Dahari Harel, Canini Laetitia, Graw Frederik, Uprichard Susan L, Araújo Evaldo S A, Penaranda Guillaume, Coquet Emilie, Chiche Laurent, Riso Aurelie, Renou Christophe, Bourliere Marc, Cotler Scott J, Halfon Philippe
The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA; Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.
J Hepatol. 2016 Jun;64(6):1232-9. doi: 10.1016/j.jhep.2016.02.022. Epub 2016 Feb 22.
BACKGROUND & AIMS: Recent clinical trials of direct-acting-antiviral agents (DAAs) against hepatitis C virus (HCV) achieved >90% sustained virological response (SVR) rates, suggesting that cure often took place before the end of treatment (EOT). We sought to evaluate retrospectively whether early response kinetics can provide the basis to individualize therapy to achieve optimal results while reducing duration and cost.
58 chronic HCV patients were treated with 12-week sofosbuvir+simeprevir (n=19), sofosbuvir+daclatasvir (n=19), or sofosbuvir+ledipasvir in three French referral centers. HCV was measured at baseline, day 2, every other week, EOT and 12weeks post EOT. Mathematical modeling was used to predict the time to cure, i.e., <1 virus copy in the entire extracellular body fluid.
All but one patient who relapsed achieved SVR. Mean age was 60±11years, 53% were male, 86% HCV genotype-1, 9% HIV coinfected, 43% advanced fibrosis (F3), and 57% had cirrhosis. At weeks 2, 4 and 6, 48%, 88% and 100% of patients had HCV<15IU/ml, with 27%, 74% and 91% of observations having target not detected, respectively. Modeling results predicted that 23 (43%), 16 (30%), 7 (13%), 5 (9%) and 3 (5%) subjects were predicted to reach cure within 6, 8, 10, 12 and 13weeks of therapy, respectively. The modeling suggested that the patient who relapsed would have benefitted from an additional week of sofosbuvir+ledipasvir. Adjusting duration of treatment according to the modeling predicts reduced medication costs of 43-45% and 17-30% in subjects who had HCV<15IU/ml at weeks 2 and 4, respectively.
The use of early viral kinetic analysis has the potential to individualize duration of DAA therapy with a projected average cost saving of 16-20% per 100-treated persons.
近期针对丙型肝炎病毒（HCV）的直接抗病毒药物（DAA）临床试验实现了超过90%的持续病毒学应答（SVR）率，这表明治愈往往在治疗结束（EOT）前就已达成。我们试图进行回顾性评估，早期应答动力学是否能为个体化治疗提供依据，从而在缩短治疗时长并降低成本的同时实现最佳疗效。
在法国的三个转诊中心，58例慢性HCV患者接受了为期12周的索磷布韦+西米普明（n = 19）、索磷布韦+达卡他韦（n = 19）或索磷布韦+来迪派韦治疗。在基线、第2天、每隔一周、治疗结束时以及治疗结束后12周测量HCV。采用数学模型预测治愈时间，即整个细胞外体液中病毒拷贝数<1。
除1例复发患者外，所有患者均实现了SVR。平均年龄为60±11岁，53%为男性，86%为HCV基因1型，9%合并HIV感染，43%有重度肝纤维化（F3），57%有肝硬化。在第2、4和6周时，分别有48%、88%和100%的患者HCV<15IU/ml，分别有27%、74%和91%的观察结果检测不到目标病毒。模型结果预测，分别有23例（43%）、16例（30%）、7例（13%）、5例（9%）和3例（5%）受试者预计在治疗的第6、8、10、12和13周达到治愈。模型表明，复发的患者若多接受一周的索磷布韦+来迪派韦治疗可能会受益。根据模型调整治疗时长预计可使在第2周和第4周时HCV<15IU/ml的受试者的药物成本分别降低43 - 45%和17 - 30%。
使用早期病毒动力学分析有潜力实现DAA治疗时长的个体化，预计每100例接受治疗的患者平均可节省16 - 20%的成本。
