HIV/HCV混合感染者与HCV感染者感染HCV基因型分析*

目的 使用二代测序技术检测广州地区人类免疫缺陷病毒（HIV）/丙型肝炎病毒（HCV）混合感染者和HCV感染者HCV基因型,了解本地区HCV基因型的流行特点。方法 在233例HCV感染者中,包括95例HIV/HCV混合感染者和138例HCV感染者,使用Illumina Miseq平台PE300模式对HCV Core和NS5B片段进行测序,采用生物信息学分析确定HCV基因型,对测序结果提示混合基因型感染的样本,使用NS5A基因型特异引物进行验证。结果 HIV/HCV混合感染者静脉吸毒感染构成比显著高于HCV感染者（77.7%对19.6% P<0.001）,HCV感染者输血感染的构成比显著高于HIV/HCV混合感染者（48.6%对3.2% P<0.001）;HIV/HCV混合感染者HCV Core基因片段平均数据量为（15456±6689） reads,HCV感染者为（14323±5321） reads,两组无显著差异（P>0.05）;HIV/HCV混合感染者HCV NS5B基因片段平均数据量为（16432±3467） reads,HCV感染者为（17611±5632） reads,也无显著差异（P>0.05）;本组228例（97.9%）HCV感染者为单一HCV基因型感染,HIV/HCV混合感染者HCV 6a型和3b型感染率显著高于HCV感染者（分别为47.4%对26.8%,P=0.001和13.7%对3.6%,P=0.005）,HCV 1b型感染率显著低于HCV感染者（20.0%对59.4%,P<0.001）;在233例入组的HCV感染者中,发现5例（2.1%）为混合基因型感染,其中4例为HIV/HCV混合感染者,1例为HCV感染者。结论 广州地区HIV/HCV混合感染者与HCV感染者感染HCV基因型构成比存在差异,其临床意义还需要探讨。     

HIV/HCV混合感染者与HCV感染者感染HCV基因型分析

目的使用二代测序技术检测广州地区人类免疫缺陷病毒(HIV)/丙型肝炎病毒(HCV)混合感染者和HCV感染者HCV基因型,了解本地区HCV基因型的流行特点。方法在233例HCV感染者中,包括95例HIV/HCV混合感染者和138例HCV感染者,使用Illumina Miseq平台PE300模式对HCV Core和NS5B片段进行测序,采用生物信息学分析确定HCV基因型,对测序结果提示混合基因型感染的样本,使用NS5A基因型特异引物进行验证。结果 HIV/HCV混合感染者静脉吸毒感染构成比显著高于HCV感染者(77.7%对19.6%P0.001),HCV感染者输血感染的构成比显著高于HIV/HCV混合感染者(48.6%对3.2%P0.001);HIV/HCV混合感染者HCV Core基因片段平均数据量为(15456±6689) reads,HCV感染者为(14323±5321) reads,两组无显著差异(P0.05);HIV/HCV混合感染者HCV NS5B基因片段平均数据量为(16432±3467) reads,HCV感染者为(17611±5632) reads,也无显著差异(P0.05);本组228例(97.9%)HCV感染者为单一HCV基因型感染,HIV/HCV混合感染者HCV 6a型和3b型感染率显著高于HCV感染者(分别为47.4%对26.8%,P=0.001和13.7%对3.6%,P=0.005),HCV 1b型感染率显著低于HCV感染者(20.0%对59.4%,P0.001);在233例入组的HCV感染者中,发现5例(2.1%)为混合基因型感染,其中4例为HIV/HCV混合感染者,1例为HCV感染者。结论广州地区HIV/HCV混合感染者与HCV感染者感染HCV基因型构成比存在差异,其临床意义还需要探讨。     

格卡瑞韦/哌仑他韦治疗HCV感染者和人类免疫缺陷病毒合并HCV感染者疗效及安全性研究

目的 评估应用格卡瑞韦/哌仑他韦治疗丙型肝炎病毒(HCV)感染和人类免疫缺陷病毒(HIV)合并HCV感染者的疗效及安全性。方法 2021年4月～2021年12月凉山彝族自治州越西县第一人民医院诊治的HCV感染者25例和HIV合并HCV感染者27例,均接受格卡瑞韦/哌仑他韦治疗8～12周,随访12周。结果 两组静脉注射毒品感染HCV的比率分别为60.0%和63.0%;HCV感染者实现持续病毒学应答(SVR)为92.0%,而HIV合并HCV感染者为88.9%,两组间差异无统计学意义(P=1.000);两组患者对该药耐受性良好,均未发生不良事件导致的治疗方案调整或中止。结论 应用格卡瑞韦/哌仑他韦治疗HCV感染者和HIV合并HCV感染者具有较好的近期疗效和较高的安全性。     

上海地区HIV/HCV重叠感染者HCV准种的分子流行病学研究

目的 观察HIV/HCV重叠感染和高效抗反转录病毒治疗(HAART)对HCV准种的影响.方法 通过PCR、测序及单链构象多态性分析建立HCV高变1区(HVR1)准种变异率检测方法,运用该方法对我国上海地区48例HIV/HCV重叠感染者HCV准种变异的分子流行病学进行研究.结果 与单独HCV感染组和HIV/HCV重叠感染...     

广西地区HCV 1b型感染者NS5B区基因耐药多态性分析

目的分析我国广西地区HCV 1b型感染者NS5B区耐药基因相关变异(RAV)的发生率及不同性别间的差异。方法选取2016年4月-2018年9月广西医科大学第一附属医院收治的60例HCV 1b型感染初治患者,留取基线血清样本,采用巢式聚合酶链式反应扩增NS5B区片段并进行基因测序,测序结果与基因库标准株进行比对。不同性别患者间的年龄、HCV RNA、ALT和AST水平比较采用t检验,耐药位点变异率采用Fisher确切概率法检验。结果入选的60例患者中,55例获得完整的NS5B区序列信息,RAV发生率为96. 3%,其中C316 (94. 5%)、A338(70. 9%)、T19(74. 5%)为主要的变异位点,同时检测到C316+T19、C316+T19+A338等多位点联合突变。男性RAV发生率为95. 8%(23/24),女性为96. 8%(30/31),差异无统计学意义(P=1. 000)。结论广西地区HCV 1b型感染者NS5B区存在较高的RAV发生率,既有单位点突变,也存在多位点联合突变,且不同性别间RAV发生率无明显差异。     

重庆地区192例HIV/HCV合并感染者的回顾性研究

目的分析重庆地区艾滋病病毒(HIV)/丙型肝炎病毒(HCV)合并感染的发生率及危险因素;了解HIV合并慢性HCV感染者HCV-IgG抗体的产生情况,分析部分病人不能产生HCV-IgG的可能危险因素。方法回顾性收集HIV/HCV合并感染者资料,分析合并感染的可能危险因素;统计HIV合并慢性HCV感染者HCV-IgG阴性发生率,分析其HCV-IgG阴性的可能危险因素。结果 3 013例HIV感染者/艾滋病病人中合并HCV感染192例(6.37%);合并感染HCV者的HIV病毒载量[(4.97±0.89)log拷贝/mL]低于单纯HIV感染者[(5.15±0.81)log拷贝/mL](P0.05);合并感染者中吸毒人数的比例(64.06%)高于单纯HIV感染者(0.92%)(P0.05)。合并感染者中13例(6.77%)HCV-IgG阴性。单因素分析显示,HCV-IgG阴性组较阳性组年龄偏大(P0.05),HCV-IgG阴性组通过性途径导致感染所占比例(92.31%)高于阳性组(31.84%)(P0.05);多因素分析显示,通过性途径导致合并感染者出现HCV-IgG阴性的风险,为通过静脉吸毒途径导致感染者的52.669倍。结论重庆地区HIV/HCV合并感染发生率较高,静脉吸毒是合并感染的高危因素;合并HCV感染可能抑制HIV复制;年龄、传播途径为HIV/HCV合并感染者产生HCV-IgG的危险因素,其中性传播为影响HCV-IgG产生的独立危险因素。     

河南部分地区HIV/HCV合并感染者HCV基因型的分布特征

目的了解河南部分地区艾滋病病毒(HIV)合并丙型肝炎病毒(HCV)感染者HCV基因型的分布特征。方法收集河南地区129例HIV/HCV共感染患者,119例单纯HCV感染患者,采取横断面调查的方法,收集研究对象的年龄、性别、职业、HIV传播途径等人口学资料,并进行HCV-核糖核酸(RNA)及HCV基因分型检测,结果录入数据库,用SPSS 23.0软件统计分析。结果该地区HIV/HCV合并感染者HCV基因亚型1b型最多,占54.3%(70例)。其次为2a型,占44.2%(57例)。单纯HCV感染者HCV基因亚型1b型最多,占70.6%(84例);其次为2a型,占26.1%(31例);3b和6a型各占0.8%(各1例)。两组患者间HCV基因型分布差异有统计学意义(χ2=10.578,P0.05),HIV/HCV合并感染者的HCV1b型所占百分比(54.3%)低于单纯HCV感染者(70.6%),而HCV 2a型所占百分比(44.2%)高于单纯HCV感染者(26.1%)。HIV/HCV合并感染者中,HCV1b型在经血感染中占92.9%(65/70),HCV2a型经血感染者中占98.2%(56/57)。结论河南部分地区HIV/HCV合并感染者的HCV基因分型以1b型为主,2a型次之,与单纯HCV感染者HCV基因型分布相似,经血感染是主要的传播途径。     

阿舒瑞韦联合达拉他韦治疗慢性丙型肝炎患者初步疗效及其病毒准种变化和耐药变异特征分析*

目的 观察应用阿舒瑞韦(ASV)联合达拉他韦(DCV)治疗慢性丙型肝炎(CHC)或代偿期丙型肝炎肝硬化患者的初步疗效,并分析复发患者丙型肝炎病毒(HCV)耐药变异和准种变化特征。方法 27例CHC和13例丙型肝炎肝硬化患者接受ASV联合DCV治疗24周,随访12周。纳入患者均为HCV 1b基因型感染。结果 在随访结束时,38例(95.0%)获得持续病毒学应答(SVR),2例治疗失败的患者基线均存在NS5A抑制剂相关的耐药变异;在治疗过程中有7例(17.5%)患者出现血清谷丙转氨酶或尿酸升高和血小板或血红蛋白下降;1例治疗失败的患者基线和复发时均存L31V+Y93H NS5A抑制剂相关的耐药变异,但复发时血清耐药株的比例显著高于基线时(100.0%+100.0%对 2.1%+56.2%),复发血清HCV各基因片段准种复杂度(Sn为0.91±0.02对0.40±0.07,t=19.127,P<0.001)和多样性(d为17.70±6.63对1.65±0.36,t=6.75,P<0.001;dN为3.55±2.18 对1.37±0.41,t=2.801,P=0.026;dS为48.11±10.06对2.06±0.90,t=13.598,P<0.001)均显著低于基线血清,Tajima中性检验提示复发时血清HCV各基因片段的D值显著低于基线血清(1.84±1.20对-2.30±0.18,t=10.352,P<0.001)。结论 ASV联合DCV治疗HCV 1b基因型感染的CHC和丙型肝炎肝硬化患者具有良好的近期疗效和安全性,存在NS5A抑制剂相关耐药变异者可能导致治疗失败。     

HAART对HIV/HCV合并感染者PBMCs中MxA表达水平及其对后续抗HCV疗效的影响

目的纵向研究高效抗逆转录病毒治疗(HAART)对HIV单一感染者和HIV/HCV合并感染者外周血单个核细胞(PBMCs)中粘病毒抵抗蛋白Mx A mRNA表达水平的影响,分析HAART后HIV/HCV合并感染者抗HCV前基线Mx A mRNA水平是否与后续干扰素抗HCV疗效有关。方法以广州市第八人民医院收治的艾滋病患者(HIV单一感染组,HAART前CD4+T淋巴细胞200个/mm3,42例)和HIV/HCV合并感染患者(HIV/HCV合并感染组,HAART前CD4+T淋巴细胞200个/mm3,33例)为研究对象,并以22名健康自愿者作为对照;观察患者在抗HCV治疗前的HAART的不同时间点(0 W、4 W、12 W、24 W、48 W、72 W、96 W)PBMCs中Mx A mRNA表达水平;对比分析后继抗HCV治疗效果(有早期病毒学应答EVR,无早期病毒学应答NEVR)与Mx A mRNA表达水平的关系。结果 HIV单一感染组PBMCs中Mx A mRNA水平在HAART 4 W后下降(P0.05),其他各时间点及与健康对照组之间差异均无统计学意义(P0.05);HIV/HCV合并感染组PBMCs中HAART各时间点及与健康对照组之间差异均无统计学意义(P0.05);HAART 96 W后进行抗HCV治疗,EVR组抗HCV治疗前Mx A mRNA水平较NEVR组高(P0.05)。结论长期HAART对HIV/HCV合并感染者PBMCs中Mx A mRNA表达水平无显著影响;但HAART后抗HCV治疗前PBMCs中Mx A mRNA水平可作为HIV/HCV合并感染者抗HCV疗效的预测指标之一。     

HIV对HCV感染者病程影响的探讨

目的通过比较HIV/HCV共感染与HCV单纯感染患者的肝组织病理学改变,研究HIV对HCV自然病程的影响,了解HIV在共感染者肝脏病理改变中所起的作用。方法选取HCV单纯感染者50例,HIV/HCV共感染者18例,在两组临床及实验室资料无显著性差异的情况下,对两组肝脏组织病理进行比较、分析。结果两组在炎症活动度(G)和纤维化程度(S)上均无明显差异(P>0.05)。但是HIV/HCV共感染组较HCV单纯感染组汇管区淋巴细胞明显减少(P<0.001),小叶内库普弗细胞增生较活跃(P<0.001),有明显统计学意义。而在汇管区胆管损伤和炎细胞浸润程度,小叶内炎症浸润程度及范围,有无纤维化和纤维化程度,有无脂肪变性和脂肪变性的程度及类型等多方面的比较中两组标本均无明显差异(P>0.05)。结论合并HIV感染并未明显改变HCV感染者的疾病进程,在其肝脏病理改变中仅使淋巴细胞明显减少,库普弗细胞增生活跃,对炎症活动度和纤维化程度均无明显影响。     

Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1

Background

The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region.

Methods

Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing.

Results

Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently.

Conclusions

History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.

     

Retreatment with sofosbuvir,ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy

Background

The optimal retreatment regimen for patients with hepatitis C virus (HCV) infection who failed interferon-free, direct-acting antiviral (DAA) therapy is undetermined. In this study, we aimed to evaluate the efficacy and safety of 12-week retreatment with ledipasvir (LDV) and sofosbuvir (SOF) with add-on ribavirin (RBV) for patients who previously failed to respond to HCV-NS5A inhibitor, daclatasvir (DCV), and HCV-NS3 inhibitor, asunaprevir (ASV), therapy.

Methods

This multicenter, prospective study enrolled 15 patients with genotype-1 HCV infection who failed DCV/ASV combination therapy. They were retreated with SOF, LDV, and RBV for 12 weeks and underwent physical examinations and blood tests at baseline, during treatment, and after therapy. At baseline and relapse, NS3/NS5A and NS5B resistance-associated variants (RAVs) were evaluated.

Results

Of the 15 enrolled patients, 73.3% (11/15), 86.7% (13/15), and 0% (0/15) had RAVs in NS3 D168A/V/T/E, NS5A L31I/M/F/V plus Y93H, and NS5B S282T, respectively. Overall, 86.7% (13/15) of patients achieved a sustained viral response, and all patients completed therapy. No patients experienced severe adverse events. Two patients who failed to respond to SOF, LDV, and RBV combination therapy were elderly women, had the IL28B non-TT genotype, and NS5A RAVs in L31I/Y93H or NS5A A92 K at baseline.

Conclusions

This study revealed that SOF, LDV, and RBV combination therapy was effective and well-tolerated for patients with genotype-1 HCV infection who failed DCV and ASV combination therapy. Thus, RBV added to DAA therapy for difficult-to-treat patients might improve treatment outcomes.

     

Emergence of resistant variants detected by ultra‐deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1

Daclatasvir (DCV) and asunaprevir (ASV) are NS5A and NS3 protease‐targeted antivirals respectively, currently under development for the treatment of chronic hepatitis C virus (HCV) infection. We analysed the relationship between pre‐existing drug‐resistant variants and clinical outcome of the combination treatment with DCV and ASV. Ten patients with HCV genotype 1b were orally treated with a combination of ASV and DCV for 24 weeks. The frequencies of amino acid (aa) variants at NS3 aa positions 155, 156 and 168 and at NS5A aa31 and 93 before and after treatment were analysed by ultra‐deep sequencing. We established a minimum variant frequency threshold of 0.3% based on plasmid sequencing. Sustained virological response (SVR) was achieved in 8 out of 10 patients (80%), and relapse of HCV RNA after cessation of the treatment and viral breakthrough occurred in the other two patients. Pre‐existing DCV‐resistant variants (L31V/M and/or Y93H; 0.9–99.4%) were detected in three out of eight patients who achieved SVR. Pre‐existing DCV‐resistant variants were detected in a relapsed patient (L31M, Y93H) and in a patient with viral breakthrough (Y93H); however, no ASV‐resistant variants were detected. In these patients, HCV RNA rebounded with ASV‐ and DCV‐ double resistant variants (NS3 D168A/V plus NS5A L31M and Y93H). While pre‐existing DCV‐resistant variants might contribute to viral breakthrough in DCV and ASV combination therapy, the effectiveness of prediction of the outcome of therapy based on ultra‐deep sequence analysis of pre‐existing resistant variants appears limited.     

Successful treatment of three patients with human immunodeficiency virus and hepatitis C virus genotype 1b co-infection by daclatasvir plus asunaprevir

Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) often accelerates the course of HCV-associated liver disease. Daclatasvir (DCV) plus asunaprevir (ASV) have been shown to be highly effective for HCV-infected patients with genotype 1b. Three patients co-infected with HIV/HCV genotype 1b were enrolled in this study. Prior to initiation of HCV treatment, the variants associated with L31 and Y93 in the non-structural protein 5A (NS5A) region of the HCV genome were confirmed to be absent using a direct sequencing method. Taking into consideration the lower risk of drug–drug interaction and the need for immediate treatment, the patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. In one patient, the alanine aminotransferase level was elevated to 228 IU/L at 24 weeks after the start of treatment, but he completed the 24-week treatment course. All three patients achieved sustained viral response, without severe complications (including HIV virological rebound). Thus, in cases where NS5A variants are confirmed to be absent and patients are antiretroviral therapy-naïve, with CD4+ over 500/μL or HIV well controlled by RAL-based cART, DCV plus ASV may represent a good treatment option for HIV and HCV genotype 1b co-infected patients.     

NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b

Background

Little real-world cohort data has been reported for Asians who have received interferon-free regimens with sofosbuvir (SOF) for chronic hepatitis C virus (HCV) infection. We evaluated the effectiveness and safety in clinical practice of ledipasvir (LDV) plus SOF for Japanese patients infected with HCV genotype 1.

Methods

This large, multicenter, real-world cohort study consisted of 772 patients treatment-naive or -experienced, with or without compensated cirrhosis, who were treated with LDV (90 mg)/SOF (400 mg) for a fixed 12-week duration. Direct sequence analysis of the NS5A genes (L31 and Y93) was performed at baseline.

Results

Almost all (99.6%) were infected with HCV genotype 1b. The overall sustained virological response 12 weeks after the end of treatment (SVR12) rate was 98.8% (763/772). Multivariable logistic regression analysis extracted male (odds ratio [OR] 6.62, p = 0.024), cirrhosis (OR 20.1, p = 0.0054), and baseline NS5A resistance-associated variants (RAVs) (OR 29.3, p = 0.0018) as independently associated with treatment failure. Notably, the SVR12 rate for cirrhosis patients with baseline NS5A RAVs (87.5%, 49/56) was statistically lower than for the other groups. This tendency was found except for patients with prior daclatasvir/asunaprevir failure. All patients with treatment failure had NS5A Y93H at relapse, whether or not they had NS5A RAVs at baseline. Serious adverse effects were very rare, and discontinuation was required for only five (0.6%) patients.

Conclusions

LDV/SOF for HCV genotype 1b was exceptionally effective, however, NS5A RAVs undermined the virological effect for cirrhosis patients. Moreover, LDV/SOF was shown to be safe, irrespective of age or fibrosis status.

     

Efficacy of 12 or 18 weeks of elbasvir plus grazoprevir with ribavirin in treatment‐naïve,noncirrhotic HCV genotype 3‐infected patients

Elbasvir (EBR; HCV NS5A inhibitor) and grazoprevir (GZR; HCV NS3/4A protease inhibitor) are approved as a fixed‐dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+GZR was assessed in HCV GT3‐infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+GZR with ribavirin (RBV) in treatment‐naïve, noncirrhotic HCV GT3‐infected patients. Randomized patients received open‐label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy (SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+GZR+RBV for 12 weeks or 18 weeks, respectively. On‐treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance‐associated substitutions (RASs) with a >five‐fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+GZR+RBV was suboptimal in HCV GT3‐infected patients due to a high rate of on‐treatment virologic failure and treatment‐emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+GZR+RBV in GT3‐infected patients.clinicaltrials.gov: NCT01717326.     

Real‐world effectiveness of glecaprevir/pibrentasvir and ledipasvir/sofosbuvir for mixed genotype hepatitis C infection: A multicenter pooled analysis in Taiwan

Data on direct‐acting antiviral agent (DAA) treatment for mixed genotype hepatitis C virus (HCV) infection are scant. This study examined the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) and ledipasvir/sofosbuvir (LDV/SOF) for mixed HCV genotype infection in a real‐world setting in Taiwan. We analysed the data from all patients with mixed HCV genotype infections treated with GLE/PIB or LDV/SOF from 2017 to 2019 in three Chang Gung Memorial Hospitals in Taiwan. The primary treatment outcome was sustained virologic response 12 weeks after treatment cessation (SVR12). Adverse events (AEs) were also evaluated. A total of 5190 HCV patients received DAA treatment during this time period. Among them, 116 patients (2.2%) had mixed infections of any 2 or 3 genotypes of 1a, 1b, 2, 3 and 6. Fifty‐four patients received GLE/PIB and 62 received LDV/SOF. SVR12 rates for LDV/SOF vs GLE/PIB therapy were 96.6% (56/58) vs 100% (51/51) by the per‐protocol analysis and 90.3% (56/62) vs 94.4% (51/54) by the evaluable population analysis. Two patients with 1b + 6 and 1b + 2 genotype infections in the LDV/SOF group had relapse. Evaluating the GLE/PIB vs LDV/SOF groups for the most common AEs revealed pruritus (16.7% vs 4.8%), abdominal discomfort (5.6% vs 8%) and fatigue (5.6% vs 4.8%). One patient with AE‐related treatment discontinuation presented with liver decompensation after 4‐week GLE/PIB therapy. DAA‐related significant laboratory abnormalities occurred in two patients with >3× elevated bilirubin level in the GLE/PIB group. GLE/PIB and LDV/SOF are well tolerated and achieve high SVR12 rates for patients with mixed HCV genotype infection.     

Resistance Analyses of Japanese Hepatitis C‐Infected Patients Receiving Sofosbuvir or Ledipasvir/Sofosbuvir Containing Regimens in Phase 3 Studies

High rates of sustained virologic response (SVR) has been achieved in Japanese patients with chronic hepatitis C virus (HCV) genotype (GT)1 and GT2 infection treated with ledipasvir/sofosbuvir (LDV/SOF) ±ribavirin (RBV) and SOF+RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance‐associated variants (RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A (GT1 only) and NS5B (GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/mL). In patients with HCV GT1 infection, 22.3% (GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/SOF and LDV/SOF+RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection (GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/SOF and SOF+RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/SOF for 12 weeks.