Prevalence, genetic and clinical characteristics in first-degree relatives of patients with familial cerebral cavernous malformations in China.

OBJECTIVE: This study aims to investigate the prevalence of familial cerebral cavernous malformations (FCCMs) in first-degree relatives (FDRs) using familial screening, to describe the distribution of initial symptoms, lesion count on cranial MRI and pathogenic gene in patients. METHODS: Patients with multiple CCMs who enrolled from the Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in China database were considered as probands and FDRs were recruited. Cranial MRI was performed to screen the CCMs lesions, and whole-exome sequencing was performed to identify CCM mutations. MRI and genetic screening were combined to diagnose FCCM in FDRs, and the results were presented as prevalence and 95% CIs. The Kaplan-Meier (KM) method was used to calculate the cumulative incidence of FCCM. RESULTS: 33 (76.74%) of the 43 families (110 FDRs) were identified as FCCM (85 FDRs). Receiver operating characteristic analysis revealed three lesions on T2-weighted imaging (T2WI) were the strong indicator for distinguishing probands with FCCM (sensitivity, 87.10%; specificity, 87.50%). Of the 85 FDRs, 31 were diagnosed with FCCM, resulting in a prevalence of 36.5% (26.2%-46.7%). In families with FCCMs, the mutation rates for CCM1, CCM2 and CCM3 were 45.45%, 21.21% and 9.09%, respectively. Furthermore, 53.13% of patients were asymptomatic, 17.19% were intracranial haemorrhage and 9.38% were epilepsy. The mean age of symptom onset analysed by KM was 46.67 (40.56-52.78) years. CONCLUSION: Based on MRI and genetic analysis, the prevalence of CCMs in the FDRs of families with FCCMs in China was 36.5%. Genetic counselling and MRI screening are recommended for FDRs in patients with more than three CCM lesions on T2WI.

Naoxueshu Oral Liquid Accelerates Post-Craniotomy Hematoma Absorption in Patients: An Open-Label, Multicenter, and Randomized Controlled Trial.

OBJECTIVE: To investigate whether Naoxueshu Oral Liquid (NXS) could promote hematoma absorption in post-craniotomy hematoma (PCH) patients. METHODS: This is an open-label, multicenter, and randomized controlled trial conducted at 9 hospitals in China. Patients aged 18-80 years with post-craniotomy supratentorial hematoma volume ranging from 10 to 30 mL or post-craniotomy infratentorial hematoma volume less than 10 mL, or intraventricular hemorrhage following cranial surgery were enrolled. They were randomly assigned at a 1:1 ratio to the NXS (10 mL thrice daily for 15 days) or control groups using a randomization code table. Standard medical care was administered in both groups. The primary outcome was the percentage reduction in hematoma volume from day 1 to day 15. The secondary outcomes included the percentage reduction in hematoma volume from day 1 to day 7, the absolute reduction in hematoma volume from day 1 to day 7 and 15, and the change in neurological function from day 1 to day 7 and 15. The safety was closely monitored throughout the study. Moreover, subgroup analysis was performed based on age, gender, history of diabetes, and etiology of intracerebral hemorrhage (ICH). RESULTS: A total of 120 patients were enrolled and randomly assigned between March 30, 2018 and April 15, 2020. One patient was lost to follow-up in the control group. Finally, there were 119 patients (60 in the NXS group and 59 in the control group) included in the analysis. In the full analysis set (FAS) analysis, the NXS group had a greater percentage reduction in hematoma volume from day 1 to day 15 than the control group [median (Q1, Q3): 85% (71%, 97%) vs. 76% (53%, 93%), P<0.05]. The secondary outcomes showed no statistical significance between two groups, either in FAS or per-protocol set (P>0.05). Furthermore, no adverse events were reported during the study. In the FAS analysis, the NXS group exhibited a higher percentage reduction in hematoma volume on day 15 in the following subgroups: male patients, patients younger than 65 years, patients without diabetes, or those with initial cranial surgery due to ICH (all P<0.05). CONCLUSIONS: The administration of NXS demonstrated the potential to promote the percentage reduction in hematoma volume from day 1 to day 15. This intervention was found to be safe and feasible. The response to NXS may be influenced by patient characteristics. (Registration No. ChiCTR1800017981).

Enhanced Treatment Options for Dural Arteriovenous Fistulas at the Craniocervical Junction: Endovascular Embolization Versus Microsurgery? A Single-Center 23-Year Experience.

OBJECTIVE: The occurrence of dural arteriovenous fistulas (DAVFs) at the craniocervical junction (CCJ) is an uncommon vascular malformation. The diagnosis and treatment of CCJ DAVFs present a formidable challenge. This study aims to investigate the effect of endovascular embolization and microsurgery on improving patient prognosis. METHODS: This retrospective study included patients diagnosed with CCJ DAVFs who received treatment at the First Affiliated Hospital of Fujian Medical University between January 2000 and January 2023. The clinical records, imaging data, and treatment methods were obtained from the hospital's medical record system. The patients were classified into microsurgery and embolization groups based on the surgical technique employed for treatment. The primary outcome measures were surgical-associated neurological dysfunction (SAND) and long-term neurological outcomes. The Cox proportional hazard regression was utilized to determine hazard ratios and 95% confidence intervals (CI) to assess the relationship between treatment methods and prognosis. Kaplan-Meier survival analysis was employed to evaluate the incidence of SAND in both cohorts. RESULTS: This study recruited 46 patients with an average age of 53.72 ± 13.83 years. In the microsurgery group, there were 12 cases (26.1%) observed. While in the embolization group, there were 34 cases (73.9%). Of these patients, 16 (34.8%) experienced SAND after treatment. In the microsurgery group, there were 8 cases (75.0%), while in the embolization group, only 8 cases (23.5%) were reported. Specifically, the embolization group exhibited a significantly lower risk of SAND [adjusted hazard ratio = 0.259, 95% CI = 0.096-0.700; P = 0.008)] compared to the microsurgery group. Additionally, the combined Borden grade 2-3 was found to be significantly associated with SAND (adjusted hazard ratio = 3.150, 95% CI = 1.132-8.766; P = 0.028). The results of the Kaplan-Meier survival analysis indicated a statistically significant difference in the occurrence of favorable functional outcomes between the 2 groups (log-rank P = 0.0081). CONCLUSIONS: CCJ DAVFs are uncommon disorders characterized by a diverse range of clinical manifestations. The functional prognosis of endovascular treatment may be superior to microsurgery.

High Plasma Fibrinogen Level Elevates the Risk of Cardiac Complications Following Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Cardiac complications are related to poor prognosis after spontaneous intracerebral hemorrhage (ICH). This study aims to predict the cardiac complications arising from small intracranial hematoma at ultraearly stage. METHODS: The data of this work were derived from the Risk Stratification and Minimally Invasive Surgery in Acute ICH Patients study (ClinicalTrials.gov Identifier: NCT03862729). This work included patients with ICH but without brain herniation, as confirmed by a brain computed tomography scan within 48 hours of symptom onset. Every Patient's information recorded at the emergent department, including clinical, laboratory, electrocardiogram, and medical records, was derived from the electronic data capture. Cardiac complications were defined as the occurrence of myocardial damage, arrhythmias, and ischemic electrocardiogram changes during hospitalization. Variables associated with cardiac complications were filtrated by univariate and multivariate regression analyses. Independent risk factors were used to form the early predictive model. The restricted cubic splines were employed to investigate the nonlinear associations in a more sophisticated and scholarly manner. RESULTS: A total of 587 ICH patients were enrolled in this work, including 72 patients who suffered from cardiac complications after ICH. Out of the 78 variables, 24 were found to be statistically significant in the univariate logistic regression analysis. These significant variables were then subjected to multivariate logistic regression analysis and utilized for constructing risk models. Multivariate logistic regression analysis showed high plasma fibrinogen (FIB) level [odds ratio (OR) per standard deviation (SD) 1.327, 95% confidence intervals (CI) 1.037-1.697; P = 0. 024)] and older age (OR per SD 1.777, 95% CI 1.344-2.349; P ＜0.001) were associated with a higher incidence of cardiac complications after ICH. High admission pulse rate (OR 0.620, 95% CI 0.451-0.853; P = 0. 003) was considered a protective factor for cardiac complications after ICH. In the restricted cubic spline regression model, FIB and cardiac complications following ICH were positively correlated and almost linearly (P for nonlinearity = 0.073). The reference point for FIB in predicting cardiac complications after ICH was 2.64 g/L. CONCLUSIONS: Emergent factors, including plasma FIB level, age, and pulse rate, might be independently associated with cardiac complications after ICH, which warrants attention in the context of treatment.

A novel KRIT1/CCM1 mutation accompanied by a NOTCH3 mutation in a Chinese family with multiple cerebral cavernous malformations.

Family cerebral cavernous malformations (FCCMs) are mainly inherited through the mutation of classical CCM genes, including CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. FCCMs can cause severe clinical symptoms, including epileptic seizures, intracranial hemorrhage (ICH), or functional neurological deficits (FNDs). In this study, we reported a novel mutation in KRIT1 accompanied by a NOTCH3 mutation in a Chinese family. This family consists of 8 members, 4 of whom had been diagnosed with CCMs using cerebral MRI (T1WI, T2WI, SWI). The proband (II-2) and her daughter (III-4) had intracerebral hemorrhage and refractory epilepsy, respectively. Based on whole-exome sequencing (WES) data and bioinformatics analysis from 4 patients with multiple CCMs and 2 normal first-degree relatives, a novel KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in intron 13 was considered a pathogenic gene in this family. Furthermore, based on 2 severe and 2 mild CCM patients, we found an SNV missense mutation, NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C), in NOTCH3. Finally, the KRIT1 and NOTCH3 mutations were validated in 8 members using Sanger sequencing. This study revealed a novel KRIT1 mutation, NG_012964.1 (NM_194456.1): c.1255-1G > T (splice-3), in a Chinese CCM family, which had not been reported previously. Moreover, the NOTCH3 mutation NG_009819.1 (NM_000435.2): c.1630C > T (p.R544C) might be a second hit and associated with the progression of CCM lesions and severe clinical symptoms.

A nomogram predictive model for long-term survival in spontaneous intracerebral hemorrhage patients without cerebral herniation at admission.

Stratification of spontaneous intracerebral hemorrhage (sICH) patients without cerebral herniation at admission, to determine the subgroups may be suffered from poor outcomes or benefit from surgery, is important for following treatment decision. The aim of this study was to establish and verify a de novo nomogram predictive model for long-term survival in sICH patients without cerebral herniation at admission. This study recruited sICH patients from our prospectively maintained ICH patient database (RIS-MIS-ICH, ClinicalTrials.gov Identifier: NCT03862729) between January 2015 and October 2019. All eligible patients were randomly classified into a training cohort and a validation cohort according to the ratio of 7:3. The baseline variables and long-term survival outcomes were collected. And the long-term survival information of all the enrolled sICH patients, including the occurrence of death and overall survival. Follow-up time was defined as the time from the onset to death of the patient or the last clinical visit. The nomogram predictive model was established based on the independent risk factors at admission for long-term survival after hemorrhage. The concordance index (C-index) and ROC curve were used to evaluate the accuracy of the predictive model. Discrimination and calibration were used to validate the nomogram in both the training cohort and the validation cohort. A total of 692 eligible sICH patients were enrolled. During the average follow-up time of 41.77 ± 0.85 months, a total of 178 (25.7%) patients died. The Cox Proportional Hazard Models showed that age (HR 1.055, 95% CI 1.038-1.071, P < 0.001), Glasgow Coma Scale (GCS) at admission (HR 2.496, 95% CI 2.014-3.093, P < 0.001) and hydrocephalus caused by intraventricular hemorrhage (IVH) (HR 1.955, 95% CI 1.362-2.806, P < 0.001) were independent risk factors. The C index of the admission model was 0.76 and 0.78 in the training cohort and validation cohort, respectively. In the ROC analysis, the AUC was 0.80 (95% CI 0.75-0.85) in the training cohort and was 0.80 (95% CI 0.72-0.88) in the validation cohort. SICH patients with admission nomogram scores greater than 87.75 were at high risk of short survival time. For sICH patients without cerebral herniation at admission, our de novo nomogram model based on age, GCS and hydrocephalus on CT may be useful to stratify the long-term survival outcomes and provide suggestions for treatment decision-making.

Novel machine learning models to predict pneumonia events in supratentorial intracerebral hemorrhage populations: An analysis of the Risa-MIS-ICH study.

Background: Stroke-associated pneumonia (SAP) contributes to high mortality rates in spontaneous intracerebral hemorrhage (sICH) populations. Accurate prediction and early intervention of SAP are associated with prognosis. None of the previously developed predictive scoring systems are widely accepted. We aimed to derive and validate novel supervised machine learning (ML) models to predict SAP events in supratentorial sICH populations. Methods: The data of eligible supratentorial sICH individuals were extracted from the Risa-MIS-ICH database and split into training, internal validation, and external validation datasets. The primary outcome was SAP during hospitalization. Univariate and multivariate analyses were used for variable filtering, and logistic regression (LR), Gaussian naïve Bayes (GNB), random forest (RF), K-nearest neighbor (KNN), support vector machine (SVM), extreme gradient boosting (XGB), and ensemble soft voting model (ESVM) were adopted for ML model derivations. The accuracy, sensitivity, specificity, and area under the curve (AUC) were adopted to evaluate the predictive value of each model with internal/cross-/external validations. Results: A total of 468 individuals with sICH were included in this work. Six independent variables [nasogastric feeding, airway support, unconscious onset, surgery for external ventricular drainage (EVD), larger sICH volume, and intensive care unit (ICU) stay] for SAP were identified and selected for ML prediction model derivations and validations. The internal and cross-validations revealed the superior and robust performance of the GNB model with the highest AUC value (0.861, 95% CI: 0.793-0.930), while the LR model had the highest AUC value (0.867, 95% CI: 0.812-0.923) in external validation. The ESVM method combining the other six methods had moderate but robust abilities in both cross-validation and external validation and achieved an AUC of 0.843 (95% CI: 0.784-0.902) in external validation. Conclusion: The ML models could effectively predict SAP in sICH populations, and our novel ensemble model demonstrated reliable robust performance outcomes despite the populational and algorithmic differences. This attempt indicated that ML application may benefit in the early identification of SAP.

Vitamin D receptor genetic polymorphisms are associated with oral lichen planus susceptibility in a Chinese Han population.

BACKGROUND: Vitamin D receptor (VDR) is involved in multiple immune-mediated disorders including oral lichen planus (OLP). This study investigated the association between VDR gene polymorphisms and the risk of OLP. METHODS: In total, 177 OLP patients and 207 healthy participants were recruited from the Affiliated Hospital of Stomatology, Nanjing Medical University. Eight single nucleotide polymorphisms (SNPs: rs731236, rs739837, rs757343, rs2107301, rs2239185, rs7975232, rs11574129 and rs11568820) in the VDR gene were selected and genotyped. RESULTS: The results showed that OLP risk was increased in subjects with the rs2239185 TT genotype (Recessive model: adjusted Odd ratio(OR) = 2.68, 95% Confidence interval(CI) = 1.28-5.62, P = 0.009) and rs7975232 CC genotype (Recessive model: adjusted OR = 2.25, 95% CI = 1.10-4.58, P = 0.026). Moreover, rs2239185 and rs7975232 (P < 0.01) showed significant cumulative effects on OLP risk.Haplotype analysis showed that the CC haplotype (rs2239185-rs7975232) was associated with an increased risk of OLP (OR = 3.11, 95% CI = 1.42-6.83, P = 0.005), compared with the AC haplotype. CONCLUSION: The rs2239185 and rs7975232 variants of VDR may influence OLP susceptibility, and VDR gene polymorphisms may be candidate susceptibility regions for OLP in a Chinese Han population.

Association of rs2111485 and rs1990760 Polymorphisms of Interferon Induced with Helicase C Domain 1 Gene with Hepatitis C Virus Clearance in Chinese Han Population.

Interferon induced with helicase C domain 1 (IFIH1), which is a type of cytological RNA helicase protein and an important initiator of innate immune response to RNA virus infection, may play an important role in hepatitis C virus (HCV) infection outcomes. This study was conducted to investigate the association of IFIH1 gene polymorphisms with HCV clearance in Chinese Han population. A total of 1,527 subjects positive for anti-HCV and 357 chronic hepatitis C (CHC) patients were enrolled in this study. Two single nucleotide polymorphisms in IFIH1 gene (rs2111485 and rs1990760) were selected and genotyped by TaqMan real-time polymerase chain reaction. Haplotypes analysis was further performed by HaploView software and PHASE software. Our results demonstrated that the mutant alleles of rs2111485 (dominant model: odds ratio [OR] = 1.41, 95% confidence interval [CI] = 1.11-1.79) and rs1990760 (dominant model: OR = 1.63, 95% CI = 1.30-2.06) decreased the possibility of spontaneous HCV clearance, but it had no association with HCV clearance induced by interferon-alfa (IFN-α). And, CHC risk increased with the increasing number of unfavorable alleles (ptrend < 0.001). In addition, haplotype analysis also showed that the A-C protective haplotype (rs2111485-rs1997060) promoted spontaneous HCV clearance (p < 0.001). Variants of rs2111485 and rs1990760 at IFIH1 may be associated with spontaneous HCV clearance in Chinese Han population, but have no effect on HCV clearance induced by IFN-α.

Genetic variants in RIG-I-like receptor influences HCV clearance in Chinese Han population.

Human innate immune plays an essential role in the spontaneous clearance of acute infection and therapy of HCV. We investigated whether the SNPs in retinoic acid-inducible gene I-like receptor family were associated with HCV spontaneous clearance and response to treatment. To evaluate the clinical value of DDX58 rs3824456, rs10813831 and rs10738889 genotypes on HCV spontaneous clearance and treatment response in Chinese Han population, we genotyped 1001 HCV persistent infectors, 599 participants with HCV natural clearance and 354 patients with PEGylated interferon-α and ribavirin (PEG IFN-α/RBV) treatment. People carrying rs10813831-G allele genotype were more liable to achieve spontaneous clearance than the carriage of the T allele (dominant model: adjusted OR 1.35, 95% CI 1.08-1.71, P = 0.008). In rs10738889, the rate of persistent infection was significantly lower in patients with the TC genotype compared to those with TT genotype (dominant model: adjusted OR 1.36, 95% CI 1.06-1.74, P = 0.015). Multivariate stepwise analysis indicated that rs10738889, age, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were independent predictors for HCV spontaneous clearance. However, there were no significant differences in the three selection SNPs between the non-SVR group and the SVR group. These results suggest the DDX58 rs10813831 and rs10738889 are associated with spontaneous clearance of HCV, which may be identified as a predictive marker in the Chinese Han population of HCV.

Genetic variants in IFIH1 and DDX58 influence hepatitis C virus clearance in Chinese Han population.

AIMS: To investigate the association between two RIG-I-like receptor gene polymorphisms and hepatitis C virus (HCV) infection in Chinese Han population. METHODS: The current study genotyped two selected SNPs (IFIH1 rs3747517 and DDX58 rs9695310) using TaqMan allelic discrimination assay to assess their association with the susceptibility and clinical outcome of HCV infection among 3065 participants (1545 non-HCV infection individuals, 568 spontaneous HCV clearance cases, and 952 persistent infection patients). RESULTS: IFIH1 rs3747517 (dominant model: Adjusted odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.07-1.68; P = 0.009) and DDX58 rs9695310 (dominant model: Adjusted OR = 1.43, 95% CI = 1.15-1.78; P = 0.001) were associated with chronic hepatitis C (CHC). And the risk of CHC increased when people were carrying more unfavorable rs3747517-GA/AA and rs9695310-GC/CC genotypes from zero to two with the chronic rates of 56.72%, 59.38%, and 69.01%, respectively (Ptrend < 0.001). CONCLUSION: Genetic variations at IFIH1 rs3747517 and DDX58 rs9695310 were independent predictors of chronic hepatitis C in Chinese Han population.

Correction to: Association of CXCR2 genotype variations with HCV clearance in a Chinese population.

Unfortunately, the funding statement was published with error in original publication and is corrected here.

Association of CXCR2 genotype variations with HCV clearance in a Chinese population.

Chemokines are known to play a vital role in guiding and regulating the immune response to viral infections. The chemokine CXC subfamily is a major subfamily in the chemokine family. Outcomes of hepatitis C virus (HCV) infection, as well as the response to treatment, depend on virus and host factors. Here we recruited chronic hepatitis C (CHC) patients to perform an association study between three single nucleotide polymorphisms (SNPs) (CXCR2 rs1126579, CXCL10 rs8878 and CXCL10 rs3921) and HCV infection outcomes and treatment responses among a Chinese population, using primarily a TaqMan assay. Multivariate logistic regression analysis was performed to identify the influencing factors on HCV infection outcome and treatment response. The results showed that subjects with the CXCR2 rs1126579 TT genotype had a significantly increased possibility of HCV spontaneous clearance (Dominant model: adjusted OR = 1.32, 95% CI = 1.06-1.64; P = 0.013). Additionally, CHC patients carrying the CXCR2 rs1126579 TT genotype were also more likely to achieve a sustained virological response (SVR) (Dominant model: adjusted OR = 0.49, 95% CI = 0.29-0.84; P = 0.010). We also established a predictive model for HCV treatment response including the CXCR2 rs1126579 SNP status, albumin (ALB) levels and baseline HCV RNA levels, which produced an area under the curve (AUC) of about 0.660. These findings highlight that variant CXCR2 rs1126579 genotypes are associated with HCV clearance within the Chinese population.

Genetic variants in chemokine CC subfamily genes influence hepatitis C virus viral clearance.

Chemokine genes may influence both hepatitis C virus (HCV) spontaneous clearance in acute infection and treatment response in chronic infection. We conducted this study to evaluate whether the genetic variants in several CC family genes influence HCV spontaneous clearance and treatment response. The current research genotyped eight SNPs, including CCR1 rs3733096, rs13096371, CCR5 rs746492, rs1800874, CCL3 rs1130371, CCL5 rs3817656, CCL8 rs1133763, CCL14 rs854625, to explore their associations with HCV spontaneous clearance and response to treatment in two populations. We identified that the CCR1 rs3733096 (dominant model: adjusted OR = 2.29, 95% CI = 1.49-3.53, additive model: adjusted OR = 2.21, 95% CI = 1.50-3.25) and CCL5 rs3817656 (dominant model: OR = 1.37, 95% CI = 1.10-1.70, additive model: OR = 1.33, 95% CI = 1.12-1.58) were associated with HCV spontaneous clearance in Chinese Han population, while we found no association with treatment response. Moreover, the expression quantitative trait loci (eQTL) analysis showed that the risk alleles of rs3817656 were significantly associated with downregulated expression of CCL5 in whole blood (P < 0.001). The polymorphism of CCR1 rs3733096 and CCL5 rs3817656 are associated with spontaneous clearance of HCV in Chinese Han population.

The association of CCL3 and CCL4 polymorphisms with HCV clearance in Chinese Han population.

AIM: To explore the association of CCL3 (rs1063340) and CCL4 (rs1049807) polymorphisms with hepatitis C virus (HCV) clearance and sustained virologic response (SVR). METHODS: Two populations were enrolled in the current study; one was a general population including 1585 untreated individuals, with HCV infection and the other was a treatment population comprising 353 HCV-infected patients treated with pegylated interferon-α and ribavirin (pegIFN-α/RBV). Two single nucleotide polymorphisms (SNPs) were genotyped, and the relationship between HCV clearance and treatment outcome was analysed. RESULTS: The general population comprised 995 persistent HCV cases (both HCV RNA and anti-HCV were positive) and 590 spontaneous clearance cases (HCV RNA was negative, but anti-HCV was positive). An association between the SNPs and HCV clearance was not found in our study. The treatment population consisted of 235 patients who achieved SVR and 118 non-responders. Variants of both SNPs (rs1063340-C and rs1049807-G) were associated with a reduction in SVR following IFN treatment (dominant model: P = 0.026 for rs1063340 and P = 0.048 for rs1049807). In addition, the ancestral alleles of rs1063340 and rs1049807 increased the likelihood of virus clearance by 62% compared to both the derived and minor alleles of the two SNPs (P = 0.040).The interaction analysis showed that the level of glucose interacted with the association of rs1063340 and SVR. CONCLUSIONS: Our results suggested that genetic variants at the CCL3 and CCL4 loci may be marker SNPs for risk of HCV treatment outcome.

The development of hepatocellular carcinoma in HCV-infected patients treated with DAA: A comprehensive analysis.

It has been proven that hepatitis C virus (HCV) eradication after interferon-based treatment can reduce the risk of hepatocarcinogenesis. However, there were some arguments about whether the treatment of direct-acting antivirals (DAAs) boosts the development of hepatocellular carcinoma (HCC). We systematically review this crucial topic by combining all the relevant articles to calculate the pooled HCC density after DAA treatment. Studies reporting the recurrence or occurrence in chronic hepatitis C patients who received DAA regimen were selected from three retrieval library screening. Data on baseline and outcomes were extracted independently by three observers. Primary outcomes were incidence density of HCC. Pooled estimates of HCC occurrence and recurrence rate per 100 person-years (py) were undertaken by random-effects meta-analysis. Sixteen studies with 61334 patients, embracing 20 cohorts, were enrolled in this study and divided into two groups (HCC occurrence and HCC recurrence). In the pooled analysis, HCC developed at a rate of 3.5/100 py [95% confidence interval (CI): 2.4, 5.3] among patients without a history of HCC compared with 17.4/100 py (95% CI: 7.8, 39.0) among patients existed. Furthermore, HCC occurrence rate following DAA-induced sustained virological response (SVR) was 2.1/100 py (95% CI: 1.4, 3.4); however, the rate in patients without SVR was 9.1/100 py (95% CI: 5.4, 15.3). HCV cured after DAA therapy could induce a reduction of 78% in the risk of HCC occurrence compared with non-responders. There is no strong evidence for an increased risk of HCC occurrence or recurrence in patients treated by DAA. There was a significant decline in the incidence of HCC occurrence after SVR.