Continuous versus intermittent therapy for chronic hepatitis C with recombinant interferon alfa-2a

1994$07:479-455

GA5lROENTEROLOGY

Continuous Versus Intermittent Therapy for Chronic Hepatitis C With Recombinant Interferon Alfa-2a FRANCESCO NEGRO,* MONIQUE CHANEAC,”

MAURIZIO BALDI,* ALESSANDRA MONDARDINI,* GIOACCHINO LEANDRO,l PAOLA MANZINI, * MARIA LORENA ABATE,* FRIEDERIKE ZAHM,§

GIUSEPPE DASTOLI,” MARCO and FERRUCCIO BONINO*

BALLARt,’

JEAN-CHARLES

RYFF,§ GIORGIO

VERME,*

*Department of Gastroenterology, Ospedale Molinette, Torino, Italy; ?RCCS De Bellis, Castellana Grotte, Italy; Hoffmann-La Roche, “Basei, Switzerland and “Milan, Italy; and ‘Second Division of Internal Medicine, Ospedale Maggiore, Novara, Italy

Bac~round/Aims: Prolonged interferon administration to patients with chronic hepatitis C, although increasing the sustained response rate, is poorly accepted and may favor drug resistance. A pulse-treatment schedule would be preferred for compliance and costs. Methods: One hundred thirty-five patients with chronic hepatitis C received 6 MU units of interferon alfa-2a, three times weekly, continuously for 9 months (group 1: 66 patients) or for two S-month cycles, separated by 6 months pause (group 2: 69 patients). Results: At the end of therapy, 25 of 54 patients of group 1 (46.3%) and 28 of 60 of group 2 (46.7%) had normal serum aminotransferase levels. Six months after the end of treatment, sustained responders were still similar in the two groups (11 or 16.7% vs. 7 or 10.1%; NS). A loss of response before the end of therapy was seen in 10 patients of group 1 and 6 of group 2; interferonneutralizing antibodies developed in 1 of 7 and 6 of 6 of such patients, respectively. Conclusions: The intermittent administration of interferon alfa-2a to patients with chronic hepatitis C shows a sustained response rate comparable with that achieved with continuous treatment at the same dosage. Hepatitis breakthroughs during pulse therapy appeared to be limited to interferon neutralizing antibodies, whereas a prolonged, continuous treatment is more likely to induce other forms of interferon resistance.

C

hronic

hepatitis

recently

Although without tancy,3 progress to fatal cellular

identified

chronic

C is a common RNA

hepatitis

virus,

C mostly

treatment

of hepatitis

C.‘-16 Both drugs share a definite

rate of success in the long term, depending and apparently

the length

lar, administration times

biochemical

at the dose of 2 or 3 MU

alfa-2b

a week for 6-9 response

months

in 33%-50%

ever, more than 50% of patients undergo

a relapse

withdrawal.

of their

Moreover,

tially responding

disease

as many

tance or even a drug

toxicity,

biochemical

while

This phenomenon,

virus

could

as suggested

after

the interferon

as shown still

viral strains,

an inter-

to avoid the selection

as shown

tolerated

by treatment

interferon.

breakthrough,

Theoretically,

Furthermore,

be better

ini-

by the loss of

receiving

referred to as hepatitis

infections.‘7S’8

courses

to treatment

may develop a drug resis-

therapy would be preferred

of drug-resistant

by a How-

as 20% of patients

has not been fully characterized. mittent

is followed of patients.

responding

to treatment

response

In particu-

alfa-2a at the dose of 6

of interferon

MU or of interferon three

on the dosage

of administration.

for other RNA

repeated

therapy

and equally

effective,

of other infectious

diseases.19S20

We report here of a durable control of the chronic hepatitis C disease activity with a pulse treatment of interferon separated

alfa-2a, administered by a 6-month period

was withdrawn.

The

long-term

for two 3-month cycles during which the drug success

rate was then

disease caused by a

compared with that observed among patients treated at the same dosage according to a more conventional sched-

hepatitis

ule, i.e., consecutively

C virus.lS2

runs a mild course

apparently affecting the patient’s life expecit is estimated that in lo%-25% of cases it will towards liver cirrhosis that, eventually, may lead decompensation and/or development of hepatocarcinoma.4

There is no therapy invariably efficacious against hepatitis C. Corticosteroid? and acyclovir’ are ineffective. Interferons alfa and beta have both been widely used for

ize the occasional

for 9 months.

de novo occurrence

To better characterof drug resistance

during treatment, we studied the development interferon antibodies and interferon-neutralizing in those patients losing response while still interferon.

of antiactivity receiving

Abbreviations used in this paper: AIAb, anti-interferon alfs2a antibodies. 0 1994 by the American Gastroenterological Association 00185055/94/$3.00

480

NEGRO

ET AL.

GASTROENTEROLOGY

Materials and Methods

up. In 13 patients before starting

Patients

RNA

We studied

135 patients

age who had persistently

between

hepatitis history

Exclusion

of antibodies criteria

of any serious

metabolic,

of decompensated B surface antigen,

>40;

immunomodulants intake

>80

receive

with

eligible

interferon

alfa-2a

1, 6 MU, intramuscularly, 3 months,

followed

tional

ethical

obtained

by a 6-month

3-month

three times a week for period

of withdrawal,

fol-

pulse of therapy at the same dosage.

was approved

review

group

by the appropriate

committee,

from all patients

and informed

institu-

consent

was

before treatment.

these

time

points,

a complete

response

of serum

(ALT) level, a partial response

schedules.

was defined

alanine

Statistical standardized

tients

failing

hepatitis

and

basis for 6 months.

was made at this time point. as the presence the entire

to meet this criterion

achieving

a complete

A sustained

of persistently

normal

follow up. All other pawere considered

was defined

to have a

as a new increase

at any time during

or partial

treatment

of

after

response.

Serum Assays Serum anti-HCV enzyme-linked tic Systems, HCV;

was evaluated

immunosorbent Milano,

by a second generation

assay (ELISA; Ortho

Italy) and by an immunoblot

Sotin Biomedica,

to internationally

for frequency

tion was not satisfied,

assess-

accepted

cri-

tables

with

more than 4

of variance adjustment

the smallest for continuity

for repeated

measures,

when sphericity

was used for ALT evaluation

assump-

during

the

follow up. All computations

were made by means of Biomedical

Data Processing

of California,

(University

Los Angeles,

CA).

Baseline Clinical Characteristics of the Patients Patients’ summarized to group

1 and

Saluggia,

Italy).

Serum

Diagnos-

assay (LIAHCV

RNA

was detected by a semiquantitative, reverse transcription polymerase chain reaction-based assay that amplifies a portion of the highly conserved, 5’ noncoding region of HCV genome.*’ Both anti-HCV and HCV RNA were assayed before and at the end of treatment and at the end of the 6 months follow

were body

transferase ties.

characteristics

in Table

age,

comparable weight, patients (n

=

6) or accidental

14 patients

another

had

in terms

the trial

of therapy, aspartate

amino-

illicit

drug

(n =

of blood intravenous

previous

blood

15>, parenteral

a history

4 reported

activi-

1 reported

contaminated needle-stick

the

of male-to-female

serum

of group

are

were allocated

2. At start

mean

potentially

hemotransfusion

into

patients

ALT, and y-glutamyltransferase

Twenty-two to

at entry

1. Sixty-six

69 to group

(AST),

exposure (n =

serum ALT levels occurring

from all patients

analysis was made by means of x2 test with

in all other cases. Analysis

as the

but still abnormal,

up on a monthly

breakthrough

according

with Greenhouse-Geisser

aminotransferase

relapse.

A hepatitis

was obtained

< 5 and x2 test with Yates correction

all patients

was considered

pre-

interferon-

was assessed by a bioassay, as reported.**

deviates

expectation

two groups

serum ALT values during

the

cells, Fisher’s Exact Test for 2 X 2 tables with

ratio,

response

positive,

Statistical Methods

a lack of response as none of the above. After the end of therapy, A second assessment

and evalu-

as described

teria.23

At

as a decrease of serum ALT level

to a value less than twice the normal were followed

activity

tested

sera were col-

thereafter

immunoassay

a serum

ment was performed

was made at the end of all treatment

normalization

re-

RMUltS

cycles as well as at the end of both treatment complete

(AIAb),

3 years before entry into the trial. Histological

Efficacy Assessment A first assessment

antibodies

A liver biopsy specimen within

Roche,

schedules:

HCV

as previously

Liver Biopsy Specimens

to

three times a week for 9 months;

2, 6 MU, intramuscularly,

The study protocol

or

assigned

Hoffmann-La

to two different

and group

lowed by another

antibody

When

neutralizing

of serum

antivirals,

were randomly

semiquantitatively

by an enzyme-linked

renal,

2 years; a daily alcohol

(Roferon-A;

according

ated

g (females).

for treatment

Basel, Switzerland)

interferon,

the previous

g (males) or >50

Patients

presence

was also assayed

course of treatment.

lected before therapy and every 3 months

disorders;

or antinuclear

measured

RNA

No. 2

ported.*l

viously.**

or lactation;

gastrointestinal,

liver disease;

within

of chronic

or psychiatric

anti-HIV

a course of therapy

range

HCV (anti-HCV)

pregnancy

neurological,

hepatitis

evidence

against

included:

cardiovascular,

hematologic,

presence titer

of the normal

and had a histological

and presence

in serum.

limit

2, HCV

For serum anti-interferon

elevated serum alanine aminotransfet-

ase levels at least twice the upper for at least 6 months

14 and 65 years of

was

in group

the second S-month

Vol. 107,

through addiction

1). In group

transfusion, drug

abuse.

2,

while All

remaining patients (44 and 5 1, respectively) were considered as having a community-acquired chronic hepatitis C. Table 1 lists also the histological diagnoses of the liver biopsies performed before starting therapy. Significantly more patients of group 2 had an active cirrhosis than patients

of group

were evenly

1 (14 vs. 4), whereas all other diagnoses

distributed

between

the two groups.

Biochemical Response to Treatment Group 1. Fifty-four patients the full g-month course of therapy.

of group 1 received Of these, 38 (70%)

PULSE INTERFERON THERAPY IN CHRONIC HEPATITIS C

August 1994

Table 1. Patient Characteristics

partially,

at Entry Into the Trial

Group 1

to 39 (61.9%) and 4

decreased

(6.3%) (1st cycle) and to 27 (45%)

P

Group 2

to treatment

481

and

10 (16.7%)

(2nd cycle). After the first course of therapy was stopped, 66 45/21 47.1 lr 70.0 2 176.8 t 94.6 2 67.3 +

Number Sex (M/F) Age” Body weight” ALT (/U/L”) AST (/U/L”) GGT (/U/L”) Source of infection Sporadic Posttransfusion Drug addiction Needle-stick Liver histology CLH CPH CAH Total With cirrhosis Othe? Not done”

69 49/20 47.8 2 312.6 68.0 + 11.3 187.1 2 105.2 99.6 + 60.5 75.7 * 59.4

11.3 8.8 88.6 57.8 61.6

NS NS NS NS NS NS

hepatitis

relapsed

eral, patients

in 39 (90.7%)

responding

51 14 4 0

NS NS NS NS

8 13

8 15

NS NS

consistent (95%).

behavior

43 4 1 1

46 14 0 0

NS 0.021 NS NS

As exceptions,

therapy

response

after

response

to treatment,

decreasing

below

normal

the 6-month sustained

Nine

of these patients

suffered

from a breakthrough

of

of the

study).

At

the

(46.3%) had normal had a partial

month

course

levels,

25 patients

(Table

of therapy,

2). while

had

a complete

the

first

3-

follow

to the two cycles of therapy was, respectively, and 4 (6.3%) on the first cycle, and 31 and 10 (16.7%) on the second cycle. Overall,

41 (65.1%)

(51.7%)

six patients

had a hepatitis

up. As a result, among

breakthrough:

relapse during

the proportion

all patients

included

of

in the

compared

by means

of the analysis

the difference not significant

was made between

of variance

between

for re-

the two groups

(P = 0.9164).

A similar

the ALT levels observed

the follow up of the group

1 and during

the 6-

month period between the two courses of therapy of group 2; although, on the average, the ALT levels recorded in the latter were higher, tically

not significant

Virological

the difference

was statis-

(P = 0.3850).

Response

A decrease in titers of antibodies often observed,

proteins

against

either or

NS4 and NS5 was more

at end of therapy,

in responders

(26 of

treatment

was received by 60 patients, due to three further dropouts (see below). The proportion of complete and partial responders

1 and 31 (81.6%)

of group 2 had a hepatitis

both the nonstructural

patients

of group

Twenty-six

12 (22.2%)

and 17 (3 1.5%) were considered

2. Sixty-three

Group

of treatment,

transaminases

response,

to be nonresponders

end

of the biochemical

treatment.

significant (x2 0.741; P = 0.3892). The monthly variations of the serum ALT levels during the follow up were

during

their hepatitis 5 -9 months from the beginning (an additional patient with a hepatitis breakthrough dropped out

to respond

study was 11 of 66 (16.7%) in group 1 and 7 of 69 (10.1%) in group 2. This difference was statistically not

value

(5 cases).

the persistence

responders

with their

cases) or to a value less than twice the normal

failing

and two partially).

of the 37 responders

comparison

(33

Such

after the second pulse of

discontinuing

of 38 responders

was statistically

levels

to the

Follow-up

peated measures:

ALT

three patients

(one completely

(70.3%)

showed a biochemical

to respond)

was seen, in fact, in 57 of 60 patients

We evaluated

CLH, chronic lobular hepatitis; CPH, chronic persistent hepatitis: CAH, chronic active hepatitis. “Expressed as mean 2 SD. *One patient had a histological picture of acute hepatitis. ‘In one case, a liver biopsy was not performed due to the presence of multiple liver hemangiomas.

serum

(or failing

In gen-

first course of therapy did so also upon retreatment.

after the first cycle did respond 44 15 6 1

of responders.

two of them

during the first 3 months, another three during the second cycle, while the sixth patient, after responding completely at the end of the first cycle and showing a biochemical response at the beginning of the second 3-month treatment, had a significant serum ALT increase again, so that he was considered to be a treatment failure. As a result, at the end of each cycle of therapy, the proportion of patients responding, either completely or

Table 2. Characteristics

of Response to Interferon Alfa-2a Group 1

Total no. of patients Dropouts Completing therapy and follow-up Nonresponders Complete responders at EOT Partial responders at EOT Relapsers (% of responders) Sustained responders vs. all patients included bt, breakthrough:

66 12 (1 bt)

Group 2 69 9

54 17 (31.5%) (3 bt)

60 23 (38.3%) (6 bt)

25 (46.3%) 12 (22.2%) (6 bt)

27 (45%) 10 (16.7%)

26 (70.3%:

31 (81.6%)

11 (16.7%)

7 (10.1%)

EOT, end of therapy.

482

NEGRO ET AL.

GASTROENTEROLOGY Vol. 107, No. 2

50, or 52%) than However,

in nonresponders

this difference

(x2 1.944; P = 0.163). end of follow-up,

The trend

when

16 of 30 (53.3%)

and/or

responders

responders

(76.9%)

with a hepatitis

neither

the study

any trend

during

relapse (x2

nonresponders

the therapy.

uation

of viremia

group

2 at the beginning

Semiquantitative

in six patients;

RNA

at the beginning

whereas in the remaining at the start of therapy. was significantly shown).

At the end of therapy,

came undetectable

HCV

of the second

cycle,

pain (1 month),

a painful

lichen

a bacterial

(data not

decreased

or be-

tients

but in

patients

(x2 5.256; P = 0.022).

time point:

interferon

responders

who had a hepatitis

relapse but remained undetectable in all 14 sustained responders who were tested (x2 15.601; P < 0.001).

(12 of group

the treatment,

(acute myocardial

to the interferon

1 and 9 of group

tively. The remaining

of

though

to

severe

interrupted

the drug

thrombocytopenia

(platelet count, < 10 X lo9 per pm’) (occurring after 1 month of therapy), anemia with a hemoglobin concentration of <8 g/dL (3 months), pneumonia (3 months), peripheral neuropathy (3 months), skin allergy (4 months), severe psychic dissociation (5 months), and acute thyroiditis (6 months). In the group of patients receiving the intermittent regimen, three developed intolerable side effects (depression, flulike symptoms) forcing them out of the study (2, 10, and 11 months from start). The remaining six patients developed a severe thrombocytopenia (platelet count < 10 X 109/pm3) (1 month from the beginning), a persisting, intolerable

2

had AIAb before starting a 6-month

during

therapy

of serum

developing

activity

the two reactivities

1 and 6 in group

seven patients

because

all patients

a major

Four other

in 104 pa-

and 19 in group

3 years before being

neutralizing

one reported

unlikely

testing

therapy admitted

with to the

present study; 30 patients developed AIAb during therapy and another a month after the end of treatment.

As described

patients withdrew from the study because of intolerable side effects (mainly asthenia, depression, and dizziness) at 4,4, 4, and 6 months after starting interferon, respecadministration

alfa-2a

of group

infarction)

1 (23.5%)

he had received

the patients

administration.

for AIAb

(Table 3). One patient

the therapy:

terferon

out of the study. Among

problem

12 in group

Interestingly,

Dropouts

be related

and a generalized

(3 months).

(51 of group 1 and 53 of group 2). Overall, 32 (30.8%) had AIAb in their serum at least at one

values in 10 of 12 (83.3%)

health

(3 months)

ruber planus

(2 months),

Sera were available

viremia

(35.8%)

1 who abandoned

lichen

(2 months),

the oral cavity

none of these patterns

it was lower than

in 15 of 30 (50%) responders

2 1 patients

(35.8) (28.9) (53.3) (100)

the outcome

only 1 of 13 (7.7%) nonresponders

Overall,

19 11/38 8/15 6/6

(23.5) (16.2) (42.8) (14.3)

a psychic dissociation

involving

endocarditis

cutaneous

After 6 months of follow-up after the end of therapy, serum HCV RNA levels increased again to pretreatment

2) dropped

12 6/37 6/14 l/7

53

Hepatitis Breakthrough and Anti-interferon Antibodies, Interferon-Neutralizing Activity and HCV RNA

However, with

of

cycle: levels

in three others,

six patients,

associated

51

Total Responders Nonresponders With breakthrough

lumbar

eval-

in 15 patients

of each 3-month

were comparable

Patients studied AIAbpositive

Group 2 (%I

(data not shown). in 40 of 41 patients

was also performed

was higher

among

Group 1 (%)

were other antibodies

Serum HCV RNA was detectable tested before starting

deversus

(x2 1.555; P = 0.2 12). There were no differences the two groups of patients,

of AlAb in Continuously Versus Treated Chronic Hepatitis C

Intermittently

at the

anti-NS5

and 7 of 15 (46.7%)

showing

Table 3. Development

not significant

was confirmed

anti-NS4

creased in 10 of 13 sustained 1.24; P = 0.266)

(8 of 25, or 32%).

was statistically

AIAb also had in-

at some

time

points,

al-

did not always coincide.

above, a total of I6 patients 2) developed

after achieving

(10 in group

a hepatitis

breakthrough

a complete

normalization

ALT. Sera were available

for AIAb

testing

in

12 of these patients (seven of group 1 and five of group 2). In group 1, AIAb were detected in 6 of 37 (16.2%) patients responding to therapy and in 6 of 14 (42.8%) nonresponders

(Fisher’s Exact Test; P = 0.0664). Among

the 37 responders,

AIAb

were found

in 1 of 7 (14.3%)

patients initially responding and later suffering from a hepatitis breakthrough and in 5 of 30 (16.7%) subjects who maintained the response throughout the entire period of treatment (Fisher’s Exact Test; P = 0.6845). In group 2, AIAb were found in 11 of 38 (28.9%) responders and in 8 of 15 (5 3.3%) nonresponding patients (Fisher’s Exact Test; P = 0.0897). All six patients who responded to therapy but who had a hepatitis breakthrough were shown to have serum AIAb (100%). On the contrary, only 5 of 32 (15.6%) of the remaining responders had AIAb in their serum. This difference was highly significant (Fisher’s Exact Test; P = 0.0002). A

August

PULSE

1994

significant

difference

Exact Test; P = 0.0047)

(Fisher’s

who developed

between the two groups. The timing of the occurrence neutralizing

activity

breakthrough

of patients

domization responding

development

all occurring

of group

6 months

2, two patients

the first 3-month

with one another.

In

from

the start

developed available

artifact).

of therapy.

Cirrhotic

stringent

trials,‘-‘*

possibly

and to the higher

dosage of interferon,

of patients

In group

to interferon

alfa do so within

therapy.‘-I3

cycle was high, confirming

other

three

during

the second

3-month

response

cycle, in parallel

of the interferon-neutralizing

activ-

ity and, in two cases, of the AIAb (in the third patient, AIAb

had occurred

patient, found

AIAb

at an earlier

bleeding).

In the sixth

and interferon-neutralizing

activity

at the end of the first cycle of therapy;

the patient

lost response

month course. Serum HCV

later on, during

In group

RNA

1, serum response

was tested

the second

3-

semiquantitatively

breakthrough

HCV RNA

A fifth patient in serum

at the time of the breakthrough.

loss of bio-

to pretreatment

levels of HCV

RNA

at

in nine patients.

levels upon

were comparable

ues in four patients.

was available

however,

biochemical

val-

had undetectable

both before therapy Unfortunately,

from the only patient

and

no serum

who developed

AIAb.

who respond

the first 3 months

the observation

that a single

to induce

a long-term

of group

2 who had responded

course but relapsed

permanently

thereafter

did not respond

to the first cycle,

but they did so after the second cycle, and one of these became a sustained long-term chronic

responder.

interferon

response. hepatitis

These observations

courses can increase

So far, the successful

dosage had been only anecdotally of group 2 with hepatitis the viremia

throughout

reported.”

In patients

relapses in whom we measured the follow-up,

was slowed down and reactivated

HCV replication

upon drug withdrawal.

These findings

suggest

that a more appropriate

timing

of retreatment

would

have

after

been

alfa-2a.

If this is true, in chronic

tative measurement

DZscusdon

ing hepatitis.

We found

only expensive

that

The long-term chronic

The number

hepatitis

C can be con-

administration

of patients

with

of interferon

a sustained

bio-

chemical response to treatment was comparable among the patients receiving the pulse schedule and those treated consecutively for 9 months. The persistent normalization of serum ALT in sustained responders was paralleled by the clearance of HCV RNA from serum in all 14 patients tested. However, the proportion of sustained responders among patients treated intermittently was slightly lower than that seen among patients receiving the continuous regimen. This could be interpreted as caused by some “unfavorable” features of group 2 patients, who had a higher percentage of individuals with

of

at the same

earlier

than

expression of viral RNA and antigens might clue as to the appropriate timing of retreatment

trolled with the intermittent

suggest

the rate of

retreatment

C with the same interferon

values) in the other two, in contrast

with the loss of the

to

after the second cycle of treatment.

Three other patients

months.

response.

to the

appeared

In group 2, serum HCV RNA levels were unmodified in two patients but decreased (in one case to undetectable biochemical

of

their rate of relapse after this first

is not sufficient

Two patients first 3-month respond

among patients

response.16

that multiple

the time of the hepatitis chemical

were

However,

course of therapy

study

a higher

rate after the first 3-month

with that obtained

AIAb

with the appearance

causing

to drop out of the study.

2, the response

both

occurred

to the highly

because most patients

the loss of biochemical

for

The overall

in the present

treated for 9 months,

In an-

483

are known

owing

criteria of response adopted

at the end of the first cycle, and it was shown to contain patients,

patients

with interferon.’

cycle was comparable

activity.

C

1 (due to a ran-

during

the AIAb was

and interferon-neutralizing

with group

of therapy:

a breakthrough

for studying

In

HEPATITIS

response rate was also lower than that reported

proportion

1, the three events coincided,

cycle, both after 2 months

the closest bleeding

of the

IN CHRONIC

as compared

in other clinical

of AIAb and interferon-

of the

THERAPY

less to treatment

sustained

were then compared

the only patient group

and

liver cirrhosis

AIAb were compared

(Table 3) was also found when the proportions with breakthrough

INTERFERON

of viremia

administration

relapses

of interferon

of drug

observed

C, the quanti-

or the study of the tissue

and poorly tolerated

ated with the development by hepatitis

hepatitis

6

provide a of relapsalfa is not

but it may be associresistance,

before

as shown

the end of treat-

ment. 8*24-28The development

of interferon

resistance

has

been interpreted in different have shown the development

ways. Some investigators of anti-interferon-neu-

tralizing antibodies, thus advocating a retreatment with a different interferon. 24’25’29On the other hand, during prolonged interferon therapy of chronic viral hepatitis, some drug-resistant viral strains might be selected that cause the persistence or the reactivation of liver disease despite the continuous administration of interferon.2”,27 The phenomenon of drug resistance following prolonged monotherapies is well known for other viruses and antivi-

484

NEGRO

ET AL.

ral drugs,

GASTROENTEROLOGY

and some molecular

the development in detail,

of this resistance

Combination

therapies

been suggested

expecting

the obvious gle drugs,

advantage

the clinical

human

regimens

have

and have

of using lower dosages of the sintheir tolerability

Intermittent

posed and applied

schedules

especially

and reducing have been pro-

as preventive

measures

for

relapses of many infectious’9720Y30-32 and even

noninfectious

diseases,

or antihypertensive

such as for anti-duodenal

ulcer

therapy.33

In the present

study,

feron antibodies patients

or alternating

lower drug resistance

thus increasing

toxicity.”

with

1. 17*18

virus

the development

was observed

in both groups,

of anti-inter-

in a similar

irrespective

proportion

of

of the therapy sched-

ule and of the presence or absence of response. However, when we correlated the presence of such antibodies with the occurrence

of a hepatitis

apy, a significant tients receiving

association intermittent

riencing a breakthrough the interferon resistance mechanisms

breakthrough treatment.

antibodies.

tis C, the intermittent 2a can be proposed ical and virological

ther-

In patients

paexpe-

during continuous treatment, appeared to be associated with

other than the development

terferon-neutralizing

during

was only found among

of AIAb or in-

Thus, in chronic hepati-

administration

of interferon

not only to elicit a sustained remission

alfa-

biochem-

but also to circumvent

the

development of drug resistance due, e.g., to the selection of drug-resistant strains or to drug adaptation and even toxicity. In conclusion, rational

treatment

in view of these observations, of chronic

hepatitis

a likely

C would envisage

short, repeated courses of therapy; upon relapse after the end of therapy, a retreatment with the same interferon at the same dosage may be indicated, courses

may eventually

sponders

increase

in the long term.

retreatment

because

the proportion

multiple of re-

In the case of breakthrough,

could be performed

with a different

kind of

interferon.

4. Alter HJ. Chronic consequences of non-A, non-B hepatitis. In: Seeff LB, Lewis JH, eds. Current perspectives in hepatology: Festschrift for Hyman J. Zimmerman, M.D. New York: Plenum Medical, 1989:83-97. 5. Stokes P, Lopez WC, Balart LA. Effects of short-term corticoste roid therapy in patients with chronic non-A, non-B hepatitis (NANB) (abstr). Gastroenterology 1987;92:Al783. 6. Pappas SC, Hoofnagle JH, Young N, Straus SE, Jones EA. Treatment of chronic non-A. non-B hepatitis with acyclovir: pilot study. J Med Virol 1985; 15:1-9. 7. Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrillo RP, Carey W, Jacobson IM, Payne J, Dienstag JL, Van Thiel DH, Tamburro C, Lefkowitch J, Albrecht J, Meschievitz C, Ortega TJ, Gibas A, the Hepatitis Interventional Therapy Group. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. N Engl J Med 1989;321:1501-1506. 8. Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, Goodman Z, Banks SM, Hoofnagle JH. Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. N Engl J Med 1989;321:1506-1510. 9. Saracco G, Rosina F, Torrani Cerenzia MR, Lattore V, Chiandussi L, Gallo V, Petrino R, De Micheli AG, Donegani E, Solinas A, Deplano A, Tocco A, Cossu P, Pintus C, David E, Mazzucco G, Verme G, Rizzetto M. A randomized controlled trial of interferon alfa-2b as therapy for chronic non-A, non-B hepatitis. J Hepatol 1990; ll:S43-s49. 10. Weiland 0, Schwartz R, Wejstal R, Norkrans G, Fryden A. Therapy of chronic post-transfusion non-A, non-B hepatitis with interferon alfa-2b: Swedish experience. J Hepatol 1990; ll:S57-S62. 11. Gomez-Rubio M, Porres JC, Castillo I, Quiroga JA, Moreno A, Carreno V. Prolonged treatment (18 months) of chronic hepatitis C with recombinant alpha-interferon in comparison with a control group. J Hepatol 1990; ll:S63-S67. 12. Realdi G, Diodati G, Bonetti P, Scaccabarozzi S, Alberti A, Ruol A. Recombinant human interferon alfa-2a in community-acquired non-A, non-B chronic active hepatitis. Preliminary results of a randomized, controlled trial. J Hepatol 1990; ll:S68-S71. 13. Marcellin P. Bayer N, Giostra E, Degott C, Courouce AM, Degos F, Coppere H, Cales P, Couzigou P, Benhamou J-P. Recombinant human alpha-interferon in patients with chronic non-A, non-B hep atitis: a multicenter randomized controlled trial from France. Hep atology 1991; 13:393-397. F, Porres JC, Moreno A, Castillo I, Martinez G, 14. Saez-Rouyela Galiana F, Carreno V. High doses of recombinant alpha-interferon or beta-interferon for chronic hepatitis C: a randomized, controlled trial. Hepatology 1991;13:327-331. 15.

References Choo Q-L, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359-362. Kuo G, Choo Q-L, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, Tegtmeier GE, Bonino F, Colombo M, Lee WS. Kuo C, Berger K, Shuster JR, Overby LR, Bradley DW, Houghton M. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepa titis. Science 1989;244:362-364. Seeff LB, Buskell-Bales Z, Wright EC, Durako SJ, Alter HJ, lber FL, Hollinger FB, Gitnick G, Knodell RG, Perrillo RP, Stevens CE,

No. 2

Hollinsworth CG, the National Heart, Lung, and Blood Institute Study Group. Long-term mortality after transfusion-associated non-A, non-B hepatitis. N Engl J Med 1992;327:1906-1911.

underlying

have been analyzed

such as in the case of infection

immunodeficiency

their

mechanisms

Vol. 107,

Kiyosawa K, Sodeyama T. Nakano Y, Yoda H, Tanaka E, Hayata T, Tsuchiya K, Yousuf M, Furuta S. Treatment of chronic non-A non-B hepatitis with human interferon beta: a preliminary study. Antivir Res 1989; 12:151-162.

16. Omata M, Ito Y, Yokosuka 0, lmazeki F, Tagawa M. Takano S, Hosoda K, Tada M, Ohto M, Ito K, Okuda K. Randomized, doubleblind, placebo-controlled trial of eight-week course of recombinant alpha-interferon for chronic non-A, non-B hepatitis. Dig Dis Sci 1989;34:330-337. 17.

Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989;243:1731-1734.

18. Yarchoan R, Pluda JM, Perno C-F, Mitsuya H, Broder S. Antiretroviral therapy of human immunodeficiencyvirus infection: cur-

PULSE INTERFERON THERAPY IN CHRONIC HEPATITIS C

August 1994

rent strategies

and challenges

for the future.

324. 20. Thin RN. Management of genital herpes simplex infection. Int J STD AIDS 1991;2:313-317. 21. Abate ML, Manzini P, Negro F, Baldi M, Saracco G, Piantino P, Brunetto MR, Bonino F. Detection of Hepatitis C virus RNA by reverse-transcriptase and polymerase chain reaction: clinical ap plication of quantitative analysis. Clin Diagnos Virol 1994;l: 22.

23. 24.

25.

26.

27.

thal WS. Interferon escape (IE) in chronic hepatitis C (CHC): inci-

Blood 1991;

78:859-884. 19. LeBel M. Fluoroquinolones in the treatment of cystic fibrosis: a critical appraisal. Eur J Clin Microbial Infect Dis 1991;10:316-

289-297. Hennes U, Jucker W, Fischer EA, Krummenacher Th, Palleroni AV, Trown PW, Linder-Ciccolunghi S, Rainisio M. The detection of antibodies to recombinant interferon alfa-2a in human serum. J Biol Standard 1987; 15:231-244. Desmet VJ. Histopathology of chronic hepatitis. In: Liaw Y-F, ed. Chronic hepatitis. Amsterdam: Elsevier Science, 1986; 27-44. Milella M, Antonelli G, Giannelli G, Santantonio T, Monno L, Pastore G. Treatment with natural alpha interferon of patients with chronic hepatitis C and antibodies to recombinant interferon (abstr). Proc lnternat Symp Viral Hepatitis Liver Dis May 10-14, 1993; 232. Yokoyama K, Shoji S, Makita A. Hosoi H, Miyamoto N, Wakashima M, Takikawa H, Miyake K, Yamanaka M. Successful interferon treatment for chronic hepatitis C patients who have neutralizing antibody to interferon alfa-2a (abstr). Proc lntemat Symp Viral Hepatitis Liver Dis May 10-14, 1993;232. Finkelstein SD, Sayegh R, Uchman S, Christensen S, Swalsky P. HCV undergoes extensive mutational change in NS5 region in association with relapse/breakthrough following alpha-interferon therapy (abstr). Hepatology 1992; 16:132A. Lebovics E, Casellas A, Young K, Dworkin B, Resnick R, Rosen-

485

28. 29.

30.

31.

32.

33.

dence, cause and outcome (abstr). Hepatology 1992; 16:210A. lnglada L, Porres JS, La Banda F, Mora I, Carreno V. Anti-IFNalpha-titers during interferon therapy. Lancet 1987;2:1521. von Wussow P, Hartmann F, Freund M, Poliwoda H, Deicher H. Leucocyte-derived interferon-alpha in patients with antibodies to recombinant IFN-alfa,,. Lancet 1988;1:882-883. Montaner JS, Lawson LM, Gervais A, Hyland RH, Chan CK, Falutz JM, Renzi PM, MacFadden D, Rachlis AR, Fong IW, Garber GE, Simor A, Gilmore N, Fanning M, Taylor GD, Martel AY, Schlech WF, Schechter MT. Aerosol pentamidine for secondary prophylaxis of AIDS-related Pneumocystis carinii pneumonia. A randomized, placebo-controlled study. Ann Intern Med 1991; 114:948-953. Wormser GP, Horowitz HW, Duncanson FP, Forseter G, Javaly K, Alampur SK, Gilroy SA, Lenox T, Rappaport A, Nadelman RB. Lowdose intermittent trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection. Arch Intern Med 1991; 151:688692. Berman S, Nuss R, Roark R, Huber-Navin C, Grose K, Herrera M. Effectiveness of continuous vs. intermittent amoxicillin to prevent episodes of otitis media. Pediatr Infect Dis J 1992; 11:63-67. Schmieder RE, Rockstroh JK, Messerli FH. Antihypertensive therapy. To stop or not to stop? JAMA 1991;265:1566-1571.

Received July 29, 1993. Accepted April 28, 1994. Address requests for reprints to: Ferruccio Bonino, M.D., Department of Gastroenterology, Ospedale Molinette, Corso Bramante 88, 10126 Torino, Italy. Fax: (39) 11-595588. The authors thank Drs. Massimo Sartori, Paolo Niola, Marilisa Pesavento, Eraldo Burgay, Maria Capalbo, Maurizia Brunetto, and Filippo Oliveri for their participation in this study.