Real-world value of direct-acting antivirals for hepatitis C at Kaiser Permanente Southern California.

OBJECTIVES: Direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) lead to cure in more than 95% of recipients; however, payers may limit access to these lifesaving drugs due to high initial cost. Here, the cost-effectiveness of treating HCV with DAAs vs no treatment over a lifetime horizon is evaluated from the perspective of Kaiser Permanente Southern California (KPSC). STUDY DESIGN: A hybrid decision-tree Markov model. METHODS: The model simulated the health and economic outcomes for a real cohort of patients with HCV treated with either ledipasvir-sofosbuvir or sofosbuvir-velpatasvir between November 1, 2014, and October 31, 2019, at KPSC. Patients entered the model at different stages of liver disease and received either active treatment with DAAs or no treatment. Patients who did not achieve sustained virological response experienced disease progression; those who achieved sustained virological response experienced either significantly slower or no disease progression depending on the stage of fibrosis at model start. Demographics, treatment experience, genotype, baseline fibrosis stage, treatment rates, and treatment efficacy were sourced from KPSC real-world data. Costs and utilities were sourced from published literature. RESULTS: A total of 7255 patients with a mean age of 59 years were treated during the study period. Over a lifetime horizon, DAAs resulted in significant reduction in advanced liver disease events and a total cost savings of $1 billion compared with no treatment based on a hybrid decision-tree Markov state-transition model. Cost savings were achieved after only 3 years. DAA intervention dominated no treatment on a per-patient and cohort basis. CONCLUSIONS: DAA treatment at KPSC is predicted to significantly reduce HCV-related morbidity and mortality, providing an anticipated return on investment in drug costs after 3 years of treatment.

The Natural History of NAFLD, a Community-Based Study at a Large Health Care Delivery System in the United States.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.

Retrospective analysis of a dedicated care pathway for nonalcoholic fatty liver disease in an integrated US healthcare system demonstrates support of weight management and improved ALT.

BACKGROUND: A care pathway for nonalcoholic fatty liver disease (NAFLD) in Kaiser Permanente San Diego, California was instituted in August 2017 to improve efficiency of disease staging and promote lifestyle modification. METHODS: The NAFLD Care Pathway includes: (1) patient education (2) vibration controlled transient elastography (VCTE) examination (3) hepatology consultation for VCTE ≥ 8 kPa and (4) referral to weight management (WM). Patients referred to the pathway during the first 6 months of its implementation were studied for adherence to its components and impact on weight change and ALT values in the 12 months following referral. Retrospective assessment of WM participation, change in weight, and change in ALT were evaluated in the 12-months following referral and compared to changes 12-months prior. Student's t-test or Wilcoxon signed rank test were used as appropriate (p < 0.05). RESULTS: 632 patients were included. 575 (91.0%) completed VCTE examination with mean liver stiffness 8.5 kPa (SD 9.2). 52 patients had mean liver stiffness ≥ 15 kPa. 180/632 (28.5%) attended NAFLD education. 153/632 (24.2%) were offered hepatology clinic and 136/153 (88.9%) completed at least 1 appointment. Participation in WM was 24/632 (3.8%) prior to referral and 67/632 (10.6%) after referral and increased among patients who attended NAFLD education. Mean weight change following referral was - 0.69 kg (SD 6.58 kg) among patients without WM and - 7.78 kg (SD 13.43 kg) with WM. Overall, 44.2% of participants experienced weight gain after referral, 40.8% had weight loss < 5% and 15% had weight loss ≥ 5%. Variables associated with weight loss included WM (p < 0.0001) and higher liver stiffness (p = 0.0066). Mean ALT change was - 15.2 (SD 38.5) U/L without WM and - 28.8 (SD 29.6) U/L with WM. CONCLUSIONS: A care pathway for NAFLD within a large, integrated healthcare system provides non-invasive disease staging and minimizes hepatology clinic utilization to those with more advanced disease. Referral was associated with increased enrollment in WM, weight loss, and decreased ALT. Given its impact on healthcare resources, strategies to improve NAFLD identification, staging, and promotion of lifestyle modification are imperative.

Increased cancer rates in patients with chronic hepatitis C.

AIMS: As previous reports show an association of chronic hepatitis C (HCV) with hepatocellular carcinoma (HCC) and non-liver cancers, we examine the association of HCV with liver cancer and non-liver cancers. METHODS: Retrospective cross-sectional study at Kaiser Permanente Southern California (KPSC) evaluating HCV and non-HCV patients from 1 January 2008 to 12 December 2012. Cancer diagnoses were obtained from the KPSC-SEER-affiliated registry. Logistic regression analyses were used for rate ratios and time-to-event analyses were performed using Cox proportional hazards models, adjusted for age, gender, race, smoking and cirrhosis. Cancer rate ratios were stratified by tobacco, alcohol abuse, diabetes and body mass index (BMI). RESULTS: The initial population and final population of multivariable analysis were N = 5 332 903 and N = 2 080 335 respectively. Cancer burden (all sites) was significantly higher in HCV than in non-HCV patients and HCV patients had a high rate of liver cancer. When liver cancer was excluded, cancer rates remained significantly increased in HCV. Unadjusted cancer rates were significantly higher in HCV compared to non-HCV for oesophageal, stomach, colorectal, pancreas, myeloma, non-Hodgkin's lymphoma, head/neck, lung, renal and prostate cancer. After stratification for alcohol abuse, tobacco, diabetes and BMI, increased cancer rates remained significant for all cancer sites, liver cancer and non-Hodgkin's lymphoma. Multivariable analyses demonstrated a strong correlation between cirrhosis and cancer. Tobacco use and diabetes were also associated with cancer. In the absence of cirrhosis, HCV, tobacco use and diabetes significantly increased the cancer risk. Mediation analyses showed that cirrhosis was responsible for a large proportion on the effect of HCV on cancer risk. CONCLUSION: This study supports the concept of HCV as a systemic illness and treating HCV regardless of disease severity and prior to progression to cirrhosis.

Sofosbuvir/Velpatasvir/Voxilaprevir for patients with HCV who previously received a Sofosbuvir/Velpatasvir-containing regimen: Results from a retreatment study.

This study evaluated 12-week retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C virus (HCV) infection who did not achieve sustained virologic response after previous treatment with a sofosbuvir- and velpatasvir-containing regimen. All 31 patients maintained a sustained virologic response 12 weeks after the last sofosbuvir/velpatasvir/voxilaprevir dose.

Sclerosing mesenteritis and mesenteric panniculitis - clinical experience and radiological features.

BACKGROUND: Sclerosing mesenteritis (SM) is sometimes used as an umbrella-term for idiopathic inflammatory conditions in the mesentery. Mesenteric panniculitis (MP) is a radiological finding and its relation to clinical SM is not fully understood. The aims of this study were to determine whether any correlation could be found between the radiological findings and the clinical disease course. METHODS: Patients observed due to idiopathic inflammation of the mesentery were identified. If SM could be verified histologically or MP radiologically, the patients were included in this descriptive retro perspective study. RESULTS: Typical radiological changes were observed in 27 patients. A majority (23/27) of these patients had mild to moderate symptoms. This group with typical radiology was labelled MP. Four patients were included due to histologically verified disease but had uncharacteristic radiology involving multiple compartments of the abdomen. All four had marked systemic inflammation, fever and fluctuating radiologic findings. Three had severe disease with multiple hospitalisations and complications but responded promptly to corticosteroids. This group was denoted SM. CONCLUSIONS: We have identified two subgroups of patients; firstly, MP with stable and characteristic radiologic changes and secondly SM with atypical radiology and a more aggressive clinical course. We propose that the term SM should be reserved for this latter condition.

Factors Associated with Failure to Achieve SVR in Hepatitis C Genotype 3 Patients Within an Integrated Care Delivery System.

BACKGROUND: Achievement of sustained virologic response (SVR) and factors associated with treatment failure in hepatitis C virus (HCV) genotype 3 have been described in tertiary and referral care settings, with rates of SVR reported to range between 72% and 89%. Fewer data exist on SVR outside of these settings. OBJECTIVE: To describe rates of SVR and characterize factors associated with achievement of SVR within an integrated health care delivery system. METHODS: A retrospective cohort study of genotype 3 HCV patients treated with dual therapy (pegylated interferon-alpha plus ribavirin) was conducted at Kaiser Permanente Southern California. Adult patients diagnosed with HCV and testing positive for HCV-RNA genotype 3 were identified from electronic medical records. Data were collected on patient demographics, baseline health status, and comorbid conditions. A multivariate logistic regression model was used to determine the association between baseline patient factors and SVR. RESULTS: A total of 484 HCV genotype 3 patients met the eligibility criteria. The median age was 49 years, and 65.7% were male. Overall, 252 (52.1%) achieved SVR. Aged ≥ 45 years and male gender were associated with lower rates of SVR; cirrhosis and chronic diseases (diabetes and chronic obstructive pulmonary disease) were also associated with lower rates of SVR. CONCLUSIONS: SVR was lower in patients within an integrated care delivery system than in those in tertiary and referral centers. Males and older patients had lower rates of SVR, as well as patients with cirrhosis, diabetes, and chronic obstructive pulmonary disease.

Safety and Efficacy of Simeprevir/Sofosbuvir in Hepatitis C-Infected Patients With Compensated and Decompensated Cirrhosis.

UNLABELLED: Risks and benefits of simeprevir plus sofosbuvir (SIM+SOF) in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virological responses (SVR) of SIM+SOF with and without ribavirin (RBV) in patients with Child-Pugh (CP)-B/C versus CP-A cirrhosis and compared to matched untreated controls. This study was of a multicenter cohort of adults with hepatitis C virus genotype 1 and cirrhosis treated with SIM+SOF with/without RBV for 12 weeks. Controls were matched on treatment center, age, CP class, and Model for End-Stage Liver Disease (MELD) score. Of 160 patients treated with SIM+SOF with/without RBV, 35% had CP-B/C and 64% had CP-A, with median baseline MELD 9 (interquartile range, 8-11). Sustained virological response at week 12 (SVR12) was achieved by 73% of CP-B/C versus 91% of CP-A (P < 0.01). CP-B/C versus CP-A had more early treatment discontinuations (11% vs. 1%), adverse events (AEs) requiring hospitalization (22% vs. 2%), infections requiring antibiotics (20% vs. 1%), and hepatic decompensating events (20% vs. 3%; all P < 0.01). There were 2 deaths: 1 CP-B/C (liver related) and 1 CP-A (not liver related). In multivariate analysis, CP-B/C independently predicted lack of SVR12 (odds ratio, 0.27; 95% confidence interval: 0.08-0.92). In comparing SIM+SOF-treated patients versus matched untreated controls, AEs requiring hospitalization (9% vs. 13%; P = 0.55), infections (8% vs. 6%; P = 0.47), and events of decompensation (9% vs. 10%; P = 0.78) occurred at similar frequency. CONCLUSIONS: SIM+SOF with/without RBV has lower efficacy and higher rates of AEs in patients with CP-B/C cirrhosis, compared to CP-A. Frequency of adverse safety outcomes were similar to matched untreated controls, suggesting that safety events reflect the natural history of cirrhosis and are not related to treatment.

Infections during peginterferon/ribavirin therapy are associated with the magnitude of decline in absolute lymphocyte count: results of the IDEAL study.

BACKGROUND: Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy. METHODS: A total of 3070 treatment-naive, chronic hepatitis C genotype 1-infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2-6 weeks. Dose reduction was required for a neutrophil count <0.75 × 10(9) cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 10(9) cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0. RESULTS: A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 10(9) cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 10(9) cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection. CONCLUSIONS: Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 10(9) cells/L).

Telaprevir twice daily is noninferior to telaprevir every 8 hours for patients with chronic hepatitis C.

BACKGROUND & AIMS: We performed an open-label, multicenter, phase 3 study of the safety and efficacy of twice-daily telaprevir in treatment-naive patients with chronic hepatitis C virus (HCV) genotype 1 infection, including those with cirrhosis. METHODS: Patients were randomly assigned to groups treated with telaprevir 1125 mg twice daily or 750 mg every 8 hours plus peginterferon alfa-2a and ribavirin for 12 weeks; patients were then treated with peginterferon alfa-2a and ribavirin alone for 12 weeks if their level of HCV RNA at week 4 was <25 IU/mL or for 36 weeks if their level was higher. The primary objective was to demonstrate noninferiority of telaprevir twice daily versus every 8 hours in producing a sustained virological response 12 weeks after the end of therapy (SVR12) (based on a -11% lower limit of the 95% lower confidence interval for the difference between groups). RESULTS: At baseline, of 740 patients, 85% had levels of HCV RNA ≥800,000 IU/mL, 28% had fibrosis (F3-F4), 14% had cirrhosis (F4), 57% were infected with HCV genotype 1a, and 71% had the non-CC IL28B genotype. Of patients who were treated with telaprevir twice daily, 74.3% achieved SVR12 compared with 72.8% of patients who were treated with telaprevir every 8 hours (difference in response, 1.5%; 95% confidence interval, -4.9% to 12.0%), so telaprevir twice daily is noninferior to telaprevir every 8 hours. All subgroups of patients who were treated with telaprevir twice daily versus those who were treated every 8 hours had similar rates of SVR12. The most frequent adverse events (AEs) in the telaprevir phase were fatigue (47%), pruritus (43%), anemia (42%), nausea (37%), rash (35%), and headache (26%); serious AEs were reported in 9% of patients. Rates of AEs and serious AEs were similar or slightly higher among patients treated with telaprevir every 8 hours. CONCLUSIONS: Based on a phase 3 trial, telaprevir twice daily is noninferior to every 8 hours in producing SVR12, with similar levels of safety and tolerability. These results support use of telaprevir twice daily in patients with chronic HCV genotype 1 infection, including those with cirrhosis. ClinicalTrials.gov, Number: NCT01241760.

Effects of ribavirin dose reduction vs erythropoietin for boceprevir-related anemia in patients with chronic hepatitis C virus genotype 1 infection--a randomized trial.

BACKGROUND & AIMS: Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety. METHODS: Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251). RESULTS: Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin. CONCLUSIONS: Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Sofosbuvir for previously untreated chronic hepatitis C infection.

BACKGROUND: In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection. METHODS: We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon. CONCLUSIONS: In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.).

Efficacy and safety of boceprevir plus peginterferon-ribavirin in patients with HCV G1 infection and advanced fibrosis/cirrhosis.

BACKGROUND & AIMS: We assessed the safety and efficacy of boceprevir (BOC) plus peginterferon-ribavirin (PR) in patients with HCV-G1 infection and advanced fibrosis/cirrhosis (Metavir F3/F4). METHODS: In two randomized controlled studies of previously untreated and previous treatment failures, patients received a 4-week lead-in of PR followed by PR plus placebo for 44 weeks (PR48); PR plus BOC using response guided therapy (BOC/RGT); or PR plus BOC for 44 weeks (BOC/PR48). RESULTS: The trials enrolled 178 patients with F3/4. HCV RNA levels at week 4 and 8 were highly predictive of response. No patient with F3/4 in the PR48 arm with a <1 log(10) decline in HCV RNA at week 4 achieved SVR, whereas those randomized to BOC/RGT or BOC/PR48 had SVR rates of 11-33% (F3) and 10-14% (F4). In these latter groups, patients with high baseline viral load (>2 × 10(6)IU/ml) had an overall SVR rate of 6% (2/33). For patients with a ≥1 log(10) decline at week 4, SVR rates in the BOC/PR48 arm of SPRINT-2 and RESPOND-2, respectively, were 77% and 87% vs. 18% and 50% for PR48; SVR rates in early responders (undetectable HCV RNA at week 8) were 90-93% in the BOC/PR48 arm. Neutropenia and thrombocytopenia were more common in cirrhotics than non-cirrhotics. CONCLUSIONS: BOC improves SVR rates in patients with F3/4, and longer treatment duration provides the most benefit. With triple therapy, SVR rates are modest in F4 patients with a <1 log(10) decline at week 4, thus the 4-week PR lead-in aids in the assessment of early futility.

Self-stress vs manual stress in talar tilt radiography.

BACKGROUND: Radiographic study following inversion ankle sprain commonly is used to determine the presence of anatomic laxity across the talocrural joint. PURPOSE: To compare the degree of talar tilt derived from a radiographic ankle stress exam under 2 conditions: self-stress vs manual stress applied by the clinician. METHODS: Twenty-four subjects seeking medical care following ankle sprain underwent talar tilt stress exams of both ankles. The involved ankle was imaged with self-stress by use of a strap and with the clinician providing manual stress during the imaging exam. Mean talar tilt for the self-stress method was 2.2 degrees, compared with 5.9 degrees for the manual stress method (P < .001). RESULTS: Significantly greater and clinically meaningful differences in talar tilt angle were found when manual stress was provided by the clinician. To avoid false negative findings of anatomic laxity in stress talar tilt studies at the ankle, a standardized procedure in which the clinician provides manual stress may be necessary.

Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus.

BACKGROUND & AIMS: We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. METHODS: HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). RESULTS: In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). CONCLUSIONS: In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.

Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.

BACKGROUND: Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. METHODS: At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 microg per kilogram of body weight per week or a low dose of 1.0 microg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 microg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. RESULTS: Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], -2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and -1.1% (95% CI, -5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. CONCLUSIONS: In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials.gov number, NCT00081770.)

Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alpha-2a and ribavirin.

UNLABELLED: Treatment response remains suboptimal for many patients with chronic hepatitis C, particularly those with genotype 1 and high levels of viremia. The efficacy of high-dose regimens of peginterferon alfa-2a and ribavirin was compared with conventional dose regimens in patients with features predicting poor treatment responses. Eligible treatment-naïve adults with genotype 1 infection, hepatitis C virus (HCV) RNA >800,000 IU/mL and body weight >85 kg were randomized to double-blind treatment with peginterferon alfa-2a at 180 or 270 microg/week plus ribavirin at 1200 or 1600 mg/day for 48 weeks (four regimens were evaluated). The primary endpoint was viral kinetics during the first 24 weeks of therapy. Among patients receiving peginterferon alfa-2a (270 microg/week) the magnitude of HCV RNA reduction was significantly greater than for patients randomized to the conventional dose of peginterferon alfa-2a (180 microg/week) for the pairwise comparison for ribavirin at 1600 mg/day (P = 0.036) and numerically greater for the pairwise comparison for ribavirin at 1200 mg/day (P = 0.060). Patients randomized to the highest doses of peginterferon alfa-2a (270 microg/week) and ribavirin (1600 mg/day) experienced the numerically highest rates of sustained virologic response (HCV RNA < 50 IU/mL) and the lowest relapse rate (47% and 19%, respectively). The arm with the higher doses of both drugs was less well-tolerated than the other regimens. CONCLUSION: Higher fixed doses of peginterferon alfa-2a (270 microg/week) and ribavirin (1600 mg/day) may increase sustained virologic response rates compared with lower doses of both drugs in patients with a cluster of difficult-to-treat characteristics.

R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.

UNLABELLED: R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a +/- ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa-2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa-2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa-2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa-2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log(10) IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions. CONCLUSION: A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a +/- ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway.

Kinetics of hepatitis C virus reinfection after liver transplantation.

Improved understanding of hepatitis C virus (HCV) dynamics during and after liver transplantation can be useful in optimizing antiviral therapy in transplant recipients. We analyzed serum HCV ribonucleic acid (RNA) levels during and after cadaveric liver transplantation in 6 HCV patients. After removal of the liver and before the new liver started producing virions, HCV RNA levels dropped with an average half-life (t(1/2)) of 0.8 hours. Viral loads then continued to drop up to 23 hours postimplantation (t(1/2) = 3.4 hours), and began to rise (doubling-time = 2.0 days) as soon as 15 hours after the anhepatic phase. In 3 patients the viral load reached a plateau before rising, suggesting that a nonhepatic source supplied virions and balanced their intrinsic clearance. However, from the decline in viral load over the first 24 hours of the postanhepatic phase, we estimate that nonhepatic sources can at most correspond to 4% of total viral production, 96% of which occurs in the liver, even after we corrected for fluid exchanges during surgery. As the new liver was reinfected, production increased and viral load rose to a new steady state. Using nonlinear regression, we were able to fit the patients' HCV RNA data to a viral dynamic model and estimate the de novo infection rate (mean 1.5 x 10(-6) mL/virion/day), as well as the average percentage of hepatocytes infected at the posttransplantation steady state (19%). In conclusion, we have quantified liver reinfection dynamics in the absence of posttransplantation antiviral therapy. Our findings support the notion that early antiviral therapy may delay or prevent reinfection.