Satawat Thongsawat

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study

BACKGROUND & AIMS TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naїve patients infected with HCV genotypes 2-6. METHODS The study consisted of 7 days of monotherapy with TMC435 (200mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from day 8 with a follow-up period up to days 37-42. RESULTS Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary end point at day 8, the mean (± standard error) change in plasma HCV ribonucleic acid (log(10)IU/ml) from baseline was the greatest for genotypes 6 (-4.35 ± 0.29) and 4 (-3.52 ± 0.43), followed by genotypes 2 (-2.73 ± 0.71) and 5 (-2.19 ± 0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period. CONCLUSIONS The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.

Diverse Contexts of Zoonotic Transmission of Simian Foamy Viruses in Asia

These infections are likely prevalent among persons who live or work near nonhuman primates.

Efficacy and safety of continuous 4-year telbivudine treatment in patients with chronic hepatitis B

In the phase‐III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2‐year treatment in HBeAg‐positive and HBeAg‐negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine‐treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2‐year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per‐protocol population. Amongst 293 HBeAg‐positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg‐negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off‐treatment follow‐up). The cumulative 4‐year resistance rate was 10.6% for HBeAg‐positive and 10.0% for HBeAg‐negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m2 (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg‐positive and HBeAg‐negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg‐positive patients.

Hepatitis C Virus NS5A Disrupts STAT1 Phosphorylation and Suppresses Type I Interferon Signaling

ABSTRACT Responses to alpha interferon (IFN-α)-based treatment are dependent on both host and viral factors and vary markedly among patients infected with different hepatitis C virus (HCV) genotypes (GTs). Patients infected with GT3 viruses consistently respond better to IFN treatment than do patients infected with GT1 viruses. The mechanisms underlying this difference are not well understood. In this study, we sought to determine the effects of HCV NS5A proteins from different genotypes on IFN signaling. We found that the overexpression of either GT1 or GT3 NS5A proteins significantly inhibited IFN-induced IFN-stimulated response element (ISRE) signaling, phosphorylated STAT1 (P-STAT1) levels, and IFN-stimulated gene (ISG) expression compared to controls. GT1 NS5A protein expression exhibited stronger inhibitory effects on IFN signaling than did GT3 NS5A protein expression. Furthermore, GT1 NS5A bound to STAT1 with a higher affinity than did GT3 NS5A. Domain mapping revealed that the C-terminal region of NS5A conferred these inhibitory effects on IFN signaling. The overexpression of HCV NS5A increased HCV replication levels in JFH1-infected cells through the further reduction of levels of P-STAT1, ISRE signaling, and downstream ISG responses. We demonstrated that the overexpression of GT1 NS5A proteins resulted in less IFN responsiveness than did the expression of GT3 NS5A proteins through stronger binding to STAT1. We confirmed that GT1 NS5A proteins exerted stronger IFN signaling inhibition than did GT3 NS5A proteins in an infectious recombinant JFH1 virus. The potent antiviral NS5A inhibitor BMS-790052 did not block NS5A-mediated IFN signaling suppression in an overexpression model, suggesting that NS5As contributions to replication are independent of its subversive action on IFN. We propose a model in which the binding of the C-terminal region of NS5A to STAT1 leads to decreased levels of P-STAT1, ISRE signaling, and ISG transcription and, ultimately, to preferential GT1 resistance to IFN treatment.

Hepatitis B 1762T/1764A Mutations, Hepatitis C Infection, and Codon 249 p53 Mutations in Hepatocellular Carcinomas from Thailand

Hepatocellular carcinoma is one of the leading causes of cancer death worldwide. The etiology of liver cancer is multifactorial, and infection with hepatitis B virus (HBV), whose pathogenesis is exacerbated by the acquisition of mutations that accelerate carcinogenesis, or hepatitis C virus (HCV) and dietary exposure to aflatoxin B1 all contribute to elevating ones risk for this disease. In this study, we sought to determine the contributions of these agents by measuring the occurrence of an HBV 1762T/1764A double mutation, an aflatoxin-specific 249G→T mutation of the p53 gene, and HCV in plasma of 34 HCC cases and 68 age- and gender-matched controls, and in 25 liver tumors from northern Thailand. In total, 14 cases, 5 controls, and 19 tumors had detectable levels of HBV DNA. All 14 cases, 2 controls (2.9%), and 17 tumors (89.5%) were positive for the HBV double mutation. Nine cases (26.5%), 10 controls (14.7%), and 6 tumors (24%) were positive for the p53 mutation. Five cases (14.7%), no controls, and 4 tumors (16%) had both mutations. The median age of HCC diagnosis in these 5 cases was 34 years versus 51 years for other cases. Five cases (14.7%) and 1 control (1.5%) were HCV enzyme immunoassay positive. Thus, specific HBV, HCV, and aflatoxin biomarkers reveal the complexity of risks contributing to HCC in northern Thailand and suggest further application of these biomarkers as intermediate end points in prevention, intervention trials, and etiologic investigations.

Risk factors for hepatitis C virus infection among blood donors in northern Thailand

BACKGROUND:  The epidemiology, virology, and risk factors for hepatitis C virus (HCV) infection among blood donors in northern Thailand have not been extensively evaluated.

Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B

Background: In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB).

Evaluation of a multiplex human immunodeficiency virus-1, hepatitis C virus, and hepatitis B virus nucleic acid testing assay to detect viremic blood donors in northern Thailand

BACKGROUND: Screening of blood donors with nucleic acid testing (NAT) for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has been implemented recently in the United States. There are limited data, however, on the additional NAT yield of donors in developing countries in Asia where the prevalence of infection is higher. In addition, data on hepatitis B virus (HBV) NAT in high prevalence areas are minimal.

Occult hepatitis C virus infection during an outbreak in a hemodialysis unit in Thailand

Control of hepatitis C virus (HCV) in hemodialysis populations is a major public health priority, but the preferred methods to prevent and rapidly detect HCV outbreaks in these populations remains subject to debate. We enrolled 231 hemodialysis patients at three dialysis centers in Chiang Mai, Thailand. Patients were followed every 6 months for 3 years and tested for the presence of serum HCV antibody and HCV RNA at each visit. We additionally isolated and tested peripheral blood mononuclear cells (PBMCs) for HCV RNA collected at the 30‐month follow‐up visit. Fifty‐one study participants negative for anti‐HCV at the baseline enrollment visit seroconverted over the course of the 3‐year follow‐up period. Of 11 individuals who transiently lost detectable serum HCV viremia, we were able to detect HCV RNA from the PBMCs of two individuals. Our results suggest that occult HCV infection may be common among hemodialysis patients, and serum HCV RNA testing may be supplemented with PBMC testing to maximize diagnostic sensitivity and aid in outbreak containment. Further work on the diagnostic implications of HCV compartmentalization in hemodialysis and other settings is urgently needed. J. Med. Virol. 80:808–815, 2008.

Correlation between mutations in the core and NS5A genes of hepatitis C virus genotypes 1a, 1b, 3a, 3b, 6f and the response to pegylated interferon and ribavirin combination therapy.

Summary.  Several studies have reported correlation between mutations in core and NS5A proteins of hepatitis C virus (HCV) and response to interferon (IFN) therapy. In particular, mutations in NS5A protein have been shown to correlate with responsiveness to IFN treatment of HCV‐1b in Japanese patients. This study investigated whether amino acid (aa) mutations in the core and NS5A proteins of HCV‐1a, 1b, 3a, 3b and 6f correlated with the response to pegylated interferon (Peg‐IFN) plus ribavirin (RBV) therapy in Thai patients. The entire sequences of core and NS5A of HCV from 76 HCV‐infected patients were analysed in comparison with corresponding reference sequences. The data revealed that the number of aa mutations in full‐length NS5A, its C‐terminus, IFN sensitivity‐determining region, variable region 3 (V3) and V3 plus flanking region of HCV‐1b NS5A protein were significantly higher in responders than in the treatment failure group (P =0.010, 0.031, 0.046, 0.020 and 0.006, respectively). Similar results were found in a putative protein kinase R binding domain region in HCV‐6f NS5A protein (P =0.022). Moreover, specific aa substitutions in NS5A that appeared to be associated with responders or the treatment failure group were observed at positions 78 and 305 for HCV‐1b (P =0.028), 64 and 52 for HCV‐1a (P =0.033) and 6f (P =0.045). Nevertheless, analysis of aa sequences of core protein revealed highly conserved sequences among HCV genotypes and no significant differences between the viruses from responders and the treatment failure group. Our findings indicate that mutations in aa residues of NS5A of HCV‐1a, 1b and 6f correlated well with responsiveness to Peg‐IFN and RBV combination therapy.