Lower Hepatitis C Virus RNA Levels Research Articles

Genetic Association of Hepatitis C-Related Mixed Cryoglobulinemia: A 10-Year Prospective Study of Asians Treated with Antivirals

Genetic profiles of hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) in Asians remain elusive. A 10-year prospective cohort study was conducted with 1043 consecutive HCV Ab-positive Taiwanese surveyed with 13 single nucleotide polymorphisms (SNPs). Of 1043, 589 (56.5%) had baseline MC, 934 (89.5%) had positive HCV RNA, 796 completed anti-HCV therapy, and 715 had sustained virological responses (SVRs). SNP associations were surveyed withgenotypic, allelic, trend, permutation and multivariate analyses. At baseline, higher male sex and MC rates were noted in HCV RNA-positive than RNA-negative patients; higher female sex and positive HCV RNA rates but lower HCV RNA levels were noted in patients with than those without MC. Baseline associations were: HLA II-rs9461776 A allele, IFNL3-rs12979860 T allele, SERPINE1-rs6976053 C allele and MC with HCV RNA positivity; IFNL3-rs12979860 C allele, ARNTL-rs6486122 T allele and HCV RNA positivity with baseline MC. In SVR patients, RETN-rs1423096 C allele and SERPINE1-rs6976053 T allele were associated with 24-week and 10-year post-therapy MC, respectively. Conclusions: HCV RNA, IFNL3-rs12979860 and ARNTL-rs6486122 were associated with baseline MC; RETN-rs1423096 and SERPINE1-rs6976053 were associated with short- and long-term post-therapy MC in SVR patients, respectively. Links with HCV RNA and immune-associated SNPs suggest MC an immune reaction to expel HCV.

Rapid virologic response in chronic hepatitis C genotype 1: Evaluation of pretreatment factors in patients

Background and study aimsRapid virologic response (RVR) is defined as undetectable hepatitis C virus (HCV) RNA in serum after 4 weeks of treatment for chronic hepatitis C (CHC). Paritaprevir/ritonavir/ombitasvir (PRO) and/or dasabuvir (D), with or without ribavirin [PRO (D) ± ribavirin], which are direct-acting antivirals (DAAs), is the currently approved treatment regimen for CHC genotype 1; this regimen can also be used in patients with end-stage renal failure (ESRF). In this study, we aimed to evaluate the effect of pretreatment factors on RVR in patients treated with PRO (D) ± ribavirin. Patients and methodsThis study included 60 patients with CHC genotype 1 who were treated with PRO (D) ± ribavirin and achieved RVR. Patients’ demographic data; baseline HCV RNA levels; HCV genotype information; biochemical, histologic, and radiologic results; and previous treatment history were recorded. Patients were categorized into two groups: virologic responses achieved in the first week (group 1) and in the first to the fourth week (group 2). Pretreatment factors were compared between the groups. ResultsPatients in group 1 who achieved ultraRVR (undetectable HCV RNA after 1 week of treatment) had significantly lower mean pretreatment HCV RNA levels and lower prevalence of ESRF than patients in group 2. ConclusionsRVR has been indicated to be a robust positive predictor of sustained virologic response. We concluded that some pretreatment factors such as low HCV RNA level and absence of ESRF might lead to faster RVR and shorter treatment duration with DAAs for CHC.

Effect of Low Positive End of Treatment Viral Load with Direct-Acting Antiviral Therapy on Sustained Virologic Response.

Background Direct-acting antivirals (DAAs) are highly effective treatments against hepatitis C virus (HCV), with sustained virologic response (SVR) rates of 93–100% against all genotypes. In most patients, viral load (VL) becomes undetectable four weeks into treatment, but rarely a low positive VL may be observed at the end of treatment (EOT). This study was conducted to determine the effect of low positive EOT VLs with DAA therapies on SVR at 12 and 24 weeks. Methods A retrospective chart review was conducted from January 2014 to December 2018 on 1256 HCV patients of all genotypes (1–6) who had received DAA therapy at two large hepatology referral centers. Baseline demographic data, along with VL at week four, EOT, and SVR12/24 time points were collected for patients that had positive EOT VL. Treatment outcome for any patient with positive EOT VL was noted. Results Eight out of 1256 patients treated with varying DAA therapies were observed to have low positive EOT VLs ranging from <15 to 235 IU/mL. One patient had a negative EOT VL, but 23 IU/mL at week four after EOT. All eight patients who had low positive EOT VLs and one patient who had a low positive VL at four weeks after EOT achieved SVR at weeks 12 and 24. One of the eight patients had cirrhosis. The majority of patients were genotype 1a. Conclusion In the DAA treatment era, low levels of detectable HCV RNA at EOT does not predict treatment failure.

Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection

Direct-acting antivirals (DAAs) cure most cases of chronic hepatitis C virus (HCV) infection. However, a small percentage of patients relapse with reappearance of viremia after a full course of therapy. Although most who relapse require retreatment, some patients spontaneously clear HCV without additional therapy. We studied patients who relapsed with detectable HCV RNA after a full course of DAA therapy and then spontaneously cleared the HCV infection without retreatment. We performed a case-control study of patients who spontaneously cleared chronic HCV infection following a documented relapse after DAA therapy at the Toronto Centre for Liver Disease, from January 2014 through December 2017. We collected clinical information at baseline, 12 weeks after treatment, and 6 months after relapse and compared data among spontaneous clearers, patients with persistent relapse, and patients who achieved a sustained virologic response to therapy 12 weeks after treatment (SVR12). The strength and breadth of interferon gamma cytokine secretion by HCV-specific T cells from peripheral blood were quantified using the ELISPOT assay. Of the 1032 individuals with chronic HCV infection who were treated with DAAs, 93 patients had a documented relapse. Of these patients, 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy. The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse, much like patients with an SVR12. There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses. In a case-control study of patients who spontaneously cleared chronic HCV infection following a relapse after DAA therapy, we found that it is important to confirm viremia prior to retreatment after the relapse-particularly for individuals with low levels of HCV RNA and normal or near-normal levels of alanine aminotransferase after treatment.

Platelet count is associated with sustained virological response rates in treatments for chronic hepatitis C.

Background/AimsThis study was conducted to clarify the sustained virological response (SVR) prediction ability of baseline and treatment-related factors in patients with chronic hepatitis C virus (HCV) infection.MethodsThis retrospective study collected data at four tertiary referral hospitals between June 2004 and July 2012. Out of 476 patients, 330 treatment-naïve patients with chronic HCV infection were recruited. Pegylated interferon α-2a/- 2b plus ribavirin was administered for either 24 or 48 weeks depending on the HCV genotype. The baseline and treatment-related predictive factors of SVR were evaluated by analyzing data measured before treatment (i.e., baseline) and during treatment.ResultsSVR rates for genotypes 1 and 2 were 63% (97/154) and 79.5% (140/176), respectively (p = 0.001). Multivariate analysis for baseline factors revealed that young age (p = 0.009), genotype 2 (p = 0.001), HCV RNA level of < 800,000 IU/mL (p < 0.001), and a baseline platelet count of > 150 × 103 /µL (p < 0.001) were significant SVR predictors, regardless of the genotype. In particular, predictive accuracy for achievement of SVR was 87.3% for a baseline platelet count of > 150 × 103 /µL. In multivariate analysis for treatment-related factors, SVR was associated with achievement of a rapid virological response (RVR; p < 0.001), treatment adherence of ≥ 80/80/80 (p < 0.001).ConclusionsYoung age, genotype 2, low HCV RNA level, RVR, and treatment adherence were significantly associated with SVR. In addition, platelet count was an independent predictive factor for SVR. Therefore, platelet count could be used to develop individualized treatment regimens and to optimize treatment outcomes in patients with chronic HCV infection.

Daclatasvir Plus Asunaprevir for the Treatment of Patients with Hepatitis C Virus Genotype 1b Infection: Real-World Efficacy, Changes in Liver Stiffness and Fibrosis Markers, and Safety.

Background/AimsThe treatment with daclatasvir plus asunaprevir (DCV+ASV) is associated with potent antiviral effects in patients with genotype 1b hepatitis C virus (HCV) infection. We investigated the real-world efficacy, changes in liver stiffness and noninvasive fibrosis markers, and the safety of DCV+ASV treatment in Korean patients.MethodsIn total, 363 patients with chronic hepatitis C were treated with DCV+ASV between August 2015 and January 2017. Finally, we analyzed the data of 270 patients who were monitored for at least 12 weeks after the end of treatment.ResultsThe mean age was 60.7 years, and females predominated (60.4%). Most patients (64.8%) were treatment-naïve, and 56 patients (20.7%) had cirrhosis. Two hundred fifty-seven (95.2%) and 251 (93.0%) patients achieved end-of-treatment responses and sustained virological responses at 12 weeks posttreatment (SVR12), respectively. The SVR12 rates were higher in patients who were <65 years of age, males, without cirrhosis and had lower HCV RNA levels. All LS values and fibrosis-4 and aspartate aminotransferase-to-platelet ratio index values declined from baseline to the time of assessment of SVR12.ConclusionsThe DCV+ASV therapy resulted in a high SVR12 and improved liver fibrosis; the treatment was well tolerated in patients with genotype 1b HCV infections.

Hepatitis C viral load, genotype, and increased risk of developing end-stage renal disease: REVEAL-HCV study.

This study reveals that chronic HCV infection is associated with an increased risk of developing ESRD and suggests that elevated serum levels of HCV RNA (>167,000 IU/mL) and HCV genotype 1 are strong predictors of ESRD, indicating clinical implications for the management of chronic HCV. (Hepatology 2017;66:784-793).

HIV-positive men who have sex with men are at high risk of development of significant liver fibrosis after an episode of acute hepatitis C.

Acute hepatitis C virus infection remains a major health concern in human immunodeficiency virus(HIV)-infected men who have sex with men (MSM). New direct-acting antiviral agent (DAA) combination therapy has not yet been approved for the treatment for acute hepatitis C virus(HCV), thereby potentially causing deferral of HCV treatment. Therefore, we aimed to study the course of liver disease after an episode of acute HCV. This study is a retrospective single-centre cohort of HIV-positive MSM with acute HCV infection. Liver fibrosis was estimated by Fibroscan® and Fibrotest® . Liver-related and non-liver-related outcomes were documented. Overall 213 episodes of acute HCV infection in 178 men were documented. Median follow-up for all included patients was 38.7months. Spontaneous HCV clearance was found in 10.8% of patients, which was significantly associated with older age, lower HCV RNA levels, and higher ALT levels upon initial acute HCV diagnosis. Treatment with interferon-based therapy was initiated in 86.3% of cases, resulting in a sustained virological response(SVR) rate of 70.7%. After 3years' follow-up, significant liver fibrosis of METAVIR F2 stage or higher was found in 39.4% of patients after first acute HCV diagnosis. Higher age, physician-declared alcoholism, and nonresponse to acute HCV therapy were independently associated with higher fibrosis stages. Ten patients died during the observation period (IR 1.4/100 patient-years) and four during interferon treatment. Significant liver fibrosis is a common finding in HIV-positive MSM following acute HCV infection despite high treatment uptake and cure rates, suggesting the need for close liver disease monitoring particularly if HCV treatment is deferred.

Efficacy of 24-week pegylated interferon alpha and ribavirin combination therapy in highly selected patients infected with hepatitis C virus genotype 1.

Background:Previous studies using pegylated interferon (Peg-IFN) and ribavirin (RBV) combination therapy suggested that patients with hepatitis C virus (HCV) genotype 1 and low pretreatment HCV RNA level who achieved rapid virological response (RVR) can be treated for 24 weeks without compromising sustained virological response (SVR) rate.Objectives:The current study aimed to investigate the efficacy of Peg-IFN-alfa-2a plus RBV administered for a 24-week treatment course in patients with chronic HCV genotype 1 infection and possessing the following criteria: low baseline serum HCV RNA level, absence of significant fibrosis and achievement of RVR.Patients and Methods:In this case-control study, 20 patients with HCV genotype 1 infection and favorable baseline characteristics and on-treatment response were treated with Peg-IFN and RBV for 24 weeks as the case group. Furthermore, 23 patients with the same characteristics who underwent a 48-week treatment course were selected as the control group.Results:The majority of patients had no fibrosis on liver elastography. There was no statistical difference regarding age, gender, alanine transaminase (ALT) level, rs12979860 polymorphism and the level of fibrosis between the two studied groups. All patients in the 24-week treatment course achieved SVR and all the subjects who received the 48-week treatment course achieved SVR as well (P > 0.99).Conclusions:The current study confirmed that the efficacy of a 24-week regimen of Peg-IFN-alfa-2a plus RBV was similar to the 48-week treatment in the patients infected with HCV genotype 1, and low baseline HCV RNA level who achieved RVR. Response guided therapy can be efficient and cost-effective among the selected HCV genotype 1-infected patients.

Factors associated with sustained virological response in 24‐week telaprevir‐based triple therapy for chronic hepatitis C genotype 1b patients with the IL28B minor genotype

Single nucleotide polymorphisms (SNP) near the interleukin-28B (IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus (HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. Pretreatment and on-treatment factors associated with sustained virological response (SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non-TT). Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response (P = 0.0041), high fasting serum low-density lipoprotein cholesterol (LDL-C) concentration (P = 0.0068) and low serum HCV RNA levels (P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response (RVR) were significantly and independently associated with SVR (P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response (P = 0.0018), low pretreatment serum fasting LDL-C (P = 0.0062) and achieving RVR (P = 0.0021) were significantly and independently associated with SVR. In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL-C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy.

Peginterferon alfa-2a and peginterferon alfa-2b combined with ribavirin in patients with genotype 1 chronic hepatitis C: Results of a prospective single-centre study

PurposeThis prospective, randomized, single-centre study compared peginterferons alfa-2a and alfa-2b, combined with ribavirin, in treating patients infected with hepatitis C virus (HCV) genotype 1. Material/methodsHundred-and-one patients received 48 weeks of open-label treatment with peginterferon alfa-2a (180μg/week) and 111 patients received peginterferon alfa-2b (1.5μg/kg/week). All patients received the same dose of ribavirin 1000/1200mg/day, depending on weight. The primary efficacy endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<50IU/mL) 24 weeks after the end of treatment. ResultsEarly virologic response (EVR), defined as at least 2log10IU/mL reduction of viral load at 12 weeks, was more common in patients treated with peginterferon alfa-2a (88% vs. 74.8%; p=0.04). However, the difference in SVR was not statistically significant (49.5% vs. 44.1%; p=0.43). ConclusionsPeginterferon alfa-2a treated patients were also more likely to be HCV RNA negative at the end of treatment (67.3% vs. 57.7%), but this difference did not reach statistical significance. Multivariate logistic regression analysis found that SVR was associated with low fibrosis stage (F1–2 by Scheuer; p=0.001) and low serum HCV RNA level (<400,000IU/L; p=0.023). While both forms of peginterferon showed similar efficacy as measured by SVR, use of peginterferon alfa-2b could lower the number of patients receiving unnecessary treatment beyond 12 weeks.

Usefulness of combined application of double‐filtration plasmapheresis and twice‐daily injections of interferon‐β in hemodialysis patients with hepatitis C virus genotype 1b infection and a high viral load

Hepatitis C virus (HCV) infection is common among hemodialysis (HD) patients and has been recognized as an important prognostic factor. Therefore, the aggressive antiviral therapy is necessary for HCV infection in HD patients. However, various treatment limitations exist in HD patients such as the inability to use ribavirin. We have previously reported that HCV RNA can be eradicated by administration of interferon (IFN)-β during HD in patients with HCV infection caused by genotypes known to be sensitive to IFN therapy and low serum HCV RNA levels. In this case report, we tried to clarify the efficacy of combined application of double-filtration plasmapheresis (DFPP) and IFN-β in HD patients with HCV genotype 1b infection and high serum HCV RNA levels. We report two HD patients with HCV genotype 1b infection and high viral loads who were successfully treated by five sessions of DFPP undertaken prior to treatment with IFN-β (twice-daily injections for 2 weeks). HCV was eradicated by this combination therapy in both patients. We revealed the efficacy of combined application of DFPP and IFN-β in HD patients with HCV genotype 1b infection and high serum HCV RNA levels. This combined therapy may be useful for the HD patients who are resistant to conventional IFN monotherapy.

Pretransplant Serum Hepatitis C Virus RNA Levels Predict Response to Antiviral Treatment after Living Donor Liver Transplantation

BackgroundGiven the limited efficacy and high adverse event rate associated with treatment of recurrent hepatitis C after liver transplantation, an individualized treatment strategy should be considered. The aim of this study was to identify predictors of response to antiviral therapy for hepatitis C after living donor liver transplantation (LDLT) and to study the associated adverse events.MethodsA retrospective chart review was performed on 125 hepatitis C virus (HCV)-positive LDLT recipients who received interferon plus ribavirin and/or peginterferon plus ribavirin therapy at Kyoto University between January 2001 and June 2011.ResultsSerum HCV RNA reached undetectable levels within 48 weeks in 77 (62%) of 125 patients, and these patients were defined as showing virological response (VR). Of 117 patients, 50 (43%) achieved sustained VR (SVR). Predictive factors associated with both VR and SVR by univariate analysis included low pretransplant serum HCV RNA levels, a non-1 HCV genotype, and low pretreatment serum HCV RNA levels. In addition, LDLT from ABO-mismatched donors was significantly associated with VR, and white cell and neutrophil counts before interferon therapy were associated with SVR. Multivariate analysis showed that 2 variables–pretransplant serum HCV RNA level less than 500 kIU/mL and a non-1 HCV genotype–remained in models of both VR and SVR and that an ABO mismatch was associated with VR. No variables with a significant effect on treatment withdrawal were found.ConclusionsVirological response to antiviral therapy in patients with hepatitis C recurring after LDLT can be predicted prior to transplant, based on pretransplant serum HCV-RNA levels and HCV genotype. LDLT from ABO-mismatched donors may contribute to more efficacious interferon therapy.Trial RegistrationUMIN-CTR UMIN000003286

Pegylated interferon monotherapy in patients with chronic hepatitis C with low viremia and its relationship to mutations in the NS5A region and the single nucleotide polymorphism of interleukin‐28B

Previous studies have suggested that patients with chronic hepatitis C with a low pretreatment hepatitis C virus (HCV) level have a high sustained virological response (SVR) rate, and that there would be a subpopulation of patients in which HCV can be eradicated with pegylated interferon (PEG IFN) alone without a decrease in SVR. However, the efficacy of PEG IFN monotherapy in patients with low HCV RNA levels is unclear. Several studies have reported that interferon sensitivity-determining region (ISDR) and the single-nucleotide polymorphism (SNP) of interleukin-28B (IL-28B) contribute to IFN response, but these relationships are controversial. The aim of this study was to determine whether the SNP of IL-28B (rs8099917) and amino acid substitutions in the ISDR among patients with low HCV levels affect the response to PEG IFN monotherapy. One hundred and four patients with low-level HCV infection were studied. Low HCV level was defined as 100 KIU/mL or less. SVR was achieved in 94 patients (92.2%). HCV levels (≤50 KIU/mL) and ISDR (≥2 mutations) were associated with SVR on univariate analysis. The rates of SVR in the patients with IL-28B genotypes TT, TG and GG were 94.5%, 77.8% and 100%, respectively. The G allele tended to be associated with poor response to IFN therapy (P = 0.0623). On multivariate analysis, the ISDR was the factor predictive of SVR (P = 0.004). The ISDR is significantly associated with a good response to PEG IFN monotherapy in patients with low HCV levels.

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

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. 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. 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). 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.

Role of Viral Genotypes and Hepatitis B Viral Mutants in the Risk of Hepatocellular Carcinoma Associated with Hepatitis B and C Dual Infection

Background/Aims: The independent and interactive effects of hepatitis B virus (HBV) and hepatitis C virus (HCV) factors on the development of hepatocellular carcinoma (HCC) in chronic HBV/HCV dually-infected patients remain unclear. Methods: In a cross-sectional and case-controlled study, the HBV and HCV loads and genotypes and the sequences of pre-S and precore/core promoter regions were determined in 146 HCC patients and 167 chronic carriers with HBV/HCV dual infection. Results: Age (odds ratio (OR) 1.1), male sex (OR 2.3), pre-S deletion (OR 5.0), A1762T/G1764A mutant (OR 2.5), HCV genotype-1 (OR 2.4) and platelet count <15 × 10⁴/μl (OR 1.9) were independently associated with HCC by stepwise logistic regression analysis. Patients with combined HBV mutations (pre-S deletion and A1762T/G1764A mutant) and HCV genotype-1 had a 39-fold increased risk of developing HCC compared to those with A1762T/G1764A and pre-S wild-type strains and HCV genotype non-1. In the nested case-control study, patients with HCC had a higher HBV DNA level (p < 0.001), a higher frequency of pre-S deletion (p < 0.001) and A1762T/G1764A mutant (p = 0.005), a lower HCV RNA level (p = 0.012) and a higher prevalence of HCV genotype-1 (p = 0.002) than those without. Conclusions: Pre-S deletion, A1762T/G1764A mutation and HCV genotype-1 are important in hepatocarcinogenesis in chronic HBV/HCV dual infection.

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa‐2a/ribavirin

It is unclear whether the current threshold for 'high' hepatitis C virus (HCV) RNA level (800,000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono-infected and 176 HIV-HCV co-infected patients treated with peginterferon alfa-2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono-infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400,000 IU/mL was used and 16% (59%vs 43%) when 800,000 IU/mL was used. In HIV-HCV genotype 1 co-infected patients, the difference was 51% (71%vs 20%) when 400,000 IU/mL was used and 43% (61%vs 18%) when 800,000 IU/mL was used. A lower threshold (200,000 IU/mL) was identified for genotype 1 mono-infected patients with 'normal' alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400,000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1-infected individuals with elevated ALT.

New perspectives in occult hepatitis C virus infection

Occult hepatitis C virus (HCV) infection, defined as the presence of HCV RNA in liver and in peripheral blood mononuclear cells (PBMCs) in the absence of detectable viral RNA in serum by standard assays, can be found in anti-HCV positive patients with normal serum levels of liver enzymes and in anti-HCV negative patients with persistently elevated liver enzymes of unknown etiology. Occult HCV infection is distributed worldwide and all HCV genotypes seem to be involved in this infection. Occult hepatitis C has been found not only in anti-HCV positive subjects with normal values of liver enzymes or in chronic hepatitis of unknown origin but also in several groups at risk for HCV infection such as hemodialysis patients or family members of patients with occult HCV. This occult infection has been reported also in healthy populations without evidence of liver disease. Occult HCV infection seems to be less aggressive than chronic hepatitis C although patients affected by occult HCV may develop liver cirrhosis and even hepatocellular carcinoma. Thus, anti-HCV negative patients with occult HCV may benefit from antiviral therapy with pegylated-interferon plus ribavirin. The persistence of very low levels of HCV RNA in serum and in PBMCs, along with the maintenance of specific T-cell responses against HCV-antigens observed during a long-term follow-up of patients with occult hepatitis C, indicate that occult HCV is a persistent infection that is not spontaneously eradicated. This is an updated report on diagnosis, epidemiology and clinical implications of occult HCV with special emphasis on anti-HCV negative cases.

Steatosis Is an Independent Predictor of Relapse Following Rapid Virologic Response in Patients With HCV Genotype 3

It is recommended that patients with chronic hepatitis C virus (HCV) genotype 3 infections receive 24 weeks of treatment. A rapid virologic response (RVR; at week 4) predicts a sustained virologic response (SVR), although not all patients with an RVR achieve an SVR. We explored the relationships among hepatic steatosis, level of HCV RNA, relapse, and RVR in a phase 3 randomized controlled trial of 932 patients infected with HCV genotype 2 (n = 427) or 3 (n = 505) who received 24 weeks of therapy with interferon-α. In patients with an RVR (HCV RNA <43 IU/mL), the presence of an SVR was modeled using multivariate logistic regression as a function of age, sex, weight, body mass index, insulin resistance, steatosis, and levels of γ-glutamyl transpeptidase, alanine aminotransferase, liver fibrosis, and baseline HCV RNA. RVR, SVR, and relapse rates among patients with HCV genotype 3 were 79.6%, 79.2%, and 15.6%, respectively; corresponding rates among patients with HCV genotype 2 were 86.7%, 84.3%, and 10.1%. An RVR had high predictive value for an SVR in patients with HCV genotypes 2 (88.9%) and 3 (88.1%). The strongest independent predictors of relapse in patients with genotype 3 and an RVR were steatosis (odds ratio 3.0; P = .003) and HCV RNA ≥400,000 IU/mL (odds ratio 2.5; P = .04). Relapse rates in patients with steatosis were 17.4% and 20.9% for low and high baseline levels of HCV RNA, respectively; corresponding rates in those without steatosis were 2.5% and 8.8%. Steatosis was associated with significantly higher rates of relapse, irrespective of viral load, in patients infected with HCV genotype 3 who had an RVR. Further studies are needed to determine if longer treatment durations are effective in patients with an RVR and these risk factors.

Efficacy of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan

It is still not known which patients with chronic hepatitis C who failed to respond to previous pegylated interferon (Peg-IFN) plus ribavirin therapy can benefit from re-treatment. Seventy-four patients (HCV genotype 1, n = 56, genotype 2, n = 18) were re-treated with Peg-IFN plus ribavirin. On re-treatment, the sustained virologic response (SVR) rate was 41% for genotype 1 and 56% for genotype 2. With genotype 1, the factors associated with an SVR were previous treatment response and the serum hepatitis C virus (HCV) RNA level at the start of re-treatment. Patients with a ≥ 2-log decrease in HCV RNA at week 12 (partial early virologic response, p-EVR) in previous treatment had significantly higher SVR rates than those without these decreases (p < 0.001); no patient without a p-EVR in the previous treatment attained an SVR with re-treatment (0/16). All patients with <5 log(10) IU/ml of HCV RNA at the start of re-treatment attained an SVR (6/6), while only 33% (15/45) of those patients with ≥ 5 log(10) IU/ml of HCV RNA attained an SVR (p < 0.01). Among the patients with relapse in the previous treatment, those who attained an SVR on re-treatment required a longer duration of re-treatment than the duration of the previous treatment (re-treatment, 63.8 ± 13.0 weeks vs. previous treatment, 53.9 ± 13.5 weeks, p = 0.01). Re-treatment of genotype 1 patients should be limited to patients with a p-EVR in the previous treatment and a low HCV RNA level at the start of re-treatment. In re-treatment with Peg-IFN plus ribavirin, longer treatment duration can contribute to increasing the anti-viral effect.