Antiviral Therapy in Patients With Chronic Hepatitis C Is Associated With a Reduced Risk of Parkinsonism.

BACKGROUND: The risk of parkinsonism after antiviral treatment against chronic hepatitis C (CHC) is unclear. OBJECTIVES: To investigate the association between CHC and parkinsonism and the efficacy of antiviral therapy. METHODS: Using the National Health Insurance Research Database of Taiwan from 2004 to 2012, patients with and without CHC, patients receiving pegylated interferon-based antiviral therapy, and those without such therapy were matched by age, gender, and comorbidities by propensity scores and followed for new diagnoses of parkinsonism and Parkinson's disease (PD). Multivariable Cox proportional hazards regression analyses were performed. RESULTS: Overall, 49,342 patients with CHC were matched with 49,342 non-CHC patients. After adjustment for confounding factors, there was a significantly increased risk (31%) of parkinsonism (hazard ratio [HR] 1.306; 95% confidence interval [CI], 1.208-1.412) in those with CHC and the risk of parkinsonism requiring anti-Parkinson medication (HR 1.323; 95% CI, 1.214-1.441). Furthermore, 23,647 untreated CHC patients were matched with 23,647 patients receiving antiviral therapy. Patients receiving antiviral therapy had a significantly lower risk of developing parkinsonism (38%; HR 0.618; 95% CI, 0.498-0.765) and a reduced risk of parkinsonism requiring anti-Parkinson medication (HR 0.651; 95% CI, 0.515-0.823). In sensitivity analyses, antiviral therapy significantly reduced the risk of parkinsonism and PD after adjustment for detection, selection, disease latency biases, and competing mortality. Our results suggest successful antiviral therapy associates with a reduced risk of hepatitis C virus-related parkinsonism compared with those with treatment failure. CONCLUSIONS: CHC infection is associated with an increased risk of parkinsonism or PD. Antiviral therapy against CHC is associated with a reduced risk of parkinsonism or PD. © 2019 International Parkinson and Movement Disorder Society.

Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C.

MicroRNA-122 (miR-122) facilitates hepatitis C virus replication in vitro. Serum miR-122 has been implicated as a biomarker for various liver diseases; however, its role in chronic hepatitis C remains unclear. To address this issue, 126 patients with chronic hepatitis C who completed pegylated IFN plus ribavirin therapy with sustained virologic response (SVR) or nonresponse (NR) were retrospectively included, and their pretreatment clinical profiles and treatment responses were collected. Serum miR-122 was quantified before and during treatment. Another 51 patients in SVR and NR groups were prospectively enrolled for validation. Serum miR-122 was found to be a surrogate for hepatic miR-122 and positively correlated with hepatic necroinflammation. Patients who showed complete early virologic response and SVR had significantly higher pretreatment serum miR-122 levels than those with NR (P = 0.001 and P = 0.008, respectively), especially in subgroups of patients with hepatitis C virus genotype 2 and IL-28B rs8099917 TT genotype. Patients with IL-28B TT genotype had significantly better treatment responses and higher pretreatment serum miR-122 level than those with GT or GG genotypes. Univariate analysis showed that pretreatment body mass index, γ-glutamyl transpeptidase, triglyceride, IL-28B TT genotype, and serum miR-122 are predictors for SVR. Multivariate analysis specifically in IL-28B TT genotype demonstrated that pretreatment serum miR-122 independently predicted SVR. The validation cohort confirmed a significantly greater pretreatment serum miR-122 level in patients with SVR compared with NR (P = 0.025). In conclusion, serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.

Perspectives on dual hepatitis B and C infection in Taiwan.

Dual hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is not rare in HBV or HCV endemic areas, and can be found in populations at risk of parenteral viral transmission. Clinical observatory studies suggest a higher risk of liver disease progression in patients with dual HCV/HBV infection than in HBV or HCV monoinfected patients. Recent trials confirmed that combination therapy of peginterferon alfa-2a or alfa-2b and ribavirin was effective and safe in dually infected patients with positive HCV RNA. Moreover, about 30% of the dually infected patients cleared hepatitis B surface antigen within 5 years after the start of peginterferon-based therapy. The optimal treatment strategies for dually infected patients with active hepatitis B, with decompensated cirrhosis, or in other clinical situations should be explored in further studies. Finally, the advent of new direct-acting antiviral-based anti-HCV therapy may lead to the development of strategies for the treatment of dually infected patients with active hepatitis C, particularly for those not tolerating or not eligible for peginterferon-based therapy. Notably, direct-acting antivirals would not have any activity against HBV infection; simultaneous or on-demand nucleos(t)ide analogs would be needed if clinically indicated.

Clinical and virological features of occult hepatitis B in patients with HBsAg seroclearance post-treatment or spontaneously.

BACKGROUND: Occult hepatitis B virus (HBV) infection (OHB) may exist in patients experiencing hepatitis B surface antigen (HBsAg) seroclearance. AIMS: We examined the clinical and virological features of OHB in patients who lost HBsAg post-treatment or spontaneously. METHODS: We collected 44 patients with HBsAg seroclearance: 15 patients with dual HBV/hepatitis C virus (HCV) infection who lost HBsAg after peginterferon alfa-2a (PEG-IFN) plus ribavirin therapy; 13 HBV mono-infected patients who lost HBsAg after various oral antiviral therapies; and 16 patients who lost HBsAg spontaneously. OHB was defined as detectable serum HBV DNA in the absence of HBsAg. Viral mutations associated with OHB were identified by comparison with matched controls that remained positive for HBsAg, and further characterized in vitro. RESULTS: The prevalence of OHB was 34.1% (15/44) in all patients, which was not significantly different among three groups. One mutation in surface promoter/polymerase region, C3050T (preS1T68I), was identified to be associated with the seroclearance of HBsAg in six cases. This mutation does not change the amino acid sequence of the polymerase protein. The S promoter activity was significantly lower in the construct containing C3050T mutation as compared with the wild-type (P = 0.0008). However, this mutation did not affect HBV replication, transcription and translation in the context of the full-length HBV genome. OHB was not rare in patients with HBsAg seroclearance. CONCLUSIONS: One mutation, C3050T (preS1T68I), decreased S promoter activity; nevertheless, other factors may play more important role in the clearance of HBsAg in these OHB patients.

Association of IL28B gene variations with mathematical modeling of viral kinetics in chronic hepatitis C patients with IFN plus ribavirin therapy.

Asian patients with chronic hepatitis C (CHC) are known to have better virological responses to pegylated (Peg) IFN-based therapy than Western patients. Although IL28B gene polymorphisms may contribute to this difference, whether favorable hepatitis C virus (HCV) kinetics during treatment plays a role remains unclear. We enrolled 145 consecutive Taiwanese patients with CHC receiving Peg-IFN α-2a plus ribavirin for the study. Blood samples were taken more frequently at defined intervals in the first 3 d. Peg-IFN was administered at week 1. It was then administered weekly in combination with daily ribavirin for 24 or 48 wk. A mathematical model fitted to the observed HCV kinetics was constructed, which could interpret the transient HCV titer elevation after Peg-IFN treatment. The results demonstrated a comparable viral clearance rate (c = 3.45 ± 3.73) (day(-1), mean ± SD) but lower daily viral production rate (P = 10(6)-10(12)) in our patients than those reported previously in Western patients. Of 110 patients with a sustained virological response (SVR), 47 (43%) had a transient elevation of viral titer within 12 h (proportion of 12 h/3 d: 44% in non-SVR vs. 70% in SVR; P = 0.029). Among 91 patients with available rs8099917 data, patients with the TT genotype had an early surge of viral titer after therapy and a higher SVR and viral clearance rate than those with the GT genotype. In conclusion, Taiwanese patients with CHC receiving Peg-IFN plus ribavirin therapy have a lower daily viral production rate than Western patients, and the rs8099917 TT genotype may contribute to the increased viral clearance rate and better virological responses in these patients.

A pilot study of add-on oral hypoglycemic agents in treatment-naïve genotype-1 chronic hepatitis C patients receiving peginterferon alfa-2b plus ribavirin.

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.

Early antiviral therapy reduces the risk of lymphoma in patients with chronic hepatitis C infection.

BACKGROUND: Chronic hepatitis C infection is linked to lymphoma development. AIM: To investigate whether antiviral therapy prevents the risk of HCV-related lymphoma. METHODS: Patients diagnosed with chronic hepatitis C were retrieved from the Taiwan National Health Insurance Research Database during 2004-2012. We included patients who received pegylated interferon and ribavirin (PegIFN/RBV) antiviral therapy for ≥24 weeks (PegIFN/RBV cohort) or hepatoprotectants for ≥90 days without antiviral therapy (HCV-untreated cohort). Both cohorts were matched by age, sex, and comorbidities through propensity scores and followed for newly diagnosed lymphoma or non-Hodgkin's lymphoma (NHL). RESULTS: In total, 24 133 patients were included in both the PegIFN/RBV and HCV-untreated cohort. The lymphoma incidence was significantly higher in the untreated than in the treated cohort (66.48 vs 43.34 per 100 000 person-years, P = 0.029). After adjusting for confounders, the patients who received PegIFN/RBV therapy were at a lower risk of developing lymphoma compared with the untreated patients (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.43-0.96, P = 0.030). Moreover, this beneficial effect was mainly observed in patients with chronic hepatitis C <60 years old with a relative risk reduction of 51% for all lymphoma (HR: 0.49, 95% CI: 0.29-0.82, P = 0.007) and 48% for non-Hodgkin's lymphoma (HR: 0.52, 95% CI: 0.30-0.91, P = 0.022). The risk of all lymphoma or non-Hodgkin's lymphoma development after antiviral therapy was lowered to that of subjects without HCV. CONCLUSIONS: PegIFN/RBV-based antiviral therapy significantly reduced the risk of lymphoma, especially non-Hodgkin's lymphoma; the reduction was mostly among patients <60 years old. Early antiviral therapy for chronic hepatitis C is suggested.

Clinical significance of circulating miR-122 in patients with dual chronic hepatitis B and C virus infection.

BACKGROUND: The clinical significance of serum microRNA-122 (miR-122) has been shown in viral hepatitis B and C, respectively. Specifically, miR-122 stimulates hepatitis C virus (HCV) replication but suppresses hepatitis B virus (HBV) replication. The profile and clinical significance of serum miR-122 in patients with dual chronic hepatitis B and C would be an interesting and important clinical issue. METHODS: A total of 76 patients with HBV/HCV dual infection, 105 with HCV monoinfection and 39 with HBV monoinfection were enrolled. All patients received peginterferon alfa-2a (PEG-IFN)-based treatment. Serum miR-122 levels were quantified by using a sensitive hybridization-based assay. RESULTS: At baseline, the serum miR-122 level was lower in HCV-monoinfected patients than in HBV-monoinfected patients, whereas HBV coinfection increased the expression of miR-122. In multivariate analysis, the serum miR-122 level was positively correlated with the serum HBsAg level in patients with HBV/HCV dual infection and those with HBV monoinfection. In dually infected patients who received PEG-IFN-based treatment, a high baseline miR-122 level was positively correlated with a greater reduction of the posttreatment serum HBsAg level. CONCLUSION: In summary, the serum miR-122 level is highly correlated with the HBsAg level in HBV/HCV dually infected patients and may serve as a biomarker to predict posttreatment HBsAg decline.

Peginterferon α in the treatment of chronic hepatitis B.

INTRODUCTION: Hepatitis B virus (HBV) infection is a global health problem. Peginterferon α (PEG-IFN), which includes PEG-IFN α-2a (Pegasys) and PEG-IFN α-2b (Peg-Intron), can be used to treat patients with chronic hepatitis B (CHB) infection. A finite duration of PEG-IFN therapy may lead to long-term viral suppression. Clinically, it is important to identify super-responders and null-responders to PEG-IFN due to its substantial side effects. AREAS COVERED: From the literature review, it is known that PEG-IFN is more effective for hepatitis B e antigen (HBeAg)-positive patients who have high pre-treatment alanine aminotransferase level, lower HBV DNA level and genotype A (vs genotype D), as well as those with more favourable viral predictors, such as precore stop codon or basal core promoter mutants infections in Asian patients and wild-type virus in Caucasian patients. For HBeAg-positive patients and HBeAg-negative patients with genotype D infection, PEG-IFN therapy could be terminated early at week 12 or 24 in primary non-responders defined by the Hepatitis B surface antigen stopping rules. With regard to host factors, single nucleotide polymorphisms of IL28B do not seem to affect the treatment outcomes in Asian patients, but its role in Caucasian patients remains disputed. EXPERT OPINION: Most of the known predictors need validation by large prospective trials. In addition, we need to identify more baseline predictors for super-responders in order to achieve personalised PEG-IFN treatment for CHB.

Profound week 4 interferon responsiveness is mandatory for hepatitis C genotype 1 patients with unfavorable IL-28B genotype.

BACKGROUND: Viral kinetics and host interleukin 28B (IL-28B) genotype determine treatment outcome in hepatitis C virus genotype 1 (HCV-1) infection. OBJECTIVES: We aimed to explore the interplay between interferon responsiveness at treatment week 4 and IL28B genotype in the achievement of a sustained virological response (SVR; undetectable HCV RNA 24-weeks after end-of-treatment). STUDY DESIGNS: Rs8099917 genotypes were determined in 528 HCV-1 patients with peginterferon/ribavirin. Interferon responsiveness were evaluated by the degree of week 4 viral reduction: <1 log(10) IU/mL, 1-2 logs(10) IU/mL, 2-3 logs(10) IU/mL, 3-4 logs(10) IU/mL and ≥4 logs(10) IU/mL reduction and/or undetectable HCV RNA, respectively. RESULTS: The SVR rate was significantly higher in patients with great interferon responsiveness at week 4. A great interferon responsiveness was associated with younger age (P < 0.0001), lower body mass index (P = 0.0056), lower aspartate aminotransferase levels (P = 0.0009), higher hemogloblin concentration (P = 0.0033), higher platelet counts (P < 0.0001), male gender (P < 0.0001) and rs809997 TT-genotype (P < 0.0001). Comparing to non-TT genotype patients, TT genotype patients had a significantly higher SVR rate with moderate viral reduction (1-3 logs(10) IU/mL) at week 4 (58.9% vs. 18.2%, P < 0.001), and the SVR rate did not differ between TT/non-TT patients on the extreme ends (<1 or >3 log(10) IU/mL reduction) of week 4 interferon responsiveness. For non-TT genotype carriers who were with <3 logs(10) reduction, none (0/15) could have a complete early virological response and only 10.9% (7/64) of the patients had an SVR. CONCLUSIONS: More profound interferon responsiveness is mandatory for HCV-1 patients with unfavorable IL-28B genotype.

Revisiting the stopping rule for hepatitis C genotype 1 patients treated with peginterferon plus ribavirin.

BACKGROUND: The current stopping rule for peginterferon/ribavirin therapy in hepatitis C virus genotype-1 (HCV-1) patients is based on an early virological response (EVR, defined as >2 log(10) viral reduction at treatment week 12). We aimed to explore rapid stopping rules at week 4. METHODS: We randomly allocated 528 HCV-1 patients into training and validation sets (at a 1∶2 ratio). The interleukin-28B rs8099917 genotypes and on-treatment virological responses were evaluated to determine the negative predictive value (NPV) for achieving a sustained virological response (SVR, defined as undetectable HCV RNA 24 weeks after end-of-treatment). The study was approved by the ethics committees of the participating hospitals. All of the patients gave written informed consent before enrollment. RESULTS: A poor week 4 response (W4R), defined as a HCV RNA reduction of <1 log(10) IU/mL at week 4 or a week 4 HCV RNA>10,000 IU/mL with interleukin-28B non-TT genotype, had the highest NPV (95%). In the complete sample, poor W4R could identify 43.4% (59/136) of the non-responders, with an NPV of 95% and a false negative rate of only 0.8% (3/396). The multivariate analysis revealed that a poor W4R was the most important negative predictor (odds ratio/95% confidence intervals: 49.01/13.70-175.37), followed by the lack of an EVR. In addition to HCV RNA<1 log(10) IU/mL reduction, using the criteria of HCV RNA>10,000 IU/mL/non-TT genotype helped identifying an additional one-third of non-SVR patients at W4.Using the strategy of sequential rapid stopping rule strategy could identify 53.7% (73/136) of the non-responders (43.4% at week 4 and an addition 11.3% at week 12), as compared to 40.4% for the classical week-12 early stopping rule. CONCLUSIONS: Sequential rapid stopping rules using on-treatment virological responses and interleukin-28B genotype can rapidly identify additional peginterferon/ribavirin non-responders.

Interleukin 28B genetic polymorphisms and viral factors help identify HCV genotype-1 patients who benefit from 24-week pegylated interferon plus ribavirin therapy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Effect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon-α-2a therapy.

BACKGROUND: Pegylated interferon (PEG-IFN)-α-2a improves the hepatitis B e antigen (HBeAg) seroconversion rate in HBeAg-positive chronic hepatitis B patients. However, baseline factors predicting favourable responses to PEG-IFN-α-2a remain largely unknown. METHODS: A total of 115 HBeAg-positive chronic hepatitis B patients who had a pre-therapy serum alanine aminotransferase (ALT) level over two times the upper limit of normal and received PEG-IFN-α-2a for 6-12 months were consecutively enrolled according to the local reimbursed guidelines. HBeAg seroconversion and combined response defined as HBeAg seroconversion, HBV-DNA level <20,000 IU/ml as well as ALT normalization at 6 months off therapy were primary and secondary therapeutic end points, respectively. Baseline viral factors, including viral load, genotype and major sequences of precore stop codon/basal core promoter (BCP), and host factors, including three single nucleotide polymorphisms among the HLA-DPA1, HLA-DPB1 and IL28B regions, were determined to correlate with therapeutic end points. RESULTS: HBeAg seroconversion and combined response rates were 26.1% and 18.3%, respectively. By multivariate analysis, BCP mutation (OR 8.04, 95% CI 2.00-32.28) and rs3077 G/G genotype (OR 3.49, 95% CI 1.12-10.84) were associated with a higher HBeAg seroconversion rate; BCP mutation (OR 9.28, 95% CI 1.92-44.99) and baseline viral load <2 × 10(6) IU/ml (OR 4.78, 95% CI 1.37-16.69) were associated with a higher combined response rate. CONCLUSIONS: BCP mutation is associated with higher HBeAg seroconversion and combined response rates at 6 months off therapy in HBeAg-positive chronic hepatitis B patients treated with PEG-IFN-α-2a. Genetic variants in the HLA-DPA1 region may also affect treatment-induced HBeAg seroconversion.