4mang.oa

The new england journal of medicine for 12 vs. 24 Weeks in HCV Genotype 2 or 3 Alessandra Mangia, M.D., Rosanna Santoro, Bs.D., Nicola Minerva, M.D., Giovanni L. Ricci, M.D., Vito Carretta, M.D., Marcello Persico, M.D., Francesco Vinelli, M.D., Gaetano Scotto, M.D., Donato Bacca, M.D., Mauro Annese, M.D., Mario Romano, M.D., Franco Zechini, M.D., Fernando Sogari, M.D., Fulvio Spirito, M.D., and Angelo Andriulli, M.D.
b a c k g r o u n d
We hypothesized that in patients with hepatitis C virus (HCV) genotype 2 or 3 in whom From the Gastroenterology Unit, IRCCS HCV RNA is not detectable after 4 weeks of therapy, 12 weeks of treatment is as effective San Giovanni Rotondo (A.M., R.S., F. Spiri- to, A.A.); the Department of Internal Med-icine, Hospital Canosa, Canosa (N.M.); the Department of Internal Medicine, Uni-versity La Sapienza, Rome (G.L.R.); the A total of 283 patients were randomly assigned to a standard 24-week regimen of Department of Internal Medicine, Hospi- peginterferon alfa-2b at a dose of 1.0 µg per kilogram weekly plus ribavirin at a dose of tal Venosa, Venosa (V.C.); the Department of Internal Medicine, Federico II Univer- 1000 mg or 1200 mg daily, on the basis of body weight. Of these, 70 patients were as- sity, Naples (M.P.); the Department of signed to the 24-week regimen (standard-duration group) and 213 patients to a variable Gastroenterology, Ospedali Riuniti, Foggia regimen (variable-duration group) of 12 or 24 weeks, depending on whether tests for (F.V.); the Department of Infectious Dis- ease, University of Foggia, Foggia (G.S.); HCV RNA were negative or positive at week 4. The primary end point was HCV that was the Department of Internal Medicine, Hos- not detectable by polymerase-chain-reaction (PCR) assay 24 weeks after the completion pital Casarano, Casarano (D.B.); the De- partment of Internal Medicine, HospitalPolicoro, Policoro (M.A.); the Departmentof Internal Medicine, Sant’Andrea Hospi- tal, Rome (M.R.); the Liver Unit, Sovrano In the standard-duration group, 45 (64 percent) patients had HCV that was not detect- Ordine di Malta, Rome (F.Z.); and the De- partment of Internal Medicine, Santissima able by PCR assay at week 4, as compared with 133 (62 percent) in the variable-duration Annunziata Hospital, Taranto (F. Sogari) group (difference [the rate in the standard-duration group minus that in the variable- — all in Italy. Address reprint requests to duration group], 2 percent; 95 percent confidence interval, ¡11 to 15 percent). Fifty- Dr. Mangia at the Gastroenterology Unit, three patients (76 percent) in the standard-duration group and 164 patients (77 percent) IRCCS, 71013 San Giovanni Rotondo, Italy, in the variable-duration group had a sustained virologic response (difference, ¡1 per- or at [email protected].
cent; 95 percent confidence interval, ¡13 to 10 percent). Fewer patients in the variable- duration group receiving the 12-week regimen had adverse events and withdrew than Copyright 2005 Massachusetts Medical Society. in the group receiving the 24-week regimen (P=0.045). The rate of relapse (defined asHCV not detectable at the end of treatment but detectable at the end of follow-up) was3.6 percent in the standard-duration group and 8.9 percent in the variable-durationgroup (P=0.16). Overall, the rate of sustained virologic response was 80 percent amongpatients with HCV genotype 2 and 66 percent among those with genotype 3 (P<0.001).
c o n c l u s i o n s
A shorter course of therapy over 12 weeks with peginterferon alfa-2b and ribavirin is aseffective as a 24-week course for patients with HCV genotype 2 or 3 who have a responseto treatment at 4 weeks.
Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine weeks. The primary measure of efficacy was a sus- titis C virus (HCV) genotype 2 or 3 infection, tained virologic response, defined as HCV RNA that itherapy with pegylated interferon and ribavirin was not detectable in the serum 24 weeks after administered for a period of 24 or 48 weeks ensures treatment was stopped. This open-label trial wasa sustained virologic response.1-3 Although these conducted in 12 centers in Italy as an investigator-schedules are effective, side effects increase with sponsored study without financial support fromthe length of treatment.4 Furthermore, there have industry. The study was approved by a central ethicsbeen isolated reports of patients who, with ther- committee and was conducted according to theapy withdrawn after only 8 to 12 weeks, have a re- guidelines of the International Conference on Har-sponse.5 Therefore, current recommendations may monization for Good Clinical Practice. Eligiblelead to overtreatment of some patients with chronic patients were 18 to 70 years of age; had antibodiesHCV infection.
to HCV, infection with genotype 2 or 3, and abnor- Experimental data substantiate these observa- mal alanine aminotransferase levels; and had not tions. On the initiation of interferon therapy, there received therapy. All patients provided written, in-is a rapid decline in viral load, reflecting the efficien- formed consent. Enrollment started in June 2002,cy of interferon-dependent inhibition of the produc- and the trial ended in January 2004. Exclusion cri-tion of the virus, its release, or both. This rapid de- teria included a leukocyte count lower than 3000cline is followed by a slower one that is dependent per cubic millimeter, a platelet count lower thanon the rate of death of infected cells and that is esti- 80,000 per cubic millimeter, a hemoglobin levelmated to vary from 1.7 days to more than 70 days.6 lower than 12 g per deciliter for women and lowerBoth the effectiveness of interferon in blocking pro- than 13 g per deciliter for men, infection with theduction of the virus in the first phase of decline human immunodeficiency virus, alcohol intakeand the rate of decline in the second phase differ in greater than 20 g daily, and the presence of drugpatients with HCV genotype 1 and in those with abuse, chronic disease, psychiatric disease, auto-genotype 2 or 3, with a decline eight times faster immune disease, or pregnancy and lactation.
in patients with genotypes other than 1.7,8 This Patients were randomly assigned in a 1:3 ratio difference suggests that patients with HCV geno- to receive peginterferon alfa-2b (PEG-Intron, Scher-type 2 or 3 infection need shorter courses of ther- ing) at a dose of 1.0 µg per kilogram of body weightapy than the regimens currently recommended.9,10 weekly plus oral ribavirin (Rebetol, Schering) at aChanges in viremia levels over the first weeks of dose of 1000 mg (for those with a weight of <75 kg)therapy correlate with the likelihood of the eradica- or 1200 mg (for those with a weight of ≥75 kg) daily,tion of HCV, and undetectable viral levels at week administered either for the standard period of 2412 are predictive of a response after 48 weeks of weeks (in the control standard-duration group of 70therapy.6,8,11 Moreover, the early viral response can patients) or for a variable duration (in the variable-vary in patients with HCV genotype 1 and those duration group of 213 patients), according to HCVwith genotypes other than 1, and this variation is an RNA status at week 4 (Fig. 1). In the variable-dura-independent predictor of sustained virologic re- tion group, 133 patients with an early responsesponse.12-15 (those in whom HCV RNA was not detectable at Data on viral kinetics have led to the hypothesis week 4) stopped therapy at week 12, whereas 80 that in patients with HCV genotype 2 or 3 in whom patients with detectable levels of virus at week 4 re-HCV RNA is not detectable after 4 weeks of ther- ceived therapy until week 24. The treatment of pa-apy, 12 weeks of treatment may be as effective as tients with detectable HCV RNA at week 4 wasthe recommended course of 24 weeks.
similar, whether they were in the standard-durationgroup or the variable-duration group. Participantswere assessed on an outpatient basis at weeks 4, 8, 12, and 24 during treatment and at week 24 after s t u d y d e s i g n
We conducted a randomized trial in patients with
HCV genotype 2 or 3 comparing the standard 24- virologic and histologic evaluation
week regimen with a variable-duration regimen. Pa- At each participating center, blood samples were
tients with a virologic response at 4 weeks received collected at weeks 4, 12, and 24 during treatment
treatment for 12 weeks and those without a viro- and at week 24 of follow-up, and hematologic and
logic response at 4 weeks received treatment for 24 virologic testing was performed within 10 days af-
Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved. s h o r t - t e r m t r e a t m e n t f o r h c v g e n o t y p e 2 o r 3 Figure 1. Progress of Patients through the Trial.
ter collection on samples stored at ¡20°C (¡4° F). safety analysis
Serum levels of HCV RNA were evaluated qualita- Adverse events were graded as mild, moderate, or
tively at each time point by polymerase-chain-reac- severe. When severe events other than anemia oc-
tion (PCR) assay (Amplicor HCV test, version 2.0, curred, the dose of peginterferon alfa-2b was de-
Roche Diagnostics) and quantitatively at baseline creased by 50 percent and the dose of ribavirin was
(Cobas Monitor test, version 2.0, Roche Diagnos- lowered to 800 mg daily; full doses were resumed
tics). HCV genotyping was performed with the when the event abated. If the event persisted, both
use of a hybridization technique (Innolipa HCV, drugs were discontinued. In the presence of ane-
Innogenetics). A total of 266 patients underwent mia, the dose of ribavirin was lowered to 800 mg
liver biopsy before therapy, and histologic evalua- per day if hemoglobin levels were lower than 9.5 g
tion was carried out according to the Scheuer clas- per deciliter, and ribavirin was discontinued if the
sification system.16 Steatosis was graded as mild concentrations fell below 8.0 mg per deciliter.
(<30 percent), moderate (30 to 60 percent), or se-
vere (>60 percent), according to the percentage of statistical analysis
hepatocytes with macrovesicular steatosis. Treat- The study was designed as a noninferiority trial
ment was started within one or two months after comparing the standard-duration and variable-
liver biopsy.
duration strategies. It was recognized that data on Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine the standard-duration group would provide little ues and odds ratios for the effect of prognostic fac-new information and that experience gained with tors and length of treatment on the response. At thethe new variable-treatment schedule would be ad- start of the analysis, all considered variables werevantageous. Therefore, for randomization a 3:1 ratio included in the model. A backward procedure waswas considered, with approximately 210 subjects then applied, and a maximum-likelihood methodto be assigned to the variable-duration group and was used for entering or removing terms (SPSS for70 to the standard-duration group. Randomization Windows, version 11.0). All reported P values arewas performed centrally, without stratification ac- two-sided and have not been adjusted for multiplecording to genotype and with the use of a permuted- testing.
block method, in which each block included 28 pa-tients, to ensure the 3:1 proportion of subjects in the two treatment groups. These sample sizes would
provide the study with 80 percent power to rule out Patients in the two treatment groups were well
a difference of at least 12.5 percent, assuming an matched for baseline characteristics (Table 1). The
80 percent rate of sustained virologic response in ratio of those with HCV genotype 2 or 3 was ap-
each group and with the use of a one-sided 95 per- proximately 3 to 1 in each group at the start of the
cent confidence interval. If a rate of response of 80 trial.
percent was observed in the two treatment groups,
a difference of at least 9.1 percent would be ruled response rates according to therapy
out. Given the very high response rates attained by and genotype
treatment of the standard duration and the consid- In the standard-duration group, 45 of 70 patients
erable advantage of a shorter treatment as offered (64 percent) had undetectable levels of HCV RNA
by the variable-duration regimen, a noninferiority at week 4, as compared with 133 of 213 patients
margin of 12.5 percent was considered to be accept- (62 percent) in the variable-duration group (dif-
able in this setting.
ference [the rate in the standard-duration group mi- Patients who dropped out of the trial were clas- nus that in the variable-duration group], 2 percent; sified as not having a virologic response. Patients 95 percent confidence interval, ¡11 to 15 percent).
with relapse were considered to be those with tests Twenty-four weeks after completing treatment, 53that were negative for HCV RNA at the end of ther- patients (76 percent) in the standard-duration groupapy but positive at the end of follow-up. No interim and 164 patients (77 percent) in the variable-dura-analyses were performed, and the analyses included tion group had a sustained virologic response (dif-all randomized subjects for whom there were out- ference, ¡1 percent; 95 percent confidence interval,come data. Differences in baseline characteristics ¡13 to 10 percent). Since our prespecified marginbetween the two groups were assessed with the use was 12 percent and the upper limit of the confidenceof the chi-square test with Yates’s correction for interval for the standard-duration group as com-discrete variables and the two-sided t-test with con- pared with the variable-duration group was 10 per-fidence intervals set at 95 percent. The primary cent, the criterion for noninferiority was satisfied.
comparison was between patients in the standard- In the standard-duration group (45 patients) and duration group treated for 24 weeks and those in in the variable-duration group treated for 12 weeksthe variable-duration group treated for either 12 or (133 patients), 41 patients (91 percent) and 113 pa-24 weeks. Patients assigned to the standard-dura- tients (85 percent), respectively, had a sustained vi-tion group were subdivided at the end of week 4 into rologic response, a difference of ¡6 percent (95 per-those in whom HCV RNA was not detectable (early cent confidence interval, ¡16 to 4 percent). Twelveresponse) and those with detectable levels of HCV of 25 patients (48 percent) in the standard-durationRNA (no early response).
group without an early response and 51 of 80 pa- A prediction model for sustained virologic re- tients (64 percent) in the variable-duration group sponse based on undetectable HCV RNA levels at treated for 24 weeks were HCV RNA-negative 24week 4 was developed that included HCV genotype, weeks after the completion of treatment, a differ-HCV RNA levels, body-mass index, alanine amino- ence of ¡16 percent (95 percent confidence inter-transferase values, and the presence or absence of val, ¡6 to 38 percent).
bridging fibrosis or cirrhosis. Stepwise logistic- Overall, 171 of 213 patients with HCV genotype 2 regression analysis was performed to compare P val- (80 percent) and 46 of 70 patients with HCV geno- Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved. s h o r t - t e r m t r e a t m e n t f o r h c v g e n o t y p e 2 o r 3 Table 1. Baseline Characteristics of the Patients.*
Standard-Duration Group
Variable-Duration Group
Characteristic
* Plus–minus values are means ±SD.
† The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡ The upper limit of normal for alanine aminotransferase was 40 U per liter.
§ Liver histology was unavailable for 17 patients, 2 in the standard-duration group and 15 in the variable-duration group.
type 3 (66 percent) had a sustained virologic re- the response rates were 87 percent in the variable-sponse, a difference of 14 percent (95 percent con- duration group treated for 12 weeks and 89 percentfidence interval, 2 to 27 percent; P<0.001). There in the standard-duration group (P=0.90); contin-was no significant difference in the numbers of pa- ued treatment in patients with viremia at week 4 re-tients with genotype 2 or 3 in whom HCV RNA was sulted in response rates of 50 percent among thoseundetectable by week 4: 137 patients with HCV in the standard-duration group without an earlygenotype 2 (64 percent) and 41 with genotype 3 (59 response and 72 percent in the variable-durationpercent) (P=0.47). Among patients with HCV geno- group treated for 24 weeks (P=0.13). In patientstype 2, the rate of sustained virologic response was with HCV genotype 3 and an early response, sus-76 percent in the standard-duration group and 82 tained virologic response rates were 77 percentpercent in the variable-duration group (Table 2). among those in the variable-duration group treat-Response rates among patients with HCV geno- ed for 12 weeks and 100 percent among those intype 2 with undetectable HCV on PCR assay at the the standard-duration group with an early responseend of follow-up were 89 percent in the standard- (P= 0.24), whereas among patients with viremiaduration group and 87 percent in the variable-dura- at week 4, the response rates were 43 percent amongtion group (difference, ¡1.3 percent; 95 percent those in the standard-duration group without anconfidence interval, ¡11 to 14 percent). When pa- early response and 41 percent among those intients with HCV genotype 2 and an early response the variable-duration group treated for 24 weekswere considered in relation to length of treatment, (P=0.68).
Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 2. Patients Who Were HCV RNA–Negative at the End of Treatment and Follow-up, According to HCV Genotype and Regimen.*
Patients and Point
Standard-Duration Regimen (24 Weeks)
Variable-Duration Regimen (12 or 24 Weeks)
duration group and 16 of 180 (8.9 percent) in the In the variable-duration group, adverse events (de- variable-duration group had detectable HCV RNApression and thyroid dysfunction) occurred in 8 pa- 24 weeks after the end of follow-up (P=0.16).
tients treated for 12 weeks (6 percent) and in 19 Among patients with relapse in 24 weeks of follow-treated for 24 weeks (13 percent) (P=0.056). In the up who were HCV-negative at the end of treatment,variable-duration group, fewer patients (one) treat- 1 of 42 was in the standard-duration group with aned for 12 weeks reported side effects that required early response (2 percent), 1 of 13 was in the stan-withdrawal from the study therapy than those treat- dard-duration group without an early responseed for 24 weeks (eight patients) (P=0.045) (Fig. 1). (8 percent), 13 of 126 were in the variable-durationHemoglobin levels were reduced to less than 9.5 g group treated for 12 weeks (10 percent), and 3 ofper deciliter in 6 patients (4 percent) in the variable- 54 were in the variable-duration group treated forduration group treated for 12 weeks and in 14 pa- 24 weeks (6 percent). The rate of relapse amongtients (9 percent) treated for 24 weeks (P=0.17). patients in the variable-duration group treated forAnemia (defined as a hemoglobin level of <12 g per 12 weeks was not different from that among pa-deciliter in women or <13 g per deciliter in men) and tients in the standard-duration group with an earlyneutrophil counts of less than 1000 per cubic milli- response (P=0.19). All patients with relapse in themeter required a reduction in the dose of the study variable-duration group who were treated for 12drug in 7 patients treated for 12 weeks (5 percent) weeks were offered retreatment with the same doseand 18 patients treated for 24 weeks (12 percent). of peginterferon alfa-2b and ribavirin for an addi- tional 24 weeks. Most of these patients (10 of 13) p r e d i c t o r s o f r a p i d r e s p o n s e
agreed to be retreated, and 9 had a sustained viro- In the univariate analyses, low levels of viremia were logic response. No baseline characteristic was as-significantly associated with an early response to sociated with relapse among the 133 patients intreatment (P=0.049), and high alanine aminotrans- the variable-duration group treated for 12 weeksferase levels approached significance (P=0.06) (Ta- who had an initial response; however, there was able 3). In the multivariate analysis, no factors re- trend toward a higher rate of relapse among pa-mained statistically significant (Table 3).
tients with alanine aminotransferase levels no morethan three times the upper limit of normal than r e l a p s e r a t e s
among those with levels more than three times Among patients who were HCV-negative at the end the upper limit of normal (14 percent vs. 2 percent,of treatment, 2 of 55 (3.6 percent) in the standard- P=0.06) (Table 4).
Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved. s h o r t - t e r m t r e a t m e n t f o r h c v g e n o t y p e 2 o r 3 Table 3. Factors Associated with Early Virologic Response at 4 Weeks.*
Patients with Early
Patients with
Response
Odds Ratio
* Patients with early response were in the standard-duration group and those in the variable-duration group treated for 12 weeks. Patients with viremia were in the standard-duration group and those in the variable-duration group treated for 24 weeks. CI denotes confidence interval.
† Of 178 patients, 165 had a liver biopsy.
‡ Of 105 patients, 101 had a liver biopsy.
an uncontrolled Norwegian study in which 85 of 95 patients (89 percent) with HCV genotype 2 or 3 had In patients with HCV genotype 2 or 3, a strategy of a response 14 weeks after peginterferon alfa-2b andvariable-duration treatment with peginterferon alfa- ribavirin therapy was initiated.17 That investigation2b and ribavirin (so that patients with a response at and our study differed in the weekly dose of peg-week 4 were treated for 12 weeks rather than 24 interferon alfa-2b: the Norwegian study adminis-weeks) achieved rates of sustained virologic re- tered 1.5 µg per kilogram of body weight, whereassponse similar to those achieved with the standard the current trial used 1.0 µg per kilogram. In anoth-treatment (24 weeks). Patients treated for 12 weeks er study, by Manns et al., the benefit of a high-dosewere spared the expense and inconvenience of ex- regimen was most apparent in patients with HCVtended treatment and still had a high response rate. genotype 1 infection, whereas those with genotypeThe shorter regimen was associated with fewer side 2 or 3 achieved similar response rates with high- andeffects and, consequently, less frequent withdraw- low-dose peginterferon alfa-2b regimens.2 How-als from therapy. Moreover, patients assigned to 12 ever, because modification of the dose of ribavirinweeks of treatment were less likely to require a re- in patients with anemia was less stringent in ourduction in the dose of peginterferon alfa-2b or of trial than in other trials,2,4,18 the overall dose ofribavirin. The proportion of patients with relapse ribavirin received by our patients may have beenwas higher among those treated for 12 weeks than higher than in previous trials. Furthermore, prelim-those treated for the standard 24 weeks. However, inary results have been presented from a random-90 percent of patients with a relapse after 12 weeks ized study comparing 16 weeks with 24 weeks ofof treatment had a response after an additional 24- combination therapy with peginterferon alfa-2aweek course of therapy. Therefore, even taking into plus ribavirin in patients infected with HCV geno-consideration the rate of relapse, treatment for 12 type 2 or 3, in which combination therapy for 16weeks rather than 24 weeks appears to be appro- or 24 weeks achieved similar rates of sustained vi-priate for patients with an early response.
rologic response among patients with an early re- These results are consistent with the results of sponse at week 4.19 Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine evaluation of HCV RNA has been used as a criteri- Table 4. Association between Baseline Characteristics and Rate of Relapse
on for stopping therapy in patients with HCV geno- among 133 Patients in the Variable-Duration Group with Early Response
type 1 without early virologic response, but this cri- Assigned to 12 Weeks of Treatment.
terion has not been used to tailor the length of therapy. It has recently been reported that antiviral Characteristic
Patients
Relapse (%)
therapy is more beneficial in patients with HCV genotype 2 than those with genotype 3,18 and data from our trial support these findings. Overall, re- sponse rates were 80 percent and 66 percent, re- spectively, in patients with these two genotypes (P<0.001). However, our findings suggest that stop- ping therapy after 12 weeks in patients with a re-sponse at 4 weeks is appropriate for patients with either genotype, because the rates of sustained virologic response were similar in patients with ge- notype 2 or 3 who had an early response and who were treated for 12 or 24 weeks. In keeping with a preliminary report from the DITTO study,13 after early viral clearance has been obtained, the role of genotype appears to be relatively small. From the current trial, it is evident that prolonging treatment in patients with detectable HCV RNA at week 4 of therapy achieved higher rates of response in those with genotype 2 than those with genotype 3; among patients who did not have an early response andwere treated for 24 weeks, the rate of sustained vi- rologic response was higher among those with HCV genotype 2 than among those with genotype 3.
In conclusion, our findings suggest that patients with HCV genotype 2 or 3 infection who have unde- tectable HCV RNA after 4 weeks of treatment with peginterferon alfa-2b and ribavirin achieve high re- sponse rates with 12 weeks of therapy and do notrequire 24 weeks of treatment. Tailoring treatment * One patient declined to undergo the biopsy.
so that those with an early response are given ashorter course may make therapy more appealing No quantitative estimation of HCV viremia was to patients, without adversely affecting outcomes.
planned in the current study, because we defined an Dr. Andriulli reports having served as a speaker for and received early virologic response as a negative test for HCV institutional research grants from the Italian branch of Schering-RNA after 4 weeks of treatment. So far, quantitative Plough.
r e f e r e n c e s
Hepatitis C viral dynamics in vivo and the al. Peginterferon alfa-2a plus ribavirin for antiviral efficacy of interferon-alpha therapy.
chronic hepatitis C virus infection. N Engl J Zeuzem S, Herrmann E, Lee J-H, et al.
Viral kinetics in patients with chronic hepa- SC, et al. Peginterferon alfa-2b plus ribavirin infected patients with chronic hepatitis C.
titis C treated with standard or peginter- compared with interferon alfa-2b plus riba- feron alpha2a. Gastroenterology 2001;120: virin for initial treatment of chronic hepati- tis C: a randomised trial. Lancet 2001;358: Neumann AU, Lam NP, Dahari H, et al.
Sustained virological response after a short Differences in viral dynamics between geno- course of treatment with interferon and ri- types 1 and 2 of hepatitis C virus. J Infect Dis et al. Peginterferon-alpha2a and ribavirin bavirin in two chronic hepatitis C patients.
combination therapy in chronic hepatitis C: Neumann AU, Lam NP, Dahari H, et al.
Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved. s h o r t - t e r m t r e a t m e n t f o r h c v g e n o t y p e 2 o r 3 agement of hepatitis C 2002 — June 10–12, DITTO-HCV early viral kinetics report — nov- Treatment with pegylated interferon and ri- 2002. Hepatology 2002;36:Suppl 1:S3-S20.
el decline patterns in gen 1 but not gen 2-3 bavirin in HCV infection with genotype 2 or 10. Italian Association for the Study of the
patients treated with Peg-IFN-alfa-2a and ri- 3 for 14 weeks: a pilot study. Hepatology Liver. Guidelines: online final statement.
bavirin. J Hepatol 2002;36:Suppl 1:121.
(Accessed May 31, 2005, at http://www.
14. Cheng DM, Lagakos SW. The one-
18. Zeuzem S, Hultcrantz R, Bourliere M, et
al. Peginterferon alfa-2b plus ribavirin for 11. Zeuzem S, Lee JH, Franke A, et al. Quan-
of chronic viral infection. Biometrics 2000; treatment of chronic hepatitis C in previously tification of the initial decline of serum hep- untreated patients infected with HCV geno- atitis C virus RNA and response to interfer- 15. Zeuzem S, Pawlotsky JM, Hagai E, et al.
types 2 or 3. J Hepatol 2004;40:993-9. [Erra- on alfa. Hepatology 1998;27:1149-56.
International, multicenter, randomized, con- 12. Neumann AV, Zeuzem S, Brunda MJ,
19. von Wagner M, Huber M, Berg T, et al.
Hoffman JH. Rapid viral response to treat- dynamically individualized treatment in pa- ment with pegylated (40KD) interferon alfa- tients with chronic hepatitis C (DITTO-HCV 2a (Pegasys) is strongly predictive of a sus- project). Hepatology 2003;38:310A. abstract.
with peginterferon alfa-2a plus ribavirin in tained virologic response in patients with 16. Scheuer PJ. Classification of chronic
patients chronically infected with HCV ge- chronic hepatitis C (CHC). Hepatology 2000; viral hepatitis: a need for reassessment.
13. Neumann AV, Zeuzem S, Ferrari C, et al.
17. Dalgard O, Bjoro K, Hellum KB, et al.
Copyright 2005 Massachusetts Medical Society. clinical trial registration
The Journal encourages investigators to register their clinical trials in a public trials registry. The members of the International Committee of Medical Journal Editors plan to consider clinical trials for publication only if they have been registered (see N Engl J Med 2004;351:1250-1). The National Library of Medicine’s www.clinicaltrials.gov is a free registry, open to all investigators, that meets Downloaded from www.nejm.org at UNIVERSITY OF BRITISH COLUMBIA on June 28, 2005 . Copyright 2005 Massachusetts Medical Society. All rights reserved.

Source: http://cmdr.ubc.ca/trainingprogram/papers/jp_July%2015a_05.pdf