| Abstract: | 臺灣地區慢性肝炎的發生率以B和C型病毒感染分佔1及2位，一般健康成人C型肝炎抗體盛行率約為1~2%，估計全臺約有20萬以上的C型肝炎帶原者。臺灣地區，約15%肝癌患者是C型肝炎病毒感染所致。由於C型肝炎至目前為止尚未發展出適當的疫苗及免疫球蛋白供臨床使用，相信繼B型肝炎之後， C型肝炎勢將造成臺灣肝炎防治上的一大難題及公共衛生上的極大隱憂。
目前對於C型肝炎的治療還是以interferon alfa為主，本研究的目的在探討慢性C型肝炎病人以interferon alfa 併用Ribavirin治療並且與單獨使用interferon alfa的病人進行療效及安全性之比較，希望本研究能確認合併療法的療效及提供安全性資料供臨床參考。
Interferon alfa併用ribavirin治療慢性C型肝炎之合併療法經証實可提高臨床反應率，並且療效優於interferon alfa單一療法，1998年由美國FDA核准合併療法。在抗病毒藥物-ribavirin於臺灣地區上市之前進行此研究，探討合併療法對於國內慢性C型肝炎患者的療效及安全性。
本研究為人體臨床試驗，從1998年1月1日至2000年3月31日止，由醫師診斷選擇符合治療資格之病患共計75位，隨機進入實驗組及對照組，其中使用ribavirin併用interferon alfa合併療法者共42名為實驗組，使用interferon alfa 單獨療法者共 33名為對照組，整個療程共6個月，停藥後持續追蹤觀察6個月， ribavirin使用劑量每日1000-1200 mg，interferon alfa使用劑量3 million units每星期3次。療效評估包括治療結束時的反應 (end-of-treatment, ETR)及追蹤6個月後的持續反應 (sustained response, SR)。療效評估項目包括ALT值的正常化 (normal alanine aminotransferase levels)反應、或無法偵測HCV RNA。安全性評估包括不良反應的發生率及因不良反應而中止治療的發生率等。以two sample t test、pair t test來分析連續變數；使用Chi-square test來分析類別變數。本研究經沙鹿童綜合醫院藥事委員會同意及行政院衛生署核准，每位參與研究之病患皆已簽署「人體試驗同意書」。
本研究結果顯示，受試者共75人 (實驗組共計42人，對照組共計33人)。治療12星期之後，ALT值恢復正常者，共計47人 (63%) ，HCV RNA轉陰者共計7人 (9%)；治療24星期後，也就是治療結束時的反應(ETR)，ALT恢復正常者共42人 (56%)，HCV RNA轉陰性者共24人 (32%)；治療結束後6個月的持續反應結果，ALT持續正常者有24人(32%)，HCV RNA持續陰性者共11人 (15%)。
1.生化血液反應( Biochemical response):
治療12星期， ALT值恢復正常者，實驗組共計29人 (69%)，而對照組共計18人 (55%)(Odds ratio=1.9; P=0.197)；治療24星期後即治療結束時的反應，實驗組共計28人 (67%)，而對照組共計14人 (42%)(Odds ratio=2.7; P=0.036)；治療結束後再追蹤6個月之持續反應，實驗組ALT持續正常者有15人 (36%)，復發率54%，對照組有9人 (27%)，復發率64% ( Odds ratio=1.5; P=0.437)。
2.病毒學反應 (Virologic response):
治療12星期，實驗組HCV RNA轉陰者共5人 (12%)，對照組HCV RNA轉陰者共2人 (6%)( Odds ratio=2.1; P=0.388)；治療24星期後，也就是治療結束時的反應 (ETR)，發現實驗組HCV RNA轉陰性者共18人 (43%)，對照組HCV RNA轉陰性者共6人 (18%)( Odds ratio=3.4; P=0.023)；治療結束後再追蹤6個月發現，實驗組HCV RNA持續陰性者共8人 (19%)，復發率44%，對照組HCV RNA持續陰性者共3人 (9%)( Odds ratio=2.4; P=0.226)，復發率50%。實驗組中對治療沒有反應者 (noresponse) 有4例；對照組中對治療沒有反應者有3例。
對於不良反應的發生率整體而言，實驗組發生率 (71%) 高於對照組 (61%)，但兩者間之差異不具統計意義 (P=0.146)；根據身體組織系統分類，研究結果發現胃腸道系統的不良反應發生率最高，佔全部受試者的30%，其中實驗組有21位 (50%)、 對照組有9位 (27%)，兩組差異具有統計上的意義 (Odds ratio=2.7; P=0.046)，即實驗組發生胃腸道的不良反應發生率高於對照組，其他組織系統的不良反應發生率並無差異。因嚴重不良反應而需要停止治療者共有7位，其中實驗組有6位，停止治療的原因分別為2例嚴重腹痛、1例甲狀腺機能亢進、1例為嚴重脾臟腫大、1例為病情無法改善且無法忍受副作用及1例因焦慮較嚴重而停藥，另外有一例因治療順從性不佳而無法判斷。對照組有1例因血小板減少症而停止治療及1位因治療順從性不佳而無法判斷。
綜觀本研究之結果顯示慢性C型肝炎病患接受24星期治療之後，ribavirin併用interferon alfa療效優於單獨使用interferon，持續反應兩組無統計上之差異，停止治療後復發率高，不良反應發生率兩組類似，所以在治療之前須評估各個病患的情況考慮其治療效益，採取不同的治療策略。由於尚有50%左右病人對現今療法反應不佳，且有效的病毒持續反應偏低，所以尚待更有效藥物和C型肝炎疫苗的開發，以提高C型肝炎的治愈率。
Abstract
One objective of this study was to assess the distribution of hepatitis B virus (HBV) and hepatitis C (HCV) infection in patients with chronic hepatitis in Taiwan. We found that HBV was the most widely distributed and HCV was the second. Generally, the prevalence of hepatitis C anti-HCV in healthy adults was 1~2%. There are more than 200000 hepatitis C carriers and 15% are hepacellular cancer patients in Taiwan. The hepatitis C vaccine and immunoglobin has not yet been developed for clinical practice in Taiwan. After hepatitis B infection, hepatitis C infection is the greatest public health problem in Taiwan.
Now patients with hepatitis C are treated using interferon alfa. Our research focused on comparing the efficacy and safety of interferon alfa combined with ribavirin and interferon alone. The results of our research established the efficacy and safety data for use in clinical practice.
The combination of interferon alfa with ribavirin increased responses of hepatitis C patients during treatment more than interferon alfa alone. In 1998, the FDA approved the combination antiviral therapy using interferon alfa with ribavirin for patients with chronic hepatitis C, however, it is not on the market yet in Taiwan. Research of this combination for efficacy and safety is now being done in Taiwan.
From January 1998 through March 2000, 75 patients were evaluated and randomized for eligibility in our clinical trial. A total of 42 patients were included in the experimental group and 33 patients were in the control group. The treatment duration was 6 months. After 6 months, the treatment was discontinued. All participants were followed for 6 months after discontinuation of treatment.
During treatment, each patient in the experiment group received 1000 ~ 1200 mg oral ribavirin daily plus 3 million units of the interferon alfa combination three times a week. Participants in the control group received 3 million units of interferon alone three times a week. Assessment of efficacy occurred at the end-of-treatment (ETR) and participants were followed for 6 months to assess the sustained response (SR). Assessment of efficacy contained normalization of serum ALT (alanine aminotransferase) levels and absence of serum HCV RNA at ETR and after 6 months of follow up. Assessment safety included measurements for incidence of adverse effects and withdrawals due to adverse effects. Two-sample t tests and pair t tests were used to describe the distribution of continue variables. The chi-squared test was used to analysis categorical variables. This trial was submitted by Shalu Tungs'' Memorial Hospital Pharmacy Therapeutics Committee and the Executive Yuan Department of Health. Medical records of the patients were submitted to the Joint Institution Review Board of our hospital.
The results from this trial showed that 75 patients of which 47 (63%) patients had normal serum ALT levels and seven (9%) patients had absence of serum after 12 weeks treatment. At the end of 24 weeks of treatment, 42 (56%) patients had normal serum ALT levels and 24 (32%) patients had absence of serum HCV RNA. After the follow up of 6 months, 24 (32%) patients had normal serum ALT levels and 11 (15%) patients had absence of serum HCV RNA.
3. Biochemical response:
After the 12 weeks of treatment, 29 patients (69%) had normal serum ALT levels in the experimental group and 18 (55%) (Odds ratio=1.9; P=0.197) . At the end of 24 weeks of treatment, 28 (67%) patients had normal ALT levels in the experimental group and 14 (42%) patients (Odds ratio=2.7;P=0.036). After the 6 month follow up,15 (36%) patients had normal serum ALT levels (recurrence rate, 54%) in the experimental group and nine (27%) (Odds ratio=1.5; P=0.437) patients had normal serum ALT levels in the control group (recurrent rate, 64%).
4. Virologic response:
After 12 weeks of treatment, five (12%) patients in the experimental group and two (6%) patients (Odds ratio=2.1; P=0.388) in the control group had absence of serum HCV RNA. At the end of 24 weeks of treatment, 18 (43%) patients in the experimental group and six (18%) (Odds ratio=3.4; P=0.023) in the control group had absence of serum HCV RNA. After the 6 months of follow up, eight (19%) patients (recurrent rate=44%) in the experimental group, and three (9%) (Odds ratio=2.4; P=0.226) in the control group had absence of serum HCV RNA, and the recurrent rate was 50%. At the end of treatment four patients had no response in the experimental group and three patients in the control group had no response.
We found that the incidence of adverse effects was 71% in the experimental group and 61% in the control group. There were no differences in statistical significance between the two groups (P=0.146). According to the tissue systems, the adverse effects in the gastroenterologic system were higher than in other tissue systems; the incidence was about 30% in all patients with 21 patients (50%) in the experimental group and nine (27%) patients in the control group. There were differences in statistical significance between the two groups (Odds ratio=2.7; P=0.046). The experimental group had more adverse effects in the gastroenterologic system than the control group; differences between the adverse effects in other tissue systems showed no statistical significance. Withdrawals due to severe adverse effects rarely occurred in either group; six patients in the experimental group, withdrew due to two patients had severe abnormal pain, one patient had hyperthyroidism, one patient had severe splenomegaly, one patient had disease with no remission and poor tolerance of adverse effect, one patients had severe anxiety and one patient had poor compliance. Only two withdrawals due to severe adverse effects occurred in the control group in which one patient had thrombocytopenia, and one patients had poor compliance.
The results from this trial showed that patients with chronic hepatitis C who received treatment with ribavirin plus interferon alfa combination therapy for 24 weeks had better results than those who received monotherapy of interferon alfa alone, however, sustained response showed no difference in statistical significance between the two groups. At end of treatment, the recurrent rate between two groups was high. The prevalence of adverse effects was the same in the two groups. Assessment of individual situations gives different treatment strategies. About 50% of patients had poor responses to the current therapy and low virologic sustained responses. Better efficacy from the drug and the hepatitis C vaccine is needed in order to increase the rate of cure. |
