ISSN 1007-9327 CN 14-1219/R World J Gastroenterol 2010 September 21; 16(35): 4400-4409
ORIGINAL ARTICLE
Mosaburo Kainuma, Norihiro Furusyo, Eiji Kajiwara, Kazuhiro Takahashi, Hideyuki Nomura, Yuichi Tanabe, Takeaki Satoh, Toshihiro Maruyama, Makoto Nakamuta, Kazuhiro Kotoh, Koichi Azuma, Junya Shimono, Shinji Shimoda, Jun Hayashi,
The Kyushu University Liver Disease Study Group
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Mosaburo Kainuma, Norihiro Furusyo, Jun Hayashi, Department of General Internal Medicine, Kyushu University Hospital, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan
Eiji Kajiwara, Department of Internal Medicine, Nippon Steel Yawata Memorial Hospital, Harunomachi, Yahatahigashi-ku, Kitakyushu 805-0050, Japan
Kazuhiro Takahashi, Department of Medicine, Hamanomachi Hospital, Maiduru Chuo-ku, Fukuoka 810-8539, Japan
Hideyuki Nomura, The Center for Liver Disease, Shin-Kokura Hospital, Kanada, Kokurakita-ku, Kitakyushu, Fukuoka 803-8505, Japan
Yuichi Tanabe, Department of Medicine, Fukuoka City Hospital, Yoshiduka-honmachi, Hakata-ku, Fukuoka 812-0046, Japan
Takeaki Satoh, Center for Liver Disease, National Hospital Organization Kokura Medical Center, Harugaoka, Kokuraminami-ku, Kitakyushu 802-0803, Japan
Toshihiro Maruyama, Department of Medicine, Kitakyushu Municipal Medical Center, Bashaku, Kokurakita-ku Kitakyushu 802-0077, Japan
Makoto Nakamuta, Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Jigyohama, Chuou-ku, Fukuoka 810-8563, Japan
Kazuhiro Kotoh, Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan
Koichi Azuma, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan
Junya Shimono, Saiseikai Yahata General Hospital, Haruno-machi, Yahatahigashi-ku, Kitakyushu, Fukuoka 805-0050, Japan
Shinji Shimoda, Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, Higashi-Ku, Fukuoka 812-8582, Japan
The Kyushu University Liver Disease Study Group, Kyushu University, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan
Author contributions: Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Satoh T, Maruyama T, Nakamuta M, Kotoh K, Azuma K, Shimono J, Shimoda S and The Kyushu University Liver Disease Study Group carried out the field research for the study; Kainuma M analyzed the data and wrote the paper; Furusyo N and Hayashi J were instrumental in developing and coordinating the research project and reviewed the manuscript.
Correspondence to: Jun Hayashi, MD, PhD, Professor, Department of General Internal Medicine, Kyushu University Hospital, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan. hayashij@gim.med.kyushu-u.ac.jp
Telephone: +81-92-6425909 Fax: +81-92-6425916
Received: February 18, 2010 Revised: April 19, 2010
Accepted: April 26, 2010
Published online: September 21, 2010
Abstract
AIM: To analyze the efficacy and safety of a combination therapy of pegylated interferon (PEG-IFN) a-2b plus ribavirin (RBV) in older Japanese patients (65 years or older) infected with hepatitis C virus (HCV).
METHODS: This multicenter study included 938 patients with HCV genotype 1 who received 1.5 mg/kg per week PEG-IFN a-2b plus RBV 600-1000 mg/d for 48 wk and 313 HCV genotype 2 patients who received this treatment for 24 wk.
RESULTS: At 24 wk after the end of combination therapy, the overall sustained virological response (SVR) for genotypes 1 and 2 were 40.7% and 79.6%, respectively. The SVR rate decreased significantly with age in each genotype, and was markedly reduced in genotype 1 (P < 0.001). Moreover, the SVR was significantly higher in patients with genotype 1 who were less than 65 years (47.3% of 685) than in those 65 years or older (22.9% of 253) (P < 0.001) and was higher in patients with genotype 2 who were less than 65 years (82.9% of 252) than in those 65 years or older (65.6% of 61) (P = 0.004). When patients received a dosage at least 80% or more of the target dosage of PEG-IFN a-2b and 60% or more of the target dosage of RBV, the SVR rate significantly increased to 66.5% in patients less than 65 years and to 45.2% in those 65 years or older (P < 0.001). Adverse effects resulted in treatment discontinuation more often in patients with genotype 1 (14.4%) than in patients with genotype 2 (7.3%), especially by patients 65 years or older (24.1%).
CONCLUSION: PEG-IFN a-2b plus RBV treatment was effective in chronic hepatitis C patients 65 years or older who completed treatment with at least the minimum acceptable treatment dosage.
© 2010 Baishideng. All rights reserved.
Key words: Hepatitis C virus; Gerontology; Pegylated interferon; Ribavirin
Peer reviewer: Emanuel K Manesis, MD, Professor of Medicine, Athens University School of Medicine, Liver Unit, Euroclinic, 19 Mavromateon Street, Athens 10 34, Greece
Kainuma M, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Satoh T, Maruyama T, Nakamuta M, Kotoh K, Azuma K, Shimono J, Shimoda S, Hayashi J, The Kyushu University Liver Disease Study Group. Pegylated interferon a-2b plus ribavirin for older patients with chronic hepatitis C. World J Gastroenterol 2010; 16(35): 4400-4409 Available from: URL: http://www.wjgnet.com/1007-9327/full/v16/i35/4400.htm DOI: http://dx.doi.org/10.3748/wjg.v16.i35.4400
INTRODUCTION
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, affecting 170 million individuals worldwide[1]. It is well known that patients with chronic hepatitis C eventually develop hepatocellular carcinoma (HCC)[2]. Previous studies have made clear that interferon (IFN) treatment is effective for eliminating HCV[3,4] and that it significantly reduces the progression of liver fibrosis and the risk of HCC[5,6]. Antiviral treatment for chronic hepatitis C has greatly improved, and the combination treatment of pegylated (PEG)-IFN a-2b plus ribavirin (RBV) has been approved and recommended in Japan since 2004, as the first choice for chronic hepatitis C. This combination treatment attained a sustained virological response (SVR) rate of 50%-60% for genotype 1 in the United States and Europe[7]. However, SVR was relatively low (42.4%) in Japan[8], where chronic hepatitis C patients are older, indicating that older patients did not respond well to IFN treatment[9]. Moreover, the combination treatment was associated with more adverse effects than IFN monotherapy[7,10]. Older patients who have decreased cardiovascular, pulmonary and renal function have a higher incidence of adverse effects than younger patients. The rate of discontinuation due to adverse effects was reported to be significantly higher in patients aged 65 years or more than in those less than 65 years[11]. Older patients with HCV infection are at risk for progressive liver disease. It was reported that clearance of HCV after IFN therapy significantly reduces the incidence of HCC and death in older chronic hepatitis C patients[6,12]. Ikeda et al[13] demonstrated that IFN treatment is needed for 65-70-year-old patients with chronic hepatitis C to prevent the occurrence of HCC. We also consider older patients to be acceptable candidates for antiviral treatment to prevent the development of HCC, and previously reported that monotherapy with natural IFN a was not effective in older patients[9]. Therefore, in an attempt to ameliorate these problems, we decided to treat older patients with a combination of PEG-IFN plus RBV therapy.
Little data concerning the response and safety of this combination treatment in a large number of older patients with chronic HCV infection has been published. A multicenter study of the efficacy and safety of antiviral treatments for Japanese patients with chronic liver disease, the Kyushu University Liver Disease Study (KULDS), was launched in 2003[8,14]. The present prospective study was carried out to analyze the efficacy and safety of the combination treatment of PEG-IFN a-2b plus RBV in older patients.
MATERIALS AND METHODS
Patients
Treatment of chronic hepatitis C with a combination of PEG-IFN a-2b plus RBV was accepted by the Japanese Ministry of Health in October, 2004. We used this combination treatment from December 2004 to July 2008, and enrolled chronic hepatitis C patients with exclusion criteria which included: (1) clinical or biochemical evidence of hepatic decompensation, advanced cirrhosis identified by bleeding, high-risk esophageal varices, history of gastrointestinal bleeding, ascites, encephalopathy, or HCC; (2) hemoglobin level < 11.5 g/L, white blood cell count < 3 × 109/L, and platelet count < 50 × 109/L; (3) concomitant liver disease other than hepatitis C (hepatitis B surface antigen positive or HIV positive); (4) excessive active alcohol consumption > 60 g/d or drug abuse; (5) severe psychiatric disease; or (6) antiviral or corticosteroid treatment within 12 mo prior to enrollment. Patients who fulfilled the above criteria were recruited at Kyushu University Hospital and 32 affiliated hospitals in the northern Kyushu area of Japan. We have treated 2270 Japanese patients aged 18 years or older with PEG-IFN a-2b plus RBV. All patients who were positive for both antibody to HCV and HCV RNA for over 6 mo were enrolled in KULDS. Three months before the start of treatment and every 3 mo during the treatment period, each patient was tested for a-fetoprotein (AFP) and had an abdominal ultrasonographic examination. If an abnormal AFP level of 40 ng/mL and/or focal lesions on ultrasonographic examination were found at any testing, further testing for HCC was carried out, which included dynamic computed tomography, and angiography. Patients confirmed to have HCC within 3 mo after starting treatment were excluded from this study (n = 14). Of 2270 patients, 1021 were currently under combination treatment or we were not yet able to judge the effect of the combination treatment. This left the data of 1251 patients (938 with genotype 1 and 313 with genotype 2) available for analysis.
Informed consent was obtained from all patients before enrollment in this study. The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization of guidelines for good clinical practice.
Table 1 (genotype 1) and Table 2 (genotype 2) show the baseline characteristics of the enrolled patients, who were further classified into four groups according to age and genotype status: group A, genotype 1 aged less than 65 years (n = 685); group B, genotype 1 aged 65 years or older (n = 253); group C, genotype 2 aged less than 65 years (n = 252); and group D, genotype 2 aged 65 or older (n = 61). In group B, body mass index, prior combined IFN plus RBV treatment, alanine aminotransferase, albumin, white blood cell count, hemoglobin, platelet count, and creatinine clearance calculated using the Modification of Diet in Renal Disease equation[15] were significantly lower than in group A (P < 0.010). In group D, albumin, hemoglobin, platelet count, creatinine clearance and serum HCV RNA level were significantly lower than in group C (P < 0.010). The percentage of patients with platelet counts below 10 × 1010/L was significantly higher in group B (36 of 253, 14.2%) than in group A (56 of 685, 8.2%) (P = 0.006), however, there was no significant difference between group C (16 of 252, 6.3%) and group D (7 of 61, 11.5%).
Liver histology
Liver biopsy was performed in 555 patients (59.2%) with genotype 1 and 209 patients (66.8%) with genotype 2. The other patients refused liver biopsy. Fibrosis was staged on a 0-4 scale as follows: F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = portal fibrosis with few septa, F3 = numerous septa without cirrhosis, F4 = cirrhosis. Liver fibrosis was more advanced in group B than in group A and was more advanced in group D than in group C (P = 0.008, P < 0.001, respectively).
Treatment regimen
All patients were treated with a weight-based, 1.5 mg/kg weekly dose of subcutaneous PEG-IFN a-2b (PegIntron, Schering-Plough, Osaka, Japan), in combination with RBV (Rebetol, Schering-Plough), which was given orally at a daily dose of 600-1000 mg based on body weight (600 mg for patients weighing less than 60 kg, 800 mg for those weighing 60-80 kg, and 1000 mg for those weighing 80 kg or over). The length of treatment was 48 wk for patients with HCV genotype 1 and 24 wk for patients with genotype 2. The above duration and dosage are those approved by the Japanese Ministry of Health, Labor and Welfare. Patients were considered to have RBV-induced anemia if the hemoglobin level decreased to less than 100 g/L. In such cases, a reduction in the dose of RBV was required. Patients aged 65 years or older had a significantly higher frequency of RBV dose reduction during the treatment period than those aged less than 65 years old (HCV genotype 1: group A vs group B, 41.2% vs 49.0%, P = 0.032, genotype 2: group C vs group D, 28.6% vs 54.1%, P < 0.001). Some patients also had PEG-IFN a-2b-induced psychological adverse effects or a decrease in white blood cell and platelet counts. In such cases, a reduction in the dosage of PEG-IFN a-2b was required. Both PEG-IFN a-2b and RBV were discontinued if the hemoglobin level, white blood cell count, or platelet count fell below 85 g/L, 1 × 109/L, and 25 × 109/L, respectively. The treatment was discontinued if severe general fatigue, hyperthyroidism, interstitial pneumonia, or severe hemolytic disorders developed, continuation of treatment was judged not to be possible by the attending physician, or if the patient desired discontinuation of treatment.
Determination of baseline HCV RNA level and HCV genotype
The pretreatment, baseline, serum HCV RNA level was measured by a quantitative HCV RNA polymerase chain reaction (PCR) assay (COBAS Amplicor HCV Monitor Test v 2.0 using the 10-fold dilution method; Roche Diagnostics, Tokyo, Japan), which has a lower limit of quantitation of 5000 IU (13 500 copies)/mL (5 kIU/mL) and an outer limit of quantitation of 5 100 000 IU/mL (5100 kIU/mL). The HCV genotype was determined by type-specific primers of the core region of the HCV genome. The protocol for genotyping was carried out as previously described[3].
Efficacy of treatment
End of treatment (EOT) response and SVR were defined as serum HCV RNA undetectable at the end of treatment and at 24-wk follow-up after the end of treatment, respectively. EOT response and SVR were defined as non-detectable HCV-RNA as measured by qualitative COBAS Amplicor HCV Monitor Test v 2.0, with the results labeled as positive or negative. The lower limit of detection was 50 IU/mL (0.5 kIU/mL). The analysis of EOT and SVR was performed on an intention-to-treat basis.
Statistical analysis
Continuous data are expressed as mean ± SD. The statistics were carried out using a commercially available software package (BMDP Statistical Software Inc., Los Angeles, CA, USA) for the IBM 3090 system computer. The c2 test, Fisher’s exact test and Kruskal-Wallis test were used to determine the differences in baseline clinical characteristics, safety, efficacy of the combination therapy, adherence to the total dose, and the association between the adherence and SVR. Logistic regression analysis was used to identify the association between age and SVR. A P < 0.05 was considered significant.
RESULTS
EOT response rate by intention-to-treat analysis
Among patients with genotype 1, the EOT response rate was significantly higher in group A (497 of 685, 72.5%) than in group B (129 of 253, 45.0%) (P < 0.001). Among patients with genotype 2, there was no significant difference between groups C (239 of 252, 94.8%) and D (55 of 61, 90.1%).
SVR rate by intention-to-treat analysis
Of 1251 patients, 631 (50.4%) achieved SVR in the intention-to-treat analysis. The SVR rate was significantly higher for genotype 2 (249 of 313, 79.6%) than for genotype 1 patients (382 of 938, 40.7%) (P < 0.001). Among patients with genotype 1, the SVR rate was significantly higher in group A (324 of 685, 47.3%) than in group B (58 of 253, 22.9%) (P < 0.001). Among patients with genotype 2, SVR was also significantly higher in group C (209 of 252, 82.9%) than in group D (40 of 61, 65.6%) (P = 0.004). The rate of SVR was significantly higher for females (113 of 128, 88.3%) than for males (96 of 124, 77.4%) in group C only (Figure 1). Furthermore, we analyzed whether or not the SVR rate differed according to the age at which the combination treatment of PEG-IFN a-2b plus RBV was started. The results showed that the SVR rate decreased significantly with age for both genotype 1 and 2. SVR was achieved by 5.6%-26.3% of genotype 1 patients aged 70 years or older, and by 57.1%-100% of genotype 2 patients aged 70 years or older (Figure 2).
We previously reported a minimum acceptable dose of at least 80% or more of the target dosage of PEG-IFN a-2b and 60% or more of the target dosage of RBV for the successful treatment of Japanese patients with genotype 1[8]. Therefore, we analyzed the SVR rates in patients with genotype 1 by the dosage they actually received during treatment (a total dose of at least 80% or more of PEG-IFN a-2b and 60% or more of RBV) (Table 3). The number who received at least this minimum acceptable dosage during treatment were 278 (40.6%) of 685 patients in group A and 62 (24.5%) of 253 in group B, significantly lower in group B than in group A (P < 0.001). Compared with patients who received less than the minimum acceptable dosage, in patients who received at least this minimum dosage, the SVR rates increased from 34.2% to 66.5% in group A patients and from 15.7% to 45.2% (P < 0.001) in group B patients. No significant difference between groups C and D was observed. On comparing patients whose platelet count was under 10 × 1010/L, the SVR rate for genotype 1 was significantly lower in group B (2 of 36, 5.6%) than in group A (16 of 56, 28.6%) (P < 0.001). Among the patients with genotype 2, SVR was not significantly different between group C (9 of 16, 56.3%) and group D (2 of 7, 28.6%).
In a comparison of the SVR rate in patients with or without one or more previous courses of IFN plus RBV, there was no significant difference between the genotypes (genotype 1: 118 of 310, 38.1% vs 264 of 628, 42.0%, genotype 2: 44 of 72, 61.1% vs 141 of 241, 58.5%). Furthermore, we compared the EOT response rate and SVR rate of cirrhosis patients whose liver fibrosis was F4, and found no significant difference between groups A (EOT: 16 of 30, 53.3%, SVR: 7 of 30, 23.3%) and B (EOT: 6 of 17, 35.3%, SVR: 2 of 17, 11.8%). In addition, no significant difference was found between groups C (EOT: 8 of 10, 80.0%, SVR: 6 of 10, 60.0%) and D (EOT: 9 of 12, 75.0%, SVR: 5 of 12, 41.7%).
Discontinuation of PEG-IFN a-2b plus RBV treatment and adverse effects
Of 1251 patients, 314 (25.1%) did not complete PEG-IFN a-2b plus RBV treatment due to adverse effects or other reasons. The discontinuation rate was significantly higher in patients with genotype 1 (273 of 938, 29.1%) than in those with genotype 2 (41 of 313, 13.1%) (P < 0.001) (Tables 4 and 5). Furthermore, the rate of discontinuation due to adverse effects was significantly higher in patients with genotype 1 (135 of 938, 14.4%) than in those with genotype 2 (23 of 313, 7.3%) (P < 0.010). The rates of discontinuation due to lack of treatment efficacy and for economic reasons (loss of job, inability to pay the medical costs) were also significantly higher in patients with genotype 1 (55 of 938, 5.9%, 15 of 938, 1.6%) than in those with genotype 2 (1 of 313, 0.3%, 0 of 938, 0%) (P < 0.001 and P = 0.025, respectively).
For genotype 1 patients, the discontinuation rate was significantly higher in group B (106 of 253, 42.9%) than in group A (167 of 685, 24.4%) (P < 0.001), and the rate of discontinuation due to adverse effects was also significantly higher in group B (61 of 253, 24.1%) than in group A (74 of 685, 10.8%) (P < 0.001). General fatigue was the most frequent adverse effect, and was significantly more frequent in group B than in group A (P < 0.001). However, in these group 1 patients, RBV was reduced due to anemia in 12.5% (3 of 24) of group A and in 30.4% (7 of 23) of group B. Furthermore, rash and thrombocytopenia were significantly more frequent in group B than in group A (P = 0.014 and P = 0.007, respectively). In group A, depression was significantly more frequent in females than in males (P = 0.012). In genotype 2 patients, treatment discontinuation did not differ between group C (33 of 252, 13.1%) and group D (8 of 61, 13.1%), and the rate of discontinuation due to adverse effects did not differ between these groups (17 of 252, 6.7%, 6 of 61, 9.8%, respectively).
The mean time to discontinuation in group A (21.6 ± 11.9 wk) was not significantly different from group B (21.5 ± 12.6 wk), and the mean time in group C (11.0 ± 6.8 wk) was also not significantly different from group D (11.6 ± 6.0 wk). There was no significant difference between male and female patients in each group (male: 21.0 ± 12.4 vs female: 22.1 ± 11.8 in group 1, male: 11.3 ± 7.1 vs female: 10.9 ± 6.1 in group 2).
HCC was not seen in genotype 2 patients; only in patients with genotype 1 (29.5 ± 9.9 wk) and was more frequent in group B (5 of 253, 2.0%) than in group A (2 of 685, 0.3%) (P = 0.008).
DISCUSSION
In a large, national, multicenter Greek study involving 993 treated and 734 untreated patients with chronic hepatitis C, patients with cirrhosis, showed a protective effect of treatment even among those without SVR. For patients without cirrhosis, the beneficial effect of IFN a treatment was particularly evident in older patients; patients with the worst prognosis if left untreated. Therefore, IFN a-based treatment should be offered to older persons, as these are the patients with the greatest potential benefit and may achieve SVR[16]. In Japan, the prevalence of chronic HCV infection increases with age, however, the optimal management of older patients has not yet been accurately defined. Whether or not to treat patients older than 65 years with antiviral treatment is highly debated, especially in terms of cost/benefit ratio. In addition, the natural history of chronic hepatitis C in elderly patients is not accurately known, as the presence of comorbidity can affect illness progression and life expectancy. HCV became more prevalent in Japan decades before the United States[17]. Japanese patients with chronic hepatitis C treated with IFN are currently 10 to 15 years older than corresponding patients in the United States and European countries, where patients treated with antiviral treatment tend to average 45 years of age[18-20]. Therefore, our results can serve as a world-wide model for the treatment of older chronic hepatitis C patients.
It has been well documented that the combination therapy of PEG-IFN a-2b plus RBV is more effective than previous IFN monotherapy in chronic hepatitis C patients[7,8]. There have been four studies on the efficacy of PEG-IFN plus RBV therapy in patients 65 years or older with genotype 1, which revealed low rates of SVR (31.1%-51.9%)[21-24]. However, these studies were too small (11-93 patients) for conclusive recommendations to be made. Because the present study was a large multicenter design, it is useful for clarifying the efficacy and safety of PEG-IFN plus RBV combination therapy in older patients. The present study confirmed the results of our previous study which showed that the SVR rate was significantly higher for genotype 2 than for genotype 1 patients[8]. Another important result was that the ability to take at least a minimum acceptable dosage during treatment increased the SVR rate by about three times in older patients with genotype 1. This result also confirmed previous studies which indicated the importance of giving at least the minimum acceptable treatment dosage in patients infected with HCV genotype 1, especially older patients[23,24].
Secondly, we compared discontinuation of treatment by genotype and sex. In genotype 1 patients, adverse effects were seen more often in older than in younger patients. This was the most important reason why the rate of treatment discontinuation was higher in older than in younger patients, and affected the outcome of PEG-IFN a-2b plus RBV combination therapy. General fatigue was the most common adverse effect in older patients. Because older patients often have impaired renal function, they have increased blood levels of RBV[25,26]. They are also inclined to be anemic and to have general fatigue. However, only a small number of older patients in the present study had reduced RBV due to anemia. Therefore, general fatigue is probably a direct adverse effect of PEG-IFN a-2b. We previously reported that herbal medicine relieved the adverse effects of IFN, including general fatigue[27]. Herbal medicine may be useful for mitigating general fatigue during PEG-IFN a-2b plus RBV combination treatment, especially in older patients.
The rate of discontinuation was lower in patients with genotype 2 than in patients with genotype 1, and there was no difference between the older and the younger patients with genotype 2. These results are possibly a consequence of the shorter term of treatment in genotype 2 and the many genotype 1 patients who discontinued due to lack of efficacy.
Two of the characteristics of older patients in the present study were that both hemoglobin and platelet count were significantly lower than in younger patients. The SVR rate was significantly lower when the platelet count was less than 10 × 1010/L. Furthermore, the older genotype 1 patients were often forced to discontinue treatment due to thrombocytopenia and the occurrence of HCC. These findings appear to result from advanced liver fibrosis in older chronic hepatitis C patients. Therefore, the possibility of HCC during long-term IFN treatment in older patients must be considered.
We previously reported that older female patients had a low response to IFN-a monotherapy[9], and other investigators have reported that older female patients have a poor response to PEG-IFN a-2b plus RBV[22,28]. Although our data showed that sex was not related to SVR, the reason for this finding was not fully elucidated. In any case, studies have conclusively shown that it is important to begin treatment with PEG-IFN a-2b plus RBV combination therapy as soon as possible. Our data suggest that age may be a more important factor than sex for increasing the rate of SVR. Resistance to treatment in older patients may be due to IFN-immunomodulation, advanced liver fibrosis, or reduced dosage.
To maximize adherence to the optimal treatment regimen, the treatment schedule can be modified or other therapeutic modalities added, such as hematopoietic growth factors[29] or the new thrombopoietin-receptor agonist, eltrombopag, for the antiviral treatment of older patients with chronic hepatitis C[30]. A further individualized treatment protocol based on viral kinetics might be more practical[31].
In conclusion, PEG-IFN a-2b plus RBV treatment was effective in the treatment of older chronic hepatitis C patients when they received at least the minimum acceptable treatment dosage. However, there were frequent adverse effects and treatment discontinuation. It is necessary to control for adverse effects that might interrupt treatment and to begin this combination therapy as soon as possible, especially in older patients.
ACKNOWLEDGMENTS
We greatly thank Drs. Yasunori Sawayama, Masayuki Murata, Shigeru Otaguro, Hiroaki Taniai, Eiichi Ogawa, Kazuhiro Toyoda, Haru Mukae, Tsunehisa Koga, Kunimitsu Eiraku, Takeshi Ihara, Hiroaki Ikezaki and Takeo Hayashi of our department for their clinical and research assistance with the present study.
COMMENTS
Background
Whether or not to treat patients older than 65 years with antiviral treatment is highly debated, especially in terms of cost/benefit ratio. However, there is little data concerning the response and safety of combination treatment for a large number of older patients with chronic hepatitis C virus infection. Therefore, in an attempt to ameliorate these problems, the authors decided to treat older patients with pegylated interferon (PEG-IFN) a-2b plus ribavirin (RBV) combination therapy.
Research frontiers
The combination treatment of PEG-IFN a-2b plus RBV improved the sustained virological response rate in chronic hepatitis C patients. However, the current issue is whether or not to treat older patients because of low response and high dropout rate.
Innovations and breakthroughs
There have been four studies on the efficacy of PEG-IFN plus RBV therapy in patients 65 years or older with genotype 1. However, these studies were too small (11-93 patients) for conclusive recommendations to be made. This study is very useful for clarifying the efficacy and safety of PEG-IFN plus RBV combination therapy in older patients, because of its large scale, multicenter design.
Applications
The study demonstrated that PEG-IFN a-2b plus RBV treatment was effective in chronic hepatitis C patients 65 years or older who completed treatment with at least the minimum required treatment dosage. Furthermore, this study suggested that the combination treatment and beginning this therapy as soon as possible are important, especially in older patients.
Peer review
The study has been well conducted and includes a large number of patients. Results have been described in a lucid and informative manner and are of clinical relevance.
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11 Arase Y, Suzuki F, Suzuki Y, Akuta N, Kawamura Y, Kobayashi M, Hosaka T, Sezaki H, Yatsuji H, Kobayashi M, Ikeda K, Kumada H. Side effects of combination therapy of peginterferon and ribavirin for chronic hepatitis-C. Intern Med 2007; 46: 1827-1832
12 Arase Y, Ikeda K, Suzuki F, Suzuki Y, Saitoh S, Kobayashi M, Akuta N, Someya T, Koyama R, Hosaka T, Sezaki H, Kobayashi M, Kumada H. Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C. Intervirology 2007; 50: 16-23
13 Ikeda K, Arase Y, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Saitoh S, Suzuki F, Suzuki Y, Kumada H. Necessities of interferon therapy in elderly patients with chronic hepatitis C. Am J Med 2009; 122: 479-486
14 Furusyo N, Katoh M, Tanabe Y, Kajiwara E, Maruyama T, Shimono J, Sakai H, Nakamuta M, Nomura H, Masumoto A, Shimoda S, Takahashi K, Azuma K, Hayashi J. Interferon alpha plus ribavirin combination treatment of Japanese chronic hepatitis C patients with HCV genotype 2: a project of the Kyushu University Liver Disease Study Group. World J Gastroenterol 2006; 12: 784-790
15 Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982-992
16 Manesis EK, Papatheodoridis GV, Touloumi G, Karafoulidou A, Ketikoglou J, Kitis GE, Antoniou A, Kanatakis S, Koutsounas SJ, Vafiadis I. Natural course of treated and untreated chronic HCV infection: results of the nationwide Hepnet.Greece cohort study. Aliment Pharmacol Ther 2009; 29: 1121-1130
17 Tanaka Y, Hanada K, Mizokami M, Yeo AE, Shih JW, Gojobori T, Alter HJ. Inaugural Article: A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades. Proc Natl Acad Sci USA 2002; 99: 15584-15589
18 Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, Shiffman ML, Zeuzem S, Craxi A, Ling MH, Albrecht J. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339: 1493-1499
19 McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339: 1485-1492
20 Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, Albrecht J. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998; 352: 1426-1432
21 Antonucci G, Longo MA, Angeletti C, Vairo F, Oliva A, Comandini UV, Tocci G, Boumis E, Noto P, Solmone MC, Capobianchi MR, Girardi E. The effect of age on response to therapy with peginterferon alpha plus ribavirin in a cohort of patients with chronic HCV hepatitis including subjects older than 65 yr. Am J Gastroenterol 2007; 102: 1383-1391
22 Thabut D, Le Calvez S, Thibault V, Massard J, Munteanu M, Di Martino V, Ratziu V, Poynard T. Hepatitis C in 6,865 patients 65 yr or older: a severe and neglected curable disease? Am J Gastroenterol 2006; 101: 1260-1267
23 Honda T, Katano Y, Shimizu J, Ishizu Y, Doizaki M, Hayashi K, Ishigami M, Itoh A, Hirooka Y, Nakano I, Urano F, Yoshioka K, Toyoda H, Kumada T, Goto H. Efficacy of peginterferon-alpha-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C. Liver Int 2010; 30: 527-537
24 Huang CF, Yang JF, Dai CY, Huang JF, Hou NJ, Hsieh MY, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY, Chuang WL, Yu ML. Efficacy and safety of pegylated interferon combined with ribavirin for the treatment of older patients with chronic hepatitis C. J Infect Dis 2010; 201: 751-759
25 Paroni R, Del Puppo M, Borghi C, Sirtori CR, Galli Kienle M. Pharmacokinetics of ribavirin and urinary excretion of the major metabolite 1,2,4-triazole-3-carboxamide in normal volunteers. Int J Clin Pharmacol Ther Toxicol 1989; 27: 302-307
26 Bruchfeld A, Lindahl K, Schvarcz R, Ståhle L. Dosage of ribavirin in patients with hepatitis C should be based on renal function: a population pharmacokinetic analysis. Ther Drug Monit 2002; 24: 701-708
27 Kainuma M, Hayashi J, Sakai S, Imai K, Mantani N, Kohta K, Mitsuma T, Shimada Y, Kashiwagi S, Terasawa K. The efficacy of herbal medicine (kampo) in reducing the adverse effects of IFN-beta in chronic hepatitis C. Am J Chin Med 2002; 30: 355-367
28 Sezaki H, Suzuki F, Kawamura Y, Yatsuji H, Hosaka T, Akuta N, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Miyakawa Y, Kumada H. Poor response to pegylated interferon and ribavirin in older women infected with hepatitis C virus of genotype 1b in high viral loads. Dig Dis Sci 2009; 54: 1317-1324
29 Afdhal NH, Dieterich DT, Pockros PJ, Schiff ER, Shiffman ML, Sulkowski MS, Wright T, Younossi Z, Goon BL, Tang KL, Bowers PJ. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126: 1302-1311
30 McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, Blackman N, Jenkins J, Afdhal NH. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007; 357: 2227-2236
31 Berg T, Weich V, Teuber G, Klinker H, Möller B, Rasenack J, Hinrichsen H, Gerlach T, Spengler U, Buggisch P, Balk H, Zankel M, Neumann K, Sarrazin C, Zeuzem S. Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients. Hepatology 2009; 50: 369-377
S- Editor Tian L L- Editor Webster JR E- Editor Lin YP
Source
October 1, 2010
Impact of early elevation of serum bilirubin during treatment with pegylated interferon and ribavirin in patients with chronic hepatitis C
Hepatology Research
Volume 40, Issue 10, pages 963–970, October 2010
Masatoshi Ishigami, Kazuhiko Hayashi, Yoshiaki Katano, Akihiro Itoh, Yoshiki Hirooka, Hidemi Goto
Department of Gastroenterology, Nagoya University School of Medicine, Nagoya, Japan
*Correspondence: Dr Masatoshi Ishigami, Department of Gastroenterology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. Email: masaishi@med.nagoya-u.ac.jp
Article first published online: 28 SEP 2010
DOI: 10.1111/j.1872-034X.2010.00711.x
Keywords:
bilirubin;hemolytic anemia;hepatitis C virus;pegylated interferon and ribavirin
Aim: Hemolytic anemia is a well-known adverse effect of interferon and ribavirin combination treatment. Herein, we analyzed the impact of early elevation of serum bilirubin level as a marker for predicting severe anemia during treatment.
Methods: We studied 245 chronic hepatitis C patients who received pegylated interferon and ribavirin combination treatment, and divided them using two different threshold levels: (i) elevation of total bilirubin of 0.5 mg/dL or more within 1 week of starting treatment; and (ii) drop of hemoglobin (Hb) by 3 g/dL or more within 4 weeks of starting treatment. We compared the dynamics in each group and then investigated independent factors for predicting a severe Hb drop (≥3 g/dL) at 4 weeks after beginning treatment and dose reduction of ribavirin.
Results: Total bilirubin levels at 1 week were significantly higher in patients with a Hb drop of 3 g/dL or more as compared to those with a drop of less than 3 g/dL (P < 0.0001). Hb levels at 4 weeks were significantly lower in the group of 0.5 mg/dL or more increase of total bilirubin levels than in the group with a less than 0.5 mg/dL increase (P < 0.0001). Therefore, elevation of total bilirubin after 1 week of treatment was shown to be an independent factor for predicting severe Hb drop (≥3 g/dL) at 4 weeks (P < 0.0001), and dose reduction of ribavirin during treatment (P = 0.0321).
Conclusion: Early elevation of serum bilirubin level was found to be a possible predictive marker of both a severe drop of Hb in the early phase of treatment and dose reduction of ribavirin.
Source
Volume 40, Issue 10, pages 963–970, October 2010
Masatoshi Ishigami, Kazuhiko Hayashi, Yoshiaki Katano, Akihiro Itoh, Yoshiki Hirooka, Hidemi Goto
Department of Gastroenterology, Nagoya University School of Medicine, Nagoya, Japan
*Correspondence: Dr Masatoshi Ishigami, Department of Gastroenterology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. Email: masaishi@med.nagoya-u.ac.jp
Article first published online: 28 SEP 2010
DOI: 10.1111/j.1872-034X.2010.00711.x
Keywords:
bilirubin;hemolytic anemia;hepatitis C virus;pegylated interferon and ribavirin
Aim: Hemolytic anemia is a well-known adverse effect of interferon and ribavirin combination treatment. Herein, we analyzed the impact of early elevation of serum bilirubin level as a marker for predicting severe anemia during treatment.
Methods: We studied 245 chronic hepatitis C patients who received pegylated interferon and ribavirin combination treatment, and divided them using two different threshold levels: (i) elevation of total bilirubin of 0.5 mg/dL or more within 1 week of starting treatment; and (ii) drop of hemoglobin (Hb) by 3 g/dL or more within 4 weeks of starting treatment. We compared the dynamics in each group and then investigated independent factors for predicting a severe Hb drop (≥3 g/dL) at 4 weeks after beginning treatment and dose reduction of ribavirin.
Results: Total bilirubin levels at 1 week were significantly higher in patients with a Hb drop of 3 g/dL or more as compared to those with a drop of less than 3 g/dL (P < 0.0001). Hb levels at 4 weeks were significantly lower in the group of 0.5 mg/dL or more increase of total bilirubin levels than in the group with a less than 0.5 mg/dL increase (P < 0.0001). Therefore, elevation of total bilirubin after 1 week of treatment was shown to be an independent factor for predicting severe Hb drop (≥3 g/dL) at 4 weeks (P < 0.0001), and dose reduction of ribavirin during treatment (P = 0.0321).
Conclusion: Early elevation of serum bilirubin level was found to be a possible predictive marker of both a severe drop of Hb in the early phase of treatment and dose reduction of ribavirin.
Source
Chronic cough associated with interferon/ribavirin therapy for hepatitis C
Journal of Clinical Pharmacy and Therapeutics
Early View (Articles online in advance of print)
P. V. Dicpinigaitis MD, F. R. Weiner MD
Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
*Correspondence: Peter Dicpinigaitis, MD, Weiler Division/Montefiore Medical Center, 1825 Eastchester Road, Bronx, NY 10461, USA. Tel.: (718) 904 2676; fax (718) 904 2880; e-mail: pdicpinigaitis@pol.net
Article first published online: 30 SEP 2010
DOI: 10.1111/j.1365-2710.2010.01182.x
© 2010 Blackwell Publishing Ltd
Summary
What is known and Objective: The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy.
Case summary: Four patients without history of respiratory symptoms developed chronic cough temporally related to initiation of therapy with pegylated interferon and ribavirin for chronic hepatitis C infection. Cough resolved within 2–6 weeks after completion of a 48-week course of therapy. To measure cough reflex sensitivity, capsaicin cough challenge testing was performed 1 month prior to cessation of therapy, and 1 and 2 months after completion of treatment. In all patients, cough reflex sensitivity, as measured by C5, the concentration of capsaicin inducing 5 or more coughs, was significantly enhanced during treatment compared to 1 month after completion of therapy (P = 0·016).
What is new and Conclusion: Previous studies have observed that cough occurs more commonly in patients receiving the combination of interferon and ribavirin compared to interferon alone, thus implicating ribavirin as the causal agent. Our data demonstrate that it does so by reversible enhancement of cough reflex sensitivity. Clinicians should be aware of this potential treatment-related effect, so as to avoid unnecessary and costly diagnostic evaluations seeking an alternative aetiology of cough.
Source
Early View (Articles online in advance of print)
P. V. Dicpinigaitis MD, F. R. Weiner MD
Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA
*Correspondence: Peter Dicpinigaitis, MD, Weiler Division/Montefiore Medical Center, 1825 Eastchester Road, Bronx, NY 10461, USA. Tel.: (718) 904 2676; fax (718) 904 2880; e-mail: pdicpinigaitis@pol.net
Article first published online: 30 SEP 2010
DOI: 10.1111/j.1365-2710.2010.01182.x
© 2010 Blackwell Publishing Ltd
Summary
What is known and Objective: The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy.
Case summary: Four patients without history of respiratory symptoms developed chronic cough temporally related to initiation of therapy with pegylated interferon and ribavirin for chronic hepatitis C infection. Cough resolved within 2–6 weeks after completion of a 48-week course of therapy. To measure cough reflex sensitivity, capsaicin cough challenge testing was performed 1 month prior to cessation of therapy, and 1 and 2 months after completion of treatment. In all patients, cough reflex sensitivity, as measured by C5, the concentration of capsaicin inducing 5 or more coughs, was significantly enhanced during treatment compared to 1 month after completion of therapy (P = 0·016).
What is new and Conclusion: Previous studies have observed that cough occurs more commonly in patients receiving the combination of interferon and ribavirin compared to interferon alone, thus implicating ribavirin as the causal agent. Our data demonstrate that it does so by reversible enhancement of cough reflex sensitivity. Clinicians should be aware of this potential treatment-related effect, so as to avoid unnecessary and costly diagnostic evaluations seeking an alternative aetiology of cough.
Source
September 30, 2010
NVHR: In Fighting for 'Six Winnable Battles,' CDC May Lose the Nation's Overall Public-Health War
WASHINGTON, Sept. 30 /PRNewswire-USNewswire/ -- In response to the Centers for Disease Control (CDC) Director Dr. Thomas Frieden's release of "six winnable battles" in health care, Ms. Lorren Sandt, Chair of the National Viral Hepatitis Roundtable (NVHR) and Executive Director of Caring Ambassadors Program, based in Portland, Oregon, released the following statement:
"The CDC's newly released 'six winnable battles' strategy makes a mockery of the broad-based, comprehensive, and integrated public-health strategy that our nation so desperately needs. In seeking to win six narrowly defined health care battles, the CDC may well lose the overall public-health war.
"Chronic viral hepatitis B and C are among dozens of conditions that are shortchanged by this PR-driven public-health approach from CDC. We can and must do better. How can a vaccine preventable virus, hepatitis B, and the only virus we can cure, hepatitis C, fail to make this list?
"Chronic viral hepatitis afflicts more than 5 million Americans directly and, by extension, tens of millions more of their loved ones. Most Americans are not aware they are infected until they present with serious related illnesses. Without adequate screening and treatment, chronic viral hepatitis often progresses to cirrhosis, liver cancer, and liver failure.
"Over the past year, experts from the Institute of Medicine, the American Association for the Study of Liver Diseases, and the Trust for America's Health have all identified how best to address the viral hepatitis epidemic with common-sense action plans. Regrettably, the Administration is lacking the political will to implement them.
"The CDC's omission of viral hepatitis from its list of 'winnable battles' is not simply an oversight – it's an abdication of duty to many Americans who may well lose their battle with chronic viral hepatitis in the decades to come."
NVHR is a coalition of more than 170 public, private, and voluntary organizations dedicated to reducing the incidence of infection, morbidity, and mortality from chronic viral hepatitis that afflicts more than 5 million Americans. http://www.nvhr.org/
SOURCE National Viral Hepatitis Roundtable
RELATED LINKS
http://www.nvhr.org/
Source
Also See: CDC chief picks 6 'winnable battles' in health
"The CDC's newly released 'six winnable battles' strategy makes a mockery of the broad-based, comprehensive, and integrated public-health strategy that our nation so desperately needs. In seeking to win six narrowly defined health care battles, the CDC may well lose the overall public-health war.
"Chronic viral hepatitis B and C are among dozens of conditions that are shortchanged by this PR-driven public-health approach from CDC. We can and must do better. How can a vaccine preventable virus, hepatitis B, and the only virus we can cure, hepatitis C, fail to make this list?
"Chronic viral hepatitis afflicts more than 5 million Americans directly and, by extension, tens of millions more of their loved ones. Most Americans are not aware they are infected until they present with serious related illnesses. Without adequate screening and treatment, chronic viral hepatitis often progresses to cirrhosis, liver cancer, and liver failure.
"Over the past year, experts from the Institute of Medicine, the American Association for the Study of Liver Diseases, and the Trust for America's Health have all identified how best to address the viral hepatitis epidemic with common-sense action plans. Regrettably, the Administration is lacking the political will to implement them.
"The CDC's omission of viral hepatitis from its list of 'winnable battles' is not simply an oversight – it's an abdication of duty to many Americans who may well lose their battle with chronic viral hepatitis in the decades to come."
NVHR is a coalition of more than 170 public, private, and voluntary organizations dedicated to reducing the incidence of infection, morbidity, and mortality from chronic viral hepatitis that afflicts more than 5 million Americans. http://www.nvhr.org/
SOURCE National Viral Hepatitis Roundtable
RELATED LINKS
http://www.nvhr.org/
Source
Also See: CDC chief picks 6 'winnable battles' in health
Achillion Announces Dosing of First Patient in Phase II Trial of ACH-1625 for the Treatment of Hepatitis C
Sept. 30, 2010, 4:00 p.m. EDT
NEW HAVEN, Conn., Sep 30, 2010 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. /quotes/comstock/15*!achn/quotes/nls/achn (ACHN 3.02, -0.03, -0.98%) , a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today announced that the Company has initiated patient dosing in a Phase II clinical trial of ACH-1625 for the treatment of hepatitis C virus (HCV) infection. ACH-1625 is a potent small molecule inhibitor of HCV protease, an enzyme necessary for viral replication. The drug candidate was discovered and is being advanced by Achillion.
The clinical trial is a Phase IIa, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and antiviral activity of oral ACH-1625 in combination with pegylated interferon alfa-2a and ribavirin after 28 days of dosing and after 12 weeks of dosing in subjects with chronic hepatitis C virus genotype 1. The trial will take place in the United States and Europe and is designed to enroll approximately 120 HCV-infected patients. The 28-day and 12-week trial data are anticipated to be announced in the first and fourth quarters of 2011, respectively.
"This Phase II clinical trial will allow us to establish the most appropriate once-daily dose to use in longer-term trials, and will augment our existing safety database for ACH-1625 in humans," stated Elizabeth A. Olek, D.O., Vice President and Chief Medical Officer of Achillion. "The results will also provide important combination data for use of ACH-1625 with standard of care. We anticipate that the 28-day segment of the trial will provide us with rapid viral response (RVR) data early next year, and that the 12-week segment will provide extended viral response (cEVR) data by the end of next year."
"The initiation of Phase II dosing for ACH-1625 is a very important step in further solidifying this compound's profile as a potentially best-in-class protease inhibitor for HCV treatment," said Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "We believe ACH-1625 has the potential to provide an improved safety and tolerability profile, a more convenient dosing schedule and an extended period of viral suppression compared to currently available treatments for HCV-infected patients."
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies completed to date, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no serious adverse events, and no clinically significant changes in vital signs, electrocardiograms (ECGs) or laboratory evaluations. HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 1log10 from baseline through day 12, the last day of viral load measurement in the study.
About HCV
The hepatitis C virus (HCV) is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, injectable route of administration and high cost.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease --hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including additional dosing cohorts. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are uncertainties relating to results of clinical trials and unexpected regulatory actions or delays. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
ACHN-G
This news release was distributed by GlobeNewswire, http://www.globenewswire.com/
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Lippert/Heilshorn & Associates, Inc.
Anne Marie Fields
(212) 838-3777
afields@lhai.com
Bruce Voss
(310) 691-7100
bvoss@lhai.com
Source
NEW HAVEN, Conn., Sep 30, 2010 (GlobeNewswire via COMTEX) -- Achillion Pharmaceuticals, Inc. /quotes/comstock/15*!achn/quotes/nls/achn (ACHN 3.02, -0.03, -0.98%) , a leader in the discovery and development of small molecule drugs to combat the most challenging infectious diseases, today announced that the Company has initiated patient dosing in a Phase II clinical trial of ACH-1625 for the treatment of hepatitis C virus (HCV) infection. ACH-1625 is a potent small molecule inhibitor of HCV protease, an enzyme necessary for viral replication. The drug candidate was discovered and is being advanced by Achillion.
The clinical trial is a Phase IIa, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and antiviral activity of oral ACH-1625 in combination with pegylated interferon alfa-2a and ribavirin after 28 days of dosing and after 12 weeks of dosing in subjects with chronic hepatitis C virus genotype 1. The trial will take place in the United States and Europe and is designed to enroll approximately 120 HCV-infected patients. The 28-day and 12-week trial data are anticipated to be announced in the first and fourth quarters of 2011, respectively.
"This Phase II clinical trial will allow us to establish the most appropriate once-daily dose to use in longer-term trials, and will augment our existing safety database for ACH-1625 in humans," stated Elizabeth A. Olek, D.O., Vice President and Chief Medical Officer of Achillion. "The results will also provide important combination data for use of ACH-1625 with standard of care. We anticipate that the 28-day segment of the trial will provide us with rapid viral response (RVR) data early next year, and that the 12-week segment will provide extended viral response (cEVR) data by the end of next year."
"The initiation of Phase II dosing for ACH-1625 is a very important step in further solidifying this compound's profile as a potentially best-in-class protease inhibitor for HCV treatment," said Michael D. Kishbauch, President and Chief Executive Officer of Achillion. "We believe ACH-1625 has the potential to provide an improved safety and tolerability profile, a more convenient dosing schedule and an extended period of viral suppression compared to currently available treatments for HCV-infected patients."
About ACH-1625
ACH-1625 is an HCV protease inhibitor designed and synthesized based on crystal structures of enzyme/inhibitor complex. ACH-1625 is an open chain, non-covalent, reversible inhibitor of NS3 protease. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures. With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios demonstrated in preclinical studies, Achillion believes that ACH-1625 has the potential for once daily dosing. ACH-1625 has shown low single-digit nanomolar potency that is specific to HCV. It is equipotent against HCV genotypes 1a and 1b at IC50~1nM.
In clinical studies completed to date, subjects receiving both single and multiple ascending doses ranging from 50 mg to 2000 mg for periods up to 5 days demonstrated that ACH-1625 was well tolerated at all doses and there were no serious adverse events, and no clinically significant changes in vital signs, electrocardiograms (ECGs) or laboratory evaluations. HCV-infected patients receiving doses ranging from 200 to 600 mg twice daily, and 400 to 600 mg once daily, showed mean maximal reductions in viral load ranging from of 3.07 log10 to 4.25 log10. Furthermore, all patients had viral loads that remained suppressed for at least 7 days after dosing was completed, maintaining a mean reduction of more than 1log10 from baseline through day 12, the last day of viral load measurement in the study.
About HCV
The hepatitis C virus (HCV) is the most common cause of viral hepatitis, which is an inflammation of the liver. It is currently estimated that more than 170 million people are infected with HCV worldwide and The American Association of Liver Disease estimates that up to 80% of individuals become chronically infected following exposure. If left untreated, chronic hepatitis can lead to permanent liver damage, which can result in the development of liver cancer, liver failure or death. Few therapeutic options currently exist for the treatment of HCV infection. The current standard of care is limited by its specificity for certain types of HCV, significant side-effect profile, injectable route of administration and high cost.
About Achillion
Achillion is an innovative pharmaceutical company dedicated to bringing important new treatments to patients with infectious disease. Achillion's proven discovery and development teams have advanced multiple product candidates with novel mechanisms of action. Achillion is focused on solutions for the most challenging problems in infectious disease --hepatitis C, resistant bacterial infections and HIV. For more information on Achillion Pharmaceuticals, please visit www.achillion.com or call 1-203-624-7000.
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including statements with respect to the potency, safety and other characteristics of ACH-1625, which may not be duplicated in future cohorts at different doses or in future clinical studies of longer duration; Achillion's expectations regarding timing and duration of other clinical trials, including additional dosing cohorts. Among the factors that could cause actual results to differ materially from those indicated by such forward-looking statements are uncertainties relating to results of clinical trials and unexpected regulatory actions or delays. These and other risks are described in the reports filed by Achillion with the U.S. Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009.
All forward-looking statements reflect Achillion's expectations only as of the date of this release and should not be relied upon as reflecting Achillion's views, expectations or beliefs at any date subsequent to the date of this release. Achillion anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Achillion may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.
ACHN-G
This news release was distributed by GlobeNewswire, http://www.globenewswire.com/
SOURCE: Achillion Pharmaceuticals, Inc.
CONTACT: Achillion Pharmaceuticals, Inc.
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Lippert/Heilshorn & Associates, Inc.
Anne Marie Fields
(212) 838-3777
afields@lhai.com
Bruce Voss
(310) 691-7100
bvoss@lhai.com
Source
CDC chief picks 6 'winnable battles' in health
By MIKE STOBBE (AP) – 37 minutes ago
ATLANTA — Where would you start if you were charged with keeping the nation healthy? Dr. Thomas Frieden, director of the Centers for Disease Control and Prevention, has chosen six priorities — winnable battles, he calls them.
They are smoking, AIDS, obesity/nutrition, teen pregnancy, auto injuries and health care infections. These are long-standing, major challenges that get a lot of attention already.
But elevating a handful of problems above dozens of others is a bold move for a public health official. So far, it's been received like a bucket of cold water — invigorating some, infuriating others.
Many advocates, legislators and others in public health have devoted their lives to problems that did not make Frieden's short list. So there are complaints.
A CDC employee blog is peppered with postings like, "I guess climate change is not a battle worth winning," and "Don't we still owe the patients of tomorrow an investment in things that may not pay off immediately?"
Some advocates wonder aloud just how targeted federal public health dollars are going to be. A particular point of concern is hepatitis C, a long under-recognized liver-destroying virus which has infected more than 3 million Americans. Some experts consider the issue a ticking time bomb and have called for the government to step up efforts to prevent it and better diagnose and treat people who already are infected.
Hepatitis B and C already are "badly neglected" by the CDC, and their omission from Frieden's winnable battles list is more bad news, said Bruce Burkett, past president of the National Hepatitis C Advocacy Council.
"I was very disappointed that it wasn't on there. This is going to affect millions by not being on there," he said.
Frieden, who took over CDC in June last year, already had a reputation as something of a public health maverick. When he started his previous job as New York City's health commissioner in 2002, he began by identifying the city's most pressing health issues. He led campaigns to ban smoking in the workplace, tax soda, cut salt in processed foods, and ban artificial trans fats in restaurants.
It's no surprise that he is boldly painting targets at the CDC, said Dr. Jo Ivey Boufford, president of the New York Academy of Medicine. She's a fan of Frieden's who worked with him as a member of an advisory council to the city health department.
Frieden's CDC job, ironically, does not provide the same kind of power he had in New York City to engineer bans or tax increases. But Frieden calls his new short list "winnable battles" because, he says, proven programs can save lives and reduce harm from each of these health problems. He believes government can make dramatic improvements if available money and manpower are focused.
"In each of these areas we know what to do to make a difference and we need to do it to a much greater extent," he said in an interview.
Frieden, with a low-key demeanor, has said relatively little about this to the public, though he seems to be building support within the public health community.
There is some nervousness about how far Frieden's going to take this.
"I think everyone is going to be cautious in how the focus on winnable battles is balanced against other areas" that are also deemed important but may not be as easy to dent, said Jeff Levi, who heads Trust for America's Health, a research group.
Top CDC officials have been quick to say they have no intention of walking away from other public health missions. They couldn't even if they wanted to, because much of the agency's funding is directed to certain causes by Congress. According to one estimate, less than one-tenth of 1 percent of CDC's $6.6 billion budget is discretionary money that can be channeled into the winnable battles campaign. Indeed, the agency has been asking for more flexibility.
But there's power in perception, especially concerning CDC's grant money to states. Nearly a quarter of that is targeted at the six battle areas, which already were major areas of interest. State health officers say they're acutely aware of Frieden's priorities and want him to know it when they apply for CDC money.
"We're in the position of focusing pretty much on what we can get federal funds for," said Will Humble, director of the Arizona Department of Health Services.
Humble and several other public health leaders applaud Frieden's priorities as an overdue attempt to narrow the public health message and better market health improvement to Americans.
"You can't market if your message is too diffuse," Humble said. "If we're all on the same page and working in the same direction, we can get a lot more momentum."
This isn't how many public health officials traditionally operate, partly because they tend to worry about alienating employees, legislators and advocates, observed Stanton Glantz, a University of California-San Francisco expert on the health effects of smoking.
Other top federal health officials have not been as specific. U.S. Surgeon General Dr. Regina Benjamin, the government's chief health educator, has made the broader themes of prevention and wellness her focus.
But Frieden clearly has the blessing of his Obama administration bosses to set clear targets.
"Getting focused, and getting some quick wins under your belt, is terribly important," said Victor Strecher, a University of Michigan health behavior expert.
Progress in these areas has long been measured by health statistics. What exactly will constitute a win? Frieden hasn't said yet.
___
Online:
CDC Web page describing winnable battles: http://bit.ly/bCd8Lr
Source
ATLANTA — Where would you start if you were charged with keeping the nation healthy? Dr. Thomas Frieden, director of the Centers for Disease Control and Prevention, has chosen six priorities — winnable battles, he calls them.
They are smoking, AIDS, obesity/nutrition, teen pregnancy, auto injuries and health care infections. These are long-standing, major challenges that get a lot of attention already.
But elevating a handful of problems above dozens of others is a bold move for a public health official. So far, it's been received like a bucket of cold water — invigorating some, infuriating others.
Many advocates, legislators and others in public health have devoted their lives to problems that did not make Frieden's short list. So there are complaints.
A CDC employee blog is peppered with postings like, "I guess climate change is not a battle worth winning," and "Don't we still owe the patients of tomorrow an investment in things that may not pay off immediately?"
Some advocates wonder aloud just how targeted federal public health dollars are going to be. A particular point of concern is hepatitis C, a long under-recognized liver-destroying virus which has infected more than 3 million Americans. Some experts consider the issue a ticking time bomb and have called for the government to step up efforts to prevent it and better diagnose and treat people who already are infected.
Hepatitis B and C already are "badly neglected" by the CDC, and their omission from Frieden's winnable battles list is more bad news, said Bruce Burkett, past president of the National Hepatitis C Advocacy Council.
"I was very disappointed that it wasn't on there. This is going to affect millions by not being on there," he said.
Frieden, who took over CDC in June last year, already had a reputation as something of a public health maverick. When he started his previous job as New York City's health commissioner in 2002, he began by identifying the city's most pressing health issues. He led campaigns to ban smoking in the workplace, tax soda, cut salt in processed foods, and ban artificial trans fats in restaurants.
It's no surprise that he is boldly painting targets at the CDC, said Dr. Jo Ivey Boufford, president of the New York Academy of Medicine. She's a fan of Frieden's who worked with him as a member of an advisory council to the city health department.
Frieden's CDC job, ironically, does not provide the same kind of power he had in New York City to engineer bans or tax increases. But Frieden calls his new short list "winnable battles" because, he says, proven programs can save lives and reduce harm from each of these health problems. He believes government can make dramatic improvements if available money and manpower are focused.
"In each of these areas we know what to do to make a difference and we need to do it to a much greater extent," he said in an interview.
Frieden, with a low-key demeanor, has said relatively little about this to the public, though he seems to be building support within the public health community.
There is some nervousness about how far Frieden's going to take this.
"I think everyone is going to be cautious in how the focus on winnable battles is balanced against other areas" that are also deemed important but may not be as easy to dent, said Jeff Levi, who heads Trust for America's Health, a research group.
Top CDC officials have been quick to say they have no intention of walking away from other public health missions. They couldn't even if they wanted to, because much of the agency's funding is directed to certain causes by Congress. According to one estimate, less than one-tenth of 1 percent of CDC's $6.6 billion budget is discretionary money that can be channeled into the winnable battles campaign. Indeed, the agency has been asking for more flexibility.
But there's power in perception, especially concerning CDC's grant money to states. Nearly a quarter of that is targeted at the six battle areas, which already were major areas of interest. State health officers say they're acutely aware of Frieden's priorities and want him to know it when they apply for CDC money.
"We're in the position of focusing pretty much on what we can get federal funds for," said Will Humble, director of the Arizona Department of Health Services.
Humble and several other public health leaders applaud Frieden's priorities as an overdue attempt to narrow the public health message and better market health improvement to Americans.
"You can't market if your message is too diffuse," Humble said. "If we're all on the same page and working in the same direction, we can get a lot more momentum."
This isn't how many public health officials traditionally operate, partly because they tend to worry about alienating employees, legislators and advocates, observed Stanton Glantz, a University of California-San Francisco expert on the health effects of smoking.
Other top federal health officials have not been as specific. U.S. Surgeon General Dr. Regina Benjamin, the government's chief health educator, has made the broader themes of prevention and wellness her focus.
But Frieden clearly has the blessing of his Obama administration bosses to set clear targets.
"Getting focused, and getting some quick wins under your belt, is terribly important," said Victor Strecher, a University of Michigan health behavior expert.
Progress in these areas has long been measured by health statistics. What exactly will constitute a win? Frieden hasn't said yet.
___
Online:
CDC Web page describing winnable battles: http://bit.ly/bCd8Lr
Source
Bleeding Complication With Liver Biopsy: Is It Predictable?
Clinical Gastroenterology and Hepatology
Volume 8, Issue 10 , Pages 826-829, October 2010
Stephen Caldwell, MD, Patrick G. Northup, MD
published online 28 June 2010.
Liver biopsy remains a cornerstone of diagnosis and disease staging and an important measure of natural history and therapeutic outcomes in many forms of liver disease. The major limitations of biopsy are the risk of procedure-related complications especially bleeding and adequacy of the sample to ensure accurate histologic interpretation. In the current issue of Clinical Gastroenterology and Hepatology, Seeff et al report liver biopsy complication rates in 1 of the largest cohorts of patients with histologically advanced disease.1
The study involved 2740 percutaneous biopsies performed over 7 years at 10 centers as part of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial. The study assessed the efficacy of low dose maintenance peginterferon alfa-2a therapy in patients with histologically advanced hepatitis C—related fibrosis undergoing biopsy at baseline (n = 1187), 1.5 years (n = 852), and 3.5 years (n = 701) of treatment. Eighty percent of the biopsies were performed with ultrasound guidance, 40% used an aspiration needle, and 60% used a cutting needle. Single passes were reported in 40% and 2 passes in 60%. Complication rates were determined prospectively with no difference between baseline and follow-up biopsies.
Overall, serious adverse events (AE) occurred in 29 of the biopsies with no deaths. Severe bleeding was the most common cause seen in 16 (0.6%) of the biopsies including hemoperitoneum in 8, subcapsular hematoma in 4, hemobilia in 3, and hemothorax in 1. About one fourth of the adverse events were due to severe pain and one fourth were due to other causes including punctured gallbladder in 2, pneumothorax in 1, syncope in 1, and hypotension in 2. Because of its higher frequency and potential severity, the authors focused on bleeding risk assessment. No difference in those who bled versus those who did not was seen between 2 passes versus a single pass, use of a cutting needle versus an aspiration needle, or performance by a fellow as opposed to an attending physician. Factors that were statistically different between those with bleeding and those without were lower albumin, presence of varices, platelets less than 60,000 and INR ≥ 1.3 although it should be noted that among the 8 patients with international normalized ratio (INR) > 1.5, none had bleeding. Moreover, while these variables were statistically significant, the clinical differences were not clinically dramatic as is evident in Tables 6 and 7 of the report. The relationship to varices and albumin levels suggests that the variation in risk may be due to changes in hepatic vasculature in more advanced disease rather than changes in hemostatic mechanisms.
Although several other factors limit interpretation of the data including preset study inclusion criteria (based in part on conventional coagulation parameters) and the retrospective acquisition of procedure details by questionnaire as discussed by the authors, the study raises the interesting and challenging issue of bleeding risk assessment with percutaneous liver biopsy. Reassuringly, the mortality was zero although the incidence of nonfatal severe bleeding was higher in this cohort of advanced fibrosis stage patients, 1 in 200, compared with about 1 in 500 biopsies from a compilation of past reports of patients of all stages.2
Is the INR useful to predict bleeding in a cirrhosis patient? Despite the implications of the current study, the answer to this is clearly no. Although this test unfortunately continues to hold on to some adherents as a valid indicator of bleeding risk in cirrhosis patients, the practice is unfounded both physiologically (see below) and methodologically as the conventional INR in cirrhosis patients is not normalized to the various thromboplastin reagents used in the test.3 This problem is very evident by the marked interlaboratory variation consistently reported now in a number of studies represented in Figure 1.4, 5, 6, 7, 8 Thus an INR of 1.2 in 1 clinical reference laboratory can be an INR of 2 on the identical sample in another clinical reference laboratory. The problem lies with variation in activity of the thromboplastin and normalization of the test to warfarin-treated patients (international sensitivity index; ISI) rather than to liver disease patients.9 In the present study, liver disease—corrected INR (termed INRLiver) was not utilized so the degree of variation between the 10 involved centers is unknown. Even ignoring this, it is noteworthy that 6 of the patients who had bleeding had INR <1 while none of the 8 patients with INR >1.5 had bleeding.
Clearly, the problem with INR as an index of bleeding risk in cirrhosis is more profound than simply marked interlaboratory variation. Because the test is derived from the prothrombin time, it is a reflection only of procoagulant factor activity and fails to account for the full breadth of both anti- and pro-hemostatic disturbances which are now known to exist in cirrhotic patients. It is especially notable that in stable cirrhosis patients the magnitude of procoagulant thrombin generation can be on the order of congenital protein C deficiency.10 This results from a relative resistance to endothelial-derived thrombomodulin (a protein C cofactor) due itself to decreased protein C levels and increased factor VIII activity. Hypercoagulability in cirrhosis is also supported by increased von Willebrand factor and decreased antithrombin III the latter of which can also lead to heparin resistance in this group of patients.11 Clinically, the presence of a hypercoagulable state is evident in the prevalence of deep vein thrombosis in this group.12, 13
On the other hand, bleeding is clearly a problem in these patients especially during episodes of decompensation requiring hospitalization. In a recent survey from our inpatient service, we observed 34 bleeding events (12 variceal and 22 nonvariceal) over a 42-day period about three fourths of which warranted transfusion of human blood products (Shah N, unpublished survey). Nonvariceal sources included mucosal bleeding, puncture wound bleeding, severe epistaxis, severe limb hematomas, and contusions and severe bleeding after dental extractions. Thus the issue is not an absence of bleeding risk but rather it is how to measure the risk and how to respond to a poorly balanced pro- and anti-hemostatic system. Other more discrete variables also contribute significantly to impaired hemostasis in this setting. These include hyperfibrinolysis seen in about 10% of cirrhosis patients and which should be suspected with delayed bleeding following a procedure,14, 15 renal insufficiency with uremic changes in platelets, and associated volume expansion which engorges the portal system,16 infection and associated release of endogenous heparinoids, and the very poorly characterized condition of dysfibrinogenemia which occurs in cirrhosis.16, 17 These complicated interactions are not measured by conventional coagulation indices such as INR. On the other hand, although INR clearly is limited as a bleeding risk measure, it remains unknown whether or not it is useful as a marker of dose effect of hemostatic agents used when cirrhosis patients bleed and it remains as a useful indicator of prognosis albeit with some unresolved problems arising from interlaboratory variation.
Are platelet levels useful to predict bleeding? The data are clearer with regard to platelet levels. While qualitative platelet changes which may be either pro- or anti-coagulant are largely unmeasured, convincing data have been published that show platelet levels of around 56,000/mL are associated with adequate in vitro thrombin production.18 Similar to the conclusions in the present study, a prior report also indicated a greater bleeding risk in liver biopsy when platelet levels were <60,000/mL.19 On the other hand it should be recalled that laparoscopically measured liver biopsy bleeding was unrelated to conventional coagulation parameters including platelet count in another study.20 Similarly, in the present study, 11 of the bleeding episodes occurred in patients with platelet levels >60,000/mL and 3 of them had platelet levels >150,000/mL.
Postbiopsy bleeding occurs in several forms ranging from arterial spurting to portal venous oozing to internalized hemobilia. Of these, arterial spurting is the most dramatic and usually becomes evident early in the postbiopsy period with associated hemodynamic changes. Although the timing of the bleeding episode after the biopsy and details of the management were not available, a number of the patients underwent interventional vascular imaging and embolization consistent with inadvertent small arterial puncture and bleeding. Such small vessels are not easily seen by conventional ultrasound and the incidence of arterial bleeding may well represent roughly the same frequency of incidental transgression of these structures. Histologic analysis of the specimens was not available to determine the presence or absence of these structures in those who bled versus those who did not bleed but it is our experience (thankfully infrequent) that such structures are evident on the histopathology slides when arterial bleeding is encountered (Figure 2). Because of changes in the hepatic vascular bed as early cirrhosis transitions to advanced cirrhosis with atrophy, it is possible that the likelihood of such an event increases with more advanced disease. Such a relationship is suggested by the association of bleeding with varices and lower albumin in the present study. As the authors likely have these biopsies in repository, it would be helpful to review these with attention to the presence or absence of vascular structures vis-à-vis the history of bleeding.
Figure 2.
(A) A 48-year-old male with human immunodeficiency virus (HIV) in remission and possible drug-induced liver disease underwent ultrasound-guided biopsy with 16-gauge automated needle with a single pass. Prebiopsy INR = 0.9 and platelets 71,000/mL. Developed pain and decreased blood pressure postbiopsy. Computerized tomography (CT) showed site of bleeding (arrow). (B) Same patient underwent arteriography showing arterial extravasation (arrow). (C) Same patient status post coiling of the bleeding site. (D) Biopsy sample shows vessel wall of very small artery which likely represents the site of bleeding (H&E 200×). (E) Closer view of (D) (H&E 400×)..
The role of ultrasound (US) guidance either as real time imaging or prebiopsy site marking was not directly addressed as a potential risk modifier in the present study. This is probably because the majority (80%) of the biopsies were described as ultrasound-guided which likely limited the comparison. Whether or not the patients with bleeding were equally distributed in the US-guided group versus those without image guidance would be interesting but is not reported. However, given the size of the small arteriolar vessels that may be the source of severe hemorrhage (Figure 2) and the limitations of ultrasound resolution, it seems very unlikely that ultrasound guidance will have an effect on the risk of severe hemorrhage. This assessment is supported by several prior observational studies and a controlled trial of US-guided versus nonguided biopsy.21, 22, 23 In the latter study, a substantial difference in the complication rate (including bleeding) between US-guided and non-US-guided biopsy was only reported as a difference which included both severe pain and significant bleeding combined. Based on these studies, the use of US guidance is likely to have its greatest impact on the incidence of postbiopsy pain and more significantly on organ puncture including gall bladder puncture (seen in 2 patients in the present study) and pneumothorax (seen in 1) which is more likely to be reduced with US guidance. In the present study, it would be helpful to know the relative incidence of these events in those with US guidance versus those without.
Although other parameters may eventually supplant biopsy as a measure of the natural history of liver diseases and/or as an indicator of treatment response, at this time biopsy remains a key part of the evaluation in these patients. Acquisition of an adequate sample while ensuring safe performance remains paramount in this situation. Current data supports aiming for platelet levels in the range of at least 55,000/mL–60,000/mL and taking into account the possibility of coexisting conditions such as hyperfibrinolysis which might be evident from a history of easy bleeding for example. For the reasons discussed above, the INR warrants much less emphasis and certainly no data exist to support a specific cutoff. Transvenous biopsy may at first appear to offer a safer approach but a close review of the literature reveals a complication rate similar to that of percutaneous biopsy albeit the patient population may be selected with higher inherent risk.2 Most clearly, better measures of the hemostatic system balance in cirrhosis and the possible role of other prophylactic measures such as emerging procoagulants need clinical investigation to complement recent laboratory advances in this field.
References
1.Seeff LB, Everson GT, Morgan TR, et al. HALT-C TRIAL GROUP Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C Trial. Clin Gastroenterol Hepatol. 2010;8:877–883
2.Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology. 2009;49:1017–1044
3.Malloy PC, Grassi CJ, Kundu S, et al. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol. 2009;20:S240–S249
4.Tripodi A, Chantarangkul V, Primignani M, et al. The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology. 2007;46:520–527
5.Bellest L, Eschwege V, Poupon R, et al. A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology. Hepatology. 2007;46:528–534
6.Lisman T, van Leeuwen Y, Adelmeijer J, et al. Interlaboratory variability in assessment of the model of end-stage liver disease score. Liver Int. 2008;28:1344–1351
7.Trotter JF, Brimhall B, Arjal R, et al. Specific laboratory methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation. Liver Transpl. 2004;10:995–1000
8.Trotter JF, Olson J, Lefkowitz J, et al. Changes in international normalized ratio (INR) and model for endstage liver disease (MELD) based on selection of clinical laboratory. Am J Transplant. 2007;7:1624–1628
9.Porte RJ, Lisman T, Tripodi A, et al. The International Normalized Ratio (INR) in the MELD score: problems and solutions. Am J Transplant. 2010;10:1349–1353
10.Tripodi A, Primignani M, Chantarangkul V, et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology. 2009;137:2105–2111
11.Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44:53–61
12.Northup PG, McMahon MM, Ruhl AP, et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006;101:1524–1528quiz 1680
13.Sogaard KK, Horvath-Puho E, Gronbaek H, et al. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol. 2009;104:96–101
14.Ferguson JW, Helmy A, Ludlam C, et al. Hyperfibrinolysis in alcoholic cirrhosis: relative plasminogen activator inhibitor type 1 deficiency. Thromb Res. 2008;121:675–680
15.Gunawan B, Runyon B. The efficacy and safety of epsilon-aminocaproic acid treatment in patients with cirrhosis and hyperfibrinolysis. Aliment Pharmacol Ther. 2006;23:115–120
16.Smalberg JH, Leebeek FW. Superimposed coagulopathic conditions in cirrhosis: infection and endogenous heparinoids, renal failure, and endothelial dysfunction. Clin Liver Dis. 2009;13:33–42
17.Cunningham MT, Brandt JT, Laposata M, et al. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med. 2002;126:499–505
18.Tripodi A, Primignani M, Chantarangkul V, et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology. 2006;44:440–445
19.Sharma P, McDonald GB, Banaji M. The risk of bleeding after percutaneous liver biopsy: relation to platelet count. J Clin Gastroenterol. 1982;4:451–453
20.Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci. 1981;26:388–393
21.Lindor KD, Bru C, Jorgensen RA, et al. The role of ultrasonography and automatic-needle biopsy in outpatient percutaneous liver biopsy. Hepatology. 1996;23:1079–1083
22.Manolakopoulos S, Triantos C, Bethanis S, et al. Ultrasound-guided liver biopsy in real life: comparison of same-day prebiopsy versus real-time ultrasound approach. J Gastroenterol Hepatol. 2007;22:1490–1493
23.Stone MA, Mayberry JF. An audit of ultrasound guided liver biopsies: a need for evidence-based practice. Hepatogastroenterology. 1996;43:432–434
Conflicts of interest The authors disclose the following: Dr Caldwell consults for and has research support from CL Behring and consults for Bioengineering Inc, Charlottesville, VA. Dr Northup discloses no conflicts.
PII: S1542-3565(10)00607-5
doi:10.1016/j.cgh.2010.06.010
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Volume 8, Issue 10 , Pages 826-829, October 2010
Stephen Caldwell, MD, Patrick G. Northup, MD
published online 28 June 2010.
Liver biopsy remains a cornerstone of diagnosis and disease staging and an important measure of natural history and therapeutic outcomes in many forms of liver disease. The major limitations of biopsy are the risk of procedure-related complications especially bleeding and adequacy of the sample to ensure accurate histologic interpretation. In the current issue of Clinical Gastroenterology and Hepatology, Seeff et al report liver biopsy complication rates in 1 of the largest cohorts of patients with histologically advanced disease.1
The study involved 2740 percutaneous biopsies performed over 7 years at 10 centers as part of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial. The study assessed the efficacy of low dose maintenance peginterferon alfa-2a therapy in patients with histologically advanced hepatitis C—related fibrosis undergoing biopsy at baseline (n = 1187), 1.5 years (n = 852), and 3.5 years (n = 701) of treatment. Eighty percent of the biopsies were performed with ultrasound guidance, 40% used an aspiration needle, and 60% used a cutting needle. Single passes were reported in 40% and 2 passes in 60%. Complication rates were determined prospectively with no difference between baseline and follow-up biopsies.
Overall, serious adverse events (AE) occurred in 29 of the biopsies with no deaths. Severe bleeding was the most common cause seen in 16 (0.6%) of the biopsies including hemoperitoneum in 8, subcapsular hematoma in 4, hemobilia in 3, and hemothorax in 1. About one fourth of the adverse events were due to severe pain and one fourth were due to other causes including punctured gallbladder in 2, pneumothorax in 1, syncope in 1, and hypotension in 2. Because of its higher frequency and potential severity, the authors focused on bleeding risk assessment. No difference in those who bled versus those who did not was seen between 2 passes versus a single pass, use of a cutting needle versus an aspiration needle, or performance by a fellow as opposed to an attending physician. Factors that were statistically different between those with bleeding and those without were lower albumin, presence of varices, platelets less than 60,000 and INR ≥ 1.3 although it should be noted that among the 8 patients with international normalized ratio (INR) > 1.5, none had bleeding. Moreover, while these variables were statistically significant, the clinical differences were not clinically dramatic as is evident in Tables 6 and 7 of the report. The relationship to varices and albumin levels suggests that the variation in risk may be due to changes in hepatic vasculature in more advanced disease rather than changes in hemostatic mechanisms.
Although several other factors limit interpretation of the data including preset study inclusion criteria (based in part on conventional coagulation parameters) and the retrospective acquisition of procedure details by questionnaire as discussed by the authors, the study raises the interesting and challenging issue of bleeding risk assessment with percutaneous liver biopsy. Reassuringly, the mortality was zero although the incidence of nonfatal severe bleeding was higher in this cohort of advanced fibrosis stage patients, 1 in 200, compared with about 1 in 500 biopsies from a compilation of past reports of patients of all stages.2
Is the INR useful to predict bleeding in a cirrhosis patient? Despite the implications of the current study, the answer to this is clearly no. Although this test unfortunately continues to hold on to some adherents as a valid indicator of bleeding risk in cirrhosis patients, the practice is unfounded both physiologically (see below) and methodologically as the conventional INR in cirrhosis patients is not normalized to the various thromboplastin reagents used in the test.3 This problem is very evident by the marked interlaboratory variation consistently reported now in a number of studies represented in Figure 1.4, 5, 6, 7, 8 Thus an INR of 1.2 in 1 clinical reference laboratory can be an INR of 2 on the identical sample in another clinical reference laboratory. The problem lies with variation in activity of the thromboplastin and normalization of the test to warfarin-treated patients (international sensitivity index; ISI) rather than to liver disease patients.9 In the present study, liver disease—corrected INR (termed INRLiver) was not utilized so the degree of variation between the 10 involved centers is unknown. Even ignoring this, it is noteworthy that 6 of the patients who had bleeding had INR <1 while none of the 8 patients with INR >1.5 had bleeding.
Figure 1.
Variation between different clinical reference laboratories in INR values on identical samples from patients with cirrhosis. High and low values for identical sample sets are shown. The variation is thought to result from differences in thromboplastin reagents. The values straddle the 1.5 cutoff in 8 of 19 cases. Aside from the substantial physiological limitations of this test (based on abnormalities of the hemostatic system in cirrhosis; see text), this degree of interlaboratory variation renders nonsensical the application of a universal clinical cutoff value as a measure of bleeding risk in cirrhosis patients although it remains a valid indicator in warfarin therapy for which the test was developed..
Clearly, the problem with INR as an index of bleeding risk in cirrhosis is more profound than simply marked interlaboratory variation. Because the test is derived from the prothrombin time, it is a reflection only of procoagulant factor activity and fails to account for the full breadth of both anti- and pro-hemostatic disturbances which are now known to exist in cirrhotic patients. It is especially notable that in stable cirrhosis patients the magnitude of procoagulant thrombin generation can be on the order of congenital protein C deficiency.10 This results from a relative resistance to endothelial-derived thrombomodulin (a protein C cofactor) due itself to decreased protein C levels and increased factor VIII activity. Hypercoagulability in cirrhosis is also supported by increased von Willebrand factor and decreased antithrombin III the latter of which can also lead to heparin resistance in this group of patients.11 Clinically, the presence of a hypercoagulable state is evident in the prevalence of deep vein thrombosis in this group.12, 13
On the other hand, bleeding is clearly a problem in these patients especially during episodes of decompensation requiring hospitalization. In a recent survey from our inpatient service, we observed 34 bleeding events (12 variceal and 22 nonvariceal) over a 42-day period about three fourths of which warranted transfusion of human blood products (Shah N, unpublished survey). Nonvariceal sources included mucosal bleeding, puncture wound bleeding, severe epistaxis, severe limb hematomas, and contusions and severe bleeding after dental extractions. Thus the issue is not an absence of bleeding risk but rather it is how to measure the risk and how to respond to a poorly balanced pro- and anti-hemostatic system. Other more discrete variables also contribute significantly to impaired hemostasis in this setting. These include hyperfibrinolysis seen in about 10% of cirrhosis patients and which should be suspected with delayed bleeding following a procedure,14, 15 renal insufficiency with uremic changes in platelets, and associated volume expansion which engorges the portal system,16 infection and associated release of endogenous heparinoids, and the very poorly characterized condition of dysfibrinogenemia which occurs in cirrhosis.16, 17 These complicated interactions are not measured by conventional coagulation indices such as INR. On the other hand, although INR clearly is limited as a bleeding risk measure, it remains unknown whether or not it is useful as a marker of dose effect of hemostatic agents used when cirrhosis patients bleed and it remains as a useful indicator of prognosis albeit with some unresolved problems arising from interlaboratory variation.
Are platelet levels useful to predict bleeding? The data are clearer with regard to platelet levels. While qualitative platelet changes which may be either pro- or anti-coagulant are largely unmeasured, convincing data have been published that show platelet levels of around 56,000/mL are associated with adequate in vitro thrombin production.18 Similar to the conclusions in the present study, a prior report also indicated a greater bleeding risk in liver biopsy when platelet levels were <60,000/mL.19 On the other hand it should be recalled that laparoscopically measured liver biopsy bleeding was unrelated to conventional coagulation parameters including platelet count in another study.20 Similarly, in the present study, 11 of the bleeding episodes occurred in patients with platelet levels >60,000/mL and 3 of them had platelet levels >150,000/mL.
Postbiopsy bleeding occurs in several forms ranging from arterial spurting to portal venous oozing to internalized hemobilia. Of these, arterial spurting is the most dramatic and usually becomes evident early in the postbiopsy period with associated hemodynamic changes. Although the timing of the bleeding episode after the biopsy and details of the management were not available, a number of the patients underwent interventional vascular imaging and embolization consistent with inadvertent small arterial puncture and bleeding. Such small vessels are not easily seen by conventional ultrasound and the incidence of arterial bleeding may well represent roughly the same frequency of incidental transgression of these structures. Histologic analysis of the specimens was not available to determine the presence or absence of these structures in those who bled versus those who did not bleed but it is our experience (thankfully infrequent) that such structures are evident on the histopathology slides when arterial bleeding is encountered (Figure 2). Because of changes in the hepatic vascular bed as early cirrhosis transitions to advanced cirrhosis with atrophy, it is possible that the likelihood of such an event increases with more advanced disease. Such a relationship is suggested by the association of bleeding with varices and lower albumin in the present study. As the authors likely have these biopsies in repository, it would be helpful to review these with attention to the presence or absence of vascular structures vis-à-vis the history of bleeding.
Figure 2.
(A) A 48-year-old male with human immunodeficiency virus (HIV) in remission and possible drug-induced liver disease underwent ultrasound-guided biopsy with 16-gauge automated needle with a single pass. Prebiopsy INR = 0.9 and platelets 71,000/mL. Developed pain and decreased blood pressure postbiopsy. Computerized tomography (CT) showed site of bleeding (arrow). (B) Same patient underwent arteriography showing arterial extravasation (arrow). (C) Same patient status post coiling of the bleeding site. (D) Biopsy sample shows vessel wall of very small artery which likely represents the site of bleeding (H&E 200×). (E) Closer view of (D) (H&E 400×)..
The role of ultrasound (US) guidance either as real time imaging or prebiopsy site marking was not directly addressed as a potential risk modifier in the present study. This is probably because the majority (80%) of the biopsies were described as ultrasound-guided which likely limited the comparison. Whether or not the patients with bleeding were equally distributed in the US-guided group versus those without image guidance would be interesting but is not reported. However, given the size of the small arteriolar vessels that may be the source of severe hemorrhage (Figure 2) and the limitations of ultrasound resolution, it seems very unlikely that ultrasound guidance will have an effect on the risk of severe hemorrhage. This assessment is supported by several prior observational studies and a controlled trial of US-guided versus nonguided biopsy.21, 22, 23 In the latter study, a substantial difference in the complication rate (including bleeding) between US-guided and non-US-guided biopsy was only reported as a difference which included both severe pain and significant bleeding combined. Based on these studies, the use of US guidance is likely to have its greatest impact on the incidence of postbiopsy pain and more significantly on organ puncture including gall bladder puncture (seen in 2 patients in the present study) and pneumothorax (seen in 1) which is more likely to be reduced with US guidance. In the present study, it would be helpful to know the relative incidence of these events in those with US guidance versus those without.
Although other parameters may eventually supplant biopsy as a measure of the natural history of liver diseases and/or as an indicator of treatment response, at this time biopsy remains a key part of the evaluation in these patients. Acquisition of an adequate sample while ensuring safe performance remains paramount in this situation. Current data supports aiming for platelet levels in the range of at least 55,000/mL–60,000/mL and taking into account the possibility of coexisting conditions such as hyperfibrinolysis which might be evident from a history of easy bleeding for example. For the reasons discussed above, the INR warrants much less emphasis and certainly no data exist to support a specific cutoff. Transvenous biopsy may at first appear to offer a safer approach but a close review of the literature reveals a complication rate similar to that of percutaneous biopsy albeit the patient population may be selected with higher inherent risk.2 Most clearly, better measures of the hemostatic system balance in cirrhosis and the possible role of other prophylactic measures such as emerging procoagulants need clinical investigation to complement recent laboratory advances in this field.
References
1.Seeff LB, Everson GT, Morgan TR, et al. HALT-C TRIAL GROUP Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C Trial. Clin Gastroenterol Hepatol. 2010;8:877–883
2.Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology. 2009;49:1017–1044
3.Malloy PC, Grassi CJ, Kundu S, et al. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol. 2009;20:S240–S249
4.Tripodi A, Chantarangkul V, Primignani M, et al. The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology. 2007;46:520–527
5.Bellest L, Eschwege V, Poupon R, et al. A modified international normalized ratio as an effective way of prothrombin time standardization in hepatology. Hepatology. 2007;46:528–534
6.Lisman T, van Leeuwen Y, Adelmeijer J, et al. Interlaboratory variability in assessment of the model of end-stage liver disease score. Liver Int. 2008;28:1344–1351
7.Trotter JF, Brimhall B, Arjal R, et al. Specific laboratory methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation. Liver Transpl. 2004;10:995–1000
8.Trotter JF, Olson J, Lefkowitz J, et al. Changes in international normalized ratio (INR) and model for endstage liver disease (MELD) based on selection of clinical laboratory. Am J Transplant. 2007;7:1624–1628
9.Porte RJ, Lisman T, Tripodi A, et al. The International Normalized Ratio (INR) in the MELD score: problems and solutions. Am J Transplant. 2010;10:1349–1353
10.Tripodi A, Primignani M, Chantarangkul V, et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology. 2009;137:2105–2111
11.Lisman T, Bongers TN, Adelmeijer J, et al. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology. 2006;44:53–61
12.Northup PG, McMahon MM, Ruhl AP, et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol. 2006;101:1524–1528quiz 1680
13.Sogaard KK, Horvath-Puho E, Gronbaek H, et al. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol. 2009;104:96–101
14.Ferguson JW, Helmy A, Ludlam C, et al. Hyperfibrinolysis in alcoholic cirrhosis: relative plasminogen activator inhibitor type 1 deficiency. Thromb Res. 2008;121:675–680
15.Gunawan B, Runyon B. The efficacy and safety of epsilon-aminocaproic acid treatment in patients with cirrhosis and hyperfibrinolysis. Aliment Pharmacol Ther. 2006;23:115–120
16.Smalberg JH, Leebeek FW. Superimposed coagulopathic conditions in cirrhosis: infection and endogenous heparinoids, renal failure, and endothelial dysfunction. Clin Liver Dis. 2009;13:33–42
17.Cunningham MT, Brandt JT, Laposata M, et al. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med. 2002;126:499–505
18.Tripodi A, Primignani M, Chantarangkul V, et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology. 2006;44:440–445
19.Sharma P, McDonald GB, Banaji M. The risk of bleeding after percutaneous liver biopsy: relation to platelet count. J Clin Gastroenterol. 1982;4:451–453
20.Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci. 1981;26:388–393
21.Lindor KD, Bru C, Jorgensen RA, et al. The role of ultrasonography and automatic-needle biopsy in outpatient percutaneous liver biopsy. Hepatology. 1996;23:1079–1083
22.Manolakopoulos S, Triantos C, Bethanis S, et al. Ultrasound-guided liver biopsy in real life: comparison of same-day prebiopsy versus real-time ultrasound approach. J Gastroenterol Hepatol. 2007;22:1490–1493
23.Stone MA, Mayberry JF. An audit of ultrasound guided liver biopsies: a need for evidence-based practice. Hepatogastroenterology. 1996;43:432–434
Conflicts of interest The authors disclose the following: Dr Caldwell consults for and has research support from CL Behring and consults for Bioengineering Inc, Charlottesville, VA. Dr Northup discloses no conflicts.
PII: S1542-3565(10)00607-5
doi:10.1016/j.cgh.2010.06.010
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Use of Statins in Patients with Chronic Hepatitis C
Southern Medical Journal:
October 2010 - Volume 103 - Issue 10 - pp 1018-1024
doi: 10.1097/SMJ.0b013e3181f0c6b4
CME Topics, Questions, Submission Forms
Andrus, Miranda R. PharmD, BCPS, FCCP; East, Jessica PharmD
Author Information
From the Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Huntsville, AL.
Reprint requests to Miranda R. Andrus, PharmD, BCPS, FCCP, Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, 301 Governors Drive, Suite 385B, Huntsville, AL 35801. Email: andrumr@auburn.edu
Dr. Andrus and Dr. East have no financial disclosures to declare and no conflicts of interest to report.
Accepted February 12, 2010.
Abstract
Hepatitis C is a leading cause of liver failure and transplantation in the United States and a major public health issue. Studies have shown that patients with hepatitis C are at an increased risk of cardiovascular disease, which make statins of particular benefit in this patient population. However, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statin therapy. The available literature regarding the safety of statins in this patient population is limited, but has not shown clinically significant differences in aminotransferase elevations or evidence of hepatotoxicity in patients with hepatitis C who have received statins versus those who have not. Statins should continue to be avoided in advanced end-stage liver disease, as there is a lack of safety data in these patients and drug metabolism would be severely compromised. Treatment with statins can be used in those with chronic, stable hepatitis C with elevated cardiac risk or a previous cardiac event.
Key Points
* Patients with chronic hepatitis C often have elevated cardiac risk and could benefit from statin therapy.
* The National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statins.
* Studies of statins in patients with chronic hepatitis C have not shown a clinically significant risk for hepatotoxicity.
* Statins should be considered in patients with chronic hepatitis C with elevated cardiac risk.
Hepatitis C is a major public health issue and a leading cause of liver failure and transplantation in the United States.1 The most recent data estimate that 1.6% of the United States population (about 4.1 million people) is infected with hepatitis C.2 Of these, over three-fourths (about 3.2 million) have chronic hepatitis C infection.
Two studies have shown that patients with hepatitis C are at an increased risk for cardiovascular disease based on an increased carotid intima-media thickness. In a Japanese study, a higher percentage of patients with persistent hepatitis C infection were found to have carotid plaque (P < 0.0001) and carotid intima-media thickening (P < 0.05) compared to a control group.3 Multivariate logistic regression analysis also showed persistent hepatitis C infection to be an independent predictor of carotid plaque, with an odds ratio of 5.61 (95% confidence interval [CI] 2.06–15.26, P < 0.001). A second study also demonstrated that patients with hepatitis C had greater carotid intima-media thickness compared to control (P < 0.001).4
These increases in markers of early atherosclerosis in chronic hepatitis C may make 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) of particular benefit in this patient population. However, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statin therapy.5 The guideline authors state that it is not known if statins worsen outcomes in patients with chronically elevated aminotransferase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) due to hepatitis C. They do recognize that it is unknown if elevated aminotransferase levels due to statin therapy represents true hepatotoxicity, and that progression to liver failure is rare. Clinical trials of statins have generally excluded patients with a history of chronic liver disease, so safety data in this patient population are limited. However, patients with hepatitis C may actually have increased cardiovascular risk, and could greatly benefit from the lipid lowering and pleiotropic effects of statins.
The Liver Expert Panel of the National Lipid Association has affirmed that there is a relationship between statin therapy and elevations in aminotransferase levels.6 However, these experts acknowledge that liver failure associated with statins is extremely rare. Although there are reports of liver failure requiring transplantation, there are no reported deaths due to liver failure associated with statins.6 Elevations in aminotransferase levels of greater than 3 times the upper limit of normal (ULN) have been seen in less than 1% of patients receiving starting or intermediate doses of statins, and up to 2–3% of those receiving maximal doses.7 Most of these elevations are asymptomatic, and usually return to baseline if the statin is discontinued.7 Often, these elevations are transient and resolve spontaneously, even if the statin is continued.7 The elevations also appear to be dose-related, with higher doses of statins more likely to cause enzyme elevations.7–9 Single, unconfirmed enzyme elevations may not be related to statin therapy at all, and these elevations generally do not indicate liver damage or failure.6,7
The exact mechanism by which statins cause increased aminotransferase levels is not clearly understood; however, the mechanism appears to be hepatocellular injury.7 The adverse effect is thought to be more related to the dose and concentration of the statin in tissues, rather than the degree of low density lipoprotein (LDL) reduction.7 Conditions that can increase statin concentrations—and therefore increase the risk of adverse effects—include advanced age, small body frame, declining renal function, infection, untreated hypothyroidism, drugs which inhibit the metabolism of statins, and alcohol abuse.7 The Liver Expert Panel has concluded that all marketed statins can cause elevations in aminotransferase levels, and that no particular statin causes these adverse effects more frequently than the others.6
Several review articles recommend that statins be considered, with careful monitoring, in chronic hepatitis C patients.7–9 The potential benefits of statins in patients with coexisting chronic hepatitis C and elevated cardiovascular risk led us to review the primary literature for specific evidence regarding the safety of statins in this population.
Literature Review
A literature search was conducted using Ovid Medline (1950 to January, Week 1, 2010), combining the medical subject heading search terms “hydroxymethylglutaryl-CoA reductase inhibitors” and “hepatitis C.” References of relevant articles were also reviewed. Studies examining the safety of using statins in patients with hepatitis C are limited to 1 prospective study, 3 retrospective studies in the Veterans Affairs (VA) population (1 of which only included 17 patients), and 1 retrospective study in patients with human immunodeficiency virus (HIV). A summary of these trials is provided in the Table.
A prospective, randomized, double-blind, placebo-controlled, parallel-group trial was designed to determine the efficacy and safety of high-dose pravastatin (80 mg daily) in hypercholesterolemic subjects with well-compensated liver disease.10 The study enrolled 326 patients, of which 62% had nonalcoholic fatty liver (NAFL)/nonalcoholic fatty liver disease (NAFLD), 27% had chronic hepatitis C, and the remainder had other liver diseases.
Inclusion criteria were a LDL cholesterol ≥100 mg/dL after a 4-week lead-in phase of lifestyle modifications, triglycerides <400 mg/dL, age ≥18 years old, and chronic, well-compensated liver disease. Patients were excluded if they were pregnant or breastfeeding, had AST or ALT levels >5 times the upper limit of normal (ULN), total bilirubin level above normal, serum creatinine >1.5 mg/dL, creatinine kinase >3 times the ULN, albumin less than the lower limit of normal, prothrombin time >2 seconds, or platelet count less than the lower limit of normal. Patients were also excluded if they had ascites, jaundice, or cirrhosis with a Child-Pugh score >5, had a disorder affecting serum bilirubin, were taking antiviral therapy for hepatitis B or C, had lipid lowering therapy in the previous 8 weeks or more, had cancer or cancer chemotherapy, or had significant cardiovascular, cerebrovascular, renal or thyroid disease, or uncontrolled diabetes mellitus within 6 months prior to randomization.
The safety objective was to determine the number of patients who had an increase in the ALT ≥2 times the ULN for those with a normal ALT at baseline, or a doubling of the baseline ALT in those who had an elevated ALT at baseline. By these definitions, fewer patients in the pravastatin group experienced ALT elevations compared to the placebo group. The proportion of subjects who had sustained elevations in ALT was comparable, with 8/160 (5%) in the pravastatin group, and 11/160 (7%) in the placebo group. Side effects were experienced in 26.4% of pravastatin patients and 25.2% of placebo patients. Six patients receiving pravastatin and 4 patients receiving placebo experienced treatment-emergent adverse effects associated with aminotransferase elevations, and no clinically apparent hepatotoxicity was experienced in either group. The terminology “treatment-emergent adverse effects” and “clinically apparent hepatotoxicity” was not clearly defined by the study. No patients experienced an acute exacerbation of their underlying liver disease. The study was not specifically powered for the safety endpoint; however, the authors calculated that a sample size of 150 per treatment group would provide approximately 20% power for this endpoint.
A retrospective, multicenter study in the VA population was conducted to determine whether statin therapy increased the risk for developing hepatotoxicity in patients with hepatitis C.11 Eight hundred and thirty patients were divided into 3 cohorts, and the antibody to hepatitis C virus (anti-HCV) was used as a surrogate marker for hepatitis C virus (HCV) infection. Cohort 1 included 166 patients positive for anti-HCV on statin therapy, Cohort 2 included 332 patients anti-HCV positive without statin therapy, and Cohort 3 included 332 patients who were anti-HCV negative and on statin therapy. Patients were excluded from Cohorts 1 and 3 if they did not have liver function tests checked within 1 year before and after initiation of statin therapy. Patients were excluded from Cohort 2 if they did not have liver function tests checked within 1 year before and after hepatitis C diagnosis. The majority of patients were taking simvastatin or lovastatin.
Patients in Cohort 1 (anti-HCV positive + statin) had a lower percentage change in median aminotransferase levels compared with those in Cohort 2 (anti-HCV positive + no statin; AST: 1% versus 5%, respectively, P = 0.032, ALT: 7.3% versus 6.0%, respectively, P < 0.01), and Cohort 3 (anti-HCV negative + statin; AST 5%, P = 0.004; ALT 4.8%, P = 0.002). However, none of the median changes were clinically significant, as all were less than 8%. A higher percentage of patients in Cohort 1 developed mild to moderate increases in aminotransferase levels (defined as AST or ALT ≤10 times the ULN or from baseline) compared to Cohort 2 (22.9% vs. 13.3%, P = 0.009). However, Cohort 2 had a higher percentage of patients with severe increases in liver function tests (defined as serum bilirubin value >3 mg/dL, or AST or ALT >10 times the ULN or baseline) compared to Cohort 1 (6.6% versus 1.2%, P = 0.015). There was no statistically significant difference in the percentage of patients with increased aminotransferase levels who discontinued statin therapy between Cohort 1 (21.6%) and Cohort 3 (9.2%; P = 0.147). The study was not adequately powered to detect idiosyncratic drug reactions.
In another retrospective study conducted in the VA system, 146 males who were seropositive for hepatitis C and received a statin between January 1, 1995, and September 9, 2003 were evaluated.12 Patients were excluded if there were no documented baseline lipid and aminotransferase levels before the start of statin therapy, or no documented follow-up levels. Patients were also excluded if triglyceride levels were ≥400 mg/dL. Hepatotoxicity was defined as an increase in ALT >3 times the ULN.
More than 90% of patients were taking simvastatin (the formulary agent), and statins were taken for a mean of 2.5 years in the study. At baseline, 66% had ALT levels greater than the ULN, and 8% had ALT levels >3 times the ULN. There was no significant increase in ALT at short-term follow up (3–6 months), or long-term follow up (mean 22 months). One patient discontinued statin therapy due to ALT levels >3 times the ULN.
A post hoc analysis did not show a statistically significant increase in the frequency of patients with ALT levels >3 times the ULN at any point in time. When patients who had ALT levels >3 times the ULN at baseline or after statin discontinuation were excluded, only 10 patients had ALT levels >3 times the ULN while receiving statin therapy during the study period. In 3 of these patients, levels later returned to normal. Statin therapy was discontinued in 1 of the 10 patients due to excessive alcohol intake. Of the remaining 6 patients, 3 continued receiving the statin and had subsequent ALT levels between 1 and 3 times the ULN, 1 had subsequent ALT levels 4 to 5 times the ULN, 1 had therapy discontinued, and 1 was lost to follow up.
In another very small retrospective VA study, 17 male patients with a diagnosis of chronic hepatitis C taking statins were reviewed.13 Only 5 patients had elevations of aminotransferase levels while taking statins, and the greatest increase was 1.5 times the ULN.
In a retrospective Italian study reported as a letter to the editor, the safety of statin therapy in patients infected with both HIV and hepatitis C was examined.14 Patients with HIV who had taken statins were divided into 2 groups. Group A included 38 patients with HIV and hepatitis C co-infection who started statin therapy at least 6 months after diagnosis of hepatitis C. Group B included 42 patients with HIV who were hepatitis C and hepatitis B negative who were on statin therapy. Patients were excluded if they had a history of alcohol abuse, concomitant hepatotoxic medications other than antiretrovirals, or were on treatment for hepatitis C. The median age was 45.5 years, and 76.2% of patients were male.
No significant difference was found between the groups in aminotransferase levels. The percentage of patients with an increase of ≥1.5 times the baseline level of AST was 7.9% in Group A and 4.8% in Group B, and for ALT was 7.9% in Group A and 14.3% in Group B. No patients had an increase of aminotransferase levels ≥3 times the ULN, and no patients discontinued a statin due to liver toxicity. About 40% of patients actually experienced a decrease in their aminotransferase levels while on statin therapy. A positive correlation was found between patients who had a decrease in ALT and those who had higher baseline levels of ALT.
All of these studies had weaknesses, limiting their clinical applicability. Almost all patients in the studies were male, and though hepatitis C is more common in males, this may limit the applicability to female patients. Only 1 study was prospective, and it had extensive exclusion criteria, which limits the applicability to the general hepatitis C population (which often has numerous comorbidities). The other 4 studies were retrospective, and therefore not blinded or controlled. Some of the studies used positive anti-HCV as a marker for chronic HCV, which could have included patients without the disease. Other studies did not state how chronic hepatitis C was defined. The safety endpoints and definitions were not consistent between studies, and were not always the most appropriate endpoints. For example, one of the VA studies used the outcome percentage change in aminotransferase levels. If the enzymes were already increased at baseline, a percentage change would not be as significant as it would if the enzymes were normal at baseline. In general, the studies were probably not powered with a large enough sample size to detect a statistically significant difference in safety outcomes.
Potential Benefits of Statins
Interestingly, there is literature to support the theory that statins actually have anti-HCV activity that might be beneficial, in addition to lowering cholesterol. Statins have been identified to have antiviral properties by inhibiting hepatitis C replication.15 Lipid metabolism is part of the life cycle of many viruses, and the resulting metabolites are incorporated into a lipid raft membrane, which is enriched with cholesterols and sphingolipids.16 The hepatitis C virus also forms a replication complex on the lipid raft membrane; therefore, a reduction in cholesterol from the lipid raft structure could theoretically decrease hepatitis C viral replication.15,16 The authors of 1 in vitro study have suggested that the antiviral effect of statins might be useful in treating hepatitis C in combination with interferon alpha.17 In vivo studies have been small and inconclusive at this time.18,19
Conclusion
In summary, the available literature has not shown clinically significant differences in aminotransferase levels or evidence of hepatotoxicity in patients with hepatitis C who have received statins versus those who have not. Statins should continue to be avoided in advanced end-stage liver disease, as there is a lack of safety data in these patients, and drug metabolism would be severely compromised. Treatment with statins should be considered in those with chronic, stable hepatitis C with elevated cardiac risk or a previous cardiac event. If baseline AST or ALT levels are >3 times the ULN statins should be used cautiously, but can be considered if the disease is stable, as the benefit is likely to outweigh the risk of treatment.
When used in patients with hepatitis C, statins should be started at low doses, and the AST and ALT should be monitored more closely than in patients without underlying liver disease, especially at drug initiation. If elevations of >3 times the ULN do occur with statin therapy, these should be repeated and confirmed before discontinuing the drug. After enzymes return to baseline, another statin can be tried if there are no other signs of hepatitis. Alcohol use should be avoided.
We feel that, with careful monitoring of the AST and ALT, statins can be used to reduce cardiovascular risk in patients with chronic, stable hepatitis C.
References
1.Ghany MG, Strader DB, Thomas DL, et al; American Association for the Study of Liver Diseases. Diagnosis, management and treatment of hepatitis C: an update. Hepatology 2009;49:1335–1374.
2.Armstrong GL, Waley A, Simard EP, et al. The prevalence of hepatitis C infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705–714.
3.Ishizaka Y, Ishizaka N, Takahashi E, et al. Association between hepatitis C virus core protein and carotid atherosclerosis. Circ J 2003;67:26–30.
4.Targher G, Bertolini L, Padovani R, et al. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol 2007;46:1126–1132.
5.National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421.
6.Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol 2006;97:77C–81C.
7.McKenney JM, Davidson MH, Jacobson TA, et al; National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C–94C.
8.Anfossi G, Massucco P, Bonoma K, et al. Prescription of statins to dyslipidemic patients affected by liver disease: a subtle balance between risk and benefits. Nutr Metab Cardiovasc Dis 2004;14:215–224.
9.Russo MW, Jacobson IM. How to use statins in patients with chronic liver disease. Cleve Clin J Med 2004;71:58–62.
10.Lewis JH, Mortensen ME, Zweig S, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007;46:1453–1463.
11.Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol 2006;4:902–907.
12.Segarra-Newnham M, Parra D, Martin-Cooper EM. Effectiveness and hepatotoxicity of statins in men seropositive for hepatitis C virus. Pharmacotherapy 2007;27:845–851.
13.Gibson K, Rindone JP. Experience with statin use in patients with chronic hepatitis C infection. Am J Cardiol 2005;96:1278–1279.
14.Milazzo L, Menzaghi B, Corvasce S, et al. Safety of statin therapy in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2007;46:258–260.
15.Kim SS, Peng LF, Lin W, et al. A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication. Gastroenterology 2007;132:311–320.
16.Ikeda M, Kato N. Life style-related diseases of the digestive system: cell culture system for the screening of anti-hepatitis C virus (HCV) reagents: suppression of HCV replication by statins and synergistic action with interferon. J Pharmacol Sci 2007;105:145–150.
17.Ikeda M, Abe K, Yamada M, et al. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology 2006;44:117–125.
18.O'Leary JG, Chan JL, McMahon CM, et al. Atorvastatin does not exhibit antiviral activity against HVC at conventional doses: a pilot clinical trial. Hepatology 2007;45:895–898.
19.Bader T, Fazili J, Madhoun M, et al. Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol 2008;103:1383–1389.
Source
October 2010 - Volume 103 - Issue 10 - pp 1018-1024
doi: 10.1097/SMJ.0b013e3181f0c6b4
CME Topics, Questions, Submission Forms
Andrus, Miranda R. PharmD, BCPS, FCCP; East, Jessica PharmD
Author Information
From the Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, Huntsville, AL.
Reprint requests to Miranda R. Andrus, PharmD, BCPS, FCCP, Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, 301 Governors Drive, Suite 385B, Huntsville, AL 35801. Email: andrumr@auburn.edu
Dr. Andrus and Dr. East have no financial disclosures to declare and no conflicts of interest to report.
Accepted February 12, 2010.
Abstract
Hepatitis C is a leading cause of liver failure and transplantation in the United States and a major public health issue. Studies have shown that patients with hepatitis C are at an increased risk of cardiovascular disease, which make statins of particular benefit in this patient population. However, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statin therapy. The available literature regarding the safety of statins in this patient population is limited, but has not shown clinically significant differences in aminotransferase elevations or evidence of hepatotoxicity in patients with hepatitis C who have received statins versus those who have not. Statins should continue to be avoided in advanced end-stage liver disease, as there is a lack of safety data in these patients and drug metabolism would be severely compromised. Treatment with statins can be used in those with chronic, stable hepatitis C with elevated cardiac risk or a previous cardiac event.
Key Points
* Patients with chronic hepatitis C often have elevated cardiac risk and could benefit from statin therapy.
* The National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statins.
* Studies of statins in patients with chronic hepatitis C have not shown a clinically significant risk for hepatotoxicity.
* Statins should be considered in patients with chronic hepatitis C with elevated cardiac risk.
Hepatitis C is a major public health issue and a leading cause of liver failure and transplantation in the United States.1 The most recent data estimate that 1.6% of the United States population (about 4.1 million people) is infected with hepatitis C.2 Of these, over three-fourths (about 3.2 million) have chronic hepatitis C infection.
Two studies have shown that patients with hepatitis C are at an increased risk for cardiovascular disease based on an increased carotid intima-media thickness. In a Japanese study, a higher percentage of patients with persistent hepatitis C infection were found to have carotid plaque (P < 0.0001) and carotid intima-media thickening (P < 0.05) compared to a control group.3 Multivariate logistic regression analysis also showed persistent hepatitis C infection to be an independent predictor of carotid plaque, with an odds ratio of 5.61 (95% confidence interval [CI] 2.06–15.26, P < 0.001). A second study also demonstrated that patients with hepatitis C had greater carotid intima-media thickness compared to control (P < 0.001).4
These increases in markers of early atherosclerosis in chronic hepatitis C may make 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) of particular benefit in this patient population. However, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statin therapy.5 The guideline authors state that it is not known if statins worsen outcomes in patients with chronically elevated aminotransferase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) due to hepatitis C. They do recognize that it is unknown if elevated aminotransferase levels due to statin therapy represents true hepatotoxicity, and that progression to liver failure is rare. Clinical trials of statins have generally excluded patients with a history of chronic liver disease, so safety data in this patient population are limited. However, patients with hepatitis C may actually have increased cardiovascular risk, and could greatly benefit from the lipid lowering and pleiotropic effects of statins.
The Liver Expert Panel of the National Lipid Association has affirmed that there is a relationship between statin therapy and elevations in aminotransferase levels.6 However, these experts acknowledge that liver failure associated with statins is extremely rare. Although there are reports of liver failure requiring transplantation, there are no reported deaths due to liver failure associated with statins.6 Elevations in aminotransferase levels of greater than 3 times the upper limit of normal (ULN) have been seen in less than 1% of patients receiving starting or intermediate doses of statins, and up to 2–3% of those receiving maximal doses.7 Most of these elevations are asymptomatic, and usually return to baseline if the statin is discontinued.7 Often, these elevations are transient and resolve spontaneously, even if the statin is continued.7 The elevations also appear to be dose-related, with higher doses of statins more likely to cause enzyme elevations.7–9 Single, unconfirmed enzyme elevations may not be related to statin therapy at all, and these elevations generally do not indicate liver damage or failure.6,7
The exact mechanism by which statins cause increased aminotransferase levels is not clearly understood; however, the mechanism appears to be hepatocellular injury.7 The adverse effect is thought to be more related to the dose and concentration of the statin in tissues, rather than the degree of low density lipoprotein (LDL) reduction.7 Conditions that can increase statin concentrations—and therefore increase the risk of adverse effects—include advanced age, small body frame, declining renal function, infection, untreated hypothyroidism, drugs which inhibit the metabolism of statins, and alcohol abuse.7 The Liver Expert Panel has concluded that all marketed statins can cause elevations in aminotransferase levels, and that no particular statin causes these adverse effects more frequently than the others.6
Several review articles recommend that statins be considered, with careful monitoring, in chronic hepatitis C patients.7–9 The potential benefits of statins in patients with coexisting chronic hepatitis C and elevated cardiovascular risk led us to review the primary literature for specific evidence regarding the safety of statins in this population.
Literature Review
A literature search was conducted using Ovid Medline (1950 to January, Week 1, 2010), combining the medical subject heading search terms “hydroxymethylglutaryl-CoA reductase inhibitors” and “hepatitis C.” References of relevant articles were also reviewed. Studies examining the safety of using statins in patients with hepatitis C are limited to 1 prospective study, 3 retrospective studies in the Veterans Affairs (VA) population (1 of which only included 17 patients), and 1 retrospective study in patients with human immunodeficiency virus (HIV). A summary of these trials is provided in the Table.
A prospective, randomized, double-blind, placebo-controlled, parallel-group trial was designed to determine the efficacy and safety of high-dose pravastatin (80 mg daily) in hypercholesterolemic subjects with well-compensated liver disease.10 The study enrolled 326 patients, of which 62% had nonalcoholic fatty liver (NAFL)/nonalcoholic fatty liver disease (NAFLD), 27% had chronic hepatitis C, and the remainder had other liver diseases.
Inclusion criteria were a LDL cholesterol ≥100 mg/dL after a 4-week lead-in phase of lifestyle modifications, triglycerides <400 mg/dL, age ≥18 years old, and chronic, well-compensated liver disease. Patients were excluded if they were pregnant or breastfeeding, had AST or ALT levels >5 times the upper limit of normal (ULN), total bilirubin level above normal, serum creatinine >1.5 mg/dL, creatinine kinase >3 times the ULN, albumin less than the lower limit of normal, prothrombin time >2 seconds, or platelet count less than the lower limit of normal. Patients were also excluded if they had ascites, jaundice, or cirrhosis with a Child-Pugh score >5, had a disorder affecting serum bilirubin, were taking antiviral therapy for hepatitis B or C, had lipid lowering therapy in the previous 8 weeks or more, had cancer or cancer chemotherapy, or had significant cardiovascular, cerebrovascular, renal or thyroid disease, or uncontrolled diabetes mellitus within 6 months prior to randomization.
The safety objective was to determine the number of patients who had an increase in the ALT ≥2 times the ULN for those with a normal ALT at baseline, or a doubling of the baseline ALT in those who had an elevated ALT at baseline. By these definitions, fewer patients in the pravastatin group experienced ALT elevations compared to the placebo group. The proportion of subjects who had sustained elevations in ALT was comparable, with 8/160 (5%) in the pravastatin group, and 11/160 (7%) in the placebo group. Side effects were experienced in 26.4% of pravastatin patients and 25.2% of placebo patients. Six patients receiving pravastatin and 4 patients receiving placebo experienced treatment-emergent adverse effects associated with aminotransferase elevations, and no clinically apparent hepatotoxicity was experienced in either group. The terminology “treatment-emergent adverse effects” and “clinically apparent hepatotoxicity” was not clearly defined by the study. No patients experienced an acute exacerbation of their underlying liver disease. The study was not specifically powered for the safety endpoint; however, the authors calculated that a sample size of 150 per treatment group would provide approximately 20% power for this endpoint.
A retrospective, multicenter study in the VA population was conducted to determine whether statin therapy increased the risk for developing hepatotoxicity in patients with hepatitis C.11 Eight hundred and thirty patients were divided into 3 cohorts, and the antibody to hepatitis C virus (anti-HCV) was used as a surrogate marker for hepatitis C virus (HCV) infection. Cohort 1 included 166 patients positive for anti-HCV on statin therapy, Cohort 2 included 332 patients anti-HCV positive without statin therapy, and Cohort 3 included 332 patients who were anti-HCV negative and on statin therapy. Patients were excluded from Cohorts 1 and 3 if they did not have liver function tests checked within 1 year before and after initiation of statin therapy. Patients were excluded from Cohort 2 if they did not have liver function tests checked within 1 year before and after hepatitis C diagnosis. The majority of patients were taking simvastatin or lovastatin.
Patients in Cohort 1 (anti-HCV positive + statin) had a lower percentage change in median aminotransferase levels compared with those in Cohort 2 (anti-HCV positive + no statin; AST: 1% versus 5%, respectively, P = 0.032, ALT: 7.3% versus 6.0%, respectively, P < 0.01), and Cohort 3 (anti-HCV negative + statin; AST 5%, P = 0.004; ALT 4.8%, P = 0.002). However, none of the median changes were clinically significant, as all were less than 8%. A higher percentage of patients in Cohort 1 developed mild to moderate increases in aminotransferase levels (defined as AST or ALT ≤10 times the ULN or from baseline) compared to Cohort 2 (22.9% vs. 13.3%, P = 0.009). However, Cohort 2 had a higher percentage of patients with severe increases in liver function tests (defined as serum bilirubin value >3 mg/dL, or AST or ALT >10 times the ULN or baseline) compared to Cohort 1 (6.6% versus 1.2%, P = 0.015). There was no statistically significant difference in the percentage of patients with increased aminotransferase levels who discontinued statin therapy between Cohort 1 (21.6%) and Cohort 3 (9.2%; P = 0.147). The study was not adequately powered to detect idiosyncratic drug reactions.
In another retrospective study conducted in the VA system, 146 males who were seropositive for hepatitis C and received a statin between January 1, 1995, and September 9, 2003 were evaluated.12 Patients were excluded if there were no documented baseline lipid and aminotransferase levels before the start of statin therapy, or no documented follow-up levels. Patients were also excluded if triglyceride levels were ≥400 mg/dL. Hepatotoxicity was defined as an increase in ALT >3 times the ULN.
More than 90% of patients were taking simvastatin (the formulary agent), and statins were taken for a mean of 2.5 years in the study. At baseline, 66% had ALT levels greater than the ULN, and 8% had ALT levels >3 times the ULN. There was no significant increase in ALT at short-term follow up (3–6 months), or long-term follow up (mean 22 months). One patient discontinued statin therapy due to ALT levels >3 times the ULN.
A post hoc analysis did not show a statistically significant increase in the frequency of patients with ALT levels >3 times the ULN at any point in time. When patients who had ALT levels >3 times the ULN at baseline or after statin discontinuation were excluded, only 10 patients had ALT levels >3 times the ULN while receiving statin therapy during the study period. In 3 of these patients, levels later returned to normal. Statin therapy was discontinued in 1 of the 10 patients due to excessive alcohol intake. Of the remaining 6 patients, 3 continued receiving the statin and had subsequent ALT levels between 1 and 3 times the ULN, 1 had subsequent ALT levels 4 to 5 times the ULN, 1 had therapy discontinued, and 1 was lost to follow up.
In another very small retrospective VA study, 17 male patients with a diagnosis of chronic hepatitis C taking statins were reviewed.13 Only 5 patients had elevations of aminotransferase levels while taking statins, and the greatest increase was 1.5 times the ULN.
In a retrospective Italian study reported as a letter to the editor, the safety of statin therapy in patients infected with both HIV and hepatitis C was examined.14 Patients with HIV who had taken statins were divided into 2 groups. Group A included 38 patients with HIV and hepatitis C co-infection who started statin therapy at least 6 months after diagnosis of hepatitis C. Group B included 42 patients with HIV who were hepatitis C and hepatitis B negative who were on statin therapy. Patients were excluded if they had a history of alcohol abuse, concomitant hepatotoxic medications other than antiretrovirals, or were on treatment for hepatitis C. The median age was 45.5 years, and 76.2% of patients were male.
No significant difference was found between the groups in aminotransferase levels. The percentage of patients with an increase of ≥1.5 times the baseline level of AST was 7.9% in Group A and 4.8% in Group B, and for ALT was 7.9% in Group A and 14.3% in Group B. No patients had an increase of aminotransferase levels ≥3 times the ULN, and no patients discontinued a statin due to liver toxicity. About 40% of patients actually experienced a decrease in their aminotransferase levels while on statin therapy. A positive correlation was found between patients who had a decrease in ALT and those who had higher baseline levels of ALT.
All of these studies had weaknesses, limiting their clinical applicability. Almost all patients in the studies were male, and though hepatitis C is more common in males, this may limit the applicability to female patients. Only 1 study was prospective, and it had extensive exclusion criteria, which limits the applicability to the general hepatitis C population (which often has numerous comorbidities). The other 4 studies were retrospective, and therefore not blinded or controlled. Some of the studies used positive anti-HCV as a marker for chronic HCV, which could have included patients without the disease. Other studies did not state how chronic hepatitis C was defined. The safety endpoints and definitions were not consistent between studies, and were not always the most appropriate endpoints. For example, one of the VA studies used the outcome percentage change in aminotransferase levels. If the enzymes were already increased at baseline, a percentage change would not be as significant as it would if the enzymes were normal at baseline. In general, the studies were probably not powered with a large enough sample size to detect a statistically significant difference in safety outcomes.
Potential Benefits of Statins
Interestingly, there is literature to support the theory that statins actually have anti-HCV activity that might be beneficial, in addition to lowering cholesterol. Statins have been identified to have antiviral properties by inhibiting hepatitis C replication.15 Lipid metabolism is part of the life cycle of many viruses, and the resulting metabolites are incorporated into a lipid raft membrane, which is enriched with cholesterols and sphingolipids.16 The hepatitis C virus also forms a replication complex on the lipid raft membrane; therefore, a reduction in cholesterol from the lipid raft structure could theoretically decrease hepatitis C viral replication.15,16 The authors of 1 in vitro study have suggested that the antiviral effect of statins might be useful in treating hepatitis C in combination with interferon alpha.17 In vivo studies have been small and inconclusive at this time.18,19
Conclusion
In summary, the available literature has not shown clinically significant differences in aminotransferase levels or evidence of hepatotoxicity in patients with hepatitis C who have received statins versus those who have not. Statins should continue to be avoided in advanced end-stage liver disease, as there is a lack of safety data in these patients, and drug metabolism would be severely compromised. Treatment with statins should be considered in those with chronic, stable hepatitis C with elevated cardiac risk or a previous cardiac event. If baseline AST or ALT levels are >3 times the ULN statins should be used cautiously, but can be considered if the disease is stable, as the benefit is likely to outweigh the risk of treatment.
When used in patients with hepatitis C, statins should be started at low doses, and the AST and ALT should be monitored more closely than in patients without underlying liver disease, especially at drug initiation. If elevations of >3 times the ULN do occur with statin therapy, these should be repeated and confirmed before discontinuing the drug. After enzymes return to baseline, another statin can be tried if there are no other signs of hepatitis. Alcohol use should be avoided.
We feel that, with careful monitoring of the AST and ALT, statins can be used to reduce cardiovascular risk in patients with chronic, stable hepatitis C.
References
1.Ghany MG, Strader DB, Thomas DL, et al; American Association for the Study of Liver Diseases. Diagnosis, management and treatment of hepatitis C: an update. Hepatology 2009;49:1335–1374.
2.Armstrong GL, Waley A, Simard EP, et al. The prevalence of hepatitis C infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705–714.
3.Ishizaka Y, Ishizaka N, Takahashi E, et al. Association between hepatitis C virus core protein and carotid atherosclerosis. Circ J 2003;67:26–30.
4.Targher G, Bertolini L, Padovani R, et al. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol 2007;46:1126–1132.
5.National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421.
6.Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol 2006;97:77C–81C.
7.McKenney JM, Davidson MH, Jacobson TA, et al; National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C–94C.
8.Anfossi G, Massucco P, Bonoma K, et al. Prescription of statins to dyslipidemic patients affected by liver disease: a subtle balance between risk and benefits. Nutr Metab Cardiovasc Dis 2004;14:215–224.
9.Russo MW, Jacobson IM. How to use statins in patients with chronic liver disease. Cleve Clin J Med 2004;71:58–62.
10.Lewis JH, Mortensen ME, Zweig S, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007;46:1453–1463.
11.Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol 2006;4:902–907.
12.Segarra-Newnham M, Parra D, Martin-Cooper EM. Effectiveness and hepatotoxicity of statins in men seropositive for hepatitis C virus. Pharmacotherapy 2007;27:845–851.
13.Gibson K, Rindone JP. Experience with statin use in patients with chronic hepatitis C infection. Am J Cardiol 2005;96:1278–1279.
14.Milazzo L, Menzaghi B, Corvasce S, et al. Safety of statin therapy in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr 2007;46:258–260.
15.Kim SS, Peng LF, Lin W, et al. A cell-based, high-throughput screen for small molecule regulators of hepatitis C virus replication. Gastroenterology 2007;132:311–320.
16.Ikeda M, Kato N. Life style-related diseases of the digestive system: cell culture system for the screening of anti-hepatitis C virus (HCV) reagents: suppression of HCV replication by statins and synergistic action with interferon. J Pharmacol Sci 2007;105:145–150.
17.Ikeda M, Abe K, Yamada M, et al. Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology 2006;44:117–125.
18.O'Leary JG, Chan JL, McMahon CM, et al. Atorvastatin does not exhibit antiviral activity against HVC at conventional doses: a pilot clinical trial. Hepatology 2007;45:895–898.
19.Bader T, Fazili J, Madhoun M, et al. Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol 2008;103:1383–1389.
Source
September 29, 2010
Hepatitis C Virus Faces New Weapon From Scientists
Released: 9/29/2010 12:00 PM EDT Source: Florida State University
Newswise — In recent human trials for a promising new class of drug designed to target the hepatitis C virus (HCV) without shutting down the immune system, some of the HCV strains being treated exhibited signs of drug resistance.
In response, an interdisciplinary team of Florida State University biologists, chemists and biomedical researchers devised a novel genetic screening method that can identify the drug-resistant HCV strains and the molecular-level mechanisms that make them that way –– helping drug developers to tailor specific therapies to circumvent them.
The potentially life-saving technology also works when screening other viruses with drug-resistance issues, notably human immunodeficiency virus (HIV) and influenza.
More than 170 million people worldwide are infected with HCV, which leads to both acute and chronic liver diseases.
“In collaboration with pharmaceutical firm Gilead Sciences and researchers from the University of Heidelberg (Germany), what our research team discovered was how the latest drug for HCV works and what changes in the virus that makes it resistant to this unique therapy,” said Hengli Tang, a Florida State University molecular biologist.
“This is knowledge that is essential to drug developers focused on HCV,” said Tang, “but equally important is that our method, which we call ‘CoFIM’ (Cofactor-independent mutant) screening, can also be applied to other drug targets and other viruses.
“And, since we now understand how this latest class of drug works and what causes resistance to it, we can better select other classes of drugs with distinct mechanisms –– in other words, those that target other parts of the virus –– in order to craft a combination therapy, which is the future of HCV therapy and the key to overcoming drug resistance.”
The groundbreaking research is described in a paper published online in the September 2010 issue of the journal PLoS Pathogens.
Florida State biology doctoral student Feng Yang led the research team. The award-winning scholar earned her Ph.D. in August 2010 and is now a postdoctoral associate at Yale University. Yang designed the CoFIM screening methodology with fellow FSU graduate students, postdoctoral associates and distinguished faculty colleagues –– including Associate Professor Tang; chemistry/biochemistry Professor Timothy M. Logan, director of FSU’s Institute of Molecular Biophysics; and Research Assistant Professor Ewa A. Bienkiewicz, of the FSU College of Medicine, where she directs the Biomedical Proteomics Laboratory.
Driving the team’s development of CoFIM screening was the need to identify key “cellular cofactors” and their mechanisms of action –– a fundamental aspect of virus-host interaction research.
“’Cellular cofactors’ are proteins that normally exist in host cells that have been hijacked by viruses to facilitate viral replication.” Tang said. “They became accomplices to the invading viruses.
“Our research team was the first to show that ‘cyclophilin A’ (CyPA) is an essential cellular cofactor for hepatitis C virus infection and the direct target of a new class of clinical anti-HCV compounds, which include cyclosporine A (CsA)-based drugs that are devoid of immunosuppressive function,” Tang said.
“In addition, we went a step further than other research teams by employing our newly developed CoFIM screening method, which we used to demonstrate not only HCV’s dependence on cellular cofactor cyclophilin A and susceptibility to cyclosporine A drugs but also to uncover the molecular-level regulators that determine those two traits in the virus.”
Those molecular-level regulators are known as “small interfering RNA libraries” –– collections of molecules so named for their size and ability to suppress gene expression. They act to individually suppress every gene in the cell, resulting in different consequences depending upon which gene is suppressed by a given member in the library.
The CoFIM screening method involves inducing or “coaxing” the HCV virus to mutate by itself, in vitro, absent the replication assistance it normally receives from a particular cellular cofactor. Then, CoFIM tracks the changes in the virus’s response both to CsA-based drugs and any other drug designed to inhibit the cofactor.
Funding for the research conducted at Florida State University came in largest part from a $1.4 million grant awarded by the National Institutes of Health (NIH). And, because chronic liver disease caused by HCV can lead to liver cancer, a grant from the American Cancer Society provided additional support.
In addition to now-doctoral alumna Feng Yang and faculty members Hengli Tang, Timothy M. Logan and Ewa A. Bienkiewicz, the Florida State University co-authors of the PLoS Pathogen paper (“A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach”) are current biology doctoral students Henry Grise and Stephen Frausto and postdoctoral associates Anita Nag and Jason M. Robotham. Co-authors from the University of Heidelberg Department of Infectious Diseases are Vanesa Madan, Margarita Zayas and Ralf Bartenschlager, and from Gilead Sciences (Foster City, Calif.), Andrew E. Greenstein and Margaret Robinson.
Source
Newswise — In recent human trials for a promising new class of drug designed to target the hepatitis C virus (HCV) without shutting down the immune system, some of the HCV strains being treated exhibited signs of drug resistance.
In response, an interdisciplinary team of Florida State University biologists, chemists and biomedical researchers devised a novel genetic screening method that can identify the drug-resistant HCV strains and the molecular-level mechanisms that make them that way –– helping drug developers to tailor specific therapies to circumvent them.
The potentially life-saving technology also works when screening other viruses with drug-resistance issues, notably human immunodeficiency virus (HIV) and influenza.
More than 170 million people worldwide are infected with HCV, which leads to both acute and chronic liver diseases.
“In collaboration with pharmaceutical firm Gilead Sciences and researchers from the University of Heidelberg (Germany), what our research team discovered was how the latest drug for HCV works and what changes in the virus that makes it resistant to this unique therapy,” said Hengli Tang, a Florida State University molecular biologist.
“This is knowledge that is essential to drug developers focused on HCV,” said Tang, “but equally important is that our method, which we call ‘CoFIM’ (Cofactor-independent mutant) screening, can also be applied to other drug targets and other viruses.
“And, since we now understand how this latest class of drug works and what causes resistance to it, we can better select other classes of drugs with distinct mechanisms –– in other words, those that target other parts of the virus –– in order to craft a combination therapy, which is the future of HCV therapy and the key to overcoming drug resistance.”
The groundbreaking research is described in a paper published online in the September 2010 issue of the journal PLoS Pathogens.
Florida State biology doctoral student Feng Yang led the research team. The award-winning scholar earned her Ph.D. in August 2010 and is now a postdoctoral associate at Yale University. Yang designed the CoFIM screening methodology with fellow FSU graduate students, postdoctoral associates and distinguished faculty colleagues –– including Associate Professor Tang; chemistry/biochemistry Professor Timothy M. Logan, director of FSU’s Institute of Molecular Biophysics; and Research Assistant Professor Ewa A. Bienkiewicz, of the FSU College of Medicine, where she directs the Biomedical Proteomics Laboratory.
Driving the team’s development of CoFIM screening was the need to identify key “cellular cofactors” and their mechanisms of action –– a fundamental aspect of virus-host interaction research.
“’Cellular cofactors’ are proteins that normally exist in host cells that have been hijacked by viruses to facilitate viral replication.” Tang said. “They became accomplices to the invading viruses.
“Our research team was the first to show that ‘cyclophilin A’ (CyPA) is an essential cellular cofactor for hepatitis C virus infection and the direct target of a new class of clinical anti-HCV compounds, which include cyclosporine A (CsA)-based drugs that are devoid of immunosuppressive function,” Tang said.
“In addition, we went a step further than other research teams by employing our newly developed CoFIM screening method, which we used to demonstrate not only HCV’s dependence on cellular cofactor cyclophilin A and susceptibility to cyclosporine A drugs but also to uncover the molecular-level regulators that determine those two traits in the virus.”
Those molecular-level regulators are known as “small interfering RNA libraries” –– collections of molecules so named for their size and ability to suppress gene expression. They act to individually suppress every gene in the cell, resulting in different consequences depending upon which gene is suppressed by a given member in the library.
The CoFIM screening method involves inducing or “coaxing” the HCV virus to mutate by itself, in vitro, absent the replication assistance it normally receives from a particular cellular cofactor. Then, CoFIM tracks the changes in the virus’s response both to CsA-based drugs and any other drug designed to inhibit the cofactor.
Funding for the research conducted at Florida State University came in largest part from a $1.4 million grant awarded by the National Institutes of Health (NIH). And, because chronic liver disease caused by HCV can lead to liver cancer, a grant from the American Cancer Society provided additional support.
In addition to now-doctoral alumna Feng Yang and faculty members Hengli Tang, Timothy M. Logan and Ewa A. Bienkiewicz, the Florida State University co-authors of the PLoS Pathogen paper (“A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach”) are current biology doctoral students Henry Grise and Stephen Frausto and postdoctoral associates Anita Nag and Jason M. Robotham. Co-authors from the University of Heidelberg Department of Infectious Diseases are Vanesa Madan, Margarita Zayas and Ralf Bartenschlager, and from Gilead Sciences (Foster City, Calif.), Andrew E. Greenstein and Margaret Robinson.
Source
Hep C may benefit from genetic fingerprinting, research says
September 28, 2010 Genetic fingerprinting may predict who will benefit from early hepatitis C treatment and who will clear the virus spontaneously, new research shows.
The way doctors think about hepatitis C treatment is changing, with researchers saying it is now possible to use genotyping to predict which patients are likely to clear the infection spontaneously and which will benefit from early therapy.
A team of UNSW researchers, led by Professor Gregory Dore and Dr. Jason Grebely, has determined that genetic changes near the human IL28B gene - identified recently as linked to the ability to control hepatitis C infection - may also be used to identify those patients with recent infection whose own immune system is likely to clear the virus without therapy.
“The use of human genotyping may change the landscape of how we treat patients with recent HCV infection,” said Dr. Grebely, a lecturer in the Viral Hepatitis and Clinical Research Program at UNSW’s National Centre in HIV Epidemiology and Clinical Research (NCHECR).
It’s the first time that patients with early hepatitis C infection, who are likely to clear the virus on their own, might be identified and spared treatment, which is expensive and has side effects, Dr. Grebely said.
“IL28B genetic testing, prior to treatment for HCV infection, is likely to be incorporated into clinical care to identify those most likely to respond,” Dr. Grebely said. “For those patients without the favourable genotype, the doctor can proceed with treatment, knowing it is better to treat early than waiting until the condition has become chronic.”
The findings will be published this week in the journal Hepatology.
Source
The way doctors think about hepatitis C treatment is changing, with researchers saying it is now possible to use genotyping to predict which patients are likely to clear the infection spontaneously and which will benefit from early therapy.
A team of UNSW researchers, led by Professor Gregory Dore and Dr. Jason Grebely, has determined that genetic changes near the human IL28B gene - identified recently as linked to the ability to control hepatitis C infection - may also be used to identify those patients with recent infection whose own immune system is likely to clear the virus without therapy.
“The use of human genotyping may change the landscape of how we treat patients with recent HCV infection,” said Dr. Grebely, a lecturer in the Viral Hepatitis and Clinical Research Program at UNSW’s National Centre in HIV Epidemiology and Clinical Research (NCHECR).
It’s the first time that patients with early hepatitis C infection, who are likely to clear the virus on their own, might be identified and spared treatment, which is expensive and has side effects, Dr. Grebely said.
“IL28B genetic testing, prior to treatment for HCV infection, is likely to be incorporated into clinical care to identify those most likely to respond,” Dr. Grebely said. “For those patients without the favourable genotype, the doctor can proceed with treatment, knowing it is better to treat early than waiting until the condition has become chronic.”
The findings will be published this week in the journal Hepatology.
Source
Launch of Novel Agents for the Treatment of Hepatitis C Virus Will Precipitate Treatment of At Least Half of 'Warehoused' Patients
Novel Agents Will Also Yield Faster Treatment Initiation of Newly Diagnosed HCV Patients, According to a New Report from Decision Resources
BURLINGTON, Mass., Sept. 27 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that the launch of novel therapies for the treatment of Hepatitis C Virus (HCV), including Vertex/Johnson & Johnson/Mitsubishi Tanabe's telaprevir and Merck's boceprevir, will precipitate several changes in HCV treatment. According to Patient Flow in Hepatitis C Virus, surveyed physicians plan to initiate treatment in at least half of their "warehoused" HCV1 patients one year after novel therapies become available. Patient "warehousing" is a term that has been coined to characterize the phenomenon of HCV patients opting out of treatment with current standard of care in anticipation of new therapies; psychiatric events, adverse events and liver health are top reasons keeping patients away from current therapies.
The report also finds that time from initial diagnosis to treatment initiation will decrease once novel HCV therapies are available. On average, surveyed physicians stated they wait 17 months to initiate treatment in HCV1 treatment-naive patients; this time will decrease to 7 months once novel treatment options are available.
"The arrival of telaprevir and boceprevir will alter more than the drug-treatment rate and treatment initiation timing in HCV," said Alexandra Makarova, M.D., Ph.D. "Physicians indicate they would increase the capacity of their HCV practice to accommodate the additional patients expected once novel therapies are available."
About Patient Flow in Hepatitis C Virus
Patient Flow in Hepatitis C Virus is a 15-year, annualized patient forecast for each of the G7 countries that estimates the total size of the declining prevalent HCV population and segments it by viremic status, HCV genotype and line of therapy. It includes two components: an Excel workbook containing quantitative analysis, including patient forecast and modifiable assumptions and a PowerPoint slide deck of primary research survey results of 100 U.S. gastroenterologists and hepatologists.
About Decision Resources
Decision Resources (http://www.decisionresources.com/) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.
About Decision Resources, Inc.
Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources, Inc. at http://www.decisionresourcesinc.com/.
All company, brand or product names contained in this document may be trademarks or registered trademarks of their respective holders.
For more information, contact:
Decision Resources
Lisa Osgood
781-993-2606
losgood@dresources.com
Decision Resources, Inc.
Chris Comfort
781-993-2597
ccomfort@dresources.com
SOURCE Decision Resources
RELATED LINKS
http://www.decisionresources.com/
Source
BURLINGTON, Mass., Sept. 27 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that the launch of novel therapies for the treatment of Hepatitis C Virus (HCV), including Vertex/Johnson & Johnson/Mitsubishi Tanabe's telaprevir and Merck's boceprevir, will precipitate several changes in HCV treatment. According to Patient Flow in Hepatitis C Virus, surveyed physicians plan to initiate treatment in at least half of their "warehoused" HCV1 patients one year after novel therapies become available. Patient "warehousing" is a term that has been coined to characterize the phenomenon of HCV patients opting out of treatment with current standard of care in anticipation of new therapies; psychiatric events, adverse events and liver health are top reasons keeping patients away from current therapies.
The report also finds that time from initial diagnosis to treatment initiation will decrease once novel HCV therapies are available. On average, surveyed physicians stated they wait 17 months to initiate treatment in HCV1 treatment-naive patients; this time will decrease to 7 months once novel treatment options are available.
"The arrival of telaprevir and boceprevir will alter more than the drug-treatment rate and treatment initiation timing in HCV," said Alexandra Makarova, M.D., Ph.D. "Physicians indicate they would increase the capacity of their HCV practice to accommodate the additional patients expected once novel therapies are available."
About Patient Flow in Hepatitis C Virus
Patient Flow in Hepatitis C Virus is a 15-year, annualized patient forecast for each of the G7 countries that estimates the total size of the declining prevalent HCV population and segments it by viremic status, HCV genotype and line of therapy. It includes two components: an Excel workbook containing quantitative analysis, including patient forecast and modifiable assumptions and a PowerPoint slide deck of primary research survey results of 100 U.S. gastroenterologists and hepatologists.
About Decision Resources
Decision Resources (http://www.decisionresources.com/) is a world leader in market research publications, advisory services and consulting designed to help clients shape strategy, allocate resources and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.
About Decision Resources, Inc.
Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources, Inc. at http://www.decisionresourcesinc.com/.
All company, brand or product names contained in this document may be trademarks or registered trademarks of their respective holders.
For more information, contact:
Decision Resources
Lisa Osgood
781-993-2606
losgood@dresources.com
Decision Resources, Inc.
Chris Comfort
781-993-2597
ccomfort@dresources.com
SOURCE Decision Resources
RELATED LINKS
http://www.decisionresources.com/
Source
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