Safety analysis of glecaprevir/pibrentasvir in patients with markers of advanced liver disease in clinical and real-world cohorts.

Chronic hepatitis C virus (HCV) infection has the greatest health impact in patients with advanced liver disease. The direct-acting antiviral (DAA) regimen glecaprevir/pibrentasvir (G/P) is approved for treatment of HCV-infected patients without cirrhosis and with compensated cirrhosis. However, events of liver decompensation/failure have been reported in patients treated with protease-inhibitor-containing DAA regimens, often in patients with advanced liver disease. This study examines the safety of on-label G/P treatment in patients with compensated cirrhosis (F4 at baseline) with markers of advanced liver disease. Patients with cirrhosis were categorized into 4 subgroups, based on different noninvasive markers of advanced liver disease identified using laboratory measures: platelet count < or ≥ 100 × 109 /L, and Child-Pugh score 5 or 6. Separate analyses were performed using pooled data from clinical trials and from real-world post-marketing observational studies. G/P was well tolerated in patients with platelet count ≥100 × 109 /L (n = 800), platelet count <100 × 109 /L (n = 215), a Child-Pugh score of 5 (n = 915) and a Child-Pugh score of 6 (n = 95). In the clinical trial and real-world cohorts two patients and no patients experienced a serious adverse event (AE) possibly related to study drug, respectively; three patients and no patients experienced an AE of special interest for hepatic decompensation and hepatic failure. This analysis reaffirms G/P's safety profile in indicated patients with compensated cirrhosis, including those with markers of more advanced liver disease. Increasing the number of patients treated with short-duration G/P therapy may contribute to meeting HCV elimination targets.

Simplified monitoring for hepatitis C virus treatment with glecaprevir plus pibrentasvir, a randomised non-inferiority trial.

BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy for HCV has high efficacy and limited toxicity. We hypothesised that the efficacy of glecaprevir-pibrentasvir for chronic HCV with a simplified treatment monitoring schedule would be non-inferior to a standard treatment monitoring schedule. METHODS: In this open-label multicentre phase IIIb trial, treatment-naïve adults with chronic HCV without cirrhosis were randomly assigned (2:1) to receive glecaprevir-pibrentasvir 300 mg-120 mg daily for 8 weeks administered with a simplified or standard monitoring strategy. Clinic visits occurred at baseline and post-treatment week 12 in the simplified arm, and at baseline, week 4, week 8, and post-treatment week 12 in the standard arm. Study nurse phone contact occurred at week 4 and week 8 in both arms. Participants requiring adherence support were not eligible, including those reporting recent injecting drug use. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12), with a non-inferiority margin of 6%. RESULTS: Overall, 380 participants (60% male, 47% genotype 1, 32% genotype 3) with chronic HCV were randomised and treated with glecaprevir-pibrentasvir in the simplified (n = 253) and standard (n = 127) arms. In the intention-to-treat population, SVR12 was 92% (95% CI 89%-95%) in the simplified and 95% (95% CI 92%-99%) in the standard arm (difference between arms -3.2%; 95% CI -8.2% to 1.8%) and did not reach non-inferiority. In the per-protocol population, SVR12 was 97% (95% CI 96%-99%) in the simplified and 98% (95% CI 96%-100%) in the standard arm. No treatment-related serious adverse events were reported. CONCLUSIONS: In patients with chronic HCV infection without cirrhosis, treatment with glecaprevir-pibrentasvir was safe and effective. In comparison to standard monitoring, a simplified monitoring schedule did not achieve non-inferiority. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT03117569. LAY SUMMARY: Direct-acting antiviral (DAA) therapy for hepatitis C is highly effective and well tolerated. The SMART-C randomised trial evaluated an 8-week regimen of glecaprevir-pibrentasvir for hepatitis C treatment, using a simplified monitoring schedule that included no pathology tests or clinic visits during treatment. This simplified strategy produced a high cure rate (92%), but this was not equivalent to the standard monitoring schedule cure rate (95%).

HEPLA: A multicenter study on demographic and disease characteristics of patients with hepatitis C in Latin America.

INTRODUCTION AND OBJECTIVES: Currently, there are limited data on the epidemiology and disease characteristics of patients with chronic hepatitis C (CHC) in Latin America. The primary objective of this study was to evaluate demographic and disease characteristics of patients with CHC in Latin America. PATIENTS AND METHODS: HEPLA was a non-interventional, multicenter study of the epidemiology and disease characteristics of patients with CHC in Argentina, Brazil, Chile, Colombia, and Mexico. RESULTS: Of the 817 included patients, the median age was 58 years, 53.9% were female, and 39.3% had cirrhosis. Overall, 41.2% were treatment naive, 49.8% were treatment experienced, and 8.9% were currently undergoing treatment. In patients with available data, genotype 1b accounted for 41.6% of infections, followed by genotype 1a (29.9%) and genotype 3 (11.3%). Probable mode of infection was transfusion in 46.8% of patients. Liver-related comorbidities were present in 26.4% of patients and non-liver-related comorbidities were present in 72.3%. Most patients (71.8%) received concomitant medications, with proton-pump inhibitors (20.8%) being the most commonly reported. CONCLUSIONS: At the time the HEPLA study was carried out, the data from this cross-section of patients in Latin America showed that the CHC population has variation in disease and viral characteristics, with a minority of patients receiving treatment and many patients having advanced disease. Increased awareness and access to treatment are necessary in Latin America in order to meet the goal of hepatitis C virus elimination by 2030.

Ribavirin dose management in HCV patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin.

BACKGROUND & AIMS: Some individuals with hepatitis C virus infection treated with direct-acting antivirals require ribavirin to maximize sustained virological response rates. We describe the clinical management of ribavirin dosing in hepatitis C virus-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. METHODS: We performed a post hoc analysis of patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in six phase 3 trials. Multivariate stepwise logistic regression models assessed predictors associated with ribavirin dose adjustments and with developing anaemia. RESULTS: Of 1548 patients, 100 (6.5%) modified ribavirin dose due to haemoglobin declines, of which 99% achieved sustained virological response at 12 weeks post-treatment. Median time to first ribavirin dose reduction was 37 days. Low baseline haemoglobin was significantly associated with an increased risk of requiring ribavirin dose modification (odds ratio: 0.618 [0.518, 0.738]; P < .001) and developing anaemia (odds ratio: 0.379 [0.243, 0.593]; P < .001). CONCLUSIONS: Ribavirin dose reductions were infrequent, occurred early in treatment, and did not impact sustained virological response at 12 weeks post-treatment. Patients with low baseline haemoglobin should be monitored for on-treatment anaemia.

Safety of the 2D/3D direct-acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis - A pooled analysis.

BACKGROUND & AIMS: Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis. METHODS: Twelve phase II or III clinical trials of the 2-DAA regimen of OBV/PTV/r±ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r+DSV±RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported. RESULTS: In 1,066 patients with Child-Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% confidence interval [CI]: 4.1-6.8) and 2.2% (95% CI: 1.4-3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7-2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2). CONCLUSIONS: This pooled analysis in 1,066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r±DSV±RBV in this population. These results support the use of OBV/PTV/r±DSV±RBV in this high-priority population. Lay summary: This pooled safety analysis in 1,066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was similar to previously reported rates in untreated patients.

Ribavirin revisited in the era of direct-acting antiviral therapy for hepatitis C virus infection.

Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. However, because of treatment-limiting side effects and its additive toxicity with interferon, the search for interferon- and ribavirin-free regimens has been underway. The recent approvals of all-oral direct acting antivirals (DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co-administered with all-oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all-oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups.

A tool for selecting patients with a high probability of sustained virological response to peginterferon alfa-2a (40kD)/ribavirin.

BACKGROUND & AIMS: Pretreatment identification of patients likely to achieve a sustained virological response (SVR) with peginterferon alfa-2a/ribavirin would be useful for individualizing treatment choices. The aim of this analysis was to devise a simple scoring system to identify patients with high probability of achieving an SVR with peginterferon alfa-2a/ribavirin. METHODS: Using data from 2109 Caucasian treatment-naive hepatitis C virus (HCV) genotype 1 mono-infected patients from the PROPHESYS cohorts, the relationship between favourable baseline characteristics and SVR was explored using generalized additive model analysis, and a scoring system was devised to predict SVR. RESULTS: Points were assigned for: age (years) (≤35: 2; >35, ≤45: 1; >45: 0); body mass index (kg/m(2)) (≤20: 2; >20, ≤22: 1; >22: 0); HCV RNA (IU/ml) (≤100,000: 3; >100,000-400,000: 2; >400,000-800,000: 1; >800,000: 0); platelets (>150 ×10(9)/l: 1; ≤150 ×10(9)/l: 0); alanine aminotransferase [×upper limit of normal (ULN)] (>3: 1; ≤3: 0); serum aspartate aminotransferase (×ULN) (≤1: 1; >1: 0). 1029, 698 and 382 patients had scores of 0-2, 3-4 and ≥5, respectively, among whom SVR rates were 35.0, 54.9 and 76.7%. SVR in patients with scores ≥5 and undetectable HCV RNA by week 4 was 86.7%. The score was tested against two databases of patients who received peginterferon alfa-2a/ribavirin in other clinical trials; similar high SVR rates in patients with scores ≥5 were reported. CONCLUSIONS: The scoring system can reliably identify treatment-naive HCV genotype 1 mono-infected Caucasian patients who have a high probability of achieving an SVR with peginterferon alfa-2a/ribavirin and will be particularly useful where protease inhibitors are not readily available.

In routine clinical practice, few physicians use early viral kinetics to guide HCV dual therapy treatment decisions.

BACKGROUND & AIMS: PROPHESYS is a large, multinational, non-interventional prospective cohort study of chronic hepatitis C patients treated with peginterferon alfa/ribavirin. This subanalysis assesses rates of premature treatment discontinuation stratified by on-treatment virological response (VR). METHODS: This PROPHESYS subanalysis is restricted to treatment-naive, hepatitis C virus (HCV) genotype (G)1/2/3 mono-infected patients who received peginterferon alfa-2a (40KD)/ribavirin with intended treatment duration of 48 (G1) or 24 weeks (G2/3). Early virological responses were classified into four mutually exclusive categories [rapid VR (RVR), complete early VR (cEVR), partial EVR (pEVR), no RVR/EVR], using standard criteria. RESULTS: The likelihood for shortening treatment owing to good efficacy was highest among patients with an RVR and HCV RNA≤400 000 IU/ml (G1 10.0%; G2/3 5.8%) whereas for poor efficacy, it was highest in G1 non-RVR/EVR patients with HCV RNA>400 000 IU/ml (56.6%). Factors significantly associated with early treatment discontinuation as a result of good efficacy in G1 patients included RVR vs. no RVR/EVR and, at baseline, lower HCV RNA, lower FIB-4 score, HCV infection via injection drug use. For G2/3 patients, factors included lower baseline HCV RNA and G2 vs. G3 infection. Most patients started with the recommended peginterferon alfa-2a dose, but a high proportion received a higher-than-recommended ribavirin dose. CONCLUSIONS: Despite international guidelines, few physicians used early viral kinetics to abbreviate treatment. Therefore, relatively few patients with an RVR and low baseline HCV RNA abbreviated treatment. In addition, there were deviations in ribavirin starting doses, suggesting that physicians tailor treatment according to local guidelines or previous experience.

High sustained virologic response rates in rapid virologic response patients in the large real-world PROPHESYS cohort confirm results from randomized clinical trials.

UNLABELLED: The ability to predict which patients are most likely to achieve a sustained virologic response (SVR) with peginterferon/ribavirin would be useful in optimizing treatment for hepatitis C virus (HCV). The objective of this large international noninterventional cohort study was to investigate the predictive value (PV) of a virologic response (VR) by weeks 2, 4, and 12 of treatment on SVR. Treatment-naive HCV monoinfected patients (N = 7,163) age ≥ 18 years were prescribed peginterferon/ribavirin at the discretion of the treating physician according to country-specific requirements in accordance with the local label. The main outcome measure was the PV of a VR (HCV RNA <50 IU/mL) by weeks 2, 4, and 12 of treatment for SVR24 (HCV RNA <50 IU/mL after 24 weeks of untreated follow-up) by HCV genotype. The overall SVR24 rate was 49.4% (3,541/7,163; 95% confidence interval [CI]: 48.3-50.6%). SVR24 rates in patients with an HCV RNA titer <50 IU/mL by weeks 2, 4, and 12, respectively, were 66.2% (95% CI: 60.4-71.7%), 68.4% (95% CI: 65.7-71.0%), and 60.3% (95% CI: 58.5-62.1%) among genotype 1 patients; 82.0% (95% CI: 76.8-86.5%), 76.3% (95% CI: 73.3-79.1%), and 74.2% (95% CI: 71.3-76.9%) among genotype 2 patients; 67.3% (95% CI: 61.1-73.1%), 67.3% (95% CI: 64.2-70.3%), and 63.8% (95% CI: 61.0-66.6%) among genotype 3 patients; and 59.4% (95% CI: 40.6-76.3%), 63.3% (95% CI: 54.3-71.6%), and 54.3% (95% CI: 47.5-60.9%) among genotype 4 patients. The absence of a VR by week 12 had the highest negative PV across all genotypes. CONCLUSION: A VR by week 2 or 4 had the highest positive PV for SVR24 and differed according to HCV genotype.

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.

Intensified peginterferon α-2a dosing increases sustained virologic response rates in heavy, high viral load hepatitis C genotype 1 patients with high low-density lipoprotein.

BACKGROUND AND GOAL: Patients infected with hepatitis C virus (HCV) with elevated low-density lipoprotein (LDL) levels achieve higher sustained virologic response (SVR) rates after peginterferon (PegIFN)/ribavirin treatment versus patients with lower LDL. Our aim was to determine whether SVR rates in patients with low/elevated LDL can be improved by dose intensification. STUDY: In PROGRESS, genotype 1 patients with baseline HCV RNA ≥ 400,000 IU/mL and body weight ≥ 85 kg were randomized to 48 weeks of 180 µg/wk PegIFN α-2a (40 kDa) plus ribavirin (A: 1200 mg/d; B: 1400/1600 mg/d) or 12 weeks of 360 µg/wk PegIFN α-2a followed by 36 weeks of 180 µg/wk, plus ribavirin (C: 1200 mg/d; D: 1400/1600 mg/d). This retrospective analysis assessed SVR rates among patients with low (<100 mg/dL) or elevated (≥ 100 mg/dL) LDL. Patients with high LDL (n=256) had higher baseline HCV RNA (5.86 × 10(6) IU/mL) versus patients with low LDL (n=262; 4.02 × 10(6) IU/mL; P=0.0003). RESULTS: Multiple logistic regression analysis identified a significant interaction between PegIFN α-2a dose and LDL levels on SVR (P=0.0193). The only treatment-related SVR predictor in the nested multiple logistic regression was PegIFN α-2a dose among patients with elevated LDL (P=0.0074); therefore, data from the standard (A+B) and induction (C+D) dose arms were pooled. Among patients with low LDL, SVR rates were 40% and 35% in the standard and induction-dose groups, respectively; SVR rates in patients with high LDL were 44% and 60% (P=0.014), respectively. CONCLUSIONS: Intensified dosing of PegIFN α-2a increases SVR rates in patients with elevated LDL even with the difficult-to-cure characteristics of genotype 1, high baseline viral load, and high body weight.

Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin.

BACKGROUND & AIMS: It is unclear whether the magnitude of reduction in hepatitis C virus (HCV) RNA between baseline and week 4 of treatment influences the probability of achieving a sustained virological response (SVR) in patients without a week 4 rapid virological response (RVR). METHODS: Data were retrospectively analyzed from two studies in which treatment-naive patients received peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 1000/1200 mg/day for 48 weeks. Five hundred and fifty-eight genotype 1 patients with evaluable HCV RNA at baseline and week 4 were grouped according to RVR status: RVR (HCV RNA<50 IU/ml) or no RVR. Non-RVR patients were subdivided into discrete mutually exclusive categories according to week 4 HCV RNA; the proportion of patients with undetectable HCV RNA at week 12 was calculated per each category, and among them, the proportion with an SVR. RESULTS: Overall, 88% of RVR patients and 43% of non-RVR patients achieved an SVR (p<0.0001). Among non-RVR patients, SVR rates were 77%, 61%, 43%, 27% and 13%, respectively (trend test p<0.0001) in those with unquantifiable HCV RNA or ≥ 3 log(10), ≥ 2 log(10), ≥ 1 log(10), or<1 log(10) drop to week 4. In patients HCV RNA positive at week 4, SVR rates were 67% for those negative at week 12 vs. 17% (HCV RNA positive patients or who had missing values at week 12 [p<0.0001]). CONCLUSIONS: The probability of achieving SVR is graded in relation to the magnitude of reduction in HCV RNA at week 4 and 12. Patients with a ≥ 3 log(10) drop in HCV RNA at week 4 have a high probability of achieving an SVR.

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.

Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial.

INTRODUCTION: A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care(pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after ≥ 24 weeks of treatment with conventional interferon plus ribavirin. MATERIAL AND METHODS: Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (40KD) 180 µg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin). RESULTS: The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (< 50 IU/mL) at end of follow-up (week 72). Among patients with a previous non-response, 12/53 (22.6%; 95% confidence interval [CI] 12.3-36.2%) randomized to triple therapy achieved an SVR compared with 16/52 (30.8%; 95% CI 18.7-45.1%) randomized to the standard of care. Among patients with a previous relapse 22/39 (56.4%; 95% CI 39.6-72.2%) randomized to triple therapy achieved an SVR compared with 23/38 (60.5%; 95% CI 43.4-76.0%) randomized to the standard of care. Undetectable HCV RNA (< 50 IU/mL) at week 12 had a high positive predictive value for SVR. A substantial proportion of non-responders and relapsers to conventional interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin. CONCLUSION: Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting.

Safety of Patients with Hepatitis C Virus Treated with Glecaprevir/Pibrentasvir from Clinical Trials and Real-World Cohorts.

INTRODUCTION: More than 70 million people are estimated to be infected with hepatitis C virus (HCV) globally. If left untreated, HCV infection can lead to complications such as extensive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Evolution of treatments has resulted in highly effective and well-tolerated all-oral direct-acting antivirals. The pangenotypic regimen of glecaprevir/pibrentasvir is approved for treating HCV for patients without cirrhosis or with compensated cirrhosis (CC). Guidelines have evolved to simplify treatment to enable non-specialists to manage and treat HCV-infected patients. Simultaneously, such treatment algorithms provide guidance on the pretreatment identification of small subsets of patients who may require specialist treatment and long-term follow-up for advanced liver disease, including those at risk of developing HCC. This study describes the safety profile of glecaprevir/pibrentasvir in patients identified using previously described noninvasive laboratory measures who may be eligible for treatment by non-liver specialists. METHODS: This post hoc analysis of glecaprevir/pibrentasvir in patients, identified by noninvasive laboratory measures, intended to exclude patients with advanced liver disease and severe renal impairment, who can be managed within non-liver specialist settings. Patients were included from clinical trials and real-world studies of glecaprevir/pibrentasvir for HCV treatment. Baseline demographics, clinical characteristics, and safety assessments, including adverse events and laboratory abnormalities, were summarized. RESULTS: Data across these large-scale studies confirm that glecaprevir/pibrentasvir is well tolerated across different patient populations, with fewer than 0.1% of patients experiencing a serious adverse event related to treatment drugs, and few patients developing HCC during or after treatment. CONCLUSION: The safety profile of glecaprevir/pibrentasvir enhances the confidence of non-liver specialists to treat the majority of HCV-infected patients, and provides an opportunity to expand the treater pool, potentially increasing diagnosis and treatment rates for HCV, contributing to elimination of HCV.

[Hemoglobin levels in hemodialysis patients treated with epoetin: a Brazilian experience]. / Variação dos níveis de hemoglobina de pacientes em hemodiálise tratados com eritropoetina: uma experiência brasileira.

OBJECTIVE: Correction of anemia using epoetin decreases morbidity and increases survival and quality of life in end-stage renal disease. Maintaining hemoglobin levels within the range proposed by guidelines has become a major challenge, with hemoglobin cycling affecting more than 90% of patients undergoing hemodialysis. The variability of hemoglobin levels over time was assessed in our patients. METHODS: Data were retrospectively collected on 249 patients undergoing hemodialysis over a 3-year period at seven centers in Brazil. Hemoglobin was measured at least monthly, and target levels were those between 10.5 g/dL and 12.5 g/dL. Patients were grouped into six categories of variability consistently low (<10.5 g/dL), consistently target range (10.5 to 12.5 g/dL), consistently high (>12.5 g/dL), low amplitude fluctuation with low hemoglobin levels, low amplitude fluctuation with high hemoglobin levels and high amplitude fluctuation. None of the patients maintained stable hemoglobin levels for the entire 36-month period. RESULTS: The mean monthly proportion of patients that had hemoglobin levels within the target range was 50% (range, 42% to 61%). Mean levels above the target (30%) were more frequent than those below it (20%). During 6, 12, and 36 months, proportions of patients with consistently low levels of hemoglobin decreased from 3.6% to 0%, from 31.7% to 2.8% for those with consistently high, from 7.6% to 0% for those with low amplitude fluctuation with low hemoglobin levels and from 41.3% to 8.3% for those with low amplitude fluctuation with high hemoglobin levels. However, the proportions of patients with high amplitude fluctuation increased from 21.5% to 88.9%. CONCLUSION: Maintaining hemoglobin levels within the target range is difficult, especially for longer periods of time. Missing the target seems more often due to levels above it, but high-amplitude fluctuations eventually occur in the majority of patients.

Effect of amantadine on depressive symptoms in chronic hepatitis C patients treated with pegylated interferon: a randomized, controlled pilot study.

OBJECTIVE: Assess the effect of amantadine on depressive symptoms during interferon alfa therapy for hepatitis C virus infection. METHODS: We performed a randomized, controlled trial with 14 hepatitis C virus-infected patients, treated with pegylated interferon alfa-2a 180 microg/wk plus ribavirin 1.200 mg/d. Eight patients were randomized to receive amantadine 200 mg/d, and 6 other individuals were randomized to control group without amantadine. Severity of depression and anxiety was measured using the Hospital Anxiety and Depression Scale, before starting re-treatment, and 4, 12, and 24 weeks after immunotherapy with pegylated interferon alfa-2a. Evaluations were performed by psychiatrists blinded in reference to the state of amantadine treatment. Friedman chi(2) test for repeated measures and Mann-Whitney test for nonparametric data were used to assess significant differences. RESULTS: From baseline to follow-up, no significant increase in mean Hospital Anxiety and Depression Scale scores of depressive symptoms were seen in amantadine group (P = 0.142), meanwhile there was a statistical increase of depression scores in the control group (P = 0.001). CONCLUSIONS: Our randomized pilot study, though small, clearly indicates that interferon alfa-induced depressive symptoms can be prevented by the use of amantadine. However, double-blind placebo-controlled trials with a higher sample size are required to confirm these preliminary findings.

Pharmacoeconomics applied to chronic hepatitis C.

Life expectancy has increased over the last century as it had never been before. This is the result of a combination of many favorable variables such as level of education, improved socio-economic environment and development of medicine. However, new improvements demand heavy investment. Thus, the incorporation of medical technology became a health and economic issue. The pharmacoeconomic knowledge field is being developed to help in the analysis of medical costs and patient needs. The applies to hepatitic C, a common and chronic worldwide disease. In this article, the authors describe the rational behind this type of health economic analysis and review a hepatitis C model. Overall, in a non-Brazilian scenario, it was demonstrated that peginterferon alfa-2a (40KD) is cost effective in the treatment of HCV disease.