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.
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).
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).
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.
The efficacy and safety of the boceprevir (BOC)-containing triple therapy in Taiwanese treatment-experienced patients remains elusive. After 4 weeks of peginterferon/ribavirin lead-in therapy, ...patients with cirrhosis or previous null-response received triple therapy for 44 weeks; whereas others received 32 weeks of triple therapy followed by 12 weeks of peginterferon/ribavirin therapy. Patients with HCV RNA > 100 IU/mL at week 12 or with detectable HCV RNA at week 24 of treatment were viewed as futile. A total of 123 patients received treatment. The rates of sustained virological response (SVR) and relapse were 66.7% and 8.9%, respectively by using intention-to-treat analysis. Multivariate analysis revealed that factors associated with SVR included HCV-1b (odds ratio OR/ 95% confidence intervals CI: 19.23/1.76-525.15, P = 0.01), BOC adherence (7.69/1.55-48.78, P = 0.01), serum albumin (OR/CI:6.25/1.14-40.07, P = 0.03) levels and HCV RNA levels (OR/CI:0.34/0.12-0.79, P = 0.01). Twenty-six (21.1%) patients experienced severe adverse events (SAEs). Multivariate analysis revealed that APRI > 1.5 was the single factor associated with occurring SAEs (OR/CI: 3.77/ 0.97-14.98, P = 0.05). Merging the cut-off values of HCV RNA > 7 log IU/mL at baseline and HCV RNA > 6 log IU/mL at week 4 provided the earliest and best combing viral kinetics in predicting week 12/24 futility with the PPV of 100% and accuracy of 93.5%. HCV-1 treatment experienced Taiwanese patients treated with boceprevir-containing triple therapy in real world had comparable efficacy and safety profiles with those reported in clinical trials. Early viral kinetics before week 4 of treatment highly predicted futility at week 12 or 24 of treatment.
Background and Aims: Metabolic profiles are associated with severity of liver histology in chronic hepatitis C (CHC) infection. However, the influence of hepatitis C virus (HCV) genotypes, ...especially genotype 1 and 2, on the association between metabolic profiles and hepatic fibrosis remains unknown.
Methods: We consecutively enrolled 528 CHC patients infected by HCV genotype 1 or 2, and used univariate and multivariate approaches to determine the influence of HCV genotype on the association of metabolic characteristics with severity of liver histology.
Results: In univariate analysis, diabetes mellitus, obesity, higher grades of hepatic steatosis, homeostasis model assessment–insulin resistance index and alanine aminotransferase level, but lower serum total cholesterol and low‐density lipoprotein level, were associated with advanced hepatic fibrosis. Advanced hepatic fibrosis was associated with an adjusted odds ratio of 13.72 (95% confidence interval, 2.15–87.7) for serum fasting blood glucose, 1.07 (1.01 to 1.13) for body mass index (BMI), and 0.03 (0.00–0.32) for total cholesterol level. Older age, lower serum total cholesterol level and more necro‐inflammatory activity were associated with advanced hepatic fibrosis in both genotype 1 and 2 patients (P < 0.05). Advanced hepatic fibrosis was associated with an adjusted odds ratio of 31.18 (2.31–421.4) for fasting blood glucose level in genotype 1 infection, whereas 1.16 (1.05–1.28) for BMI in genotype 2 infection.
Conclusions: Age, serum total cholesterol, and hepatic necro‐inflammation have important associations with severity of hepatic fibrosis in CHC patients. Moreover, these associations are different between HCV genotype: the effects of fasting blood glucose level and BMI are increased on genotype 1 and genotype 2 patients, respectively.
We synthesized three pluronic-based cationic pentablock copolymers with different hydrophilic/lipophilic balance (HLB) values using atom transfer radical polymerization (ATRP), including ...PF127-block-poly(N,N-dimethylamino-2-ethyl methacrylate) (PF127-b-pDMAEMA), pluronic P123-block-poly(N,N-dimethylamino-2-ethyl methacrylate) (PP123-b-pDMAEMA), and PL121-block-poly(N,N-dimethylamino-2-ethyl methacrylate) (PL121-b-pDMAEMA). The copolymers self-assembled into core-shell structures, which could be used to co-deliver a plasmid DNA (pEGFP) and a hydrophobic drug (epirubicin, EPI). The physicochemical properties of the copolymers and drug-loaded micelles were thoroughly characterized. The micelles had a high EPI encapsulation efficiency, similar to 6%, and the EPI-loaded micelles exhibited a similarly cytotoxic effect to free EPI. Among the three copolymers, the gene transfection efficiency of PL121-b-pDMAEMA was the highest, indicating that the greater the hydrophobic effect the greater cellular internalization was. The co-delivery effect of pEGFP and EPI was directly visualized using a confocal laser scanning microscope. Thus, the pluronic-b-pDMAEMA micelles are a promising co-delivery system for therapeutic pDNA and hydrophobic anticancer drugs.
Percutaneous liver biopsy is the gold standard for staging hepatic fibrosis of hemodialysis patients with chronic hepatitis C before renal transplantation or antiviral therapy. Concerns exist, ...however, about serious post-biopsy complications. To evaluate a more simple approach using standard laboratory tests to predict hepatic fibrosis and its evolution, we studied 279 consecutive hemodialysis patients with chronic hepatitis C and a baseline biopsy. Among them, 175 receiving antiviral therapy underwent follow-up biopsy to evaluate the histological evolution of fibrosis. Multivariate analysis of routine laboratory tests at baseline showed the aspartate aminotransferase-to-platelet ratio index was an independent predictor of significant hepatic fibrosis. The areas under curves of this ratio to predict fibrosis stages F2-4 were 0.83 and 0.71 in the baseline and follow-up sets; and 0.75 and 0.80 respectively, for patients with sustained or non-sustained virological response groups in the follow-up sets. By a judicious setting of cut-off levels for the baseline and non-sustained groups, and the sustained virological response group, almost half and 60 percent of the baseline and follow-up sets could be correctly diagnosed without biopsy. Our study found the aminotransferase-to-platelet ratio index is accurate and reproducible for assessing hepatic fibrosis in hemodialysis patients with chronic hepatitis C. Applying this simple index could decrease the need of percutaneous liver biopsy in this clinical setting.
This follow-up study enrolled chronic hepatitis C patients to evaluate the treatment efficacy and to identify post-treatment seromarkers associated with risk of hepatocellular carcinoma (HCC) among ...patients with a sustained virological response (SVR) or nonsustained virological response (NSVR). A total of 4639 patients who received pegylated interferon and ribavirin during 2004-2013 were followed until December 2014. HCC was confirmed through health examinations and data linkage with a national database. A total of 233 HCC cases were reported after 26,163 person-years of follow-up, indicating an incidence of 8.9 per 1000 person-years: 6.9 for SVR and 21.6 for NSVR per 1000 person-years. The associated risk of HCC in patients with SVR was 0.37 (0.22-0.63) for those without cirrhosis and 0.54 (0.31-0.92) for those with cirrhosis compared with their respective counterparts with NSVR. Among patients with SVR, advanced age, male gender, cirrhosis, decreased platelet count, and increased aspartate aminotransferase and α-fetoprotein levels were associated with HCC (p < 0.001). The treatment of chronic hepatitis C patients before they developed cirrhosis showed a higher efficacy than did the treatment of those who had already developed cirrhosis. Patients with SVR may still have a risk of HCC and need to be regularly monitored.
Background/Purpose Insulin resistance (IR) affects sustained virological response (SVR) to peginterferon alfa plus ribavirin (PR) in patients with chronic hepatitis C (CHC). Whether add-on oral ...hypoglycemic agents (OHAs) to PR improve SVR remains unclear; therefore, we conducted a prospective, randomized pilot trial on 23 consecutive patients with genotype 1 CHC and IR in Taiwan. Methods Patients were randomized to receive acarbose (Arm A; n = 7) or metformin (Arm B; n = 6) or pioglitazone (Arm C; n = 5) in addition to peginterferon alfa-2b (1.5 μg/kg/week) plus ribavirin (1000–1200 mg/day) or just PR (Arm D; n = 5). The primary end point was SVR, and secondary end points were viral clearance at Weeks 17, 29, and 53. There were no differences among all arms at baseline. Results Using intent-to-treat analysis, SVR was observed in 66.7% (4/6), 83.3% (5/6), 66.7% (4/6), and 60% (3/5) in Arms A, B, C, and D, respectively. SVR was higher in female patients receiving OHA 90% (9/10) than in male patients 50% (4/8). Results of per protocol analysis showed that SVR was 80.0% (4/5) in Arm A, 100% (5/5) in Arm B, 66.7% (4/6) in Arm C, and 60% (3/5) in Arm D. Patients receiving OHA had a higher rapid virologic response: 11/18 (61%) versus 2/5 (40%). Complete early virologic response was comparable between patients receiving OHA and PR 15/18 (83%) vs. 4/5 (80%). Conclusion Our preliminary data show add-on OHAs to PR might achieve better early viral kinetics and SVR. However, further larger studies are needed to confirm these findings.
Interleukin 28B (IL28B) single nucleotide polymorphism (SNP) genotypes and viral factors can predict sustained virological response (SVR) in HCV genotype-1 (HCV-1) patients receiving 48 weeks of ...pegylated interferon and ribavirin. Whether these factors would identify those patients who can benefit from a shorter duration of therapy remains unclear.
Treatment-naive HCV-1 patients (n=662) receiving 24 or 48 weeks of combination therapy were enrolled. Baseline demographic data, HCV viral load, IL28B SNP genotypes (rs8099917), duration of therapy and rapid virological response (RVR) were evaluated to predict SVR. The SVR rates were further stratified by the independent factors and compared.
The IL28B rs8099917 TT genotype, low baseline viral load (HCV RNA≤600,000 IU/ml), RVR and 48-week therapy independently predicted SVR. In RVR patients with the IL28B rs8099917 TT genotype, the SVR rate of 24-week therapy was comparable to 48-week therapy (95% versus 99%; P=0.21) at low baseline viral load, but was inferior to 48-week therapy (70% versus 97%; P<0.001) at high baseline viral load. In non-RVR patients, the SVR rate of 24-week therapy was inferior to 48-week therapy for those with the IL28B rs8099917 TT genotype but high baseline viral load (23% versus 62%; P<0.001), and those with the IL28B rs8099917 GT/GG genotype but low baseline viral load (0% versus 33%; P=0.02).
HCV-1 patients simultaneously bearing the IL28B rs8099917 TT genotype, low baseline viral load and RVR can benefit from a shorter duration of combination therapy.
Abstract
Background
Incarcerated persons are a special population with higher hepatitis C virus (HCV) prevalence and should be prioritized for micro-elimination. This study aimed to investigate the ...seroprevalence and to evaluate the effectiveness and safety of direct acting antiviral (DAA) therapy in the custodial settings.
Methods
Incarcerated persons in Yunlin Prison were recruited to receive anti-HCV antibody screening. Patients with positive HCV ribonucleic acid (HCV RNA) were treated with glecaprevir/pibrentasvir (GLE/PIB) in our special chronic hepatitis C (CHC) clinic in prison. The primary endpoint was sustained virologic response at week 12 off therapy (SVR12).
Results
A total of 1402 incarcerated persons were invited to anti-HCV screening and 824 (58.7%) accepted. The prevalence of anti-HCV positivity was 33.5% (276/824) and the viremic rate (detectable HCV RNA) was 69.2% (191/276). According to FIB-4 index, patients with F3 stage were six (3.1%), but none met the criteria of F4 stage. However, six (3.1%) had liver cirrhosis with splenomegaly, confirmed by findings of ultrasonography. The median log10 HCV RNA level at baseline was 6.235 (2.394-7.403). Genotype (GT) 6 was predominant (39.3%), followed by GT 1a (22.0%) and 1b (14.1%). Mixed genotype HCV infection accounted for 3.6% of total infections. In total, 165 patients received GLE/PIB therapy. The overall SVR12 rates were 100%.
Conclusions
DAA therapy is highly effective and safe for incarcerated patients in Taiwan. Our special prison-based CHC clinic, linking universal screening to medical care, can serve as a model for micro-elimination of HCV in custodial settings.
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