Efficacy of peginterferon-α-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C

CL IN ICAL STUDIES

E⁄cacyofpeginterferon-a-2bplusribavirin in patientsaged65yearsandolder with chronic hepatitis CTakashi Honda1, Yoshiaki Katano1, Junichi Shimizu1, Yoji Ishizu1, Masao Doizaki1, Kazuhiko Hayashi1, MasatoshiIshigami1, Akihiro Itoh1, Yoshiki Hirooka1, Isao Nakano1, Fumihiro Urano2, Kentaro Yoshioka3, Hidenori Toyoda4,Takashi Kumada4 and Hidemi Goto1

1 Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan

2 Department of Gastroenterology, Toyohashi Municipal Hospital, Toyohashi, Japan

3 Division of Liver and Biliary Diseases, Department of Internal Medicine, Fujita Health University, Toyoake, Japan

4 Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan

Keywords

elderly patient – hepatitis C virus –

peginterferon – ribavirin – sustained

virological response

Correspondence

Yoshiaki Katano, Department of

Gastroenterology, Nagoya University Graduate

School of Medicine, 65 Tsuruma-cho, Showa-

ku, Nagoya 466-8550, Japan

Tel: 181 52 744 2169

Fax: 181 52 744 2178

e-mail: [email protected]

Received 22 October 2008

Accepted 13 May 2009

DOI:10.1111/j.1478-3231.2009.02064.x

AbstractObjectives: The aim of this study was to evaluate the efficacy and indication ofcombination therapy with ribavirin plus peginterferon-a-2b in chronichepatitis C virus (HCV) patients aged 65 years and older. Methods: Fivehundred and ninety-one consecutive HCV patients were treated with combi-nation therapy. These patients were divided into elder patients (Z65 years)(n = 115) and younger patients (o 65 years) (n = 476). The clinical character-istics, sustained virological response (SVR) rates and discontinuation rateswere compared between the two groups. Results: Compared with youngerpatients, baseline haemoglobin levels and baseline platelet counts weresignificantly lower (Po 0.0001, P = 0.013 respectively) and fibrosis was moreadvanced in elderly patients (P = 0.0310). Moreover, the SVR rate wassignificantly lower (37.4 vs. 51.5%; P = 0.0067) while the combination therapydiscontinuation rate was significantly higher (32.2 vs. 17.0%; P = 0.0003) inelderly patients. A multivariate analysis revealed that HCV load and genotypewere significantly associated with an SVR in elderly patients. An SVR wasachieved in over 50% of elderly male patients with genotype 1 and HCV RNAconcentrations under 2 000 000 IU/ml. In contrast, the SVR rate was under30% in elderly male patients with genotype 1 and with HCV RNA concentra-tions over 2 000 000 IU/ml and in all elderly female patients with genotype 1.Conclusions: The SVR rate was lower in elderly patients than in youngerpatients. However, in elderly patients combination therapy was most bene-ficial for genotype 1 patients, male patients with HCV RNA concentrationso 2 000 000 IU/ml and patients with genotype 2.

Hepatitis C virus (HCV) infection is a widespread viralinfection that often leads to chronic hepatitis, cirrhosisand hepatocellular carcinoma (HCC). The need forchronic HCV therapies for elderly patients is increasingin Japan and is expected to rise in the US and otherWestern countries (1). Moreover, HCC has become arecent and growing problem in elderly patients withchronic hepatitis C.

Sustained virological responders who are negative forserum HCV RNA 6 months after interferon (IFN)treatment are reported to be likely to remain in virologi-cal and biochemical remission with histological improve-ment (2, 3). Moreover, IFN therapy reduces the risk ofHCC among virological or biochemical responders(4–6). Ribavirin is now generally used in combinationwith IFN to treat chronic hepatitis C, and this combina-

tion therapy is reportedly more effective than IFNmonotherapy, with a higher rate of HCV eradication(7–10).

It is important to determine whether elderly hepatitisC patients should be treated with IFN. Arase et al. (11)reported that HCV clearance after IFN therapy signifi-cantly reduced the risk of HCC and death in olderhepatitis C patients. In addition, Veldt et al. (12) reportedthat a sustained virological response (SVR) to treatmentis associated with improved clinical outcomes in thegeneral population with chronic hepatitis C and ad-vanced fibrosis.

Several studies have shown that IFN monotherapy hascomparable efficacy in elderly and younger patients withchronic hepatitis C (13, 14). IFN and ribavirin combina-tion therapy has greater efficacy than IFN monotherapy

Liver International (2009)c� 2009 John Wiley & Sons A/S 527

Liver International ISSN 1478-3223

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(7, 9). However, elderly patients with genotype 1 andhigh HCV loads have a lower SVR rate than youngerpatients because of higher dose reduction rates anddiscontinuation rates because of ribavirin-related anae-mia (15, 16). In a previous study, we examined patientswith a similar background, except for age, and found thattreating chronic hepatitis C with combination therapywas comparably effective between patients Z60 years oldand those o 60 years old, although the ribavirin dis-continuation rate was higher among older patients (17).Similar results were obtained from chronic hepatitispatients treated with peginterferon and ribavirin;although the probability of a positive response to pegin-terferon-a plus ribavirin combination therapy was de-creased for genotype 1- or 4-infected patients older than40 years, patients older than 65 years had a response ratesimilar to those aged 40–64 years (18). There are fewreports on the efficacy of ribavirin and peginterferon inthe elderly patients with chronic hepatitis C. Moreover,no study has determined which patients will benefit fromcombination therapy among elderly patients withchronic hepatitis C. This study was designed to examinethe background and treatment efficacy of peginterferonand ribavirin combination therapy according to genderin older patients with chronic hepatitis C and to identifywhich patients will achieve an SVR in this patientpopulation.

Methods

Patients

This nonrandomized, prospective study was originallydiscussed in December 2004 by a committee composedof members from Nagoya University Hospital and 63affiliated hospitals in Japan. Diagnostic criteria forchronic hepatitis C patients, peginterferon and ribavirinregimens and follow-up protocols were determined.Patients were divided by age into two groups: those agedZ65 years and those aged o 65 years. Patients werecompared with respect to background and treatmentefficacy according to gender and tolerability of combina-tion therapy with peginterferon and ribavirin. The studyprotocol was approved by the ethics committee of eachhospital, and written informed consent was obtainedfrom each patient before therapy.

Five hundred and ninety-one consecutive patientswith chronic hepatitis C were treated with peginterferonand ribavirin combination therapy between December2004 and February 2007 at 64 institutions: NagoyaUniversity Hospital and affiliated hospitals. The indica-tions for treatment were under 75 years old, positive forantibody to HCV and a serum HCV RNA level4 100 000 IU/ml by a quantitative PCR assay (AmplicorGT-HCV Monitor version 2.0; Roche Molecular Systems,Pleasanton, CA, USA) within 12 weeks preceding thetreatment. In Japan, combination with peginterferon andribavirin therapy for patients with an HCV RNA level4 100 000 IU/ml (high viral load in Japan) was approved

for medical insurance coverage. Exclusion criteria in-cluded pretreatment haemoglobin (Hb) levels o 10 g/dl,positive for serum hepatitis B surface antigen, drugaddiction, alcohol abuse, autoimmune hepatitis, primarybiliary cirrhosis, human immunodeficiency virus, coex-isting serious psychiatric or medical illness and preg-nancy. To exclude any patient bias, only complete cohortsfrom each hospital were enrolled. HCV genotypes weredetermined by PCR with genotype-specific primers thatwere described previously by Ohno et al. (19). Allgenotyping was performed at one institution.

All patients were treated with 1.5 mg peginterferon-a-2b (Pegintrons; Schering-Plough K. K., Osaka, Japan)per kilogram of body weight subcutaneously once weeklyfor 24 weeks for genotype 2 patients and for 48 weeks forgenotype 1 patients. When the virus was eradicatedbetween 16 and 24 weeks from the beginning of treat-ment, the treatment duration was prolonged up to 72weeks for genotype 1 patients. Treatment was discontin-ued when a patient’s Hb concentration declined below8.5 g/dl because of drug-induced haemolytic anaemia orwhen a patient’s white blood cell count declined below1000/mm3, the neutrophil count declined below 500/mm3 or the platelet count declined below 50 000/mm3.Some patients discontinued treatment because the viruscould not be eradicated after 24 weeks, as determined bythe physician. We considered these cases to be discon-tinued. Oral ribavirin (Rebetol; Schering-Plough K. K.)was administered for the same duration as peginterferonat 600 mg/day for patients who weighed o 60 kg,800 mg/day for those who weighed 4 60 kg buto 80 kg and 1000 mg/day for those who weighed4 80 kg during the treatment period. The dose ofribavirin was reduced by 200 mg/day when the patient’sHb concentration declined below 10 g/dl because ofdrug-induced haemolytic anaemia. Ribavirin was discon-tinued when peginterferon therapy was discontinued. InJapan, peginterferon and ribavirin combination therapywas not approved for medical insurance coverage untilNovember 2004.

Liver histology

Pretreatment liver biopsy specimens were analysed forfibrosis on a scale of F0–F4 (F0, no fibrosis; F1, portalfibrosis without septa; F2, few septa; F3, numerous septawithout cirrhosis; and F4, cirrhosis) and for necroin-flammatory activity on a scale of A0–A3 (A0, no histolo-gical activity; A1, mild activity; A2, moderate activity;and A3, severe activity) (20).

Assessment of efficacy

A virological response was assessed using a qualitativeHCV RNA assay with a lower detection limit of 100 IU/ml (Amplicor HCV version 2.0; Roche Molecular Sys-tems). According to the qualitative HCV RNA results, theresponses were defined as follows: SVR (no HCV RNA

Liver International (2009)528 c� 2009 John Wiley & Sons A/S

Treatment for elderly patients with HCV Honda et al.

detected at the end of the 24-week follow-up period aftercompletion of treatment), relapse (no HCV RNA at theend of treatment and reappearance of serum HCV RNAduring the 24-week follow-up period) or nonresponse(persistent positive serum HCV RNA throughout treat-ment).

Comparison of characteristics and efficacy of treatmentaccording to age

Patients were divided by age into two age groups: (1)Z65 years old (n = 115) and (2)o 65 years old (n = 476).The following baseline parameters were compared be-tween the two groups: gender ratio, age, body weight,body mass index (BMI), alanine aminotransferase (ALT)levels, g-glutamyl transpeptidase (GGT), Hb levels, pla-telet counts, HCV genotype and viral load, histologicalactivity and fibrosis. The SVR rate, rapid virologicalresponse (RVR) (HCV RNA negative by a qualitativeassay at week 4) rate, early virological response (HCVRNA negative by a qualitative assay at week 12) rate andend of treatment virological response (ETR) rate wereobtained by an intention-to-treat (ITT) analysis and per-protocol (PP) analysis, and the ribavirin or peginterferonreduction rate and combination therapy discontinuationrate were compared between the two age groups.

Comparison of treatment efficacy between patients whodid and did not achieve a sustained virological response

To identify factors that predict an SVR among patientstreated with combination therapy, we first determinedthe factors associated with an SVR in combinationtherapy with respect to the same factors above baselineparameters by a univariate analysis. Next, we identifiedthe factors associated with an SVR in combinationtherapy, including gender, age, BMI, baseline serumALT, GGT, Hb, platelet counts, genotype and HCVRNA, using a multivariate stepwise analysis with forwardinclusion methods.

Comparison of treatment efficacy between older patientswho did and did not achieved a sustained virologicalresponse

To identify elderly patients who may particularly benefitfrom combination therapy, we determined factors asso-ciated with an SVR using a univariate analysis of thesame background factors as above. Then we determinedfactors associated with an SVR in elderly patients treatedwith combination therapy by a multivariate stepwiseanalysis with forward inclusion methods. In addition,we analysed the virological responses to combinationtherapy according to the age and gender of patientsinfected with each genotype because the age distributionof the treated patients differed according to gender.

Statistical analysis

Values are expressed as means� standard deviation(SD). Between-group differences in the mean quantita-tive values were analysed using Student’s t-test, anddifferences in nonparametrical data were analysed usingthe Mann–Whitney U-test. Differences in proportionswere tested by a w2-test. The SVR rate between agegenerations in females was assessed using Fisher’s exacttest. Multiple logistic regression analysis was used toidentify factors related to SVR. Statistical analyses wereperformed using SPSS software version 16.0 (SPSS JapanInc., Tokyo, Japan) for multiple logistic regression analy-sis and SAS software (SAS Institute Inc., Cary, NC, USA)for another analysis. All P values were two-tailed, andPo 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 658 patients were screened, and 591 patientswere enrolled in this study (Fig. 1). The patients included327 men and 264 women aged 20–74 years (mean� SD,54.7� 11.6). Patients Z65 years old comprised 19.5% ofthe patient population (115/591). The clinical character-istics of the two study groups are shown in Table 1. Bodyweight was significantly lower in patients aged Z65 yearsthan that in patients aged o 65 years (P = 0.0006). Hblevels and platelet counts were significantly lower inpatients aged Z65 years than those in patients agedo 65 years (Po 0.0001 and P = 0.0013 respectively). Thefibrosis stage was more advanced in patients aged Z65years than that in patients aged o 65 years (P = 0.0310).

Response to therapy

The ribavirin dose reduction rate was significantly higherin patients aged Z65 years than that in patients agedo 65 years (P = 0.00013) (Table 2), while the peginterfer-on dose reduction rate did not differ significantlybetween the two groups. The treatment discontinuationrate in patients aged Z65 years was significantly higherthan that in patients o 65 years (P = 0.0003). As a result,the SVR rate by ITT analysis in patients aged Z65 yearswas significantly lower than that in patients aged o 65years (P = 0.0067). However, the SVR and ETR rate by PPanalysis were not significantly different between the twogroups.

The factors associated with an SVR were determinedby univariate analysis. The SVR rate was significantlyhigher in male patients than that in female patients(P = 0.0153) (Table 3). Age was significantly lower inpatients who achieved an SVR than in patients who didnot achieve an SVR (Po 0.0001). Hb levels and plateletcounts were significantly higher in patients who achievedan SVR than those in patients who did not achieved anSVR (P = 0.0202 and P = 0.0002 respectively). The HCVload in patients who achieved an SVR was significantlylower than that in patients who did not achieved an SVR


Honda et al. Treatment for elderly patients with HCV

(P = 0.0132). The rate of genotype 2 patients whoachieved an SVR was significantly higher than that inpatients who did not achieve an SVR (Po 0.0001). Thefibrosis stage was more advanced in patients who did notachieve an SVR than that in those who did achieve anSVR (P = 0.0186).

The factors associated with an SVR in combinationtherapy were determined by multivariate analysis (Table4). Age [Po 0.0001, odds ratio 0.959 (0.942–0.975)] andgenotype [Po 0.0001, odds ratio 0.415 (0.255–0.676)]were significantly associated with an SVR. Including theRVR (ITT) factor after starting treatment, the factorsassociated with an SVR in combination therapy weredetermined using a multivariate analysis (Table 5). Age

[Po 0.0001, odds ratio 0.961 (0.944–0.978)] and RVR[Po 0.0001, odds ratio 8.168 (4.511–14.789)] were sig-nificantly associated with an SVR.

Then, we separately analysed male and female patientsin different age groups. The virological responses tocombination therapy according to the gender of geno-type 1 patients are shown by age groups in Figure 2. Inboth males and females, the SVR rate decreased with age,and the SVR rates of patients o 40 years old were over50%. In patients aged Z65 years, the SVR rate of femalepatients was lower than that in patients aged o 65 yearsand was lower than that of male patients aged Z65 years[20.8% (10/48) vs. 40.5% (64/158) and 20.8% (10/48) vs.42.2% (19/45); P = 0.0261 respectively].

Table 1. Baseline clinical characteristics of patients treated with combination therapy

Total patients(n = 591)

Patients aged o 65years (n = 476)

Patients aged Z65years (n = 115) P value

Sex ratio (male/female) 327/264 270/206 57/58 0.1659Age (years) 54.7�11.6 51.5� 10.6 67.9�2.2 o 0.0001Body weight (kg) 60.1�11.3 60.9� 11.4 56.7�10.1 0.0006Body mass index 22.9�3.2 22.9� 3.2 22.9�3.2 0.9221Baseline serum ALT (IU/L) 64.8�57.3 66.5� 60.6 57.7�40.4 0.1425GGT (IU/L) 57.8�76.7 58.9� 78.9 53.3�67.3 0.4880Haemoglobin (g/dl) 14.1�1.3 14.2� 1.4 13.7�1.2 o 0.0001Platelets (�104/ml) 17.7�5.7 18.0� 5.9 16.1�4.3 0.0013Genotype (1/2) 467/124 374/102 93/22 0.5870HCV RNA (kIU/ml) 1863.3�1456.3 1896.4� 1454.9 1726.2�1460.5 0.2611Activity (A0/A1/A2/A3) 16/255/141/19 13/202/115/13 3/53/26/6 0.6053Fibrosis (F0/F1/F2/F3/F4) 37/228/107/56/5 31/191/83/37/3 6/37/24/19/2 0.0310

ALT, alanine aminotransferase; GGT, g-glutamyl transpeptidase; HCV RNA, hepatitis C virus RNA; kIU, kilo international units.

658 Patients screened for eligibility

3 Patients with indeterminate genotype

118 Patients discontinued treatment73 For adverse events

1 Unknown44 Noneradication of HCV

473 Patients completed treatment

473 Patients completed follow-up period

64 Patients not enrolled56 Did not meet entry protocol criteria

8 Met exclusion criteria

591 Patients included in efficacy analysis

Fig. 1. Flow chart for patient selection.



Virological responses to combination therapy accord-ing to the gender of genotype 2 patients are shown by agegroups in Figure 3.

The SVR rate was similar for all age groups amongmale patients. In both male and female patients o 40years old, the SVR rate was over 75%. In both male andfemale patients over 40 years old, the SVR rate wasapproximately 60%.

Response to therapy in older patients

In patients aged Z65 years, the factors associated with anSVR were determined by univariate analysis (Table 6).The SVR rate of male patients was significantly higherthan that of female patients (P = 0.0284). The ratio ofgenotype 1 in patients who achieved an SVR wassignificantly lower than that in patients who did not

Table 3. Factors associated with a sustained virological response in combination therapy by a univariate analysis

Total patients (n = 591)Patients who achievedan SVR (n = 288)

Patients who did notachieved an SVR (n = 303) P value

Sex ratio (male/female) 327/264 171/114 153/150 0.0153Age (years) 54.7� 11.6 51.9�12.6 57.3� 9.8 o0.0001Body weight (kg) 60.1� 11.3 60.7�10.8 59.6� 11.8 0.2661Body mass index 22.9� 3.2 23.0�2.9 22.9� 3.5 0.8785Baseline serum ALT (IU/L) 64.8� 57.3 65.8�63.8 63.8� 50.5 0.6758GGT (IU/L) 57.8� 76.7 54.7�91.0 60.7� 60.2 0.3425Haemoglobin (g/dl) 14.1� 1.3 14.2�1.4 14.0� 1.3 0.0202Platelets (�104/ml) 17.7� 5.7 18.6�6.1 16.8� 5.1 0.0002Genotype (1/2) 467/124 204/84 263/40 o0.0001HCV RNA (kIU/ml) 1863.3� 1456.3 1711.2�1415.4 2007.8� 1482.0 0.0132Activity (A0/A1/A2/A3) 16/255/141/19 7/121/70/9 9/134/71/10 0.9596Fibrosis (F0/F1/F2/F3/F4) 37/228/107/56/5 18/122/46/20/0 19/106/61/36/5 0.0186

ALT, alanine aminotransferase; GGT, g-glutamyl transpeptidase; HCV RNA, hepatitis C virus RNA; kIU, kilo international units.

Table 2. Efficacy of combination therapy


Patients aged o 65 years(n = 476)

Patients aged Z65 years(n = 115) P value

SVR rate (intention-to-treat) 48.7 (288/591) 51.5 (245/476) 37.4 (43/115) 0.0067SVR rate (per-protocol) 59.2 (280/473) 60.3 (238/395) 53.8 (42/78) 0.2927RVR rate (intention-to-treat) 20.0 (118/591) 21.2 (101/476) 14.8 (17/115) 0.1213RVR rate (per-protocol) 22.0 (104/473) 22.8 (90/395) 17.9 (14/78) 0.3460EVR rate (intention-to-treat) 62.6 (370/591) 64.5 (307/476) 54.8 (63/115) 0.0534EVR rate (per-protocol) 71.0 (336/473) 71.1 (281/395) 70.5 (55/78) 0.9113ETR rate (intention-to-treat) 81.0 (479/591) 83.2 (396/476) 72.2 (83/115) 0.0068ETR rate (per-protocol) 92.8 (439/473) 92.9 (367/395) 92.3 (72/78) 0.8504Ribavirin dose reduction rate 43.1 (255/591) 39.9 (190/476) 56.5 (65/115) 0.0013PEGIFN dose reduction rate 34.3 (203/591) 33.2 (158/476) 39.1 (45/115) 0.2289Combination therapy discontinuation rate 20.0 (118/591) 17.0 (81/476) 32.2 (37/115) 0.0003Combination therapy discontinuationrate�

12.5 (74/591) 9.9 (47/476) 23.5 (27/115) o0.0001

�Except genotype 1 patients which therapy was discontinued because the virus could not be eradicated after 24 weeks.

ETR, end of treatment virological response; EVR, early virological response; PEGIFN, peginterferon; RVR, rapid virological response; SVR, sustained

virological response.

Table 5. Multivariate analysis of factors (including treatment re-sponse) associated with a sustained virological response in combina-tion therapy

Variable Odds ratio (95% CI) P value

Age 0.961 (0.944–0.978) o0.0001RVR RVR vs. nonRVR 8.168 (4.511–14.789) o0.0001

CI, confidence interval; RVR, rapid virological response.

Table 4. Multivariate analysis of factors associated with a sustainedvirological response in combination therapy


Age 0.959 (0.942–0.975) o0.0001Genotype 1 vs. 2 0.415 (0.255–0.676) o0.0001

CI, confidence interval.



NR

Relapser

SVRMale Female

ITT analysis

(n=28) (n=188) (n=45)

% %

0

20

40

60

80

100

–39 40–64 65– Age (years) 65– Age (years)–39 40–64(n=14) (n=144) (n=48)

0

20

40

60

80

100

Fig. 2. A virological response to combination therapy according to the age and gender of patients with genotype 1. ITT, intention-to-treat;NR, nonresponder; SVR, sustained virological response.

Table 6. Univariate analysis of factors associated with sustained virological response in patients aged Z65 years treated with combinationtherapy


Patients who achieveda SVR (n = 43)

Patients who did notachieved a SVR (n = 72) P value

Sex ratio (male/female) 57/58 27/16 30/42 0.0284Age (years) 67.9�2.2 67.9�2.3 67.8�2.1 0.7666Body weight (kg) 56.7�10.1 56.9�7.1 56.5�11.4 0.8417Body mass index 22.9�3.2 22.8�1.9 23.0�3.7 0.6980Baseline serum ALT (IU/L) 57.7�40.4 57.2�41.3 58.0�40.2 0.9178GGT (IU/L) 53.3�67.3 61.2�98.3 48.8�40.4 0.3471Haemoglobin (g/dl) 13.7�1.2 13.8�1.2 13.6�1.3 0.3341Platelets (�104/ml) 16.1�4.3 16.3�4.7 16.0�4.1 0.7412Genotype (1/2) 93/22 29/14 64/8 0.0047HCV RNA (kIU/ml) 1726.2�1460.5 1383.6�1247.0 1930.9�1546.4 0.0514Activity (A0/A1/A2/A3) 3/53/26/6 1/17/10/4 2/36/16/2 0.4132Fibrosis (F0/F1/F2/F3/F4) 6/37/24/19/2 0/16/9/7/0 6/21/15/12/2 0.2538

ALT, alanine aminotransferase; GGT, g-glutamyl transpeptidase; HCV RNA, hepatitis C virus RNA; kIU, kilo international units; SVR, sustained virological

response.

NRRelapser

SVRMale Female

ITT analysis

(n=12) (n=42) (n=12)

% %

0

20

40

60

80

100

–39 40–64 65– Age (years) 65– Age (years)–39 40–64(n=11) (n=37) (n=10)

0

20

40

60

80

100

Fig. 3. A virological response to combination therapy according to the age and gender of patients with genotype 2. ITT, intention-to-treat;NR, nonresponder; SVR, sustained virological response.



achieve an SVR (P = 0.0047). The HCV load tended to belower in patients who achieved an SVR than that inpatients who did not achieve a SVR (P = 0.0514).

In patients aged Z65 years, the factors associated withan SVR with combination therapy were determinedusing multivariate analysis (Table 7). Viral load[P = 0.015, odds ratio 1.000 (0.999–1.000)] and genotype[P = 0.022, odds ratio 0.268 (0.087–0.830)] were signifi-cantly associated with an SVR. Gender [P = 0.052, oddsratio 0.410 (0.166–1.009)] tended to be associated withan SVR.

To identify patients aged Z65 years with genotype 1(hard-to-treat population) who may benefit from com-bination therapy, we examined the efficacy of combina-tion therapy according to viral load and gender (Fig. 4).Even among older male patients with high viral loads,patients with viral loads o 2 000 000 IU/ml had a sig-nificantly higher SVR than patients with viral loads over2 000 000 IU/ml [56.7% (17/30) vs. 13.3% (2/15)](P = 0.0094). In contrast, there was no significant differ-ence in the SVR rate between older female patients withviral loads o 2 000 000 IU/ml and those with viral loadsover 2 000 000 IU/ml.

To evaluate the ribavirin dose during the first quarter(12 weeks) in each group of genotype 1 patients at twoinstitutions, we calculated the percent intake of theexpected dose during the first quarter. The percentage ofpatients who achieved a drug intake rate over 80% during

the first quarter was significantly lower in elderly patientsthan in younger patients (75.0 vs. 88.4%; P = 0.0442).Similarly, the patients who achieved an SVR were morelikely to have a drug intake rate over 80% than patientswho did not achieve an SVR (91.7 vs. 80.7%; P = 0.0464).

Adverse events

The combination therapy discontinuation rate of pa-tients aged Z65 years was significantly higher than thatof patients aged o 65 years (P = 0.0003) (Table 2). Evenwhen excluding genotype 1 cases in which therapy wasdiscontinued because the virus could not be eradicatedafter 24 weeks, the combination therapy discontinuationrate of patients aged Z65 years was significantly higherthan that of patients aged o 65 years (Po 0.0001).Ribavirin discontinuation was higher in older patients(P = 0.0013). The reasons for discontinuing combinationtherapy and the times when therapy was discontinued areshown in Table 8. One case with a serious adverse effectoccurred in each group: insulin-dependent diabetesmellitus in the younger group and bleeding from duode-nal varices in the older group. The discontinuation ratebecause of general fatigue or anaemia was higher in olderpatients than that in younger patients [5.22% (6/115) vs.1.90% (9/476) (P = 0.0418) and 5.22% (6/115) vs. 0.63%(3/476) (P = 0.0024) respectively].

Discussion

It is important to eradicate HCV by IFN to reduce therisk of HCC (4, 5). In addition, IFN reportedly reducesliver-related mortality in chronic hepatitis C patientsover age 60 years old (11, 21, 22). However, these findingsare based on studies of IFN monotherapy. The presentstudy examined the effect of a combination of ribavirinand peginterferon. Ribavirin has been used in combina-tion with IFN or peginterferon to treat chronic hepatitisC, and this combination therapy has been reported to bemore effective than IFN monotherapy in eradicating

Table 7. Multivariate analysis of factors associated with a sustainedvirological response in patients aged Z65 years treated withcombination therapy


HCV RNA (kIU/ml) 1.000 (0.999–1.000) 0.015Genotype 1 vs. 2 0.268 (0.087–0.830) 0.022Gender Female vs. male 0.410 (0.166–1.009) 0.052

HCV RNA, hepatitis C virus RNA; kIU, kilo international units; SVR,

sustained virological response.

NRRelapser

SVRMale Female

ITT analysis

(n=30) (n=15)

% %

0

20

40

60

80

100

∼1999 2000∼(n=30) (n=18)∼1999 2000∼

0

20

40

60

80

100

KIU/mL KIU/mL

Fig. 4. A virological response to combination therapy according to virus load and gender of older patients with genotype 1. ITT, intention-to-treat; kIU, kilo international units; NR, nonresponder; SVR, sustained virological response.



HCV (7–10). However, ribavirin and IFN or peginterfer-on in combination produce a common adverse effect, i.e.Hb levels decrease in 20–36% of treated patients withchronic hepatitis C, necessitating dose reduction ordiscontinuation (8, 10, 23, 24). Among elderly patientstreated with combination therapy, ribavirin dose reduc-tion is often required, resulting in a reduced SVR in olderpatients (15, 16). In this study, ribavirin dose reductionwas higher in elderly patients than that in youngerpatients.

Previous studies have reported that there is no sig-nificant difference in the efficacy of IFN monotherapybetween older and younger patients after normalizing fordifference in background clinical characteristics, suggest-ing that age does not influence the outcome of IFNmonotherapy (13, 14).

Adding ribavirin to IFN improves the treatment effi-cacy. However, ribavirin reduces Hb levels, causing great-er dose reductions. Elderly patients with genotype 1 andhigh HCV loads have a lower SVR rate than youngerpatients because of a higher ribavirin dose reduction rateand discontinuation rate because of ribavirin-relatedanaemia (15, 16). We examined chronic hepatitis Cpatients with a similar background, except for age, andfound that combination therapy was comparably effec-tive between patients aged Z60 years and those agedo 60 years, although the ribavirin discontinuation rate

was higher among older patients (17). Similar resultswere obtained in the chronic hepatitis C patients treatedwith peginterferon and ribavirin, and positive responsesto combination treatment were decreased for genotype 1-or 4-infected patients older than 40 years, but compar-able between patients older than 65 and patients aged40–64 years (18).

However, the background, efficacy and tolerability ofpeginterferon and ribavirin combination therapy inelderly patients according to gender have not been fullyelucidated. Moreover, there are no data identifying whichpatients will achieve an SVR among older patients. Ourprevious report examined a 24-week regimen of ribavirinplus interferon therapy and defined advanced age as over60 years (17). However, currently, the most commontreatment protocol is prolonged ribavirin plus peginter-feron-a treatment. Moreover, the patient age distributionhas shifted to a more advanced age. Therefore, we need tore-evaluate an additional protocol including peginterfer-on and define advanced age as 65 years. We conducted amulti-institution study to evaluate the efficacy and toler-ability of ribavirin plus peginterferon-a in older patientswith chronic hepatitis C.

An ITT analysis indicated that the SVR rate in elderlypatients was lower than that in younger patients, while aPP analysis showed that the SVR rate in elderly patientswas not statistically different from that of younger

Table 8. Reasons for discontinuing combination therapy

Reason NumberWeeks afterstarting treatment Reason Number

Weeks afterstarting treatment

Patients aged o 65 years (n = 476) Patients aged Z65 years (n = 115)Fatigue 9 4, 8, 8, 10, 13, 20, 25, 33 Fatigue� 6 1, 4, 6, 8, 19, 32Depression 7 1, 2, 4, 8, 13, 15, 18 Anaemia� 6 3, 8, 12, 12, 13, 15Self-discontinuation 6 8, 16, 23, 24, 25, 28 Rash 3 1, 4, 9Headache 3 2, 36, 37 Depression 2 2, 9Anaemia 3 4, 11, 24 Jaundice 1 1Rash 2 18, 25 Fiver 1 7Hepatocellular carcinoma 2 19, 43 Bleeding from duodenal variesz 1 8Bronchitis 1 2 Anorexia 1 10Alopecia 1 13 Hyperthyroidism 1 15Progression of diabetes 1 14 Cholecystitis 1 16Peritonitis due to appendicitis 1 16 Symptoms of Parkinson’s disease 1 16Fundal hemorrhage 1 17 Suspicion of interstitial pneumonia 1 20Pneumonia 1 18 Gastric cancer 1 21Body weight loss 1 22 Hepatocellular carcinoma 1 21Vertigo 1 25Elevation of TSH 1 25Unknown 1 25Lack of funds 1 27Hypothyroidism 1 28Gastric cancer 1 38Insulin-dependentdiabetes mellitusz

1 44

Reappearance of pancreatitis 1 46Noneradication of HCVw 34 Noneradication of HCVw 10

�The ratio of discontinuation was significantly different between the two groups Po 0.05.

wDiscontinued because the virus could not be eradicated after 24 weeks.

zSerious adverse effects are shown in bold.



patients. These results indicated that when treatment isnot discontinued, the SVR rate of elderly patients will behigh.

Multivariate analysis showed that baseline age andgenotype are factors significantly associated with anSVR. Many studies have shown that baseline viral loadand genotype are factors significantly associated with anSVR (8, 24). Age was associated with an SVR and theSVR rate of patients aged Z65 years was lower than thatof patients aged o 65 years (37.4 vs. 51.5%; P = 0.0067).

Because the SVR differs according to genotype, weclassified patients by genotype and compared the SVRrate for both male and female patients. In both male andfemale patients with genotype 1, the SVR rate decreasedwith age, and the SVR rate of both patients o 40 yearswas over 60%. These results were similar to previousstudies where the SVR rate of patients o 40 years oldwas higher than that of another generation (17, 18, 24,25). In patients Z65 years old, the SVR rate of femalepatients was significantly lower than that of male patients[in patients with both genotype 1 and 2, 27.6% (16/58)vs. 47.4% (27/57); P = 0.0284; in patients with genotype1, 20.8% (10/48) vs. 42.2% (19/45); P = 0.0261]. Theresult that female patients are less likely to achieve anSVR than male patients differs from that of a previousreport (25). However, our results are consistent withSezaki and colleagues, who reported that females have apoorer response to peginterferon and ribavirin combina-tion therapy than males among patients with hepatitis Caged Z50 years. In the older population, the genderassociated with an SVR changes from male to female(26). In both male and female patients with genotype 2,the SVR of all generations was over 60%. A study byAntonucci et al. (18)and our previous report suggest thatgenotype 2 patients have a higher SVR rate, which is age-independent.

We cannot exclude the bias that better candidates weremore likely to be selected among older patients thanyounger patients in the outpatient department. However,regardless of potential bias, elderly patients had low bodyweight, low Hb levels and an advanced fibrosis stage.Regarding fibrosis, elderly patients are more likely tohave a long disease duration as it was reported previouslythat fibrosis progression was mainly dependent on ageand the duration of infection (27). In this study, ITT andPP analyses indicated that the SVR rate did not differbetween younger and older patients with F2–F4 fibrosiswho needed treatment to prevent liver-related deaths(data not shown).

Several reports suggested that the efficacy of peginter-feron and ribavirin combination therapy is lower inelderly patients with genotype 1 than in younger patients,but there are no reports establishing which elderlypatients will benefit from this combination therapy. Toidentify genotype 1 patients Z65 years old (hard-to-treatpopulation) who will particularly benefit from combina-tion therapy, we examined the efficacy of combinationtherapy according to viral load and gender. In older male

patients with genotype 1 and HCV RNA concentrationso 2 000 000 IU/ml, the SVR rate was over 50%. Based onthese results, combination therapy should be consideredfor male patients with genotype 1 and with HCV RNAconcentrations o 2 000 000 IU/ml. Even if the treatmentschedules differ between western countries and Japan,age will have to be considered, and viral load will be animportant issue when treating elderly patients.

In conclusion, elderly patients in Japan who receivedcombination therapy with peginterferon and ribavirinhad a low body weight, low Hb levels and advancedfibrosis. Elderly patients had higher treatment disconti-nuation rates and lower SVR rates than younger patients.However, an SVR was achieved in over 50% of elderlypatients with genotype 2 and in male patients with geno-type 1 and HCV RNA concentrations o 2 000 000 IU/ml.

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Appendix 1

The following institutions participated in this study:� Aihoku Hospital� Aichi Cancer Center� Aichi Cancer Center Aichi Hospital� Aichi Saiseikai Hospital� Aichi Sannomaru Hospital� Atsumi Hospital� Anjo Kosei Hospital� Ichinomiya Municipal Hospital� Ichinomiya Municipal Hospital Imaise Branch� Inazawa City Hospital� Ogaki Municipal Hospital� Okazaki City Hospital� Kainan Hospital� Kakegawa City General Hospital� Kamo Hospital� Kariya Toyota General Hospital� Gifu Social Insurance Hospital� KumiaiKosei Hospital� Aichi Cardiovascular and Respiratory Center� Showa Hospital� Tosei General Hospital� Komaki City Hospital� Komaki Daiichi Hospital� Sakashita Hospital� Saishukan Hospital� Shizuoka Kosei Hospital� Shizuoka Saiseikai General Hospital� Yokkaichi Municipal Hospital� Holy Spirit Hospital� Kamiiida daiichi General Hospital� Daido Hospital� Chita City Hospital� Chubu Rosai Hospital� National Center for Geriatrics and Gerontology� Tsushima City Hospital� Tokai Memorial Hospital� Tokai Sangyo Central Hospital� Tokai Municipal Hospital� Tokai Central Hospital� Tokai Hospital� Tohno Kousei Hospital



� Toki General Hospital� Tokoname Municipal Hospital� Toyota Memorial Hospital� Toyohashi Medical Center� Toyohashi Municipal Hospital� Nakatsugawa Municipal General Hospital� Nagoya Medical Center� Nagoya Ekisaikai Hospital� Nagoya Memorial Hospital� Nagoya Kyouritu Hospital� Japanese Red Cross Nagoya First Hospital� Nishio Municipal Hospital

� Handa City Hospital� Fukuroi Municipal Hospital� Fujita Health University Hospital� Brother Hospital� Hekinan Municipal Hospital� Mitsubishi Nagoya Hospital� Miyoshi Municipal Hospital� Meijo Hospital� Meitetsu Hospital� Yachiyo Hospital� Yamashita Hospital



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Efficacy of peginterferon-α-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C