Resistance-associated substitution and ledipasvir/sofosbuvir therapy in Mongolian chronic hepatitis C patients.

BACKGROUND: Mongolia has the highest prevalence of hepatitis C virus (HCV) infection worldwide. Ledipasvir/sofosbuvir (LDV/SOF) was introduced to Mongolia since 2016 for HCV eradication. It has been reported that HCV resistance-associated substitutions (RASs) would affect the effectiveness of LDV/SOF in western chronic hepatitis C (CHC) patients. We thus investigated the effectiveness of LDV/SOF and the impact of RAS on the treatment outcome in Mongolian CHC patients. METHODS: Patients with genotype (GT) 1b HCV infection were prospectively enrolled in Mongolia and treated with LDV/SOF for 12 weeks. The proportion of pre-treatment NS5A Y93H RAS in viral quasispecies was measured with next-generation sequencing. The endpoint of LDV/SOF effectiveness was sustained virological response at post-treatment week 12 (SVR12). RESULTS: A total of 94 CHC patients were evaluated. The baseline Y93H proportion was <1% in 74 patients, 1-15% in 7, 15-50% in 2, and ≥50% in 11. All patients completed 12-week LDV/SOF treatment and the SVR rate was 90.4%. The rate of failure to achieve SVR12 for patients with Y93H < 1%, 1-15%, and ≥15% were 0%, 14.3%, and 61.5%, respectively (p for trend = 0.001). In univariable analysis, older age, baseline alanine transaminase level <40 U/mL, and a higher proportion of Y93H were associated with treatment failure. In multivariable analysis, only a higher proportion of Y93H was associated with treatment failure (p = 0.022). CONCLUSION: LDV/SOF therapy achieves a high SVR rate in Mongolian CHC GT1b patients without baseline Y93H RAS. A higher proportion of Y93H may severely undermine the effectiveness of LDV/SOF.

Efficacy and safety of ledipasvir/sofosbuvir in 5,028 Mongolian patients infected with genotype 1 hepatitis C virus: A multicenter study.

BACKGROUND/AIMS: Ledipasvir/sofosbuvir (LDV/SOF) shows high efficacy and safety in patients with genotype 1-hepatitis C virus (HCV). We aimed to investigate the efficacy and safety of LDV/SOF in real-world Mongolian patients. METHODS: Between 2015 to 2019, 23 (0.5%) and 5,005 patients (99.5%) with genotype 1a and 1b HCV, respectively, were treated with a fixed-dose tablet containing 90 mg ledipasvir and 400 mg sofosbuvir for 12 weeks, and 81 patients (1.6%) with previous experience of interferon (IFN)-based treatment received additional 1,000 mg ribavirin. HCV RNA was measured at 4, 12, and 24 weeks after the first dose to determine rapid virologic response, end of treatment response (ETR), and sustained virologic response at 12 weeks after end of treatment (SVR12). RESULTS: Most patients (n=5,008; 99.6%) achieved ETR and SVR12 without virologic relapse. Patients with genotype 1a showed low rates of ETR and SVR12 in only 16 patients (69.6%). There was no significant difference in SVR12 rate between patients regardless of IFN experience (n=81; 1.6%), cirrhosis (n=1,151; 22.9%), HCV RNA >6×106 IU/mL (n=866; 17.2%), or liver stiffness >9.6 kPa (n=1,721; 34.2%) (100.0%, 99.3%, 99.4%, and 99.4%, respectively). No severe adverse events (AEs) were reported, and there was no dose reduction or interruption due to AE. The most common AEs were headache (n=472; 9.4%), fatigue (n=306; 6.2%), abdominal discomfort (n=295; 5.9%), and skin rash (n=141; 2.8%). CONCLUSION: LDV/SOF showed high efficacy and safety for patients with genotype 1, especially 1b HCV, in Mongolia. The real-world data might be applicable to patients in other Asian-Pacific countries.

Epidemiology, Genotype Distribution, Prognosis, Control, and Management of Viral Hepatitis B, C, D, and Hepatocellular Carcinoma in Mongolia.

Mongolia is located between Russia and China. The total population of Mongolia as of December 2017 is estimated to be 3.2 million people. According to our previous study results, the prevalence of HBV was 11.8%, and anti-HDV was detected in 4.8% among the HBsAg-positive subjects. Interestingly, most HCV infection is caused by genotype 1b. Among all HBV DNA-positive samples, 98.5% were classified into genotype D, and regarding HDV genotypes, all HDV RNA-positive samples, 100%, were classified into genotype I. The second study is the baseline survey of a Nationwide Cancer Cohort Study. Prevalence of HBsAg was 10.6%. Additionally, HCV infection was observed in 9.9%, and 0.8% were coinfected with HBV and HCV among the general population aged from 10 to 64 years. The third study investigated the population-based prevalence of hepatitis B and C virus in apparently healthy population of Ulaanbaatar city, Mongolia. The anti-HCV prevalence was 9.0%. In addition, the prevalence of HBV was 8.0%. The fourth study is on the prevalence of HCV and coinfections among nurses in a tertiary hospital in Mongolia. The prevalence of HCV was 18.9%. Additionally, HBV infection was observed in 23.1%, and 1.2% were coinfected with HCV and HBV. Mongolia has the highest HCC incidence in the world (78.1/100,000, 3.5* higher than China). As a result, the Mongolia government has launched The National Viral Hepatitis Program, which is a comprehensive program that involves all aspects from prevention to care and disease control to meet a reduction goal for morbidity and mortality due to HBV, HCV, and HDV. Consequently, access to antiviral therapies is now improving in Mongolia. How to cite this article: Baatarkhuu O, Gerelchimeg T, Munkh-Orshikh D, Batsukh B, Sarangua G, Amarsanaa J. Epidemiology, Genotype Distribution, Prognosis, Control, and Management of Viral Hepatitis B, C, D, and Hepatocellular Carcinoma in Mongolia. Euroasian J Hepato-Gastroenterol 2018;8(1):57-62.

Clinical features and prognosis of hepatocellular carcinoma in Mongolia: a multicentre study.

PURPOSE: Hepatocellular carcinoma (HCC) is the most common cancer in Mongolia. We aimed to investigate the clinical features, therapeutic modalities, overall survival and prognostic factors for Mongolian patients with HCC. METHOD: One hundred ninety-five patients with HCC were consecutively enroled in our study. RESULTS: The mean age was 61.7 years. The most common etiology for HCC was HCV infection (n = 89, 45.6%), followed by HBV infection (n = 67, 34.4%). The mean tumor diameter was 6.0 ± 2.6 cm. Only 29 (14.9%) patients had a single lesion, while 39 (20.2%) had >3 lesions. Extrahepatic metastasis to lung (n = 23), bone (n = 10) and lymph node (n = 3) were detected in 36 (18.5%) patients. Most patients had advanced HCC-88 (45.1%) in stage III and 57 (29.2%) in stage IV. Surgical resection was performed in 27 (13.8%) patients, RFA in 23 (11.8%) and TACE in 107 (54.9%). When all the patients were categorized as 'treated' (n = 156) and 'not treated' (n = 39), the 3-year survival was significantly lower in the 'not treated' group than in the 'treated' group (11 vs. 0%, P < 0.001). Tumor diameter (<3 cm vs. ≥3 cm), extrahepatic metastasis, TNM stage (I/II vs. III/IV) and treatment (or supportive care) were selected as independent predictors for survival. CONCLUSIONS: High proportion of patients with HCC in Mongolia is diagnosed at an advanced stage and survival of these patients is lower compared to other countries. A surveillance system and referral policy for high-risk groups should be urgently established and implemented in Mongolia.

Relationship between nuclear factor-kappaB activation and virulence factors of Helicobacter pylori in Japanese clinical isolates.

BACKGROUND: Several factors have been proposed as a possible virulence determinant of Helicobacter pylori infection. The aim of the present study was to evaluate these candidates in nuclear factor (NF)-kappaBeta activation, which is a critical regulator of genes involved in inflammatory reactions. METHODS: We determined the status of cagE, iceA, HP0441 (a virB4 homolog), the s1 signal sequence of vacA and babA2 by polymerase chain reaction, all of which are candidate virulence determinants, in 107 H. pylori strains isolated from Japanese patients. Nuclear factor-kappaBeta activation was evaluated by the luciferase reporter assay. The gastric mucosa of the hosts was examined histologically. RESULTS: The cagE gene was positive in 102 (95.3%) strains, iceA1 was positive in 71 (66.4%) strains, HP0441 was positive in 68 (63.6%) strains, vacA s1 was positive in 105 (98.1%) strains and babA2 was positive in 103 (96.3%) strains. Nuclear factor-kappaBeta was activated by all cagE-positive strains, but was not activated by any of the cagE-negative strains. The status of iceA or HP0441 was not associated with NF-kappaBeta activation. Neutrophil infiltration in gastric mucosa was significantly more severe in patients infected with cagE-positive strains than in patients infected with negative strains. No association was found between the degree of neutrophil infiltration and the status of HP0441 or iceA. Due to very high positivity of vacA s1 and babA2 in Japanese strains, their roles remain to be investigated. CONCLUSIONS: The cag pathogenicity island (PAI) status, as determined by cagE polymerase chain reaction, but not the status of iceA or HP0441, is closely associated with NF-kappaBeta activation and the degree of gastric mucosal inflammation in the hosts.

Proteomic analysis of the TGF-beta signaling pathway in pancreatic carcinoma cells using stable RNA interference to silence Smad4 expression.

Smad4 is a tumor-suppressor gene that is lost or mutated in 50% of pancreatic carcinomas. Smad4 is also an intracellular transmitter of transforming growth factor-beta (TGF-beta) signals. Although its tumor-suppressor function is presumed to reside in its capacity to mediate TGF-beta-induced growth inhibition, there seems to be a Smad4-independent TGF-beta signaling pathway. Here, we succeeded in establishing Smad4 knockdown (S4KD) pancreatic cancer cell lines using stable RNA interference. Smad4 protein expression and TGF-beta-Smad4 signaling were impaired in S4KD cells, and we compared the proteomic changes with TGF-beta stimulation using two-dimensional gel electrophoresis (2-DE) and mass spectrometry. We identified five proteins that were up-regulated and seven proteins that were down-regulated; 10 of them were novel targets for TGF-beta. These proteins function in processes such as cytoskeletal regulation, cell cycle, and oxidative stress. Introducing siRNA-mediated gene silencing into proteomics revealed a novel TGF-beta signal pathway that did not involve Smad4.