen Males (O/o) 77 70 serum aliquots collected every week during Homo/heterosexual (n) 12/11 7/14 Weight (kg) 66 (13) 68 (12) and one month after the first course of ARA Known duration of HBV infection AMP. (month) 36 (41) 56 (47) Serum values* The response to ARA AMP was analysed at Alanine aminotransferase (IU/l) 159 (109) 202 (176) the end of treatment and during the six month Albumin (g/l) 47 (4) 45 (7) Prothrombin (% of normal) 85 (10) 79 (13) post-treatment follow up. A response was Serum HBV DNA (pg/ml) 227 (182) 42 (26) defined as negativation of serum hepatitis B Patients with cirrhosis (%) 7 17 virus DNA concentrations; a complete *The normal reference range for alanine aminotransferase is 0 to 40 U per litre; for albumin, 35 response as negativation of serum hepatitis B to 50 g per litre. Data shown as mean (SD). HBV=hepatitis B virus. virus DNA concentrations with HBeAg to antiHBe seroconversion. hepatitis B virus replication was arbitrarily defined as high when the mean pretreatment hepatitis B virus DNA concentration was STATISTICAL ANALYSIS above 100 pg/ml or as low when the mean Values are expressed as mean (SD). hepatitis B virus DNA concentration was less Proportions were compared using Fisher's than or equal to 100 pg/ml. The mean hepati- exact test or the x2 test. Means were compared tis B virus DNA concentration was calculated using Student's test or variance analysis (with based on three values determined before the Scheffe's F test and Dunnett's t test). start of ARA AMP administration. More patients with high concentrations than patients with low concentrations of serum hepatitis B Results virus DNA were seen; therefore, inclusions in Nineteen of 60 patients (32%) included in our the first group were stopped while inclusions in study were homosexuals. Before ARA AMP the second group necessitated a more pro- administration, 10 patients (17%) had serum longed time. hepatitis B virus DNA concentrations higher This study was approved by the ethics com- than 200 pg/ml; 26 patients (43%) had serum mittee of the Faculte de Medecine Xavier ALT activities below three times the upper http://gut.bmj.com/ Bichat. Informed consent was obtained from limit of normal and seven patients (12%) had all patients. cirrhosis. There were no significant differences between low and high replication groups for TREATMENT age, weight, sex ratio, proportion of homosex- All patients received a 28 day course of ARA uals, known duration of hepatitis B virus infec- AMP (Parke Davis, Courbevoie, France) by tion, serum ALT activities, serum albumin, on September 29, 2021 by guest. Protected copyright. intramuscular injection at 12 hourly intervals plasma prothrombin, and presence of cirrhosis at a dose of 10 mg/kg/day for the first five days (Table I). Mean serum hepatitis B virus DNA and then 5 mg/kg/day for the remaining 23 concentrations were 42 (26) pg/ml and 227 days. A second course of ARA AMP with the (182) pg/ml in patients with low and high repli- same schedule, was given six months after the cation, respectively. During the study, one first course to patients who did not respond or patient dropped out seven days after the start experienced side effects and who accepted a of ARA AMP and treatment was withdrawn second course.