Effect of Interferon-a Induction Therapy on Genotype 2b/3a and LowViral Load Hepatitis C Virus Infection

A Randomized Multicentre Study

K. Bjøro, H. Bell, B. Myrvang, K. Skaug, N. Raknerud, P. Sandvei, S. Størseth, S. Ritland,S. Lund-Tønnesen, A. Bucher & K. B. HellumMedical Depts. of National Hospital, Aker University Hospital, Ullevaal Hospital, Oslo; Dept. ofVirology, National Institute of Public Health, Oslo; Dept. of Pathology, Aker University Hospital,Oslo; Medical Depts. of Central Hospital, Fredrikstad, Central Hospital, Stavanger, Buskerud CentralHospital, Drammen, Haukeland Hospital, Bergen, Bñrum Hospital, Bñrum, Akershus CentralHospital, Akershus, Norway

Bjøro K, Bell H, Myrvang B, Skaug K, Raknerud N, Sandvei P, Størseth S, Ritland S, Lund-Tønnesen S,Bucher A, Hellum KB. Effect of interferon -a induction therapy on genotype 2b/3a and low viral loadhepatitis C virus infection . A randomized multicentre study. Scand J Gastroentero l 2002;37:344–349.

Background: Interferon monotherapy for chronic hepatitis C virus (HCV) infection leads to sustainedviral eradication in a minority of patients . However, in selected groups of patients , sustained virologica lresponse is observed in as many as 50% of patients . High initial interferon dose (induction therapy) hasbeen reported to increase the initial response rate. We have studied the effect of interferon inductiontherapy in patients infected with HCV genotype 2b/3a, low viral load and no cirrhosis . Methods: A totalof 71 treatment-naive HCV RNA-positive patients with biopsy-con � rmed chronic hepatitis , withgenotype 2b or 3a, viral load µ3 million copies per ml and no cirrhosis were randomized to receive eitherstandard interferon therapy (3 MIU interferon -a-2a thrice weekly) for 26 weeks or 6 MIU interferon-a-2adaily for 4 weeks (induction group) followed by the standard dose (3 MIU thrice weekly) for 22 weeks.Those with persisten t HCV RNA at 4 weeks stopped treatment. Patients were monitored for HCV RNAduring and following treatment, and data were interpreted according to intention-to-trea t analysis.Results: Viral clearance occurred more rapidly (after 4 weeks) in the induction group (33/36 = 92%)compared to the standard interferon group (21/35 = 60%) (P = 0.01). Among the initial responders , 23/33(induction group) compared to 16/21 (standard group) were persistentl y HCV RNA-negative at the end oftreatment. At 52 weeks (6 months’ follow-up) , 22/36 (61%) (induction group) compared to 10/35 (29%)(standard group) were HCV RNA-negative. Among initial responders , 22/33 (induction group) and 10/21(standard group) achieved a sustained virologica l response . Among end-of-treatmen t responders , 22/24(induction group) and 10/16 (standard group) were HCV RNA-negative at 6 months’ follow-up(P = 0.013). Conclusions: In patients infected with HCV genotype 2b/3a, low viral load and withoutcirrhosis , IFN induction therapy increases the initial viral clearance and reduces the risk of relapse in end-of-treatment responders . A sustained virologica l response was achieved in 61% of the patients receivingIFN induction therapy.

Key words: Hepatitis C; interferon

Kristian Bjøro, M.D., Ph.D., Section of Hepatology and Gastroenterology , National Hospital, NO-0027Oslo, Norway (fax. ‡47 23070451, e-mail. kristian.bjoro@labmed.uio.no )

The overall sustained virological response rate forinterferon (IFN) monotherapy for chronic hepatitisC virus (HCV) infection is 10%–25% (1–4). How-

ever, response rates vary considerably depending on geno-type, and patients infected with genotype 2b or 3a havesigni� cantly higher response rates: 25%–50% (4–6). Thepresence of cirrhosis may also be of major importance for theoutcome of treatment (7, 8).

The response rates are improved by increasing the dose ofIFN or by prolonging treatment (9, 10). In several studies,induction therapy with high initial doses of IFN has been

applied with rapid viral clearance (11–13). A few studies havefailed to show any increase in the sustained response ratewhen increasing the initial IFN dose (14, 15). Thus the effectof IFN induction therapy on the sustained response ratesremains unclear.

In the present study we have compared the ef� cacy of IFNinduction therapy with standard IFN therapy in a highlyselected group of HCV patients—presumed to be goodresponders to IFN monotherapy—i.e. patients infected withgenotype 2b or 3a, with low viral load and without cirrhosis.

The rationale for the present study protocol was based

ORIGINAL ARTICLE

Ó 2002 Taylor & Francis

Scan

d J

Gas

troe

nter

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

9/13

For

pers

onal

use

onl

y.

partly on a hypothesis that IFN induction therapy might besuf� cient for this selected group of patients and partly on thefact that this treatment schedule is favourable from both thepatients’ point of view, fewer side effects than combinationtherapy (16, 17), and for society (reduced cost of drugs).

Patients and Methods

PatientsA total of 327 HCV patients were enrolled in two

Norwegian multicentre studies during the period March1998 to November 1999. They were all HCV RNA-positive,with elevated serum-alanine aminotransferase (ALT) levels(above upper reference limit twice during the last 6 months),and none had previously received treatment for HCVinfection. The patients were examined for HCV genotypeand viral load prior to study enrolment. On the basis of theseparameters they were allocated to one of two studies. Patients(n = 256) with genotype 1a or 1b infection (irrespective ofviral load) and those with genotype 2b/3a infection and a viralload >3 million copies per ml, or with cirrhosis, wereallocated to a randomized study (IFN/ribavirin combinationtherapy with/without IFN induction) (18). The remaining 71patients who were infected with genotype 2b or 3a, and whohad a viral load µ3 million copies and did not haveradiological, histological or clinical signs of cirrhosis, wereenrolled in the present study.

A liver biopsy had been obtained within the 2 years prior toenrolment demonstrating histological changes compatiblewith HCV infection. The exclusion criteria were the follow-ing: alcohol or drug abuse during the previous 6 months, livercirrhosis, concurrent infection with hepatitis B (HBsAgpositivity) or HIV (anti-HIV positivity), autoimmune hepa-tobiliary disease, metabolic liver disease, previous severepsychiatric disease, severe coronary heart disease anddisability to comply with the study protocol. Patients withlow levels of anti-nuclear antibodies (titres µ1/128) and/orsmooth muscle antibodies (titres µ1/64) were included in thestudy.

The study was approved by the local Ethics Committee andall patients gave written informed consent.

IFN treatmentPatients were randomized to receive: group A (n = 36),

IFN-a2a (Roceron1, AF Hoffmann La-Roche Ltd, Basel,Switzerland) 6 MIU daily for 4 weeks followed by 3 MIUthrice weekly for 22 weeks, or group B (n = 35), IFN-a2a 3MIU thrice weekly. All patients were evaluated after 4 weeksfor response (qualitative HCV RNA). Those who were HCVRNA-positive (non-responders) terminated treatment after 4weeks. All patients were evaluated every 2nd week for 4weeks and then every 4th week during the � rst 26 weeks, and4, 12 and 26 weeks thereafter.

Patients who were HCV RNA-positive at 4 weeks (non-responders) stopped IFN monotherapy and were offered

treatment with IFN 3 MIU thrice weekly and ribavirin(1000/1200 mg daily ¡ weight </> 75 kg). Likewise, pa-tients with breakthrough (HCV RNA reappearance duringtreatment) and relapse (HCV RNA reappearance followingend of treatment) were offered IFN/ribavirin combinationtreatment. Combination therapy was performed outsideprotocol and the results are not included in this study.

Evaluation of treatment responseThe primary end-point of the study was HCV RNA status

52 weeks following the start of treatment (6 months follow-up); patients who were HCV RNA-negative were categorizedas sustained responders. Patients who were HCV RNA-positive at 4 weeks after the start of treatment and thosedropping out of the study were recorded as non-responders.Serum-ALT levels during and following treatment and HCVRNA during treatment were secondary end-points. Data wereanalysed according to an intention-to-treat analysis.

VirologyHCV RNA was measured with an in-house polymerase

chain reaction (PCR) method with a detection limit of 500copies per ml (19, 20). Viral load was measured with abranched DNA technique (Quantiplex 2.0, Chiron, Emery-ville, Calif., USA). Viral genotype was determined with ahybridization technique (Inno-Lipa HCV, Innogenetics,Zwijnaarde, Belgium). Viral load and genotype were deter-mined prior to inclusion. A qualitative HCV RNA wasperformed prior to inclusion, at the start of treatment and at2, 4, 12 and 26 weeks. HCV RNA was also measured 39 and52 weeks after the start of therapy (3 and 6 months’ follow-up).

Liver biopsyA liver biopsy was obtained prior to treatment (maximum

24 months before the start of treatment) in all patients exceptfour; three haemophiliacs and one patient who refrained fromhaving a biopsy were also included in the study. The liverbiopsy was initially evaluated by a local pathologist. Allbiopsies were evaluated by one pathologist (NR) who had noknowledge of clinical or biochemical data. The Knodellhistology activity index score (HAI) was used (21). At least� ve portal tracts had to be present in the specimen for thebiopsy to be accepted for evaluation. In� ammation wasassessed by haematoxylin and eosin staining and � brosis withthe Gomori technique.

Statistical analysisVariables were compared using the Pearson chi-square test,

the Fisher exact test (two-tailed) or the Mann-Whitney U-testwhere appropriate. Spearman correlation coef� cient was usedfor correlation analysis. Univariate and multivariate analyseswere performed using logistic regression. When performingmultivariate analysis, interactions between variables wereincluded in the equation. Calculations were performed using

Scand J Gastroenterol 2002 (3)

IFN Induction and Hepatitis C 345

Scan

d J

Gas

troe

nter

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

9/13

For

pers

onal

use

onl

y.

SPSS for Windows (release 9.0, Chicago, Ill., USA) andStatistica, version 4.5 for Windows. A P level <0.05 wasconsidered signi� cant. Data were analysed according to anintention-to-treat analysis unless otherwise stated.

Results

Baseline characteristicsThe study populations in the two groups were similar as

concerns both demographic and laboratory data (Table I). Itappears from the table that none of the patients had severehyperbilirubinaemia, thrombocytopenia or coagulopathy.

Virological response during treatmentAll response data were analysed according to an intention-

to-treat analysis. Table II shows that HCV RNA clearanceoccurred much more rapidly in the induction group, whereonly 3/36 patients were not HCV RNA-negative after 4 weeks(one of these was enrolled but did not start treatment and onepatient dropped out after 1 week and was lost to follow-up).

Of the initial responders (4 weeks) who continuedtreatment, the virological breakthrough rate was similarbetween group A and group B; 24/33 and 16/21 of initial

responders in group A and B, respectively, were HCV RNA-negative at end of treatment (26 weeks).

Sustained virological responseAt 52 weeks (6 months’ follow-up), 22/36 (61%) and 10/35

(29%) of the patients were HCV RNA-negative in groups Aand B, respectively (statistical analysis of this difference hasnot been performed because a strict selection of patients wasmade after 4 weeks of treatment). Among initial responders (4weeks’ HCV RNA-negative), 22/33 and 10/21 were HCVRNA-negative at 52 weeks in groups A and B, respectively(P = 0.09). Of end-of-treatment responders, 22/24 and 10/16in groups A and B were HCV RNA-negative (P = 0.026) at 6months’ follow-up.

The sustained virological response rates among patientswho completed treatment and follow-up without dose reduc-tion (per protocol analysis) were 71% (22/31) in group A and33% (10/30) in group B.

Biochemical responseAmong sustained virological responders, none had elevated

ALT levels at 6 months’ follow-up. The number of virologicalresponders with elevated ALT levels at the different time-points is indicated in Table IV. It also appears that IFN

Table I. Demographic data of study patients

Group A (Induction IFN; n = 36) Group B (Standard IFN; n = 35)

Age (median–range) 35.6 (18–63) 36.8 (19–68)Men/Women 19/17 20/15Body weight (kg) median (range) 72.3 (47–112) 73.2 (48–97)Genotype

2b 7 63a 29 29

Viral load genotype median (range) 0.78 (0.2–3.0) 1.12 (0.2–3.0)Previous intravenous drug users 66% 62%ALT levels (U/l) median (range) 109 (48–376) 102 (50–418)Albumin (g/l) mean (range) 43.4 (34–53) 43.9 (32–497)Platelets (109/l) mean (range) 232 (112–347) 246 (128–382)Coagulation factors (% of normal) mean (range) 91 (57–120) 90 (53–150)Bilirubin (mmol/l) mean (range) 11.6 (3–39) 11.4 (4–32)HAI index—mean (s) 5.7 (2.2) 5.6 (2.1)

HAI = hepatic activity index.s = standard deviation .

Table II. Number of patients and percentage s being HCV RNA-negative during and following treatment

Weeks after start of treatment

2 4 12 26 39* 52**

Group A (n = 36) 31 (86%) 33 (92%) 24 (67%) 24 (67%) 23 (64%) 22 (61%)Group B (n = 35) 14 (40%) 21 (60%) 16 (46%) 16 (46%) 12 (34%) 10 (35%)P 0.006 0.01

Data presented as intention-to-treat-analysis . All non-responder s (HCV RNA-positive at 4 weeks) were considered HCV RNA-positive atall later time points.

* 3 months’ follow-up. ** 6 months’ follow-up.P values are not given for time points after 4 weeks because patients continuing treatment were selected on the basis of the 4 weeks’ HCV

RNA result.

Scand J Gastroenterol 2002 (3)

346 K. Bjøro et al.

Scan

d J

Gas

troe

nter

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

9/13

For

pers

onal

use

onl

y.

induction patients much more frequently had an early viralclearance without concomitant ALT normalization.

Predictors of sustained virological responseIn order to evaluate the in� uence of pretreatment factors on

the possibility of achieving a sustained virological response,uni- and multivariate analyses were used. In a univariateanalysis, the following parameters were associated with asustained virological response (intention-to-treat-analysis);low age (r = 0.12, P = 0.01), female gender (r = 0.15,P = 0.02) and HCV RNA negativity at 14 days (r = 0.33,P < 0.0001). The following factors were not associated withsustained virological response: weight, viral load, ALT levels,GT levels, Knodell’s score, � brosis score, steatosis score andmode of acquisition. In a multivariate analysis, low age(r = 0.14, P = 0.04) and HCV RNA negativity at 14 days(r = 0.18, P = 0.02) remained as the only independentsigni� cant predictors of sustained virological response.

Adverse eventsAdverse events were reported by most patients (56/69) who

started therapy. During the � rst 4 weeks, group A patientsreported more adverse events (fever, muscle pain, asthenia

and headache) than those in group B (90% versus 68% ofpatients). Severe neutropenia (<1.0 109/l), however, was theonly reason for dose reduction during the � rst 4 weeks (4patients in group A compared to 1 patient in group B). Onepatient in group A stopped treatment (unknown reason)during the � rst 4 weeks and was lost to further follow-up.Adverse events during the later part of treatment (weeks 5–26) were similar in the two groups of patients. Dose reductionduring the last 22 weeks of treatment was necessary in onepatient in both groups—psoarisis in one and neutropenia inanother. Thyroid disorders were seen in two patients in groupA and in one patient in group B.

Discussion

In the present study, we have randomized a highly selectedgroup of patients to receive standard IFN monotherapy orhigh initial IFN monotherapy followed by the standard dose.The patients were selected on the basis of genotype, viral loadand the absence of cirrhosis. Most patients who achieve asustained virological response to IFN montherapy are HCVRNA-negative within 4 weeks of treatment (22). We thuschose to evaluate our patients for response after 4 weeks.

Fig. 1. Flow chart of patients included in the study.

Table III. Number of initial (4 weeks) responder s who were HCV RNA-negative during rest of treatment and during follow-up

12 weeks 26 weeks 39 weeks* 52 weeks** Relapse rate

Group A (n = 33*) 24 (73%) 24 (73%) 23 (70%) 22 (67%) 2/24 (8%)Group B (n = 21*) 16 (76%) 16 (76%) 12 (58%) 10 (48%) 6/16 (38%)#

* Only 4-week responder s are included in the table, as non-responder s at 4 weeks stopped treatment and were offered interferon /ribavirincombination therapy.

# P = 0.026 as compared to group A.

Scand J Gastroenterol 2002 (3)

IFN Induction and Hepatitis C 347

Scan

d J

Gas

troe

nter

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

9/13

For

pers

onal

use

onl

y.

Those who did not respond to treatment by becoming HCVRNA-negative, were offered combination treatment (IFN andribavirin) outside protocol.

The treatment period in the present study was limited to 26weeks. It is well known that 52 weeks’ IFN monotherapy issuperior to 26 weeks (23). However, no such data areavailable for our highly selected group of patients. The veryhigh sustained virological response rate among those receiv-ing IFN induction in our study supports the shorter treatmentduration selected. Admittedly, the response rate might havebeen further increased if all patients had been treated for 52weeks. The overall sustained response rate (61%) amongthose receiving IFN induction, however, was only slightlylower than that reported by Poynard et al. (24) for genotype 2/3 and low viral load patients receiving IFN-ribavirincombination therapy (71% and 65% with 24 and 48 weeks’treatment, respectively) and clearly higher than that observedwith IFN monotherapy (26% and 40% with 24 and 48 weeks’treatment, respectively).

IFN induction therapy increased the initial viral clearancesigni� cantly and thus more of these patients continuedtreatment than did those receiving standard IFN monotherapy.Sustained response and end-of-treatment response can only beevaluated among those who had responded at 4 weeksbecause non-responders at 4 weeks stopped IFN monother-apy. A few of these patients might have achieved viralclearance by prolonging the treatment. As the initial responsediffered markedly between the two groups, comparing end-of-treatment and follow-up data between all patients in bothgroups is not justi� ed. Comparison of the further courseamong initial responders, however, is of major interest. Ourstudy indicates a slightly higher breakthrough rate amongthose receiving IFN induction, which is not surprising as theinitial response might depend on the high IFN dose. Thenumber of patients is small, however, and the difference notstatistically signi� cant.

Of more interest, however, is the fact that IFN inductionseems to protect against relapse in end-of-treatment respon-ders. Only 2/24 (8%) of the IFN induction patients who wereHCV RNA-negative at 26 weeks had a relapse compared with6/16 patients (38%) among those receiving standard IFN; thelatter relapse rate is in concordance with previous observa-tions (2–4).

Even though the initial high IFN dose (induction) causedmore side effects than the standard dose, preterm terminationof treatment was not necessary in any patients, and the drop-out rate was remarkably low and not higher in the inductiongroup compared to the standard group.

This study demonstrates a high response rate to IFNmonotherapy in patients with genotype 2b/3a, a low viral loadand no cirrhosis. IFN induction therapy seems to protectagainst relapse following the end of treatment. However, thestudy does not provide data on whether this highly selectedgroup of patients should be offered IFN monotherapy withinduction rather than IFN and ribavirin as � rst-line treatment.Further, the study demonstrates that induction IFN mono-therapy might be a valid approach to treatment in suchpatients—at least if they do not tolerate ribavirin. The presentmodel of treating this highly selected group of patients mightthus represent an alternative to IFN and ribavirin combinationtherapy.

AHA study group

Patients were included at the following centres: AkerUniversity Hospital (H. Bell), Akershus Central Hospital(K. B. Hellum), Buskerud Central Hospital (S. Ritand),Bñrum Hospital (A. Bucher), Haugesund Hospital (J.é stborg), Harstad Hospital (Walle), Haukeland UniversityHospital (N. Langeland, S. Lund-Tønnesen), KongsvingerHospital (S. Wetterhus), Lovisenberg Hospital (P. Gerlyng),Molde Hospital (O. Lange), National Hospital (K. Bjøro),Oppland Central Hospital (E. Reinertsen), Orkdal Hospital (J.Langtind), Rogaland Central Hospital (B. Døskeland, S.Størset), Telemark Central Hospital (J. Paulsen), TromsøUniversity Hospital (J. Kvamme), Trondheim UniversityHospital (B. Viggen), Tynset Hospital (V. Høeg), UllevaÊ lUniversity Hospital (B. Myrvang, A. Mñland, B. von derLippe), é stfold Central Hospital (P. Sandvei, T. Søberg).

Acknowledgements

Lien My Diep provided invaluable help with the statisticalanalysis and Benedikte R. Bjøro has ensured that the databasehas been maintained and data retrieved and recorded.

References

1. Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr,Perrillo RP, et al. Treatment of chronic hepatitis C withrecombinant interferon alfa. A multicenter randomized , con-trolled trial. Hepatitis Interventiona l Therapy Group. N Engl JMed 1989;32:1501–6.

2. Tine F, Magrin S, Craxi A, Pagliaro L. Interferon for non-A, non-B chronic hepatitis . A meta-analysi s of randomised clinical trials.Meta-Analysis . J Hepatol 1991;13:192 –9.

3. Poynard T, Leroy V, Cohard M, Thevenot T, Mathurin P, OpolonP, et al. Meta-analysi s of interferon randomized trials in thetreatment of viral hepatitis C: effects of dose and duration.Hepatology 1996;24:778 –89.

4. Bjøro K, Krarup H, Bell H, Christopherse n P, Evensen S, Froland

Table IV. Number of virologica l responder s having elevated ALTlevels during and following treatment (pooled data from bothgroups)

Weeks after start of treatment

2 4 12 26 39 52

HCV RNA-negative 45 54 40 40 35 32HCV RNA-negative

with elevated ALT10 8 5 4 2 0

Group A/Group B 9/1 7/1 3/2 2/2 1/1

Scand J Gastroenterol 2002 (3)

348 K. Bjøro et al.

Scan

d J

Gas

troe

nter

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

9/13

For

pers

onal

use

onl

y.

SS, et al. Two dose regimens of recombinant interferon-alpha-2 bin chronic hepatitis C virus infection . Biochemistry , hepatitis Cvirus RNA, and liver histology as response indices. Scand JGastroentero l 1995; 30:1119–24.

5. Bell H, Hellum K, Harthug S, Maeland A, Ritland S, Myrvang B,et al. Genotype, viral load and age as independen t predictors oftreatment outcome of interferon-alph a 2a treatment in patientswith chronic hepatitis C. Construct group. Scand J Infect Dis1997;29:17–22.

6. Zein NN, Rakela J, Krawitt EL, Reddy KR, Tominaga T, PersingDH. Hepatitis C virus genotypes in the United States:epidemiology , pathogenicity , and response to interferon therapy.Collaborative Study Group. Ann Int Med 1996;125:634–9.

7. Liang TJ, Rehermann B, Seeff LB, Hoofnagle JH. Pathogenesis ,natural history, treatment, and prevention of hepatitis C. Ann IntMed 2000;132:296 –305.

8. Idilman R, De Maria N, Colantoni A, Dokmeci A, Van Thiel DH.Interferon treatment of cirrhotic patients with chronic hepatitis C.J Viral Hepatit 1997;4:81–91.

9. Reichard O, Foberg U, Fryden A, Mattsson L, Norkrans G,Sonnerborg A, et al. High sustained response rate and clearanceof viremia in chronic hepatitis C after treatment with interferon -alpha 2b for 60 weeks. Hepatology.1994;19:280 –5.

10. Poynard T, Leroy V, Cohard M, Thevenot T, Mathurin P, OpolonP, et al. Meta-analysi s of interferon randomized trials in thetreatment of viral hepatitis C: effects of dose and duration.Hepatology. 1996;24:778 –89.

11. Lam NP, Neumann AU, Gretch DR, Wiley TE, Perelson AS,Layden TJ. Dose-dependen t acute clearance of hepatitis Cgenotype 1 virus with interferon alfa. Hepatology 1997;26:226–31.

12. Ouzan D, Babany G, Valla D, Opolon P. Comparison of highinitial and � xed-dose regimens of interferon-alpha2 a in chronichepatitis C: a randomized controlled trial. French MulticenterInterferon Study Group. J Viral Hepatitis 1998;5:53–9.

13. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE,Layden TJ, et al. Hepatitis C viral dynamics in vivo and theantiviral ef� cacy of interferon-alph a therapy. Science 1998;282:103–7.

14. Reddy RK, Layden T, Hollinger B. Interferon alfacon-1induction therapy: a multicenter trial in subjects with chronichepatitis C virus infection. Hepatology 2000;32 Suppl 4:837A.

15. Sjogren MH, Holtzmuller C, Sjogren. Failure of interferoninduction dosing to alter sustained response rates in patients withchronic hepatitis C. Gastroenterolog y 2000;118 Suppl 4: 6739A.

16. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, LeeWM, Rustgi VK, et al. Interferon alfa-2b alone or in combinationwith ribavirin as initial treatment for chronic hepatitis C.Hepatitis Interventiona l Therapy. N Engl J Med 1998;339:1485–92.

17. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G,et al. Randomised trial of interferon alpha2b plus ribavirin for 48weeks or for 24 weeks versus interferon alpha2b plus placebo for48 weeks for treatment of chronic infection with hepatitis Cvirus. Internationa l Hepatitis Interventiona l Therapy Group.Lancet 1998;352:1426 –32.

18. Bjøro K, Bell H, Hellum KB, Skaug K, Raknerud N, Sandvei P,et al. The effect of combined interferon-a induction therapy andribavirin on chronic hepatitis C virus infection—a randomisedmulticenter study. Scand J Gastroenterol . In press.

19. Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T. Hepatitis Cinfection in patients with primary hypogammaglobulinemi a aftertreatment with contaminated immune globulin. N Engl J Med1994;331:1607 –11.

20. Garson JA, Ring CJA, Tuke PW. Improvement of HCV genomdetection with `short’ PCR products. Lancet 1991;338:1466 –7.

21. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, KaplowitzN, et al. Formulation and application of a numerical scoringsystem for assessing histologica l activity in asymptomaticchronic active hepatitis . Hepatology 1982;5:431–8

22. Lee WM, Reddy KR, Tong MJ, Black M, van Leeuwen DJ,Hollinger F, et al. Early hepatitis C virus-RNA responses predictinterferon treatment outcomes in chronic hepatitis C. TheConsensus Interferon Study Group. Hepatology 1998;28:1411 –5.

23. Poynard T, Leroy V, Cohard M, Thevenot T, Mathurin P, OpolonP, et al. Meta-analysi s of interferon randomized trials in thetreatment of viral hepatitis C: effects of dose and duration.Hepatology 1996;24:778 –89.

24. Poynard T, McHutchison J, Goodman Z, Ling MH, Albrecht J. Isan `A la carte’ combination interferon alfa-2b plus ribavirinregimen posible for the � rst line treatment in patients withchronic hepatitis C? Hepatology 2000;31:211–8.

Received 5 April 2001Accepted 29 August 2001

Scand J Gastroenterol 2002 (3)

IFN Induction and Hepatitis C 349

Scan

d J

Gas

troe

nter

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/2

9/13

For

pers

onal

use

onl

y.