D P Manns, H Wedemeyer, M Cornberg

The treatment of hepatitis C has dramatically improved over the past decade. Unlike any other

chronic viral infection, a significant proportion of patients with chronic hepatitis C can be

cured. However, the current standard therapy—pegylated interferon alpha and ribavirin—

has its limitations. Limited efficacy in patients with hepatitis C virus (HCV) genotype 1 and the

side effect profile will necessitate the development of new therapeutic approaches. This review

describes the efficacy and optimisation of the current standard therapy of hepatitis C and its

problems in special patient populations. New treatment directions beyond interferon alpha based

therapies are on the horizon.

c MANAGEMENT OF ACUTE HEPATITIS C

Early identification of patients with acute HCV infection is important for their optimal

management. The rate of chronic evolution is 50–90%, and the natural course of chronic hepatitis

C can be associated with severe complications. Patients with chronic hepatitis C have the

potential risk of developing liver cirrhosis and hepatocellular carcinoma.1 The social burden of

HCV infection is high, including for health care workers. Extrahepatic manifestations of HCV are

often troublesome and may not be reversible with viral eradication.2 These are good reasons for

the design of a prophylactic vaccine but as this has yet to be accomplished, early treatment of

acute HCV infection with interferon alpha (IFN) is the only option to prevent chronicity.

Immediate treatment of patients with symptomatic acute hepatitis C with recombinant IFN or

pegylated IFN (PEG-IFN) monotherapy for 24 weeks can prevent the development of chronic

hepatitis C in approximately 90% of cases.3–5 Combination with ribavirin is not necessary.6

However, symptomatic patients also have a good chance to clear HCV spontaneously.78 This

usually occurs in the first 12 weeks after the onset of symptoms. A wait and see strategy (that is,

treatment of only those patients who remain HCV-RNA positive 12 weeks after the onset of

symptoms) resulted in an overall sustained virological response (self limited and treatment

induced) in 91% of patients.8 A study coordinated by the German competence network for viral

hepatitis (Hep-Net)9 is underway to test if a wait and see strategy may be as effective as

immediate treatment (www.kompetenznetz-hepatitis.de/study_house/hcv_III_studie.htm).

Asymptomatic patients however should be treated immediately as they have a higher risk for

chronic evolution. Post exposure prophylaxis (for example, short duration IFN administration

after a needlestick injury to prevent HCV infection) is not necessary.10 The future may bring highly

effective antiviral drugs which allow short term treatment for all acutely infected patients.

STANDARD THERAPY OF CHRONIC HEPATITIS C

The importance of an effective treatment against hepatitis C is reflected by the 170 million people

that are chronically infected with HCV. Despite implementation of blood donor screening in the

early 1990s, an increase in HCV related cirrhosis, hepatic decompensation, and hepatocellular

carcinoma over the next 10–20 years is still anticipated.11

Before identification of HCV as the infectious agent for non-A, non-B hepatitis,12 it was found

See end of article for authors’ that IFN may lead to normalisation of transaminases and improvement in liver histology.13 After

affiliations identification of HCV, it became possible to measure the success of therapy as long lasting

disappearance of HCV-RNA from serum, a so-called sustained virological response (SVR). Since

Correspondence to: that time, the SVR rate has increased from 5% to 20% with IFN monotherapy and from 40% to

Professor M P Manns,

Department of 50% with the combination of IFN and ribavirin (fig 1). 14–17 The development of PEG-IFN was a

Gastroenterology, further milestone in the treatment of chronic hepatitis C.18 Two PEG-IFNs are available: PEG-IFN

Hepatology, and alpha-2b (PEG-Intron; Schering-Plough, Kenilworth, New Jersey, USA) and PEG-IFN alpha-2a

Endocrinology, Medical

School of Hannover, (PEGASYS; Roche). Pegylation of IFN allows once weekly administration due to an improved

Carl-Neuberg-Str 1, D-30625 pharmacokinetic profile. PEG-IFN/ribavirin combination therapy improved the overall SVR to

Hannover, Germany; 54–63% (fig 1).16 19 20 There seems to be no difference between both PEG-IFNs in combination

mh-hannover.de with ribavirin in terms of SVR.21 However, both PEG-IFNs have different pharmacokinetic profiles

_________________________ due to their different polyethylene glycol moieties. PEG-IFN alpha-2b is bound to a single linear

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TREATING VIRAL HEPATITIS C

12 kDa polyethylene glycol molecule whereas PEG-IFN

alpha-2a is covalently attached to a 40 kDa branched chain

polyethylene glycol moiety. The distinct sizes of the PEG-IFNs

influence the volume of distribution. PEG-IFN alpha-2b is

given adjusted for body weight (1.5 mg/kg once weekly) while

the larger PEG-IFN alpha-2a is given in a fixed dose of 180 mg

once weekly (reviewed by Cornberg and colleagues18 and

Pedder22) (table 1).

Ribavirin should be administered according to the body

weight of the patient. A retrospective analysis of a large PEGIFN

alpha-2b/ribavirin pivotal trial revealed that the optimal

ribavirin dose is at least 10.6 mg/kg (table 2).16 Therefore,

ribavirin (Rebetol; Schering-Plough) is recommended at a

concentration of approximately 11 mg/kg body weight in

combination with PEG-IFN alpha-2b (table 1). When

combined with PEG-IFN alpha-2a, a ribavirin (Copegus;

Roche, Basel, Switzerland) dose of 1000 mg if ,75kg or

1200 mg if >75 kg is recommended for HCV genotype 1

patients, while 800 mg ribavirin are suggested for patients

with HCV genotypes 2 and 3 (tables 1, 2). The benefit of

higher ribavirin doses has not been observed for genotype 2/3

patients in combination with PEG-IFN alpha-2a.20 The

Hadziyannis study20 also confirmed the 24 week schedule

for HCV genotype 2/3 patients whereas patients with HCV

genotype 1 require 48 weeks of therapy (table 2). The

24 week regimen for patients with HCV genotypes 2 and 3

has also been confirmed for the combination of PEG-IFN

alpha-2b and ribavirin (table 2).23 24

SVR.

Early HCV-RNA kinetics predict the outcome and success

of treatment. Patients with HCV genotype 1, who do not

show a HCV-RNA decline of more than 2 log10 or have serum

concentrations of more than 30 000 IU/ml HCV-RNA after

12 weeks of therapy (TW12), have no chance of achieving an

25 26 Thus therapy should be discontinued in these

patients.

The main challenge for the future is to improve the success

rates for the difficult to treat and non-responsive HCV

genotype 1 patients. While patients with HCV genotypes 2

and 3 can be cured in more than 75% of cases, the 40–50%

SVR for patients with HCV genotype 1 is still unsatisfactory.

80

54–63%

60

45–47%

38–43%

40 31–35%

13–19%

30

6%

0

IFN IFN IFN/RBV IFN/RBV IFN/RBV PEG-IFN/RBV

24 weeks 48 weeks 24 weeks 48 weeks 48 weeks 48 weeks

1998 2001/2

IFN plus ribavirin trials PEG-IFN plus ribavirin trials

USA trial15

PEG-IFN-.-2b + 0.8 g RBV

Int trial14

IFN-.-2b control + 1/1.2 g RBV16

PEG-IFN-.-2a/IFN-.-2b control

+ 1/1.2 g RBV19

PEG-IFN-.-2a + 1/1.2 g RBV20

Figure 1 Development of therapy for chronic hepatitis C is a story of

success. Sustained virological response rates have been improved from

approximately 5% with interferon (IFN) monotherapy in the early

1990s to .60% with the optimised standard therapy of pegylated IFN

(PEG-IFN) and ribavirin.

Sustained virological response (%)

INDIVIDUALISATION AND OPTIMISATION OF THE

CURRENT STANDARD THERAPY

Adherence to therapy

Adherence to therapy is one of the most important factors

associated with the success of therapy.17 The definition of

adherence used here is the 80/80/80 rule, as patients who

received more than 80% of IFN, more than 80% of ribavirin,

and were treated for more than 80% of the planned duration

of treatment are considered adherent. One of the first studies

investigating the effect of adherence demonstrated that

patients who fulfilled the 80/80/80 rule had a 63% sustained

response compared with 52% of those with less than 80%

adherence.17 This was statistically significant for HCV

genotype 1 patients. Therefore, it is important to reduce side

effects and motivate patients to adhere to treatment in order

to optimise treatment responses, especially in difficult to treat

genotype 1 patients.

Optimal treatment duration

Optimal treatment duration may also improve the management

of chronic hepatitis C. There are two different concepts

to optimise treatment duration. While some patients with

HCV genotype 1 may need longer treatment to improve the

response, patients with HCV genotypes 2 and 3 may be

treated for a shorter period of time to reduce costs and side

effects.

Many studies are investigating reductions in treatment

duration for HCV genotypes 2 and 3 to 16, 14, or even

12 weeks. The first reported results are very promising but we

have to consider individual factors when treating patients for

less than 24 weeks. The early virological response (EVR) after

four weeks of therapy (HCV-RNA negative in serum at TW4)

is one of the critical factors associated with the success of

shorter therapy. Only patients who showed an EVR at week 4

had high SVR rates after 16 weeks27 (table 2), 14 weeks,28 or

even after 12 weeks of therapy,29 whereas those without an

EVR had low response rates, even with the 24 week schedule.

However, 12 weeks seems to be the limit for some patients as

relapse rates after 12 weeks were higher compared with the

standard 24 week schedule.29 In addition to EVR, other

factors are associated with response in patients with HCV

genotypes 2 and 3. These are HCV genotype and baseline viral

load. Patients with HCV genotypes 2 and 3 should be

analysed separately because those with HCV genotype 2

respond better to PEG-IFN and ribavirin therapy than those

infected with HCV genotype 3 (table 2).24 29 Furthermore, the

shorter treatment schedules revealed that HCV genotype 3

patients with low baseline viraemia (HCV-RNA ,600 000–

800 000 IU/ml) had a much better chance of responding than

those with a high viral load (HCV-RNA .600 000–

800 000 IU/ml).27 28 In conclusion, patients with HCV genotype

2 and those with HCV genotype 3 and low viral load who

have an EVR after four weeks of therapy may be treated for

less than 24 weeks, and patients without an EVR (especially

HCV genotype 3 and high viral load) may be treated for more

than 24 weeks (fig 2). The promising results obtained in

these pilot studies need to be confirmed in large multicentre

studies for both PEG-IFNs. Tailoring treatment individually

for patients with HCV genotype 2 and 3 will reduce costs, side

effects, and further optimise response rates.

We face the opposite problem in patients with HCV

genotype 1. Extending treatment duration beyond 48 weeks

is one strategy that may improve response rates in some of

these difficult to treat patients. The rationale is to extend the

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TREATING VIRAL HEPATITIS C

1352

Table 1 Current treatment recommendations for patients with chronic hepatitis C

HCV genotype

Duration

(weeks) PEG-IFN dose (16/week sc)

Ribavirin dose

(daily orally)

Genotype 1 48 180 mg PEG-IFN alpha-2a 1000 mg (,75 kg)

Genotypes 4–6*1200 mg (>75 kg)

1.5 mg/kg PEG-IFN alpha-2b 800 mg (,65 kg)

1000 mg (65–85 kg)

1200 mg (.85 kg)

Genotypes 2/3 24 180 mg PEG-IFN alpha-2a 800 mg (all)

1.5 mg/kg PEG-IFN alpha-2b 800 mg (,65 kg)

1000 mg (65–85 kg)

1200 mg (.85 kg)

*Hepatitis C virus (HCV) genotypes 4–6 may respond better to pegylated IFN (PEG-IFN)/ribavirin than HCV

genotype 1 patients. For HCV genotype 4, 36 weeks may be sufficient.109 Data are limited for HCV genotypes 5/6.

sc, subcutaneously.

time of HCV-RNA negativity, especially in patients with a

slow viral decline (first time HCV-RNA negative between

TW12 and TW24) to reduce relapse rates in these so called

‘‘late responders’’ (fig 2). Several studies investigated the

efficacy and safety of 48 weeks versus 72 weeks of treatment

with PEG-IFN plus ribavirin in patients with chronic

hepatitis C. Sanchez-Tapias et al reported the benefit of

extended therapy in patients who were HCV-RNA positive at

treatment week 4. Relapse rate after 72 weeks of therapy was

significantly reduced in these patients.30 However, treatment

duration beyond one year may lead to higher dropout rates

which results in lower intent to treat responses.30 31

Multivariate analyses of these studies will hopefully reveal

factors such as viral kinetics that will help to identify patients

who will benefit from extended therapy. In conclusion,

extension of therapy to 72 weeks may improve response rates

for patients with a slow viral response (.2 log10 decline but

.50 IU/ml at TW12 (fig 2)) but high motivation and

compliance of the patient is mandatory.

On the other hand, it is possible to reduce treatment

duration to 24 weeks in patients with HCV genotype 1 who

have a low viral load at baseline and an EVR after four weeks

of therapy (table 2, fig 2).32

Amantadine

Another strategy to enhance the success of therapy in

patients with HCV genotype 1 may be the additional use of

amantadine. In 1997, JP Smith reported that amantadine

treatment could improve both biochemical and virological

markers in patients with hepatitis C who had previously not

responded to treatment with IFN.33 The effect of amantadine

monotherapy could not be confirmed in other studies.

However, these data led to numerous studies analysing the

efficacy of amantadine in combination with IFN or IFN/

Table 2 Efficacy of hepatitis C treatment with pegylated interferon (PEG-IFN) plus

ribavirin

Study Treatment HCV genotype

Duration

(weeks) SVR (%)

Manns16 1.5 mg/kg PEG-IFN alpha-2b HCV-1 48 42

800 mg ribavirin HCV-2/3 48 82

1.5 mg/kg PEG-IFN alpha-2b HCV-1 48 48 (retrospective)

.10.6 mg/kg ribavirin HCV-2/3 48 88 (retrospective)

Fried19 180 mg PEG-IFN alpha-2a HCV-1 48 46

1000/1200 mg ribavirin HCV-2/3 48 76

Hadziyannis20 180 mg PEG-IFN alpha-2a HCV-1 24 29

800 mg ribavirin 48 40

HCV-2/3 24 78

48 73

180 mg PEG-IFN alpha-2a HCV-1 24 41

1000/1200 mg ribavirin 48 51

HCV-2/3 24 78

48 77

Zeuzem24 1.5 mg/kg PEG-IFN alpha-2b HCV-2 24 93

800–1400 mg ribavirin HCV-3 79

Kamal109 1.5 mg/kg PEG-IFN alpha-2b HCV-4 24 29

1000/1200 mg ribavirin 36 66

48 69

von Wagner27 180 mg PEG-IFN alpha-2a HCV-2/3 24 36 if TW4 HCV-RNA

>600 IU/ml

800–1200 mg ribavirin 24 80 if TW4 HCV-RNA

,600 IU/ml

16 82 if TW4 HCV-RNA

,600 IU/ml

Zeuzem32 1.5 mg/kg PEG-IFN alpha-2b HCV-1 LVL 24 50

800–1400 mg ribavirin (,600 000 IU/ml) 89 if TW4 HCV-RNA

negative (,29 IU/ml)

Sustained virological response rates (SVR) depend on hepatitis C virus (HCV) genotype, dose, and duration of

treatment.

TW4, four weeks of therapy.

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TREATING VIRAL HEPATITIS C

Figure 2 Optimisation of treatment duration for patients with hepatitis

C virus (HCV) genotype 1 (A), 2/3 (B), and 4 (C). Sensitive HCV RNA

assays at weeks 4, 12, and 24 may determine treatment duration.

*Approved for pegylated interferon (PEG-IFN) alpha-2b only; [1]not yet

approved but supported by preliminary study results.27–29 30 31; `longer

treatment may be necessary for some patients who were HCV RNA

positive at week 4.

ribavirin. Brillanti et al were among the first who demonstrated

promising SVR with the triple therapy (IFN/ribavirin/

amantadine) in prior IFN non-responders.34 The dilemma of

all of these small studies was that the results varied from

study to study. While some studies confirmed the results,

others demonstrated no additional benefit of amantadine in

combination with IFN or IFN/ribavirin. A large German

placebo controlled multicentre study treated 400 na.¨ve

patients with IFN/ribavirin/placebo or with IFN/ribavirin/

amantadine. Triple therapy increased SVR by 8% in HCV

genotype 1 patients but this was not statistically significant.35

A placebo controlled study with more than 700 patients in

cooperation with Hep-Net, testing the addition of amantadine

to PEG-IFN/ribavirin therapy in treatment na.¨ve patients

will hopefully provide the final answer. Perhaps addition of

amantadine can reduce IFN side effects such as fatigue and

depression36 and thus help patients to adhere to treatment.

Amantadine is inexpensive. However, amantadine may cause

QT prolongation in the electrocardiogram and thus is

contraindicated in patients with prolonged QT times.

Other interferons

There are other type 1 interferons in development. Albuferonalpha

(Human Genome Sciences, Rockville, Maryland, USA),

which is an 85.7 kDa protein consisting of interferon

alpha-2b genetically fused to human serum albumin, further

extends the half life of the IFN to approximately 148 hours

(table 3). The pharmacokinetic profile of albuferon allows

dosing at intervals of 2–4 weeks compared with one week

with PEG-IFNs. Results of a phase II trial testing multiple

doses of albuferon in HCV genotype 1 patients demonstrated

high antiviral efficacy.37 These data led to the initiation of

phase III clinical trials evaluating the efficacy of albuferon in

combination with ribavirin.

Consensus interferon (CIFN) or interferon alphacon-1

(Infergen; Valeant, Costa Mesa, California, USA) is another

type 1 interferon that is already in use for the treatment of

chronic hepatitis C. The ‘‘consensus’’ molecule, composed of

conserved amino acids of type 1 interferons, shows greater

biological activity than other type 1 interferons in vitro.38 39

Despite this in vitro advantage, a head to head study

comparing CIFN and standard IFN monotherapy revealed

only minor differences in efficacy. The results suggested that

patients with HCV genotype 1 may have a small advantage

with CIFN.40 A recent study reported better SVR in na.¨ve

patients with chronic hepatitis C when treated with CIFN in

combination with ribavirin compared with standard IFN plus

ribavirin.41 Some studies investigating the effect of high and

daily dosing of CIFN, in combination with ribavirin in na.¨ve

as well as in non-responders, demonstrated promising

SVR.42 43

However, daily dosing requires high levels of

motivation and compliance as adherence to therapy is an

important factor influencing treatment outcome.

Side effects and complications

Severe side effects may reduce adherence to therapy and may

result in dose modifications which will result in less

1353

Table 3 Future drugs for the treatment of hepatitis C

Future therapies Characteristics

Albuferon-alpha (Human Genome Science) phase III Longer half life than PEG-IFN due to fusion of albumin to IFN (85.7 kDa).

Viramidine (Valeant) phase III Prodrug of ribavirin with less anaemia.

HCV protease inhibitors, HCV polymerase inhibitors phase I/II

(see table 5)

Direct antiviral action with fewer side effects than IFN. Direct inhibition of the HCV

protease/HCV polymerase which are crucial for viral replication.

Other small molecules (eg ribozymes, siRNA, antisense molecules)

phase I/II

Direct antiviral effect with potentially fewer side effects than IFN. Interference with the

HCV genome or blocking translation leading to inhibition of viral replication.

Caspase inhibitors (eg IDN-6556, Pfizer) phase I/II Antifibrogenic effect. Reduction of hepatocyte apoptosis and reduction of hepatic

stellate cell activation.

Toll-like receptor agonists (CpG 10101-TLR-9 agonist, Coley;

ANA-975 TLR-7 agonist; Anadys) phase I

Therapeutic stimulation of Toll-like receptor pathways to modulate (Th1 shift) immune

responses and to stimulate innate immunity.

Therapeutic vaccination (E1y—protein vaccine, Innogenetics;

IC-41—peptide vaccine, Intercell) phase I/II

Stimulation of the impaired HCV specific immune response in order to control viral

replication or alter the natural course of the disease (regression of fibrosis).

HCV, hepatitis C virus; PEG-IFN, pegylated interferon.

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TREATING VIRAL HEPATITIS C

1354

Table 4 Common side effects (.20% of patients)

recorded in major pegylated interferon (PEG-IFN)/

ribavirin trials16 19 20

Side effect

Incidence with

PEG-IFN alpha

and ribavirin16 19 20 (%)

Headache 47–62

Pyrexia 40–46

Myalgia 37–56

Rigors 24–48

Arthralgia 24–34

Nausea 35–43

Loss of appetite 21

Weight loss 29

Diarrhoea 22

Alopecia 21–36

Rash/dermatitis 20–24

Injection site inflammation 25

Pruritus 25–29

Dyspnoea 26

Fatigue 48–64

Insomnia 33–40

Irritability 24–35

Depression 22–31

The incidence of side effects between different studies is difficult to

compare as the studies had significant differences in genetic and

socioeconomic backgrounds. Furthermore, there were methodological

differences in assessing the side effects. Patients were selected on the

basis of well defined inclusion and exclusion criteria. Normal thyroid

stimulating hormone levels pretreatment were a prerequisite.

response. Both IFN and ribavirin induce side effects that have

to be considered in the management of patients with chronic

hepatitis C (table 4). IFN related side effects can be divided

into IFN induced bone marrow depression, flu-like symptoms,

neuropsychiatric disorders, and autoimmune syndromes.

The main problem with ribavirin is haemolytic

anaemia. Overall, side effects result in 10–20% premature

withdrawals from therapy and an additional 20–30% of

patients require dose modifications. These numbers are lower

in recent than in earlier studies, suggesting improved

understanding and management of adverse events,44 potentially

also leading to higher SVR (fig 1). However, these

percentages were recorded from registration trials using

careful selection of patients. This may differ in general

clinical practice where patients with, for example, a history of

depression, low platelets, or thyroid disease are being treated.

IFN side effects

The effect of IFN on bone marrow results in decreased

granulocytes and thrombocytes during treatment. These are

usually moderate if normal counts are present initially.

However, dose modifications are necessary, especially in

patients with initially low counts. This limits the use of IFN

in patients with advanced liver cirrhosis who often have low

platelets and are also more vulnerable to infections.

Neutropenia is one of the most common reasons for dose

modifications. This granulocyte macrophage-colony-stimulating

factor could potentially be used to stabilise neutrophil

counts during IFN therapy.45 46 Cost benefit analyses and

further trials are required to recommend routine use of these

agents. However, our own experience and other reports

suggest that IFN induced neutropenia is generally not

associated with an increased risk of bacterial infections.47

Flu-like symptoms usually occur during the first weeks of

treatment and severity declines in the later treatment period.

These side effects include fever, chills, headaches, arthralgia,

and myalgia (table 4). Antipyretic drugs such as paracetamol

can help to prevent or reduce these side effects.

Neuropsychiatric side effects such as irritability, severe

fatigue, and apathy are frequent (table 4) and a great

problem for many patients, which also affect family

members. Severe depression can occur and even suicide has

been reported.48 Psychiatric care and the use of antidepressants,

especially serotonin uptake inhibitors, may help to

reduce IFN induced depression49 and consequently improve

adherence to therapy and response rates.50 Prospective

placebo controlled trials are underway to confirm these

preliminary findings.

IFN has immunomodulatory properties, and treatment can

induce autoimmune phenomena.51 The most frequent problem

is the development of autoimmune thyroiditis. In most

cases thyroiditis starts with hyperthyroidism that later

becomes hypothyroidism. Autoimmune thyroiditis has been

reported in up to 20% of patients under or after IFN based

therapies. This may not be reversible after stopping therapy.52

Predisposed patients with pre-existing thyroid antibodies

have a higher risk and it is possible that hepatitis C itself may

be a cause of autoimmune thyroiditis.53

Other autoimmune diseases can also be aggravated by IFN

therapy (for example, diabetes or autoimmune hepatitis).

Patients with documented hepatitis C infection may deteriorate

during IFN treatment if an underlying autoimmune

hepatitis is present. This has been observed particularly in

LKM antibody positive individuals. These patients require

careful monitoring if IFN is considered as firstline treatment.

However, IFN therapy seems to be safe in most HCV/anti-

LKM-1 positive patients.54 55

Ribavirin side effects

The main side effect of ribavirin is haemolytic anaemia as this

complication may frequently result in ribavirin dose reduction

or even discontinuation, which may significantly affect

the overall SVR, especially in patients with HCV genotype 1.16

Treatment with erythropoietin can effectively reverse

ribavirin associated anaemia and allow full adherence to

ribavirin therapy.56 This will improve response rates but the

treatment is expensive and not reimbursed in many

countries. This problem emphasises the need for alternative

ribavirin-like drugs with less toxicity and/or higher antiviral

efficacy. Unfortunately, the mechanism by which ribavirin

enhances the efficacy of IFN treatment and prevents relapse

remains largely unknown. Proposed mechanisms are immunmodulatory

effects, inhibition of inosine monophosphate

dehydrogenase (IMPDH) activity, and induction of RNA

mutagenesis.57 58 More potent IMPDH inhibitors such as

mycophenolate mofetil (MMF, Cell Cept; Roche) or VX-497

have been studied59 but with limited effects.60 Another

approach is the development of a ribavirin prodrug.

Viramidine is the amidine version of ribavirin and is

converted by the enzyme adenosine deaminase to ribavirin,

mainly in hepatocytes (table 3). Therefore, there is less

uptake of ribavirin into red blood cells after administration of

viramidine and consequently less haemolytic anaemia.61 First

results of a phase II study demonstrated that viramidine in

combination with PEG-IFN alpha-2a led to significantly less

anaemia compared with ribavirin plus PEG-IFN.62 Phase III

studies with both PEG-IFNs in combination with viramidine

have been carried out (VISER 1 and 2). Preliminary data

(VISER 1) confirmed the superior safety profile of viramidine

plus PEG-IFN alpha-2b but viramidine did not meet the

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TREATING VIRAL HEPATITIS C

non-inferiority to ribavirin efficacy endpoint on an intent-totreat

basis (SVR: 38% v 52%).[63a] Further subanalyses, the

VISER 2 trial, and possibly weight based dosing of

viramidine, may be awaited to draw final conclusions.

Meanwhile, drug monitoring of ribavirin could be an

option to optimise the ribavirin dose without losing efficacy.64

The pharmacokinetic properties of ribavirin suggest that not

only body weight but also renal function (glomerular

filtration rate) should be considered when selecting the

ribavirin dose.65

TREATMENT OF HEPATITIS C IN SPECIAL

POPULATIONS

Patients with normal aminotransferase levels

Approximately 30% of patients with chronic hepatitis C

maintain persistently normal alanine aminotransferase (ALT)

levels despite having detectable HCV-RNA in serum.

Treatment indications for these patients are questionable.

Firstly, these patients have generally mild liver disease and

show a slow progression to cirrhosis. Secondly, treatment

with IFN has been shown to be associated with ALT flares in

the past (reviewed by Tassopoulos66). Thirdly, the efficacy of

therapy may be lower as patients with elevated transaminases

seem to respond better.67 However, up to one third of

patients with normal ALT can present with significant liver

fibrosis which necessitates an effective treatment.68 69 Zeuzem

et al demonstrated that 48 weeks of PEG-IFN alpha-2a and

ribavirin combination led to SVR rates of 52% in patients

with chronic hepatitis C and persistently normal ALT levels.

Treatment related flares in ALT activity were not observed.68

The efficacy and tolerability of PEG-IFN/ribavirin combination

therapy in patients with persistently normal ALT levels

seem to be comparable with patients with elevated ALT

levels. The decision to treat or not to treat patients with

chronic hepatitis C and persistently normal ALT levels should

be made on an individual basis, independent of ALT levels.

HIV/HCV coinfection

A significant portion of individuals infected with the human

immune deficiency virus (HIV) are coinfected with HCV.70

patients with cirrhosis need careful monitoring and didanosine

should be avoided. With added experience and the

development of PEG-IFN, SVR increased to more than 40%

(fig 3) and early discontinuation due to adverse events

declined to 12–17%.77–80 The efficacy of PEG-IFN and ribavirin

in HCV/HIV coinfected patients is comparable with HCV

mono infected patients if the adequate ribavirin dose is used.

In particular, for these patients, approaches to improve the

adherence to therapy would further improve the success of

treatment in coinfected patients. A dilemma of antiviral

therapy with IFN is that GBV-C (hepatitis G) may also be

cleared. However, GBV-C coinfection is associated with an

improved natural course of HIV infection,81–83 even with

HAART. A recent study showed that patients who lost GBV-C

had the poorest prognosis.84 GBV-C status should be

considered and careful follow up monitoring after anti-HCV

therapy may reveal the impact of HCV/HIV/GBV-C coinfections.

HCV and liver transplantation

HCV reinfection occurs in almost all patients after liver

transplantation. While the course of hepatitis C in liver

transplant recipients was believed to be rather benign in the

late 1980s and early 1990s,85 HCV has led to a more rapid

course post transplant in recent years86 with progression to

cirrhosis within the first 5–10 years in 20–30% of patients.

Thus HCV takes a more rapid course post-transplant than in

immunocompetent individuals, and treatment needs are

obvious.

Antiviral therapy for HCV may be administered before

transplantation to prevent reinfection of the graft. If this

approach is successful, reinfection can be prevented in two

thirds of patients.87 However, treatment with IFN and

ribavirin is only poorly tolerated in decompensated cirrhosis

and thus this approach will be feasible in only a minority of

patients.88 Pre-emptive treatment within the first 4–6 weeks

post transplantation has been disappointing, with SVR

1355

Sustained virological response (%)

50

The first European Consensus Conference on the treatment of

chronic hepatitis B and C in HIV coinfected patients was held

in February 2005.71 HCV induced liver disease is now a major

cause of morbidity for these patients following the introduc

tion of highly active antiretroviral therapy (HAART).

Hepatitis C liver disease may progress much more rapidly in

HIV infected patients than in immunocompetent patients.

Effective anti-HCV treatment is therefore needed for HIV

patients. The first studies using conventional IFN plus

27–40%

40

44%

30

12–20% 21%

19%

20

9–11%

10

0

ribavirin showed disappointing SVR (fig 3). Side effects

leading to frequent early discontinuation may have contributed

to these results.70 72 73 In addition, ribavirin induced

haemolysis is a particular problem for HIV patients and thus

the ribavirin dose was often not adequate in these studies.

Another problem of ribavirin is exacerbation of mitochondrial

toxicity caused by anti-HIV drugs, such as didanosine.74

This may explain the reported cases of pancreatitis in patients

treated with didanosine containing antiretroviral regimens in

some studies (reviewed by Manns and Wedemeyer75).

Didanosine treatment was also associated with an increased

risk of hepatic decompensation in patients with cirrhosis who

were treated with PEG-IFN and ribavirin.76 However, the

overall risk for hepatic decompensation in HIV/HCV coinfected

patients without cirrhosis was rather low. Therefore,

IFN tiw IFN daily IFN tiw IFN tiw PEG-IFN PEG-IFN

0.8 g RBV 0.8 g RBV 0.8 g* RBV 0.8–1.2 g RBV 0.8 g* RBV 0.8–1.2 g RBV

48 weeks 48 weeks 48 weeks 48 weeks 48 weeks 48 weeks 

IFN plus ribavirin trials PEG-IFN plus ribavirin trials

Sulkowski72 (PEG)-IFN-.-2b: RIBAVIC study: Carrat76

Br.u 71 (PEG)-IFN-.-2a: US trial: Chung78

*Ribavirin dose escalation 600–1000 mg

(PEG)-IFN-.-2a: APRICOT study: Torriani77

(PEG)-IFN-.-2b: Laguno79

Figure 3 Development of therapy for chronic hepatitis C in human

immune deficiency virus (HIV) coinfected patients. Sustained virological

response rates were improved from approximately 10% with interferon

(IFN) plus ribavirin (RBV) to .40% with the optimised standard therapy

of pegylated IFN (PEG-IFN) and ribavirin. Sustained virological

response rates for hepatitis C virus (HCV) genotype 1 patients were

14–38% in these PEG-IFN/RBV trials.76–79

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TREATING VIRAL HEPATITIS C

1356

between 0% and 33% for different regimens, including IFN

monotherapy and IFN plus ribavirin combination therapy.89 90

There is more experience on the treatment of established

recurrent hepatitis C. The most recent studies using PEG-IFN

in combination with ribavirin showed an initial virological

response rate of up to 55%.91 Treatment duration should be at

least similar to non-transplanted patients considering early

viral kinetics and HCV genotype. However, bone marrow

toxicity, depression, and rejection are limiting factors that

require aggressive management (for example, growth factors).

92 93 The ribavirin dose may have to be adjusted as

several patients have some degree of renal insufficiency.

Interestingly, the risk for IFN induced graft rejection seems to

be higher if ribavirin is not used.

Overall, several issues in the sometimes rather complicated

management of post transplant hepatitis C have yet to be

resolved. Patients with established graft hepatitis should be

treated with PEG-IFN and ribavirin. Whether reinfection can

be prevented in future either by the new direct antivirals

inhibiting HCV replication or by a combination with anti-

HCV antibodies with neutralising properties will have to be

addressed in studies performed in the near future.

Dialysis patients

Treatment needs for dialysis patients with hepatitis C are

obvious, especially if patients are considered for kidney

transplantation. The outcome of HCV post kidney transplantation

is worse than for HCV negative patients after renal

transplantation. However, IFN based therapies are contraindicated

post transplantation as they may induce rejection.

Thus, if possible, HCV should be eliminated before transplantation.

There have been several smaller reports on the

treatment of HCV with IFN monotherapy in patients with

end stage renal disease.94 Surprisingly, the results for IFN

monotherapy under dialysis were better than in patients not

undergoing dialysis, with SVR of 21–64%. Data on combination

therapies with ribavirin are limited as ribavirin has

traditionally been considered to be contraindicated in this

setting. However, ribavirin can be given at lower doses in

dialysis patients, usually between 200 and 400 mg daily.95

Several trials on the use of PEG-IFNs plus ribavirin in dialysis 

patients are ongoing and final data are not available yet.

However, it has to be considered that there might be

significant differences between the two pegylated interferons

in the setting of dialysis as PEG-IFN alpha-2a is eliminated

mainly by the liver while PEG-IFN alpha-2b is cleared via the

kidney.18 Future studies need to evaluate the potential of

viramidine in particular for this special patient population.

TREATMENT OF THE FUTURE AND DRUGS IN THE

PIPELINE

Future aims should be to develop a treatment beyond IFN

with less side effects and higher efficacy. Knowledge of the

molecular structure of the hepatitis C proteins has allowed

the design of new drugs that directly target the sites of HCV

encoded enzymes that are important for the replication of the

virus. The HCV protease and HCV polymerase are the main

targets for these enzyme inhibitors (tables 3, 5). The first

drug that has been tested in patients and demonstrated the

proof of concept in humans for a HCV protease inhibitor was

BILN-2061 (Boehringer-Ingelheim, Biberach, Germany).

BILN-2061 given twice daily as monotherapy for two days

reduced HCV-RNA by 2–3 log10 in most patients infected

with HCV genotype 1.96 Unfortunately, further clinical trials

are on hold due to preclinical cardiac toxicity issues. Other

promising HCV protease inhibitors97–99 and HCV polymerase

inhibitors100 101 are under investigation (table 5). Drug

resistance may become a problem with these new compounds102

and combination therapies may be unavoidable.

Phase II trials investigating these new drugs in combination

with PEG-IFN are ongoing. The majority of these new

compounds were developed using an in vitro replicon

system103 which was derived from patients with HCV

genotype 1. This probably explains why BILN-2061, for

example, was less effective in patients with HCV genotypes 2

and 3.104 Thus other in vitro replicon systems derived from

patients with non-genotype 1 disease need to be developed.

Recently, a new in vitro culture generated HCV clone derived

from a patient infected with HCV genotype 2a was

established and for the first time this was shown to be

infectious in a chimpanzee.105 The HCV polymerase inhibitor

valopicitabine (NM-283; Idenix Pharmaceuticals, Cambridge,

Massachusetts, USA) was developed using a bovine diarrhoea

Table 5 Current status of hepatitis C virus (HCV) enzyme inhibitor development

(April/2006)

Stage of development

HCV protease inhibitors

BILN-2061 (Boehringer Ingelheim) Phase I (2–3 log10 decline in HCV-RNA after 2 days). More effective in

HCV genotype 1 than 3 patients.96 104 Program halted

VX-950 (Vertex) Phase I monotherapy (4.4 log10 decline in HCV-RNA after 14 days),97 in

combination with PEG-IFN. 5.5 log decline in HCV-RNA after 14 days.111

Phase IIb studies have been initiated (prove 1 and 2).

SCH503034 (Schering-Plough) Phase I monotherapy (2.06 log10 decline of HCV-RNA after 14 days),

stronger antiviral effect in combination with PEG-IFN.98 99 Phase IIb trial

started

HCV polymerase inhibitors

NM-283, Valopicitabine (Idenix) Phase I (,1 log decline after 14 days), phase II (NM-283 plus PEG-IFN

stronger effect compared with PEG-IFN plus ribavirin after 12 weeks

therapy).100 101 112 However, 800 mg dose group was stopped due to

gastrointestinal symptoms. Studies are ongoing with 200–400 mg NM283.112

R1626 (Roche) Phase I (1.2 log decline in HCV-RNA after 14 days with 1500 mg bid).113

Large phase II trials in combination with pegylated interferon (PEG-IFN) with or without ribavirin have started. The

combination of PEG-IFN may be necessary to prevent drug resistance. More HCV enzyme inhibitors are in

development (for example, GS-9132, Gilead, Achillion; ITMN-191, Intermune; JTK-002/3, Japan Tobacco; HCV796,

ViroPharma, Wyeth; BILB-1941, Boehringer Ingelheim).

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TREATING VIRAL HEPATITIS C

Key points

cSustained clearance of HCV can be achieved in 50–60%

of patients with chronic hepatitis C.

cPatients with HCV genotypes 2 and 3 are more sensitive to

treatment than patients with HCV genotypes 1 and 4.

cTreatment with pegylated interferon alpha and ribavirin

can be associated with a wide variety of side effects.

cOptimal management of side effects and optimisation of

standard therapy can enhance response rates.

virus in vitro model. Therefore, this drug may by HCV

genotype independent.

Another approach to treatment of HCV infection is

induction of HCV specific immune responses (table 3).

Spontaneous recovery after acute HCV infection is associated

with a strong and broad immune response while development

of chronic hepatitis C is associated with an impaired

immune response.106 107 The aim of therapeutic vaccination is

to stimulate the hepatitis C specific immune responses to

control viral replication. The first therapeutic vaccines are

currently being tested in phase I/II studies.108 109

Other advances include the development of small molecules

such as ribozymes, antisense oligonucleotides, and

small interfering RNAs that have been designed to control

viral gene expression. There are many more approaches to

fight hepatitis C and its complications. Tables 3 and 5 give an

overview of the drugs in the pipeline.

ACKNOWLEDGEMENTS

Supported by the German Competence Network for Viral Hepatitis

(Hep-Net), funded by the German Ministry of Education and

Research (BMBF-O1 KI 0401).

Conflict of interest: declared (the declaration can be

viewed on the Gut website at http://www.gutjnl.com/

supplemental).

..................

Authors’ affiliations

M P Manns, H Wedemeyer, M Cornberg, Department of

Gastroenterology, Hepatology, and Endocrinology, Medical School of

Hannover, Hannover, Germany, and German Competence Network for

Viral Hepatitis (Hep-Net)

Conflict of interest: None declared.

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1359

EDITOR’S QUIZ: GI SNAPSHOT ..................................................................

Answer

From question on page 1339

At colour Doppler bowel ultrasound (US), intense vascular

signals with low resistance (fig 1D) suggesting the presence

of intestinal varices were found within and around the wall

of the ascending colon and hepatic flexure (fig 1A–C). Other

relevant US findings included slight bowel wall thickening of

ileal loops in the left flank and dilated (3 cm in diameter)

proximal ileal loops containing stagnating fluid in the left

upper quadrant of the abdomen. Upper endoscopy was

unremarkable. Colonoscopy revealed large varices in the

ascending colon and at the hepatic flexure of the colon (fig 2).

A four channel multidetector spiral computed tomography

(CT) enteroclysis demonstrated narrowing of the jejunal

segment with significant proximal dilatation and, moreover,

a voluminous varicose complex extending from the caecum

towards the ascending colon and surrounding the hepatic

flexure where it was mostly represented (fig 3). CT revealed

collateral circulation in the mesentery suggesting chronic

Figure2 Endoscopic view of dilated and tortuous colonic varices in the

ascending region.

mesenteric venous thrombosis. Despite meticulous examination

of the CT images, no thrombosis was found.

These observations, together with the clinical history,

suggested the presence of recurrent bleeding from colonic

varices. Likewise, the subocclusive symptoms appeared to be

due to extensive and significant adhesions or, less likely, to a

recurrent bowel stricture. Colonic varices, secondary to

adhesions, in the absence of portal hypertension were found

at laparotomy.

Postoperative adhesions have already been recognised as a

possible cause of colonic varices and gastrointestinal bleeding.

1 These complications may result from chronic mesenteric

venous thrombosis that often remains asymptomatic on

account of extensive collateral venous drainage.

doi: 10.1136/gut.2005.086157

Reference

1 ManziD, Samanta AK. Adhesion-related colonic varices. J Clin Gastroenterol

1985;7:71–5.

Figure3 Reconstructed oblique-coronal image from a contrast

enhanced computed tomography (CT) enteroclysis showing a

voluminous varicose complex extending from the caecum towards the

ascending colon and surrounding hepatic flexure. CT also showed the

presence of thickened bowel walls of several loops situated in the left

flank, thus confirming the ultrasound findings.

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