Infections in cirrhosis.

Cirrhosis is an immune dysfunction state, and as such, patients with cirrhosis are susceptible to bacterial, fungal, and viral infections. Because of infection, these patients have a propensity to develop multiorgan failure, which is associated with high mortality. Bacterial infections are the most prevalent type of infection in patients with cirrhosis, with the prevalence of bacterial infections in patients admitted for an acute decompensating event ranging from 24% to 29%. Together with invasive fungal infections, bacterial infections are the most severe. Multidrug-resistant organisms have been evolving at a rapid and alarming rate around the world, which presents enormous challenges. The development of effective measures for the prevention, early detection, and treatment of infections in patients with cirrhosis is challenging, given the rising incidence of infections in this patient population.

Poor immune response to coronavirus disease vaccines in decompensated cirrhosis patients and liver transplant recipients.

BACKGROUND AND AIMS: Recent studies have reported poor humoral immune response to mRNA vaccines in patients with chronic liver disease (CLD). However, the immunogenicity of ChAdOx1 (vector-based) and BBV152 (inactivated virus) vaccines in patients with CLD and liver transplant recipients (LTRs) is unknown. Therefore, we aimed to assess the immunogenicity of ChAdOx1 and BBV152 vaccines in patients with CLD (including cirrhosis patients) and LTRs. METHODS: In this single-center prospective study, consecutive completely vaccinated (ChAdOx1 or BBV152) non-cirrhosis CLD patients, those with cirrhosis, and LTRs were compared with matched healthy controls for anti-spike antibody and cellular response. RESULTS: Sixty healthy individuals, 50 NCCLD patients, 63 compensated and 50 decompensated cirrhosis, and 17 LTRs were included. The proportion of non-responders was similar among the healthy control (8 %), non-cirrhosis CLD (16 %), and compensated cirrhosis groups (17.5 %;p = 0.3). However, a higher proportion of patients with decompensated cirrhosis (34 %) and LTRs (59 %) were non-responders than the healthy controls (p = 0.001). Cluster of differentiation (CD) 4-effector cells were lower in patients with non-cirrhosis CLD and compensated cirrhosis. CD4-naïve, CD4-effector, B, and B-memory cells were lower in the decompensated cirrhosis group. Although the central memory cells were higher in the decompensated cirrhosis group, they could not differentiate into effector cells. CD4- and CD8-naïve cells were higher in the marrow in the LTRs, while the CD4-effector memory cells and CD4- and CD8-effector cells were lower in the LTRs. Furthermore, B cells were more deficient in the LTRs, suggesting poor antibody response. CONCLUSION: Patients with decompensated cirrhosis and LTRs demonstrated suboptimal humoral and cellular immune responses against recombinant and inactivated COVID-19 vaccines.

Immunogenicity, Safety, and Tolerability of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Immunocompetent Adults Aged 18-49 Years With or Without Risk Factors for Pneumococcal Disease: A Randomized Phase 3 Trial (PNEU-DAY).

BACKGROUND: Adults with certain medical and behavioral factors are at increased risk for pneumococcal disease (PD). Sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults in some countries. METHODS: This phase 3 trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults aged 18-49 years with or without predefined risk factors for PD (NCT03547167). Overall, 1515 participants were randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. RESULTS: Most common solicited adverse events (AEs) following administration of V114 or PCV13 as well as PPSV23 were injection-site pain and fatigue. The proportion of participants with AEs was comparable in both groups. V114 and PCV13 were immunogenic based on opsonophagocytic activity (OPA) geometric mean titers (GMTs) 30 days postvaccination for all serotypes contained in each respective vaccine. OPA GMTs to the 2 unique serotypes in V114 were robust in the V114 group. PPSV23 was immunogenic for all 15 serotypes contained in V114 in both vaccination groups, including 22F and 33F. CONCLUSIONS: V114 administered alone or sequentially with PPSV23 is well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, in immunocompetent adults aged 18-49 years with or without certain medical or behavioral risk factors for PD. CLINICAL TRIALS REGISTRATION: NCT03547167 and EudraCT 2017-004915-38.

A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study.

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

Patient-reported outcomes 12 months after hepatitis C treatment with direct-acting antivirals: Results from the PROP UP study.

BACKGROUND & AIMS: The long-term impact of hepatitis C virus (HCV) therapy with all-oral direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) has not been well-described. We characterized changes in PROs from pre-treatment to 12 months post-treatment in a real-world cohort. METHODS: PROP UP was a multi-centre observational cohort study of 1601 patients treated with DAAs at 11 US gastroenterology/hepatology practices from 2015 to 2017. PROs were evaluated pre-treatment (T1) and 12 months post-treatment (T5). A minimally important change (MIC) threshold was prespecified as >5% change in PRO scores from T1 to T5. Multivariable analyses identified predictors of change. RESULTS: Three-quarters of patients were 55 or older; 45% were female, 60% were white, 33% were black, nearly half had cirrhosis. The most commonly-prescribed DAA regimens were sofosbuvir-based (83%) and grazoprevir/elbasvir (11%). Study retention was >95%. On average, small improvements were observed at 3 months post-treatment in all PROs and sustained at 12 months post-treatment among patients with sustained virologic response (SVR). Clinically meaningful improvements were achieved in fatigue (mean change score: -3.7 [-4.2, -3.1]), sleep (mean change score: -3.1 [-3.7, -2.5]), abdominal pain (mean change score: -2.6 [-3.3, -1.9]) and functional well-being (mean change score: -7.0 [-6.0, -8.0]). Symptom improvements were generally not sustained with no SVR (n = 52). Patients with cirrhosis and MELD ≥12 had the greatest improvements in functional well-being (-12.9 [-17.6, -8.1]). CONCLUSIONS: The improvements in patient-reported outcomes reported by patients who achieved SVR following HCV DAA therapy were durable at 12 months post-treatment.

Increased Risk of ACLF and Inpatient Mortality in Hospitalized Patients with Cirrhosis and Hepatic Hydrothorax.

BACKGROUND: Hepatic hydrothorax (HH) remains a difficult-to-treat complication of cirrhosis. AIM: To define the mortality, length of stay (LOS), and risk of ACLF in patients admitted with HH. METHODS: We utilized the North American Consortium for the Study of End-stage Liver Disease, a prospective cohort of 2868 non-electively hospitalized patients with cirrhosis from 14 tertiary care hepatology centers in North America. A total of 121 patients who required an inpatient thoracentesis (HH group) were compared to 736 patients with refractory ascites without HH, and to 1639 patients without these complications (Other). Patients with a TIPS before or during admission were excluded. RESULTS: There were no differences between the groups in age, gender, or liver disease etiology. Admission MELD (20.5, 21.6 vs. 18.7; p < 0.0001) was lower in HH than RA patients but lowest in other patients, respectively. In hospital, HH patients' rate of second infections and ICU transfer were the highest, and their LOS was the longest of all groups. Despite a similar mean discharge MELD compared to RA patients, the 90-day transplant rate was lower. Multivariable modeling showed patients with HH had an increased risk of ACLF (HR = 2.37 vs. RA, HR = 2.56 vs. Other; p = 0.01) even when controlling for MELD score, AKI, second infection, and history of prior 6-month hospitalization. Multivariable modeling also showed that HH increased the risk of inpatient mortality (HR = 2.22 vs. RA alone, HR = 2.31 vs. Other; p = 0.04). CONCLUSIONS: HH that required a therapeutic thoracentesis more than doubled the risk of ACLF and inpatient mortality among hospitalized patients with cirrhosis.

Correction: Silymarin in non-cirrhotics with non-alcoholic steatohepatitis: A randomized, double-blind, placebo controlled trial.

[This corrects the article DOI: 10.1371/journal.pone.0221683.].

Patient-reported symptoms during and after direct-acting antiviral therapies for chronic hepatitis C: The PROP UP study.

BACKGROUND & AIMS: A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs. METHODS: PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment. RESULTS: Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements. CONCLUSIONS: In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities. LAY SUMMARY: Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.

T1ρ MRI of healthy and fibrotic human livers at 1.5 T.

BACKGROUND: Liver fibrosis is a public health problem worldwide. There is a need of noninvasive imaging based methods for better diagnosis of this disease. In the current study, we aim to evaluate the potential of T1ρ MRI technique in detecting and characterizing different grades of liver fibrosis in vivo in humans. METHODS: Healthy subjects and patients with liver fibrosis were prospectively recruited for T1ρ MRI of liver on a 1.5 T MR scanner. Single slice T1ρ weighted images were acquired at different spin lock duration (0, 10, 20 and 30 ms) with spin lock amplitude of 500 Hz in a single breath-hold. Additionally, liver's T1ρ images were acquired from five healthy subjects on the same day (n = 2) and different day (n = 2) sessions for test-retest study. Liver biopsy samples from patients were obtained and used to calculate the METAVIR score to define the stage of fibrosis and inflammation grade. T1ρ maps were generated followed by computation of mean and standard deviation (SD) values. Coefficient of variation (COV) of T1ρ values between two MRI scans was computed to determine reproducibility in liver. T test was used to compare T1ρ values between healthy and fibrotic liver. Pearson correlation was performed between stages of liver fibrosis and T1ρ values. RESULTS: The mean (SD) T1ρ value among subject with healthy liver was 51.04 (3.06) ms. The COV of T1ρ values between two repetitions in the same day session was 0.83 ± 0.8% and in different day session was 5.4 ± 2.7%. T1ρ values in fibrotic liver were significantly higher compared to those of healthy liver (p < 0.05). A statically significant correlation between stages of fibrosis and T1ρ values was observed (r = 0.99, p < 0.05). Inflammation score for one patient was 2 and for remaining patients it was 1. CONCLUSIONS: Proposed T1ρ pulse sequence design and protocol enabled acquisition of a single slice T1ρ weighted images in a single breath-hold and hence mitigated breathing motion related artifacts. Preliminary results have shown the sensitivity of T1ρ values to changes induced by liver fibrosis, and may potentially be used as a clinical biomarker to delineate the stages of liver fibrosis. Further, studies on a large number of subjects are required to validate the observations of the current study. Nevertheless, T1ρ imaging can be easily setup on a clinical scanner to monitor the progression of liver fibrosis and to the evaluate efficacy of anti-fibrotic drugs.

ACG clinical guideline: the diagnosis and management of focal liver lesions.

Focal liver lesions (FLL) have been a common reason for consultation faced by gastroenterologists and hepatologists. The increasing and widespread use of imaging studies has led to an increase in detection of incidental FLL. It is important to consider not only malignant liver lesions, but also benign solid and cystic liver lesions such as hemangioma, focal nodular hyperplasia, hepatocellular adenoma, and hepatic cysts, in the differential diagnosis. In this ACG practice guideline, the authors provide an evidence-based approach to the diagnosis and management of FLL.

Liver transplantation and cirrhotomimetic hepatocellular carcinoma: classification and outcomes.

Liver transplantation has become the standard-of-care treatment for hepatocellular carcinoma (HCC) that falls within certain size and numerical criteria for patients with cirrhosis. Cirrhotomimetic (CMM) HCC is an uncommon growth pattern that infiltrates cirrhotic parenchyma, can become extensive in size, and can evade detection via radiological studies. Liver transplant outcomes for this type of HCC are not well reported but generally are considered to be poor. We wished to better describe this variant of HCC in explanted livers, derive a classification system for this tumor type, and assess the outcomes of liver transplantation for this tumor variant. All patients undergoing transplantation for HCC at a single center in 1996-2009 (358 patients) were retrospectively analyzed, and 26 patients exhibiting a CMM growth pattern were identified. We developed a classification system for this tumor growth pattern variant and determined patient and tumor-specific outcomes. We derived a classification schema for CMM HCC based on the tumor extent and cellular histopathology, with a clear cell pathology being associated with favorable outcomes. We noted 100.0% 3-year recurrence-free survival and 58.3% 5-year recurrence-free survival after transplantation for those patients with tumors confined to 1 lobe that had a clear cell pathology and 16.2% 3- and 5-year recurrence-free survival for those patients who did not meet these criteria. In conclusion, CMM HCC features were noted in 7% of the patients undergoing transplantation for HCC at our center, with favorable outcomes observed for inpatients with clear cell histology and growth involving less than or equal to 50% of the liver.

Transjugular intrahepatic portosystemic shunts in liver transplant recipients.

The insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive procedure used to relieve the signs and symptoms of portal hypertension in patients with liver disease. The most common indications for placement are refractory ascites and variceal hemorrhage. In properly selected candidates, TIPS placement can serve as a bridge to liver transplantation. Expertise in TIPS placement after transplantation has significantly increased, which has allowed the procedure to become a viable option for retransplant candidates suffering the consequences of recurrent portal hypertension due to portal vein thrombosis, recurrent liver disease, or hepatic venous outflow obstruction (HVOO). However, TIPSs in liver transplant recipients are associated with a lower clinical response rate and a higher rate of complications in comparison with patients with native liver disease, and they are, therefore, generally reserved for patients with a Model for End-Stage Liver Disease (MELD) score ≤ 15 and ≤ 12 in patients with HCV. The role of TIPS placement in nonliver transplant recipients has been well studied in large trials, and it translates well into clinical applicability to candidates for orthotopic liver transplantation (OLT). However, the experience with OLT recipients is heterogeneous and restricted to small series. Thus, we focus here on reviewing the current literature and discussing the proper use of TIPSs in liver transplant recipients.

Impact of oral silymarin on virus- and non-virus-specific T-cell responses in chronic hepatitis C infection.

Silymarin displays anti-inflammatory effects on T lymphocytes in vitro. The immunomodulatory properties of oral silymarin in vivo in humans with chronic hepatitis C have not previously been characterized. We hypothesized that silymarin would suppress T-cell proliferation and pro-inflammatory cytokine production of virus- and non-virus-specific T cells while increasing anti-inflammatory IL-10 production in vivo. Patients from one site of the SyNCH-HCV double-masked, placebo-controlled study of oral silymarin in prior interferon nonresponders with chronic hepatitis C provided blood samples at baseline and treatment week 20. Mononuclear cells were stimulated with recombinant HCV proteins and controls in (3) H-thymidine proliferation assays, IFNγ ELISPOT and IL-10 ELISPOT. The frequency of CD4(+) CD25(hi) and CD4(+) foxp3(+) regulatory T cells, serum cytokine levels, serum IP-10 and lymphocyte interferon-stimulated gene expression were also quantified at baseline and week 20. Thirty-two patients were recruited (10; placebo, 11; 420 mg three times a day, 11; 700 mg three times a day). Serum ALT and HCV RNA titres did not change in any group. HCV-specific CD4(+) T-cell proliferation and the frequency of IFNγ- and IL-10-producing T cells were not significantly changed in silymarin-treated subjects. However, C. albicans-induced T-cell IFNγ and phytohaemagglutinin-induced T-cell proliferation were suppressed by silymarin therapy. A trend towards augmentation of interferon-induced ISG15 expression was present in the high-dose silymarin group. While no effect on HCV-specific T cells was identified, these data confirm that high-dose oral silymarin exerts modest nonspecific immunomodulatory effects in vivo. The impact of this anti-inflammatory effect on long-term liver health in chronic hepatitis C merits future clinical investigation.

Adherence to assigned dosing regimen and sustained virological response among chronic hepatitis C genotype 1 patients treated with boceprevir plus peginterferon alfa-2b/ribavirin.

BACKGROUND: Adherence to therapeutic regimens affects the efficacy of peginterferon alfa (P) and ribavirin (R) therapy in patients with chronic hepatitis C virus genotype 1. AIM: To determine if medication adherence impacts efficacy [sustained virological response (SVR)] with triple therapy that includes boceprevir (BOC) plus P/R. METHODS: Adherence was determined in two Phase 3 clinical studies with BOC: SPRINT-2 (previously untreated patients) and RESPOND-2 (patients who failed previous therapy with P/R). Adherence to the assigned duration of the dosing regimen and adherence to the three times a day (t.d.s.) dosing interval of 7-9 h for BOC were assessed by the recording of data from patients' dosing diaries and by the amount of study drug dispensed and returned. RESULTS: Most patients (63-71%) adhered to ≥80% of their assigned treatment duration and achieved SVR rates of 86-90%. In contrast, patients who adhered to <80% of their assigned treatment duration achieved SVR rates of 8-32% (P < 0.0001), particularly low in patients who failed previous therapy (SVR = 8-15%). Different rates of adherence (<60% to >80%) to the t.d.s. dosing interval (7-9 h) with BOC did not influence the SVR rates (SVR = 60-83%) with the exception of patients who failed previous treatment and adhered to <60% of the t.d.s. dosing interval with BOC (SVR = 48-50%; P = 0.005). CONCLUSIONS: The achievement of an SVR is more dependent on adherence to the assigned duration of treatment than adherence to the t.d.s. dosing interval with boceprevir. Adherence to >60% of t.d.s. dosing with boceprevir is important in patients who failed previous therapy.

Chronic kidney disease after liver transplantation in human immunodeficiency virus/hepatitis C virus-coinfected recipients versus human immunodeficiency virus-infected recipients without hepatitis C virus: results from the National Institutes of Health multi-site study.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are both associated with chronic kidney disease (CKD), a major complication after orthotopic liver transplantation (OLT). The aim of this study was to assess predictors of post-OLT CKD in HIV/HCV-coinfected recipients versus HIV-infected recipients without HCV (HIV/non-HCV recipients). Data from a National Institutes of Health study of 116 OLT recipients (35 HIV/non-HCV recipients and 81 HIV/HCV-coinfected recipients) from 2003 to 2010 (Solid Organ Transplantation in HIV: Multi-Site Study) were analyzed for the pretransplant CKD prevalence [estimated glomerular filtration rate (eGFR) < 60 mL/minute for ≥3 months] and the incidence of CKD up to 3 years posttransplant. Proportional hazards models were performed to assess predictors of posttransplant CKD. A contemporaneous cohort of HCV-monoinfected transplant recipients from the Scientific Registry of Transplant Recipients database was also analyzed. The median age at transplant was 48 years, the median serum creatinine level was 1.1 mg/dL, and the median eGFR was 77 mL/minute. Thirty-four patients were suspected to have pretransplant CKD; 20 of these patients (59%) had posttransplant CKD. Among the 82 patients without pretransplant CKD (26 HIV/non-HCV patients and 56 HIV/HCV-coinfected patients), the incidence of stage 3 CKD 3 years after OLT was 62% (55% of HIV/non-HCV patients and 65% of HIV/HCV-coinfected patients), and the incidence of stage 4/5 CKD was 8% (0% of HIV/non-HCV patients and 12% of HIV/HCV-coinfected patients). In a multivariate analysis, older age [[hazard ratio (HR) = 1.05 per year, P = 0.03] and the CD4 count (HR = 0.90 per 50 cells/µL, P = 0.01) were significant predictors of CKD. HCV coinfection was significantly associated with stage 4/5 CKD (HR = 10.8, P = 0.03) after adjustments for age. The cumulative incidence of stage 4/5 CKD was significantly higher for HIV/HCV-coinfected patients versus HIV/non-HCV transplant recipients and HCV-monoinfected transplant recipients (P = 0.001). In conclusion, CKD occurs frequently in HIV-infected transplant recipients. Predictors of posttransplant CKD include older age and a lower posttransplant CD4 count. HCV coinfection is associated with a higher incidence of stage 4/5 CKD.

Predicting early and sustained virological responses in prior nonresponders to pegylated interferon alpha-2b plus ribavirin retreated with peginterferon alpha-2a plus ribavirin and the benefit-risk ratio of retreatment.

GOALS: To evaluate the predictive value of complete early virological response (cEVR) on sustained virological response (SVR) following retreatment with peginterferon alpha-2a (40 kDa) plus ribavirin in previous nonresponders to peginterferon alpha-2b (12 kDa). BACKGROUND: In the randomized multinational retreatment with Pegasys in patients not responding to PegIntron therapy study, a 72-week regimen of peginterferon alpha-2a (40 kDa) plus ribavirin improved SVR rates over a standard 48-week regimen in previous nonresponders to peginterferon alpha-2b (12 kDa). cEVR, defined as hepatitis C virus RNA <50 IU/mL at treatment week 12, was an important predictor of SVR. STUDY: We conducted an exploratory analysis of the retreatment with Pegasys in patients not responding to PegIntron therapy study data to better define the predictive value of cEVR for SVR in this patient population. RESULTS: In total, 157 of the 942 patients achieved a cEVR (16.7%). SVR rates were higher with 72 versus 48 weeks of retreatment in patients with a cEVR (57% vs. 35%), whereas SVR rates were <5% in patients without cEVR in both groups. The relative adverse event (AE) burden was lower with 72 weeks of treatment (8.1 vs. 10.1 AEs/y of treatment) as was the estimated number of AEs per SVR achieved (55 vs. 100). Cumulative treatment duration required to achieve 1 SVR was lower with 72 weeks of treatment (6.7 vs. 10.0 y/SVR) and lower still assuming that treatment was stopped at week 12 for non-cEVR patients (3.6 vs. 7.1 y/SVR). CONCLUSIONS: cEVR is a reliable predictor of SVR in patients retreated with peginterferon alpha-2a (40 kDa) plus ribavirin. Seventy-two-week retreatment has a more favorable benefit-risk ratio than 48 weeks, especially when cEVR is used to identify patients most likely to be cured.