TREATMENT OF HEPATITIS C IN 2011
AbstractNew knowledge on the treatment of Hepatitis C is accruing at an extraordinarily rapid rate and myaim in this editorial based on a talk I gave at the Pakistan Society of Gastroenterology AnnualInternational Congress this year, is to outline how patients may be treated both currently and overthe next two to three years.One aspect is certain, namely, that carefuldocumentation is essential in determining the optimalcourse of therapy for an individual patient. The firstkey event to be documented in a patient being giventreatment is whether a rapid virological response(RVR) is obtained with a negative HCV RNA at 4weeks. Seen in around 20% only of genotype Iinfections, frequencies are considerably higher withgenotype II and III. A RVR predicts an 80–90%chance of obtaining a sustained virological response(SVR) which is the ultimate goal of treatment. Thenext key measurement is at 12 weeks —the earlyvirological response (EVR). A complete EVR withRNA negativity is also highly predictive of an SVRwhereas with a partial EVR will achieve this. Noresponse makes later clearance of the virus veryunlikely and in clinical practice is usually taken as anindication for discontinuing therapy. Slow and nonresponders with either some or no reduction in viralload at 24 weeks are also important to define as even apartial response to antiviral therapy may lead toimprovement in histological appearances and toreduced frequency in later life of HCC.1Being able to confidently predict the chances of,or of not, obtaining an SVR before starting on treatmentwith all the attendant side effects, would represent a majoradvance. Distinct gene signatures in liver tissue andblood have been reported and there are many paperscurrently on IL-28B gene polymorphisms involved inregulation of the host’s innate immune responses. Thechances of an SVR are much higher for the CC genotypethan for CT and TT genotypes.2 Response rates are evenless with the combination of an unfavourable IL-28B anda high serum level of interferon gamma inducible proteinwhich interferes with Interferon signalling pathways inthe liver. Such pre-treatment prediction may still behelpful with the higher responses obtainable from the newprotease and polymerase inhibitor drugs.Whether IFN alpha-2a or 2b is used marks littledifference. What is important in the current standard ofcare treatment regime is an adequate dosage of Ribavirinas this agent has a major influence in preventing relapseafter cessation of treatment. Overall SVR’s in genotype Inaive patients are around 50–55%, but when there is aRVR as well as a low level of viraemia (<600,000 IU/ml)pre-treatment, SVR’s as high as 80% can beobtained and the period of treatment shortenedfrom 48 to 24 weeks. Similarly for genotypes IIand III —with overall SVR’s higher at 70% to90%, when an RVR is obtained, treatment can beshortened —from 24 weeks to 12 weeks. If riskfactors for impaired responsiveness, namely,obesity and severe fibrosis/cirrhosis are present,the duration of the first course of treatment shouldbe extended from 24 to 48 weeks. For slowresponders extending the duration of treatmentfrom 48 to 72 weeks gave a substantial increase inSVR from 19% to 38% consequent on a markedreduction in relapses from 59% to 20%.3A difficult question is whetherretreatment is of value in genotype I nonresponders or relapsers. Identifiable reasons forthe initial failure of treatment may be correctablesuch as inadequate Ribavirin dosage andinterruptions in therapy. Weight reduction in theobese should be attempted but is often difficult toachieve and in one trial of subjects weighing >85Kg, increasing the dose of Ribavirin to 1600mgdaily gave an improvement in SVR of 28% to47%.4 In the EPIC 3 retreatment trial, SVR’s were38% for the relapsers and 14% for nonresponders.5 In the REPEAT trial, treatmentduration was extended from 48 to 72 weeks with adoubling of SVR in non-responders —8% to16%.6 Both the EPIC 3 and the REPEAT trialshad a high percentage of cirrhotics —the hardestto treat category which emphasises the need forearly diagnosis and treatment of chronic hepatitisC infection. Both trials showed that furthertreatment was pointless if there was no EVR at 12weeks.The new and encouragingly potentantiviral drugs, namely, Telaprevir andBoceprevir specifically inhibit protease activity ofthe virus. Late 2011 is the projected date forrelease onto the market. Early trials of Telapreviras monotherapy showed that a rapid fall in viraltitre over the first week was followed by a highbreakthrough rate from development of viralresistance. This could be prevented by givingJ Ayub Med Coll Abbottabad 2010;22(3)2 http://www.ayubmed.edu.pk/JAMC/PAST/22-3/Roger.pdfadditional PegIFN and Ribavirin with Telaprevir beingdiscontinued after 12 weeks and the PegIFN/Ribavirincontinued for a further 12 weeks. The PROVE phase 2btrials of this triple therapy regime in genotype I naivesubjects showed over 80% achieving a RVR giving anSVR rate of 61% at 24 weeks versus 41% in the controlarm of PegIFN/Ribavirin given for 48 weeks.7 Thus notonly is a higher SVR obtainable with Telaprevir buttreatment duration is shortened. In the PROVE 3 trial ofnon-responders and prior relapsers, SVR’s of 39% and69% were obtained compared with 9% and 20%respectively in control arms. Viral breakthrough in thenon responders was high at 22% which is not surprisingas these patients were essentially on Telaprevirmonotherapy. Side-effects of rash and anaemia lead to adiscontinuation rate for severe adverse events of around20%. The drug has to be given in tds dosage at exactly 8hour intervals and as it is metabolised through the P450enzyme system, drug interactions may occur with thecommonly used statins.Boceprevir similarly has significant side effectsincluding anaemia requiring Epoetin support,gastrointestinal disturbances and unpleasant taste in themouth (dysgeusia) with discontinuation of therapy inaround 25% of cases. In contrast to Telaprevir, the drug isstarted after a lead in period of Peg IFN/Ribavirin for 4weeks. By obtaining steady state concentrations prior tothe start of Boceprevir, the emergence of resistantmutations to the drug is reduced. Depending on level ofRNA reduction during the lead in period, Boceprevir isgiven for a further 24 or 44 weeks along withPegIFN/Ribavirin. In the Sprint-I phase 2 study, the SVRwas nearly double that in the control arm —75% vs 39%.8With a RVR achieved in nearly two thirds of the cases,the SVR was 82% and treatment duration can beshortened.There is progress too in what we are all hopingfor, namely, an antiviral regime without Interferon andbased on oral medication only. Gane et al, reported at theAASLD Meeting in 2009 that combining the proteaseinhibitor drug Danoprevir with a polymerase inhibitorR7128 resulted in rapid viral suppression over 14 dayswithout the emergence of resistance to either compound,and confirmatory results of this approach were publishedrecently.9 Targeting different steps of viral replicationconcurrently, as we have learnt from HIV infection, mayprevent or delay the emergence of drug resistance.Many other compounds targeting different areasof the virus and with potentially less severe side effectsare in Phase 1–2 trials and the reader is referred tothe abstract book of the recent EASL meeting inBerlin. One can but hope that the lead time in theirintroduction to clinical practice will be less thanthe 10 years interval between introduction ofcurrent standard of care —PegIFN & Ribavirinand release of the new Protease inhibitors.
Pockros PJ, Hamzeh FM, Martin P, Lentz E, Zhou X,
Govindarajan S, et al. Histologic outcomes in hepatitis Cinfected patients with varying degrees of virologic
response to interferon-based treatments. Hepatology
Darling JM, Aerssens J, Fanning G, McHutchison JG,
Goldstein DB, Thompson AJ, et al. Quantitation of
pretreatment serum IP-10 improves the predictive value
of an IL28B gene polymorphism for hepatitis C treatment
response. Hepatology 2010;52(4) Suppl:128A.
Pearlman BL, Ehleben C, Saifee S. Treatment extension
to 72 weeks of Peginterferon and Ribavirin in hepatitis C
genotype 1-infected slow responders. Hepatology
Pattullo V, Heathcote. Morbid obesity and HCV:
management strategies. In: Clinical Dilemmas in Viral
Liver Disease. Graham R. Foster, K. Rajender Reddy,
Eds. Blackwell Publishing Ltd, UK. 2010;61–4.
Poynard T, Colombo M, Bruix J, Schiff E, Terg R,
Flamm S, et al. Peginterferon alfa-2b and ribavirin:
effective in patients with hepatitis C who failed interferon
alfa/ribavirin therapy. Gastroenterology
Jensen DM, Marcellin P, Freilich B, Andreone P, Di
Bisceglie A, Brandão-Mello CE, et al. Re-treatment of
patients with chronic hepatitis C who do not respond to
peginterferon-alpha2b: a randomized trial. Ann Intern
McHutchison JG, Everson GT, Gordon SC, Jacobson IM,
Sulkowski M, Kauffman R, et al. Telaprevir with
peginterferon and ribavirin for chronic HCV genotype 1
infection. N Engl J Med 2009;360(18):1827–38. Erratum
in: N Engl J Med. 2009;361(15):1516.
Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM,
Pound D, et al. Efficacy of boceprevir, an NS3 protease
inhibitor, in combination with peginterferon alfa-2b and
ribavirin in treatment-naive patients with genotype 1
hepatitis C infection (SPRINT-1): an open-label,
randomised, multicentre phase 2 trial. Lancet
;376(9742):705–16. Erratum in: Lancet.
Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie
B, Elston R, et al. Oral combination therapy with a
nucleoside polymerase inhibitor (RG7128) and
danoprevir for chronic hepatitis C genotype 1 infection
(INFORM-1): a randomised, double-blind, placebocontrolled, dose-escalation trial. Lancet
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