Natural history of HCV related chronic hepatitis is influenced and modified by many factors: virus features, coinfections and host characteristics. In particular, a peculiar genetic background of the host by conditioning the occurrence of intracellular metabolic derangements (i.e., insulin resistance) might contribute to accelerate the rate of progression to cirrhosis and eventually the occurrence of hepatocellular carcinoma (HCC) and death. Likely, direct interplays between virus genotype and host genetic background might be hypothesized at this level. Morbidity and mortality in cirrhosis is primarily associated with complications of liver cirrhosis (ascites, hepatic encephalopathy, jaundice, and gastroesophageal bleeding) and HCC occurrence. Therefore the main goal of therapy is to clear viral infection and decrease liver necro-inflammation that directly relates to development of cirrhosis and HCC. Among patients treated with Interferon-based therapy, those with sustained viral response showed a significant reduction of progression to cirrhosis and development of HCC. However, a residual risk of hepatocellular carcinoma still remains indicating the need for careful follow-up using ultrasonography every six months in cirrhotic patients, even in those showing persistently normal ALT and undetectable HCV RNA levels after antiviral therapy.
1. Introduction
The natural history of HCV infection is usually characterized by the transition from no perceivable acute to chronic infection, which may progress from a long-lasting asymptomatic condition up to a decompensated hepatic disease and/or hepatocellular carcinoma (HCC) development, which represents the main cause of liver-related death and liver transplantation in the Western World [1–5] (Figure 1). One hundred seventy million of people are infected worldwide, more than 30 million are affected by cirrhosis, and the incidence of HCC is about 1-2 million new cases/year. The actual estimated incidence is markedly decreased, and this is attributable to the employment of a safe transfusion’s screening policy with a very high decrease number of new infections.
Natural history of chronic HCV infection.
Recovery from acute infection is estimated to occur in 10–25% of patients, and the onset of the disease remains largely unknown since it is symptomless in the vast majority of cases. Moreover, since the availability of effective therapies has led to treat patients, the outcome and natural history of untreated people in order to analyse the events, their timing, and type of evolution has not been fully evaluated [6–12]. Furthermore, another essential phenomenon that has hampered the difficulty to obtain reliable information of the progression of the disease is because many cofactors can change the rate of progression of the disease. In particular, alcohol consumption together with other several factors (iron overload, hepatic steatosis, metabolic syndrome, viral coinfections) may play an important role in accelerating the progression of the disease [13].
A wide range of study designs (i.e., case-series, cross-sectional, case-control, cohort, clinical trial) has been developed in clinical investigation, and, among them, cohort studies have been largely employed. This type of studies represents a valid approach to by-pass the above-mentioned difficulties to assess the natural history of HCV infection. In fact, based on the statistical concept of “analysis by segments,” a typical approach for the cohort studies, the progression of HCV infection can be designed as the sequence of different, limited, and of presumably known duration stages of the disease.
2. Natural History of HCV Infection2.1. Studies Estimating Disease Progression
To define the natural history of an infectious disease, it is mandatory to establish the time of infection, to define the onset of the symptoms, to prospectively monitor expected end-points, to record the occurrence of risk factors (alcohol, other viruses, metabolic disorders, etc.), and to follow untreated patients for a long period of time. Unfortunately, although any possible HCV infection was demonstrable since 1989 [14], there is no hope to find such data in the studies published on this topic and a great heterogeneity among them might be mostly due to the diversity in the design of the studies themselves. In fact, in retrospective cohort studies, the presence of cirrhosis was ascertained in 17% up to 55% of chronic infected adults, and HCC in 1% up to 23% [15, 16]; on the other hand, in prospective cohort studies, the rate of progression to cirrhosis was of 7% to 16% and HCC of 0.7% to 1.3% per year [6, 17, 18]. In retrospective-prospective cohort studies, the prognosis of patients with chronic hepatitis C (CHC) was reported as benign and only a minority of the infected subjects ultimately developed cirrhosis [19, 20]. Similarly, Vogt and coworkers described a low rate of liver disease occurrence in children who underwent cardiac surgery before the implementations of the new rules for blood-donors screening [21]. By contrast, other studies reported a relative high rate of cirrhosis [22, 23], and, in particular, 5.9% of cirrhosis and liver-related death was found in a small cohort of anti-HCV US military recruits during a 45-year follow-up study [24].
2.2. Prognostic Factors of Disease Progression
A long-lasting elevated necroinflammatory activity seems to play a crucial role in the progression of the disease, and this clinical evidence seems to be supported also by data from patients with persistently normal ALT. Within this peculiar context, no progression of the disease was found at a second liver biopsy taken after 5 years of followup, with the exception of subjects in which the occurrence of flares-up seemed modifying the benign course of the disease [25–27]. However, even if the biochemistry is only partially indicative, no other reliable marker able to predict the progression of the disease has been identified so far. Moreover, the prognosis of subjects infected by HCV can also be affected by different variables, and many factors, either virus-related or host-related, have been investigated in order to understand the natural history of this infection.
2.3. Viral Factors
Regardless the evidence that genotype 1b more than genotype 2 was reported to be associated with the development of HCC [28] and with a poor outcome of the disease [28–30], no data are available, so far, about other HCV genotypes. By contrast, while the viral load seems not to be associated with the histology activity index, it has relevant implications rather with viral response to therapy [31–34]. The presence of other viral coinfections (i.e., HIV, HBV) speeds up the clinical course of the disease [35, 36]. The coinfection with HBV is most common in several high-risk populations, such as injection drug users (IDU) [37, 38], patients on hemodialysis [39], patients undergoing organ transplantation [40], HIV-positive individuals [41, 42], and β-thalassemia patients [43, 44]. In all these categories, liver injury was more severe in terms of progression of fibrosis and liver cirrhosis, hepatic decompensation [45–50]. Moreover in this subgroup has been shown an increased risk of developing HCC [51–53]. Also, the presence of HIV has a negative impact on the natural history of HCV since the progression to cirrhosis is higher in coinfected [54, 55]. HCV/HIV coinfection is associated to develop other complications, such as hematologic disorders [56, 57], kidney disease [58, 59], cardiovascular disease [60, 61], and neurologic status [62–65].
2.4. Host Factors
Among the host-related factors, female gender and young age seem to influence the outcome of CHC [66]. In the last few years, another important aspect represented by the presence of comorbidities was shown to impact on the evolution of chronic HCV infection. Hepatic steatosis, obesity, and/or an insulin resistance must be considered important determinants of the disease progression [67–70]. Recent data also show that genotype 1 might specifically interfere with a peculiar host genetic background conditioning an altered intracellular insulin signalling [71, 72]. However, the relationship between body mass, insulin resistance, steatosis, and clinical outcomes is still complex. In study of long-term peginterferon treatment (HALT-C), the modifiable risk factors for liver disease progression were studied, and insulin resistance was strongly associated with outcomes [73]. On the other hand, the significance of both iron overload and “occult” HBV infection remains still controversial [74–77]. The iron overload plays an important role. The complexity of the interplay between iron and CHC is underscored by recent finding that mutations in HFE, particularly the common H63D variation, while being associated with higher hepatic and total body iron, is also related to a significantly higher likelihood of complete and sustained responses to antiviral therapy [78]. A recent study shows that stainable iron in hepatocytes and portal tract cells is a predictor of progression and clinical and histological outcomes in advanced chronic hepatitis C while chronic administration low-dose of peginterferon did not improve outcomes, nor iron variables [79].
2.5. External Factors
Among investigated cofactors, the alcohol abuse is the most important one which can dramatically change the course of the disease. Persistent intake even of low alcohol amount may seriously interfere with the progression of the disease [80]. Alcohol consumption, even at low daily intake, has been proposed as a risk factor for the progression of liver disease in chronic HCV infection [81, 82]. Alcohol consumption has a very significant impact on both the histologic and clinical progression of chronic HCV infection. The mechanisms whereby alcohol enhances HCV infection and histologic damage are still unclear [83].
Geographical differences in the evolution of chronic HCV infection to cirrhosis should also be considered: in USA, and Europe, this percentage is almost 15% (range 8–24%), but in Japan it ranges between 30% and 46%. Similarly, the percentage of evolution to HCC is 0.7–1.3% in Western countries, but significantly higher in the Far East and Japan where the rate ranges from 10% to 19% [84].
3. The Natural Course of HCV-Induced Cirrhosis
The natural history of HCV-induced chronic liver disease remains poorly measurable. As discussed above, a practical approach used to by-pass the above-mentioned difficulties is represented by the “analysis by segments” [85–88]. All these studies agreed that the development of HCC represents the main cause of death in cirrhotic patients and male sex, older age, high alpha-fetoprotein levels, and HBV coinfection were considered the main risk factors of development of the tumor. Interestingly, some studies have also described as risk of HCC occurrence the presence of oesophageal varices [29, 89]. The presence of gastrooesophageal varices is commonly considered an important risk factor of hepatic decompensation, and certainly they are expression of portal hypertension. Based on this assumption, the hypothesis that explains the association between varices and HCC development is based on the assumption that an impaired regional blood flow due to portal hypertension might determine local hypoxia which stimulates the synthesis of angiogenic factors [90]. Moreover, HCV genotype 1b was recently confirmed as a risk factor associated with HCC development in a prospective study [91, 92]. Accordingly, a biological plausibility has been recently provided showing a possible interplay by HCV and a cellular oncosuppressor determining a linkage between a mutated viral site and a different sensitive to damage-induced apoptosis [93].
Taking into account all the available information, patterns of progression to cirrhosis are very different: fast if it occurs in less than 20 years, intermediate in 20–50 years, slow in more than 50 years. Moreover, in some patients, there is no progression at all. The causes of this divergence in outcome are still poorly understood. However, survival at 5 years is reduced to 50% after an episode of decompensation [94–96].
Future studies on the natural history of HCV disease should be aimed to identify patients with high risk of disease progression and to assess the impact of therapy on disease outcome.
4. The Impact of Antiviral Therapy on Natural Course of the Disease
The lack of randomised studies hampers a reliable estimation of the impact of antiviral treatment on the long-term outcome of patients with HCV infection. Several cohort studies, designed to assess the response to Interferon (IFN) therapy in cirrhotic patients, documented a better prognosis for patients who received IFN regardless of HCV-RNA eradication. Two retrospective reports [97, 98] confirmed these data, and altogether these studies have demonstrated that sustained virological response (SVR) is significantly associated with a reduction of decompensation rate, HCC occurrence, and liver-related mortality. Therefore, liver disease morbidity and mortality is dependent on successful antiviral therapy, and peginterferon plus ribavirin is, at present time, the treatment of choice before direct-acting antivirals (DAAs) will be available [99].
4.1. Progression from Chronic Hepatitis C to Cirrhosis
The assessment of histological activity and fibrosis stage of liver biopsies performed before and after antiviral treatment remains the most reliable parameter to evaluate short-term benefit of viral clearance. In 487 Japanese patients who underwent paired liver biopsy, samples obtained from 1 to 10 years apart showed a regression of fibrosis related to SVR [100]. Accordingly, other European studies by analyzing the impact of SVR on the long-term clinical outcome of chronic hepatitis C concluded that SVR was significantly associated with a decrease in fibrosis score [11, 101–103]. More recently, George et al. demonstrated in a large cohort that clinical, virologic, biochemical, and histological outcomes of patients followed up to 5 years after SVR are favourable, and recovery of normal or nearly normal liver architecture is possible [104].
The available literature on the likelihood of progression to cirrhosis in treated patients is limited [105–117]. Once SVR is achieved the histological progression is uncommon (7 out of 1,662 treated patients with SVR) (Table 1). On the contrary, in relapsers or nonresponder patients, the rate of disease evolution to cirrhosis is much more frequent (162 out of 2,078).
Cumulative rate of development of cirrhosis in patients with HCV-related chronic hepatitis according to sustained viral response (SVR); n/a: not available.
Author
Reference
Treated patients
Followup (years)
Rate of cirrhosis after SVR
Rate of cirrhosis in absence of SVR
Marcellin et al.
[105]
450
1–7.6
0/75
n/a
Sata et al.
[106]
63
0.6–3.8
0/25
9/38 (23.7%)
Lau et al.
[107]
10
10–13
0/5
2/5 (40.0%)
Cammà et al.
[108]
62
0.7–9
0/62
5/360 (1.3%)
Ajello et al.
[109]
31
10
1/10 (10.0%)
n/a
Morisco et al.
[110]
191
4
0/39
12/115 (10.4%)
Gallego et al.
[111]
79
4
0/11
33/87 (37.9%)
Giannini et al.
[112]
36
1–6
0/15
3/21 (14.3%)
Shindo et al.
[113]
250
8–11
0/67
62/183 (33.9%)
Swain et al.
[114]
997
8
0/989
8/997 (0.8%)
Veldt et al.
[115]
343
1.6
6/110 (5.5%)
3/15 (20%)
Ciancio et al.
[116]
97
7
0/83
3/86 (3.5%)
Chavalitdhamrong and Tanwandee
[117]
n/a
3
0/171
27/171 (15.8%)
7/1,662 (0.42%)
162/2,078 (7.8%)
4.2. Progression from Compensated to Decompensated Cirrhosis and Hepatocellular Carcinoma
Unsatisfactory SVR rates have been attained in patients with cirrhosis when using traditional monotherapy regimens of recombinant IFN alfa or peginterferon [118], and all clinical trials for drug registration considered decompensated liver disease as an exclusion criterion [119–122]. In these studies, SVR rates were calculated by pooling together patients with different degree of hepatic fibrosis, ranging from marginal bridging fibrosis to compensated cirrhosis. As a consequence, no definite conclusion could be reached about the efficacy and safety of treatment in this cohort of patients. Nevertheless, results emerging from these studies suggested that treatment of patients with well-compensated HCV-induced cirrhosis using PEG-IFN alfa-2b plus RBV may be considered a reliable option in “easy to treat” “genotypes” (2a/c, 3a), while in the “difficult to treat” ones (1a, 1b, and 4 genotype), the results are not satisfactory. In this subgroup of patients, the use of baseline and on-treatment predictors of response may enhance virologic outcomes and refinement of the regimens investigated is warranted. Further studies are also needed to develop treatment schedules for individual genotype populations.
5. Summary
Natural history of HCV-related chronic hepatitis is conditioned by virus features, coinfections, and host characteristics. In particular, a peculiar genetic background of the host by conditioning the occurrence of intracellular metabolic derangements (i.e., insulin resistance) might contribute to accelerate the rate of progression to cirrhosis and eventually the occurrence of HCC. Likely, direct interplays between virus genotype and host genetic background might be hypothesized at this level.
Morbidity and mortality in cirrhosis is primarily associated with complications of liver cirrhosis and HCC occurrence. Therefore, the main goal of therapy is to inhibit viral replication and decrease liver necroinflammation that directly relates to development of cirrhosis and HCC.
Among patients treated with IFN-based therapy, those with SVR showed a significant reduction of progression to cirrhosis and development of HCC. However, a residual risk of hepatocellular carcinoma still remains indicating the need for careful followup using ultrasonography every six months in cirrhotic patients, even in those showing persistently normal ALT and undetectable HCV RNA levels after antiviral therapy.
FattovichG.PantalenaM.ZagniI.RealdiG.SchalmS. W.ChristensenE.Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients20029711288628952-s2.0-0036840812SerfatyL.AumaîtreH.ChazouillèresO.BonnandA. M.RosmorducO.PouponR. E.PouponR.Determinants of outcome of compensated hepatitis C virus-related cirrhosis1998275143514402-s2.0-003196004310.1002/hep.510270535HuK. Q.TongM. J.The long-term outcomes of patients with compensated hepatitis C virus- related cirrhosis and history of parenteral exposure in the United States1999294131113162-s2.0-0032955838BenvegnùL.GiosM.BoccatoS.AlbertiA.Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications20045357447492-s2.0-234244454210.1136/gut.2003.020263FattovichG.GiustinaG.DegosF.TremoladaF.DiodatiG.AlmasioP.NevensF.SolinasA.MuraD.BrouwerJ. T.ThomasH.NjapoumC.CasarinC.BonettiP.FuschiP.BashoJ.ToccoA.BhallaA.GalassiniR.NoventaF.SchalmS. W.RealdiG.Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients199711224634722-s2.0-003104192410.1053/gast.1997.v112.pm9024300MannsM. P.McHutchisonJ. G.GordonS. C.RustgiV. K.ShiffmanM.ReindollarR.GoodmanZ. D.KouryK.LingM. H.AlbrechtJ. K.Peginterferon alfa-2b plus ribavirin compared with interferonalfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial200135892869589652-s2.0-003593456810.1016/S0140-6736(01)06102-5FriedM. W.ShiffmanM. L.Rajender ReddyK.SmithC.MarinosG.GoncalesJ. F. L.HäussingerD.DiagoM.CarosiG.DhumeauxD.CraxiA.LinA.HoffmanJ.YuJ.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection2002347139759822-s2.0-003717969810.1056/NEJMoa020047MchutchisonJ. G.GordonS. C.SchiffE. R.ShiffmanM. L.LeeW. M.RustgiV. K.GoodmanZ. D.LingM. -H.CortS.AlbrechtJ. K.Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C1998339211485149210.1056/NEJM199811193392101HadziyannisS. J.SetteH.Jr.MorganT. R.BalanV.DiagoM.MarcellinP.RamadoriG.BodenheimerH.BernsteinD.RizzettoM.ZeuzemS.PockrosP. J.LinA.AckrillA. M.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose200414053463552-s2.0-1542378867GeorgeS. L.BaconB. R.BruntE. M.MihindukulasuriyaK. L.HoffmanJ.Di BisceglieA. M.Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients20094937297382-s2.0-6274920330210.1002/hep.22694VeldtB. J.HeathcoteE. J.WedemeyerH.ReichenJ.HofmannW. P.ZeuzemS.MannsM. P.HansenB. E.SchalmS. W.JanssenH. L. A.Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis2007147106776842-s2.0-38449091418Di MarcoV.AlmasioP. L.FerraroD.CalvarusoV.AlaimoG.PeraltaS.Di StefanoR.CraxìA.Peg-interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial20074744844912-s2.0-3454822708510.1016/j.jhep.2007.04.020SerfatyL.Poujol-RobertA.CarbonellN.ChazouillèresO.PouponR. E.PouponR.Effect of the interaction between steatosis and alcohol intake on liver fibrosis progression in chronic hepatitis C2002977180718122-s2.0-003631846410.1016/S0002-9270(02)04149-7KuoG.ChooQ. L.AlterH. J.GitnickG. L.RedekerA. G.PurcellR. H.MiyamuraT.DienstagJ. L.AlterM. J.StevensC. E.TegtmeierG. E.BoninoF.ColomboM.LeeW. S.KuoC.BergerK.ShusterJ. R.OverbyL. R.BradleyD. W.HoughtonM.An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis198924449023623642-s2.0-0024511734SeeffL. B.Natural history of chronic hepatitis C2002365S35S462-s2.0-003682981610.1053/jhep.2002.36806TongM. J.El-FarraN. S.ReikesA. R.CoR. L.Clinical outcomes after transfusion-associated hepatitis C199533222146314662-s2.0-002899814510.1056/NEJM199506013322202Di BisceglieA. M.GoodmanZ. D.IshakK. G.HoofnagleJ. H.MelpolderJ. J.AlterH. J.Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis19911469699742-s2.0-002632083310.1016/0270-9139(91)90113-AKoretzR. L.AbbeyH.ColemanE.GitnickG.Non-A, non-B post-transfusion hepatitis: looking back in the second decade199311921101152-s2.0-0027380991Kenny-WalshE.ShanahanF.fshanahan@bureau.ucc.ieClinical outcomes after hepatitis C infection from contaminated anti-D immune globulin1999340161228123310.1056/NEJM199904223401602WieseM.BerrF.LafrenzM.PorstH.OesenU.Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in Germany: a 20-year multicenter study200032191962-s2.0-0034235962VogtM.LangT.FrösnerG.KlinglerC.SendlA. F.ZellerA.WiebeckeB.LangerB.MeisnerH.HessJ.Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening1999341128668702-s2.0-003357600110.1056/NEJM199909163411202SeeffL. B.HollingerF. B.AlterH. J.WrightE. C.CainC. M. B.BuskellZ. J.IshakK. G.IberF. L.ToroD.SamantaA.KoretzR. L.PerrilloR. P.KallooD.DesorV.SchellhaseL.OrebaughC.BartonL.OrringtonM.DeMedinaM.GrohE.HancockD.CurrierJ.NewtonM.MannixR.HauserD.DowneyK.LluberesR.StarkeyJ.FridleyL.DiFiglioH.JacksonS.HaasR.CraigC.SanbornJ.MelpolderJ.FewellL.ElderB.HernandezP.MulliganC.LeeT.ColemanB.AbbeyH.BodickyC.GorgonJ.MontgomeryJ.HarrisB.DurakoS.KorelitzJ.OhanP.BykoskiJ.ReillyJ.RobinetteD.Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart, Lung, and Blood Institute Collaborative Study20013324554632-s2.0-1774439529910.1053/jhep.2001.21905RodgerA. J.RobertsS.LaniganA.BowdenS.BrownT.CroftsN.Assessment of long-term outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 197520003235825872-s2.0-0033839753SeeffL. B.MillerR. N.RabkinC. S.Buskell-BalesZ.Straley-EasonK. D.SmoakB. L.JohnsonL. D.LeeS. R.KaplanE. L.45-Year follow-up of hepatitis C virus infection in healthy young adults200013221051112-s2.0-0033970836PersicoM.PersicoE.SuozzoR.ConteS.De SetaM.CoppolaL.PalmentieriB.SassoF. C.TorellaR.Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels200011847607642-s2.0-0034120835RossiS.De FilippiF.SaibeniS.PersicoM.BollaniS.CameraA.RizzoloL.CroceA. M.BrunoS.A 15-Yr prospective histological follow-up study in patients with persistently normal aminotransferase levels (PNAL) carrying HCV infection200710211260426062-s2.0-3544900839010.1111/j.1572-0241.2007.01514_5.xRumiM. G.De FilippiF.DonatoM. F.Del NinnoE.ColomboM.Progressive hepatic fibrosis in healthy carriers of hepatitis C virus with a transaminase breakthrough20029171742-s2.0-003690569510.1046/j.1365-2893.2002.00328.xRaimondiS.BrunoS.MondelliM. U.MaisonneuveP.Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis2009506114211542-s2.0-6734910562910.1016/j.jhep.2009.01.019BrunoS.ZuinM.CrosignaniA.RossiS.ZadraF.RoffiL.BorzioM.RedaelliA.ChiesaA.SiliniE. M.AlmasioP. L.MaisonneuveP.Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a long-term prospective study20091045114711572-s2.0-6694911219410.1038/ajg.2009.31BrunoS.CrosignaniA.FacciottoC.RossiS.RoffiL.RedaelliA.De FranchisR.AlmasioP. L.MaisonneuveP.Sustained virologic response prevents the development of esophageal varices in compensated, child-pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study2010516206920762-s2.0-7795270422810.1002/hep.23528KobayashiM.TanakaE.SodeyamaT.UrushiharaA.MatsumotoA.KiyosawaK.The natural course of chronic hepatitis C: a comparison between patients with genotype 1 and 2 hepatitis C viruses200134764767RoffiL.RicciA.OgliariC.ScaloriA.MinolaE.ColloredoG.DonadaC.CerianiR.RinaldiG.ParisB.FornaciariG.MoralesR.Del PoggioP.SangiovanniA.BuonocoreM.BelliaV.RiboliP.NavaM. C.PanizzutiF.PipernoA.PozziM.PioltelliP.ManciaG.HCV genotypes in Northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients19982957017062-s2.0-003221255610.1016/S0168-8278(98)80249-3ZeuzemS.FrankeA.LeeJ. H.HerrmannG.RüsterB.RothW. K.Phylogenetic analysis of hepatitis C virus isolates and their correlation to viremia, liver function tests, and histology1996245100310092-s2.0-002990843810.1053/jhep.1996.v24.pm0008903367FarciP.ShimodaA.CoianaA.DiazG.PeddisG.MelpolderJ. C.StrazzeraA.ChienD. Y.MunozS. J.BalestrieriA.PurcellR. H.AlterH. J.The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies200028854643393442-s2.0-003464699610.1126/science.288.5464.339SotoB.Sánchez-QuijanoA.RodrigoL.OlmoJ. A. D.García-BengoecheaM.Hernández-QueroJ.ReyC.AbadM. A.RodríguezM.Sales GilabertM.GonzálezF.MirónP.CaruzA.RelimpioF.TorronterasR.LealM.LissenE.Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis1997261152-s2.0-034260140610.1016/S0168-8278(97)80001-3PontissoP.GerottoM.BenvegnuL.ChemelloL.AlbertiA.Coinfection by hepatitis B virus and hepatitis C virus1998331371422-s2.0-0031767537SterlingR. K.SulkowskiM. S.Hepatitis C virus in the setting of HIV or hepatitis B virus coinfection2004242, supplement61682-s2.0-444438183610.1055/s-2004-832930PallásJ. R.Fariñas-ÁlvarezC.PrietoD.Delgado-RodríguezM.Coinfections by HIV, hepatitis B and hepatitis C in imprisoned injecting drug users199915869970410.1023/A:1007619614350ReddyG. A.DakshinamurthyK. V.NeelaprasadP.GangadharT.LakshmiV.Prevalence of HBV and HCV dual infection in patients on haemodialysis200523141432-s2.0-14844333245AroldiA.LamperticoP.MontagninoG.PasseriniP.VillaM.CampiseM. R.LunghiG.TarantinoA.CesanaB. M.MessaP.PonticelliC.Natural history of hepatitis B and C in renal allograft recipients2005799113211362-s2.0-2084443596310.1097/01.TP.0000161250.83392.73Kalinowska-NowakA.Bociaga-JasikM.GarlickiA.SkwaraP.Prevalence of hepatotropic viruses HBV and HCV in HIV-infected patients from Southern region of Poland2000442328ZhouJ.DoreG. J.ZhangF.LimP. L.ChenY. M. A.Hepatitis B and C virus coinfection in the TREAT Asia HIV Observational Database2007229151015182-s2.0-3454798368910.1111/j.1440-1746.2007.05062.xAngelucciE.MurettoP.NicolucciA.BaroncianiD.ErerB.GazievJ.RipaltiM.SodaniP.TomassoniS.VisaniG.LucarelliG.Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation2002100117212-s2.0-003666018910.1182/blood.V100.1.17Di MarcoV.CapraM.GagliardottoF.BorsellinoZ.CabibiD.BarbariaF.FerraroD.CucciaL.RuffoG. B.BronteF.Di StefanoR.AlmasioP. L.CraxìA.Liver disease in chelated transfusion-dependent thalassemics: the role of iron overload and chronic hepatitis C2008938124312462-s2.0-4874909597410.3324/haematol.12554ZarskiJ. P.BohnB.BastieA.PawlotskyJ. M.BaudM.Bost-BezeauxF.Van NhieuJ. T.SeigneurinJ. M.BuffetC.DhumeauxD.Characteristics of patients with dual infection by hepatitis B and C viruses199828127332-s2.0-1924437770110.1016/S0168-8278(98)80198-0CrespoJ.LozanoJ. L.De la CruzF.RodrigoL.RodriguezM.San MiguelG.ArtinanoE.Pons-RomeroF.Prevalence and significance of hepatitis C viremia in chronic active hepatitis B1994898114711512-s2.0-0027993917MohamedA. E.Ali Al KarawiM.MesaG. A.Dual infection with hepatitis C and B viruses: clinical and histological study in Saudi patients19974417140414062-s2.0-9844260075ZarskiJ. P.BohnB.BastieA.PawlotskyJ. M.BaudM.Bost-BezeauxF.Van NhieuJ. T.SeigneurinJ. M.BuffetC.DhumeauxD.Characteristics of patients with dual infection by hepatitis B and C viruses199828127332-s2.0-1924437770110.1016/S0168-8278(98)80198-0FattovichG.TaggerA.BrolloL.GiustinaG.PontissoP.RealdiG.AlbertiA.RuolA.Hepatitis C virus infection in chronic hepatitis B virus carriers199116324004022-s2.0-0025967740FongT. L.Di BisceglieA. M.WaggonerJ. G.BanksS. M.HoofnagleJ. H.The significance of antibody to hepatitis C virus in patients with chronic hepatitis B199114164672-s2.0-0025807840KuperH. E.Tzonou AM.Kaklamani EG. A.Hepatitis B and C viruses in the etiology of hepatocellular carcinoma; a study in Greece using third-generation assays200021711752-s2.0-9844260075KaklamaniE.TrichopoulosD.TzonouA.ZavitsanosX.KoumantakiY.HatzakisA.HsiehC. C.HatziyannisS.Hepatitis B and C viruses and their interaction in the origin of hepatocellular carcinoma199126515197419762-s2.0-002575842610.1001/jama.265.15.1974KewM. C.YuM. C.KeddaM. A.CoppinA.SarkinA.HodkinsonJ.The relative roles of hepatitis B and C viruses in the etiology of hepatocellular carcinoma in southern African blacks199711211841872-s2.0-0031014425KirkG. D.LesiO. A.MendyM.AkanoA. O.SamO.GoedertJ. J.HainautP.HallA. J.WhittleH.MontesanoR.The Gambia Liver Cancer Study: infection with hepatitis B and C and the risk of hepatocellular carcinoma in West Africa20043912112192-s2.0-144230666010.1002/hep.20027Panel on Antiretroviral Guidelines for Adults and AdolescentsGuidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services, pp.1–166, January 2011LapinskiT. W.ParfieniukA.Rogalska-PlonskaM.CzajkowskaJ.FlisiakR.Prevalence of cryoglobulinaemia in hepatitis C virus- and hepatitis C virus/human immunodeficiency virus-infected individuals: implications for renal function2009298115811612-s2.0-7035007444310.1111/j.1478-3231.2009.02052.xReingoldJ. S.WankeC.KotlerD. P.LewisC. E.TracyR.HeymsfieldS.TienP. C.BacchettiP.ScherzerR.GrunfeldC.ShlipakM. G.Association of HIV infection and HIV/HCV coinfection with C-reactive protein levels: the fat redistribution and metabolic change in HIV infection (FRAM) study20084821421482-s2.0-4644909122910.1097/QAI.0b013e3181685727WyattC. M.MalvestuttoC.CocaS. G.KlotmanP. E.ParikhC. R.The impact of hepatitis C virus coinfection on HIV-related kidney disease: a systematic review and meta-analysis20082214179918072-s2.0-6634910716210.1097/QAD.0b013e32830e0152FischerM. J.WyattC. M.GordonK.GibertC. L.BrownS. T.RimlandD.Rodriguez-BarradasM. C.JusticeA. C.ParikhC. R.Hepatitis C and the risk of kidney disease and mortality in veterans with HIV20105322222262-s2.0-7564912559710.1097/QAI.0b013e3181b980d4BedimoR.WestfallA. O.MugaveroM.DrechslerH.KhannaN.SaagM.Hepatitis C virus coinfection and the risk of cardiovascular disease among HIV-infected patients20101174624682-s2.0-7795512434710.1111/j.1468-1293.2009.00815.xDe CastroI. F.MicheloudD.BerenguerJ.Guzmán-FulgencioM.CatalánP.MirallesP.ÁlvarezE.LópezJ. C.CosínJ.LorenteR.Muñoz-FernándezM. Á.ResinoS.Hepatitis C virus infection is associated with endothelial dysfunction in HIV/hepatitis C virus coinfected patients20102413205920672-s2.0-7795542652110.1097/QAD.0b013e32833ce54dLetendreS.PaulinoA. D.RockensteinE.AdameA.CrewsL.ChernerM.HeatonR.EllisR.EverallI. P.GrantI.MasliahE.AtkinsonJ. H.McCutchanJ. A.MarcotteT. D.WallaceM. R.SchierR.JerniganT.HesselinkJ.MasysD. R.FrybargerM.AbramsonT.DeutschR.WolfsonT.Pathogenesis of hepatitis C virus coinfection in the brains of patients infected with HIV200719633613702-s2.0-3444762430610.1086/519285VivithanapornP.MaingatF.LinL. T.NaH.RichardsonC. D.AgrawalB.CohenÉ. A.JhamandasJ. H.PowerC.Hepatitis C virus core protein induces neuroimmune activation and potentiates human immunodeficiency virus-1 neurotoxicity2010591142-s2.0-7795845874310.1371/journal.pone.0012856e12856AronowH. A.WestonA. J.PezeshkiB. B.LazarusT. S.Effects of coinfection with HIV and hepatitis C virus on the nervous system200818143482-s2.0-38549092577HinkinC. H.CastellonS. A.LevineA. J.BarclayT. R.SingerE. J.Neurocognition in individuals co-infected with HIV and hepatitis C200827211172-s2.0-5204909394110.1300/J069v27n02_02MinolaE.PratiD.SuterF.MaggioloF.CaprioliF.SonzogniA.FraquelliM.PaggiS.ConteD.Age at infection affects the long-term outcome of transfusion-associated chronic hepatitis C20029912458845912-s2.0-003709773710.1182/blood-2001-12-0192CammàC.BrunoS.Di MarcoV.Di BonaD.RumiM.VinciM.RebucciC.CividiniA.PizzolantiG.MinolaE.MondelliM. U.ColomboM.PinzelloG.CraxìA.Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C200643164712-s2.0-3364480668410.1002/hep.20983OrtizV.BerenguerM.RayónJ. M.CarrascoD.BerenguerJ.Contribution of obesity to hepatitis C-related fibrosis progression2002979240824142-s2.0-003673590910.1016/S0002-9270(02)04352-6MontoA.Hepatitis C and steatosis200213140462-s2.0-0036207473D'SouzaR.SabinC. A.FosterG. R.Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy20051007150915152-s2.0-2274443591410.1111/j.1572-0241.2005.41403.xPersicoM.CapassoM.PersicoE.SveltoM.RussoR.SpanoD.CrocèL.La MuraV.MoschellaF.MasuttiF.TorellaR.TiribelliC.IolasconA.Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: insulin resistance and response to antiviral therapy2007464100910152-s2.0-3634903037910.1002/hep.21782PersicoM.RussoR.PersicoE.SveltoM.SpanoD.AndolfoI.La MuraV.CapassoM.TiribelliC.TorellaR.IolasconA.SOCS3 and IRS-1 gene expression differs between genotype 1 and genotype 2 hepatitis C virus-infected HepG2 cells20094710121712252-s2.0-7034982349210.1515/CCLM.2009.280EverhartJ. E.LokA. S.KimH. Y.MorganT. R.LindsayK. L.ChungR. T.BonkovskyH. L.GhanyM. G.Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial200913725495572-s2.0-6765109583710.1053/j.gastro.2009.05.007BonkovskyH. L.BannerB. F.RothmanA. L.Iron and chronic viral hepatitis19972537597682-s2.0-003104401910.1002/hep.510250345Di BisceglieA. M.BonkovskyH. L.ChopraS.FlammS.ReddyR. K.GraceN.KillenbergP.HuntC.TamburroC.TavillA. S.FergusonR.KrawittE.BannerB.BaconB. R.Iron reduction as an adjuvant to interferon therapy in patients with chronic hepatitis C who have previously not responded to interferon: a multicenter, prospective, randomized, controlled trial20003211351382-s2.0-0034235427ThorburnD.CurryG.SpoonerR.SpenceE.OienK.HallsD.FoxR.McCrudenE. A. B.MacSweenR. N. M.MillsP. R.The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C20025022482522-s2.0-003615598410.1136/gut.0500248..MatsuokaS.NireiK.TamuraA.NakamuraH.MatsumuraH.OshiroS.ArakawaY.YamagamiH.TanakaN.MoriyamaM.Influence of occult hepatitis B virus coinfection on the incidence of fibrosis and hepatocellular carcinoma in chronic hepatitis C20095153523612-s2.0-5814915926510.1159/000187720BonkovskyH. L.bonkovsky@uchc.eduNaishadhamD.LambrechtR. W.ChungR. T.HoefsJ. C.NashS. R.RogersT. E.BannerB. F.SterlingR. K.DonovanJ. A.FontanaR. J.Di BisceglieA. M.GhanyM. G.MorishimaC.Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C200613151440145110.1053/j.gastro.2006.08.036LambrechtR. W.SterlingR. K.NaishadhamD.StoddardA. M.RogersT.MorishimaC.MorganT. R.BonkovskyH. L.herbert.bonkovsky@carolinashealthcare.orgIron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C2011140514901500.e310.1053/j.gastro.2011.01.053CorraoG.AricoS.Independent and combined action of hepatitis C virus infection and alcohol consumption on the risk of symptomatic liver cirrhosis19982749149192-s2.0-003194869310.1002/hep.510270404OstapowiczG.WatsonK. J. R.LocarniniS. A.DesmondP. V.Role of alcohol in the progression of liver disease caused by hepatitis C virus infection1998276173017352-s2.0-003174910910.1002/hep.510270637PessioneF.DegosF.MarcellinP.DuchatelleV.NjapoumC.Martinot-PeignouxM.DegottC.VallaD.ErlingerS.RueffB.Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C1998276171717222-s2.0-1734436703210.1002/hep.510270635WileyT. E.MccarthyM.BreidiL.MccarthyM.LaydenT. J.Impact of alcohol on the histological and clinical progression of hepatitis C infection19982838058092-s2.0-0031721879FattovichG.StroffoliniT.ZagniI.DonatoF.Hepatocellular carcinoma in cirrhosis: incidence and risk factors2004127supplementS35S502-s2.0-704427263010.1053/j.gastro.2004.09.014HuK. Q.TongM. J.The long-term outcomes of patients with compensated hepatitis C virus- related cirrhosis and history of parenteral exposure in the United States1999294131113162-s2.0-0032955838BenvegnùL.GiosM.BoccatoS.AlbertiA.Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications20045357447492-s2.0-234244454210.1136/gut.2003.020263SangiovanniA.PratiG. M.FasaniP.RonchiG.RomeoR.ManiniM.Del NinnoE.MorabitoA.ColomboM.The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients2006436130313102-s2.0-3374555976510.1002/hep.21176DegosF.ChristidisC.Ganne-CarrieN.FarmachidiJ. P.DegottC.GuettierC.TrinchetJ. C.BeaugrandM.ChevretS.Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death20004711311362-s2.0-003391764410.1136/gut.47.1.131RipollC.GroszmannR. J.Garcia-TsaoG.BoschJ.GraceN.BurroughsA.PlanasR.EscorsellA.Garcia-PaganJ. C.MakuchR.PatchD.MatloffD. S.Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis20095059239282-s2.0-6454912106310.1016/j.jhep.2009.01.014KimK. W.BaeS. K.LeeO. H.BaeM. H.LeeM. J.ParkB. C.Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma19985823483512-s2.0-0031974197BrunoS.SiliniE.CrosignaniA.BorzioF.LeandroG.BonoF.AstiM.RossiS.LarghiA.CerinoA.PoddaM.MondelliM. U.Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study19972537547582-s2.0-003105584110.1002/hep.510250344BrunoS.CrosignaniA.MaisonneuveP.RossiS.SiliniE.MondelliM. U.Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a seventeen-year prospective cohort study2007465135013562-s2.0-3634895019610.1002/hep.21826NishiseY.SaitoT.SugaharaK.ItoJ. I.SaitoK.TogashiH.Nagano-FujiiM.HottaH.KawataS.Risk of hepatocellular carcinoma and secondary structure of hepatitis C virus (HCV) NS3 protein amino-terminus, in patients infected with HCV subtype 1b20071967100610092-s2.0-3534883411510.1086/521309BenvegnùL.GiosM.BoccatoS.AlbertiA.Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications20045357447492-s2.0-234244454210.1136/gut.2003.020263D'AmicoG.Garcia-TsaoG.PagliaroL.Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies20064412172312-s2.0-2884449054710.1016/j.jhep.2005.10.013DurandF.VallaD.Assessment of prognosis of cirrhosis20082811101222-s2.0-4014909977210.1055/s-2008-1040325BrunoS.StroffoliniT.tommaso.stroffolini@iss.itColomboM.BollaniS.BenvegnùL.MazzellaG.AscioneA.SantantonioT.PiccininoF.AndreoneP.MangiaA.GaetaG. B.PersicoM.FagiuoliS.AlmasioP. L.Sustained virological response to interferon-α is with improved outcome in HCV-related cirrhosis: a retrospective study200745357958710.1002/hep.21492VeldtB. J.HeathcoteE. J.WedemeyerH.ReichenJ.HofmannW. P.ZeuzemS.MannsM. P.HansenB. E.SchalmS. W.JanssenH. L. A.Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis2007147106776842-s2.0-38449091418AsselahT.MarcellinP.New direct-acting antivirals' combination for the treatment of chronic hepatitis C2011311, supplement68772-s2.0-7865092887810.1111/j.1478-3231.2010.02411.xShiratoriY.ImazekiF.MoriyamaM.YanoM.ArakawaY.YokosukaO.KurokiT.NishiguchiS.SataM.YamadaG.FujiyamaS.YoshidaH.OmataM.Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy200013275175242-s2.0-17144455384CammàC.Di BonaD.SchepisF.HeathcoteJ.ZeuzemS.PockrosP. J.MarcelilnP.BalartL.AlbertiA.CraxìA.Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: a meta-analysis of individual patient data20043923333422-s2.0-1074423246510.1002/hep.20073PoynardT.McHutchisonJ.MannsM.TrepoC.LindsayK.GoodmanZ.LingM.AlbrechtJ.Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C20021225130313132-s2.0-0036242165MarcellinP.BoyerN.DegottC.Martinot-PeignouxM.DuchatelleV.GiostraE.AreiasJ.ErlingerS.BenhamouJ. P.Long-term histologic and viral changes in patients with chronic hepatitis C who responded to alpha interferon19941463023072-s2.0-0027972001GeorgeS. L.BaconB. R.BruntE. M.MihindukulasuriyaK. L.HoffmanJ.Di BisceglieA. M.Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients20094937297382-s2.0-6274920330210.1002/hep.22694MarcellinP.BoyerN.GervaisA.MartinotM.PouteauM.CastelnauC.KilaniA.AreiasJ.AuperinA.BenhamouJ. P.DegottC.ErlingerS.Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-α therapy1997127108758812-s2.0-15644380122SataM.IdeT.AkiyoshiF.Effects of interferon alpha 2a on incidence of hepatocellular carcinoma in chronic active hepatitis without cirrhosis199744171177LauD. T. Y.KleinerD. E.GhanyM. G.ParkY.SchmioP.HoofnagleJ. H.10-year follow-up after interferon-α therapy for chronic hepatitis C1998284 I112111272-s2.0-003170492710.1002/hep.510280430CammàC.Di MarcoV.Lo IaconoO.AlmasioP.GiuntaM.FuschiP.VaccaroA.FabianoC.MagrinS.Di StefanoR.BonuraC.PagliaroL.CraxìA.Long-term course of interferon-treated chronic hepatitis C19982845315372-s2.0-003197238810.1016/S0168-8278(98)80274-2AjelloA.FreniM. A.SpadaroA.AlessiN.ImpellizzeriF.ConsoloP.RestaM. L.FerraúO.Ten year follow-up of patients with chronic hepatitis C treated with interferon19994628244724502-s2.0-0032827773MoriscoF.MarmoR.IasevoliP.SessaG.TuccilloC.Del Vecchio BlancoC.CaporasoN.Clinical outcome of chronic hepatitis C in patients treated with interferon: comparison between responders and non-responders1999316454458GallegoA.TorrasX.Sancho-PochF. J.EnriquezJ.Long term follow-up of patient with chronic hepatitis C after IFN therapy200134supplement 1234GianniniE.FasoliA.BottaF.TestaE.RomagnoliP.CeppaP.TestaR.rtesta@unige.itLong-term follow up of chronic hepatitis C patients after α-interferon treatment: a functional study200116439940510.1046/j.1440-1746.2001.02463.xShindoM.HamadaK.OdaY.OkunoT.Long-term follow-up study of sustained biochemical responders with interferon therapy2001335129913022-s2.0-003503195410.1053/jhep.2001.24100SwainM.LaiM. Y.ShiffmanM. L.Durability of sustained virological response (SVR) after treatment with peginterferon alfa 2A (40 kD) (PEGASYS) alone or in combination with ribavirin (Copegus): results of an ongoing long-term follow-up study200440supplement 1400AVeldtB. J.SaraccoG.CammàC.BoyerN.BellobuonoA.HopfU.CastilloI.WeilandO.NevensF.HansenB. E.SchalmS. W.Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy20045310150415082-s2.0-464430869110.1136/gut.2003.038257CiancioA.SmedileA.GiordaninoC.CollettaC.CroceG.PozziM.CaritiG.MacorA.BiglinoA.Di NapoliA.TapperoG. F.AndreoniM.MancaA.PrandiG.CalleriG.OrsiP. G.CicconeG.RizzettoM.SaraccoG.Long-term follow-up of previous hepatitis C virus positive nonresponders to interferon monotherapy successfully retreated with combination therapy: are they really cured?20061018181118162-s2.0-3374671621510.1111/j.1572-0241.2006.00669.xChavalitdhamrongD.TanwandeeT.Long-term outcomes of chronic hepatitis C patients with sustained virological response at 6 months after the end of treatment20061234553255352-s2.0-33749413206HeathcoteE. J.ShiffmanM. L.CooksleyW. G. E.DusheikoG. M.LeeS. S.BalartL.ReindollarR.ReddyR. K.WrightT. L.LinA.HoffmanJ.De PamphilisJ.Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis200034323167316802-s2.0-003461998010.1056/NEJM200012073432302MannsM. P.McHutchisonJ. G.GordonS. C.RustgiV. K.ShiffmanM.ReindollarR.GoodmanZ. D.KouryK.LingM. H.AlbrechtJ. K.Peginterferon alfa-2b plus ribavirin compared with interferonalfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial200135892869589652-s2.0-003593456810.1016/S0140-6736(01)06102-5FriedM. W.ShiffmanM. L.ReddyK. R.SmithC.MarinosG.GoncalesJ. F. L.HäussingerD.DiagoM.CarosiG.DhumeauxD.CraxiA.LinA.HoffmanJ.YuJ.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection2002347139759822-s2.0-003717969810.1056/NEJMoa020047HadziyannisS. J.SetteH.Jr.MorganT. R.BalanV.DiagoM.MarcellinP.RamadoriG.BodenheimerH.BernsteinD.RizzettoM.ZeuzemS.PockrosP. J.LinA.AckrillA. M.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose20041405346I672-s2.0-1542378867ZeuzemS.HultcrantzR.BourliereM.GoeserT.MarcellinP.Sanchez-TapiasJ.SarrazinC.HarveyJ.BrassC.AlbrechtJ.Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 320044069939992-s2.0-244268390510.1016/S0168-8278(04)00060-1