Ribavirin plus interferon versus interferon for chronic hepatitis C

 

Abstract

Background

Hepatitis C is a major cause of liver-related morbidity and mortality. Standard therapy is ribavirin plus pegylated interferon to achieve undetectable level of virus in the blood, but the effect on clinical outcomes is controversial.

Objectives

To assess the beneficial and harmful effects of ribavirin and interferon combination therapy versus interferon monotherapy for chronic hepatitis C.

Search methods

We identified trials through electronic databases, manual searches of bibliographies and journals, approaching authors of trials, and pharmaceutical companies until March 2009.

Selection criteria

We included randomised trials, irrespective of blinding, language, or publication status, comparing ribavirin plus interferon versus interferon for treatment of chronic hepatitis C.

Data collection and analysis

The primary outcome measures were serum sustained loss of hepatitis C virus, liver-related morbidity plus all-cause mortality, and adverse events. We performed subgroup analyses of patients who were naive, relapsers, or non-responders to previous antiviral treatment. All outcomes were analysed with the random-effects model. We used Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of morbidity plus mortality. The remaining outcomes were presented as relative risks (RR). We used trial sequential analyses to examine the robustness of our findings.

Main results

We included 83 randomised trials with 12,707 patients. Most trials had unclear or high risk of bias. We did not find any significant influence of bias on our results but cannot exclude outcome measure reporting bias as many trials did not report on the primary outcomes of this review. Compared with interferon, ribavirin plus interferon had a significant beneficial effect on sustained virological response in subgroups of naive patients (RR 0.72, 95% confidence interval (CI) 0.68 to 0.75), relapsers (RR 0.62, 95% CI 0.54 to 0.70), non-responders (RR 0.89, 95% CI 0.84 to 0.93), and in all patients (RR 0.75, 95% CI 0.71 to 0.79). Combination therapy significantly reduced morbidity plus mortality in all patients (Peto OR, 0.43, 95% CI 0.23 to 0.79), but not in naive, relapsers, or non-responders individually. Combination therapy significantly increased the risk of haematological, dermatological, gastrointestinal, infectious, and miscellaneous (cough, dyspnoea, fatigue) adverse reactions. Accordingly, combination therapy significantly increased the risk of treatment discontinuation and dose reductions. Trial sequential analyses confirmed our findings regarding virological effects, but not regarding liver-related morbidity and all-cause mortality.

Authors' conclusions

Compared with interferon alone, ribavirin plus interferon is more effective in clearing hepatitis C virus from the blood. Combination therapy may reduce liver-related morbidity and all-cause mortality, but we need more evidence. The number needed to treat to obtain a beneficial effect is considerable considering the increased risk of several severe adverse reactions and costs.

 

Plain language summary

Adding ribavirin to interferon increases the number of patients who clear hepatitis C virus but also leads to several adverse reactions

Globally about 170 million people are chronically infected with hepatitis C virus. Hepatitis C is a blood-borne virus and routes of transmission include intravenous drug use, mother-to-infant transmission, unsafe medical practices, high-risk sexual behavior, and blood transfusion. Chronic hepatitis C is in most patients a benign viral infection, but a minority of patients develop liver cirrhosis and may suffer from complications due to cirrhosis or die.

It is known that treatment with the drug interferon clears hepatitis C virus from the blood in about 15% of patients. This review identified studies comparing ribavirin plus interferon with interferon alone in patients with chronic hepatitis C. This review shows, by combining the results from all trials, that adding ribavirin to interferon increases the number of patients who clear the hepatitis C virus to about 40% as well as the number of patients who demonstrate improved liver histology. Ribavirin and interferon may also reduce the risk of liver-related morbidity or all-cause mortality. However, the number needed to treat to prevent one patient developing morbidity or dying seems very large. Furthermore, combination therapy was associated with increased risk of anaemia and several other adverse reactions.

The results gives rise to a dilemma - should we, by adding ribavirin to interferon, increase the risk of haematological, dermatological, gastrointestinal, infectious, and miscellaneous adverse reactions in a situation where it has not yet been clearly demonstrated that the antiviral effect of the intervention is directly linked to the reduction of all-cause mortality? We, therefore, suggest that the combination intervention is applied only with stringent emphasis on the individual patients' well-being. Furthermore, we suggest that all future trials within the area should focus more on adverse reactions and long-term clinical outcomes.

 

摘要

背景

Ribavirin合併干擾素對照單一干擾素治療慢性C型肝炎

C型肝炎是引起和肝臟相關的發病率和死亡率的主因。這種疾病經幾十年無症狀的狀態後惡化，多數病人的確診主要根據存在C型肝炎病毒的核糖核酸和升高的血清轉氨?。

目標

評估ribavirin合併干擾素治療對照干擾素單一治療慢性C型肝炎的利弊。

搜尋策略

透過搜索截至2004年5月的電子資料庫，手動搜索目錄和期刊，聯繫試驗作者和製藥公司，以找出試驗。

選擇標準

我們收納ribavirin合併干擾素治療對照干擾素單一治療慢性C型肝炎的隨機試驗，不受盲法、語言、發表狀態的限制。

資料收集與分析

主要結果的測量值是指C型肝炎病毒的持續性消失，和肝臟相關的發病率及全因死亡率。我們分別分析了未曾接受抗病毒治療之病人，治療後復發的病人，或治療後無反應的病人，採用隨機效果模式和固定效果模式對所有結果實施統合分析。我們使用Peto odds ratios (OR)，95% 信賴區間 (CI) 來分析發病率和死亡率。其餘結果以相對風險度 (relative risks，RR)表示。

主要結論

我們收納了72 個隨機試驗，共 9991位病人。多數試驗的研究方法品質較差。從我們得到的結果裏，我們沒有發現對品質有顯著影響。和干擾素相比，合併治療對未曾接受治療之病人(RR 0.72, 95% CI 0.68 to 0.76)，復發的病人 (RR 0.63, 95% CI 0.54 – 0.73)和無反應的病人 (RR 0.89, 95% CI 0.84 – 0.94)等亞組分析中的持續性病毒學反答(RR 0.73, 95% CI 0.71 0.75)存在明顯有益的作用。 合併治療明顯降低發病率和加上死亡率 (Peto OR 0.46, 95% CI 0.22 0.96)，但是沒有降低未曾接受治療之病人，復發性病人和無反應病人的發病率和死亡率。合併治療對於組織學反應明顯有益。合併治療明顯增加貧血風險 (RR 10.48, 95% CI 5.34 – 20.55), 合併治療有22%的病人患有貧血。合併治療明顯增加皮膚感染，胃腸感染和其他(咳嗽、 呼吸困難、疲勞) 不良事件發生的風險。因此，合併治療明顯增加治療中斷的風險(RR 1.19, 95% CI 1.01 – 1.39)。

作者結論

和干擾素單一治療相比，ribavirin合併干擾素能夠更加有效的清除C型肝炎病毒，改善肝臟病理。 這樣可以降低發病率和死亡率。 但是合併治療明顯提高了幾種不良事件發生的風險。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

干擾素加上ribavirin可以提高清除C型肝炎病毒的數量，但是也增加了幾種不良事件發生的風險。C型肝炎感染是慢性肝病的常見病因，一些病人可能發展為肝硬化、肝癌或死亡。 本次文獻回顧包括72個隨機試驗，共9991位病人，顯示和干擾素單一治療相比，ribavirin合併干擾素治療可以增加C型肝炎病毒被清除的病人數，改善肝臟組織學的病人數。這樣可以降低和肝臟相關的發病或死亡的風險。但是為避免病人發病或死亡而需要治療的人數似乎很多。 另外，合併治療和貧血及其他幾種不良事件發生的風險增加相關。