直接作用性抗病毒药物的治疗中断率很高

一项研究显示，在接受直接作用性抗病毒药物治疗的退伍军人丙型肝炎患者中，尽管早期临床应答率很高，但24周时仍有多达30%的患者中断治疗。

加州帕洛阿尔托退伍军人保健系统的Belperio医生对2012年1月1日之前开始在94家退伍军人事务部(VA)医疗机构接受聚乙二醇化干扰素、利巴韦林以及波普瑞韦(n=661)或特拉匹韦(n=198)三联治疗的患者进行了研究。如在最近一次分析中发现HCV RNA水平为无法检出，则将患者归类为“无法检出”的应答。患者平均年龄为57岁；多数为男性。排除合并感染HIV或乙型肝炎病毒、合并肝细胞癌或肝脏移植的患者。即使如此，“根据特拉匹韦试验中使用的血液学排除标准，在接受波普瑞韦和特拉匹韦治疗的退伍军人患者中，仍分别有多达13%和24%被从这些治疗的Ⅲ期试验中排除”。

尽管如此，结果显示，在12周时，在所有之前未接受过治疗的波普瑞韦组非肝硬化患者中，有76%达到病毒载量无法检出，这一比例在特拉匹韦组患者中为78%。24周时，波普瑞韦组和特拉匹韦组病毒载量无法检出的患者比例分别为74%和60%。

但研究者同时发现，在24周之前，波普瑞韦组和特拉匹韦组均有大约1/3的患者中断治疗(分别为30%和34%；P=0.37)，两组血液学不良事件的发生率均高于直接作用性抗病毒药物(DAAs)临床试验报告的比率，并且更为严重。两组中均有50%的患者发生≥1级贫血(血红蛋白低于正常下限，但≥10 g/dl)，“较其他文献中报告的贫血发生率增加多达15%。”两种药物治疗者中血小板减少发生率也显著增加，为临床试验中的4倍。实际上，波普瑞韦组和特拉匹韦组分别有66%和59%的患者发生1级血小板减少(血小板计数低于正常下限，但≥75,000/mm³)。“这可能反映了我们的队列中肝硬化患者的比例高于临床试验，但也可能与目前血小板减少的治疗选择有限以及PEG剂量降低对含DAA治疗的持续病毒学应答的未知影响有关。”

根据美国食品药品管理局的规定，部分患者的治疗被确定为无效：波普瑞韦组9%的患者在12周时、5%的患者在24周时，以及特拉匹韦组6%的患者在4周时、4%的患者在12周时和7%的患者在24周时，被确认为治疗无效。

作者披露，有一名合著者之前曾接受HCV治疗药物的生产商吉利德公司提供的资金支持，除此之外无其他利益冲突。

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By: DENISE NAPOLI, Internal Medicine News Digital Network

Despite high rates of early clinical response, 30% of veterans taking direct-acting antivirals for hepatitis C discontinued treatment by week 24.

The findings highlight "the challenges associated with maintenance of these regimens" in a real-world cohort, wrote Pamela S. Belperio, Pharm.D., and colleagues. The study appears in the August issue of Clinical Gastroenterology and Hepatology.

Dr. Belperio of Veterans Affairs Palo Alto (Calif.) Health Care System, looked at 859 patients registered with the VA’s Clinical Case Registry for HCV who initiated triple therapy with pegylated interferon, ribavirin, and either boceprevir (n = 661) or telaprevir (n = 198) before Jan. 1, 2012, at 94 different VA facilities.

The authors determined how long the patient took the drug by looking at medication dispensed dates, and patients were classified as having response rates of "undetectable" if HCV RNA levels at their most recent assay were undetectable.

Patients’ mean age was 57 years; most of the patients were male. Patients with HIV or hepatitis B virus coinfection, hepatocellular carcinoma, or liver transplantation were excluded.

Even so, "Up to 13% of boceprevir-treated veterans and 24% of telaprevir-treated veterans would have been excluded from the phase III trials [of these therapies] based on hematologic exclusion criteria used in the telaprevir trials," Dr. Belperio wrote.

Despite this, the authors found that by week 12, 76% of all treatment-naive, noncirrhotic patients taking boceprevir had achieved undetectable viral loads, as had 78% of telaprevir patients.

By 24 weeks, those numbers were 74% for boceprevir patients and 60% for telaprevir patients.

However, the researchers also found that about one-third of patients discontinued treatment with either boceprevir or telaprevir before 24 weeks (30% and 34%, respectively; P = .37), with an incidence of hematologic adverse events that was both higher and more pronounced than has been reported in clinical trials of direct-acting antivirals (DAAs), wrote Dr. Belperio.

Indeed, anemia of at least grade 1 (hemoglobin below normal limits but greater than or equal to 10 g/dL) occurred in 50% of patients in both DAA groups, "which is up to a 15% increased incidence of anemia over what has been reported elsewhere."

There was also significant thrombocytopenia for both drugs, which Dr. Belperio said was four times higher than in clinical trials. In fact, her group reported that 66% of patients taking boceprevir had grade 1 thrombocytopenia. (platelets below normal limits but greater than or equal to 75,000/mm3), as did 59% of patients taking telaprevir.

"This may reflect the greater proportion of cirrhotic patients in our cohort compared with the clinical trials; however, it is concerning given the limited strategies currently available to manage thrombocytopenia and the unknown effect that PEG dose reductions may have on sustained virologic response in the context of DAA-based therapies," they wrote.

There also was a portion of patients for whom treatment was determined to be futile, according to Food and Drug Administration specifications: 9% of patients receiving boceprevir at week 12 and 5% at week 24, as well as 6% of telaprevir patients at week 4, 4% at week 12, and 7% at week 24.

The authors conceded several limitations to this study, including that they were unable to assess reasons for early treatment discontinuation.

Nevertheless, the data "offer clinicians a perspective on expectations of early response and safety of DAA regimens in routine clinical practice, allowing a more nuanced discussion between providers and patients regarding the risks and benefits of embarking on DAA-based treatment."

The authors disclosed that one coinvestigator has previously received grant support from Gilead Sciences, maker of HCV therapies. They disclosed no other conflicts of interest.