Journal of Viral Hepatitis, 2011, 18, 1–7
doi:10.1111/j.1365-2893.2010.01366.x
REVIEW
Prevalence of thrombocytopenia among patients with chronic hepatitis C: a systematic review K. S. Louie,1 J. M. Micallef,1 J. M. Pimenta1 and U. M. Forssen2
1
Worldwide Epidemiology, GlaxoSmithKline,
2
Stockley Park, Middlesex, UK; and Biometrics and Epidemiology, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA Received April 2010; accepted for publication June 2010
SUMMARY. Thrombocytopenia (TCP) is a haematological
condition known to occur in chronically infected hepatitis C (HCV) patients and may interfere with diagnostic procedures, such as liver biopsy, because of risk of bleeding. It may also exclude patients from effective antiviral treatment. We conducted a systematic literature review of articles and conference abstracts, to assess the prevalence of TCP among those with HCV and to describe demographics, liver disease stage and treatment characteristics of these patients. Studies of individuals with confirmed chronic HCV infection were included in the review if the study had a clear definition of thrombocytopenia and a sample size of at least 50 subjects. The final selection included 27 studies (21 articles and six abstracts). The definitions of thrombocytopenia varied between studies and were based either on platelet counts, with threshold levels ranging between £100 · 109
INTRODUCTION Chronic hepatitis C (HCV) infection has been associated with the development of several extrahepatic manifestations including thrombocytopenia (TCP), a haematological condition defined by reduced platelet count [1]. TCP can cause major complications at liver biopsy, a procedure that may be required in this patient group to determine the stage of disease. The risk of extensive bleeding in patients with TCP may prevent the patients from having biopsies as well as other invasive procedures [2]. Furthermore, HCV patients with TCP may be ineligible for initiation of antiviral treatment or if able to start therapy, may receive a dose reduction or even discontinue treatment. This could potentially decrease their probability of successful HCV treatment [1]. Abbreviations: ALT, alanine transaminase; ASH, American Society of Haematology; HCV, hepatitis C; IFN, interferon; ITP, idiopathic thrombocytopenic purpura; TCP, thrombocytopenia. Correspondence: Ulla M. Forssen, Biometrics and Epidemiology, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. E-mail:
[email protected]
2010 Blackwell Publishing Ltd
and £180 · 109/L, or on criteria set in haematological guidelines. The prevalence of TCP ranged from 0.16% to 45.4% and more than half of the studies reported a TCP prevalence of 24% or more. Because of the different TCP definitions, heterogeneity in study design and insufficient data on study characteristics such as age, gender, HCV treatment rates and disease severity an overall summary estimate of TCP prevalence among patients with HCV was not feasible. However, the relatively large prevalence in the majority of the studies suggests that there may be a substantial number of HCV patients at risk of bleeding complications and reduced likelihood of successful HCV antiviral treatment. Keywords: chronic hepatitis C, systematic review, thrombocytopenia.
The pathophysiology of TCP in patients with HCV infection is not completely understood but is believed to be multifactorial [3]. In patients with chronic liver disease, TCP appear to be related to the severity of disease and is more common in patients with cirrhosis [4–6]. However, a number of other mechanisms have also been proposed to explain the association, including hypersplenism, formation of antiplatelet antibodies caused by aberration of the immune system (autoimmune thrombocytopenia) and decreased thrombopoietin production [3,6]. Other studies have indicated that TCP among patients with HCV is associated with older age, male gender and co-infection with hepatitis B and HIV [7,8]. In addition, patients with HCV who undergo antiviral treatment with interferon (IFN) and ribavirin can typically experience TCP as a common side effect. [3]. The overall occurrence of TCP in patients with chronic HCV is not well established. The objective of this study was to perform, to our knowledge, the first systematic literature review to assess the prevalence of TCP among those with HCV and to describe demographic, liver disease stage and treatment characteristics in the chronic HCV population.
2
K. S. Louie et al.
MATERIAL AND METHODS Literature search A computer-assisted literature search of two bibliographic databases was conducted to identify relevant published papers and conference abstracts on the prevalence of TCP among patients with chronic HCV. The MEDLINE database was searched from January 1966 to July 2008 using medical subject heading (MeSH) terms Ôhepatitis CÕ, ÔthrombocytopeniaÕ or ÔplateletsÕ. Studies were restricted to the English language. A second search was performed using identical search criteria in a database, internal to GlaxoSmithKline, called Searchlight. Searchlight includes published conference abstracts from international scientific meetings. A manual search of the reference lists of included papers was also undertaken to identify any additional studies that may have been missed in the initial search strategy.
Selection of studies Two reviewers (KSL and JMM) independently reviewed the titles and abstracts of all citations identified by the literature search to isolate potentially relevant studies. All studies that met the following inclusion criteria were included in the review: (i) patients chronically infected with HCV, defined as either HCV RNA positive, histologically proven HCV infection, or having two times the upper limit of alanine transaminase (ALT), (ii) a clear definition of TCP based on platelet count or by haematological guidelines and (iii) a study sample size of ‡50 patients. Studies meeting these inclusion criteria but comprised of patients only with hepatocellular carcinoma were excluded, because the severe disease stage would likely bias the results.
Definition of TCP The most widely used definition of TCP is a platelet count £150 · 109/L. However, there are varying definitions used to define TCP depending on the clinical relevance of interest. In this review, any definition of TCP based on platelet count was accepted, regardless of threshold. In addition, studies using the TCP definition published by the American Society of Haematology (ASH) idiopathic thrombocytopenic purpura (ITP) Practice Guidelines were also accepted. The guidelines define TCP as a low platelet count with otherwise normal results on complete blood count and peripheral blood smear in a patient with no clinically apparent associated conditions or factors that can cause TCP [9].
Data abstraction The two reviewers (KSL and JMM) performed a parallel data abstraction from the included articles and systematically extracted the following variables: country, study design,
sample size, age (mean or median), gender distribution, definition of TCP (platelet count threshold level and/or haematological guidelines) and prevalence of thrombocytopenia. Where available, they also extracted the proportion of patients who had cirrhosis, the proportion of patients who were on current or prior antiviral HCV treatment and any information about co-infection with HIV or HBV. For articles where study methods suggested that appropriate data for abstraction was available but were not reported, data were requested from the author, and in this way, additional data were provided for three studies [10–12].
Statistical analyses For each study, an exact 95% confidence interval around the TCP prevalence was calculated based on the study size and number of TCP cases that was either reported or derived from the study. A meta-analytic approach as a way to estimate an overall or average effect estimate for TCP prevalence was also explored, however, given the varying definitions of TCP, an overall TCP prevalence estimate was not feasible. In addition, data on study characteristics were too sparse to conduct a meta-regression to explore the effects of study characteristics within definitions. All analyses were performed using STATA (StataCorp. 2007. Stata Statistical Software: Release 10; StataCorp LP, College Station, TX, USA).
RESULTS Demographics and study characteristics A total of 540 articles from the MEDLINE search and 976 conference abstracts from the Searchlight database were identified. In total, 27 studies met the inclusion criteria, of which 21 were articles [8,10–29] and six were abstracts [30– 35]. One of the conference abstracts [32] had been published since the search was carried out and is hereafter referred to by the published paper only [36]. Study characteristics and reported TCP prevalence, grouped by TCP definition are displayed in Table 1. The size of the study populations ranged from 54 to 4345 subjects. In total, the included studies provided almost 11 641 subjects. Thirteen of the studies were among patients with HCV in Europe (France, Greece, Italy, Russia, Spain and Switzerland), seven in Asia (Japan, Korea, Malaysia, and Taiwan) and seven studies in North America (Canada and the United States). Most of the subjects came from European studies, as the largest study of more than 4000 patients with HCV was performed there [36]. Of the included studies, 18 (67%) were cross-sectional and nine were cohort studies. With the exception of two population-based studies [8,28], all studies were hospital-based. Twenty-one studies reported gender; the proportion of men ranged from 47% to 97%. Among 17 studies that reported the mean or median age of the subjects, the average age ranged between 27.5 and 61.7 years. 2010 Blackwell Publishing Ltd
Thrombocytopenia in HCV
3
Table 1 Study characteristics of chronically infected hepatitis C (HCV) populations reporting the prevalence of thrombocytopenia (TCP)
Author Platelets £100 · 109/L Cicardi et al. [14] Nahon et al.* [22] Wang et al. [28] Platelets £130 · 109/L Hu et al. [16] Kim et al. [19] Renou et al. [12] Talreja et al. [33] Platelets £140 · 109/L Borroni et al. [13] Dalekos et al. [10] Kaul et al. [18] Luo et al. [20] Prieto et al. [24] Romagnuolo et al. [25] Zachou et al. [29] Platelets £150 · 109/L Ikeda et al. [17] Moriyama et al. [21] Nagamine et al. [11] Ordi-Ros et al. [23] Parkeh et al. [35] Poynard et al. [34] Sylvestre et al. [26] Shanmuganathan et al. [31] Taliani et al. [27] Platelets £175 · 109/L Streiff et al. [8] Platelets £180 · 109/L Ivanova et al. [30] American Society of Hematology Guidelines Dufour et al.– [32,36] Giordano et al. [15]
TCP Current Average Prevalence Cirrhosis antiviral No. in Males age treatment (%) (%) (years) (%) study (%)
Country
Study design
Italy France Taiwan
Cohort Cohort Cross-sectional
360 97 140
53.0 54.0 NR
NR 58 NR
24.0 100.0 5.0
0.0 NR NR
16.4 45.4 15.7
United States Korea France United States
Cohort Cross-sectional Cross-sectional Cross-sectional
112 141 110 79
50.0 57.4 NR 96.3
52.1à NR NR 54
100.0 7.4 12.7 50.0
43.8 NR 0.0 NR
30.3 24.8 18.2 36.7
Italy Greece United States Taiwan Spain Canada Greece
Cross-sectional Cohort Cohort Cross-sectional Cross-sectional Cross-sectional Cohort
228 75 264 111 100 54 174
72.8 58.7 61.0 69.4 63.0 68.5 47.1
44.1 NR 45 52 51.2 40.1 NR
13.2 NR 3.3 20.7 25.0 7.4 20.7
0.0 NR NR NR 16.0§ 0.0 30.0
9.6 13.3 28.0 28.9 45.0 24.1 31.2
Japan Japan Japan Spain
Cohort 1056 Cohort 654 Cross-sectional 368 Cross-sectional 230
67.3 62.7 61.6 49.4
50à 48.9 NR 50
9.7 NR 0.0 11.0
38.7 29.2 41.0 18.3
United States France United States Malaysia
Cross-sectional 314 Cross-sectional 1354 Cross-sectional 409 Cross-sectional 182
97.0 NR 55.5 75.3
51à NR 49 37.5
NR NR NR 9.9
8.2§ 0.0 NR 8.3 current; 27.0§ NR 0.0 NR NR
Italy
Cross-sectional
78
69.2
56.3
48.7
0.0
44.8
United States Cross-sectional
279
NR
NR
NR
13.7
62
NR
NR
NR
3.2
0.12 40.4
0.21 NR
0.16** 2.6
Russian Federation
Cross-sectional
Switzerland Italy
Cohort 4345 Cross-sectional 265
NR 47.5
NR 28.3
NR 61.7
16.0 31.1 31.1 28.0
NR, not reported. *TCP definition £90 · 109/L; Age is based on the original study population n = 100, and those included in the review are a subset of those evaluated for TCP; TCP definition £134 · 109/L; àMedian; §Previously treated; –Prevalence of antiviral treatment with interferon and/or ribavirin for patients with thrombocytopenia only; **Estimate is period prevalence in the study period January 2000 – June 2006. Dufour et al. reported annual incidence of 53 cases/100 000 person-years.
Platelets and thrombocytopenia Among studies using a platelet count definition for TCP, six different threshold levels were used; one study defined TCP as platelets £180 · 109/L [30], one as platelets £175 · 109/L 2010 Blackwell Publishing Ltd
[8], nine studies as platelets £150 · 109/L [11,17,21,23,26,27,31,34,35], seven studies as platelets £140 · 109/L [10,13,18,20,24,25,29], four studies as platelets £130 · 109/L [12,16,19,33] and three studies as platelets £100 · 109/L [14,22,28]. Two of the studies
4
K. S. Louie et al.
[15,36] defined TCP according to the ASH ITP Practice Guidelines [9]. Figure 1 presents the TCP prevalence and exact 95% confidence intervals for each study according to TCP definition. The prevalence of thrombocytopenia ranged from 0.16% to 45.4%, with more than half of the studies reporting a TCP prevalence of 24% or more. Only four studies reported a prevalence of 60 to be independently associated with a decreased platelet count. Men represented the majority of the study populations in this review but it was not possible to further
6
K. S. Louie et al.
explore the differences between men and women. Age could also potentially affect the prevalence of TCP as an indicator of duration of infection and progression of liver disease. In this review, HCV populations with a mean/median age >50 years also typically reported a higher prevalence of thrombocytopenia. Immune deficiency and co-infection with HBV may predispose the patient with HCV to chronicity of HCV infection and disease progression [37]. Very few of the studies included in this review reported on the impact on TCP by co-infection with HIV or HBV. The results in general indicated, however, that co-infection is likely to increase the prevalence of TCP among patients with chronic HCV. Although thrombocytopenia is one of a number of extrahepatic manifestations associated with long-term consequences of chronic HCV infection, it is also among the numerous side effects of current HCV antiviral treatment, and the condition can potentially be induced or exacerbated during treatment [38]. This offers another explanation for the wide range of TCP prevalence and further illustrates that thrombocytopenia is multifactorial and estimating the prevalence is not straightforward. The proportion of chronic HCV patients ineligible for treatment or requiring dose reduction during treatment because of thrombocytopenia was not reported in any of the included studies. These data could facilitate the understanding of the extent to which thrombocytopenia affects patients with chronic HCV and antiviral treatment. Additionally, it would be relevant to identify the definitions of thrombocytopenia used in clinical practice which exclude HCV patients from treatment or reduce their treatment dose. Given that only 55% of treatment naı¨ve patients with HCV [39,40] and 43% of cirrhotic patients [41] are able to sustain a virological response, management of comorbid conditions, such as TCP, prior to or during treatment could potentially increase the number of people achieving effective treatment. Although cirrhotic patients might not be eligible for antiviral treatment because of other co-morbidities, controlling severe TCP in this patient group might improve prognosis by reducing the risk of developing complications of cirrhosis (variceal bleeding), need for liver transplantation and death [3]. This review revealed that there are numerous definitions of TCP currently being used in clinical practice; this heterogeneity precluded the estimation of a pooled estimate of TCP prevalence. In addition, insufficient data on study characteristics such as age, gender, HCV treatment rates, disease severity and co-infection with HIV or HBV meant that the relationship between these factors and TCP prevalence could not be clearly elucidated. Future studies should evaluate how these contributing factors may impact the occurrence of thrombocytopenia in HCV populations. However, apart from these limitations, the results from this review indicate that there may be a substantial number of chronically infected HCV patients suffering from thrombocytopenia and thereby at risk of bleeding complications and reduced possibility of effective HCV antiviral treatment.
ACKNOWLEDGEMENT The authors acknowledge Jeanenne J. Nelson at GlaxoSmithKline for valuable input.
DISCLOSURES Karly S. Louie undertook this study as part of a pre-doctoral fellowship within Worldwide Epidemiology at GlaxoSmithKline. Joanne M. Micallef was employed as a consultant at GlaxoSmithKline for the duration of this work. Jeanne M. Pimenta and Ulla M. Forssen are full-time employees of GlaxoSmithKline.
REFERENCES 1 Karasu Z, Tekin F, Ersoz G et al. Liver fibrosis is associated with decreased peripheral platelet count in patients with chronic hepatitis B and C. Dig Dis Sci 2007; 52(6): 1535–1539. 2 Seeff LB, Everson GT, Morgan TR et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010; [Epub ahead of print]. 3 Weksler BB. Review article: the pathophysiology of thrombocytopenia in hepatitis C virus infection and chronic liver disease. Aliment Pharmacol Ther 2007; 26(Suppl. 1): 13–19. 4 Koruk M, Onuk MD, Akcay F, Savas MC. Serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis, and its relationship with circulating thrombocyte counts. Hepatogastroenterology 2002; 49(48): 1645–8. 5 Peck-Radosavljevic M. Thrombocytopenia in liver disease. Can J Gastroenterol 2000; 14(Suppl. D): 60D–66D. 6 Giannini EG. Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options. Aliment Pharmacol Ther 2006; 23(8): 1055–1065. 7 Stasi R, Willis F, Shannon MS, Gordon-Smith EC. Infectious causes of chronic immune thrombocytopenia. Hematol Oncol Clin North Am 2009; 23(6): 1275–97. 8 Streiff MB, Mehta S, Thomas DL. Peripheral blood count abnormalities among patients with hepatitis C in the United States 1. Hepatology 2002; 35(4): 947–952. 9 Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. The American Society of Hematology ITP Practice Guideline Panel. Ann Intern Med 1997; 126(4): 319–326. 10 Dalekos GN, Kistis KG, Boumba DS et al. Increased incidence of anti-cardiolipin antibodies in patients with hepatitis C is not associated with aetiopathogenetic link to anti-phospholipid syndrome 4. Eur J Gastroenterol Hepatol 2000; 12(1): 67–74. 11 Nagamine T, Ohtuka T, Takehara K, Arai T, Takagi H, Mori M. Thrombocytopenia associated with hepatitis C viral infection. J Hepatol 1996; 24(2): 135–140. 12 Renou C, Muller P, Jouve E et al. Revelance of moderate isolated thrombopenia as a strong predictive marker of cirrhosis in patients with chronic hepatitis C virus. Am J Gastroenterol 2001; 96(5): 1657–1659.
2010 Blackwell Publishing Ltd
Thrombocytopenia in HCV 13 Borroni G, Ceriani R, Cazzaniga M et al. Comparison of simple tests for the non-invasive diagnosis of clinically silent cirrhosis in chronic hepatitis C. Aliment Pharmacol Ther 2006; 24(5): 797–804. 14 Cicardi M, Cesana B, Del Ninno E et al. Prevalence and risk factors for the presence of serum cryoglobulins in patients with chronic hepatitis C. J Viral Hepat 2000; 7(2): 138–143. 15 Giordano N, Amendola A, Papakostas P et al. Immune and autoimmune disorders in HCV chronic liver disease: personal experience and commentary on literature. New Microbiol 2005; 28(4): 311–317. 16 Hu KQ, Tong MJ. The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. Hepatology 1999; 29(4): 1311–1316. 17 Ikeda M, Fujiyama S, Tanaka M et al. Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C after sustained response to interferon 3. J Gastroenterol 2005; 40(2): 148–156. 18 Kaul V, Friedenberg FK, Braitman LE et al. Development and validation of a model to diagnose cirrhosis in patients with hepatitis C 1. Am J Gastroenterol 2002; 97(10): 2623–2628. 19 Kim YS, Lee HS, Ahn YO. Factors associated with positive predictability of the anti-HCV ELISA method with confirmatory RT-PCR. J Korean Med Sci 1999; 14(6): 629–634. 20 Luo JC, Hwang SJ, Chang FY et al. Simple blood tests can predict compensated liver cirrhosis in patients with chronic hepatitis C. Hepatogastroenterology 2002; 49(44): 478–481. 21 Moriyama M, Matsumura H, Aoki H et al. Long-term outcome, with monitoring of platelet counts, in patients with chronic hepatitis C and liver cirrhosis after interferon therapy. Intervirology 2003; 46(5): 296–307. 22 Nahon P, Ganne-Carrie N, Degos F et al. Serum albumin and platelet count but not portal pressure are predictive of death in patients with Child-Pugh A hepatitis C virusrelated cirrhosis. Gastroenterol Clin Biol 2005; 29(4): 347– 352. 23 Ordi-Ros J, Villarreal J, Monegal F, Sauleda S, Esteban I, Vilardell M. Anticardiolipin antibodies in patients with chronic hepatitis C virus infection: characterization in relation to antiphospholipid syndrome 2. Clin Diagn Lab Immunol 2000; 7(2): 241–244. 24 Prieto J, Yuste JR, Beloqui O et al. Anticardiolipin antibodies in chronic hepatitis C: implication of hepatitis C virus as the cause of the antiphospholipid syndrome 5. Hepatology 1996; 23(2): 199–204. 25 Romagnuolo J, Jhangri GS, Jewell LD, Bain VG. Predicting the liver histology in chronic hepatitis C: how good is the clinician? 1. Am J Gastroenterol 2001; 96(11): 3165–3174. 26 Sylvestre DL, Clements BJ. The utility of indirect predictors of hepatitis C viremia 1. Drug Alcohol Depend 2004; 74(1): 15–19. 27 Taliani G, Duca F, Clementi C, De Bac C. Platelet-associated immunoglobulin G, thrombocytopenia and response to interferon treatment in chronic hepatitis C 2. J Hepatol 1996; 25(6): 999. 28 Wang CS, Yao WJ, Wang ST, Chang TT, Chou P. Strong association of hepatitis C virus (HCV) infection and thrombocytopenia: implications from a survey of a community
2010 Blackwell Publishing Ltd
29
30
31
32
33
34
35
36
37 38
39
40
41
7
with hyperendemic HCV infection. Clin Infect Dis 2004; 39(6): 790–796. Zachou K, Liaskos C, Christodoulou DK et al. Anti-cardiolipin antibodies in patients with chronic viral hepatitis are independent of beta2-glycoprotein I cofactor or features of antiphospholipid syndrome. Eur J Clin Invest 2003; 33(2): 161–168. Ivanova L, Maximov S, Kravchenko A, Tishkevich O, Ivannikov E. The comparative analysis of morphological structre of a liver in patients with HIV-HCV coninfection and HCV-monoinfection in Russia. 16th International AIDS Conference, Toronto Canada 2006. Shanmuganathan G, Palaniappan S, Khor BP, Radhakrishnan A, Raj M. The clinico-epidemiological pattern of hepatitis C in a tertiary care hospital in Malaysia: the Kuala Lumpur Hospital experience. 6th Asian Pacific Digestive Week (ADPW 2006), Cebu, Philippines 2006. Dufour JF, Ruivard M, Ninet J et al. Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 15 cases. 7th Congress of the European Federation of Internal Medicine. May 7–10, 2008. Rome, Italy. 2008. Talreja J, Mihas AA, Heuman DM. Screening for esophageal varices in US veterans with chronic hepatitis C and advanced fibrosis: a pilot study. Digestive Disease Week 2006 (DDW): American Association for the Study of Liver Diseases, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Society for Surgery of the Alimentary Tract. Poynard T, Schiff E, Terg R et al. Results from the EPIC3 program: platelet counts are strong predictors of sustained viral response (SVR) in the re-treatment of previous interferon/ribavirin non-responders (NR). Digestive Disease Week. May 17–22, 2008. San Diego, California, USA. 2008. Parekh S, Simpson A, Mohamad W, Shaukat A, Kamil O. Factors associated with low platelet count in vetrans with chronic hepatitis C. 72nd Annual Meeting of the American College of Gastroenterology.October 14–17, 2007.Philadelphia, Pennsylvania, USA. 2007. Dufour JF, Pradat P, Ruivard M et al. Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: clinical description of 16 cases. Eur J Gastroenterol Hepatol 2009; 21(3): 245–53. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology 2002; 5(Suppl. 1): S21–S29. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39(4): 1147–1171. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347(13): 975–982. Manns MP, McHutchison JG, Gordon SC et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial 23. Lancet 2001; 358(9286): 958–965. Heathcote EJ. Treatment considerations in patients with hepatitis C and cirrhosis. J Clin Gastroenterol 2003; 37(5): 395–8.
