Hepatitis C virus (HCV) infection is a major global health problem with 170 million carriersworldwide and 12-13 million HCV carriers in India.[1] Of the 16250 blood units screened, theprevalence of HCV infection was 0.44% (72/16250) in healthy blood donors at our centre.[2] Inaddition, of all the chronic liver disease patients (chronic hepatitis and cirrhosis) that cometo us around 20% have been attributed to HCV infection (unpublished).

The World Health Organisation estimates that 3% of the world’s population is infectedwith the hepatitis C virus (HCV), about 20% of whom will go on to develop cirrhosis. Currentlythere are possibly 7.8 million cases of HCV cirrhosis in the world which may rise to 13.8million by 2015.[3,4] Patients who have compensated cirrhosis are at risk for progression ofdisease and clinical deterioration. Estimated rates for the development of clinical deterioration(decompensation), hepatocellular carcinoma (HCC), and death from liver disease in patientswith compensated cirrhosis are 3.6% to 6.0% per year, 1.4% to 3.3% per year, and 2.6% to4.0% per year, respectively.[4] Worldwide, HCV-associated end-stage liver disease is the mostcommon indication for liver transplantation in adults. A total of 43% of the over 6000 livertransplants done in 2004 in USA were performed in patients with chronic hepatitis C (CHC)related liver disease.[3]

Fortunately effective drugs are available for treating CHC even when they have progressedto a stage of cirrhosis. Clinical trials have identified various viral and host factors that arepredictive of response to pegylated interferon (pegIFN) and ribavirin (RBV). The strongestpredictor of nonresponse to HCV treatment is infection with genotype 1, which has asignificantly lower sustained virological response (SVR) rate compared with genotype 2 and3 infections.  Additional negative predictors for response include high viral load (>800,000IU/mL) especially with genotype 1, age more than 40 years, high body mass index, insulinresistance or diabetes mellitus, African American heritage, HIV-HCV co-infection, inability toachieve rapid virological response (RVR) and early virological response (EVR) and advancedfibrosis or cirrhosis.[5,6,7] Patients who have early-stage (noncirrhotic) disease generally achievebetter virologic response than those who have bridging fibrosis or cirrhosis. Response ispoorer in patients with cirrhosis because of poor tolerance, higher side effects, dosereductions of drugs and dropouts. Still anti-viral treatment is recommended in these patientsbecause it can reduce the occurrence of complications (decompensation), including HCCand also reduce the post-transplant HCV recurrence. Treatment for patients with Child’sstatus C is usually recommended in specialised centres with facilities for liver transplantation.

In this issue of the journal, Butt et al8 report  sustained virological response (SVR) andpredictive factors in 66 patients with cirrhosis due to genotype 3 HCV infection treated withpegIFN and RBV. Sixty one (92.4%) patients had Child’s A cirrhosis and 5 (7.6%) Child’s B.Thirty three (50%) patients received pegylated interferon alfa-2a (180 µg /week) with ribavirinand 33 (50%) received pegylated interferon alfa 2b (1 µg /kg/week) with ribavirin, both groupsfor one year. EVR was reached in 44 (66.7%), and end of treatment response (ETR) in 46(69.7%); the overall SVR was achieved in 38 (57.6%) patients. Factors predictive of SVR wereage (p value = 0.03), treatment naïve status (p value = 0.04) and EVR (p value<0.001). Fivepatients were unable to complete the treatment due to side effects or cytopenias. Theyconcluded that treatment of patients with HCV genotype 3, compensated cirrhosis, withpegylated interferon and ribavirin is effective and well tolerated.[8]

The study provides useful data  from the Indian subcontinent where the predominantHCV genotype is 3 and where there is significant load of HCV-related cirrhosis. But at thesame time, their study does raise a few important issues.

irstly there are mixed reports of response rate in patients with compensated HCVcirrhosis. In one study from Pakistan itself, 21 (13 male) of 94 patients with HCV-associatedHCC received standard interferon therapy for a total of 24 weeks. All patients had cirrhosiswith genotype 3 and were treated before the diagnosis of HCC. Fourteen (66.7%) of thesepatients had an end of treatment response but relapsed after discontinuation of treatment,with no sustained viral response.[9] On the other hand in an Indian study, 28 patients with HCV-related compensated cirrhosis (predominant genotype 3) treated with combination therapyof peg interferon alfa-2b (1 µg/kg/week) plus oral ribavirin (10-12 µg/kg/day) were analysed. End-of-treatment virologic response was seen in 24 of 28patients (85%) and sustained virologic response in 15 of 28(53%) patients. Treatment had to be stopped in 3 patients dueto decompensation of liver status in two and drug intolerancein one, whilst dose modification was required in two patients.[10]In an intention-to-treat analysis, 271 patients with cirrhosis orbridging fibrosis who received either 3 MU of IFN a-2a threetimes weekly, 90 µg of pegIFN a-2a once weekly or 180 µg ofpegIFN a-2a once weekly for 48 weeks, SVR was noted in 8%,15%, and 30% of the patients, respectively. In the subgroup of184 patients with paired liver-biopsy specimens, the rates ofhistologic response at week 72 were 31%, 44%, and 54%,respectively (p=0.02 for the comparison between 180 µg ofpeginterferon alfa-2a and interferon alfa-2a). [11] In our recentanalysis, of the 69 patients with CHC genotype 3, treated withpegIFN 2b + Ribavirin for 24 weeks, 15 patients hadcompensated cirrhosis. ETR was seen in 13 (87%) and SVRin 10 (67% ) patients with HCV cirrhosis.[12]  Hence the differencein results as reported in compensated HCV cirrhotics may beattributed to the use of pegIFN in comparison to conventionalIFN. Further, recent evidence indicates that antiviral therapy isbeneficial in HCV cirrhotics independent of viral clearance. Ina recent analysis of the histologic outcome from therapy, 78%of the subjects who had cirrhosis indicated significantimprovement in fibrosis in liver biopsies obtained 6 monthsafter the end of therapy. The greatest improvement in fibrosiswas in patients achieving SVR (p<.0001), but improvementwas also noted in relapsers (p<.001) and nonresponders(p<.07).[13]

The second issue related to the study by Butt et al[8] is thatit is limited only to compensated cirrhotics with almost allpatients with Child’s A status. It is generally assumed thatpatients who have chronic hepatitis C and decompensationmay be too sick to be treated with the combination of interferon(IFN) plus RBV. The decision to exclude patients who haddecompensation from clinical trials of antiviral therapy wasbased on the concern that therapy may lead to furtherdeterioration. The International Liver Transplantation SocietyExpert Panel Consensus Conference on liver transplantationand hepatitis C suggested that patients who have Model forEnd-Stage Liver Disease (MELD) scores 18 or less and Child-Turcotte-Pugh (CTP) score of less than 7 may be consideredfor treatment.[14] Treatment is given selectively in those withMELD 18-25 and CTP score 8-11 and is not recommended forMELD score more than 25 and CTP score more than 11. AASLDpractice guidelines state that patients referred for livertransplantation with mild degrees of hepatic compromise canbe considered for antiviral therapy, initiated at low dose, “aslong as treatment is administered by experienced clinicians,with vigilant monitoring for adverse events”.[15] Thus, incontradistinction to popular belief, it is possible that a sizableproportion of patients who have chronic hepatitis C anddecompensation might be candidates for antiviral therapy.

In addition to a few earlier studies, in a recent study,Everson et al treated 124 patients (70% genotype 1) who haddecompensated HCV-related cirrhosis using a low-doseaccelerating regimen (LADR) of interferon and RBV.[16] Sixty-three percent had clinical complications of cirrhosis (ascites,spontaneous bacterial peritonitis, varices, varicealhemorrhage, encephalopathy). The mean Child-Turcotte-Pugh(CTP) score was 7.4 ± 2.3, and the mean MELD score was11.0 ± 3.7. Fifty-six patients were CTP class A, 45 were classB, and 23 were class C. Forty-six percent were HCV RNA-negative at the end of treatment, and 24% were HCV RNA-negative at last follow-up. Sustained virological response(SVR) was 13% in patients infected with genotype 1 HCV and50% in patients infected with non-1 genotypes (p<0.0001).Non-1 genotype, CTP class A (genotype 1 only), and ability totolerate full dose and duration of treatment (p < .0001) werepredictors of SVR. Twelve of 15 patients who were HCV RNA-negative before transplantation remained HCV RNA-negative6 months or more after transplantation confirming theeffectiveness of this strategy in eliminating the risk for HCVrecurrence.[16] Hence more data are required in this select groupof patients with decompesated HCV cirrhosis.

The third issue is regarding the dose and duration oftreatment in CHC cirrhosis. Treatment of patients who haveHCV-induced cirrhosis is limited by cytopenias (anaemia,thrombocytopenia, or neutropenia) and the lack of toleranceto antiviral therapy. In addition, these patients are at risk ofdecompensation of cirrhosis secondary to treatment. Thereare two approaches in CHC patients with cytopenias. One isthe use of growth factors, which can be helpful in maintainingthe drug dosage. Otherwise in these patients, the lowaccelerating dose regimen (LADR) using IFN/pegylated IFNand ribavirin is preferred, whereas in patients who do not havecytopenias, standard doses of pegylated IFN and ribavirin maybe initiated from the beginning. Patient tolerance may limit theuse of standard doses, so the LADR regimen may beappropriate for all patients who have cirrhosis. As mentionedearlier Everson and colleagues in a study of 124 patientsrecently described the LADR approach. Treatment was initiatedwith interferon (IFN) a-2b, 1.5 million units (MU) three timesper week, pegylated-IFN a-2b, 0.5 µg/kg/week, or pegylated-IFN a-2a, 90 µg/week, plus ribavirin, 600 mg/d, for 12 monthsin genotype 1 and 6 months in non-1 genotypes. Adjustmentswere made incrementally every 2 weeks to reach maximallytolerated or standard doses. An SVR was seen in 13% ofpatients who had genotype 1 and in 50% of patients who hadnon-1 genotypes.[16]

The recommended treatment duration with pegIFN plusribavirin differs, depending on the infecting genotype. Inpatients who had genotype 1 infection, SVR was higher inpatients who received 48 weeks of treatment compared withthose who received 24 weeks of treatment (51% versus 41%,respectively). In patients who had genotype 2 or 3 infection,SVRs were similar (73%–78%) with 24 or 48 weeks oftreatment.17 In fact, few studies have evaluated shortertreatment durations of 12 to 16 weeks in patients with genotype2 and 3 CHC who achieve an RVR. Therefore, patients whohave genotype 2 or 3 infection can be treated with pegIFN incombination with ribavirin, 800 mg/d, for 24 weeks. But evenwith 24 weeks of therapy, SVR is lower in patients who havegenotype 3 infection than in those who have genotype 2infection (SVR 67%–84% versus 93%–100%, respectively).[18] Patients who are infected with genotype 3 with a baseline viralload of more than 600,000 IU/mL and steatosis have a highrelapse rate following 24 weeks of therapy with pegIFN andribavirin (23% versus 8% with low viral load). Therefore, someinvestigators have suggested that extending treatment beyond24 weeks may be beneficial in this group. But, subgroupanalysis of a large RCT found that patients who had genotype3 and a high viral load (>800,000 IU/mL) who were treatedwith pegIFN and ribavirin, 800 mg, for 24 or 48 weeks did nothave a statistically significant improvement in SVR withextended therapy.[17] Although controlled studies are notavailable, treatment longer than 6 months should beconsidered because of the decreased response rate seen in patients who have advanced fibrosis/cirrhosis. Trials areongoing that may identify a group of slow virologicalresponders who have genotype 3 that benefits from extendedtherapy. Maintenance IFN therapy with the goal of preventingdisease progression rather than viral eradication seems tooffer the potential of prolonging the time until transplantationas well as avoiding transplantation in some patients. Thisapproach is the focus of several ongoing trials.

The fourth issue is regarding the choice of pegylatedinterferon a 2a vs. 2b for the treatment of CHC. Butt et al[8] treated their patients both with pegylated interferon a 2a and2b and found similar results. Most available literature in bothcirrhotic and non-cirrhotic populations, genotype 1 and non-genotype 1, has not revealed any difference in the responserates and the safety profiles between the two forms of pegIFNs.Only a recent study made the head-to-head comparison ofpatients receiving 1.5 mg/kg/week pegIFN a-2b with 180 µg/week pegIFN a-2a including more than 200 patients in eachgroup, with similar baseline characteristics, including cirrhosis(20% vs. 18%, respectively). By intention to treat, the 2 groupsshowed similar rates of treatment-related serious adverseevents (1% vs. 1%, respectively) and drop-out rates for adverseeffects (7% vs. 6%, respectively). Overall, the sustainedvirologic response (SVR) rate was higher in pegIFN a-2a thanin pegIFN a-2b patients (66% vs. 54%, respectively, p = 0.02),48% vs. 32% in the 222 HCV 1 and 4 patients, respectively (p= 0.02), and 96% vs. 82%, respectively, in the 143 HCV-2patients (p = 0.01).[19] But the recent IDEAL study did notdocument any difference between the two interferons. Morethan 3000 patients with HCV genotype 1 infection and whohad not previously been treated were randomly assigned toundergo 48 weeks of treatment with one of three regimens:peginterferon alfa-2b at a standard dose of 1.5 µg per kilogramof body weight per week or a low dose of 1.0 µg per kilogramper week, plus ribavirin at a dose of 800 to 1400 mg per day, orpeginterferon alfa-2a at a dose of 180 µg per week plus ribavirinat a dose of 1000 to 1200 mg per day. Rates of sustainedvirologic response were similar amongst the regimens: 39.8%with standard-dose peginterferon alfa-2b, 38% with low-dosepeginterferon alfa-2b, and 40.9% with peginterferon alfa-2a(p=0.20 for standard dose vs. low-dose peginterferon alfa-2b;p=0.57 for standard dose peginterferon alfa-2b vs.peginterferon alfa-2a). Relapse rates were 23.5%, forstandard-dose peginterferon alfa-2b, 20% for low dosepeginterferon alfa-2b, and 31.5% for peginterferon alfa-2a. Thesafety profile was similar in the three groups.[20] Hence the juryis still out and both forms of pegylated interferons are probablyequal in their efficacy and tolerability.

In conclusion, it is not difficult to treat patients with HCVcirrhosis if patients are selected appropriately and treated withappropriate dosage, duration and monitoring. Treatment isstrongly considered in patients who have genotype 2 or 3infections because of the more favourable responses in thispatient population.

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