Therapeutic options for HCV—management of the infected individual

BaillieÁre's Clinical Gastroenterology Vol. 14, No. 2, pp. 255±264, 2000

doi:10.1053/bega.1999.0074, available online at http://www.idealibrary.com on

5 Therapeutic options for HCV ± management of the infected individual G. R. Foster* Senior Lecturer in Hepatology

H. C. Thomas Professor of Medicine The Liver Centre, Imperial College School of Medicine at St Mary's, St Mary's Hospital, Praed Street, London, W2 1PG, UK

Patients with chronic hepatitis C infection should be assessed by liver biopsy prior to consideration of anti-viral therapy. Patients with histologically mild disease should be observed at regular intervals and assessed with a repeat liver biopsy after an interval of 3±4 years. Those with severe disease should receive early treatment with interferon-a and ribavirin. The duration of therapy is determined by the genotype of the infecting virus±viral genotypes 2 and 3 require only 6 months of treatment but other genotypes should be treated for 12 months. Approximately 35±40% of treated patients will respond to therapy with a permanent cessation of viral replication and improvement in liver histology. New therapies including polyethylene glycol, PEGylated, interferons and combination regimes involving amantadine are currently under evaluation and it is hoped that improved regimes will be developed in the near future. Key words: hepatitis C; interferon; ribavirin; guidelines.

INTRODUCTION Appropriate management of patients chronically infected with the hepatitis C virus (HCV) requires an appreciation of the natural history of the disease coupled with an understanding of the limitations of current treatment regimes. The therapeutic options for patients with chronic HCV are limited and the clinician is usually faced with the decision of whether to treat or not, rather than what to use for therapy. In this chapter we will review the complex issue of patient selection before discussing past, present and future therapeutic regimes. PATIENT SELECTION Chronic infection with HCV is common and for many patients the disease is mild (see Chapter 2) and unlikely to lead to signi®cant liver disease in the foreseeable future.1 All correspondence to: Dr G. R. Foster, Department of Medicine, QEQM Wing, St Marys Hospital, London, W2 1PG. Tel: 0171 725 6400; Fax: 0171 724 9369; E-mail: [email protected] 1521±6918/00/020255+10 $35.00/00

c 2000 Harcourt Publishers Ltd *

256 G. R. Foster and H. C. Thomas

However, in a signi®cant proportion of infected individuals chronic HCV infection leads to progressive hepatic injury that results in cirrhosis and liver cell cancer over a time frame of 20±30 years. These patients, with moderate/severe chronic HCV disease, are at risk of severe liver damage and all agree that such patients should receive therapy.2,3 The position regarding patients with mild disease is much less clear. For some the disease will not progress and these patients are unlikely to su€er from liver disease. Treating such patients will expose them to the inconvenience and side e€ects of therapy for no gain. Furthermore there is evidence that for patients with mild hepatitis C and normal liver function tests (LFTs), inferferon-a (IFN-a) therapy may lead to an exacerbation of their disease with an increase in the serum alanine aminotransferase (ALT) levels.4 Hence there may be signi®cant risks in treating patients with mild hepatitis C. On the other hand patients infected with HCV are carrying an agent that may be, albeit rarely, transmitted to others by sexual or other contact.5 Patients with mild liver disease due to HCV infection may su€er from the non-hepatic manifestations of chronic hepatitis C, chie¯y fatigue6 and it is possible that therapy with anti-viral agents before ®brosis has developed may result in higher rates of viral clearance. Thus it may be argued that early treatment is bene®cial in patients with mild HCV infection. The important issue of whether patients with mild hepatitis C should receive immediate therapy or whether therapy should be reserved for those with more active disease is currently the subject of a number of controlled clinical trials and it is likely that the answer to this issue will become apparent over the next few years. At present most, but not all, hepatologists agree that patients with mild hepatitis C should not receive active treatment ± such patients should be monitored on a regular basis with assessment of their LFTs and if there is evidence of deterioration a further biopsy should be performed. Patients under observation with mild hepatitis C and stable LFTs should undergo a liver biopsy after an interval of 3±4 years to determine whether any increase in hepatic ®brosis has occurred. Any increase in ®brosis should lead to treatment. The precise de®nition of mild hepatitis C varies from group to group and di€erent units adopt slightly di€erent de®nitions. At our unit we de®ne mild hepatitis C on the basis of the modi®ed Ishak scoring system7 and mild hepatitis C is de®ned as a ®brosis score of less than 3 and a necroin¯ammatory score of less than 4. The algorithm currently in use in our unit is shown in Figure 1. TREATMENT OF PATIENTS WITH CHRONIC HCV DISEASE Early treatment regimes: interferon monotherapy The early clinical studies for patients with chronic hepatitis C took place before the virus was identi®ed. These studies enrolled patients with non-A, non-B hepatitis who were subsequently shown to be infected with HCV.8 These clinical trials typically used IFN-a monotherapy at a dose of 3 million international units (MIU) three times a week (t.i.w.) and treatment was usually for a period of 6 months (see, for example, Cimino et al9). These studies suggested that up to 30% of patients responded to therapy. However, these early clinical trials measured response to therapy by normalisation of LFTs and it is now clear that this end point signi®cantly overestimates the proportion of patients who respond virologically. Later clinical trials measured serum viraemia, using reverse transcriptase-polymerase chain reaction (RT-PCR), and showed that treatment regimes of 3 MIU thrice-weekly (t.i.w.) for 6 months eradicated the virus in only a small proportion of patients. Even these recent trials may have overestimated

Therapeutic options for HCV 257

Patient with chronic HCV disease

Check PCR to confirm infection

PCR positive

Liver biopsy

Mild disease

Moderate/severe disease

No therapy

Treat

Cirrhosis

Treat

Review every 6 months and repeat biopsy in 4 years

Monitor for HCC by ultrasound and alpha fetoprotein (αFP) measurement every 6 months

RECOMMENDED TREATMENT Genotype 1/4

Genotype 2/3

IFN+ribavirin 3 MIU+1000 mg for 12 months

IFN+ribavirin 3 MIU+1000 mg for 6 months

Figure 1. Management of chronic hepatitis C. The St Mary's Hospital treatment algorithm is shown along with current recommendations for therapy.

the proportion of patients who responded to therapy since the sensitivity of the ®rst generation of PCR assays was relatively low (approximately 2000 copies/ml) compared to the current assays (which have a sensitivity of 100 copies/ml). It is therefore clear that the early clinical studies with IFN monotherapy signi®cantly overestimated the proportion of patients who responded to treatment with complete eradication of the virus and recent studies using more robust criteria of virological response have shown that far fewer patients are cured.10 It is instructive to compare the response rates in the recent large scale clinical trials, which have shown sustained response rates of 6% with IFN-a monotherapy for 6 months10, with the results from early studies reporting response rates of 38%.9 It follows that great care must be taken in evaluating the success rates of early clinical studies and it is evident that meta-analyses of published clinical trials must be interpreted with caution.

258 G. R. Foster and H. C. Thomas

The pattern of response to IFN therapy is informative and patients treated with IFN monotherapy may be divided into three distinct groups: 1. Non-responders ± no detectable response to therapy. Approximately 50% of treated patients show no detectable response to therapy i.e. HCV-RNA remains detectable in serum and the LFTs do not change. These patients are typically referred to as nonresponders (NRs) but careful analysis of the viral load in such patients has led to suggestions that some of these IFN NRs do show a partial response to therapy (i.e. the level of viraemia decreases a little but the virus remains detectable (our unpublished results)). It is therefore likely that IFN NRs are, in fact, a heterogenous group composed of true NRs and patients who show a slight response to therapy. As new treatments are developed and tested in these patients it will be important to de®ne these patients more accurately ± it is probable that patients who show a slight response to IFN-a monotherapy will be more likely to respond to combination regimes and it will be important to ensure that randomized trials take account of the likely di€erences in response rates within the `non-responder' subpopulations. 2. Partial responders ± initial, unsustained, response to therapy. Nearly half of the total number of patients receiving IFN monotherapy will show an initial response to therapy ± the LFTs will return to normal and HCV-RNA will become undetectable in serum. Unfortunately up to 50% of these patients subsequently relapse, some during therapy (breakthrough) and others shortly after treatment cessation (relapse). 3. Complete responders ± response to therapy that is sustained inde®nitely. Although only a minority of treated patients achieve sustained viral clearance it is now clear that in these patients the loss of HCV viraemia is sustained over many years. Long-term follow up studies of treated patients have consistently shown that patients who are PCR negative with normal LFTs 6 months after treatment cessation remain aviraemic with normal LFTs and most show improvement in liver histology.11,12 Life long cure, by de®nition, can only be determined when a patient dies from an unrelated illness and it is therefore too early to claim that complete responders to IFN are cured but all the available information suggests that this is indeed the case. Improving the response to IFN monotherapy The relatively poor success rates with IFN monotherapy led to attempts to improve response by increasing both the duration of therapy and the dose of drug. A number of studies have shown that increasing the duration of therapy beyond 6 months increases the response to IFN monotherapy13,14 and treatment for 12 months is now recommended, although some advocate increasing the duration of therapy still further. The bene®cial e€ects of modifying the dose of IFN remain controversial. Two approaches have been used: some investigators have studied the e€ects of a small, consistent increase in the dose of IFN, typically to 6 MIU t.i.w., whilst others have used large increases in the dose (5±10 MIU IFN daily) either as a brief induction regime or as prolonged therapy. A meta-analysis of the e€ects of increases in the thrice weekly regime15 showed that increasing the dose of IFN to 6 MIU t.i.w. increased response but this was o€set by an increase in the number of patients who were unable to tolerate therapy. The authors concluded that the optimum regime was 3 MIU t.i.w. A large number of small scale clinical studies have addressed the question of whether very high doses of IFN might increase the response rates still further. These

Therapeutic options for HCV 259

studies have all lacked statistical power and have often produced con¯icting results. A recent review16 suggests that increasing the dose of IFN increases the initial response rates but does not lead to a marked increase in the sustained response, although the small numbers involved in these studies do not allow a small bene®t in sustained response to be excluded. The optimal dose of IFN thus remains to be determined but it seems likely that increases in the dose may lead to slight increases in response rates although the magnitude of the bene®t and the proportion of patients who are intolerant of the higher doses remains to be determined. Interferon and ribavirin The relatively low response rates to IFN monotherapy led to clinical trials of combination therapy involving a variety of other drugs including the anti-viral agent ribavirin. Ribavirin is an orally active synthetic guanosine nuclesoide analogue that has a broad spectrum of anti-viral activity ± it inhibits the replication of many viruses by inhibiting initiation of translation, RNA replication and viral RNA packaging.17 Early studies of ribavirin monotherapy in patients with chronic hepatitis C showed that the drug reduced hepatic in¯ammation, as measured by LFTs, but had no e€ect on viraemia.18 Subsequent trials using ribavirin in combination with IFN suggested that the combination led to signi®cant increases in the number of patients who responded to treatment and three large scale studies have now con®rmed these ®ndings and have led to the use of combination therapy with IFN/ribavirin as ®rst line therapy for chronic hepatitis C.10,19,20 It is still unclear as to how ribavirin acts in patients with chronic hepatitis C receiving combination therapy. In isolation the drug does not inhibit the replication of HCV (see above) and it has been suggested that ribavirin acts as an immunostimulant. In vitro studies show that ribavirin may enhance Th1 responses and this may lead to initiation or ampli®cation of an immune response that leads to clearance of HCV.21 Careful analysis of the response rates in patients receiving combination therapy shows that the addition of ribavirin to IFN-a signi®cantly reduces the number of patients who relapse after cessation of therapy ± for patients receiving IFN-a monotherapy 50±55% of those who have normal LFTs at the end of therapy relapse when treatment is withdrawn, but only 20% of patients receiving combination therapy relapse in this way. This is clearly consistent with a model in which ribavirin has no e€ect on the replication of HCV but does enhance the immune mediated clearance of infected hepatocytes. Further support for this model comes from studies of viral clearance in patients with chronic hepatitis C that show that combination therapy does not alter the initial decrease in viraemia seen with IFN-a but does increase the subsequent reduction in viral load22 (Figure 2). Management of patients receiving interferon and ribavirin therapy For patients with uncomplicated hepatitis C the recommended treatment regime is 3 MIU IFN-a t.i.w. plus 1000 mg/day of ribavirin. In patients who weigh more than 75 kg the dose of ribavirin should be increased to 1200 mg. The duration of therapy is determined by the viral genotype ± patients with HCV of genotype 1 require 12 months therapy and those with genotypes 2 and 3 need only receive treatment for 6 months. At present there is no information on the required duration of therapy for patients with HCV of other genotypes ± our own policy is to use 12 months therapy

260 G. R. Foster and H. C. Thomas

Serum viraemia

Phase 1

Phase 2

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Time (days) Figure 2. Schematic diagram comparing the e€ects of IFN-a monotherapy ( ) and IFN-a plus ribavirin ( ) on circulating viraemia. Following an initial lag phase IFN-a leads to a rapid fall in circulating viraemia, which is presumably due to inhibition of viral replication. The initial rapid fall in viraemia (phase 1) is followed by a very slow decline in viraemia (phase 2), which is thought to be due to clearance of IFN-a resistant viral particles by the immune system. Ribavirin has little or no e€ect on the ®rst phase but increases the rate of viral loss during phase 2. This is consistent with a model in which ribavirin enhances immunological responses against HCV.

for patients with genotypes other than 2/3 but controlled clinical trials are needed to determine the optimum duration of therapy in these patients. Combination therapy with IFN and ribavirin is e€ective in approximately 35±40% of treated patients. However the therapy is not problem free. Interferon monotherapy usually causes quite severe ¯u-like symptoms during the ®rst 2 weeks of therapy with high fevers, headaches, occasional rigours and nausea. Patients should be reassured that these side e€ects are always worst after the ®rst dose and by the end of the second week most notice that the side e€ects have reduced signi®cantly. We advise our patients to take 2 weeks o€ work and to take 1 gram of paracetamol with their IFN injection to reduce the initial side e€ects. Patients should be advised to take their injection in the early evening, since the side e€ects develop after a few hours this ensures that the worst symptoms develop during sleep. Some patients ®nd that when IFN is taken three times a week (the usual regime is Monday, Wednesday and Friday) the ®rst dose on the next Monday leads to a recurrence of the fevers seen during the ®rst 2 weeks of treatment. This loss of adaptation may resolve when the treatment regime is changed to 3 MIU IFN every other day. Paradoxically this slight increase in dose leads to an improvement in symptoms, presumably because the side e€ects are exacerbated by large changes in serum IFN levels. Although the initial ¯u-like symptoms tend to decrease with prolonged therapy other side e€ects develop as treatment is continued. Many patients receiving long term IFN therapy notice an increase in fatigue and have diculty in concentrating, patients may be reassured that these symptoms improve rapidly when treatment is stopped. The most feared complication of IFN therapy is suicidal depression ± most patients receiving IFN

Therapeutic options for HCV 261

become a little depressed and may bene®t from a short course of anti-depressants, but a minority (approximately 1 in 1000) become profoundly depressed and may commit suicide. Patients and their partners should be aware of this possibility and therapy should be stopped immediately if there is any suggestion of profound depression. In addition to its marked e€ects on patients' well-being, IFN-a also causes some degree of bone marrow suppression with a decrease in neutrophils and platelet count.23 In general the changes are minor and rapidly reverse when the dose of IFN-a is reduced. We monitor the full blood count in our patients at least weekly during the ®rst month of therapy and every 3 months thereafter. In patients with chronic HCV, IFN-a therapy may occasionally induce anti-thyroid antibodies and lead to hypothyroidism.23 It may be dicult to distinguish the IFN-a induced fatigue from early thyroid dysfunction and we evaluate thyroid function every 3 months in patients undergoing IFN-a therapy. Unfortunately ribavirin whilst increasing the e€ectiveness of IFN also increases the side e€ects. The most feared complication in patients receiving ribavirin is pregnancy. Animal studies show the drug to be teratogenic and because of the very long half-life of ribavirin, pregnancy should be avoided for at least 6 months after treatment cessation. In males ribavirin may accumulate in sperm and men receiving treatment with ribavirin should not father children for at least 6 months after treatment cessation. Most patients develop a mild, self-limiting haemolytic anaemia with a fall in haemoglobin of around 2±3 gm/dl. This tends to exacerbate the IFN related fatigue and depression. In addition to haemolytic anaemia ribavirin may cause small, painful oral ulcers which, combined with mild nausea, causes many patients to reduce their food intake and lose weight. We ®nd that advising patients to chew gum improves their oral ulcers (it induces saliva which alleviates some of the oral symptoms) and may stabilize patients' weight loss. In some patients reducing the dose of ribavirin improves the associated side e€ects. The minimum e€ective dose of ribavirin is not yet known but most hepatologists are reluctant to reduce the dose of drug below 800 mg/day. In our experience reducing the dose below this level often leads to relapse and we prefer to stop therapy completely rather than to continue with ine€ective therapy. The absolute contraindications to IFN-a and ribavirin therapy are shown in Table 1. Table 1. Contraindications to IFN-a and ribavirin therapy. Pregnancy Breast feeding Inability to take e€ective contraceptive measures Haemoglobinopathies Renal failure Severe psychiatric disorder

Management of patients who have failed to respond to standard therapy The management of patients who have failed to respond to IFN-a monotherapy has been investigated in a number of clinical trials. It is clear that for patients who have shown a partial response to IFN-a monotherapy subsequent treatment with IFN-a and ribavirin for 6 months has a high probability of success21 and should be attempted. However, for patients who have shown no response to IFN-a monotherapy the chance of a successful outcome following combination therapy is small and these patients

262 G. R. Foster and H. C. Thomas

should probably only be treated in the context of clinical trials. Novel, arti®cial Type I IFNs have been used in these patients24 and have shown greater activity than therapy with conventional IFN-a2. It will be interesting to see whether the combination of modi®ed IFN and ribavirin improves the response rates in these patients. Alternative drug regimes in patients with IFN/ribavirin resistant hepatitis C are currently under evaluation. These include high dose IFN-a, novel interferons (including polyethylene glycol (PEGylated) interferons) and combination therapies involving IFN-a, ribavirin and amantadine. The value of these experimental therapies is unknown and patients with treatment refractory hepatitis C should receive these therapies only as part of controlled clinical trials. Treatment of patients with cirrhosis The response to IFN monotherapy in patients with HCV and cirrhosis is poor, with most clinical trials showing response rates signi®cantly less than those seen in patients without cirrhosis.25 Modi®ed treatment regimes involving higher doses of IFN may be more successful and anecdotal evidence suggests that therapy with IFN and ribavirin may induce a cure in some patients.2 However, at present, controlled clinical trials of these new regimens in patients with cirrhosis have not been reported and the optimum therapy for patients with HCV related cirrhosis is not known. It is clear that these patients are at a high risk of developing hepatocellular carcinoma (HCC) and hepatic decompensation26 and most hepatologists agree that such patients should be treated ± the bene®ts of successful therapy are likely to be very great in this subgroup. We use our standard regime of 3 MIU t.i.w. of IFN-a with ribavirin at standard doses in these patients. Since many patients with HCV and cirrhosis have hypersplenism with reduced platelet and neutrophil counts it is important to monitor these patients carefully since the dose of IFN may need to be reduced if there is evidence of signi®cant thrombocytopaenia or neutropaenia. Patients with HCV and cirrhosis are at risk of developing liver cell cancer and regular monitoring using ultrasound may allow the early detection of malignant nodules at a time when transplantation is feasible.27 Although this approach has not been formally proven to reduce mortality from hepatocellular carcinoma, we screen our patients with HCV related cirrhosis using ultrasound and a-fetoprotein levels every 6 months and this approach was recommended by an Italian consensus meeting.28 Improving the response rates with interferon and ribavirin The increase in sustained response rates with IFN and ribavirin therapy is welcome, but sustained response rates remain suboptimal. Attention is now being focused on to novel therapies that may increase the response rates still further. High quality clinical trials of IFN and ribavirin tested the e€ects of increasing the duration of therapy from 6 to 12 months and showed that in patients with HCV of genotypes 2 and 3 increasing the duration of therapy beyond 6 months did not increase the sustained response rates. It remains to be determined whether increasing the duration of therapy for patients with genotype 1 will increase response but, by analogy with genotypes 2 and 3, this seems unlikely. An alternative approach is to increase the dose of IFN and a number of groups are investigating this. As outlined above, studies in patients receiving IFN monotherapy suggest that high dose, daily IFN may increase initial response rates but have only a small e€ect on sustained response rates. The addition of ribavirin to interferon reduces the proportion of patients who relapse suggesting

Therapeutic options for HCV 263

that increasing the dose of IFN to increase the number of patients who respond initially along with the addition of ribavirin, to reduce the proportion who relapse, may signi®cantly improve long term response rates. However, it remains to be seen whether these demanding treatment regimes are acceptable to patients and the results of clinical trials analysed on an intention to treat basis will be of great importance in determining the value of high dose IFN plus ribavirin. An alternative to the use of high dose daily IFN-a is to use depot preparations of IFN-a that increase the serum levels of IFN-a and avoid the wide ¯uctuations seen with daily doses. As discussed above many patients ®nd that the side e€ects of IFN-a are related to ¯uctuations in dose and a depot preparation may allow higher doses of IFN-a to be given without dose limiting side e€ects. Combining IFN-a with polyethylene glycol (PEG) signi®cantly increases the half-life of the protein and such modi®ed IFNs are currently undergoing clinical trials. A depot IFN preparation in which IFN-a2a is cleaved from a PEG moity is under development, as is a circulating 40 kDa PEGylated IFN. Early results from clinical trials of the 40 kDa PEG-IFN have been presented by the manufacturer and suggest that response rates may be as high as 30±35% for 40 kDa PEG-IFN monotherapy. Results with the combination of 40 kDa PEG-IFN and ribavirin are awaited with interest. Alternatives to ribavirin A number of possible alternatives to ribavirin have been assessed for anti-viral activity against HCV in combination with IFN-a. Drugs tested to date include amantadine, ursodeoxycholic acid and NSAIDs (for a review, see Younossi and Perrillo29). The majority of these studies have involved small numbers of patients and have not yet provided conclusive proof of bene®t. Amantadine has been most widely studied and early results are encouraging.30 Two large scale multicentre trials in naõÈ ve patients with chronic hepatitis C are on-going at present and the role of amantadine as an IFN-a adjuvant should be clari®ed in the near future. CONCLUSION Therapy for chronic HCV infection has developed rapidly over the last few years with the worldwide licensing of IFN and, more recently, ribavirin. There is still a need for improved therapies that are better tolerated than the current regimes and the intense commercial and academic activity in this area will undoubtedly lead to further innovative therapeutic agents in the near future. For the present, patients with chronic hepatitis C should be carefully examined to assess the risks and bene®ts of therapy, and for those who require treatment combination therapy with IFN and ribavirin should be dispensed by units familiar with the management of these demanding drugs. REFERENCES 1. Poynard T, Bedossa P, Opolon P et al. Natural history of liver ®brosis progression in patients with chronic hepatitis C. Lancet 1997; 349: 825±832. 2. Foster GR, Goldin RD, Main J et al. The management of chronic hepatitis C: clinical audit of a biopsy based management algorithm. British Medical Journal 1997; 315: 453±458. 3. Panel NC. National Institutes of Health Consensus Development Conference Panel Statement: management of hepatitis C. Hepatology 1997; 26: 2S±11S.

264 G. R. Foster and H. C. Thomas 4. Marcellin P, Levy S & Erlinger S. Therapy of hepatitis C: patients with normal aminotransferase levels. Hepatology 1997; 26: 133S±136S. 5. Tibbs C. Methods of transmission of hepatitis C. Journal of Viral Hepatitis 1995; 2: 113±120. 6. Foster GR, Goldin RD & Thomas HC. Chronic hepatitis C virus infection causes a signi®cant reduction in quality of life in the absence of cirrhosis [see comments]. Hepatology 1998; 27: 209±212. 7. Ishak K, Bapista A, Bianchi L et al. Histological grading and staging of chronic hepatitis. Journal of Hepatology 1995; 22: 696±699. 8. Hoofnagle JH, Mullen KD, Jones DB et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. New England Journal of Medicine 1986; 315: 1575±1578. 9. Cimino L, Nardone G, Citarella C et al. Treatment of chronic hepatitis C with recombinant interferon alfa. Italian Journal of Gastroenterology 1991; 23: 399±402. 10. McHutchison JG, Gordon SC, Schi€ ER et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group [see comments]. New England Journal of Medicine 1998; 339: 1485±1492. 11. Saracco G, Rosina F, Abate M et al. Long-term follow-up of patients with chronic hepatitis C treated with di€erent doses of interferon-alpha 2b. Hepatology 1993; 18: 1300±1305. 12. Marcellin P, Boyer N, Gervais A et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Annals of Internal Medicine 1997; 127: 875±881. 13. Chemello L, Bonetti P, Cavalletto L et al. Randomized trial comparing three di€erent regimens of alpha2a-interferon in chronic hepatitis C. The TriVeneto Viral Hepatitis Group. Hepatology 1995; 22: 700±706. 14. Poynard T, Bedossa P, Chevallier M et al. A comparison of three interferon alfa-2b regimens for the longterm treatment of chronic non-A, non-B hepatitis. Multicenter Study Group [see comments]. New England Journal of Medicine 1995; 332: 1457±1462 (Published erratum appears in New England Journal of Medicine 1996 April 25; 334: 1143). 15. Poynard T, Leroy V, Cohard M et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: e€ects of dose and duration. Hepatology 1996; 24: 778±789. 16. Shi€man ML. Use of high-dose interferon in the treatment of chronic hepatitis C. Seminars in Liver Disease 1999; 19(supplement 1): 25±33. 17. Smith R. Background and mechanisms of action of ribavirin. In Smith RA, Knight V & Smith J (eds) Clinical Applications of Ribavirin, pp 1±18. London: Academic Press, 1984. 18. Bodenheimer HC Jr, Lindsay KL, Davis GL et al. Tolerance and ecacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997; 26: 473±477. 19. Davis GL, Esteban-Mur R, Rustigi V et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group [see comments]. New England Journal of Medicine 1998; 339: 1493±1499. 20. Poynard T, Marcellin P, Lee SS et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998; 352: 1426±1432. 21. Davis GL. Combination therapy with interferon alfa and ribavirin as retreatment of interferon relapse in chronic hepatitis C. Seminars in Liver Disease 1999; 19(supplement 1): 49±55. 22. Zeuzem S, Schmidt JM, Lee SH et al. Hepatitis C virus dynamics in vivo: e€ect of ribavirin and interferon alfa on viral turnover. Hepatology 1998; 28: 245±252. 23. Fattovich G, Giustina G, Favarato S & Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. Journal of Hepatology 1996; 24: 38±47. 24. Heathcote J. Consensus interferon: a novel interferon for the treatment of hepatitis C. Journal of Viral Hepatitis 1998; 5(supplement 1): 13±18. 25. Cooksley WG. Interferon treatment of chronic hepatitis C with cirrhosis. Journal of Viral Hepatitis 1997; 4(supplement 1): 85±88. 26. Fattovich G, Giustina G, Degos F et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients [see comments]. Gastroenterology 1997; 112: 463±472. 27. Bottelli R, Tibballs J, Hochhauser D et al. Ultrasound screening for hepatocellular carcinoma (HCC) in cirrhosis: the evidence for an established clinical practice. Clinical Radiology 1998; 53: 713±716. 28. Dioguardi N. Early diagnosis of hepatocellular carcinoma in Italy: a summary of a consensus conference held in Milan by the Italian Association for the Study of the Liver. Journal of Hepatology 1992; 14: 410±413. 29. Younossi ZM & Perrillo RP. The roles of amantadine, rimantadine, ursodeoxycholic acid, and NSAIDs, alone or in combination with alpha interferons, in the treatment of chronic hepatitis C. Seminars in Liver Disease 1999; 19(supplement 1): 95±102. 30. Foster GR. Amantadine in the treatment of patients with chronic hepatitis C. Italian Journal of Gastroenterology and Hepatology 1998; 30: 614±615.