BOSTON (EGMN) – More than half of hepatitis C patients who didn’t respond to standard therapy with pegylated interferon plus ribavirin did have a sustained virologic response when the protease inhibitor boceprevir was added, results from a phase II trial have shown.
“These response rates are well above what we would normally expect to see with the conventional therapy in patients who didn’t initially respond,” Dr. Paul Y. Kwo said at the annual meeting of the American Association for the Liver Diseases.
The study’s researchers analyzed data from 206 treatment-naive patients with hepatitis C virus (HCV) genotype 1 or 1b who were enrolled in the HCV SPRINT-1 study, After a 4-week lead-in period of treatment with pegylated interferon and 800 to 1,400 mg of ribavirin per day, 50 patients were null responders, defined as having a less than 10-fold reduction in HCV RNA loads.
After adding 800 mg of boceprevir three times per day, however, 25% of those null responders had sustained virologic response (SVR) by 24 weeks of the triple therapy – and 55% of the null responders achieved SVR after 44 weeks, reported Dr. Kwo of Indiana University in Indianapolis.
An assessment of the nine “worst responders” to the 4-week lead-in therapy – those who had less than a 0.5 log decrease in HCV RNA load – showed that four of them had achieved SVR by week 48 with the addition of boceprevir.
Among the patients who had a greater than 10-fold reduction in HCV-RNA following the 4-week dual combination therapy, 72% and 81%, respectively, achieved SVR with the addition of boceprevir for 24 and 44 weeks, Dr. Kwo said.
Although multivariate regression analyses showed that response at week 4 predicted response at week 24, “we could not define a minimal peginterferon/ribavirin response that reliably predicted poor viral response,” Dr. Kwo noted. “Black race was the only significant baseline predictor of null response at week 4.”
In a related poster presentation, Dr. Kwo reported the results of a separate analysis of patients who achieved undetectable HCV RNA after 4 weeks of triple therapy. “Approximately 82% of these patients achieved SVR at 28 weeks, and 94% achieved SVR at 48 weeks,” he said. The nonsignificant difference “suggests that treatment might be shortened for patients who respond well to early treatment.”
Of the “late responders” who achieved first viral negativity between weeks 4 and 12 of triple therapy including boceprevir, 21% achieved SVR by 28 weeks. By 48 weeks, however, 79% achieved SVR. That result indicates they may be a subgroup that benefited from the longer treatment course, Dr. Kwo reported.
These data represent subanalyses of the overall SPRINT-1 trial, which randomized treatment-naive HCV-1 patients to one of five treatment arms. Those five included the two 4-week lead-in/triple-therapy arms addressed here, a pegylated interferon/ribavirin-only arm, and two immediate-treatment arms evaluating the triple therapy at 24 and 44 weeks, without the 4-week dual-therapy lead in, Dr. Kwo explained.
Because the numbers are small, the findings still need to be confirmed in larger studies, said Dr. Kwo. “Ongoing boceprevir studies will further define the relationship of the week-4 pegylated interferon/ribavirin lead-in response to achievement of SVR, and will allow us to provide the best guidance to our patients,” he said.
“While the findings of this particular study suggest the therapeutic advantage of being able to treat early null responders in particular for up to 44 weeks with the triple drug combination, the potential benefits of treatment have to be weighed against the risk of developing viral resistance to protease inhibitors in patients who do not achieve SVR,” Dr. Kwo added.
Although adverse events were not evaluated in these subanalyses, previous reports from the SPRINT-1 study have linked fatigue, anemia, nausea, and headache with boceprevir treatment, Dr. Kwo said.
The SPRINT-1 study was funded by Schering-Plough. Dr. Kwo reported relationships with Schering-Plough, Vertex, Novartis, Gilead, Abbott, Roche, Merck, GlaxoSmithKline, Celgene, Idenex, and Bristol-Myers Squibb.
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波士顿(EGMN)——一项II期试验结果表明，在经聚乙二醇干扰素加利巴韦林标准治疗后无应答的丙肝患者中，半数以上在加用蛋白酶抑制剂boceprevir后都获得了持续病毒学应答。
在美国肝病学会2009年年会上，Paul Y. Kwo博士称，“该应答率大大高于我们通常预计的初始治疗无应答的患者经传统治疗后所能达到的应答率。”
该试验的研究者对HCV SPRINT-1试验纳入的206例未曾接受过治疗的丙肝病毒(HCV)基因型1型或1b型患者的数据进行了分析。导入期采用的是聚乙二醇干扰素加利巴韦林每日800~1,400 mg。在为期4周的导入期后，50例患者无应答，定义为HCV RNA载量下降不足10倍。
美国印第安纳大学Kwo博士报告称，但在加用boceprevir 800 mg，每日3次，3药联合治疗24周后，25%的无应答者获得了持续病毒学应答(SVR)，44周后55%的无应答者获得了SVR。
共有9例患者对为期4周的导入治疗“应答最差”，即HCV RNA载量下降不足0.5个对数级。对这9例患者进行分析，结果显示，其中4例在加用boceprevir治疗48周后获得了SVR。
Kwo博士报告称，对于两药联合治疗4周后HCV RNA载量下降超过10倍的患者，分别有72%和81%的患者在加用boceprevir治疗24周和44周后获得了SVR。
Kwo博士指出，虽然多变量回归分析显示，导入治疗4周后出现应答预示着24周后也能获得应答，但“并不是患者对聚乙二醇干扰素/利巴韦林治疗应答差就一定预示着他对任何治疗的病毒学应答都差。黑色人种是唯一一项可能提示治疗4周时无应答的显著基线预测因子。”
在相关的壁报展示中，Kwo博士还报告了另一项对3药联合治疗4周后 HCV RNA转阴的患者的分析结果。他说：“大约82%的患者治疗28周后获得了SVR，94%治疗48周后获得了SVR。”差异无统计学意义，“提示对于早期治疗应答良好的患者，可适当缩短疗程。”
Kwo博士报告称，在接受含boceprevir的3药联合治疗4~12周才首次出现病毒转阴的“延迟应答者”中，21%在治疗28周后获得了SVR。但在治疗48周后，79%获得了SVR。这一结果表明，对于这个亚组的患者，应延长疗程。”
Kwo博士解释道，以上是整项SPRINT-1试验的亚分析结果，SPRINT-1试验将未曾接受过治疗的HCV-1患者随机分成了5个治疗组：上文提及的2个4周导入期/3药联合治疗组；聚乙二醇干扰素/利巴韦林治疗组；2个立即治疗组，评价3药联合治疗24周和44周时的效果，而没有设置4周的两药联合导入治疗。
Kwo博士表示，鉴于该试验的样本量较小，试验结果还有待开展大规模试验以进一步证实。“目前正在进行中的boceprevir试验将进一步确定为期4周的聚乙二醇干扰素/利巴韦林导入治疗的应答情况与获得SVR之间的关系，从而为患者提供最佳的治疗指导。”
Kwo博士补充道，“虽然这项试验结果提示3药联合治疗44周尤其对于早期无应答者在治疗效果上具有优势，但对于没有达到SVR的患者，仍应仔细权衡3药联用的潜在效益与病毒对蛋白酶抑制剂耐药风险之间的关系。”
Kwo博士指出，虽然亚分析没有对不良事件进行评价，但之前发表的SPRINT-1试验报告显示，boceprevir治疗可能导致乏力、贫血、恶心和头痛。
SPRINT-1试验由先灵葆雅公司资助。Kwo博士声明与先灵葆雅、Vertex、诺华、Gilead、雅培、罗氏、默克、葛兰素史克、Celgene、Idenex和百时美-施贵宝公司存在利益关系。
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