Monophosphate in Patients with Chronic Hepatitis B

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. Patients were seen weekly in nine patients because of side effects (eight during treatment, then every other month for for myalgia and one for vomiting). These the duration of the 12 month follow up. 10 patients (five in the high replication group and five in the low replication group) were considered non-responders. STUDY DESIGN Serum ALT activities, HBeAg, and antiHBe antibodies (RIA, Abbott Laboratories, N EFFECT ON HEPATITIS B VIRUS REPLICATION Chicago, USA) were assessed before and at the Serum hepatitis B virus DNA became end (28 days) of ARA AMP administration, undetectable during ARA AMP administration then every month for six months. Serum in 11 of 30 patients (37%) with low replication HBsAg and antiHBs were assessed before and and in one of 30 patients (30/o) with high every two months after ARA AMP administra- replication (p=0O00 12) (Table II). Serum tion. In patients who received a second course hepatitis B virus DNA concentrations of ARA AMP, additional measurements were remained undetectable during the six month performed at the end of the second course of post-treatment follow up in seven of 11 ARA AMP administration and then every patients with low replication and remained month for six months. Serum hepatitis B virus detectable in all the patients with high replica- DNA concentrations were measured using a tion. The seven patients who became negative liquid hybridisation assay (Genostics, Abbott for hepatitis B virus DNA, had the lowest Laboratories, France)7 before, at the end of pretreatment serum hepatitis B virus DNA 424 Marcellin, Pouteau, Loriot, Boyer, Degos, Cales, Bettan, Bacq, Coppere, Grange, Bernard, Degont, Erlinger, Benhamou

TABLE II Negativation ofserum HBV DNA, HBe seroconversion, and HBs low replication and in patients with high repli- seroconversion in patients with chronic hepatitis B after ARA AMP administration cation (Fig 3). Negativation ofserum HBV DNA Seroconversion

At the end of During 6 month HBeAg to HBsAg to Gut: first published as 10.1136/gut.36.3.422 on 1 March 1995. Downloaded from Patients ARA AMP offollow up* antiHBe antiHBs SIDE EFFECTS OF ARA AMP Mild side effects were seen in patients during Low HBV replication (n=30) 11 (37%)t 7 (23%)/t 5 (17%)§ 2 (7%) High HBV replication (n=30) 1 (30/o)t Ot 0§ 0 ARA AMP administration: myalgia occurred in 20 patients during the fourth week of treat- *With three normal values. tp=0.0012; *p=0015; §p=0-06. ment, vomiting occurred in six patients at the start of treatment, nausea in two patients, concentrations (below 50 pgfml). Among these fatigue in 18 patients, diarrhoea in one patient, seven patients, five had HBeAg to antiHBe and abdominal pain in four patients; however, seroconversion three or four months after treatment was completed in all these patients. treatment. In two of them, HBsAg to antiHBs Moderate side effects (vomiting) occurred in seroconversion occurred two months later (Fig two patients requiring a half dose of ARA 1). No HBe seroconversion occurred in the 30 AMP. Severe side effects affected 10 patients: patients with high replication. myalgia occurred in eight patients and required ARA AMP withdrawal 16 to 25 days after the start of treatment; vomiting in one patient EVOLUTION OF SERUM ALT required ARA AMP withdrawal. In an obese There was no significant change of mean female patient, severe peripheral neuropathy serum ALT activities in the 60 treated patients was diagnosed at the end of treatment and was during ARA AMP administration. Moderate attributed to an over estimation of ARA AMP increase of serum ALT activities was seen in dose because of overweight. two of 60 patients during treatment (from 255 IU/1 to 466 IU/1 and 145 IU/1 to 309 IU/1, respectively). These two patients had HBeAg EFFECT OF A SECOND COURSE OF ARA AMP to antiHBe seroconversion and one of them Among the 32 patients who received a second lost HBsAg (Fig 1). course of ARA AMP, serum hepatitis B virus Pretreatment serum ALT activities were DNA became negative in three patients. All higher in the five patients with HBeAg to three patients had serum hepatitis B virus antiHBe seroconversion after ARA AMP DNA concentrations below 50 pg/ml before administration than in the other patients (321 the second course of ARA AMP. HBeAg to (234) IU/ml v 173 (124) IU/ml, p<0O05). antiHBe seroconversion occurred in one of

them. These three patients had low serum http://gut.bmj.com/ hepatitis B virus DNA concentrations before KINETICS STUDY the first course (19 to 55 pg/ml) and the first The kinetics study of serum hepatitis B virus course resulted in a sustained lowering of DNA was performed in 30 patients, and hepatitis B virus DNA in one of three cases. showed a significant decrease during ARA The second course of ARA AMP was well AMP administration (Fig 2). The decrease in tolerated in all patients.

serum hepatitis B virus DNA was maximal on September 29, 2021 by guest. Protected copyright. three weeks after the initiation of ARA AMP, th en serum hepatitis B virus DNA concentra- Discussion tio5ns increased again. The kinetics and the In the patients with chronic hepatitis B in this m2agnitude of the decrease in serum hepatitis B study, a complete response to ARA AMP vir-us DNA was not different in patients with administration was only seen in the group of patients with low hepatitis B virus replication. 400 40 Indeed, all five responders had very low pre- ALT treatment serum hepatitis B virus DNA con-

320 E centrations (below 50 pg/ml). This result 30 shows that a complete antiviral effect of ARA \ AMP is only achieved in patients with a com- 240w z paratively low baseline level ofhepatitis B virus -J 20 D replication. Moreover, the five responders had E 160 \ higher pretreatment serum ALT activities than I non-responders thus showing that an active 10 E immune response is also necessary to obtain a 80 \ complete and sustained response. HBV DrMJA The low rate of HBeAg to antiHBe serocon- 0 version seen in this study (8%/o) does not -60 -30 0 0 120 150 180 210 240 270 300 330 360 support the results of other studies, in particu- Time (d) lar our previous studyl-3 but is in agreement with three other studies.±6 This low rate of

HBeAg + + + + + - - - - - sustained response may be related to a differ- Anti HBe - - - + + + + + + + + ent patient selection in this study compared HBsAg + + + - - with our previous study. An increased number Anti HBs - -- + + + of patients in whom HBsAg was detected by Figure 1: Time course of serum ALIT and serum hepatitis B virus DNA before, during, and systematic screening, were referred for antiviral after ARA AMP in a patient with chronic hepatitis B who had HBs seroconversion. treatment. Such patients will probably have Adenine arabinoside S'-monophosphate in patients with chronic hepatitis B 425

The low rate of response in our study is not ARAAMP different from the spontaneous rate of HBeAg seroconversion seen in control groups in previous studies46 showing the small sustained

< 25 effect of ARA AMP administration in chronic Gut: first published as 10.1136/gut.36.3.422 on 1 March 1995. Downloaded from 0 hepatitis B. The higher rate of response in m patients with a low initial hepatitis B virus E DNA value can be matched with a higher > 50 spontaneous rate of clearance of hepatitis B 0 virus DNA in patients with low initial hepatitis n0 B virus DNA values. The assumption, however, that the 8% HBe seroconversion rate seen , 75 o HBV a) High replication in this study might be spontaneous and not 0 * Low HBV replication related to ARA AMP administration is unlikely as (a) all patients included had stable values of 100 l serum hepatitis B virus DNA and ALT within 0 7 14 21 28 35 42 49 56 63 the pretreatment period and (b) hepatitis B Time (d) virus DNA disappearance and HBeAg to Figure 2: Percenjrtage ofdecrease ofserum hepatitis B virus DNA in patients with chronic antiHBe seroconversion were chronologically hepatitis B accor'ding to pretreatment level ofhepatitis B virus replication during and one clearly related to ARA AMP administration. month after ARi4l AMP admintstration. It is important to note that HBsAg to antiHBs seroconversion occurred in two higher hepatitis B virus DNA concentrations patients in this study (3.3%/o). In these two and lower serum ALT activities than patients patients, complete inhibition of hepatitis B previously referred to our centre. Indeed, in virus replication was confirmed by disappear- our previous study, we found that patients with ance of serum hepatitis B virus DNA, as high hepatitis B virus DNA concentrations and assessed by polymerase chain reaction.'0 This low serum ALT activity had a lower rate of result is not different from the 3-7% rate of response than other patients.3 In a recent trial HBsAg to antiHBs seroconversion seen in with recombinant alpha interferon performed some alpha interferon studies." 12 This result after this ARA AMP trial, we also saw a is lower, however, than that reported by comparatively low rate of HBeAg to antiHBe Alexander et al 13 who showed the disappear- seroconversion (23%) (unpublished data). ance of HBsAg in 22% and the appearance of Although this study showed a lower rate of HBs antibody in 13% of patients. This result

complete response with ARA AMP treatment shows that ARA AMP, like alpha interferon, http://gut.bmj.com/ than is usually seen with alpha interferon, ARA may result in a complete inhibition of hepatitis AMP should be considered in the treatment of B virus replication. chronic hepatitis B in patients who do not No significant increase of serum ALT activ- respond to, who develop side effects to, or who ity was seen in most patients during or after have contraindications to, alpha interferon. In ARA AMP administration. A mild increase of particular, ARA AMP might be useful in the serum ALT was seen in two of five responders

treatment of patients who have had a liver or but no appreciable increase of serum ALT was on September 29, 2021 by guest. Protected copyright. kidney transplant in whom alpha interferon seen in any patient with HBe seroconversion as might increase the risk of rejection.8 9 usually seen in patients responding to alpha The kinetics and the relative magnitude of interferon. This finding illustrates that ARA the decrease of serum hepatitis B virus DNA AMP acts in chronic hepatitis B by an exclu- was similar in patients with low and high repli- sive antiviral effect and that, in contrast with cation (Fig 3). A sustained effect, however, alpha interferon, an increase of hepatocytic was only obtained in patients with a low necrosis is rarely seen. pretreatment value of serum hepatitis B virus The kinetics of serum hepatitis B virus DNA DNA concentration (in whom a more com- in our patients with chronic hepatitis B plete viral inhibition was probably reached). confirms an inhibition of hepatitis B virus replication, which is rapid and considerable but usually transient. The maximal decrease of 0 240 serum hepatitis B virus DNA concentrations

c 20020 0 High HBV replication AMP, followed by an increase in these concen- F Low HBV warsentrelwescftrthtsatofnR 160 replicatiotrations during the last week oftreatment. This c. 1 finding suggests that the fourth week of ARA Z m) 120 AMP administration does not improve the D Q \ ,~~~~~~:1antiviral effect. In addition, neurotoxicity m 80 associated with ARA AMP administration is E 40 _ the4

of ARA AMP administration as previously 4 Hoofnagle JH, Hanson RG, Minuk GY, Pappas SC, Scafer DF, Dusheiko GM, et al. Randomized controlled trial of described.'6 As neurotoxicity depends on the adenine arabinoside monophosphate for chronic type B length of the treatment'4 and as the fourth hepatitis. Gastroenterology 1984; 86: 150-7. 5 Perrillo RP, Regenstein FG, Bodicky CJ, Campbell CR, week of treatment does not improve the anti- Sanders GE, Sunwoo YC. Comparative efficacy of should be adenine arabinoside 5' monophosphate and prednisone Gut: first published as 10.1136/gut.36.3.422 on 1 March 1995. Downloaded from viral effect, a three week course withdrawal followed by adenine arabinoside 5' considered. monophosphate in the treatment of chronic active hepati- A second course ofARA AMP induced sero- tis type B. Gastroenterology 1985; 88: 780-6. 6 Garcia G, Smith CI, Weissberg JI, Eisenberg M, Bissett J, conversion from HBeAg to antiHBe in only Naik PV, et al. Adenine arabinoside monophosphate one of the 32 retreated patients. This result is (vidarabine phosphate) in combination with human leu- cocyte interferon in the treatment of chronic hepatitis B. not in agreement with the 67% rate of HBe Ann Intern Med 1987; 107: 278-85. seroconversion seen in another study.'6 This 7 Kuhns MC, McNamara AL, Cabal CM, Decker RH, Thiers V, Brechot C, et al. A new assay for the quantitative discrepancy might be related to the level of detection of hepatitis B viral DNA in human serum. In: hepatitis B virus replication before treatment, Zuckerman AJ, ed. Viral hepatitis and liver disease. New York: Alan R Liss, 1988: 258-62. which might have been lower in the patients in 8 Marcellin P, Samuel D, Loriot MA, Areias J, Bismuth H, the study by Trepo et al. Indeed, the only Benhamou JP. Antiviral effect of adenine arabinoside monophosphate (ARA-AMP) in patients with recurrence responder to a second course of ARA AMP of hepatitis B virus (HBV) infection after liver transplan- had a sustained lowering of hepatitis B virus tation. Hepatology 1990; 12: 966. 9 Pol S, Saltiel C, Legendre C, Carnot F, Driss F, Berthelot DNA after the first course and had a low serum P, et al. Efficacy of adenine 5'-monophosphate in treating hepatitis B virus DNA concentration (below chronic active hepatitis B of kidney transplant recipients [Abstract]. J Hepatol 1992; 16 (suppl 1): S21. 50 pgfml) before the second course of ARA 10 Loriot MA, Marcellin P, Bismuth E, Martinot Peignoux M, AMP. Our results show that a second course Boyer N, et al. Demonstration ofhepatitis B virus DNA by polymerase chain reaction in the serum and the liver after does not seem to improve the rate of response spontaneous or therapeutically induced HBe Ag to to ARA AMP. anti-HBe of HBsAg to anti-HBs seroconversion in patients with chronic hepatitis B. Hepatology 1992; 15: In conclusion, ARA AMP induces a con- 32-6. siderable but transient antiviral effect on 11 Hoofnagle JH, Peters M, Mullen KD, Jones DB, Rustgi V, Di Bisceglie AM, et al. Randomized controlled trial of hepatitis B virus. A complete and sustained recombinant human alpha interferon in patients with inhibition of hepatitis B virus replication with chronic hepatitis B. Gastroenterology 1988; 95: 1318-25. 12 Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, this substance is rare, and only obtained in Lindsay K, Payne J, et al. A randomized controlled trial of patients with low hepatitis B virus replication. interferon alpha 2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med We thank Dr Christian Ruet and Parke Davis, France for their 1990; 5: 295-301. support. 13 Alexander GJM, Brahm J, Fagan EA, Smith HM, Daniels HM, Eddleston ALWF, et al. Loss of HBsAg with interferon therapy in chronic hepatitis B virus infection. Lancet 1 Weller IVD, Lok ASK, Mindel A, Karyiannis P, Galpin S, 1987; ii: 66-9. Monjardino J, et al. Randomized controlled trial of 14 Lok ASF, Novick DM, Karyiannis P, Dunk AA, Sherlock S, adenine arabinoside 5-monophosphate (ARA-AMP) in Thomas HC. A randomized study ofthe effects ofadenine chronic hepatitis B virus infection. Gut 1985; 26: 745-51. arabinodise 5-monophosphate (short or long courses) 2 Ouzan D, Chevalier M, Laffranchi B, Bordon F, and lymphoblastoid interferon on hepatitis B virus repli- http://gut.bmj.com/ Chossegros P, Hantz 0, et al. Therapeutic efficacy of cation. Hepatology 1985; 5: 1132-8. ARA-AMP in symptomatic HBeAg positif CAH: a ran- 15 Calmus Y, Poupon R, Marcellin P, Rambaud S, Roullet E, domized placebo control study in heterosexuels Bernuau J, et al. Vidarabine (adenine arabinoside) [Abstract]. Hepatology 1986; 6: 1151. encephalopathy. Two cases reports and review of the liter- 3 Marcellin P, Ouzan D, Degos F, Brechot C, Metman EE, ature. EurJ_ Intern Med 1992; 3: 62-7. Degott C, et al. Randomized controlled trial of adenine 16 Trepo C, Ouzan D, Fontanges T, Chevallier M, Chossegros arabinoside 5-monophosphate in chronic active hepatitis P, Degos F, et al. Therapeutic activity of vidarabine in B: comparison of efficacy in heterosexual and homosexual symptomatic chronic active hepatitis related to HBV. patients. Hepatology 1989; 3: 328-31. JrHepatol 1986; 3 (suppl 2): S97-105. on September 29, 2021 by guest. Protected copyright.