The efficacy of extended treatment with pegylated interferon plus ribavirin in patients with HCV genotype 1 and slow virologic response in Japan

Background

Which patients with hepatitis C virus (HCV) genotype 1 can benefit from extended treatment with pegylated interferon (Peg-IFN) plus ribavirin is unknown, although the overall sustained virologic response (SVR) rate has been shown to improve in patients with a late virologic response (LVR), defined as detectable serum HCV RNA at week 12 and undetectable at week 24.

Methods

Among 1163 chronic hepatitis C patients with genotype 1 treated with Peg-IFN plus ribavirin combination therapy, 213 patients with an LVR were examined in this study. In addition, we selected 81 patients of matched sex and age from each of the 48- and 72-week treatment groups, using the propensity score, to compare the efficacy of the two treatment durations.

Results

With 72-week treatment, the timing of HCV RNA disappearance and the hemoglobin level at baseline showed a strong correlation with the SVR on multivariate analysis. Earlier HCV RNA disappearance was associated with a better SVR rate, regardless of the ribavirin dose (HCV RNA disappearance at week 16, 74%; at week 20, 52%; and at week 24, 31%, p?=?0.01). The SVR rate with 72-week treatment was higher than that with 48-week treatment, irrespective of age, sex, or the platelet value, and, especially in aged patients (??65?years old), the SVR rate increased markedly with 72-week treatment (48?weeks, 25% vs. 72?weeks, 56%; p?Conclusions An earlier response predicts a higher SVR rate in patients with an LVR given 72-week treatment. Extended treatment with Peg-IFN plus ribavirin for patients with an LVR improved the treatment efficacy, even for aged patients.     

Liver stiffness measurement by acoustic radiation force impulse is useful in predicting the presence of esophageal varices or high-risk esophageal varices among patients with HCV-related cirrhosis

Background

Screening and periodic surveillance for esophageal varices (EVs) by esophagogastroduodenoscopy (EGD) are recommended for cirrhotic patients. We investigated non-invasive liver stiffness measurement using acoustic radiation force impulse (ARFI) for the diagnosis of EV presence and high-risk EVs among patients with HCV-related cirrhosis.

Methods

Among 181 consecutive patients with HCV-related cirrhosis, we studied 135 patients who had received EGD and ARFI. Serum fibrosis markers [platelet count, FIB-4, and aspartate aminotransferase-to-platelet ratio index (APRI)] were measured in a training set of 92 patients and compared with ARFI in the diagnostic performance for EV presence and high-risk EVs. Furthermore, the obtained optimal cutoff values of ARFI were prospectively examined in a validation set of 43 patients.

Results

In the training set, the ARFI value increased with the EV grade (p < 0.001). The ARFI value for high-risk EVs was significantly higher than that for low-risk EVs (p < 0.001). AUROC values for diagnosis of EV presence and high-risk EVs by ARFI were 0.890 and 0.868, which had the highest diagnostic performance among factors including serum fibrosis markers. The optimal cutoff value of ARFI for EV presence was 2.05 m/s with good sensitivity (83 %), specificity (76 %), PPV (78 %), and NPV (81 %), and that for high-risk EVs was 2.39 m/s with good sensitivity (81 %), specificity (82 %), PPV (69 %), and NPV (89 %). These cutoff values obtained in the training cohort also showed excellent performance in the validation set.

Conclusions

Liver stiffness measurement by ARFI is useful in predicting EV presence or high-risk EVs among patients with HCV-related cirrhosis.     

Early decline of hemoglobin can predict progression of hemolytic anemia during pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C.

Aim: Ribavirin, used to treat chronic hepatitis C, can induce hemolytic anemia, forcing the discontinuance of treatment. To establish a predictive measure to help circumvent this, we evaluated the relationship of hemoglobin (Hb) decline with the discontinuance of treatment during the progression of ribavirin‐induced anemia. Methods: One hundred and sixteen patients (71% male) with genotype 1 chronic hepatitis C were treated with pegylated interferon (PegIFN) α‐2b and ribavirin. The mean age was 50.6 years and 55% were IFN naïve. A decline of Hb concentration by 2 g/dL at two weeks from the start of the treatment (“2 by 2” standard) was adopted as the predictive factor for the progression of anemia. Results: By applying the “2 by 2” standard, with ΔHb ≥ 2 g/dL (34%, n = 39), treatment was discontinued in 12 cases (31%), three of which (8%) because of severe anemia. ForΔHb < 2 g/dL (64%, n = 76), treatment was discontinued in 11 (14%) cases; none due to severe anemia. Ten percent (4/39) of patients showed the minimum Hb ≤ 8.5 g/dL in the ΔHb ≥ 2 g/dL group, with none in the ΔHb < 2 g/dL group (P = 0.001). Furthermore, the patients with minimum Hb ≤ 8.5 g/dL were found only in the “2 by 2” standard‐positive and low CL/F (<15) group (4/29, 14%). Conclusion: Monitoring the Hb decline using the “2 by 2” standard can identify patients who are prone to developing severe anemia. Further prospective studies are needed using ribavirin reduction based on the “2 by 2” standard.     

Association of genetic risk score and chronic kidney disease in a Japanese population

Chronic kidney disease (CKD) is a public health problem worldwide including Japan. Recent genome‐wide association studies have discovered CKD susceptibility variants. We developed a genetic risk score (GRS) based on CKD‐associated variants and assessed a possibility that the GRS can improve the discrimination capability for the prevalence of CKD in a Japanese population. The present study consists of 11 283 participants randomly selected from 12 Japan Multi‐Institutional Collaborative Cohort Study sites. Individual GRS was constructed combining 18 single‐nucleotide polymorphisms identified in a Japanese population. Participants with eGFR <60 mL/min per 1.73 m² was defined as case (stage 3 CKD or higher) in this study. Logistic regression analysis was used to examine the association between the GRS and CKD risk with adjustment for sex, age, hypertension and type 2 diabetes mellitus. The frequency of individuals with CKD was 8.3%, which was relatively low compared with those previously reported in a Japanese population. The odds ratio of having CKD was 1.120 (95% confidence interval: 1.042–1.203) per 10 GRS increment in the fully adjusted model (P = 0.002). The C‐statistic was significantly increased in the model with the GRS, comparing with the model without the GRS (0.720 vs 0.719, P_difference = 0.008). Increment of the GRS was associated with increased risk of CKD. Additionally, the GRS significantly improved the discriminatory ability of CKD prevalence in a Japanese population; however, the improvement of discriminatory ability brought about by the GRS seemed to be small compared with that of non‐genetic CKD risk factors.     

Using early viral kinetics to predict antiviral outcome in response-guided pegylated interferon plus ribavirin therapy among patients with hepatitis C virus genotype 1

Background

HCV kinetics during treatment demonstrated strong association with the antiviral outcome of patients treated with pegylated interferon (Peg-IFN) plus ribavirin. However, the relationship between HCV kinetics and pre-treatment factors remains unclear.

Methods

Of 547 patients with HCV genotype 1 treated with Peg-IFN alfa-2b plus ribavirin, 401 completed the response-guided therapy and were assessed for per protocol analysis.

Results

The sustained virologic response (SVR) rate was 53 % for all patients, 60 % for those with genotype TT, and 19 % for those with genotype TG/GG according to IL28B (rs8099917) single nucleotide polymorphisms. The SVR rates increased with HCV decrease at week 4; 4 % (2/56) with <1 log₁₀ decrease, 13 % (7/56) with 1–2 log₁₀ decrease, 51 % (44/87) with 2–3 log₁₀ decrease, 64 % (56/87) with 3–4 log₁₀ decrease, 88 % (72/82) with more than 4 log₁₀ decrease but with detectable HCV RNA and 100 % (33/33) with undetectable HCV RNA (p < 0.001). Similarly, SVR rates increased step-by-step in proportion to HCV decrease in both IL28B TT and TG/GG groups, showing almost the same SVR rates for the same conditions. In multivariate analysis, age (p = 0.005) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with SVR. Advanced liver fibrosis (p = 0.004) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with non-response.

Conclusions

The magnitude of the HCV decrease at week 4 seems to be the most reliable marker for predicting antiviral outcome after starting Peg-IFN plus ribavirin therapy.     

A multicenter survey of re‐treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan

Aim: This study aimed to clarify the factors associated the efficacy of re‐treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment. Methods: One hundred and forty‐three patients who had previously shown relapse (n = 79), non‐response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re‐treated with PEG IFN plus ribavirin. Results: Twenty‐five patients with intolerance to previous treatment completed re‐treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re‐treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re‐treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin‐28B major genotype responded significantly better and earlier to re‐treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re‐treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05). Conclusion: Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re‐treatment for HCV genotype 1 patients. Re‐treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re‐treatment.     

Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin

Summary.  The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg-IFN) and ribavirin for patients with chronic hepatitis C (CH-C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty-four patients with CH-C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis ( P  =   0.002), the timing of HCV RNA negativiation ( P  <   0.001) and the mean doses of ribavirin ( P  <   0.001) were significantly associated with relapse, but those of Peg-IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c-EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given ≥12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg-IFN could be reduced to 0.6 μg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose-dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (≥12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg-IFN alpha-2b plus ribavirin, especially in c-EVR patients.     

Pegylated interferon alpha-2b (Peg-IFN α-2b) affects early virologic response dose-dependently in patients with chronic hepatitis C genotype 1 during treatment with Peg-IFN α-2b plus ribavirin

Summary.  Chronic hepatitis C (CH-C) genotype 1 patients who achieved early virologic response have a high probability of sustained virologic response (SVR) following pegylated interferon (Peg-IFN) plus ribavirin therapy. This study was conducted to evaluate how reducing drug doses affects complete early virologic response (c-EVR) defined as hepatitis C virus (HCV) RNA negativity at week 12. Nine hundred eighty-four patients with CH-C genotype 1 were enrolled. Drug doses were evaluated independently on a body weight base from doses actually taken. From multivariate analysis, the mean dose of Peg-IFN α-2b during the first 12 weeks was the independent factor for c-EVR ( P  = 0.02), not ribavirin. The c-EVR rate was 55% in patients receiving ≥1.2 μg/kg/week of Peg-IFN, and declined to 38% at 0.9–1.2 μg/kg/week, and 22% in patients given <0.9 μg/kg/week ( P  < 0.0001). Even with stratified analysis according to ribavirin dose, the dose-dependent effect of Peg-IFN on c-EVR was observed, and similar c-EVR rates were obtained if the dose categories of Peg-IFN were the same. Furthermore, the mean dose of Peg-IFN during the first 12 weeks affected HCV RNA negativity at week 24 ( P  < 0.0001) and SVR ( P  < 0.0001) in a dose-dependent manner. Our results suggest that Peg-IFN was dose-dependently correlated with c-EVR, independently of ribavirin dose. Thus, maintaining the Peg-IFN dose as high as possible during the first 12 weeks can yield HCV RNA negativity and higher c-EVR rates, leading to better SVR rates in patients with CH-C genotype 1.