背景:撒哈拉以南非洲有1000万人慢性感染丙型肝炎病毒(HCV)。评估该地区的病毒基因型和治疗反应对于实现世卫组织到2030年在全球消除病毒性肝炎的目标是必要的。我们的目的是调查HCV基因型的患病率和直接作用的抗病毒药物在贝宁的治疗结果。全国HCV血清阳性率为4%的国家。
方法:这项前瞻性队列研究在贝宁的两家转诊医院进行。如果个人的HCV血清呈阳性,并且愿意同意参与研究,则有资格纳入;排除标准是无法给予同意或监禁。通过PCR确认病毒血症。主要结果是确定HCV基因型并在完成治疗(SVR12)后12周测量持续的病毒学应答率,并进行为期12周的Sofosbuvir-velpatasvir或Sofosbuvir-ledipasvir疗程。有或没有利巴韦林。我们在对周期阈值(Ct)值为30个或更少的周期的样品进行下一代测序后进行了系统发育和抗性分析。使用亚基因组复制子测定法测试NS5A抑制剂的体外功效。
结果:在2019年6月2日至2020年12月30日之间,对148名个人进行了资格筛选,其中100人被招募到前瞻性研究中。来自100名参与者中79名(79%)的血浆样品通过PCR检测为HCV阳性。在研究的时候,79例患者中有52例(66%)已完成治疗,SVR12率为94%(52个中的49个)。79个样本中有57个(72%)的Ct值为30个或更少的周期,适合全基因组测序,我们将29个(51%)样本定性为基因型1,将28个(49%)样本定性为基因型2。三种新的基因型1亚型(1q,1r,和1s)并鉴定出一种新的基因型2亚型(2xa)。最常见的亚型是2d(57个样本中有12个[21%]),其次是1(8[14%]),1r(五个[9%]),1b(四个[7%]),1q(三个[5%]),2xa(三个[5%]),和2b(两个[3%])。20个样品(11个基因型2和9个基因型1)是未分配的新单例谱系。57个测序样品中的53个(93%)在NS5A基因内具有至少两个抗性相关取代。亚型2d与低于预期的SVR12率相关(10例患者中有8例[80%])。对于一个病人来说,亚型2b,治疗不成功。
结论:这项研究显示,贝宁使用sofosbuvir-velpatasvir治疗HCV的个体中SVR率高,包括那些具有高度多样化的病毒基因型。指出了对基因型2d和2b的治疗效果的进一步研究。
背景:医学研究委员会,威康,全球挑战研究基金,医学科学院,和PHARMBIOTRAC。
BACKGROUND: 10 million people are chronically infected with the hepatitis C virus (HCV) in sub-Saharan Africa. The assessment of viral genotypes and treatment response in this region is necessary to achieve the WHO target of worldwide elimination of viral hepatitis by 2030. We aimed to investigate the prevalence of HCV genotypes and outcomes of treatment with direct-acting antiviral agents in Benin, a country with a national HCV seroprevalence of 4%.
METHODS: This prospective cohort study was conducted at two referral hospitals in Benin. Individuals were eligible for inclusion if they were seropositive for HCV and willing to consent to participation in the study; exclusion criteria were an inability to give consent or incarceration. Viraemia was confirmed by PCR. The primary outcomes were to identify HCV genotypes and measure sustained virological response rates 12 weeks after completion of treatment (SVR12) with a 12-week course of sofosbuvir-velpatasvir or sofosbuvir-ledipasvir, with or without
ribavirin. We conducted phylogenetic and resistance analyses after the next-generation sequencing of samples with a cycle threshold (Ct) value of 30 or fewer cycles. The in-vitro efficacy of NS5A inhibitors was tested using a subgenomic replicon assay.
RESULTS: Between June 2, 2019, and Dec 30, 2020, 148 individuals were screened for eligibility, of whom 100 were recruited prospectively to the study. Plasma samples from 79 (79%) of the 100 participants were positive for HCV by PCR. At the time of the study, 52 (66%) of 79 patients had completed treatment, with an SVR12 rate of 94% (49 of 52). 57 (72%) of 79 samples had a Ct value of 30 or fewer cycles and were suitable for whole-genome sequencing, from which we characterised 29 (51%) samples as genotype 1 and 28 (49%) as genotype 2. Three new genotype 1 subtypes (1q, 1r, and 1s) and one new genotype 2 subtype (2xa) were identified. The most commonly detected subtype was 2d (12 [21%] of 57 samples), followed by 1s (eight [14%]), 1r (five [9%]), 1b (four [7%]), 1q (three [5%]), 2xa (three [5%]), and 2b (two [3%]). 20 samples (11 genotype 2 and nine genotype 1) were unassigned new singleton lineages. 53 (93%) of 57 sequenced samples had at least two resistance-associated substitutions within the NS5A gene. Subtype 2d was associated with a lower-than-expected SVR12 rate (eight [80%] of ten patients). For one patient, with subtype 2b, treatment was not successful.
CONCLUSIONS: This study revealed a high SVR rate in Benin among individuals treated for HCV with sofosbuvir-velpatasvir, including those with highly diverse viral genotypes. Further studies of treatment effectiveness in genotypes 2d and 2b are indicated.
BACKGROUND: Medical Research Council, Wellcome, Global Challenges Research Fund, Academy of Medical Sciences, and PHARMBIOTRAC.