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Short-duration therapy for hepatitis C & RVR: suitable for all?
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Journal of Viral Hepatitis (OnlineEarly Articles). Feb 2007
doi:10.1111/j.1365-2893.2006.00817.x
A. Mangia
Division of Gastroenterology, Hospital 'Casa Sollievo della Sofferenza', IRCCS, San Giovanni Rotondo, Italy
Abstract
Summary. Peginterferon α (PegIFN α) plus ribavirin achieves sustained virological response (SVR) in more than 50% of patients with chronic hepatitis C virus (HCV) infection. Although in the trials which led to the registration of this combination therapy, only a 48-week period of treatment had been evaluated, current international guidelines state that 48 or 24 weeks of treatment should be recommended in accordance with genotype; i.e. 48 weeks for genotypes 1 and 4, and 24 weeks for 2 and 3. However, side effects and the high cost of antiviral therapy forced investigators to evaluate further reductions in the treatment duration. Based on the new evidence that fast and persistent viral clearance is highly predictive of SVR, a week 4 negative HCV RNA by a sensitive molecular assay was recently utilized as a criterion for halving the duration of treatment to 12-16 weeks for genotypes 2 and 3, and 24 weeks for genotype 1 patients. However, some issues on this topic, are still open. In this review, existing evidence is discussed, and both the relevance and limitations of published studies are considered.
CONCLUSION: The use of RVR as a rule to guide treatment duration overcomes the possible viral and host-linked factors which may reduce SVR when the duration of treatment is truncated. Once HCV RNA becomes negative at week 4 by a very sensitive assay, patients with genotypes 2 and 3, but also a subgroup of those with genotype 1 may safely receive short-course therapy. Since genotype 3 patients who are still positive at week 4 may benefit from treatment that is longer than 24 weeks, HCV RNA status at 4 weeks is helpful in discriminating between patients who require not only shorter but also longer treatment than the currently recommended duration.
Introduction
Chronic hepatitis C is a serious global public health problem. Of the estimated 170 million people infected in the world, more than 40% require treatment [1]. Antiviral agents such as interferon (IFN) were firstly introduced in 1987, and since then no therapeutic scheme has been used without IFN [2]. Although in initial studies, it was estimated that therapy should last 24 weeks, further studies demonstrated the benefit of longer treatment duration in chronic HCV infection. In 1998, ribavirin was shown to increase IFN treatment response rates from 20% to 40%. Furthermore, international trials on combination treatment showed that patients infected with genotypes 2 and 3 or with genotype 1b and low HCV RNA levels could be treated with 24 weeks of recombinant IFN and ribavirin [3,4]. However, recently, a chemically modified type of IFN, has been shown to be more efficacious than conventional IFN, as polyethylene glycol molecules attached to the protein prolonged its half-life. Two types of pegyated IFNs (PegIFN) are now available, α2a and α2b, and can be administered only once weekly. With the advent of this IFN, a duration of 48 months was again proposed in combination with ribavirin as the standard treatment, probably to maximize the efficacy of the new drug [5,6].
Given the many complex factors involved in the treatment of patients with HCV, it would be surprising to find that all patients need the same treatment duration. As both ribavirin and IFN have marked side effects, the goal for clinicians is to find the most effective therapy with the shortest duration of treatment. Thus, predictors useful in individualizing duration of treatment are needed. Beside genotype, new concepts such as viral kinetics during treatment and early virological responses (EVRs) prompted clinicians to evaluate the possibility of tailoring treatment in chronic HCV patient subgroups.
The aim of this review is to discuss whether current evidence is strong enough to support individualized short treatment in chronic HCV infection.
Genotype Sensitivity
Results from several controlled trials have conclusively demonstrated that HCV genotype is the most important variable influencing treatment outcome, as the 85% of SVR achieved in patients with genotypes 2 and 3 is two and a half times that of genotype 1. Although the reasons for this different response are still not completely explained, many factors are relevant in this respect, above all HCV genome sequence variability in the NS5a region. The NS5a region binds and inactivates the phosphorylation domain of protein kinase R (PKR) which represents the main effector pathway inducing apoptosis, thus modulating the IFN response. PKR is therefore associated with the innate immune defence of vertebrates against viruses [7]. The degree of similarity between genotype 1 variants and PKR is higher than in other genotypes and contributes to the greater resistance of HCV genotype 1 to IFN therapy. A degree of higher substitution in the NS5a region in genotypes 2 and 3 rather than in genotype 1 may account for a less efficient inhibition of the host enzyme and for a consequent lower rate of cell-to-cell infection. In addition, NS5a is also a target for immune response. The optimal immunological recognition of the NS5 protein and the more efficient and vigorous CD4 response explain the better viral clearance in genotypes 2 and 3 rather than in genotype 1 patients [8]. Finally, the more rapid variation in hypervariable region 1 (HVR-1) viral sequences observed in genotype 2 may result from the more vigorous and frequent antibody response to the envelope 2 (E2) protein shown in several studies. Thus, the greater killing of cells infected with genotype 2 in comparison with other genotypes probably derives from the different immunological interaction with the host immune system.
Viral Kinetics During Treatment
During the first weeks of IFN treatment, the experimental data support a two-phase viral decline: a first rapid drop of RNA levels depending on the direct antiviral effect of IFN and a second slower decline, which starts approximately on day 2 and reflects the immune-mediated clearance of infected cells [9]. Differences in viral dynamics have been observed between genotypes 1 and 2, and among the same genotype. Firstly, genotype 2 has a faster-free virion clearance rate, due not only to the shorter half-life but probably also to an antibody-mediated clearance [10]. Moreover, the less variable slope of viral decline in genotype 2 appears to be due to a specific CD4 response, against NS3, that is stronger and more enhanced by IFN therapy compared to genotype 1 [11]. Finally, the variable viral kinetics within genotype 1 may be related to a different cellular response. As recently shown, the inter-individual differences in virologic response may be explained by marked differences in viral kinetics: patients with a fast viral drop show an increase in CD4+/CD8+ T-cell reactivity which definitely induces RNA clearance [12].
Predictive role of early viral clearance
Early changes in HCV RNA serum concentration during antiviral therapy may allow accurate prediction of treatment outcome. In different studies, during PegIFN and ribavirin treatment, a high predictive value of virologic non-response (98-100%) was observed for patients infected with genotypes 1-4 or 6 with a decline of HCV RNA serum concentration of less than 2 logs between baseline and week 12. In contrast, the current algorithm predicting a sustained response is not satisfactory, as a week 12 positive prediction of response is not higher than 71% (Table 1) [13].
An earlier time-point at week 4 was more recently evaluated and used to define 'rapid virologic response' (RVR) showing only marginal increase in benefit. However, when not only the rapid response but also the persistence of this response was considered, the value of week 4 assessment of HCV RNA undetectability increased (Table 2). In the Manns et al. original data, a loss of HCV RNA at week 4 was reported in 150 out of 511 patients (29%) infected by all HCV genotypes; it is worthwhile mentioning that 88.7% of these rapid responders experienced a SVR [6,13]. Of the genotype 1 patients treated in that study with Peg-Intron 1.5 mcg plus >10.6 mg of ribavirin, an EVR defined as HCV RNA negative at week 4 was achieved in 11%, and SVR among these early responders was 87% (6, Schering -Plough Corporation, data on file). When Ferenci et al. [14] analysed the data by Fried et al. [15], 65% of the patients of all genotypes achieved a rapid virological response (RVR) and 78% of them were sustained virological responders. However, a RVR only marginally increased prediction of SVR. Recently, Jennsen et al. [15] analysed the genotype 1 patient subgroup in the Hadzyiannis et al. [16] study and demonstrated that patients with HCV RNA levels lower than 50 IU/mL at week 4 (24%) who remained persistently negative had both higher end of treatment responses and SVR than patients without a RVR or with only a 2 log decrease in HCV RNA at week 4 (89%vs 19%) (Table 3).
All the evidence that has so far been reported demonstrates that genotype is not the only predictor of a favourable response and that on the basis of a very rapid HCV RNA clearance that is maintained during treatment, subgroups of patients with high sensitivity to IFN may be selected and safely treated for a shorter period of time than in the past.
Current Trials On Short-Course Treament
As part of the effort to improve and refine treatment approaches, recent studies have examined the effectiveness of shorter courses of treatment in patients with favourable genotypes. At the beginning of 2004, two large studies demonstrated that in genotypes 2 and 3 patients, length of PegIFN and ribavirin combination treatment could be reduced from 48 to 24 weeks without loss of efficacy (Table 3). The large international multicenter randomized study by Hadziyannis and colleagues compared 24-48 weeks of treatment with low or standard doses of ribavirin in combination with PegIFN-α2a, showing that genotypes 2 and 3 can be treated for only 24 weeks in combination with low doses of ribavirin (800 mg/day) [16]. A study performed using PegIFN-α2b at the standard dose of 1.5 mcg plus weight-based ribavirin similarly demonstrated that patients with favourable genotype can be safely treated for 24 weeks, instead of 48 weeks [17] (Table 2). In the event that some of these patients may have been over-treated, to further reduce cost and side effects other investigators and ourselves used RVR not as a predictor of SVR but as a guide to further reduce treatment duration.
In a prospective study, we randomized patients infected with HCV genotypes 2 and 3 to a standard 24-week treatment with PegIFN-α2b and weight-based ribavirin or to a variable duration treatment. In this arm, patients with undetectable HCV RNA by PCR at week 4 would receive only 12 weeks of therapy, while patients with detectable HCV RNA at week 4, would be treated for 24 weeks. A control group of patients in which, independently of a negative HCV RNA status at week 4, treatment would have lasted 24 weeks was the direct comparator. This group had a response rate (91%) that was absolutely comparable to that obtained after only 12 weeks of treatment (85%) [18].
In a similar non-randomized study performed in Norway, nave patients received 14 weeks of PegIFN-α2b and ribavirin if HCV RNA was undetectable by PCR at both week 4 and week 8. If HCV RNA was detectable at these time points, patients received 24 weeks of therapy. Of patients receiving 14 weeks of therapy, 90% were sustained responders compared with only 56% in the 24 weeks group [19].
A third randomized and controlled study was performed in Germany with PegIFN-α2a and ribavirin. In this study, 153 patients with genotypes 2 and 3 were randomized to 16 or 24 weeks of treatment, when negative by AMPLICOR assay (sensitivity of 600 IU) at week 4. Patients who were HCV RNA positive were treated for 24 weeks. After 16 weeks, SVR was 82%, whereas after 24 weeks it was 80% [20].
Very recently, results from a large controlled study of 1461 patients with genotype 2 or 3 randomized to 16 or 24 weeks treatment have been presented. In this study (ACCELERATE), PegIFN-α2a in combination with a fixed dose of ribavirin was used. Results demonstrated that reducing treatment duration is not advantageous: due to the high rate of relapse after 16 weeks, the SVR rate was 65%, whereas after 24 weeks it was 76% [21]. In this study, analysing patients stratified on the base of a RVR did not show a higher SVR rate among rapid responders.
Only two studies evaluated prospectively short-course treatment in genotype 1 patients. The first one is an open trial performed with PegIFN-α2b at a dose of 1.5 mcg and ribavirin 800-1400 mg based on body weight for 24 weeks, in which only patients with HCV 1 and baseline viraemia lower than 600 000 IU/mL were enrolled. Analysis performed 'a posteriori' demonstrated that when patients were HCV RNA negative from week 4, the likelihood to develop a SVR was 89%, whereas patients who turned HCV RNA negative at week 12 or 24 achieved only a 25% and 17% SVR rate, respectively. The RVR in this study in genotype 1 patients and low viral load was 47% [21]. These figures are comparable with those derived in historical controls by Manns et al. [6] (Table 3)
A second prospective uncontrolled study has been performed by Ferenci and colleagues, and is currently ongoing. It was presented at the last EASL meeting (2006) and suggested that the subgroup of genotype 1 infected patients with RVR, representing 25% of the initial genotype 1 population, achieved 75% of SVR after 24 weeks of treatment with PegIFN-α2a and weight-based ribavirin, irrespective of baseline HCV RNA levels [22].
Advantages and disadvantages of the short treatment course
One of the potential benefits of a shorter treatment course is the improved compliance and, consequently a lower rate of treatment discontinuation than that observed in patients on lower-course therapies. All studies on short-term treatment showed a lower rate of side effects and dose discontinuation. In the Italian study, SAE during the treatment period was 18% in the standard 24-week group and 6% in the short-treatment group, while in the pilot study from Norway it was also 6% [18-20]. Discontinuation of treatment due to adverse events was reported in 6% of patients in the short treatment arm in the Italian study, in 3.2% in the Norwegian and in 1.4% in the German study [18-20]. Dose reduction was reported in 5%vs 12% and in 11%vs 14% in the Italian and German studies during the short or the standard course of treatment, respectively [18,20].
In the 24-week treatment study for genotype 1, the rate of adverse events was 11%; discontinuation of treatment was required in 3% and dose reduction in 26% [23]. Among the historical controls of this study [16], the rate of adverse events leading to therapy withdrawals was 14%. Thus, the safety profile of the short-treatment course has improved compared with the standard treatment length.
The primary concern with a shorter duration of therapy is relapse. Looking at the three studies in genotypes 2 and 3 patients, relapse rates were higher in the group of patients treated for a short time: 10% in the Norwegian and Italian studies and 12% in the German study. The relapse rates were 2%, 4% and 5% in the groups treated for the standard 24 weeks in the three European studies, respectively [18-20]. In the ACCELERATE study, in the 16 weeks group the relapse rate was very high, 29% [21]. Among genotype 1 patients treated for only 24 weeks, relapse rate of patients with an early response was 8%, whereas it increased to 75% and 80% for treatments truncated at week 24 after an initial response achieved at week 12 or week 24 [23]. Presence of advanced fibrosis or cirrhosis was predictive of relapse in the Norwegian but not in the Italian and German studies. However, as about 30% of the Norwegian patients did not undergo liver biopsy, the power of this statistical feature is reduced [19]. No factors predictive of relapse were identified in the Italian study [18].
It is worthwhile noting that, in accordance with what is already known, the re-treatment of patients with favourable genotype after a relapse was successful for both Italian and Norwegian patients (Dalgard, pers. comm.). Thus, at least among the favourable genotype subset, the clinical relevance of a potential relapse is of minor impact considering the advantages of a short duration in a large number of patients.
Factors affecting rapid virologic response
Sensitivity of the assay
Strictly related to the concept of measuring RVR are the means to check this early response. Comparing the Italian and German studies, the rate of RVR may depend on the sensitivity of the assay used to evaluate HCV RNA disappearance at week 4 [18-20]. In our study, 63% of patients had undetectable HCV RNA by sensitive PCR (50 IU/mL), but in the German study with an assay with a sensitivity of 600 IU/mL, this rate was 95% [19]. The Norwegian pivotal study which utilized PCR to assess HCV RNA disappearance had an RVR rate (75%) comparable to ours (Fig. 1) [18,19]. Thus, the use of a sensitive test to measure marked decreases in HCV RNA levels may have, as a consequence, the selection of patients who are responsive to antiviral therapy for a short-treatment course; those unselected, who are probably more resistant, will have a lower rate of response even after 24 weeks of treatment. In contrast, with a less sensitive assay, a large number of patients who are less strictly selected will achieve undetectable HCV RNA at week 4 leading to a lower rate of SVR in the short-treatment group. In the German study, the final responses obtained were comparable to those obtained in the 24-week treatment, probably because of the high number of treatment withdrawals in the standard treatment duration. Anyway, German patients received four more weeks of treatment compared to the Italian ones [20].
The quality of the assay used to assess the rapid HCV RNA clearance may be even more important in genotype 1 patient subgroups with low baseline viraemia tested with the aim of shortening treatment duration to only 24 weeks, as demonstrated with the very sensitive real-time PCR (low detection limit 29 IU/mL) [23].
Dosage
In the Norwegian study, the currently approved dose of PegIFN-α2b (1.5 mcg/kg) was used, whereas in the Italian study we used a lower dose: 1.0 mcg/kg/week [18,19]. This dose has already been shown to be as effective as the 1.5 mcg/kg/week in genotypes 2 and 3 patients in the original trial by Manns et al. [6], and has also been demonstrated to be effective in other Italian studies [24]. A possible influence of lower PegIFN doses on RVR could be hypothesized, but looking at the combined data on short-term treatment from the large Italian database plus the original Norwegian data, no evidence was obtained by logistic regression analysis that PegIFN dose lower than 1.5 mcg reduces RVR treatment effectiveness [24]. Thus, 1.0 mcg of PegIFN-α2b seems sufficient in inducing RVR in patients with favourable genotypes treated for 12 weeks. In order to directly compare 1.0 mcg/kg/week of PegIFN-α2b to 1.5 mcg/kg/week for 24 weeks, Manns and colleagues have started recruiting treatment-nave patients with hepatitis C caused by genotypes 2 or 3 for an open-label, multinational, randomized clinical trial in which patients will be treated in combination with ribavirin 800-1200 mg/day based on body weight.
Regarding ribavirin dosages, in all the studies on genotypes 2 and 3, except for the ACCELERATE trial, ribavirin doses according to body weight have been administered with the expectancy to reduce the rate of relapse. The ACCELERATE study employed fixed dosages of ribavirin of 800 mg/day with a rate of relapse of 29% in the short treatment arm and of 16% in the standard 24 week course [21].
Evidence on short-course treatment in genotype 1 has been gained only with standard doses of both PegIFN and ribavirin.
Advanced liver damage
Advanced fibrosis or cirrhosis represents another factor that negatively affects the RVR in all the three studies and in the combined Italian-Norwegian database. In the latter, multivariate analysis demonstrated that a low fibrosis score was the only feature predictive of viral clearance after 4 weeks of therapy. Consequently, patients with advanced liver damage have a lower chance of response when treated with a short course of therapy [18-20,25]. Cenotype 1 short treatment predictive factors of RVR were not evaluated [23].
Twenty five percent of patients enrolled into the ACCELERATE study had advanced liver damage. No association between fibrosis and poorer response has been reported in the abstract.
Who cannot stand a short treatment course?
In the German and Italian studies, SVR in genotype 3 patients were lower than in genotype 2, 75% and 66%vs 95% and 82%, respectively. As the SVR rate in patients who were still HCV RNA positive at week 4, was 30% and 41% in the two studies, respectively, the overall lower response in genotype 3 patients may be due to the lower rate of SVR achieved in patients without RVR. This lower rate of response, consistent with that reported by Zeuzem et al. [23] after a 24-week treatment course, suggest that some patients with genotype 3 and slow response require treatment for longer than 24 weeks. So far, no data supports the view that genotype in itself is predictive of RVR or relapse.
In contrast with the German study, in Italian as in Norwegian patients, levels of viraemia at baseline in the genotype 3 subset did not influence SVR. A different level of viraemia at baseline, 600 000 IU/mL or 800 000 IU/mL, may explain the contrasting results. A similar point was raised from the results achieved in the study of 24-week treatment by Zeuzem et al. and in the analysis of the Hadzyiannis et al. data [16]. In the former, it was suggested that patients with genotype 3 and HCV RNA concentration higher than 800 000 IU/mL cannot be treated for only 24 weeks, whilst in the latter it was demonstrated that in genotype 3 patients high HCV RNA levels at baseline do not decrease SVR [26]. Therefore, the only limitation linked to a satisfactory SVR in patients with genotype 3 seems to be detectable levels of HCV RNA at week 4, which may indicate a more resistant virus.
The second issue is whether steatosis or fibrosis are factors that negatively affect the results of short term treatment. After 24 weeks of treatment in genotypes 2 and 3 patients, Zeuzem et al. [17] showed that the presence of fatty liver infiltration reduced the rate of response and increased the rate of relapse [16]. Surprisingly, in this study the steatosis percentage significantly associated with a lower rate of response was very low (5%). The role of steatosis was not confirmed in studies on the shorter course of treatment (Italian and Norway), suggesting that how the amount of fatty liver infiltration is categorized may influence the finding of a positive association [18,19].
Fibrosis is one of the known factors responsible for reducing SVR [3,4]. In the Norwegian, but not in the Italian and German studies, univariate analysis demonstrated that fibrosis in genotype 3 patients treated with a short course increased the rate of relapse [18-20]. In a combined analysis of the Italian and Norwegian data, fibrosis was a factor associated with absence of RVR, but once RVR was achieved, SVR was maintained [25]. This contrasting evidence suggests that rather than one specific factor, the combination of more than one unfavourable factor, such as advanced liver damage and high viraemia or genotype 3 and a high fibrosis score in the same patient, reduces the rate of SVR after a short course of treatment. In the only published study on short treatment for patients with genotype 1, unexpectedly, neither fibrosis nor steatosis were predictors of SVR. This result is probably due to the low number of patients with advanced fibrosis enrolled [23].
Conclusion
The use of RVR as a rule to guide treatment duration overcomes the possible viral and host-linked factors which may reduce SVR when the duration of treatment is truncated. Once HCV RNA becomes negative at week 4 by a very sensitive assay, patients with genotypes 2 and 3, but also a subgroup of those with genotype 1 may safely receive short-course therapy. Since genotype 3 patients who are still positive at week 4 may benefit from treatment that is longer than 24 weeks, HCV RNA status at 4 weeks is helpful in discriminating between patients who require not only shorter but also longer treatment than the currently recommended duration.
References
1 Perz JF, Farrington LA, Pecoraro C, Hutin YJ, Armstrong GL. Estimated global prevalence of hepatitis C virus infection A357. J Infect Dis 2004; 154.
2 Di Bisceglie AM, Martin P, Kassianides C et al. Recombinant interferon alfa therapy for chronic hepatitis C. A randomized double-blind placebo-controlled trial. N Engl J Med 1989; 22: 1506-1510.
3 Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003; 362: 2095-2100. CrossRef, Medline, ISI, CSA
4 McHutchison JG, Gordon SC, Schiff ER et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339: 1485-1492. CrossRef, Medline, ISI, CSA
5 Fried MW, Shiffaman ML, Reddy KR et al. Peginterferon alpfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982. CrossRef, Medline, ISI, CSA
6 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. Lancet 2001; 358: 958-965. CrossRef, Medline, ISI, CSA
7 Zein NN. Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 2000; 13: 223-235. CrossRef, Medline, ISI, CSA
8 Simmonds P. Genetic diversity and evolution of hepatitis C virus-15 years on. J Gen Virol 2004; 85: 3173-3188. CrossRef, Medline, ISI
9 Neumann AU, Lam NP, Dahari H et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 1998; 282: 103-107. CrossRef, Medline, ISI, CSA
10 Neumann AU, Lam NP, Dahari H et al. Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus. J Infect Dis 2000; 182: 28-35. CrossRef, Medline, ISI, CSA
11 Hultgren C, Desombere I, Leroux-Roels G et al. Evidence for a relation between the viral load and genotype and hepatitis C virus-specific T cell responses. J Hepatol 2004; 40: 971-978.
CrossRef, Medline, ISI
12 Tang KH, Herrmann E, Cooksley H et al. Relationship between early HCV kinetics and T-cell reactivity in chronic hepatitis C genotype 1 during peginterferon and ribavirin therapy. J Hepatol 2005; 43: 776-782. CrossRef, Medline, ISI
13 Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa 2b plus ribavirin inn patients with chronic hepatitis C. Hepatology 2003; 38: 645-652. CrossRef, Medline, ISI
14 Ferenci P, Fried MW, Shiffman ML et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa 2a (40 KD)/ribavirin. J Hepatol 2005; 43: 425-433. CrossRef, Medline, ISI
15 Jensen D, Morgan T, Marcellin P et al. Rapid virologic response at week 4 (RVR) of peginterferon alfa 2a (40KD) plus ribavirin treatment predicts sustained virological response (SVR) after 24 weeks in genotype 1 patients. Hepatology 2006; 43: 954-960. CrossRef, Medline, ISI
16 Hadziyannis SJ, Sette H Jr, Morgan TR et al. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346-355. Medline, ISI
17 Zeuzem S, Hultcrantz R, Bourliere M et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with genotypes 2 or 3. J Hepatol 2004; 40: 993-999. CrossRef, Medline, ISI
18 Mangia A, Santoro R, Mnerva N et al. Peginterferon alfa-2b and ribavirin for 12 vs 24 weeks in HCV genotype 2 or 3. N Engl J Med 2005; 352: 2609-2617. CrossRef, Medline, ISI
19 Dalgard O, Bjoro K, Hellman KB et al. Treatment with pegylated interferon and ribavirin in HCV infection with genotype 2 or 3 for 14 weeks: a pilot study. Hepatology 2004; 41: 1260-1263. CrossRef
20 von Wagner M, Huber M, Berg T et al. Peginterferon alfa 2a (40 kd) and ribavirin for 16 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129: 522-527. CrossRef, Medline, ISI
21 Shiffman ML, Pappas S, Nyberg L et al. Peginteferon alfa-2a (pegasys) plus ribavirin (Copegus) for 16 or 24 weeks in patients with HCV Genotype 2 or 3. Final results of the ACCELERATE trial. J Hepatol 2006; 44: S271. CrossRef
22 Ferenci P, Bergholz U, Laferl H et al. Steindl-Munda. 24 week treatment regimen with Peginterferon alfa 2a (40 KD) (Pegasys) plus Ribavirin (Copegus) in HCV genotype 1 or 4 'super-responders'. J Hepatol 2006; 44: 56. CrossRef, Medline
23 Zeuzem S, Buti M, Ferenci P et al. Efficacy of 24 weeks treatment with peginterferon alfa 2b plus ribavirin in patients with chronic hepatitis C infection with genotype 1 and low pre- treatment viremia. J Hepatol 2006; 44: 97-103. CrossRef, Medline, ISI
24 Bruno S, Camma C, Di Marco V et al. Peginterferon alfa-2b plus ribavirin for naive patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J Hepatol 2004; 41: 474-481.
CrossRef, Medline, ISI
25 Andriulli A, Dalgard O, Bjioro K, Mangia A. Short term treatment duration for HCV-2 and HCV-3 infected patients. Dig liver dis 2006; 38: 741-748. CrossRef, Medline, ISI
26 Rizzetto M. treatment of hepatitis c virus genotype 2 and 3 with pegylated interferon plus ribavirin. J Hepatol 2005; 42: 275-278.
CrossRef, Medline, ISI
27 Civeira MP, Prieto J. Early predictors of response to treatment in patients with chronic hepatitis C. J Hepatol 1999; 31: 237-243.
CrossRef, Medline, ISI
28 Di Marco V, Ferraro D, Almasio P et al. Early viral clearance and sustained response in chronic hepatitis C: a controlled trial of interferon and ribavirin after high-dose interferon induction. J Viral Hepat 2002; 9: 354-359. Synergy, Medline, ISI, CSA
29 Terrault NA, Pawlotsky JM, McHutchison J et al. Clinical utility of viral load misurements in individuals with chronic hepatitis C infection on antiviral therapy. J Viral hepat 2005; 12: 465-472.
Synergy, Medline, ISI
30 Lee SS, Heathcote EJ, Reddy KR et al. Prognostic factors and early predictability of sustained viral response with peginterferon alpha 2a. J Hepatol 2002; 37: 500-506. CrossRef, Medline, ISI
31 Pockros PJ, Carithers R, Desmond P et al. Efficacy and safety of two-dose regimens of peginterferon alpha2a compared with interferon alpha 2a in chronic hepatitis C: a multicenter randomized controlled trial. Am J Gastroenterol 2004; 99: 1298-1305.Synergy, Medline, ISI
32 Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa 2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004; 350: 2265-2271.CrossRef, Medline, ISI
33 Reddy K, Rakela J, Lopez-Talavera J, Pockros PJ. Correlation between rapid virologic response, early virologic response and sustained virologic response in HCV genotype 1 patients with pegylated interferon alfa 2a and ribavirin. Gastroenterology 2005; 128: S1540.
34 Ferenci P, Shifffman M, Fried M et al. Early prediction of response to 40KD peginteferon alfa-2a (PEGASYS) plus ribavirin (RBV) in patients with chronic hepatitis C (CHC). Hepatology 2001; 34: 351A. CrossRef, Medline, ISI
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