hepatitis c virus (hcv) rna determination after two weeks of induction interferon treatment is an...

Hepatitis C Virus (HCV) RNADetermination After Two Weeks of

Induction Interferon Treatment Is anAccurate Predictor of Nonresponse

Comparison of Two Treatment Schedules

ANGELO ROSSINI, MD,* MARCO ARTINI, MD,† MASSIMO LEVRERO, MD,†‡CRISTIANA ALMERIGHI, MD,† MARCO MASSARI, MD,§ LUCIANO BIASI, MD,*

ENRICO RADAELI, MD,* and ELISABETTA CARIANI, MD¶

The aim of this study was to analyze of HCV kinetics during interferon treatment administereddaily or three times weekly. Seventy-seven naive patients were randomized to two treatmentcourses starting with four weeks of high-dose interferon administered daily or three times weekly.Twenty-two patients (28.6%) achieved end-of-treatment response and nine (11.7%, four of whomreceived daily induction) sustained response. The initial decline of viral load was sharper inpatients receiving daily induction, but the rates of early RNA clearance were independent oftreatment schedule, being higher in patients with genotype non-1. Detectable HCV RNA duringtreatment predicted nonresponse more significantly than high pretreatment viral load or genotype1. HCV RNA at week 2 was the best predictor (100% sensitivity in patients receiving dailyinduction). In conclusion, daily induction increased the HCV decline slope, but not the rate ofvirological response. HCV RNA at week 2 reliably identified nonresponders.

KEY WORDS: viral kinetics; interferon; induction therapy; predictive factors; HCV genotypes; HCV viral load.

Interferon (IFN) treatment can eradicate hepatitis Cvirus (HCV) infection in a low percentage of patients(1). The low rate of success, the potential side effects,and the cost of treatment have led to the identifica-tion of viral and host factors able to predict theoutcome of therapy. HCV genotype and pretreatment

viral load have been indicated as the main indepen-dent predictors of response to IFN (2, 3). However,pretreatment parameters alone or in combination donot allow accurate prediction of treatment outcomein individual patients (3).

Kinetic analysis of HCV turnover rate revealed aviral half-life of a few hours (4, 5), suggesting thatdaily administration could improve the antiviral effi-cacy of IFN. The early dynamics of viral declineduring IFN treatment consists of a rapid phase re-lated to the clearance of free virions, followed by aslower phase, an expression of the infected cells deathrate (4–8). Since the latter phase appears to be linkedto the final response to IFN (4, 5, 8), early HCV RNAdetermination during IFN administration could be

Manuscript received October 9, 2000; accepted February 22,2001

From the *Hepatology Unit, III Department of Internal Medi-cine, A. O. Spedali Civili, Brescia; †Fondazione A. Cesalpino,University La Sapienza, Roma; ‡Department of Internal Medicine,University of Cagliari; §Department of Infectious Diseases, Hos-pital S. Maria Nuova, Reggio Emilia; and ¶III Laboratory, A. O.Spedali Civili, Brescia, Italy.

Address for reprint requests: Dr. Angelo Rossini, MD, Hepatol-ogy Unit, III Department of Internal Medicine, A. O. SpedaliCivili, P.le Spedali Civili, 1, 25123 Brescia, Italy.

Digestive Diseases and Sciences, Vol. 46, No. 11 (November 2001), pp. 2389–2395 (© 2001)

2389Digestive Diseases and Sciences, Vol. 46, No. 11 (November 2001)0163-2116/01/1100-2389$19.50/0 © 2001 Plenum Publishing Corporation

useful in predicting the outcome of treatment. In thisstudy we analyzed the early viral kinetics in patientsrandomized to two different IFN regimens, startingwith high-dose IFN administered daily or three timesa week. Serum HCV RNA was monitored duringtreatment by a standardized commercial assay, andviral dynamics was compared to pretreatment virolog-ical parameters as a predictor of the outcome oftherapy.

MATERIALS AND METHODS

Patients. Seventy-seven consecutive previously untreatedpatients with chronic hepatitis C were enrolled betweenJanuary and June 1998 in three hepatology units in Italy.Inclusion criteria were: age �65 years, histological diagno-sis of chronic hepatitis, presence of anti-HCV antibodiesand HCV RNA in serum, and platelet count �100,000/mm3. Patients with a histological diagnosis of liver cirrhosis;heart, kidney, or autoimmune diseases; psychiatric illnesses;infection with hepatitis B virus (HBV), hepatitis delta virus(HDV), or human immunodeficiency virus (HIV); whiteblood cell (WBC) count �4,000/mm3; prothrombin time�60%, chronic alcohol abuse; or active intravenous druguse (IVDU) were excluded. Treatment suspension wasforeseen when platelet counts fell below 50,000/mm3 orneutrophils below 900/mm3, or in the case of liver failure,appearance of non-organ-specific autoantibodies (titer�1:160), or thyroid abnormalities, psychiatric disturbances,IFN intolerance, or breakthrough.

Study Design. Patients were randomly assigned to receiveinduction treatment with IFN-�2a 6 million units (MU)daily, six days a week for four weeks (schedule A), or 6 MUIFN three times a week for four weeks (schedule B). Bothtreatment groups continued therapy with 6 MU IFN threetimes a week for an additional 12 weeks. Patients withnormal alanine aminotransferase (ALT) levels at week 16received 3 MU IFN three times a week for a further 32weeks. HCV genotype was determined before entering thestudy and randomization to schedule A or B was carried outindependently for patients with genotype 1 or genotypenon-1. Informed consent was obtained from each patientincluded in the study. The study protocol conforms to theethical guidelines of the 1975 Declaration of Helsinki asreflected in a priori approval by the human research com-mittees of the participating institutions.

HCV RNA load was determined on baseline samples.ALT activity and HCV RNA were determined after one,two, and four weeks of treatment: then ALT levels weremonitored every four weeks and HCV RNA at weeks 16,24, 36, and at the end of treatment. After treatment sus-pension, ALT levels were monitored every four weeks andHCV RNA was determined 24 weeks after discontinuation.Quantitative HCV RNA determination was performed onsamples positive for HCV RNA at weeks 1 and 2.

Definition of Response. End-of-treatment response(ETR) was defined as undetectable HCV RNA and normalALT levels at the end of treatment. Sustained response(SR) was defined as undetectable HCV RNA and normalALT levels 24 weeks after treatment suspension. Presence

of ALT values within the normal range despite persistenceof HCV RNA at the end of treatment or 24 weeks aftertreatment suspension was defined as biochemical ETR orSR, respectively.

Liver Histology. All subjects gave their informed consentto liver biopsy. Histological examination was carried out byone pathologist according to conventional criteria. Histo-logical scores were determined according to the Knodellhistological activity index (HAI) scoring system.

Serological Tests. HBV markers were tested by commer-cially available kits (Abbott Laboratories, North Chicago,Illinois, USA) Anti-HCV antibodies were assayed in dupli-cate by two ELISA assays (Ortho Diagnostic Systems, Rari-tan, New Jersey, USA, and Abbott Laboratories).

HCV RNA Analysis. Samples for HCV RNA determina-tion were processed within 2 hr and stored at �80°C untilused. Qualitative analysis of HCV RNA was performed bythe Amplicor HCV RNA kit, version 2.0 (Roche Diagnos-tics, Basel, Switzerland) with a sensitivity of 102 copies/ml.Quantitative analysis was carried out by the Amplicor HCVMonitor kit (Roche Diagnostics). HCV genotype was de-termined by the line probe assay (Inno LiPA HCV II,Innogenetics, Ghent, Belgium).

Statistical Analysis. The characteristics of patients werecompared by parametric or nonparametric tests, as appro-priate using the EPI.INFO 5.0 statistical package (Centersfor Disease Control, Atlanta, Georgia, USA). P � 0.05 wasconsidered as statistically significant. Receiver operatingcharacteristic (ROC) curve analysis was carried out by usingthe MedCalc statistical software version 5.00.019.

RESULTS

Baseline patient characteristics were similar in treat-ment groups A (daily induction) and B (Table 1). Dailyinduction caused a significant reduction in WBC countscompared to the schedule of three times a week startingfrom the first week of treatment, whereas plateletcounts were significantly different between the twogroups only at week 4 (Table 2). However, at week 16both WBC and platelet counts were similar in the twogroups (data not shown). None of the patients requireddose reduction because of altered WBC or plateletcounts. One patient in group B suspended treatment forthe appearance of autoimmune thyroiditis after eightweeks of treatment.

Normalization of ALT levels after 16 weeks of treat-ment was achieved by 48 patients (62.3%), 24 in groupA and 24 in group B (Table 3). HCV RNA clearancewas observed in 38 of them (22 in group A and 16 ingroup B). Among patients with elevated ALT at week16, 7 (5 of whom were treated with daily inductionduring the first month) had shown transient normaliza-tion of enzyme values. During the last 32 weeks oftreatment, 6 patients in group A (5 of whom wereformer virological responders) and in 10 patients ingroup B (7 of whom were former virological respond-

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2390 Digestive Diseases and Sciences, Vol. 46, No. 11 (November 2001)

ers) stopped treatment for increase in ALT levels. HCVRNA reappeared in all 12 former virological respondersthat showed an increase in ALT levels. Three patients (1in group A and 2 in group B) dropped out of treatment.At the end of treatment, 22 patients had achieved bio-chemical and virological response, whereas 7 were bio-chemical responders with persistent HCV viremia. Asustained response was observed in 9 patients, 4 ingroup A and 5 in group B. Four additional patientsmaintained biochemical response 24 weeks after stop-ping treatment (Table 3).

The kinetics of early virological response in the twotreatment groups is shown in Figure 1. In group A22.5% of patients had undetectable HCV RNA at week1, and in group B 16.2%; at week 2, the figures were30% in group A and 27% in group B; at week 4, 42.5%in group A and 35.1% in group B; at week 16, 45% ingroup A and 54% in group B (P � NS at all time

points). Late virological response (undetectable HCVRNA after 16 weeks of treatment) was significantlyassociated with breakthrough (P � 0.005); this wasobserved in 3 of 4 late responders in group A and 5 of8 in group B. The number of patients with undetectableHCV RNA was higher in genotype non-1 at week 1(P � 0.005), week 2 (P � 0.05), and week 4 (P � 0.001)independent of the treatment group. Both IFN sched-ules led to a lack of HCV RNA detection in most ofpatients with genotype non-1 from week 4, whereas inpatients with genotype 1 the rate of viral clearanceincreased progressively until week 16.

A significant decrease in ALT levels was detectedduring the first week in both treatment groups (groupA: P � 0.005; group B: P � 0.001) and during thesecond week in group A (P � 0.05). However, nodifference was observed between the two groups (Fig-ure 2, left). HCV RNA titer detected in patients that

TABLE 1. BASELINE CHARACTERISTICS OF PATIENTS

Group A(N � 40)

Group B(N � 37)

Total(N � 77)

Age (years mean � SD) 48 � 12 45 � 13 47 � 12Sex (M/F) 23/17 23/14 46/31Risk factor (N)

Transfusion 5* 3 8*IV drug use 6* 8 14*Unknown 30 26 56

Activity score (N)1–5 25 22 476–11 15 15 30

Fibrosis score (N)0–1 29 28 573 11 9 20

ALT (IU/liter, mean � SD)† 120.8 � 55.5 111.9 � 50.5 117.3 � 52.9HCV RNA (log copies/ml)

Mean � SD 5.64 � 0.76 5.64 � 0.49 5.64 � 0.64Median (range) 5.83 (3.1–6.33) 5.8 (4.15–6.27) 5.8 (3.1–6.33)

HCV genotype (N)1a 3 7 101b 18 14 321a�b 1 0 12a/c 12 10 223 4 5 94 2 1 3

*One patient had both risk factors.†Normal ALT level: �50 IU/liter.

TABLE 2. WHITE BLOOD CELLS (WBC) AND PLATELET (PLT) COUNTS DURING TREATMENT

Counts (�103/mm3, mean � SD)

Basal Week 1 Week 2 Week 4

WBC Plt WBC Plt WBC Plt WBC Plt

Group A 5.84 � 1.49 185.77 � 54.54 4.4 � 1.3* 133.59 � 49.74 4.12 � 1.35* 167.59 � 176.49 3.681 � 0.95* 119.82 � 44.18*Group B 6.58 � 2.01 202.29 � 53.29 6.02 � 1.68* 160.78 � 46.46 5.83 � 1.26* 148.75 � 39.55 5.04 � 1.76* 155.5 � 47.03*

*Significantly different between the two treatment groups (P � 0.001)

PREDICTIVE VALUE OF EARLY HCV KINETICS

2391Digestive Diseases and Sciences, Vol. 46, No. 11 (November 2001)

remained positive during the first two weeks of treat-ment decreased significantly from baseline duringweek 1, the decline being sharper in group A than ingroup B (week 1: P � 0.01; week 2: P � 0.01)(Figure 2, right).

Virological predictive factors for sustained responsewere compared between the two groups (Table 4). Ingroup A pretreatment parameters (viral load and geno-

type) were not statistically related to treatment out-come, whereas lack of HCV RNA detection duringtreatment was significantly predictive of SR startingfrom the second week of treatment. All sustained re-sponders had already achieved RNA clearance at thistime, reaching the highest level of statistical significance.In group B pretreatment viral load, but not genotype,was statistically related to SR. Undetectable HCV RNA

Fig 1. Time course of HCV RNA clearance according to treatment schedule and to genotype.

TABLE 3. OUTCOME OF TREATMENT SCHEDULES A AND B

Group A [N (%)] Group B [N (%)]

Patients randomized 40 (100) 37 (100)Week 16

Normal ALT levels 24 (60) 24 (64.9)Increased ALT levels 16* (40) 12* (32.4)Discontinuation for side effects 0 1 (2.7)

Weeks 20–44Discontinuation for breakthrough 6† (15) 10† (27)Noncompliance 1 (2.5) 2 (5.4)

Week 48 (end of treatment)Responders 12 (30) 10 (27)Biochemical responders 5 (12.5) 2 (5.4)

Week 72 (sustained)Responders 4 (10) 5 (13.5)Biochemical responders 3 (7.5) 1 (2.7)

*Transient normalization of ALT levels in 7 patients (5 in group A; 2 in group B), 2of whom (1 in each group) had transient clearance of HCV RNA

†Transient clearance of HCV RNA in 12 patients (5 in group A; 7 in group B).

ROSSINI ET AL


during treatment was associated with SR at all timepoints, with similar levels of statistical significance. Onlyone of eight late virological responders in group Bachieved SR. When both treatment groups were con-sidered together, all virological parameters (includinggenotype) were statistically related to SR. UndetectableHCV RNA from week 2 of treatment onwards showedthe highest level of significance.

To determine the best predictor of SR, the virolog-ical parameters that were statistically related to SR inat least one treatment group were compared in termsof sensitivity, specificity, positive predictive value(predictive value of response), negative predictive

value (predictive value of nonresponse), accuracy,and area under ROC curve (Table 5). For pretreat-ment viral load, median level of both groups (5.8 logcopies/ml) was considered as cutoff value. Accordingto ROC curve analysis, HCV RNA clearance at week2 was the best predictor of SR in both groups. At thistime sensitivity and negative predictive value reached100% in group A. The overall specificity and positivepredictive value were poor for all parameters ana-lyzed. This is in contrast to the high specificity of earlyHCV RNA clearance in predicting ETR (over 90%for HCV RNA negative at week 1 in both groups)(data not shown).

Fig 2. Decline of ALT levels (left) and of viral load determined in patients remaining positive for HCV RNAduring the first two weeks of treatment (right).

TABLE 4. RELATIONSHIP BETWEEN VIROLOGICAL PARAMETERS AND SUSTAINED RESPONSE

SR NR P

Group A (N) 4 36HCV RNA titer (log copies/ml, mean � SD) 4.68 � 1.29 5.75 � 0.62 NSHCV genotype 1/non-1 (N) 1/3 21/15 NSHCV RNA negative (N/total) at

Week 1 2/4 7/36 NSWeek 2 4/4 8/36 0.005Week 4 4/4 13/36 �0.05Week 16 4/4 13/36 �0.05

Group B (N) 5 32HCV RNA titer (log copies/ml, mean � SD) 4.98 � 0.78 5.74 � 0.35 �0.05HCV genotype 1/non-1 (N) 1/4 20/12 NSHCV RNA negative (N/total) at

Week 1 3/5 3/32 �0.05Week 2 4/5 6/32 �0.05Week 4 4/5 6/32 �0.05Week 16 5/5 15/32 �0.05

Total (N) 9 68HCV RNA titer (log copies/ml, mean � SD) 4.85 � 0.97 5.74 � 0.51 �0.005HCV genotype 1/non-1 (N) 2/7 41/27 �0.05HCV RNA negative (N/total) at

Week 1 5/9 10/68 �0.05Week 2 8/9 14/68 �0.001Week 4 8/9 19/68 �0.001Week 16 9/9 28/68 �0.001



DISCUSSION

Recent data on viral kinetics (4–8) have suggestedthat high-dose induction IFN regimens might be ef-fective for viral clearance in chronic HCV infectionand that early viral kinetics can be useful to predictresponse to treatment. Several studies have indicatedthat the initial decline in HCV viremia is a betterpredictive factor of sustained response than pretreat-ment parameters (9–12). However, the treatmentschedule and the sensitivity of the test used for HCVRNA determination might influence the optimal timeto perform viral detection.

In this study we compared the time dependence ofearly HCV RNA clearance during the daily inductionregimen and high-dose administration three times aweek using a standardized commercial HCV RNA as-say. The timing of HCV RNA determinations was cho-sen on the basis of viral kinetics under IFN therapy,characterized by a first phase of rapid, dose-dependentviral decline lasting about two days followed by a slowerdose-independent decline, related to the final responseto treatment (4, 5, 8). Thus, as early as a few weeks afterstarting treatment, a reliable prediction of treatmentoutcome can be expected.

Our results showed that the two treatment sched-ules were well tolerated despite a transient decreasein WBC and platelet counts during daily IFN admin-istration. The decrease in ALT levels was statisticallysignificant during the first two weeks in daily induc-tion schedule and only during the first week duringIFN administration three times a week. However,normal ALT levels at week 16 were detected in asimilar percentage of patients in the two groups.

The decline of viral load during the first two weeksof treatment was significantly sharper in patients re-ceiving daily administration, even if the number ofHCV RNA-negative patients at week 4 was similar inthe two treatment groups. This may suggest that dailyIFN for longer than four weeks could lead to viralclearance at later time points. However, the signifi-cant progressive decline in WBC and platelet countsdetermined by daily IFN suggests the need for closefollow-up and/or reduction of IFN dose in daily treat-ment longer than four weeks. The rate of early HCVRNA clearance was significantly different betweenpatients with genotype 1 or non-1. With both treat-ment schedules, most patients with genotype non-1had undetectable HCV RNA by week 4, whereas thevirological response rate of genotype 1 had a furtherincrease until week 16. However, it is interesting tonote that, in all cases except one, late virologicalresponse did not lead to sustained viral clearance.

The analysis of predictive factors for SR indicatedthat HCV RNA determination at week 2 can reliablydiscriminate nonresponders, confirming the high pre-dictive value of early viral clearance on treatmentoutcome (reviewed in ref. 13). The significance levelof HCV RNA at week 2 was higher in the dailyinduction schedule, with 100% prediction of nonre-sponse. The predictive value for sustained response totreatment was low in both treatment groups, althoughthe specificity of undetectable HCV RNA at week 1in predicting end-of-treatment response was higherthan 90% (data not shown). This observation indi-cates that very early clearance of HCV RNA does notexclude the occurrence of relapse off treatment.

TABLE 5. COMPARISON OF SENSITIVITY, SPECIFICITY, POSITIVE PREDICTIVE VALUE (PREDICTIVE VALUE OFRESPONSE), NEGATIVE PREDICTIVE VALUE (PREDICTIVE VALUE OF NONRESPONSE), ACCURACY, AND

AREA UNDER ROC CURVE OF PRETREATMENT VIRAL LOAD AND OF HCV RNA CLEARANCEDURING TREATMENT AS PREDICTORS OF SUSTAINED RESPONSE

Pretreatment HCV RNA load�5.8 log copies/ml

HCV RNA negative at

Week 1 Week 2 Week 4 Week 16

Group ASensitivity (%) 75 50 100 100 100Specificity (%) 61.1 83 77.8 64 61Positive predictive value (%) 17.6 22 33.3 24 25Negative predictive value (%) 95.7 93.5 100 100 100Accuracy (%) 62.5 77.5 80 68 55Area under ROC 0.681 0.667 0.889 0.819 0.806

Group BSensitivity (%) 80 60 80 80 100Specificity (%) 56.2 90.6 81 72 53Positive predictive value (%) 22.2 50 40 40 25Negative predictive value (%) 94.7 94 96 96 100Accuracy (%) 59.4 86 81 81 59Area under ROC 0.681 0.753 0.806 0.759 0.766

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The results of this study show that the early assess-ment of HCV RNA during IFN administration mayrepresent an useful and cost-effective parameter tomonitor therapy and to predict its final outcome. Thequantification of HCV RNA decline during the firstmonth of treatment has been identified as a strongpredictor of virological SR to standard IFN schedule(3 MU three times a week) (11). However the use ofquantitative assays in a clinical setting is hampered bytheir variable sensitivity and linearity. QualitativeHCV RNA determination is cheaper than the quan-tification of viral load and allows easier classificationof patients for clinical use, without the need to set upa quantitative threshold. Most previous studies withdifferent therapeutic schemes indicated that HCVRNA persistence at week 4 was the most accuratepredictor of nonresponse (13). We observed the high-est predictive value at week 2, possibly for the morerapid decline of viral load induced by daily adminis-tration or high-dose IFN three times a week.

Whether these findings may be extended to combi-nation therapy with IFN and ribavirin is still unclear.Ribavirin did not show an early synergistic antiviraleffect with IFN treatment three times a week (6).Early clearance of viremia during combination ther-apy was associated with sustained response in patientswho relapsed after IFN therapy (14) and in nonre-sponders to IFN (12). However, about 10% of naivepatients with sustained response to combination ther-apy are still positive for HCV RNA at week 12 (15),suggesting the possibility of a late antiviral effect ofribavirin. Consistent with our results, a recent pilotstudy of combination therapy in nonresponders tointerferon monotherapy showed a greater reductionof viral load in patients receiving daily interferoncompared to administration three times a week (16).However, no sustained response was achieved in anyof the two combination schedules.

Combination therapy with IFN and ribavirin signif-icantly increases the sustained response rate in pa-tients with chronic hepatitis C (14, 15), but it is costlyand more prone to side effects than IFN alone. Inview of this, the possibility of an accurate predictionof treatment outcome as early as two weeks afterstarting IFN administration may provide a cost-effective way to select patients that require alternativetreatment strategies.

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