Journal of Gastroenterology and Hepatology

(2002)

17,

577–581

Blackwell Science, LtdOxford, UKJGHJournal of Gastroenterology and Hepatology0815-93192002 Blackwell Science Asia Pty Ltd

172711

IFN with ribavirin for chronic hepatitis CZ Abbas

10.1046/j.0815-9319.2002.02711.xHCV AND HBV INFECTION: GENERAL PRACTICE IN AUSTRALIA AND MORTALITY IN NEWZEALAND577581BEES SGML

Correspondence: Dr Zaigham Abbas, Department of Medicine, The Aga Khan University Hospital, Stadium Road, Karachi74800, Pakistan. Email: zaigham@akunet.org

Accepted for publication 30 November 2001.

HCV AND HBV INFECTION: GENERAL PRACTICE IN AUSTRALIA AND MORTALITY IN NEW ZEALAND

High sustained response to daily dosing of interferon with ribavirin in chronic hepatitis C patients naïve to therapy

ZAIGHAM ABBAS,* SAEED HAMID

†

AND SHAESTA TABASSUM

†

Departments of Medicine,

*

Jinnah Postgraduate Medical Center and

†

The Aga Khan University Hospital, Karachi, Pakiatan

Abstract

Background

: Viral kinetics suggests that daily administration of

α

-interferon (IFN) will clear hepatitisC virus (HCV) RNA earlier and more frequently compared with standard t.i.w. To reduce the likelihoodof viral replication, mutation and subsequent development of resistance, daily dosing with IFN may beappropriate. To determine the safety and efficacy of daily IFN with ribavirin in chronic HCV infectionwe performed a prospective study.

Methods

: Thirty-five naïve adult HCV-positive patients (25 male/10 female) were treated with IFN-

α

2b;5 MU daily for 2 weeks followed by 3 MU daily for 22 weeks and ribavirin 800–1200 mg/day dependingon weight. Liver biopsy, performed in 25 patients, showed mild to moderate activity in 19 patients (76%)and severe activity in six patients (24%). Two patients showed staged IV fibrosis. Serotyping wasperformed in 29 patients by an enzyme immunoassay-based Murex assay. Type 3 was the predominantserotype, present in 14 cases. Hepatitis C virus RNA was measured by the Chiron bDNA assay.

Results

: Mean baseline HCV-RNA level was 14.2

±

18.7 MEq/mL (median 6.09; range 0.2–92.5),which became undetectable in all but three patients at week 4. Normalization of alanine aminotrans-ferase (ALT) at week 4 was seen in 27 patients. Three patients withdrew due to non-compliance. Thirty-two patients completed 24 weeks of therapy as per the protocol. At the end of treatment, the HCV-RNAlevel was negative in 29 of 32 patients (90.6%) and ALT was normal in 31 of 32 patients (97%).Sustained viral response at 6 months follow up was seen in 28 of 32 patients (88%). The ALT level wasnormal in 28 of 32 patients (88%).

Conclusion

: Daily administration of IFN with ribavirin is well tolerated in the majority of patients.There is rapid elimination of virus with normalization of ALT and a significantly high sustained viralresponse.© 2002 Blackwell Publishing Asia Pty Ltd

Key words

: daily interferon, hepatitis C, ribavirin, treatment-naïve patients.

INTRODUCTION

The beneficial effect of

α

-interferon (IFN) in patientswith chronic hepatitis C is well established.

1

Combina-tion therapy of IFN and ribavirin is found to be superiorto IFN monotherapy in achieving a sustained biochemi-cal and virologic response at the end of the treatmentand after 24 weeks treatment-free follow-up period.

2–5

Patients who attain a sustained response to IFN therapyusually show a rapid clearance of hepatitis C virus(HCV)-RNA within 4 weeks of initiation of treatment.

6,7

The HCV-RNA clearance within the first week is asso-

ciated with a 76% chance of maintaining a sustainedresponse.

8

Therefore, early elimination of virus is impor-tant and seems to be a predictor of sustained response.

Hepatitis C virus has a high rate of turnover with an

in vivo

half-life of only a few hours,

9,10

whereas the half-life of IFN is approximately 8 h. In patients receivingIFN thrice weekly, intermittent increases occur in theviral load on treatment-free days. Sustained action withdaily IFN is expected to reduce viral replication thatoccurs on days without IFN and the risk of mutationsleading to appearance of quasispecies is reduced. It hasbeen shown that daily administration of IFN in chronic

578

Z Abbas

et al.

hepatitis C patients clears HCV-RNA earlier and morefrequently compared with the standard t.i.w. sched-ule.

11,12

It appears logical to use IFN daily instead oft.i.w. to promptly attain a steady rate of drug concen-tration that totally inhibits viral replication.

Daily IFN therapy has been used in the inductionphase of treatment.

12–14

Daily IFN therapy in the con-tinuation phase is expected to improve the compliance ofpatients by reducing the total period of therapy, improvethe response rate and decrease the risk of developmentof quasispecies. The aim of the present study was to eval-uate the safety and efficacy of 24 weeks therapy of dailyIFN in combination with ribavirin during the inductionand continuation phase for treatment-naïve hepatitis Cpatients predominantly infected with type 3 HCV.

METHODS

Adult patients, 18–65 years of age, previously untreatedfor chronic hepatitis C were eligible for inclusion in thestudy. All patients were required to be HCV antibodypositive (Abbott ELISA, 3rd generation; AbbottLaboratories, North Chicago, IL, USA) and HCV-RNApositive (Amplicor HCV Monitor; Roche MolecularSystems, Nutley, NJ, USA) and hepatitis B s antigen(HBsAg) negative (Abbott ELISA). Other laboratorycriteria for inclusion were a hemoglobin concentration ofmore than 10 g/dL, a white cell count > 3000 mm

3

, plate-lets > 100 000 mm

3

, prothrombin time no more than 2 sprolonged compared with control, direct bilirubin< 0.5 mg/dL, indirect bilirubin < 1.0 mg/dL, albumin> 3.0 g/dL, serum creatinine < 1.4 mg/dL and a normalserum thyrotropin-stimulating hormone (TSH) level.Patients at risk of an ischemic coronary event, hyper-tension or poorly controlled diabetes mellitus, patientswith evidence of decompensated liver disease, such as ahistory or presence of ascites, patients with bleedingvarices, encephalopathy, any known pre-existing medicalcondition that could interfere with participation in andcompletion of the treatment, such as a pre-existing psy-chiatric condition, especially severe depression, activeseizure disorders requiring medication, hemoglobin-opathies, excluding thalassemia minor, hemophilia,chronic pulmonary disease (e.g. chronic obstructive pul-monary disease) and immunologically mediated diseasewere excluded from the study. Sexually active females ofchildbearing potential were advised to practice adequatecontraception during the treatment period and for 6months after discontinuation of therapy and to avoidbreast-feeding during the treatment period.

A liver biopsy was advised prior to therapy for everypatient. However, a patient’s refusal of a liver biopsywas not used as an exclusion criterion. Hepatic inflam-mation and fibrosis were assed by the METAVIR scor-ing system.

15

The stage of fibrosis was assessed on ascale of 0–IV and activity was graded on a scale of 0–3.An abdominal ultrasound scan was obtained to rule outthe presence of obvious cirrhosis and focal liver lesions.

This open-label study was conducted at two centersin Karachi. The Institutional Human Subject Protec-tion Committee approved the study and all patientsgave signed informed consent. Patients were given the

combination of daily IFN-

α

2b plus ribavirin for 24weeks. During the 2-week induction phase, IFN-

α

2b(Intron A; Schering Plough, Kenilworth, NJ, USA) wasgiven at a dose of 5 MU, s.c., daily which was thenreduced to 3 MU daily in the continuation phase of 22weeks. Ribavirin was given orally, 600 mg twice daily forpatients weighing more than 65 kg and 400 mg twicedaily for those weighing less than 65 kg.

After baseline assessment, patients were followed upat the end of weeks 2 and 4 of treatment, then every4 weeks during treatment and at the end of weeks 12and 24 post-treatment. Biochemical and hematologicassessment was performed during these visits and side-effects were monitored. Serum HCV-RNA was deter-mined by bDNA Assay Version 2.0 (Chiron Corpora-tion, Emeryville, CA, USA) to measure the viral load atbaseline and week 2. Follow-up HCV-RNA was deter-mined at week 4, week 12, at the end of treatment and24 weeks after the end of treatment by reverse transcrip-tion–polymerase chain reaction (RT-PCR) assay with asensitivity of 100 copies/mL. The HCV genotype wasdetermined using the Murex Serotyping assay (MurexDiagnostics Inc., Norcross, GA, USA).

Statistical analysis was performed by Fisher’s exacttest. The primary efficacy end-point was defined as aloss of detectable HCV-RNA at week 24 after treatmentand at the end of follow up, while the secondary end-point was normalization of alanine aminotransferase(ALT) levels at the same time points.

RESULTS

The patients’ characteristics are given in Table 1.Thirty-five patients were enrolled, while 32 patientscompleted the study as per protocol. Two patients were

Table 1

Baseline patient characteristics

Sex (males/females) 25/10Age (years) 37.8

±

12.3 (21–68)Weight (kg) 69.1

±

14.5 (39.0–104.0)BMI (kg/m

2

) 25.2

±

4.9 (17.7–35.5)ALT (U/L) 115

±

130 (19–776)HCV-RNA (MEq/mL) 14.2

±

18.7 (0.2–92.5)Serotype (

n

= 29)3 141 75 1Untyped 7

Liver biopsy (

n

= 25)Grade 1 8Grade 2 11Grade 3 6Stage 0–1 17Stage II–III 6Stage IV 2

Where appropriate, data are the mean

±

SD, with the rangegiven in parentheses.

BMI, body mass index; ALT, alanine aminotransferase;HCV, hepatitis C virus.

IFN with ribavirin for chronic hepatitis C

579

lost to follow up, while one patient decided to over-treatherself after 24 weeks although she had responded verywell. Treatment was not stopped in anyone due toside-effects.

The mean baseline HCV-RNA level of 35 patientswas 14.2

±

18.7 MEq/mL (median 6.09; range 0.2–92.5). At week 2, 24 patients (69%) became negative forHCV-RNA by bDNA assay. In 11 positive patients, themean HCV-RNA level was 1.37 MEq/L. At week 4, weused the RT-PCR assay. Hepatitis C virus RNA wasundetectable in all but three patients who were also pos-itive at week 2. Normalization of ALT at week 4 was seenin 27 patients. Thirty-two patients completed 24 weeksof therapy as per protocol. At the end of treatment, theHCV-RNA level was negative in 29 of 32 patients (91%)and ALT was normal in 31 of 32 patients (97%). A sus-tained viral response at 6 months follow up was seen in28 of 32 patients (88%). The ALT level was normal in28 of 32 pateints (88%; Fig. 1). There were only fourpatients who did not respond to treatment in the per-protocol analysis. All these patients were more than 40years of age, with a mean age of 54 years. One patienthad a high baseline viral load of 34.8 MEq/L; anotherpatient was infected with type 1 genotype. One patienton biopsy showed stage IV disease.

The adverse effects included a decrease in thehemoglobin concentration. Baseline hemoglobin was14.0

±

1.3 g/dL, which decreased to 12.1

±

1.5 g/dL at 4weeks and 11.3

±

1.4 g/dL at 12 weeks. The hemoglobinlevel stabilized after that. Side-effects noted during thestudy were fever in 24 patients (69%), body aches in 15patients (43%), abdominal pain in 15 patients (43%),decreased appetite in 13 patients (37%), weakness in 11patients (31%), weight loss in 10 patients (29%), hairloss in eight patients (23%), vomiting in four patients(11%), leg cramps in four patients (11%), headaches inthree patients (9%), a bad taste in the mouth in threepatients (9%), diarrhea in three patients (9%), insom-nia in two patients (6%), dryness of the mouth in twopatients (6%), itching in two patients (6%), somnolencein one patient (3%) and dizziness in one patient (3%).One patient developed insulin-dependent diabetes mel-litus near the completion of the treatment. He wasadmitted with the diagnosis of diabetic ketoacidosisfrom the emergency room. His screening blood glucoselevel before starting IFN therapy was normal.

DISCUSSION

A number of studies suggest that HCV genotype 3 dem-onstrates a better response to combination therapy ofIFN given three times a week plus ribavirin comparedwith genotype 1 infection. The present study deals withthe safety and efficacy of an aggressive regimen of IFNtherapy, in combination with ribavirin, in patientsmainly infected with the type 3 HCV, with a view todemonstrating an even better response rate in the easierto treat patients. Our patients were mostly infected withHCV type 3, did not have cirrhosis, except for twopatients, and were naïve to previous IFN therapy. Wedemonstrated that aggressive therapy in such a patientgroup can lead to an 80% sustained response rate on anintention-to-treat basis and a nearly 90% response rateon a per-protocol basis.

Understanding the kinetics of hepatitis C virus isimportant to optimizing antiviral therapy. By applyingmathematical principles, the serum half-life of thevirion has been estimated to be 3 h with a viral produc-tion rate of 1.0

×

10

12

virions/day.

9,10,16,17

Thus, hugeamounts of virus particles are produced and destroyedeach day. These studies suggest that, after initiating IFNtreatment, there is an IFN dose-dependent exponentialdecline in viral RNA levels within the first 48 h. Thisrapid 1.0–2.0-log decline is best explained by an effectof IFN in inhibiting viral production with a varyingdegree of effectiveness. After this rapid first-phasedecline, there is a slower second-phase decline in virallevels, which is dependent on the rate of elimination ofHCV-infected liver cells. The rapidity of the secondphase is a predictor of early viral clearance.

9

Consider-ing very high viral kinetics, the classical t.i.w. regimensdo not seem to be suitable and consideration of moreaggressive dosing regimens, especially daily doses, isneeded.

Induction therapy uses higher than usual doses ofIFN, given on a daily, rather than three times per week,basis for a defined period.

14

The primary aim of induc-tion is to clear HCV from the peripheral blood, whilethe objective of maintenance therapy is to preventrelapse in order to achieve a sustained virologicresponse. It has been suggested that daily IFN admin-istration could gain a higher rate of serum HCV-RNAeradication in patients with chronic hepatitis C infec-tion. Daily, high-dose IFN rapidly drops HCV-RNAand increases initial and end-of-treatment responserates compared with t.i.w regimens.

18

The major goal of daily therapy is to minimize fluc-tuations in IFN levels, preventing viral rebound in peri-ods when drug levels are low. Thus, denying the virustime to recover would prevent the emergence of quasi-species.

10

Enomoto

et al

.

19

have demonstrated thatHCV mutation can occur during intermittent t.i.w IFNtherapy. This may be due to the high rate of viral turn-over and inadequate proofreading by RNA polymerase.Daily IFN therapy may reduce the risk of evolution ofquasispecies. These findings have important implica-tions for the concept of treatment of hepatitis C, whichshould shift its focus from long-term mild treatmenttowards aggressive therapy aiming at a fast viral dis-appearance within the first few days.

Figure 1

Virological ( ) and biochemical (

�

) response inper-protocol analysis (

n

= 32).

32

31

30

29

28

27

26

31

29

28 28

97% 88% 88%91%

End of treatment End of follow up

No.

of p

atie

nts

580

Z Abbas

et al.

Combination therapy of IFN plus ribavirin has beenshown to be superior to IFN monotherapy. A meta-analysis has shown that patients without cirrhosistreated with IFN–ribavirin have a significantly highersustained response rate than those treated with IFN,approximately threefold for previously untreatedpatients (IFN–ribavirin: genotype 1, 33%; genotype 2/3, 65%; IFN: genotype 1, 8%; genotype 2/3, 24%).

20

Incirrhosis, sustained response rates with IFN–ribavirin(previously untreated: genotype 1, 7%; genotype 2/3,24%) are also significantly higher than for IFN alone(previously untreated: genotype 1, 1%; genotype 2/3,5%).

20

Applying constant pressure on viral kinetics withlong-acting pegylated IFN preparations may improvethe current results of therapy. Results of two recentstudies of pegylated IFN monotherapy are comparablewith IFN–ribavirin therapy with IFN given thriceweekly.

21,22

Combining ribavirin with pegylated IFNfurther improves the results.

23

We have achieved similarresults by giving daily IFN throughout the treatmentalong with ribavirin. This is probably due to less fluc-tuation in IFN levels with daily IFN dosing, leading tomore sustained drug action.

Patients receiving daily therapy tolerated IFN well.The side-effects reported in the present study did notdiffer much to those reported with combination therapyusing t.i.w IFN.

23

It may be postulated that a steadystate of IFN levels rather than constantly fluctuatinglevels would lead to an earlier acclimatization to IFNand, thus, cause fewer side-effects. Another study hasshown that patients’ complaints were, in fact, improvedwith daily dosing of IFN.

24

One may argue that patients in this open-labeled trialwere predominately infected with non-01 type HCV,were relatively young and were mostly non-cirrhotics.This unintentional selection bias may be due to the dis-ease pattern in our part of the world. The predominantgenotype of hepatitis C in Pakistan is type 3.

25

The excel-lent response rate in these patients shows that type 3hepatitis C is a curable disease. Seven patients infectedwith type 1 disease also showed a good response.

In summary, we have shown that response rates canbe substantially improved further with an aggressivetherapy using induction and a daily IFN regimen incombination with ribavirin in a group of patients withchronic HCV type 3 infection who do not have cirrhosisand have not had previous IFN treatment.

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