Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications.

BACKGROUND AND AIMS: Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes. METHODS: Gene mutation analysis for BA transporter deficiencies was performed using Next Generation/Sanger sequencing, with analysis for gene deletions/duplications. RESULTS: Intrahepatic cholestasis of pregnancy was early-onset (9-32 weeks gestation) and severe (peak BA 74-370 µmol/L), with premature delivery (28+1 -370 weeks gestation) in 7/8 pregnancies, in utero passage of meconium in 4/8, but overall good perinatal outcomes, with no stillbirths. There was generally no response to ursodeoxycholic acid and variable responses to rifampicin and chelation therapies; naso-biliary drainage appeared effective in 2/2 episodes persisting post-partum in each of the two sisters. Episodic jaundice occurring spontaneously or provoked by non-specific infections, and OCS-induced cholestasis, had previously occurred in 3/5 women. Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4 mutation and a fourth case was heterozygous for another ABCB4 mutation. CONCLUSIONS: Early-onset or recurrent ICP, especially with previous spontaneous or OCS-induced episodes of cholestasis and/or familial cholestasis, may be attributable to transporter mutations, including biallelic mutations of one or more transporters. Response to standard therapies for ICP is often incomplete; BA sequestering therapy or naso-biliary drainage may be effective. Optimized management can produce good outcomes despite premature birth and evidence of fetal compromise.

Nutritional care in hospitalized patients with chronic liver disease.

AIM: To evaluate the practice of nutritional assessment and management of hospitalised patients with cirrhosis and the impact of malnutrition on their clinical outcome. METHODS: This was a retrospective cohort study on patients with liver cirrhosis consecutively admitted to the Department of Gastroenterology and Hepatology at the Royal Adelaide Hospital over 24 mo. Details were gathered related to the patients' demographics, disease severity, nutritional status and assessment, biochemistry and clinical outcomes. Nutritional status was assessed by a dietician and determined by subjective global assessment. Estimated energy and protein requirements were calculated by Simple Ratio Method. Intake was estimated from dietary history and/or food charts, and represented as a percentage of estimated daily requirements. Median duration of follow up was 14.9 (0-41.4) mo. RESULTS: Of the 231 cirrhotic patients (167 male, age: 56.3 ± 0.9 years, 9% Child-Pugh A, 42% Child-Pugh B and 49% Child-Pugh C), 131 (57%) had formal nutritional assessment during their admission and 74 (56%) were judged to have malnutrition. In-hospital caloric (15.6 ± 1.2 kcal/kg vs 23.7 ± 2.3 kcal/kg, P = 0.0003) and protein intake (0.65 ± 0.06 g/kg vs 1.01 ± 0.07 g/kg, P = 0.0003) was significantly reduced in patients with malnutrition. Of the malnourished cohort, 12 (16%) received enteral nutrition during hospitalisation and only 6 (8%) received ongoing dietetic review and assessment following discharge from hospital. The overall mortality was 51%, and was higher in patients with malnutrition compared to those without (HR = 5.29, 95%CI: 2.31-12.1; P < 0.001). CONCLUSION: Malnutrition is common in hospitalised patients with cirrhosis and is associated with higher mortality. Formal nutritional assessment, however, is inadequate. This highlights the need for meticulous nutritional evaluation and management in these patients.

An Aggravated Trajectory of Depression and Anxiety Co-morbid with Hepatitis C: A Within-groups Study of 61 Australian Outpatients.

BACKGROUND: This study aimed to explore the course of depression and anxiety in chronic hepatitis C patients. METHODS:   Data were combined from two studies: (1) Hospital Anxiety and Depression Scale (HADS) scores in 395 consecutive Australian outpatients from 2006 to 2010 formed the baseline measurement; and (2) Depression Anxiety Stress Scales (DASS) scores in a survey of a sub-sample of these patients in 2011 formed the follow-up measurement. After converting DASS to HADS scores, changes in symptom scores and rates of case-ness (≥8), and predictors of follow-up symptoms were assessed. RESULTS:   Follow-up data were available for 61 patients (70.5% male) whose age ranged from 24.5 to 74.6 years (M=45.6). The time to follow-up ranged from 20.7 to 61.9 months (M=43.8). Baseline rates of depression (32.8%) and anxiety (44.3%) increased to 62.3% and 67.2%, respectively. These findings were confirmed, independent of the conversion, by comparing baseline HADS and follow-up DASS scores with British community norms. Baseline anxiety and younger age predicted depression, while baseline anxiety, high school non-completion, and single relationship status predicted anxiety. CONCLUSION:  This study demonstrated a worsening trajectory of depression and anxiety. Further controlled and prospective research in a larger sample is required to confirm these findings.

Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection.

BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS: Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS: Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.

Acceptability of psychotherapy, pharmacotherapy, and self-directed therapies in Australians living with chronic hepatitis C.

Despite the prevalence of psychiatric co-morbidity in chronic hepatitis C (CHC), treatment is under-researched. Patient preferences are likely to affect treatment uptake, adherence, and success. Thus, the acceptability of psychological supports was explored. A postal survey of Australian CHC outpatients of the Royal Adelaide Hospital and online survey of Australians living with CHC was conducted, assessing demographic and disease-related variables, psychosocial characteristics, past experience with psychological support, and psychological support acceptability. The final sample of 156 patients (58 % male) had significantly worse depression, anxiety, stress, and social support than norms. The most acceptable support type was individual psychotherapy (83 %), followed by bibliotherapy (61 %), pharmacotherapy (56 %), online therapy (45 %), and group psychotherapy (37 %). The most prominent predictor of support acceptability was satisfaction with past use. While individual psychotherapy acceptability was encouragingly high, potentially less costly modalities including group psychotherapy or online therapy may be hampered by low acceptability, the reasons for which need to be further explored.

Anxiety and depression in Australian chronic hepatitis C outpatients: prevalence and predictors.

OBJECTIVE: The present study aimed to assess the prevalence and predictors of anxiety and depression in Australian chronic hepatitis C (CHC) outpatients. METHOD: Hospital Anxiety and Depression Scale scores at referral and other patient data was analysed for 395 CHC outpatients attending the Royal Adelaide Hospital liver clinic from 2006 to 2010. RESULTS: Results revealed probable prevalence rates of 41% for anxiety and 27% for depression. CHC patients had rates of anxiety and depression 1.2 and 2.4 times higher than community norms, respectively. Younger patients were found to experience increased anxiety, while married patients or those in a de facto relationship experienced decreased anxiety and depression. CONCLUSION: Regular psychiatric screening, and subsequent referral for mental health treatment, where necessary, is recommended for Australian CHC patients. Younger patients or those lacking social supports may be at increased risk. Research is needed to develop and evaluate psychological interventions.

Safety of peginterferon alfa-2a plus ribavirin in a large multinational cohort of chronic hepatitis C patients.

BACKGROUND & AIMS: Peginterferon plus ribavirin has been the standard of care for chronic hepatitis C for a decade and an essential component of combination regimens for this disease. This large multinational open-label study aimed to better define the incidence of serious adverse events (SAEs) and non-serious adverse events of special interest in patients receiving peginterferon alfa-2a/ribavirin. METHODS: Patients were assigned at the investigator's discretion to 24- or 48-week treatment with peginterferon alfa-2a 180 µg/week and ribavirin 800 mg/day or 1000/1200 mg/day. All AEs, defined as SAEs and non-SAEs of special interest, were recorded during treatment and for 12 weeks thereafter. Non-SAEs of special interest included those leading to dose reduction/discontinuation, neutropenia, thrombocytopenia, anaemia, ALT elevations leading to dose modification and unknown/unexpected AEs. RESULTS: Of 1675 and 7178 patients assigned to 24 and 48 weeks of treatment, respectively, 87.6 and 68.3% completed therapy, whereas 6.4 and 10.3% prematurely stopped peginterferon alfa-2a treatment because of AEs. Among patients assigned to 24 and 48 weeks, 37.4 and 46.9%, respectively, reported any AE (SAE or non-SAE of special interest); 4.2 and 6.6% reported SAEs and 35.2 and 44.0% reported non-SAEs of special interest. Female gender, increasing age and cirrhosis were significantly associated with dose reductions of either drug. Increasing age (and female gender in the case of ribavirin) was significantly associated with treatment discontinuation. CONCLUSION: This study confirmed the safety and tolerability profile of peginterferon alfa-2a/ribavirin and identified patient subgroups at higher risk of dose reductions and discontinuations, thus allowing optimum management of AEs.

Help-seeking and coping with the psychosocial burden of chronic hepatitis C: a qualitative study of patient, hepatologist, and counsellor perspectives.

BACKGROUND: Chronic hepatitis C affects millions of people worldwide, may have significant physical consequences, and patients are also at increased risk of psychiatric morbidity. However, it is currently unknown how patients cope with, and seek help for the psychosocial issues which contribute to this psychiatric morbidity. OBJECTIVES: This study aimed to qualitatively explore the biopsychosocial burden of chronic hepatitis C, patients' subsequent coping and help-seeking, and the patient-health professional relationship from the different perspectives of patients, hepatologists, and counsellors. METHODS: Thirteen patients, five hepatologists, and two hepatitis C specific counsellors from South Australia participated in semi-structured interviews, which were audio-recorded, transcribed verbatim, and analysed thematically. RESULTS: All groups perceived chronic hepatitis C as a severe disease involving inextricably intertwined biological, psychological, and social impacts. Negative factors included the impact of diagnosis, stigmatisation, and often unwarranted fears regarding transmission and disease progression. The key positive influences reported across the groups involved information provision and access to informal and formal support. However, a number of barriers were noted to accessing this support, particularly stigmatisation. All respondents highlighted the importance of the patient-health professional relationship. This relationship was perceived to be enhanced by empathetic, compassionate professionals who provided comprehensive information in a sensitive and timely manner. Key negative influences on this relationship included discrimination or inappropriate treatment from mainstream health professionals, time constraints of doctors, patient non-attendance, and discordant views regarding treatment decisions. CONCLUSIONS: Reducing the psychosocial impact of chronic hepatitis C requires targeted information provision for patients, the general public, and mainstream health services. This may increase patient education, reduce the extent and impact of stigmatisation, remove barriers to help-seeking, and improve the patient-health professional relationship.

Efficacy and tolerability of pegylated interferon-α-2a in chronic hepatitis B: a multicenter clinical experience.

BACKGROUND AND AIM: Pegylated interferon-α (PEG-IFN) provides potential advantages over nucleos(t)ide analogues in the treatment of chronic hepatitis B (CHB) given its finite course, durability and lack of drug resistance. Much of the evidence is derived from controlled studies and it is unclear whether these results can be replicated in an everyday, non-controlled setting. The aim of this study was to examine the efficacy and tolerability of PEG-IFN-α2A in CHB patients in a clinical setting. METHODS: Chronic hepatitis B patients treated with PEG-IFN-α2A (180µg/week, 48 weeks) at five tertiary hospitals were retrospectively identified. Baseline demographic and clinical data, on-treatment virological and serological responses and adverse events (AE) were recorded. Treatment outcomes were defined as alanine aminotransferase (ALT) normalization, hepatitis B virus DNA <351 IU/mL and hepatitis B e antigen (HBeAg) seroconversion. RESULTS: Sixty three HBeAg positive patients were identified (65% male, 80% born in Asia, 84% with viral loads > 6log IU/mL, 9.5% advanced fibrosis). Six months after therapy 46% achieved normalization of ALT, 16% had viral loads < 351 IU/mL and 32% achieved HBeAg seroconversion. 29 HBeAg negative patients were treated (75% male, 86% born in Asia, 48% had viral loads > 6log IU/mL, 24% advanced fibrosis). Six months post-treatment, 55% and 36% maintained a normalized ALT and HBV DNA < 351 IU/mL, respectively. Optimal viral suppression was maintained in 50-75% of patients over 2 years of follow up. 6.5% of all patients discontinued therapy due to AEs. CONCLUSION: In everyday clinical practice PEG-IFN therapy in CHB is well tolerated and can achieve a similar efficacy to that seen in large controlled trials.

High prevalence of late relapse and reinfection in prisoners treated for chronic hepatitis C.

BACKGROUND AND AIM: Prisoners have a high prevalence of injection drug use (IDU) and chronic hepatitis C (CHC) infection. Treatment of CHC in these patients is effective; however, their long-term outcomes following treatment are unknown. We determined the durability of a sustained virological response (SVR) in prisoners treated for CHC. METHODS: Patients were treated as part of routine clinical practice with interferon (IFN) and ribavirin. A retrospective review of medical records and a computerized pathology system was performed for clinical and laboratory information. RESULTS: Seventy-four prisoners (70 males, mean age 34 years, IDU in 55%) were evaluable for a SVR over a 12-year period to December 2008; the mean follow-up period was 1243 days. Genotype 1, 2, 3, and 6 infection was present in 18, three, 38 and three patients, respectively; the genotype was unknown in 12. Three out of 52 biopsied had cirrhosis. Standard IFN was administered to 25 (34%; 11 with ribavirin), and 49 received pegylated IFN and ribavirin; one did not complete treatment, and two had breakthrough relapses. The end-of-treatment response was achieved in 57 and SVR in 53; 14 were non-responders. Five male patients, four with unknown genotypes and treated with standard IFN alone, relapsed late (following SVR, 9%). Five patients, all treated with pegylated IFN and ribavirin, were reinfected (one prior to and four following SVR). CONCLUSIONS: Prisoners are often successfully treated for CHC. However, this retrospective study indicates that there is a high (17%) prevalence of late recurrence of viremia that is likely a reflection of reinfection due to ongoing risk-taking behavior.

Poor outcome after liver transplantation for transthyretin amyloid neuropathy in a family with an Ala36Pro transthyretin mutation: case report.

Transthyretin amyloid polyneuropathy, caused by mutations in the transthyretin gene, is a progressive condition for which liver transplantation is an established treatment. Favorable outcomes have been described in patients with the most common transthyretin mutation, Val30Met, but outcomes have been variable in patients with other mutations. We describe the cases of 2 siblings with transthyretin amyloid polyneuropathy secondary to an infrequently reported transthyretin mutation (Ala36Pro) who underwent liver transplantation with poor outcomes.

Donor mannose-binding lectin deficiency increases the likelihood of clinically significant infection after liver transplantation.

BACKGROUND: Mannose-binding lectin (MBL) is an important mediator of innate immunity and is synthesized primarily by the liver. Low MBL levels are common, are due primarily to polymorphisms in the gene encoding MBL (MBL2), and are associated with an increased risk of infection, particularly when immunity is compromised. We report a large, retrospective study that examined the association between MBL status and clinically significant infection following orthotopic liver transplantation. METHODS: One hundred two donor-recipient orthotopic liver transplantation pairs were studied. Five polymorphisms in the promoter and coding regions of MBL2 were examined. MBL levels were measured, using the mannan-binding and C4-deposition assays, in serum samples obtained before and after transplantation. Associations between MBL status, as assessed by serum MBL levels and MBL2 genotype, and time to first clinically significant infection (CSI) after transplantation were examined in survival analysis with consideration of competing risks. RESULTS: The median duration of follow-up after orthotopic liver transplantation was 4 years. Thirty-six percent of recipients developed CSI after transplantation. The presence of MBL2 coding mutations in the donor was significantly associated with CSI in the recipient; the cumulative incidence function of infection was 55% in recipients of deficient livers, compared with 32% for recipients of wild-type livers (P = .002). Infection was not associated with recipient MBL2 genotype. Low MBL levels after orthotopic liver transplantation levels (mannan-binding <1 microg/mL or C4 deposition <0.2 C4 U/microL) were also associated with CSI (cumulative incidence function, 52% vs. 20%, P = .003; and cumulative incidence function, 54% vs. 24%, P = .007, respectively). In multivariate analysis, mutation in the MBL2 coding region of the donor (hazard ratio, 2.8; P = .005) and the use of cytomegalovirus prophylaxis (hazard ratio, 2.6; P = .005) were independently associated with CSI. CONCLUSIONS: Recipients of MBL-deficient livers have almost a 3-fold greater likelihood of developing CSI and may benefit from MBL replacement.

Differential expression of the CXCR3 ligands in chronic hepatitis C virus (HCV) infection and their modulation by HCV in vitro.

To investigate chemokine expression networks in chronic hepatitis C virus (HCV) infection, we used microarray analysis to determine chemokine expression in human infection and in chimpanzees experimentally infected with HCV. The CXCR3 chemokine family was highly expressed in both human and chimpanzee infection. CXCL10 was the only CXCR3 chemokine elevated in the serum, suggesting that it may neutralize any CXCR3 chemokine gradient established between the periphery and liver by CXCL11 and CXCL9. Thus, CXCR3 chemokines may not be responsible for recruitment of T lymphocytes but may play a role in positioning these cells within the liver. The importance of the CXCR3 chemokines, in particular CXCL11, was highlighted by replicating HCV (JFH-1) to selectively upregulate its expression in response to gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). This selective upregulation was confirmed at the transcriptional level by using the CXCL11 promoter driving the luciferase reporter gene. This synergistic increase in expression was not a result of HCV protein expression but the nonspecific innate response to double-stranded RNA (dsRNA), as both in vitro-transcribed HCV RNA and the dsRNA analogue poly(I:C) increased CXCL11 expression and promoter activity. Furthermore, we show that CXCL11 is an IRF3 (interferon regulatory factor 3) response gene whose expression is selectively enhanced by IFN-gamma and TNF-alpha. In conclusion, the CXCR3 chemokines are the most significantly expressed chemokines in chronic hepatitis C and most likely play a role in positioning T cells in the liver. Furthermore, HCV can selectively increase CXCL11 expression in response to IFN-gamma and TNF-alpha stimulation that may play a role in the pathogenesis of HCV-related liver disease.

Psychological problems in gastroenterology outpatients: A South Australian experience. Psychological co-morbidity in IBD, IBS and hepatitis C.

BACKGROUND: In independent studies, IBD, IBS and HCV have each been associated with a substantially increased risk of psychological problems such as depression and anxiety and impairment of quality of life compared to the general healthy population. However, the relative psychological burden for each of these diagnoses is unknown as it has never been compared contemporaneously at one institution. Current local data are therefore needed to enable an evidence-based allocation of limited clinical psychological resources. METHODS: Overall, 139 outpatients (64 IBD, 41 HCV, and 34 IBS) were enrolled in this cross-sectional study. The HADS, SCL90, SF-12 and appropriate disease-specific activity measures were administered. Differences between groups were assesed with ANOVA, the Chi-Square test and the independent samples t-test (two-tailed). RESULTS: Each of the three groups had significantly lower quality of life than the general population (p < 0.05). Overall, a total of 58 (42%) participants met HADS screening criteria for anxiety and 26 (19%) participants for depression. The HCV group had a significantly higher prevalence of depression than either of the other groups (HCV = 34%, IBS = 15% and IBD = 11%, p = 0.009). In the SCL90, the three disease groups differed on 7 out of 12 subscales. On each of these subscales, the HCV group were most severely affected and differed most from the general population. CONCLUSION: Patients with these common chronic gastrointestinal diseases have significant impairment of quality of life. Anxiety is a greater problem than depression, although patients with HCV in particular, should be regularly monitored and treated for co-morbid depression. Evaluation of specific psychological interventions targeting anxiety is warranted.

Liver transplantation: a small-volume unit experience.

BACKGROUND: Results of liver transplantation have improved significantly over the last three decades. Hospital volume has been cited as an important outcome factor. The South Australian (SA) programme commenced in 1992 as the fourth centre in Australia. METHODS: Patient and graft survival curves were computed from the Australian and New Zealand (ANZ) Liver Transplant Registry. SA results were compared with the rest of ANZ. All recipients of a cadaveric liver from the start of the SA programme in 1992 until the 100th case in 2005 were included and compared with recipients from ANZ in the same period. RESULTS: In SA, 100 recipients received 104 grafts (average 8.0/year). In the same period 1438 recipients received 1530 grafts in ANZ (mean 23.4/year per unit). The median follow up was 6.2 years. Patient and graft survival curves were similar (P = 0.51, log-rank test.) Survival rates at 1, 5 and 10 years were 0.93, 0.83, 0.61 and 0.88, 0.80, 0.72 for SA and ANZ, respectively (P = NS). There was trend towards a higher mortality rate of recurrent hepatitis C in SA patients when compared with the rest of ANZ (4.0 vs 1.3% respectively, P = 0.06). Recipient variables, such as age and primary liver disease did not differ between SA and ANZ. For the SA patients the biliary anastomotic stricture rate was 20%, primary non-function rate was 2%, hepatic artery thrombosis 1% and portal vein thrombosis 1%. CONCLUSION: Good results are possible in a small-volume unit for cadaveric adult liver transplant.

Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3.

BACKGROUND: Patients infected with hepatitis C virus (HCV) genotype 2 or 3 have sustained virologic response rates of approximately 80% after receiving treatment with peginterferon and ribavirin for 24 weeks. We conducted a large, randomized, multinational, noninferiority trial to determine whether similar efficacy could be achieved with only 16 weeks of treatment with peginterferon alfa-2a and ribavirin. METHODS: We randomly assigned 1469 patients with HCV genotype 2 or 3 to receive 180 mug of peginterferon alfa-2a weekly, plus 800 mg of ribavirin daily, for either 16 or 24 weeks. A sustained virologic response was defined as an undetectable serum HCV RNA level (<50 IU per milliliter) 24 weeks after the end of treatment. RESULTS: The study failed to demonstrate that the 16-week regimen was noninferior to the 24-week regimen. The sustained virologic response rate was significantly lower in patients treated for 16 weeks than in patients treated for 24 weeks (62% vs. 70%; odds ratio for 16 weeks vs. 24 weeks, 0.67; 95% confidence interval, 0.54 to 0.84; P<0.001). In addition, the rate of relapse (a detectable HCV RNA level during follow-up in patients who had undetectable HCV RNA at the end of treatment) was significantly greater in the 16-week group (31%, vs. 18% in the 24-week group; P<0.001). The sustained virologic response rates in patients with a pretreatment serum HCV RNA level of 400,000 IU per milliliter or less was 82% with the 16-week regimen and 81% with the 24-week regimen. Among patients with a rapid virologic response (an undetectable HCV RNA level by week 4), sustained virologic response rates were 79% in the 16-week group and 85% in the 24-week group (P=0.02). CONCLUSIONS: Treatment with peginterferon and ribavirin for 16 weeks in patients infected with HCV genotype 2 or 3 results in a lower overall sustained virologic response rate than treatment with the standard 24-week regimen. (ClinicalTrials.gov number, NCT00077636 [ClinicalTrials.gov].).