combination therapy with interferon-α and ribavirin for hepatitis c

Combination Therapy withInterferon-α and Ribavirin forHepatitis CPractical Treatment Issues

Jane Collier and Roger ChapmanDepartment of Gastroenterology, John Radcliffe Hospital, Oxford, England

ContentsAbstract1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

1.1 Natural History of Chronic Hepatitis C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2261.2 Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

2. Definition of Response to Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2283. Indications for Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

3.1 Presence of HCV RNA in Serum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2283.2 Abnormal Liver Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2283.3 Extent of Histological Liver Disease (Fibrosis and Inflammation) . . . . . . . . . . . . . . . . . 228

3.3.1 Noncirrhotic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2283.3.2 Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

3.4 Previous Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2293.4.1 Patients Relapsing on Interferon (IFN)-α . . . . . . . . . . . . . . . . . . . . . . . . . . . 2293.4.2 Patients Not Responding to IFNα . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

4. Contraindications to Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2305. Factors Affecting Response Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2306. Pretreatment Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

6.1 HCV RNA Level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2316.2 Liver Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2316.3 Liver Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2316.4 HCV Genotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2316.5 Other Baseline Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2316.6 Haematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2316.7 Cardiovascular Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

7. Length of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2318. Ribavirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

8.1 Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2328.2 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

9. IFNα . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2329.1 Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2329.2 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

10.Pegylated Interferon-α . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23311.Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23312.Other Patient Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

12.1 Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

THERAPY IN PRACTICEBioDrugs 2001; 15 (4): 225-238

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12.2 Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23413.Cost Effectiveness of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23414.Other Antivirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23415.Specific Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

15.1 Acute Hepatitis C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23415.2 Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23515.3 Patients with Haemophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23515.4 Human Immunodeficiency Virus Co-Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . 23515.5 Renal Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23615.6 Organ Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

16.Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

Abstract Combination therapy with ribavirin and interferon (IFN)-α for 6 to 12 monthsis currently the treatment of choice for chronic hepatitis C infection. The overallsustained response rate to treatment, defined as loss of hepatitis C virus (HCV)from serum 6 months after completion of treatment, is 40%. The indications fortreatment are serumHCVRNApositivity, abnormal serum transaminases and thepresence of portal fibrosis and/or moderate/severe inflammation.Response rates are lower in genotype 1 than in genotype 2 or 3 and in the presence

of a high viral load. Anaemia is the most common adverse event and is due toribavirin; neuropsychiatric adverse effects due to IFNα lead to premature cessa-tion of therapy in 10 to 20% of patients.The current recommended dose of interferon is 3MU given subcutaneously 3

times a week. However, it is likely that longer-acting pegylated interferons, whichmay be more effective and can be administered once weekly, will in the futurereplace currently used IFNα.

1. Background

1.1 Natural History of Chronic Hepatitis C

Chronic hepatitis C virus (HCV) infection af-fects 1% of the population in the US, with higherprevalence rates reported in other areas of theworld, such as Egypt.[1,2]The natural history of hepatitis C infection is

still unclear, as there have been no long term pro-spective histological studies. Whether everyonewith mild liver disease will ultimately progress tocirrhosis, whether progression of fibrosis is linearwith time, and the outcome beyond 20 years frominfection remain to be clarified. It is, however,clear that up to 20% of those infected will havedeveloped cirrhosis within 20 years of infection(fig. 1). Once cirrhosis has developed, 5 to 10%will develop ascites, encephalopathy or variceal

haemorrhage within the next 10 years. Once thesecomplications develop there is a 50% mortalitywithin 5 years.[3] There is an additional risk of de-veloping hepatocellular carcinoma in the presenceof cirrhosis at a rate of 1 to 2% per year.Factors that increase the risk of disease progres-

sion include:[4]• age >40 years at the time of infection• male sex• immunosuppression (including co-infectionwith HIV and liver transplantation)

• alcohol intake >50 g/day.The genetic heterogeneity of hepatitis C led to

the classification of the virus into 6 main genotypesnumbered 1 to 6. Genotype 1a is more common innorthern Europe, whereas genotype 4 is more com-mon in Egypt. Different genotypes are associatedwith different levels of risk for disease progres-sion.[5]

226 Collier & Chapman

© Adis International Limited. All rights reserved. BioDrugs 2001; 15 (4)

Although liver transplantation is a successfultreatment for end-stage hepatitis, hepatitis C uni-versally recurs in the graft and as many as 10 to20% of patients will develop cirrhosis of the graftwithin 5 years of transplantation.The aim of treatment for hepatitis C is to stop

progression of hepatic fibrosis and the develop-ment of end-stage liver disease. Asurrogatemarkerof successful treatment is the sustained loss ofHCV RNA from serum. This is associated with animprovement in liver histology in patients biopsiedup to 8 years after treatment.[6] An improvement inliver histology has also been shown in patientstreated with interferon (IFN)-α despite persistenceof serum HCV RNA.[7]It remains controversial whether treatment with

IFNα also reduces the subsequent risk of develop-ing hepatocellular carcinoma in individuals withcirrhosis, independent of its effect on slowing dis-ease progression, as most of the studies address-ing this issue have been multicentre retrospectivecohort studies. In the largest of these, comparing

2400 treated patients with 490 untreated patients,IFNα was associated with a 50% reduction in therisk of developing hepatocellular carcinoma over5 years.[8] The risk reduction was higher in patientswho achieved a sustained virological response.However, IFNα did not appear to have an effect onreducing the incidence of hepatocellular carci-noma in a subgroup of patients with cirrhosis,probably because fewer patients in this groupachieved a sustained response. In a small prospec-tive study where 45 patients with cirrhosis wererandomised to receive IFNα and 45 were controls,IFNα resulted in a reduction of the incidence ofhepatocellular carcinoma independent of a sus-tained virological response.[9] However, this wasnot confirmed by a second prospective study,[10]and larger prospective studies are needed to estab-lish if IFNα therapy, with or without ribavirin,reduces the risk of hepatocellular carcinoma incirrhosis and whether this effect is independent ofa sustained virological response.Chronic hepatitis C infection is also associated

with an impairment in quality of life even in theabsence of cirrhosis,[11] and a significant improve-ment in quality of life has been demonstrated inthose who respond to antiviral therapy.[12]

1.2 Treatment Options

Until 1998 the only licensed treatment forchronic hepatitis C was IFNαmonotherapy. In pre-viously untreated patients, this induced a sustainedresponse rate of only 10 to 15%. In contrast, theaddition of ribavirin to IFNα monotherapy (com-bination therapy) has increased the overall sus-tained response rate to 40%.[13,14] This is still farfrom ideal and so alternative treatments are under-going clinical trials. These include triple therapywith ribavirin, IFNα and amantadine, and combi-nation therapy with longer-acting pegylated inter-ferons and ribavirin. Pegylated interferons are dis-cussed in section 10; these agents are likely toprove more efficacious than standard IFNα andmay become the treatment of choice in combina-tion with ribavirin within the next few years.

Fib

rosi

s st

age

3

0

6

0 10 20

Time from infection (years)

Moderateprogression

Slowprogression

Fastprogression

Fig. 1. Schematic representation of the different rates of hepaticfibrosis seen between patients, expressed as fibrosis grade (6= cirrhosis) against time from infection. The assumption is thatprogression occurs in a linear fashion, and it is unclear whetherfibrosis increases at the same rate 20 years after infection incases of moderate progression. Factors associated with moreprogressive fibrosis (fast progression) include age at infection,immunosuppression and alcohol intake.

Combination Treatment for Hepatitis C 227


2. Definition of Response to Treatment

Individuals who clear HCV RNA from serumduring treatment may relapse in the first 6 monthsafter treatment. However, 95% of those who areHCVRNAnegative 6 months after the end of treat-ment will remain HCV RNA negative. A responseto treatment (sustained responder) is defined as theabsence of HCV RNA from serum 6 months aftercompleting treatment. This is associated with theabsence of detectable HCV RNA in liver tissue.A ‘relapser’ is an individual who lost HCVRNA

during treatment but who becomes HCV RNApositive after completing therapy. A ‘nonrespon-der’ refers to a patient in whom HCVRNApersistsin serum during therapy and at the end of treatment.

3. Indications for Treatment

Several factors affect the decision to treat withcombination therapy (fig. 2).

3.1 Presence of HCV RNA in Serum

Treatment should be reserved for individualswho are HCV RNA positive in serum by polymer-ase chain reaction (PCR) assay. Serum levels ofHCV RNA may fluctuate and so 3 negative HCVRNAsamples taken over a 6-month period are nec-essary before concluding a patient is HCV RNAnegative. About 20% of patients are consistentlyHCV RNA negative.

3.2 Abnormal Liver Biochemistry

Currently only individuals with abnormal serumtransaminases should be treated, as the responserate and safety of combination therapy given tothose with normal liver biochemistry have not beenassessed. There are, however, similar responserates to combination therapy in those with mildelevations of serum transaminases (up to 1.3 timesthe upper limit of normal) and those with higherlevels, in contrast to treatment of hepatitis B.[15]

3.3 Extent of Histological Liver Disease(Fibrosis and Inflammation)

3.3.1 Noncirrhotic DiseaseIndications for treatment based on liver histol-

ogy remain controversial, and clinical practice iseither to:• treat all patients irrespective of extent of hepaticfibrosis/inflammation

• reserve treatment for patients with moderatefibrosis and/or inflammation.Those who advocate universal treatment do so

on the premise that all patients will eventually de-velop cirrhosis and that treatment is more likely tobe effective in the presence of mild disease andearly in the course of infection.The opposing argument is that although 20% of

individuals develop cirrhosis within 20 years of in-fection, it is unclear whether all patients with milddisease will eventually progress to cirrhosis if fol-lowed up for long enough. Thus it can be arguedthat because combination therapy is less than 50%effective, this approach should be reserved forthose with evidence of liver disease who may notbe able to wait the 5 to 10 years it may take for amore effective treatment to become available.The European Association for the Study of the

Liver, National Institutes of Health consensus con-ferences, and the National Institute for ClinicalExcellence (UK) have concluded that in previouslyuntreated patients, combination therapy should beconsidered in the presence of moderate/severenecroinflammation and/or fibrosis.[16,17] Patientswith mild inflammation or no fibrosis should beobserved or entered into clinical trials.

3.3.2 CirrhosisThe response rate in patients with cirrhosis

treated with interferon monotherapy is half that ofunaffected patients. However, there are few pub-lished data on the response to combination therapywith ribavirin, as only 5% of those included in the2 combination treatment studies had cirrhosis.In the future, pegylated interferon in combina-

tion with ribavirin may prove to be effective in pa-tients with cirrhosis, as provisional data haveshown a sustained response rate of 29% to mono-



therapy with pegylated interferon, compared with6% with standard IFNα.[18]Patients with compensated cirrhosis (no ascites/

encephalopathy) should be considered for combi-nation therapy but closer monitoring for evidenceof thrombocytopenia and neutropenia is needed.Further larger studies are needed to confirm that a40% response rate can be achieved with combina-tion therapy in this group.

3.4 Previous Treatment

3.4.1 Patients Relapsing on Interferon (IFN))))-αPatients who have previously been treated with

IFNα monotherapy for 5 to 18 months but who

relapse after stopping treatment should be re-treated with IFNα and ribavirin for at least 6 monthsand probably 12months if genotype 1. The sustainedresponse rate after 6 months’ treatment in thisgroup is 30 to 40%.[19,20]

3.4.2 Patients Not Responding to IFNαSix months of combination treatment with

IFNα/ribavirin did not improve the response in pa-tients who failed to respond to IFNαmonotherapy(i.e. remained HCV RNA positive after 3 to 6months’ treatment with interferon alone).[20,21] In ameta-analysis of 9 controlled trials involving non-responders to monotherapy, the overall sustainedvirological response rate to 6 months of combina-

Repeat HCV RNA3 and 6 monthsafter treatment

Stop treatment

Sustained responder

Treat for further 6 months

Stop treatment Assess favourable factors:[18]

FemaleViral genotype 2 or 3Portal fibrosis onlyAge <40 yearsViral load <3.5 ×106/ml

Hepatitis C RNA

Liver biopsy

No hepatic fibrosis/mild inflammation

Portal fibrosis/moderate inflammation

No treatment Ribavirin/interferon-α

6-month HCV RNA

negative

4 or 5 Less than 4

positive negative

yes yes

Fig. 2. Algorithm for treatment of hepatitis C. If HCV quantification is not available, stop treatment at 6 months if genotype 2, 3;otherwise, continue for a further 6 months. HCV = hepatitis C virus.



tion therapy was 13%.[22] However, it may bepossible to eradicate HCV RNA in IFNα nonres-ponders by using a longer duration of combinationtherapy. Several recent small studies have reportedsustained response rates up to 30% following 48weeks of combination therapy.[22]

4. Contraindications to Treatment

Contraindications to treatment are shown in ta-ble I.Although a platelet count of <75 × 109/L is a

relative contraindication to treatment, it is possibleto treat patients with cirrhosis with platelet countsof 50 to 75 × 109/L provided there is careful weeklymonitoring of platelet counts and by starting IFNαat a lower dose of 1 to 1.5MU (increasing to 3MUif tolerated).

5. Factors Affecting Response Rate

The end-point of treatment with ribavirin andIFNα is loss of HCV RNA6 months after stoppingtherapy. 95% of individuals who were HCV RNA

negative 6 months after completing IFNα mono-therapy remained negative up to 8 years later.[6]Sustained loss of HCV RNA is associated with im-provement in liver histology 5 years after stoppingtreatment.The overall response rate to combined therapy

is 40% but several factors affect response rates,the most important of which is viral genotype(fig. 3).Baseline factors associated with a sustained loss

of HCV RNA following treatment include:[23]• HCV RNA <3.5 × 106 copies/ml• viral genotype 2 and 3• no fibrosis or portal fibrosis• female sex• age <40 years.Combination therapy is usually restricted to

patients aged <70 years, as treatment is unlikely toaffect mortality in the elderly because of the chro-nicity of the condition.

Sus

tain

ed r

espo

nse

(% o

f pat

ient

s)

70

60

50

40

30

20

10

0

Genotype

1,4,5,6 2 and 3

Fig. 3. Effect of viral genotype on response rates to combinationtherapy.

Table I. Contraindications to interferon-α and ribavirin combinationtherapy

Absolute RelativeRibavirin

Pregnancy Unstable CADUnreliable method of contraceptionEnd-stage renal failure

Anaemia (haemoglobin <11 g/dl)HaemoglobinopathiesInterferon-αActive alcohol consumption Neutrophils <1000/dlCurrent intravenous drug use Platelets <75 × 109/LPoor compliance Uncontrolled diabetes

Untreated depressionDecompensated cirrhosisa

Renal failurePost-organ transplantation (exceptliver)Uncontrolled seizures

Severeneutropenia/thrombocytopeniaAutoimmune diseasea Ascites, hepatic encephalopathy, jaundice, variceal haemor-

rhage, Child’s grade C.CAD = coronary artery disease.



6. Pretreatment Assessment

6.1 HCV RNA Level

HCV RNA is measured in serum by PCR. Thelower limit of detection is 100 copies/ml. HCVRNA can also be quantified by use of a variety ofhybridisation techniques. It is important to realisethat different assays have different sensitivities.[24]Quantification of viral load is needed in somepatients to decide the optimal length of treatment(see section 7).

6.2 Liver Biochemistry

The response to combination therapy is notinfluenced by the extent of elevation of serumtransaminases.[15]

6.3 Liver Biopsy

Biopsy is necessary to quantify the amount ofhepatic inflammation or fibrosis. There are severalscoring systems in use, including the Knodell,Scheuer, Ishak and more recently the METAVIRsystem.[25] Although they all produce differentscores, each evaluates the fibrosis and inflamma-tion as separate components. There is obviouslyboth interobserver variation in scoring liver biop-sies and intraindividual variation, although thelatter is not as marked as in biliary disease, whereit is possible to see all stages of fibrosis in a singleliver.

6.4 HCV Genotype

Viral genotype needs to be determined beforestarting treatment, as individuals infected withgenotype 1 virus require treatment for longer thanthose with genotype 2 or 3. Those with genotypes4, 5 and 6 should also be treated for 12 months.Treatment should be similar to that for individualswith genotypes 2 and 3.

6.5 Other Baseline Investigations

These investigations include thyroid functiontests, glucose, renal function, liver biochemistry,uric acid, prothrombin time and a pregnancy test.

6.6 Haematology

A full blood count is necessary, as low haemo-globin, platelet count or neutrophil count are rela-tive contraindications to treatment.

6.7 Cardiovascular Assessment

Abaseline chest radiograph and ECG should beperformed in patients over the age of 40 years. Un-stable coronary artery disease is a contraindicationto treatment, as ribavirin-associated falls in haemo-globin may exacerbate poorly controlled symp-toms (see section 8.2).

7. Length of Treatment

Combination treatment should initially be givenfor 24 weeks. Unlike with IFNαmonotherapy, it isnot yet possible to predict response on the basis ofan HCV RNA level at 12 weeks, as 10% of thosewho are HCV PCR positive at 12 weeks will sub-sequently clear virus. If the 24-week HCV RNAPCR remains positive, treatment should bestopped.[23] It is possible that evaluation of viralload during the early treatment phase may in thefuture allow nonresponders to be identified before6 months of treatment is completed, which obvi-ously would have cost benefits.In patients with fewer than 4 favourable prog-

nostic factors (genotype 2 or 3, female, no or portalfibrosis, initial viral load <3.5 × 106 copies/ml,age <40 years) treatment should be continued fora further 24 weeks. Thus, men with genotype 1b(the most common in Northern Europe) require 12months’ therapy.If viral load is not available, it is reasonable to

decide the length of treatment on the basis of viralgenotype alone. Patients with genotype 2 and 3should be treated for 6 months and other genotypes(predominantly type 1) for 12 months.Overall, about 10% of patients treated for 6

months will have to stop treatment because of drugtoxicity, as will 20% of those treated for 12months.The most frequent symptom requiring discontinu-ation of therapy is emotional disturbance, mainlydepression.



8. Ribavirin

8.1 Dose

The dose of ribavirin is determined by bodyweight. Ribavirin is given orally twice daily at atotal dose of 1000mg (<75kg) or 1200mg (>75kg).

8.2 Adverse Events

The principal adverse event associated withribavirin treatment is anaemia. The haemoglobinstarts to fall 1 week after starting therapy and sta-bilises at 4 weeks, with a mean fall of 2 to 3g. Ifthe haemoglobin drops below 10 g/dl or the patientis symptomatic, ribavirin dose can be reduced to600 mg/day. Dose reduction is needed in about 6%of patients (table II). The half-life of ribavirin isabout 13 days and so dosemodifications should notbe made more frequently than every 1 to 2 weeks.If ribavirin is omitted because of toxicity it shouldnot be restarted within 1 week.Dyspnoea, rash, and nausea and anorexia have

also been reported.

9. IFNα

9.1 Dose

The current standard dose is 3MU of IFNα self-administered subcutaneously 3 times per week.Prefilled pen cartridges ensure correct dosing. Theoptimum dose and timing of treatment with IFNαare still unclear. Studies using IFNα monotherapyin hepatitis C have shown that the response ratescould be improved by:• daily administration of 3MU IFNα for the first7 to 10 days

• increasing the IFNα dose to 6MU 3 times aweek

• using pegylated interferon-α.

However, to date all the trials of combinationtherapy with ribavirin and IFNα have been under-taken using IFNα 3MU 3 times per week. All thecurrently marketed IFNα (2a, 2b, recombinant andnonrecombinant) are equally efficacious.

9.2 Adverse Events

Adverse events are common. After administra-tion of IFNα, the most important early effect isflu-like symptoms after 4 hours. These symptomscan be ameliorated by taking paracetamol (acet-aminophen) 1g before the injection. Nonsteroidalanti-inflammatory drugs given short term may alsobe needed in the first week of treatment. Thesesymptoms are less severe after subsequent injec-tions and usually resolve by the second week oftreatment. Other symptoms that often persist dur-ing treatment include fatigue associated with bothincreased sleepiness and difficulty sleeping, irrita-bility, anorexia, weight loss and low mood.Other reported symptoms include:

• gastrointestinal symptoms: anorexia, vomitingand diarrhoea occur in up to 20% of cases; nau-sea is more common

• psychiatric symptoms: depression is reported inup to 36% of cases and is the most commonreason for discontinuation of therapy

• respiratory symptoms: dyspnoea occurs inabout 20% of cases; cough and pharyngitis alsooccur

• alopecia: this occurs in about 30% of cases• retinopathy: retinopathy with cotton wool spotsrarely occurs with low-dose interferon therapy(1% of cases); optic tract neuropathy has alsobeen reported[26]

• thyroid disease: thyroid dysfunction occurs in6% of cases (hypothyroidism is more commonthan hyperthyroidism); risk factors for thyroid

Table II. Dose reductions for haematological adverse events; dose reductions suggested are 600mg of ribavirin and 1.5MU of interferon-α

Parameter Drug to be altered Dose reduction Discontinuation

Haemoglobin Ribavirin <10 g/dl <8.5 g/dl

White blood count Interferon-α <1.5 × 109/L <1.0 × 109/L

Granulocytes Interferon-α <0.75 × 109/L <0.5 × 109/L

Platelets Interferon-α <50 × 109/L <25 × 109/L



dysfunction are female sex, thyroid autoanti-bodies before or during treatment and a higherdose of interferon[27]

• others: inflammation at the injection site is un-common (12%).

10. Pegylated Interferon-α

About 1 × 1010 to 1 × 1012 hepatitis C virionsare produced each day with a half-life of a fewhours.[28] This high turnover explains the viral di-versity (quasispecies) characteristic of hepatitis Cinfection, which in turn allows viral escape fromimmune mechanisms and chronic infection. HCVlevels decline rapidly in the first 24 hours after adose of IFNα and this is followed by a secondphase of slower viral decline. However, intermit-tent increases in viral load occur on treatment-freedays during thrice-weekly administration of con-ventional IFNα.[29] Polyethylene glycol (PEG) hasbeen attached to IFNα in an attempt to obtain moreuniform IFNα concentrations and thus avoid inter-mittent increases in viral load during early treat-ment. The attachment of a PEG chain results inprolongation of the half-life of IFNα and this al-lows the interferon to be given as a single doseonce a week rather than 3 times a week. Pegylatedinterferon-α is consequently more effective in re-ducing HCVRNAload in the first 2 weeks of treat-ment, resulting in greater efficacy than for standardIFNα.Several pegylated interferons, with different-

sized side chains and hence different properties,have been produced and are currently undergoingclinical trials. In one study involving patients withcirrhosis in which 12 months of standard IFNαmonotherapy (3MU 3 times per week) was com-pared with pegylated interferon-α-2a 180μg, theoverall sustained response rate increased from 8 to30%.[18] Monotherapy with pegylated interferon-αwas also more efficacious than higher doses ofstandard IFNα. In a study predominantly involvingpatientswithout cirrhosis, the sustained response rateto 12 months of pegylated interferon-α-2a 180μgwas 39%, compared with 19% in patients given

standard IFNα 6MU 3 times a week for 12 weeksthen 3MU 3 times a week for a further 36weeks.[30]In a study of 1530 predominantly noncirrhotic

patients, pegylated interferon-α-2b 1.5 μg/kg andribavirin given for 24 weeks resulted in a 42% sus-tained response rate in patients with genotype 1viral infections, compared with 33%with ribavirinand standard IFNα. A similar but, as expected,higher sustained response rate was seen in the pre-sence of genotype 2 and 3 virus (82 and 79%, re-spectively.)[31] Response rates were higher in boththe pegylated interferon-α and IFNα groups if thedose of ribavirin was greater than 10.6 mg/kg.These new compounds are likely to become the

treatment of choice because of ease of administra-tion and improved efficacy.The adverse-event profile of the pegylated in-

terferons is slightly different from that of IFNα, withdose reductions needed more frequently for haema-tological abnormalities. Leucopenia occurs within1 month of starting treatment in 3.8% of patientscompared with 1.2% for standard IFNα, but it isoften subsequently possible to increase the dosefollowing an initial dose reduction. In contrast,thrombocytopenia, reported in 5.1% comparedwith 2.2% of standard IFNα recipients, often oc-curs within the first 2 months of starting therapyand is more long lasting, necessitating a persistentdose reduction.

11. Monitoring

Patients should be reviewed at 1, 2 and 4 weeksinto treatment and then monthly until the end oftreatment (fig. 4).The following blood tests should be performed:

• full blood count, at each visit• liver biochemistry, baseline and at each visit• thyroid function tests, baseline and 3-monthly• HCV RNA, baseline and at end of therapy and6 months after completing therapy.The initial follow-up is to assess for relapse

which occurs in the first 6 months after stoppingtherapy. HCV RNA and liver biochemistry shouldbe checked 6 and 12months after completion of ther-



apy. All sustained responders should be followedup yearly, but repeat liver biopsy is not needed.Nonresponders or relapsers should be consid-

ered for future clinical trials.

12. Other Patient Information

12.1 Contraception

All patients (male and female) must practise re-liable methods of contraception during treatmentand for at least 6 months after completing therapy,as ribavirin is teratogenic in animals.

12.2 Alcohol

Alcohol increases HCVRNAlevels and reducesthe response to therapy. Alcoholic hepatitis has alsobeen reported in individuals treated with interferonwho continue to drink. Individuals should there-

fore abstain from alcohol for 6 months before start-ing therapy and during treatment.

13. Cost Effectiveness of Treatment

Although hepatitis C infection is common, theavailability of more effective treatment will notnecessarily result in large numbers of patients re-quiring treatment (fig. 5). Although combinationtherapy is more costly than IFNα monotherapy,several studies have shown it to be cost effective,with an average cost of $US7500 per life-yearsaved.[32]

14. Other Antivirals

Amantadine is an antiviral agent which has noeffect on hepatitis C when used as monotherapy.[33]It does not significantly increase the sustained re-sponse rate when given in addition to conventionalIFNα for 12 months in treatment-naïve patientswith chronic hepatitis C[34] or for 6 months in com-bination with IFNα in IFNα monotherapy non-responders.[34] Amantadine may, however, be ef-fective in combination with IFNα and ribavirin. Ina small pilot study, 48% of IFNα nonresponderswho were re-treated with IFNα, ribavirin andamantadine for 12 months had a sustained responsecompared with only 5% of those re-treated withIFNα and ribavirin alone.[35]

15. Specific Patient Groups

15.1 Acute Hepatitis C

Acute hepatitis C is usually asymptomatic andevades clinical diagnosis. Cases of acute hepatitisC infection are rare. About 15% of patients spon-taneously clear the infection. Individuals withchronic hepatitis C infection are more likely to re-spond to IFNα monotherapy if they have mild dis-ease or recent infection − this is the rationale fortreating acute infection. Several small controlledtrials have shown that 3 to 6months of IFNαmono-therapy is effective in clearing hepatitis C and sopreventing chronic infection.[36,37] The overall re-sponse rate is 30 to 40%. The timing of treatmentis open to debate: if treatment is started within the

Baseline

HCV RNA, ALT and liver biopsyHCV genotype ± viral load

Others: TFT, renal function, FBC, PT,pregnancy test, ECG, chest radiograph

Weeks 2 and 4, then monthly

FBC and LFTAssessment of adverse effects

3 monthly

TFT

6 months + 12 months

HCV RNA(if positive at 6 months stop treatment)

3 and 6 months after treatment

HCV RNALiver biochemistry

Fig. 4. How to follow up patients during combination treatmentwith interferon-α and ribavirin. ALT = alanine aminotransferase;FBC = full blood count; HCV = hepatitis C virus; LFT = liverfunction tests; PT = prothrombin time; TFT = thyroid functiontests.



first 3 months of infection some patients will betreated who would have spontaneously cleared vi-rus, and there is no evidence from the small trialsthat postponing treatment for 3 months after theonset of symptoms adversely affects the responserate. However, in practice it seems reasonable tostart treatment once a patient is known to be HCVRNA positive. Although there are no controlledstudies of combination therapy for acute hepatitisC, combination therapy should be offered to indi-viduals who develop acute hepatitis C infectionand treatment should be continued for at least 6months.

15.2 Children

As in adults, the natural history of hepatitis Cinfection in childhood is still unclear. Childrenmay lose HCV RNA spontaneously and those whoacquire the infection at birth appear to have milddisease, but these children have yet to be followed

up into adulthood. However, there are childrenwho acquired the infection through blood transfu-sions who do have hepatic fibrosis histologically.Interferon has been used in children for hepatitis Cand chronic hepatitis B, and although the adverseevents (which include weight loss, anorexia andchange in mood) may potentially affect bothgrowth and schooling, the treatment is tolerated inthe majority of cases. Several small studies haveshown that combination therapy is tolerated inchildren with similar response rates to that seen inadults.[38,39] Until large studies are completed,treatment with combination therapy should proba-bly be restricted to children with moderate fibrosisand where possible they should be entered as partof a clinical trial.

15.3 Patients with Haemophilia

The indications for and treatment with combi-nation therapy of patients with haemophilia do notdiffer from those without the disease. Patients withhaemophilia can, in the absence of factor inhibi-tors, safely undergo liver biopsy percutaneouslyunder ultrasound guidance with factor cover or viathe transjugular route.[40] Individuals in whom aliver biopsy is contraindicated should be consid-ered for combination therapy.

15.4 Human ImmunodeficiencyVirus Co-Infection

The use of antiretroviral drugs has had a majoreffect on survival in individuals with HIV infec-tion.Many patients on antiretrovirals are now lead-ing normal lives with low HIV RNA levels despitepersistently low CD4+ counts. It is therefore rea-sonable to consider treatment with ribavirin andIFNα in patients with stable HIV infection whohave hepatic fibrosis. Individuals should be stableon antiretroviral therapy before initiating treat-ment because of the adverse event profile of com-bination therapy. Results from small studies haveshown that ribavirin and IFNα can be safely givento individuals taking antiretrovirals.[41] The effi-cacy of combination therapy in the presence of

Hepatitis C RNA positiveInvestigated (including liver biopsy)

n = 100

Portal fibrosis and/ormoderate inflammation

n = 50

Patients wanting treatment andsuitable for treatment (50%)

n = 25

Patients completing therapy (80%)n = 22

Sustained response to treatment (40%)n = 9

Fig. 5. Proportions of patients from a starting group of 100 pa-tients diagnosed and investigated for chronic hepatitis C infec-tion who are likely to require combination therapy and attain asustained response to treatment.



HIV infection is unknown and trials are currentlyunder way.[42]

15.5 Renal Failure

Combination therapy is contraindicated in thepresence of renal failure because ribavirin, whichis excreted by the kidneys, is associatedwith severeanaemia in treated patients. Ribavirin is not clearedby haemodialysis. There is currently no effectiveway of eradicating hepatitis C infection in individ-uals with chronic renal failure who are candidatesfor renal transplantation. The tolerability data onlong-acting pegylated interferons in the presenceof renal impairment are still awaited.

15.6 Organ Transplantation

The rate of progression of hepatitis C is higherafter both renal and liver transplantation. Interferonis contraindicated in patients with a renal allograftbecause it induces rejection of the graft. This is lessof a problem after liver transplantation, as chronicrejection is rarer.Recurrent hepatitis C viraemia is universal fol-

lowing liver transplantation, with viral loads higherthan before transplantation. The rate of progressionof fibrosis following transplantation is variable,but about 20% of patients develop graft cirrhosiswithin 5 years of liver transplantation.Several small studies have shown that a sus-

tained virological response can be achieved in 20%of liver transplant recipients after combinationtherapy.[43-45] Ribavirin alone does not affect HCVRNA levels and should be used in combinationwith IFNα. In a study in which 21 patients weretreated with a combination of IFNα and ribavirinfor 6 months followed by 6 months of ribavirinalone, although 50%were HCV negative at the endof 6 months of combination therapy, only 10% re-mained HCV negative at 12 months.[46] In a reviewof 122 Italian patients treated for post-transplanthepatitis C with combination therapy given for 6to 12 months, despite an end-of-treatment re-sponse of 35%, only 17% remained HCV RNAnegative 6 months after completing therapy.[44] Al-though IFNα and ribavirin combination therapy is

effective in clearing HCV RNA from serum in asmall number of patients, the incidence of adverseevents is much higher than seen in nontransplantpatients. Samuel et al.[45] reported 43% of patientswithdrawing from treatment because of adverseevents, predominantly anaemia, and dose reduc-tions are often needed during treatment.[45]The timing of initiating combination therapy for

hepatitis C recurrence is also controversial. In astudy of pre-emptive treatment when 12 months ofcombination therapy was started 3 weeks aftertransplantation, only 41% were HCV RNA nega-tive at the end of treatment; no sustained responserates were reported, which is no higher than thatreported from studies when combination therapywas started after 3months.[47] However, early treat-ment was not associated with an increased inci-dence of acute or chronic rejection.So although antiviral therapy is effective in the

post-transplant setting, sustained virological re-sponse is low and there are significant adverseevents associated with treatment; these factors cur-rently rule against universal treatment with combi-nation therapy in patients with hepatitis C cirrhosisafter transplantation.Higher doses of immunosuppression are clearly

shown to be associated with more rapid diseaseprogression following transplantation and the de-velopment of cholestatic hepatitis. Post-transplantmanagement should be directed towards minimis-ing immunosuppressive therapy.

16. Conclusions

Combination therapy with ribavirin and IFNα isnow the standard treatment for chronic hepatitis Cinfection. The addition of ribavirin to IFNα mono-therapy has had a major effect on the treatment ofhepatitis C, with response rates having increasedfrom 10 to 40%. Six to 12 months’ treatment isgenerally well tolerated. However, although re-sponse rates of up to 60% can be achieved inwomen infected with genotype 2 and 3 virus, re-sults of treatment in men with genotype 1 infectionin the presence of a high viral load are still less than30%. Moreover, combination therapy is contrain-



dicated in the presence of renal failure and follow-ing organ (non-liver) transplantation. Althoughlong-acting pegylated interferons may increase ef-ficacy of combination therapy, it is likely that ad-vances in the treatment of chronic hepatitis C willhave to await the development of novel antivirals.The future of treatment of hepatitis C is likely tomirror HIV treatment with the use of multiple anti-virals and possible maintenance treatment.

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Correspondence and offprints: Dr Jane Collier, Departmentof Gastroenterology, Level 3, John Radcliffe Hospital, Head-ley Way, Headington, Oxford, OX3 9DU, England.E-mail: [email protected]



combination therapy with interferon-α and ribavirin for hepatitis c

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