Randomized controlled trial of adenine arabinoside monophosphate for chronic type B hepatitis

GASTROENTEROLOGY

1984;86:150-7

Randomized Controlled Trial of Adenine Arabinoside Monophosphate for Chronic Type B Hepatitis JAY H. HOOFNAGLE, REGINALD G. HANSON, GERALD Y. MINUK, S. CHRIS PAPPAS, DANIEL F. SCHAFER, GEOFFREY M. DUSHEIKO, STEPHEN E. STRAUS, HANS POPPER, and E. ANTHONY JONES Liver Diseases Digestive and and Infectious Laboratory for York

Section, Digestive Diseases Kidney Diseases; Laboratory Diseases, National Institutes the Study of Liver Diseases,

Branch, National Institute of Arthritis. Diabetes. and of Clinical Investigation, National Institute of Allergy of Health, Bethesda, Maryland; and Stratton Mount Sinai School of Medicine, New York, New

Twenty patients with chronic type B hepatitis were entered into a randomized, controlled study of adenine arabinoside monophosphate. Before entry, all patients were documented to have stable levels of hepatitis B surface antigen, hepatitis B e antigen, serum hepatitis B virus deoxyribonucleic acid, and deoxyribonucleic acid polymerase activity. Ten patients received adenine arabinoside monophosphate and 10 received no treatment. The two groups were well matched with respect to age, sex, known duration of hepatitis B surface antigen, presence of symptoms, serum aminotransferase levels, and hepatic histopathology. During the 4 wk of therapy, serum levels of hepatitis B virus fell dramatically. However, serum hepatitis B virus-deoxynbonucleic acid or deoxyribonucleic acid polymerase activity, or both, remained detectable, and levels of hepatitis B virus invariably rose once therapy was stopped. From 2 to 9 mo after therapy, 4 of the 10 treated patients became hepatitis B e antigen or hepatitis B virus-deoxyribonucleic acid and deoxyribonucleic acid polymerase negative, or both, and the results of

Received March 22, 1983. Accepted August 2, 1983. Address requests for reprints to: Jay H. Hoofnagle, M.D., Liver Unit, Building 10, Room 4D-52, National Institutes of Health, Bethesda, Maryland 20205. The authors thank the 9-D Nursing Staff of the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases for their help in training and monitoring patients on parenteral therapy; Drs. Paul Chang, Richard Di Gioia, Stephen Goldberg, Malcolm Henoch. Milton Koch, Henry Lesesne, Sandy Richman, Enrico Robles, Eugene Schiff, Ian Shenk, and Nelson Trujillo for referral of patients; Mrs. Jeanne Waggoner for technical assistance; and Mrs. Phyllis Kline for preparation of the manuscript. 0 1984 by the American Gastroenterological Association 0016-5085/84/$3.00

routine serum biochemical tests improved. However, 2 of these 4 patients later relapsed. In the control group, 2 patients became seronegative for hepatitis B virus-deoxyribonucleic acid and deoxyribonucleic acid polymerase and manifested improvement in serum biochemical results by 18-24 mo after randomization. Thus, long-term improvements in clinical and serologic features of disease occurred in 20% and control patients. Side effects of of both treated adenine arabinoside monophosphate therapy were common, and 3 patients developed a severe and prolonged neuropathic pain syndrome. These results suggest that a 4-wk course of adenine arabinoside monophosphate therapy does not induce an increased rate of long-term remissions in chronic type B hepatitis. There is at present no satisfactory therapy for chronic type B hepatitis (1). Several recent reports have suggested that the antiviral agent adenine arabinoside (Ara-A:vidarabine) and its analogue adenine arabinoside 5’ monophosphate (Ara-AMP:vidarabine monophosphate) may be effective in this disease (Z-6). These studies used relatively short courses of therapy (1-2 wk) and reported favorable, long-term responses in 16%-43% of patients. More recently, a higher rate of response was reported after a 4-wk course of therapy (7). Most earlier studies of Ara-AMP have lacked concurrently followed, randomized control patients. Because spontaneous remissions in chronic type B hepatitis patients may occur, the lack of untreated control patients makes interpretation of these therapeutic trials of Ara-A and Ara-AMP difficult. This paper reports a randomized controlled trial of a 4-wk course of Ara-AMP in

JdIluar\

TKIAI, OF Am-AMP

1984

20 patients with well-documented chronic type B hepatitis. Follow-up of the patients for 18-24 mo has failed to demonstrate a beneficial effect of therapy on the natural history of this disease.

Materials

and Methods

Patients Criteria for entry into this study were that patients were adults (21-65 yr old) with chronic type B hepatitis, as documented by the presence of hepatitis B surface antigen (HBsAg) and elevated aminotransferase levels in serum for at least 1 yr. Before entry, patients attended the outpatient clinic monthly for at least 3 mo to provide blood specimens for determinations of routine serum biochemical tests and hepatitis B virus (HBV) markers. Only those patients with compensated chronic liver disC2.5 mg/dl; serum albumin >3.0 pi ease [serum bilirubin (11: prothrombin time ~3 s prolonged) and stable, elevated levels of serum hepatitis B e antigen (HBeAg), hepatitis B virus-deoxyribonucleic acid (DNA), and DNA polymerase were candidates for this trial.

Protocol Patients consenting to this study were admitted to the hospital for a thorough medical evaluation and percutaneous liver biopsy. They were then randomized into either treatment or control groups. To ensure that the two groups were balanced, patients were stratified before randomization into two groups: (a] those with serum aminotransferase levels >lO times the upper limit of the normal range during the 3-mo prerandomization period, and (b) those with serum aminotransferase levels 2-10 times the upper limit of the normal range. Randomization was performed using a table of random numbers. Four additional patients with aminotransferase levels 2-10 times the upper limit of the normal range, who had received AraAMP in the past. were randomized together (2 into the treatment and 2 into the control group). Randomization was carried out within 1 wk of liver biopsy in all except 2 patients (both of whom were in the treatment group) who were randomized 6 wk and 10 wk after liver biopsy. Patients in the treatment group received a 28-day course of parenteral Ara-AMP (vidarabine monophosphate, Warner Lambert Company, Ann Arbor, Mich.). The drug was given intravenously at a dosage of 10 mgikg . day for the first 3 days and then intramuscularly at a dosage of 5 mg/kg da!, for the remaining 23 days. Patients were instructed by the nursing staff how to administer intramuscular injections to themselves. This enabled the majority of patients to be discharged after 1 wk of hospitalization and to self-administer the injections at home. During treatment, patients were seen and examined daily while in hospital and twice a week as outpatients. Patients were seen 1 \vk after therapy and then every 4-6 wk for the duration of follow-up. Patients in the nontreatment group tvere discharged from the hospital after the percutaneous liver biopsy and were seen in the outpatient clinic every 4-6 xveeks. Twelve months after randomization, all pa-

FOK CHRONIC TYPE B HEPATITIS

151

tients were readmitted for a repeat evaluation and percutaneous liver biopsy. All details of this protocol were approved by the Human Experimentation Committee of the National Institutes of Health, and written informed consent was obtained from all patients.

Methods Blood samples were obtained at least twice week11 during therapy, and every 4-6 wk thereafter. Each blood sample was tested for complete blood count, routine serum biochemical tests (SMAC. Technicon Instruments Corporation, Tarrytown, N.Y.), and HBV markers. Serum biochemical tests included serum bilirubin, albumin, globulin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Hepatitis B virus markers included HBsAg and antibody (anti-HBs). HBeAg and antibody (anti-HBe), serum DNA polymerase activity, and HB6’DNA. Hepatitis B surface antigen and anti-HBs were assayed by solid-phase radioimmunoassays (Ausria-II and Ausab, Abbott Laboratories, North Chicago, Ill.). Hepatitis Be antigen and anti-HBe were tested by immunodiffusion and radiommunoassay (HBeAg test, Abbott Laboratories). Hepatitis B virus-associated DNA polymerase activity was assayed by determining [“Hlthymidine incorporation, and results were expressed as counts per minute (cpm) per 0.2 ml of serum (negative, cl00 cpm) (8). Hepatitis B virusdeoxyribonucleic acid was assayed by molecular hybritlization using ““P-labeled. cloned HB\‘-DNA (Bethesda Research Laboratories, Bethesda, Md.). Results of HBVDNA testing were graded as 0 to 5+ based upon a visual reading of the 24-h autoradiographic spot obtained (6.9). Selected samples were also tested for HBsAg subtypes by immunodiffusion and radioimmunoassay (IO), for HBsAg titer by end point dilutions, for antibody to hepatitis A virus by radioimmunoassay (HaLrat), Abbott Laboratories). and for antibody to the HBV-associated &agent by radioimmunoassay (courtesy of Dr. John Gerin) 111). The histopathology of paired liver biopsy specimens was interpreted by a single observer (H.P.) who was unaware of whether therapy was given or of the sequence with which the biopsy specimens were obtained. Biopsy specimens were read for presence and degree of lobular necrosis and periportal necrosis. and for presence and degree of fibrosis. The two biopsy specimens were then compared and ranked as either no change, probable (1-1 or definite (2+ or 3+) improvements. or deterioration. Statistical analyses included comparison of group means by the Student’s t-test, and comparison of groups bl the rank-sum test and the x’ test using the Yates’ correction (12).

Results Comparability Groups

of Treatment

and

Control

Twenty patients were entered into this trial. Ten were randomized into the treatment group and 10 into the control group. The two groups were well matched with respect to age and sex of patients, presence of symptoms, and known duration of

152

Table

HOOFNAGLE ET AL.

I.

Pretreatment Groups

Characteristics

33 (22-39)

Age WI” Sex (% males)

90%

Symptoms (96 nlith) duration

80%

of HBsAg

(yr)” Previous therapy (No. of patients) Corticosteroids Ara-AMP Randomization strata (No. of patients) Severe Mild to moderate

DNA

polymerase

3.2 (l-9)

2 2

(cpm)l’

(O-5 +)I’

Control (n = 10) 33(23-47) 90% 80% 3.2 (1.5-91

2 2

2 8 303 + 228

ALT (IU/L]” AST (IL’IL]” Bilirubin (mgldf)” Albumin (gldl)” HBV-DNA

of the Study

Ara-AMP (n = 10)

Characteristics

Known

GASTROENTEROLOGY

118 t 89 0.8 -+ 0.4 4.0 +- 0.2 2654 + 2408 3.7 2 1.3

9

184 k 84 + 0.7 ? 4.2 k 2318 + 3.2 r

108 44 0.4 0.3 1490 1.4

‘I Mean (range). ’ Mean (+ standard deviation). Ara-AMP = adenine arabinoside monophosphatase. HBsAg = hepatitis B surface antigen. ALT = alanine aminotransferase. AST = asparate aminotransferase. DNA = deoxyribonucleic acid. HBV-DNA = hepatitis B virus-deoxyribonucleic acid.

chronic hepatitis (Table 1). Four patients (2 treated and 2 controls) had received corticosteroid therapy during the preceding 3 yr. Corticosteroids had been discontinued 3-8 mo before randomization, and no patient received corticosteroid or other immunosuppressive therapy during the course of this trial or subsequent follow-up. Four other patients (2 treated and 2 controls) had received a IO-day course of AraAMP in the past. This had been given 7-12 mo previously and had not been associated with a longlasting beneficial response (6). The initial mean aminotransferase levels were higher in the treated than in the untreated group, but this difference was not statistically significant (0.05 < p < 0.10). Other serum biochemical test results, levels of HBV-DNA and DNA polymerase, and liver histologic features were similar in the two groups. In the 10 treated patients, the probable source of HBV exposure was homosexual contact in 7, medical exposure in 1, and was unknown in the remaining 2. In the control patients, the probable source of HBV infection was homosexual contact in 6, drug addiction in 1, and was unknown in 3 patients. Short-term

Effects

of Therapy

During Ara-AMP therapy, serum levels of HBV fell markedly. Deoxyribonucleic acid polymerase activity decreased by >90% in all treated pa-

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tients and became undetectable in 5 [Figure 1). However, only 3 of the 10 patients remained seronegative for DNA polymerase for the duration of treatment. Furthermore, serum levels of DNA polymerase increased once therapy was discontinued in all except 1 patient. The partial and temporary nature of the inhibitory effects of Ara-AMP treatment were more strikingly demonstrated by results of HBV-DNA testing [Figure 2). Hepatitis B virus-deoxyribonucleic acid decreased several-fold, but remained detectable in all except 1 patient, and levels of HBV-DNA increased in every patient once AraAMP was stopped. Thus, Ara-AMP therapy did not lead to complete or permanent inhibition of serum HBV in any patient, and levels of virus invariably increased once therapy was stopped.

One-Year

Follow-up

All patients have been followed for at least 1.5 mo, mean 21 yr after randomization (range 18-24 mo). During follow-up, HBV-DNA and DNA polymerase became negative in 4 of the 10 treated patients. The disappearance of serum HBV occurred 2, 4, 5, and 9 mo after completion of therapy. Levels of HBeAg decreased and became negative in these 4 patients, and 3 patients seroconverted to anti-HBe by the time of the l-yr follow-up liver biopsy. All remained HBsAg-positive. Serum aminotransferase levels, which had not changed appreciably during therapy, decreased markedly in the 4 patients who became HBV-DNA-negative, falling to within twice the upper limit of the normal range in all 4 and to within the normal range in 2 (Figure 3). In 2 patients, the loss of HBeAg was preceeded by an abrupt increase in serum aminotransferase levels [peak ALT levels were 519 and 1194 U/L). In the control group, serum levels of HBV-DNA and DNA polymerase were unchanged in most patients, but fell to negative in 1 [Figure 4). This patient also became HBeAg-negative and seroconverted to anti-HBe. Serum aminotransferase levels decreased to within twice the upper limit of the normal range. Another control patient became HBV-DNA-negative and DNA polymerase-negative transiently during the first year of follow-up evaluation. Serum HBeAg remained positive. Thus, at the l-yr point, 4 treated patients and 1 untreated patient were HBV-DNAnegative and DNA polymerase-negative [Table 2). This difference was not statistically significant.

Hepatic

Histology

A repeat liver biopsy specimen in 18 patients (9 treated and 9 control remaining

2 patients

refused

repeat

was obtained patients); biopsy.

the The

TRIAL

12800 6400

P-4

OF Ara-AMP

FOR CHRONIC

TYPE

13 HEPATITIS

153

Ara-AMP

3200 1600 800 400 200 100 50 PRE

Figure

0

7 DAY

14 DAY

21 DAY

28 DAY

35 DAY

TIME

AFTER

2 MO START

3 MO

4 MO

5 MO

Further

8 MO

10 MO

12 MO

18 MO

OF THERAPY

1. Serial results of deoxyribonucleic acid (DNA) polymerase testing in 10 patients treated phate (Ara-AMP]. Results are expressed as counts per minute (cpm) per 0.2 ml of serum. determinants made over a 3.mo period.

follow-up liver biopsy was obtained 11-16 mo (mean 13.1 mo) after the initial biopsy. The time between the first and second biopsies was similar in the controls (mean ? SEM: 12.8 t 0.4 mo) and in the treated patients (13.4 2 0.6 mo). A definite improvement in lobular inflammation and periportal necrosis was noted in 5 treated patients and in 1 untreated patient (Table 3). Three of the 4 treated patients who had become HBV-DNA-negative and DNA polymerase-negative were ranked as having definite improvement in histologic features, and the 4th patient was ranked as having probable improvement between the initial and the follow-up liver biopsies. Liver biopsy in the single control patient who had seroconverted from HBeAg to anti-HBe did not demonstrate a significant change between the first and second liver biopsy.

6 MO

with adenine arabinoside monophosThe “pre” value is an average of three

remained adw). Neither of these patients, nor any other treated patient, developed antibody to the HBV-associated &agent. One of the control patients. but none of the treated patients, developed antibody to hepatitis A virus. During this same period, 1 further control patient improved; HBeAg levels fell, serum HBV-DNA and DNA polymerase became undetectable, and serum aminotransferase levels decreased to near normal (ALT 67 U/L; AST 28 U/L) (Figure 3). Thus, at the time of final follow-up evaluation, 2 treated patients and 2 control patients were seronegative for HBVDNA and DNA polymerase (Table 2).

Side Effects Side effects of Ara-AMP occurred complained ed patients. All 10 patients

in all treatof increased

Follow-up

Further follow-up evaluation of these 4 patients revealed that the improvement in serum biochemical tests and disappearance of serum HBV markers were not always sustained. In z of the patients. serum HBV-DNA and DNA polymerase reappeared at 14 mo and 16 mo after randomization, and HBeAg again became detectable [Figure 5) soon thereafter. In both cases, the reactivation of HBV infection was associated with marked increases in serum aminotransferase levels (ALT levels rose from 23 to 402 U/L in 1 patient, and from 83 to 750 U/L in the other). Both patients developed increased fatigue and nausea. Both have remained positive for serum HBeAg, HBV-DNA. and DNA polymerase for the duration of follow-up (ZZ and 24 mo). Subtyping of HBsAg from these 2 patients before and during these periods of reactivation revealed no change (both

Figure

2. Serial results of serum hepatitis U virus-deoxyribonucleic acid (HBV-DNA) testing in 10 patients treated with adenine arabinoside monophosphate (Ara-AMP). Results were scored from 0 to 5+ based upon visual estimation.

154

HOOFNAGLE

ET AL.

GASTKOENTEKOLOGY

TREATED loo0 \

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86. No.

1

However, the severity of this neuromuscular pain syndrome was a factor that limited the number of patients studied. A similar syndrome was not observed in the control patients.

Discussion

UNTREATED

MONTHS

Figure

AFTER

START

OF THERAPY

3. Serial serum levels of alanine aminotransferase in the 10 treated patients (upper pane)) and 10 controls (lower panel). Open circles denote patients who were seronegative for hepatitis B virus-deoxyribonucleic acid, closed circles denote those who were seropositive for hepatitis B virus-deoxyribonucleic acid.

fatigue during the 28-day course of therapy. Five also complained of anorexia, 6 of nausea, and 1 of vomiting. Most of these symptoms were mild and did not necessitate adjustment of dosage or discontinuation of therapy. During therapy, no appreciable changes occurred in serum biochemical test results, hematocrit levels, or platelet counts, but there was a signifiblood lymcant decrease (mean 40%) in peripheral phocyte counts. All of these side effects rapidly abated with discontinuation of therapy. The major and most troublesome side effect was a distinctive neuromuscular pain syndrome. Five treated patients developed cramplike and aching pains in major muscle groups, which began between days 18 and 25 of therapy. In 3 patients, the pains were severe and prolonged, lasting for 5-7 wk after Ara-AMP was stopped. The pains usually came on with rest or during sleep, lasted several hours at a time, and were partially relieved by exercise, massage, or minor analgesics. Physical examination revealed a decrease in deep tendon reflexes in the more severely affected patients. One patient developed paraesthesias in the tips of the fingers that were associated with decreased light touch and pain sensation over the distal extremities. Serum levels of creatine phosphokinase, lactic dehydrogenase, and aldolase were not elevated. Electromyographic and electroencephalographic studies performed on 1 patient with this syndrome were normal. These symptoms and signs eventually resolved in all patients.

Adenine arabinoside monophosphate and its parent analogue, Ara-A, are potent antiviral agents that have a broad spectrum of activity against several families of DNA viruses (13). The advantage of using Ara-AMP rather than Ara-A is that the phosphorylated ester is highly water-soluble. Thus, Ara-A must be given as a continuous intravenous infusion over many hours, whereas Ara-AMP at a similar dosage can be given as a bolus intravenous infusion or even intramuscularly. This allows for long-term and outpatient therapy. This study evaluated a regimen of Ara-AMP that began with a s-day, high-dose intravenous course, and was followed by a 23-day, lowerdose intramuscular course. This dosage and basic regimen has been shown by Weller and coworkers to provide a potent and usually complete inhibition of circulating HBV (7). Patients in this study selfadministered the injections, and the majority (70%) continued in their usual occupations and activities while receiving intramuscular therapy. Monitoring of serum levels of HBV, especially using the sensitive and specific technique of HBVDNA hybridization (9), revealed that the treatment did not induce complete inhibition of viral synthesis. Furthermore, serum HBV rebounded toward pretreatment levels soon after therapy was discontinued. Thus, the 4-wk course of Ara-AMP appeared to provide only partial and temporary inhibition of HBV replication. Although none of the treated patients became seronegative for HBV-DNA during therapy, in 4 of them, circulating HBV disappeared after treatment was discontinued. The clearance of HBV markers

PRE

0

2M0

4M0

‘GM0

8MO

lOM0

12MO

.. -18

TIME AFTER RANDOMIZATION

Figure

4. Serial testing

results of deoxyribonucleic acid polymerase in 10 control patients. (See key to Figure 1.1

TRIAL OF Ara-AMP FOR CHRONIC: TYPE B HEPATITIS

Januarv lY8-1

Table

2.

Outcome and

at the

of the

Two Study Groups at One Year Time of Final Evaluation (18-24

R/lonths) One year

Final

Ara-AMP

Control

Ara-AMP

ControI

HBsAg negative HBeAg negative

0 4

0

0

0

HBV-DKA and DNA polymerax

4

1 1

2 2

2 2

z

1

z

1

Featurr

negative ALT normal

HBsAg = hepatitis B surface antigen, HBeAg = hepatitis B e antigen, HB\’ = hepatitis B virus. ALT = alanine aminotransferastr. Ara-AMP = adenine arabinoside monophosphate.

was often accompanied by an abrupt increase in serum aminotransferase levels. These “delayed rewere unexpected, and were difficult to sponses” explain. Similar biochemical exacerbations of chronic type B hepatitis have been observed when seroconversion from HBeAg to anti-HBe occurs spontaneously (14). In addition, a temporary exacerbation of chronic hepatitis followed by clearance of circulating HBV often occurs after withdrawal of corticosteroids or immunosuppressive therapy. Corticosteroid therapy has been shown to augment HBV synthesis and to suppress serum aminotransferase levels in patients with chronic type B hepatitis (15). Abrupt withdrawal of immunosuppressive therapy may be followed by a temporary deterioration of serum biochemical test results, and occasionally by a delayed clearance of circulating HBV (15-18). Such observations suggest that the clearance of serum HBV markers may be immunologically mediated (19). Because Ara-AMP also has immunosuppressive properties (201, its effect 011 chronic type B hepatitis may not be totally dependent on its antiviral activities. The 4-wk course of therapy with Ara-AMP may have induced a delayed clearance of HBV by modulating the interactions between viral synthesis and host immunologic responses to the virus. Follow-up evaluation at 1 yr indicated that a 4-wk course of Ara-AMP was associated with clearance of circulating HBV in 40% of patients. During the same period, only 10% of controls had lost serum HBVDNA and DNA polymerase. None of these patients had become HBsAg-negative; however, clearance of serum markers of viral replication (HBeAg, DNA polymerase, and HBV-DNA) was usually associated with remission in disease activity as assessed by serum biochemical tests and liver biopsy histopathology. However, further follow-up at 18-24 mo revealed that the difference in outcome between the two groups was no longer present; a similar percentage of treated patients and controls were seronegative for serum HBV and had normal or only modestly

155

elevated serum aminotransferase levels. These results stress the need for long-term follow-up in the evaluation of therapies for this chronic liver disease. Half of the beneficial responses seen in treated patients in this study were not sustained. Evaluation of therapy aimed at the long-term amelioration of a disease is difficult in a study with only a l-yr period of observation. The results of this study also demonstrate the importance of including untreated patients when evaluating theraDies for chronic tvne B henatitis. Spontaneous clearance of HBV fiorn seruh and remissions of disease activity in this disease have been reported to occur in 9%30% of patients each year (3,14,21-23). For these reasons. it is not possible to state that the beneficial responses that occurred after Ara-AMP therapy in this study did not occur by chance. Based upon uncontrolled observations, both human leukocyte interferon and Ara-A have been reported to have a beneficial effect on chronic type B hepatitis (l-4). Controlled trials of both of these agents have now failed to substantiate a beneficial effect (23). The negative results of this controlled trial are discouraging. One might argue that this study was

Table

3.

Liver

Biopsy

Histopathologq

Liver biopsy reading Case Group Ara-AMP

NO.

1

2 3” 4” 5 6” 7”

a Y 10 Control

a 9” 10

Change Initial

I:inal

CAH CAH CAH CAH CPH CAHIC CAH CAH CPH CPH

(:PH (:AH (:PH CPH CAH CAH:C (:PH (:AH (:AH

CAH CPH CAH CAH CPH CPH CPH CAHIC CAHK CPH

CAH (:AH (X’H

CAH (:f’H (:PH (:PH (:AHC (:AHY:

(-3

to +3j

-2 -2 -2 -:! +1 -1

- :j 0 +1 4 +l ~3 -1 -1 +1 0 +1 0

CAH = chronic active hepatitis. CPH = chronic persistent hepatitis, CAHIC = chronic active hepatitis with cirrhosis. Change between initial and final biopsy was rated as no change (01. probable improvement (-11, definite improvement (-2 and ~3). probable worsening (+I], or definite worsening (+2 and 13). ” Seroconversion from HBeAg to anti-HBe. ” Seroconversion from HBeAg to anti-HBe but a subsequent reactivation and return ol serum HBeAg.

156

HOOFNAGLE

ET AL.

GASTKOENTEKOLOGY

5

3,200

5’

cc=

1.600

4+

r”E

EKIO

3’ 5

t,z 0‘ IIE <:8

4Kl

2’ b

200

1’ 5

is-

100

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86, No. 1

NEG 4 MONTHS AFTER START OF THERAPY

Figure 5 Kesults of serial testing for alanine aminotransferase (ALT), DNA polymerase, hepatitis B virus (HBV)-deoxyribonucleic acid and hepatitis B e antigen (HBeAg) and antibody (anti-HBe) in a patient (case No. 41 treated with adenine arabinoside monophosphate (Ara-AMP). Treatment induced an immediate decrease in serum DNA polymerase and hepatitis B virusdeoxyribonucleic acid (HBV-DNA), but levels of these markers rose soon after therapy was stopped. At 4 ma, there was an abrupt rise in serum aminotransferase levels associated with a fall in serum HBV levels to the undetectable range. At 1 yr. the patient was seronegative for HBV-DNA. DNA polymerase, and HBeAg. and a liver biopsy specimen revealed improvement in degree of both lobular and periportal necrosis. However, during extended follow-up, this patient’s disease relapsed, serum HBV markers reappeared, and serum aminotransferase levels increased markedly.

too small, that the dosage of Ara-AMP was not adequate, or that the duration of treatment was too short. Four patients in this study had received AraAMP in the past, and including 2 of them in the treatment group may have biased the study toward a negative result. Furthermore, the 4 patients who cleared serum HBV after Ara-AMP therapy had chronic active hepatitis and marked elevations in serum aminotransferase levels. These features may help to predict which patients are most likely to respond to antiviral therapy. However, these same features may indicate which patients are likely to undergo a spontaneous clearance of HBV and remission in disease activity (21,23). It is, therefore, possible that higher doses of AraAMP, given over a longer period of time, to selected patients with this disease might be shown to be effective. It should be pointed out, however, that the regimen used in this study was associated with a disturbingly high rate of toxicity. Five patients developed a distinctive neuropathic pain syndrome, and in 3 patients this syndrome was severe enough to be temporarily disabling. Similar side effects have been reported by other investigators using Ara-A and Ara-AMP (1,6,24), and higher doses of these drugs have been reported to cause more severe and even fatal neurologic complications (25, 26). The neurologic side effects of Ara-AMP make the use of higher dosages and longer treatment periods impossible.

References 1 Smith CI, Merigan TC. Therapeutic approaches to chronic hepatitis B. In: Popper H, Schaffner F, eds. Progress in liver diseases, Vol VII. New York: Grune & Stratton, 1982:481-94. 2. Pollard RB. Smith JL, Neal A, Gregory PB. Merigan TC. Robinson WS. Effects of vidarabine on chronic hepatitis B virus infection. JAMA 1978;239:1648-50. 3. Scullard GB, Pollard RB, Smith JL, et al. Antiviral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside. J Infect Dis 1981;143:772-83. 4. Smith CI, Kitchen LW, Scullard GH, et al. Vidarabine monophosphate and human leukocyte interferon in chronic hepatitis B infection. JAMA 1982;247:2261-5. 5. Bassedine MF, Chadwick KG. Salmeron J, et al. A controlled trial of adenine arabinoside in HBsAg-positive chronic liver disease. Gastroenterology 1981;80:1016-22. JH, Minuk GY, Dusheiko GM, et al. Adenine 6. Hoofnagle arabinoside 5’.monophosphate treatment of chronic type B hepatitis. Hepatology 1982;2:784-8. 7. Weller IVD, Bassendine MF, Craxi A. et al. Successful treatment of HBsAg and HBeAg positive chronic liver disease: prolonged inhibition of viral replication by highly soluble adenine arabinoside 5’-monophosphate (Ara-AMP]. Gut 1982; 23:717-23. 8. Kaplan PM, Greenman RL, Gerin JL. et al. DNA polymerase associated with human hepatitis B antigen. J Viral 1973: 12:995-1002. 9. Berninger

M, Hammer M. Hoyer B, et al. An assay for the detection of the DNA genome of hepatitis B virus in serum. J Med Viral 1982;9:57-68. 10. Hoofnagle JH, Gerety RJ, Smallwood LS. Barker LP. Subtyping of hepatitis B surface antigen and antibody by radioimmunoassay. Gastroenterology 1977;72:290-6.

janlIar>

1984

11. Kizzetto M, Shih JWK. Gerin JL. The hepatitis B virus-& associated antigen: isolation from liver, development of solid phase radioimmunoassays for fi antigen and anti-6 and partial characterization of S antigen. 1 Immunol 1980: 125:318-24. 12. Snedecor GW, Cochran WG. Statistical methods. Ames. Iowa: CJniversity of Iowa Press, 1980. 13. LYhitley KJ, Tucker BC. Kinkel A%‘, et al. Pharmacology, tolerance and antiviral activity of vidarabine monophosphate in humans. Antimicro Agents Chemother 1980;18:709-15. 14. Liaw YF:. Chu CM, Su I]. et al. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology 1983:84:216-9. 15. S&lard GH, Smith CI, Merigan TC. et al. Effects of immunosuppressive therapy on viral markers in chronic: active hepatitis B. Gastroenterology 1981:81:987-91. 16. iYeller IVD. Bassendine MF, Murray AK, et al. Effects of prednisolone;azathioprine in chronic hepatitis B viral infection. Gut 1982:23:650-5. 17. Hoofnagie JH. Dusheiko GM, Schafer DF. et al. Keactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 1982:96:447-Y. 18. ,Muller R, Vido I, Schmidt FW. Rapid withdrawal of immunosuppressive therap). in chronic active hepatitis B infection. Lanc.et 1981;i:1323-4.

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OF Ara-AMP

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19. Hoofnagle JH. Chronic type B hepatitis. Gastroenterolog! 1983:84:422-4. 20. Hafkin B, Pollard KB. Tiku ML, et al. Kffec.ts of interferon and adenine arabinoside treatment ot hepatitis B \rirus infection on cellular immune responses. Antimic:ro Agents Chemother 1979:16:781-7. 21. Realdi G. Alberti A. Kugge M. et al. SI:rocr)nvr:rsioll from hepatitis B e antigen to anti-HBe in chronic. hepatitis B virus infection. Gastroenterology 1980:79:195-9. 22. Hoofnagle JH, Dusheiko GM. Seeff LB. 1.t al. SeroLonversion from hepatitis B e antigen to antibocly in c.hrorric type B hepatitis. Ann Intern Med 1981:94:744-8. 23. Schalm SW. Heijtink RA. Spontaneous tlisappearance of viral replication and liver cell inflammation in HBsAg positive chronic active hepatitis: results of a plac.t+r) vs. interteron trial. Hepatology 1982;2:791-4. 24. Preiksaitis JK, Lan KB. Ng PK. et al. FXfect of liver disease on pharmacokinetics and toxicity of 9-8-i)-arabinofuranosyl-adenine-5’-monophosphate. J Infect Dis 1981:144:358-64. 25. Sacks SL, Smith JL. Pollard KB. et al. Toxir.itv of vidarabine. JAMA 1979:241:28-9. 26. Etta LV. Brown J. Mastri A, \d:ilson ‘1‘. Fatal vidarabine toxicity in a patient with normal renal function. lAMA 1981:246:1073-5.