Journal of Gastroenterology and Hepatology (1999) 14 (Suppl.) S12–S18

and have made this disease the leading indication forliver transplantation in the USA.4 The symptoms ofchronic HCV infection are non-specific. The standarddiagnostic tests for HCV infection are serological tech-niques to identify anti-HCV and quantitative virologi-cal assays for the detection of HCV-RNA usingpolymerase chain reaction (PCR) to amplify comple-mentary DNA following reverse transcription or abranched chain DNA assay.5 Recent advances in mole-cular biology have allowed HCV genotypic classificationinto six major genotypes, with approximately 70% ofhepatitis C patients in the USA infected with genotypes1a or 1b and the remaining 30% infected with geno-types 2 and 3; HCV genotypes 4–6 are rare in the USA.

INTRODUCTION

Infection with hepatitis C virus (HCV) is a major publichealth problem worldwide. The prevalence of HCVinfection based on antibody to HCV (anti-HCV) rangesfrom 1 to 2% in developed countries.1 Natural historystudies suggest that progression to cirrhosis occurs inapproximately 20% of patients over a 20 year period,with a smaller number of patients developing liverfailure and/or hepatocellular carcinoma (HCC) at 30years.2 The median interval from HCV infection to cir-rhosis is 30 years.3 The persistence of infection and pro-gressive liver damage that are the hallmarks of HCVinfection result in an estimated 8000 deaths annually

NEW TREATMENT STRATEGIES IN HEPATITIS B AND C

Treatment strategies for chronic hepatitis C: Update since the 1997National Institutes of Health Consensus Development Conference

AIJAZ AHMED AND EMMET B KEEFFE

Division of Gastroenterology, Department of Medicine, Stanford University School of Medicine, Stanford,California, USA

Abstract The National Institutes of Health Consensus Development Conference on the managementof hepatitis C, which took place in March 1997 and was published in September 1997, establishedguidelines for the diagnosis and management of chronic hepatitis C. The recommended treatment ofchronic hepatitis C virus (HCV) infection is interferon alpha (or equivalent) 3 MIU three times perweek for 12 months, in patients showing response to therapy after 3 months. Patients with the greatestrisk for progression to cirrhosis (i.e. persistently elevated alanine aminotransferase levels, detectableserum HCV-RNA and liver biopsy showing portal or bridging fibrosis and at least moderate inflam-mation and necrosis) are recommended as candidates for therapy. The indication for therapy is lessobvious in patients with milder histological changes, compensated cirrhosis and age less than 18 yearsor older than 60 years. Treatment is not indicated for patients with persistently normal aminotrans-ferases or decompensated cirrhosis. This review outlines the background studies that led to the recom-mendations of the National Institutes of Health for the treatment of chronic hepatitis C and reviewsnewer evolving treatment strategies over the past year. In particular, the results of studies exploringtreatment options for relapsers and non-responders to prior interferon therapy and the reported resultsto date on the safety and efficacy of combination therapy with interferon plus ribavirin are highlighted.Although aggressive suppression of HCV-RNA with induction therapy (daily and/or higher doses) orlong-acting pegylated interferon preparations may improve the current results of therapy, few data areyet available. Finally, the treatment of chronic hepatitis C with protease inhibitors holds promise buthas yet to reach the stage of clinical trials.

Key words: chronic hepatitis C, hepatitis C, treatment of chronic hepatitis C.

Correspondence: Emmet B Keeffe, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA94304–1509, USA. Email: <ekeeffe@leland.stanford.edu>

INTERFERON THERAPY

Interferons have shown efficacy in the treatment ofpatients with both chronic hepatitis B and chronichepatitis C. The interferons are a family of cytokinesthat are naturally occurring proteins secreted by manymammalian cells and induce antiviral, anti-tumour andimmunomodulatory activities.6 The specific mechanismof action of interferons in HCV infection is unknown.Interferon alpha (IFNa) represents a family of morethan 20 subspecies of proteins and glycoproteins.Potency of an IFNa product is typically determined bymeasuring antiviral activity in biological assays relativeto a number of internationally available reference stan-dards.The four types of IFNa that have been evaluatedin a large number of patients with chronic hepatitis Cinclude IFNa-2b,7 -2a,8 -n1 (lymphoblastoid inter-feron),9 and -con-1 (consensus interferon (CIFN);10

Table 1). Although these interferons demonstrate somedifferences, the National Institutes of Health (NIH)Consensus Development Conference panel concludedthat all four interferons have comparable safety and effi-cacy in the treatment of chronic hepatitis C.11

Response to interferon therapy: Definitions

Response rates to interferon therapy vary according tothe agent being tested, the dose regimen used and thebaseline characteristics of the patient population. Pre-treatment factors associated with a greater likelihood ofresponse to interferon include low serum HCV-RNAlevel, HCV genotypes 2 or 3 and absence of fibrosis orcirrhosis on biopsy.12 Virological and biochemicalresponses to interferon therapy are defined on the basisof a normal alanine aminotransferase (ALT) level (bio-chemical response) or undetectable serum HCV-RNA(virological response) or both. The time of these find-ings are expressed either as an end-of-treatmentresponse (ETR) or a long-term post-treatment sus-tained response (SR).13 Persistence of response for atleast 6 months after cessation of therapy is the gener-ally accepted definition of SR (sometimes expressed asSR-6). The virological response is the most reliablemarker of treatment efficacy, with the most sensitivePCR assay detecting serum HCV-RNA down to < 100copies/mL.14

Two other patterns of ALT or HCV-RNA responsescan occur during therapy. Breakthrough is defined as a

Treatment strategies for chronic hepatitis C S13

decrease of ALT levels into the normal range (or thedisappearance of detectable HCV-RNA) on treatmentwith subsequent elevation of ALT (or presence ofdetectable HCV-RNA) while the patient is still ontherapy. Alternatively, elevated ALT levels (ordetectable HCV-RNA) can persist at all time pointsduring treatment. Both of the latter two response pat-terns have conventionally been considered as a non-response.

Other treatment responses used in clinical trialsinclude histological evaluation by liver biopsies beforetreatment versus 6 months or more after therapy andcomparison of quality of life by standard testing devicesbefore and after therapy. In the majority of studiesreported to date, the histological activity indexdescribed by Knodell et al.15 has been used. In earlystudies, liver biopsies were typically performed at theend of the therapy and were, therefore, histologicalresponses at the ETR time point and did not reflect theeffect of relapse. In more recent studies, liver biopsieshave been performed 6 months or more after therapy,allowing histological correlation with the presence orabsence of ALT or HCV-RNA at this time point. Theultimate responses to interferon therapy, progression tocirrhosis, decompensation of cirrhosis, development of HCC and liver transplantation or death, are more difficult to study.

Recommendations for use of interferontherapy

Interferon therapy is indicated in patients with chronicHCV infection who are at the greatest risk for progres-sion to cirrhosis.11 These patients are characterized by persistent (> 6 months) elevation of ALT levels,detectable serum HCV-RNA and a liver biopsy demon-strating either portal or bridging fibrosis and at leastmoderate degrees of inflammation and necrosis. Liverhistology is the gold standard for assessing the severityof liver disease in patients infected with HCV. It isrecommended that a liver biopsy be performed inpatients with chronic hepatitis C to assess the severityof liver disease before consideration for treatment. Liverbiopsy is not usually necessary after treatment. Thecurrent recommendation is to measure the biochemical(ALT) and virological (HCV-RNA) response after 12weeks of therapy and to continue interferon for at least12 months and up to 24 months in patients with either

Table 1 Interferon therapy of hepatitis C

Name Company Approved USA dose

IFNa-2b (Intron A) Schering-Plough 3 MU, t.i.w. ¥ 18–24 monthsIFNa-2a (Roferon-A) Roche 3 MU, t.i.w. ¥ 12 monthsIFNa-con-1 (Infergen) Amgen 9 mg, t.i.w. ¥ 6 monthsIFNa-n1 (Wellferon) Glaxo-Wellcome Not licencedCombination IFN alfa-2b + RBV (Rebetron) Schering-Plough IFN 3 MU, t.i.w., RBV 1000–1200 mg/day ¥ 6 months

IFNa, interferon alpha; t.i.w., three times per week; RBV, ribavirin. Trade names of the products are in parentheses.

a normal ALT or undetectable HCV-RNA. The dura-tion of treatment appears to be more important thanthe dose of interferon in achieving a SR. Numerousstudies have shown that 40–50% of patients withhepatitis C who are treated with IFNa-2b (3 MIU,t.i.w.) for 6 months have a biochemical ETR.7,11 Unfor-tunately, relapse following the end of treatment fre-quently occurs and only 7–20% of patients have along-term SR after 6 months of therapy.Thus, it is cur-rently recommended that treatment be continued for12–24 months, which is associated with a better viro-logical SR (20–30%) and a significantly greaterdecrease in hepatic inflammation. More than 90% ofpatients who have a complete biochemical and virolog-ical SR for 6 months after treatment will maintain thatresponse and demonstrate significant improvement inhistology long term.16 Moreover, analyses suggest thatthe use of IFNa is a cost-effective means of treatingchronic hepatitis C.17

Results of therapy with different interferons

Interferon alpha-2b trialsAn independent meta-analysis of all randomized clini-cal trials of IFNa-2b in patients with chronic hepatitisC was recently performed.7 The trials that wereincluded were conducted between 1986 and 1996 andinvolved only previously untreated patients who wererandomly allocated to receive at least 2 MIU IFNa-2bthree times weekly for 24 weeks. A total of 32 trials metthese inclusion criteria. An additional 12 trials com-pared different doses, duration or strategies of treat-ment. In comparison with no treatment, IFNa-2btherapy was associated with significant improvement inall end-points measured. A biochemical ETR wasobserved in 47% of treated patients compared with 4%of controls (P < 0.0001). The biochemical responseswere sustained for at least 6 months in 23% of treatedpatients compared with 2% of controls (P < 0.0001). Avirological ETR was observed in 29% of treatedpatients compared with 5% of controls (P < 0.001), and6 month virological SR was documented in 8% of treated patients compared with 1% of controls (P < 0.001). Histological responses were noted in 73%of treated patients compared with 38% of controls (P < 0.0001). Extended therapy for 12–24 monthsresulted in significant improvement over the 6 monthSR (27 vs 14%, P < 0.001). Higher doses of interferonresulted in modest increases in the ETR (61 vs 52%; P< 0.02) and SR-6 (28 vs 19%; P < 0.01). Based on theresults of the earliest of these studies, in 1991 the Foodand Drug Administration (FDA) approved IFNa-2b(Intron A; Schering-Plough Corporation, Kenilworth,NJ, USA), a recombinant alpha interferon, at a dose of 3 MIU subcutaneously three times weekly for 6months as treatment for patients with chronic hepatitisC.This dose and duration of IFNa-2b therapy has beenthe standard of care for treatment of patients withchronic hepatitis C in the US until recently, whentreatment up to 18–24 months was approved by theFDA.

S14 A Ahmed and EB Keeffe

Interferon alpha-2a trialsInterferon alpha-2a resembles other recombinant alphainterferons in structure and pharmacology.8 A bio-chemical SR occurs in 4–49% of patients after 6–12months therapy, providing adequate doses (at least 3MIU, t.i.w.) are used. A variety of regimens of IFNa-2a have been used, including higher doses, longerperiods of treatment, induction using higher doses ini-tially and intermittent pulse therapy. Both longerperiods of therapy and induction dosing show trendstoward improvement in response rates, which reach sta-tistical significance when the two strategies are com-bined. Outcome is not significantly improved byescalating doses during therapy when inadequateresponses are seen, or by pulse therapy. Interferonalpha-2a (Roferon-A; Hoffmann-La Roche, Nutley, NJ,USA) is an IFNa made by recombinant techniques inEscherichia coli. Interferon alpha-2a was approved by theFDA in 1996 for therapy of chronic hepatitis C at aregimen of 3 MIU, three times weekly for 12 months.

Interferon alpha-n1 trialsInterferon alpha-n1 is produced from a lymphoid cellline and consists of multiple IFNa subtypes.9 Therapyof chronic hepatitis C with IFNa-n1 produced responserates comparable with those obtained with recombinantIFNa-2b.The optimal treatment regimen appears to be3 MIU, three times weekly for 12 months. Furthermore,the findings from both meta-analysis and direct com-parison studies of IFNa-n1 administered in a 6 monthtreatment schedule indicates that treatment with IFNa-n1 is associated with a significantly lower post-treat-ment relapse rate18–20 and, hence, with an improved SRcompared with recombinant IFNa. Recent trials haveshown convincingly that, similar to other interferons,21

the optimal duration for treatment with IFNa-n1 is 12months rather than 6 months.22 Although higher dosesof some recombinant IFNa have been reported toimprove treatment outcomes slightly,21–23 this may notbe the case for IFNa-n1 and doses higher than 3 MIU,three times weekly, when administered for 12 months,are associated with an increased rate of adverseeffects.24,25

Interferon alpha con-1 trialsConsensus interferon is a non-natural, synthetic com-pound that was developed by analysing subtypes ofIFNa and assigning the most frequently observedamino acid in each position of several IFNa non-allelicsubtypes to generate a consensus sequence.10 The effi-cacy and safety of CIFN in the treatment of chronichepatitis C were assessed in a large phase III trial. In a multicentre, randomized, double-blind, controlledstudy, 704 patients were treated with one of two dosesof CIFN (3 and 9 mg) or IFNa-2b, 3 MIU, three timesweekly for 24 weeks and then observed for an additional24 weeks.The results of these studies demonstrated thatCIFN at a dose of 9 mg was safe and effective as therapyfor the treatment of patients with chronic HCV infec-tion. In an extension of the initial trial, reinstitution of

CIFN at a higher dose (15 mg) and treatment for 48weeks was safe and effective in patients who had eitherfailed to respond to previous interferon therapy orrelapsed after discontinuation of therapy.The SR-6 wasgreater after retreatment of relapsers (58%) than non-responders (13%) for 48 weeks. The data also showedthat 9 mg CIFN may be more effective than 3 MIUIFNa-2b in reducing the hepatitis C viral load duringtherapy, although the clinical significance of this obser-vation remains to be determined. Finally, in patientswith high viral titres and/or infection with HCV geno-type 1, CIFN may be more efficacious.10

Patients with mild hepatitis or normalalanine aminotransferase levels

It has been argued that patients with chronic hepatitisC have a relatively benign natural history and, there-fore, may not need treatment.26,27 However, as non-fibrotic liver disease is associated with a higherlikelihood of a week 12 response to interferon11 andtreatment can be predicted to result in improved sur-vival and cost savings,17 it would seem reasonable tooffer patients with elevated ALT levels and mild histo-logical disease a therapeutic trial of interferon. If thisstrategy were to be adopted, pretreatment liver biopsyto distinguish mild from moderate disease as a basis fortreatment decisions might become optional.

The majority of data available on the treatment ofchronic hepatitis C are from studies in which patientswere selected for inclusion in studies if ALT levels weregreater than 1.5-fold the upper level of normal. Severalstudies have evaluated the clinical status and responseto treatment of patients with chronic viraemia butnormal or minimally elevated ALT levels.28 Abnormalliver histology is found in the majority of such patients,although advanced histological changes are seen lessfrequently. The results of five treatment trials indicatethat a virological SR is rare and some patients developALT elevations on treatment that persists thereafter.28

Further studies are necessary to determine the naturalhistory of HCV infection in these patients and whetherstandard therapy with interferon is warranted.

Retreatment of hepatitis C virus infectionwith interferon

Retreatment studies have been performed in patientswho received interferon and did not respond at the endof treatment, as well as those who responded to aninitial course of treatment but relapsed after treatmentwas discontinued.29 Treatment strategies include the use of the same drug at the same or higher dose or fora longer period of time or use of a different interferon.In general, biochemical ETR rates (79–85%) are muchhigher in patients who previously responded andrelapsed, than in patients who did not respond to aninitial course of therapy (14–30%).29 However, mostpatients who respond to interferon retreatment relapseonce again after withdrawal of therapy, so that no more

Treatment strategies for chronic hepatitis C S15

than 15–25% achieve a SR. The best predictors of SRto retreatment of relapsers is a negative serum HCV-RNA by PCR at the end of the first course and an initialtreatment course of only 6 months. Retreatment ofrelapsers with interferon monotherapy (e.g. IFNa-con-1, 15 mg, t.i.w. for 1 year) can achieve a 58% viro-logical SR.10 The cumulative data indicate that non-responders to interferon should not be retreated withthe same interferon alone and achieve only modestresponses with alternative interferons, such as IFNa-con-1 (15 mg, t.i.w. for 1 year; i.e. 13% virological SR).

Side effects of interferon

Interferon therapy for hepatitis C is associated with awide range of side effects, the mechanisms of which areunknown.30,31 Side effects are usually mild, rarely life-threatening and seen more frequently with higher doses.Flu-like symptoms predominate in the first severalweeks of treatment, whereas fatigue and depression aremore common later in therapy. Because interferon maycause or exacerbate depressive symptoms, cautionshould be used in treating patients who have a historyof major depression. If interferon therapy is needed insuch patients, it may be helpful to co-prescribe an anti-depressant agent.

Management of special hepatitis C viruspatient populations

Acute hepatitis CThe data from eight randomized, controlled trials ofIFN therapy of acute hepatitis C were recently sum-marized.11 Treatment with IFN in doses of 3 MIU threetimes weekly for 3 months was associated with highervirological and biochemical ETR and SR rates com-pared with no treatment.13

ChildrenResults of IFNa treatment in children appear to besimilar to results in adults,32 with 35% of childrenhaving a biochemical ETR and histological improve-ment occurring in responders.

Immunocompromised patientsThe natural history and treatment of patients withchronic hepatitis C after liver transplantation,33 end-stage renal disease and renal transplantation34 andhuman immunodeficiency virus (HIV) coinfection35

have been reviewed recently. Interferon treatment ofHCV-infected patients with immune disorders is prob-lematic and, in general, not highly effective.

Extrahepatic manifestations of hepatitis C virusinfectionThe benefits of IFNa therapy have been described inthe treatment for essential mixed cryoglobulinaemia

and glomerulonephritis associated with HCV infec-tion.36 The optimal therapeutic regimens have not yetbeen defined, but long-term therapy is required toprevent relapse of the underlying disorder.

Patients with features of autoimmune diseaseMarkers of autoimmunity are frequently found inpatients with chronic HCV infection, making the deter-mination as to whether a patient with chronic hepatitisC and features of autoimmune hepatitis should betreated with IFNa or immunosuppressive therapy dif-ficult in some patients.37 For patients with definitive fea-tures of autoimmune hepatitis, in light of the potentialfor IFNa to exacerbate this disorder, an initial thera-peutic trial with immunosuppressive therapy may bewarranted.38

Patients with cirrhosisCombined analysis of multiple large studies on patientswith cirrhosis caused by hepatitis C indicates thatcurrent regimens of IFNa (3–6 MIU, t.i.w. for 6–12months) result in a biochemical SR in 9% of patients.39

The rates of virological SR are less well documented.Virological measurements during therapy show thatonly 22% of patients become HCV-RNA negative by 4weeks and there is a high rate of breakthrough. In smallstudies, the combination of interferon and ribavirinleads to biochemical and virological SR rates of 21%,more than twice the rate achieved with interferon alone.The prognosis of decompensated cirrhosis caused byhepatitis C is poor, with a 5 year survival rate of only50%.The efficacy of interferon in patients with decom-pensated cirrhosis is not well documented and its usecannot be recommended. In contrast, 5 year survivalrates after transplantation for cirrhosis caused byhepatitis C are excellent, ranging from 70 to 80%.Recurrence of HCV infection occurs in more than 95%of patients, but in short-term, follow-up studies, recur-rence of cirrhosis and graft failure occur in only 10%of patients.33

Patients with decompensated liver diseaseAt present, only anecdotal reports are available on interferon treatment of patients with clinically decom-pensated liver disease (ascites, variceal bleeding,encephalopathy) caused by hepatitis C. Until data onthe risks and benefits of treatment are available in suchpatients, liver transplantation should be considered thetreatment of choice.39

Newer therapeutic strategies usinginterferon

Interferon induction therapy in hepatitis C virusinfectionThe critical time period with interferon therapy forchronic hepatitis C appears to be the early weeks of

S16 A Ahmed and EB Keeffe

treatment. This was shown in a recent study by Karinoet al. in which 114 HCV-RNA-positive patients weregiven 6 MIU lymphoblastoid interferon daily for either2, 4, or 8 weeks, followed by thrice-weekly treatment for24 weeks.40 The SR rate was significantly higher inpatients who lost HCV-RNA by the end of the first weekof therapy (i.e. 76%). By contrast, none of 55 patientswho had detectable HCV-RNA at the end of the first 4weeks IFN therapy had a SR. In 1986, Hoofnagle et al.performed the initial pilot study of interferon therapy.41

The first patient was treated with 5 MIU/day, was grad-ually titrated to 3 MIU/day and then further titratedlater. This patient was treated for 1 year and had a bio-chemical SR. Lamb et al. performed single-dose studiesin which 32 patients with hepatitis C genotype 1 weretreated with either 3, 5, or 10 MIU of interferon daily.42

All individuals in the study had a rapid decline of viruswithin 24 h, although this was most prominent in thepatients who received 10 MIU/day and there was arapid return of virus within 48 h.These findings suggestthat therapy thrice weekly may set up a viral cycle (i.e.disappearance, return, disappearance, return) thatmight, at least theoretically, promote the developmentof a resistant infection.

Pegylated interferon therapy in hepatitis C virusinfectionIt has long been speculated that a slow-release, long-acting formulation of interferon may help reduce thefluctuating effects seen with the thrice-weekly dosingregimen. An international research program is beingconducted by Hoffmann-La Roche Inc. and Schering-Plough Corporation to assess the safety and efficacy ofpegylated-interferon in the treatment of chronic HCVinfection. Pegylated-interferon is administered once perweek, subcutaneously and is a promising candidate fortreatment of chronic HCV infection.

COMBINATION INTERFERON ANDRIBAVIRIN THERAPY

Ribavirin is a nucleoside analogue that has been evalu-ated for the treatment of chronic hepatitis C asmonotherapy and in combination with IFNa. Ribavirinis well absorbed orally and is generally well tolerated,although haemolytic anaemia is common.The mode ofaction of ribavirin is not well understood. Ribavirin istypically given in doses of 1000–1200 mg/day. Threerandomized, placebo-controlled studies comprisingmore than 150 patients showed that therapy with rib-avirin alone for 24–48 weeks resulted in a significantreduction in serum ALT levels during therapy.43 How-ever, ribavirin therapy did not result in a reduction inHCV-RNA levels and serum ALT levels increased topretreatment values when therapy was stopped.

Combination therapy with ribavirin and IFNa hasdemonstrated promise both in earlier pilot studies anda recently completed randomized controlled trial.Reichard and colleagues44 showed recently that the useof ribavirin in combination with interferon for 6 months

doubled the SR rate (from 18 to 36%) compared withtreatment with interferon alone in previously untreatedpatients with chronic hepatitis C. However, combina-tion therapy demonstrated clear-cut superiority only inpatients with high pretreatment levels of HCV-RNA. Inpatients who relapsed after an ETR with interferonalone (relapsers), combination treatment with inter-feron and ribavirin for 24 weeks was associated withhigher SR rates than retreatment with interferon alone(49 vs 4%).45

For interferon-naive patients, it is difficult to univer-sally recommend combination therapy as the firstapproach to treatment until further data are published.Interferon alone may be preferable if the patient has afavourable clinical profile, such as young age, low viralload or infection with HCV genotypes 2 or 3, becausethese patients may respond equally well to interferonalone.43,44 Patients with high HCV-RNA levels, geno-type 1, high degrees of viral genomic diversity or histo-logical evidence of advanced fibrosis or cirrhosis maybe candidates for initial combination therapy.

Combination therapy is associated with more adversereactions than therapy with interferon alone andincreased costs.The main side effect of ribavirin therapyis haemolytic anaemia, which is reversible and usuallystabilizes after 5–6 weeks of treatment. However, somepatients become gravely anaemic and treatment mustbe discontinued. Ribavirin should be used with cautionin patients with coronary artery disease, whose diseasemay be exacerbated by anaemia. The other most com-mon side effects associated with ribavirin treatment arefatigue, skin disorders, such as pruritus, rash, alopecia,dry skin and eczema; nervous system disorders (e.g.depression, insomnia, anxiety, irritability and vertigo);gastrointestinal disorders (e.g. nausea, anorexia); and aslight rise in serum uric acid, bilirubin and platelets.Finally, ribavirin is teratogenic and pregnancy must beavoided while using this drug.

ALTERNATIVE HEPATITIS C VIRUSTREATMENT STRATEGIES

Therapy of chronic hepatitis C with IFNa is less thanideal; therefore, numerous other approaches have beenstudied, including iron reduction by phlebotomy, urso-diol and amantadine.46 Amantadine therapy has re-sulted in significant reduction in serum ALT levels inpatients with chronic hepatitis C.47 The effects of aman-tadine on hepatic histology and virological markersrequire better documentation.

Antiviral agents that inhibit proteases have a differ-ent mechanism of action from immunomodulatoryagents, such as interferon, and are the hope of futuretherapies. The most promising antiviral targets inchronic HCV infection are the replication enzymes,RNA-binding proteins, viral entry proteins and virusmaturation processes. Thus far, the most intensivelystudied molecule is the replication enzyme NS3 pro-tease, which appears to be an essential component ofthe life cycle of the virus. If this enzyme can be inacti-vated, viral replication is blocked and at least six com-

Treatment strategies for chronic hepatitis C S17

pounds that target the NS3 protease are now in pre-clinical testing.

The goal in treating hepatitis C is to either eliminatethe virus, the current traditional strategy, or to reduceviral load in order to alter the natural history of thedisease. Recent data suggest that interferon may have afavourable effect on the natural history even if it doesnot completely eradicate the virus. A course of inter-feron therapy may increase the likelihood of survival48

and decrease the chance of developing hepatocellularcarcinoma,49 particularly in those patients having a SRto interferon therapy.

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