Efficacy and tolerability of hepatitis C combination therapy in elderly patients

Efficacy of pegylated interferon-alpha-2a plus ribavirin for patients aged at least 60 years with chronic hepatitis C

Chin Med J (Engl). 2012 Jun;125(11):1852-6.

ZHENG Ying-ying, FAN Xiao-hong, WANG Li-feng, TIAN Di, HUO Na, LU Hai-ying, WU Chi-hong, XU Xiao-yuan , WEI Lai,

ZHENG Ying-ying Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; FAN Xiao-hong Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; WANG Li-feng Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; TIAN Di Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; HUO Na Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; LU Hai-ying Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; WU Chi-hong Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; XU Xiao-yuan Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China; WEI Lai Hepatology Institute, Peking University People’s Hospital, Beijing 100044, China; Hepatology Institute, Peking University People’s Hospital, Beijing 100044, China

Correspondence to: XU Xiao-yuan Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China (Tel:86-10-83575019 Fax:86-10-66221799 Email:yangpin@ public3.bta.net.cn )

This study was supported by : National Major Project for Infectious Diseases Control(No. 2008ZX10002-013) National Natural Science Foundation of China(No. 30771906) PhD Programs Foundation of Ministry of Education of China(No. 20090001110081)

Keywords: interferon·therapeutics·hepatitis C·aged

Abstract:

Background
In China, patients with hepatitis C virus (HCV)-associated liver disease are getting older, and thus the number of deaths due to such disease is increasing. The efficacy of combination therapy with ribavirin and interferon for chronic HCV infection in elderly patients has not been fully clarified. The aim of the present study was to evaluate the efficacy and tolerability of the combination therapy in the elderly patients.

Methods
Sixty-eight chronic hepatitis C patients, who received the combination therapy, were classified into two age groups: elderly group (³60 years, n=25) and non-elderly group (<60 years, n=43). Rapid virological response, complete early virological response, sustained virological response, relapse, non-response rate, and safety were compared between the elderly group and non-elderly group.

Results
 Overall sustained virological response was lower in the elderly group than non-elderly group (44% vs. 75%, P=0.012, OR=0.270, and 95% CI 0.095–0.768). Among patients with HCV genotype 1, sustained virological response was lower in the elderly group than non-elderly group (45% vs. 77%, P=0.015, OR=0.247, 95% CI 0.078–0.781). The proportions of dose reduction due to laboratory abnormalities were significantly higher in the elderly group than non-elderly group (60.0% vs. 32.6%, P=0.027). Multiple binary Logistic regression analysis confirmed that patient age was an associated factor for sustained virological response.

Conclusion
Among patients with HCV genotype 1, the elderly patients had lower sustained virological response than non-elderly patients during pegylated interferon-alpha-2a plus ribavirin combination therapy.

Hepatitis C virus (HCV) infection often leads to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).¹ The need for chronic HCV therapies for elderly patients is increasing, and even HCC has become a recent and growing problem in elderly patients with chronic hepatitis C. However, the management of elderly patients carrying high levels of HCV RNA still poses a clinical challenge.² In several studies, elderly patients who received combination therapy of conventional interferon (IFN) plus ribavirin showed a tendency of lower sustained virologic response (SVR) rates.^3-6 Currently, HCV is now found to be a common viral infection in China,⁷ and HCV infections in elderly patients are rapidly growing. Therefore, it is imminent to derive therapy and management strategy for this particular patient cohort. We conducted a retroprospective and randomized study on treatment response and safety within the standard-of-care regimen in elderly (³60 years) patients with chronic hepatitis C (CHC), in comparison with non-elderly cohort, to derive an effective management strategy for patients of this age group.

METHODS

Patients

A total of 68 CHC patients were enrolled for the treatment with pegylated interferon-alpha-2a (PEG-IFNa-2a) plus ribavirin in the Department of Infectious Diseases, Peking University First Hospital, from January 2009 to April 2010. The criteria of CHC diagnosis were based on Guideline of prevention and treatment of hepatitis C.⁸ Every patient was anti-HCV positive and/or HCV RNA positive for more than six months. The exclusion criteria were as follows: <18 years old, malignancies, co-infection with chronic hepatitis B or HIV, autoimmune diseases, coexisting of serious psychiatric or medical illness, or pregnancy. The elderly group included patients aged at least 60 years, comprising 25 patients; the non-elderly group contained patients with ages less than 60 years, including 43 patients. This study was approved by the Medical Ethics Committee of Peking University First Hospital, and informed consents were obtained from all the enrolled patients.

Laboratory tests

HCV antibodies were examined by a microsomal chemiluminescence assay with a lower detection limit of 15 IU/ml (Abbott Diagnostics Division, USA). HCV viral load was measured by a quantitative PCR kit (Da An Gene, Guangzhou, China). High viral load was defined as a serum HCV RNA level of at least 200 000 copies/ml. HCV genotyping was detected in a central laboratory by using the restriction fragment length polymorphism (RFLP) analysis of the amplified 5¢-noncoding genome region as described in previous report.⁹ The serum levels of alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), direct bilirubin (DBIL), total protein (TP), glucose (GLU), and triglyceride (TG) were measured by an automatic biochemical analyzer.

Treatment protocol

All patients were treated with 180 mg/week of PEG-IFN-a-2a subcutaneously, and oral ribavirin at a daily dose of 800–1000 mg. The numbers of naïve, relapse, and non-response patients were 42, 17, and 9, respectively. The durations of treatment were 48 weeks for naïve patients and 72 weeks for relapse and non-response patients, both with a 24-week follow-up period. All treatment decisions were made by physicians in accordance with the standard care procedures. The patients who developed cytopenia or other adverse events, were generally managed with a dose reduction or premature discontinuation of the PEG-IFNa-2a or ribavirin, as per the HCV treatment guidelines.

Efficacy assessment

Treatment responses were categorized in several types: rapid virological response (RVR) was defined as undetectable HCV RNA at week 4 of treatment; complete early virological response (cEVR) was defined as complete absence of serum HCV RNA at week 12 of therapy compared with the baseline level; sustained virologic response (SVR) was defined as the absence of HCV RNA from serum measured by a sensitive PCR assay 24 weeks following discontinuation of therapy; virological relapse (R) was the reappearance of HCV RNA in serum after treatment was discontinued; non-response (NR) was the persistent positive serum HCV RNA throughout treatment.

Statistical analysis

Group numerical variables, presented as mean ± standard deviation (SD), or median (interquartile range), were compared by two-way analysis of variance (ANOVA), Student's t test, and Mann-Whitney U test as appropriate. The difference in categorical variables presented in counts and/or percentages were tested with c² test or Fisher's exact test as appropriate. Multiple binary Logistic regression analysis was used to identify factors related to virological response. Variables entered on step one included gender (male/female), age, platelet count (PLT), DBIL, TP, creatinine, ALP, TG, HCV RNA, and HCV genotypes (1b/2a). All statistical analyses were performed using SPSS software 14.0 packages (SPSS Inc., USA). All P values were two-tailed, and P <0.05 was considered statistically significant.

RESULTS

Baseline characteristics

A total of 68 patients (37 men and 31 women), aged (49.38±15.02) years (range 19–74 years), were enrolled between January 2009 and April 2010. They were divided into elderly group (age ³60 years old, n=25) and non-elderly group (age <60 years old, n=43). The baseline characteristics of the two groups were summarized in Table 1. There were no significant differences in these baseline profiles (P >0.05).

Table 1. Baseline characteristics of patients

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Safety profile

The elderly group had similar frequencies of influenza-like symptom to that of the non-elderly group (12.0% vs. 46.5%, P=0.058). The dose reduction due to laboratory abnormalities were significantly higher in the elderly group than non-elderly group (60.0% vs. 32.6%, P=0.027), and especially the dose reduction resulted from thrombocytopenia showed significantly difference between the elderly group and non-elderly group (36.0% vs. 14.0%, P=0.035, Table 2).

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Table 2. Common adverse events and treatment discontinuation or dose modification (n (%))

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Therapy response

Overall RVR, EVR, relapse, and NR rates were not significantly different between the elderly group and non-elderly group analyzed by c² test (56% vs. 44%, 72% vs. 79%, 16% vs. 2%, and 20% vs. 14%, respectively; P=0.26, 0.508, 0.057, and 0.570, respectively). Overall SVR rate was lower in the elderly group than non-elderly group (44% vs. 75%, P=0.012, OR=0.270, 95% CI 0.095–0.768). Among patients with HCV genotype 1 (G1), SVR rate was lower in the elderly group than non-elderly group (45% vs. 77%, P=0.015, OR=0.247, 95% CI 0.078–0.781). Among patients with HCV genotype 2 (G2), SVR rate was similar in elderly group and non-elderly group (P=0.491 by Fisher's exact test; Figures 1–3), and the small number of patients with HCV G2 may limit the results.

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Figure 1. Overall treatment efficacy comparison between elderly patients and non-elderly patients. RVR: rapid virological response. EVR: early virological response. SVR: sustained virologic response. NR: non-response.

Figure 2. Comparison of treatment efficacies among HCV genotype 1 between the elderly patients and non-elderly patients. RVR: rapid virological response. EVR: early virological response. SVR: sustained virologic response. NR: non-response.

Figure 3. Treatment efficacies among HCV genotype 2. The achievement of RVR, EVR, SVR, relapse, and NR were compared between the elderly patients and non-elderly patients with HCV genotype 2.

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Figure 1

Figure 2

Figure 3

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Adjusting for the confounding factors, multiple binary logistic regression analysis performed among all patients indicated that the positive independent factors of SVR include age <60 years older (OR=4.543, 95% CI 1.410–14.642, P=0.011), HCV RNA <200 000 copies/ml (OR=0.231, 95% CI=0.056–0.950, P=0.042) and lower ALP (OR=0.972, 95% CI=0.949–0.996, P=0.022, Table 3). Among patients with HCV G1, age <60 years older (OR=4.17, 95% CI 1.164–14.936, P=0.028) and lower level of ALP (OR=0.97, 95% CI 0.944–0.996, P=0.025) were the associated factors with higher SVR rate (Table 4).

Table 3. Multiple binary Logistic regression analysis for baseline factors predictive of overall SVR

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Table 4. Multiple binary Logistic regression analysis for baseline factors predictive of SVR among HCV genotype 1

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DISCUSSION

The current study was conducted to investigate the efficacy of the combination therapy of PEG-IFNa-2a plus ribavirin among the elderly patients with CHC. Our results showed that overall SVR rates and SVR rates in patients with HCV G1 were lower in the elderly group compared to non-elderly group (44% vs. 75%, P=0.012, OR=0.270, 95% CI 0.095–0.768; 45% vs. 77%, P=0.015, OR=0.247, 95% CI 0.078–0.781). This result was consistent with previous studies,^10-12 but there were also opposite results.^13-15 The discrepancy may be due to HCV genotypes, population, antiviral treatment, and study methods in different reports. Although the elderly patients with HCV G2 had similar SVR to that of the non-elderly patients, the small number of patients with HCV G2 limited the result. So, the results from patients with HCV G2 should be considered cautiously. Besides old age, multiple binary logistic regression analysis performed among patients with HCV G1 showed that baseline lower level of ALP and HCV RNA <200 000 copies/ml may be associated with higher SVR rate among the elderly patients.

It was reported that the elderly patients were more likely to have serious side effects leading to treatment discontinuation or dose reduction,^16-20 which may partially explained the results. In our study, the proportions of patients with dose reduction due to laboratory abnormalities or other adverse events were significantly higher in the elderly group than non-elderly group (60.0% vs. 32.6%, P=0.027), and thrombocytopenia is one of the reasons showing statistical difference (P=0.035). In other words, the elderly patients had a greater frequency of dose reduction due to laboratory abnormalities, which may be the major reason for treatment inferiority. Besides the complications above, adverse events such as fever, fatigue, and other influenza-like side effects in this clinical study were common,^21-23 showing no difference between the elderly and non-elderly patients.

This study had the following limitations: the small number of the patients, and about 84% patients were HCV G1. But this study still provides us with useful information in clinical application of treatment of the elderly patients with CHC. Larger-scale randomized controlled clinical trials are needed to provide more exact proof.

In conclusion, PEG-IFNa-2a plus ribavirin combination therapy in elderly patients with HCV genotype 1 showed lower SVR than that in non-elderly patients. The dose reduction due to cytopenia during treatment and the higher baseline level of ALP in elderly patients may be the major reasons.

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