VIENNA (EGMN) – Metabolic syndrome predicts a poor response to treatment for chronic hepatitis C viral infection, according to results from a large trial – but there’s a twist.

In the 3,070-patient study, each of the individual components of metabolic syndrome was a negative predictor of sustained virologic response to 48 weeks of antiviral therapy, except one: Surprisingly, a low level of high-density lipoprotein predicted a favorable response to treatment. And a cardioprotective high HDL level was an independent predictor of treatment failure, Dr. Mark S. Sulkowski reported at the annual International Liver Congress.

Another study presented at the congress suggested that intensified doses of the standard antiviral agents – pegylated interferon and ribavirin – could significantly improve treatment success rates in difficult-to-cure hepatitis C genotype 1 patients with metabolic syndrome.

Dr. Sulkowski noted that all of the more than 3,000 participants in the IDEAL study (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) had genotype 1 hepatitis C. At baseline, 30% met the criteria for metabolic syndrome from the American Heart Association/International Diabetes Federation. Their sustained virologic response (SVR) rate of 35% after 48 weeks of pegylated interferon plus ribavirin was significantly lower than the 42% rate for patients without metabolic syndrome.

The difference was significant in both men and women, although the outcome gap was bigger in women. The SVR in women with metabolic syndrome was 35%, compared with 43% in women without metabolic syndrome. Men with metabolic syndrome had a 35% SVR, compared with 41% in those without the syndrome, reported Dr. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore.

For each additional component of metabolic syndrome that a patient had, the SVR dropped further. Multivariate regression analysis revealed that an elevated fasting blood glucose was the strongest negative predictor of SVR, with an odds ratio of 1.72 for missing this key end point. Unexpectedly, a secondary analysis showed that an HDL of at least 40 mg/dL in men or 50 mg/dL in women was another independent predictor of not attaining an SVR, with an odds ratio of 1.5. The 18% of IDEAL participants with both a high fasting blood glucose and a high HDL at baseline had a twofold increased likelihood of not achieving an SVR after 48 weeks of antiviral therapy.

Six months after completion of therapy, 56% of patients with metabolic syndrome at baseline no longer met criteria for the disorder, Dr. Sulkowski said at the congress, which was sponsored by the European Association for the Study of the Liver.

In an interim analysis of an observational study involving 2,501 German patients being treated for chronic hepatitis C, three factors were found to be independent predictors of failure to achieve an early virologic response at week 12: hypertriglyceridemia, elevated fasting blood glucose, and body mass index of 27 kg/m² or more. But a total cholesterol level higher than 190 mg/dL was associated with a threefold greater likelihood of early virologic response compared with that seen in patients with a lower cholesterol level, reported Dr. Elmar Jaeckel of Hannover (Germany) Medical School.

The strongest predictor of an early virologic response was having hepatitis C genotype 2 or 3. These genotypes were associated with a 7.6-fold greater likelihood of early virologic response compared with having genotypes 1, 4, 5, or 6, according to Dr. Jaeckel.

Dr. Mitchell L. Shiffman presented a retrospective analysis of 1,135 patients with chronic hepatitis C genotype 1 infection who were treated with pegylated interferon alfa-2a plus ribavirin in a variety of dosing schedules. Among the 34% of patients classified as having metabolic syndrome, the relapse rate in those randomized to the most intensive treatment regimen was only about half that of patients on standard therapy – 24% vs. 47% – reported Dr. Shiffman of Bon Secours Health System, Newport News, Virginia.

Similarly, the SVR rate at week 72 in patients assigned to the most intensive regimen was 43%, compared with 24% in patients on the standard approved regimen. The most intensive regimen consisted of pegylated interferon alfa-2a at 360 mcg/week for the first 12 weeks followed by 180 mcg/week out to week 48, accompanied by weight-based dosing of ribavirin at either 1,400 or 1,600 mg daily. The standard regimen was pegylated interferon alfa-2a at 180 mcg/week plus ribavirin at 1,200 mg daily.

This finding, that intensified treatment increases the treatment success rate in difficult-to-cure genotype 1 patients with metabolic syndrome, must be considered hypothesis generating, and requires confirmation in prospective randomized trials, Dr. Shiffman said.

The studies presented by Dr. Shiffman and Dr. Jaeckel were funded by F. Hoffmann-La Roche Ltd.; they serve as consultants to the company. The IDEAL study was supported by Schering-Plough Corp. Dr. Sulkowski disclosed serving as an advisor to Schering-Plough and nine other pharmaceutical companies.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

维也纳(EGMN)——来自一项大型临床研究的结果表明，患有代谢综合征意味着患者对慢性丙型肝炎病毒感染治疗的反应不佳 ，但存在一处出人意料的变化。

 

这项包括3,070例患者的研究发现，代谢综合征的每项独立指标均是患者对48周抗病毒治疗的持续病毒学反应(SVR)的阴性预测因子，但出人意料的是，高密度脂蛋白(HDL)水平较低预示着患者对病毒治疗反应良好。Mark S. Sulkowski博士在国际肝病会议年会上报告，具心脏保护作用的高水平HDL是治疗失败的独立预测因子。

 

此次大会上发布的另外一项研究表明，加大剂量的标准抗病毒药物(聚乙二醇干扰素和利巴韦林)可显著提高伴代谢综合征的难治性基因1型丙型肝炎患者的治疗成功率。

 

Sulkowski博士指出，参与IDEAL研究(获得最佳聚乙二醇干扰素疗法的个性化剂量与适量疗效比较研究)的超过3,000例的所有受试者感染有基因1型丙型肝炎病毒。基线时，30%的受试者符合美国心脏病学会/国际糖尿病联合会的代谢综合征的诊断标准。在接受48周的聚乙二醇干扰素联合利巴韦林治疗后，35%的受试者获得SVR，其比例显著低于无代谢综合征的患者(42%)。

 

巴尔的摩约翰·霍普金斯大学病毒性肝炎中心医务主任Sulkowski博士报告称，这种差异在男性和女性受试者中均较显著，而此疗效差距在女性中更大。伴代谢综合征女性的SVR为35%，而无代谢综合征女性的SVR为43%。伴代谢综合征男性的SVR为35%，而无代谢综合征女性的SVR为41%。

 

患者代谢综合征的组成成分越多，其SVR将进一步降低。多因素回归分析发现，空腹血糖水平是SVR最强的阴性预测因子，缺失此关键终点的比值比为1.72。出人意料的是，二次分析发现男性HDL水平≥40 mg/dl或女性HDL水平≥50 mg/dl是未获得SVR的另外一个独立预测因子，其比值比为1.5。同时具有空腹血糖高水平和基线HDL水平较高的18%的IDEAL研究受试者在48周抗病毒治疗后无法获得SVR的几率提高2倍。

 

Sulkowski博士在会上表示，在结束治疗6个月后，56%的基线时确诊有代谢综合征的患者已不符合代谢综合征的诊断标准。本次会议由欧洲肝脏研究学会资助。

 

一项针对2,501例接受慢性丙型肝炎治疗的德国患者进行的观察研究的中期分析发现，3种因素为治疗12周后患者无法获得早期病毒学反应的独立预测因子：高三酰甘油血症、空腹血糖升高和体质指数≥ kg/m²。德国汉诺威医学院的Elmar Jaeckel博士报告，但与胆固醇水平较低的患者相比，总胆固醇水平>190 mg/dl的患者获得早期病毒学反应的几率升高3倍。

 

Jaeckel博士表示，早期病毒学反应的最强预测因子为患者患有基因2型或3型丙型肝炎；与基因1、4、5或6型的丙型肝炎患者相比，基因2型或3型丙型肝炎患者获得早期病毒学反应的几率提高了7.6倍。

 

Mitchell L. Shiffman博士汇报了针对接受不同剂量方案聚乙二醇干扰素α-2a联合利巴韦林治疗的1,135例慢性基因1型丙型肝炎患者进行的一项回顾性研究的结果。弗吉尼亚纽波特纽斯Bon Secours卫生系统的Shiffman博士报告，在34%被确诊伴有代谢综合征的患者中，被随机分配接受最大剂量方案治疗的患者的复发率仅相当于接受标准剂量治疗者的一半(24%对47%)。

 

同样，被分配接受最大剂量方案治疗的患者72周的SVR率为43%，而在接受标准剂量治疗者为24%。最大剂量方案包括前12周每周应用360 μg聚乙二醇干扰素α-2a，然后降为每周180 μg，直到第48周，同时应用依体重调整剂量的利巴韦林(每日1400mg或1,600 mg)。标准剂量方案为每周180 μg聚乙二醇干扰素α-2a另加每日应用1,200 mg利巴韦林。

 

Shiffman博士说，强化治疗提高了伴代谢综合征的难治愈的基因1型丙型肝炎患者的治疗成功率的发现，应被视为在“提出假设”，并且需要在前瞻性随机临床研究中加以验证。

 

Shiffman博士和Jaeckel博士汇报的研究由罗氏制药公司资助；他们担任该公司的顾问。IDEAL研究由先灵葆雅制药公司资助。Sulkowski博士承认为先灵葆雅公司及其他9家制药公司的顾问。