Real-world experience for the outcomes and costs of treating hepatitis C patients: Results from the German Hepatitis C-Registry (DHC-R).

BACKGROUND & AIMS: With long-term consequences like the development of liver cirrhosis and hepatocellular carcinoma, chronic hepatitis C virus (HCV) infection is associated with a significant health burden. Information on HCV treatment outcomes and costs in routine care is still rare, especially for subgroups. The aim of this study was to analyse the treatment outcomes and costs of subgroups in routine care and to compare them over time with previous analyses. METHODS: Data were derived from a noninterventional study including a subset of 10298 patients receiving DAAs with genotypes 1 and 3. Sociodemographic, clinical parameters and costs were collected using a web-based data recording system. The total sample was subdivided according to treatment regimen, cirrhosis status as well as present HIV infection and opioid substitution treatment (OST). RESULTS: 95% of all patients achieved SVR. Currently used DAA showed higher SVR-rates and less adverse events (AE) compared to former treatments. Concerning subgroups, cirrhotic patients, HIV-coinfected patients and OST patients showed lower but still high SVR-rates. In comparison, cirrhotic had considerably longer treatment duration and more frequent (serious) AE. Overall, average treatment costs were €48470 and costs per SVR were €51129; for currently used DAAs costs amounted to €30330 and costs per SVR to €31692. After the end of treatment, physical health is similar to the general population in all patients except cirrhotic. Mental health remains far behind in all subgroups, even for currently used DAA. CONCLUSIONS: Over time, some relevant factors developed positively (SVR-rates, costs, treatment duration, adverse events, health-related quality of life (HRQoL)). Further research on HRQoL, especially on mental health, is necessary to evaluate the differences between subgroups and HRQoL over time and to identify influencing factors.

Real-World Safety, Effectiveness, and Patient-Reported Outcomes in Patients with Chronic Hepatitis C Virus Infection Treated with Glecaprevir/Pibrentasvir: Updated Data from the German Hepatitis C-Registry (DHC-R).

Using data from the German Hepatitis C-Registry (Deutsche Hepatitis C-Register, DHC-R), we report the real-world safety and effectiveness of glecaprevir/pibrentasvir (GLE/PIB) treatment and its impact on patient-reported outcomes (PROs) in underserved populations who are not typically included in clinical trials, yet who will be crucial for achieving hepatitis C virus (HCV) elimination. The DHC-R is an ongoing, non-interventional, multicenter, prospective, observational cohort study on patients treated for chronic HCV infection in Germany. The data cutoff was 17 January 2021. The primary effectiveness endpoint was sustained virologic response at post-treatment Week 12 (SVR12). Safety outcomes were assessed in all patients receiving GLE/PIB. PROs were assessed using the SF-36 survey. Of 2354 patients, 1964 had valid SVR12 data (intention-to-treat analysis). Of these, 1905 (97.0%) achieved SVR12 with rates similar across the comorbidities analyzed, except for people who actively use drugs (PWUD (active)) (86.4%). Excluding those who discontinued treatment and did not achieve SVR12, or were reinfected with HCV, the rate was 99.3%, with similar results regardless of comorbidity. PWUD (active) and those with psychiatric disorders had the most meaningful improvements in PROs. Adverse events (AEs) occurred in 631/2354 patients (26.8%), and serious AEs in 44 patients (1.9%). GLE/PIB was highly effective and well tolerated in this real-world study of patient groups key to HCV elimination.

Hepatitis C therapy with grazoprevir/elbasvir and glecaprevir/pibrentasvir in patients with advanced chronic kidney disease: data from the German Hepatitis C-Registry (DHC-R).

OBJECTIVES: Grazoprevir/elbasvir and glecaprevir/pibrentasvir (G/P) are the two preferred treatment options for patients with chronic hepatitis C virus (HCV) infection and a glomerular filtration rate (GFR) <30 mL/min. Both therapies have been separately analyzed in different real-life cohorts; however, a direct comparison has not been performed so far. We, therefore, analyzed safety and effectiveness of both regimens in a concerted real-life population. METHODS: The Germany Hepatitis C-Registry is a prospective national real-world registry. The analysis is based on 2773 patients with documented GFR at baseline treated with grazoprevir/elbasvir (N = 1041), grazoprevir/elbasvir + ribavirin (N = 53) and glecaprevir/pibrentasvir (N = 1679). RESULTS: A total of 93 patients with GFR <30 mL/min were treated with grazoprevir/elbasvir (N = 56), grazoprevir/elbasvir + ribavirin (N = 4), and glecaprevir/pibrentasvir (N = 33). They suffered significantly more frequent from diabetes mellitus, hypertension, and coronary heart disease than individuals with GFR >30 mL/min and showed the following baseline characteristics: 20.4, 55.9, 3.2, 12.9, and 5.3% were infected with HCV-genotypes 1a, 1b, 2, 3, and 4; 12.9% suffered from liver cirrhosis; 80.1% were treatment-naïve. Baseline characteristics except distribution of HCV-genotype 1b (n = 43/52 treated with grazoprevir/elbasvir) and sustained virologic response rates (SVR12) did not differ significantly between glecaprevir/pibrentasvir (SVR12: 100%) and grazoprevir/elbasvir (SVR12: 97.9%).Fatigue, headache, abdominal discomfort, and arthralgia were the most frequently reported adverse events without a statistical difference between grazoprevir/elbasvir and glecaprevir/pibrentasvir. CONCLUSION: In patients with chronic hepatitis C and a baseline GFR ≤30 mL/min grazoprevir/elbasvir and glecaprevir/pibrentasvir show an equally favorable safety profile and antiviral efficacy and can both be recommended for real-life use.

The changing characteristics of patients infected with chronic hepatitis C virus from 2014 to 2019: Real-world data from the German Hepatitis C-Registry (DHC-R).

The number of patients diagnosed with hepatitis C virus (HCV) is markedly higher than the number initiating treatment indicating gaps in the care cascade, likely centred around reaching at-risk populations. Understanding changing characteristics of patients with HCV allows for targeted programs that increase linkage to care. We investigated changes in demographic and clinical characteristics of patients registered in the German Hepatitis C-Registry (DHC-R) from 1 January 2014 to 31 December 2019. The DHC-R is an ongoing, noninterventional, multicentre, prospective, observational cohort registry including 327 German centres. Patient characteristics were analysed over time in 7 phases for all patients completing a screening visit. Overall, 14,357 patients were enrolled. The percentage of treatment-naïve/non-cirrhotic patients increased from 34.4% in phase 1 (1 January-31 December 2014) to 68.2% in phase 7 (1 August-31 December 2019). The proportion of migrants, alcohol users, people who inject drugs, and those receiving opiate substitution therapy increased in later registry phases. Most patients (60.1%) were receiving comedication at baseline. The most prescribed comedications were drugs used to treat opioid dependence which increased from 9.2% in phase 1 to 24.0% in phase 7. The patients' mean age decreased from 52.3 years in phase 1 to 48.7 years in phase 7. From 2014 to 2019, the proportion of at-risk patients enrolling in the registry increased. To eliminate viral hepatitis as a major public health threat, a continued commitment to engaging underserved populations into the HCV care cascade is needed.

Sofosbuvir, velpatasvir, and voxilaprevir for patients with failure of previous direct-acting antiviral therapy for chronic hepatitis C: Results from the German Hepatitis C-Registry (DHC-R).

Despite the high effectiveness of direct-acting antivirals for the treatment of hepatitis C, a small proportion of patients do not respond to approved regimens. The combination regimen of SOF/VEL/VOX was recently approved for patients with failure to prior NS5A-based treatment. In this German real-world cohort including patients with cirrhosis (27.3 %) and previous decompensation events, 12 weeks of SOF/VEL/VOX resulted in high virologic response rates irrespective of disease severity and prior DAA regimen. Adverse events were mostly mild or moderate and comparable to those seen in the approval studies.

Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial.

BACKGROUND: Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease. METHODS: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38. FINDINGS: Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change -27·8%, 95% repeated CI -34·7 to -14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis). INTERPRETATION: Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies. FUNDING: Dr Falk Pharma GmbH.

Real-world effectiveness and safety of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C infection: data from the German Hepatitis C-Registry.

BACKGROUND: Glecaprevir/pibrentasvir is a pangenotypic direct-acting antiviral regimen approved for treating adults chronically infected with hepatitis C virus (HCV). There are limited real-world data on glecaprevir/pibrentasvir to date. AIM: To evaluate the effectiveness and safety of glecaprevir/pibrentasvir under real-world conditions in the German Hepatitis C-Registry (DHC-R). METHODS: The DHC-R is an ongoing, non-interventional, multicentre, prospective, observational cohort study that monitors patients with chronic HCV infection. Data were collected from patients who initiated glecaprevir/pibrentasvir and completed a screening visit on or after 2 August 2017. The primary effectiveness endpoint was sustained virological response at post-treatment Week 12 (SVR12). Safety and tolerability were also assessed. RESULTS: As of 15 July 2018, 586 patients received glecaprevir/pibrentasvir and had documented SVR12 data, treatment discontinuation, loss to follow-up or HCV reinfection. Five hundred and fifty-two patients (94%) received on-label treatment. At baseline, most on-label patients were infected with HCV genotype 1 (53%) or 3 (33%), HCV treatment-naïve (90%), without cirrhosis (94%), and treated for 8 weeks (93%). Five hundred and thirty-four patients (96.7%) achieved SVR12 (intention-to-treat [ITT] analysis). By modified ITT analysis (excluding patients who discontinued and did not achieve SVR12 or patients lost to follow-up), the SVR12 rate was 99.4% (n/N = 534/537). There was one documented virological failure (relapse) and two documented HCV reinfections. One hundred and forty-two (26%) adverse events (AEs) and 9 (2%) serious AEs occurred; 2 (<1%) AEs led to treatment discontinuation. All patients treated off-label (N = 34) achieved SVR12. CONCLUSION: Glecaprevir/pibrentasvir was highly effective and well tolerated under real-world conditions. Clinical trial number: DRKS00009717 (German Clinical Trials Register, DRKS).

Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C.

BACKGROUND & AIMS: Ledipasvir/sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study, 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the Summary of Product Characteristics (SmPC), 8-week treatment may be considered in naïve non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of an 8-week regimen of LDV/SOF under real-world conditions. The aim of the present study was to characterise patients receiving 8 weeks of LDV/SOF compared to those receiving 12 weeks of LDV/SOF, and to describe therapeutic outcomes in routine clinical practice. METHODS: The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Treatment with SOF/LDV (without RBV) for 8 or 12 weeks was initiated on or before September 30, 2015. RESULTS: Overall, 84.6% (2,034/2,404) of the safety population (intention-to-treat-1 [ITT1]) and 98.2% (2,029/2,066) of the per protocol (PP) population achieved sustained virological response at week 12 (SVR12). In the 8-week group, 85.1% (824/968) of ITT1 and 98.3% (821/835) of PP patients achieved SVR12, while in the 12-week group, 85.5% (1,210/1,415) of ITT1, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). CONCLUSIONS: Under real-world conditions a high proportion of eligible patients receiving 8-week LDV/SOF treatment achieved SVR12. Relapse occurred more frequently in patients who did not meet the selection criteria according to the SmPC. LAY SUMMARY: In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8-week) resulted in equivalent cure rates to 12-week treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy. Clinical Trial number: DRKS00009717 (German Clinical Trials Register, DRKS).

Treatment of naïve patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA.

Evidence based clinical guidelines are implemented to treat patients efficiently that include efficacy, tolerability but also health economic considerations. This is of particular relevance to the new direct acting antiviral agents that have revolutionized treatment of chronic hepatitis C. For hepatitis C genotypes 2/3 interferon free treatment is already available with sofosbuvir plus ribavirin. However, treatment with sofosbuvir-based regimens is 10-20 times more expensive compared to pegylated interferon alfa and ribavirin (PegIFN/RBV). It has to be discussed if PegIFN/RBV is still an option for easy to treat patients. We assessed the treatment of patients with chronic hepatitis C genotypes 2/3 with PegIFN/RBV in a real world setting according to the latest German guidelines. Overall, 1006 patients were recruited into a prospective patient registry with 959 having started treatment. The intention-to-treat analysis showed poor SVR (GT2 61%, GT3 47%) while patients with adherence had excellent SVR in the per protocol analysis (GT2 96%, GT3 90%). According to guidelines, 283 patients were candidates for shorter treatment duration, namely a treatment of 16 weeks (baseline HCV-RNA <800.000 IU/mL, no cirrhosis and RVR). However, 65% of these easy to treat patients have been treated longer than recommended that resulted in higher costs but not higher SVR rates. In conclusion, treatment with PegIFN/RBV in a real world setting can be highly effective yet similar effective than PegIFN± sofosbuvir/RBV in well-selected naïve G2/3 patients. Full adherence to guidelines could be further improved, because it would be important in the new era with DAA, especially to safe resources.

Cost of treating hepatitis C in Germany: a retrospective multicenter analysis.

BACKGROUND: Viral hepatitis is major a public health problem affecting millions of people worldwide. Estimates assume 400 000-500 000 people chronically infected with hepatitis C virus (HCV) in Germany. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The aim of the study was to assess the costs for treating patients with chronic HCV in Germany. METHODS: We conducted a retrospective multicenter observational study. The design was approved by an ethics committee, and patients were asked for their informed consent. Patients were grouped in four different health states. Healthcare utilization data were extracted from doctor files of six medical centers in Germany. RESULTS: Data of 315 patients with chronic HCV were analyzed. The mean age was 49.4 years, 57.5% were male and 67.9% had a genotype 1 infection. The most common routes of transmission were injection drug use (39.0%) and infection through blood products (15.9%). The average total cost was €19 147 including ambulatory care and diagnostics (€1686), pharmaceuticals (€14 875), inpatient care (€1293), and sick leave (€1293). For patients in stable health states (mild and moderate HCV, compensated cirrhosis), costs did not differ significantly and were mainly influenced by antiviral treatment. For patients with decompensated cirrhosis, inpatient care accounted for the largest part of the costs. CONCLUSION: Treatment of HCV patients involves high costs, mainly associated with the length of antiviral therapy. Viral eradication can prevent severe disease stages, which are associated with high costs. It is necessary to follow current guidelines and monitor patients closely to avoid unnecessary costs.

Vitamin D levels vary during antiviral treatment but are unable to predict treatment outcome in HCV genotype 1 infected patients.

BACKGROUND: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. METHODS: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24-72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. RESULTS: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002-1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975-0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000-1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073-2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271-4.695, P = 0.007) constituted the strongest predictors of treatment response. CONCLUSIONS: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.

Baseline MELD score predicts hepatic decompensation during antiviral therapy in patients with chronic hepatitis C and advanced cirrhosis.

BACKGROUND AND AIMS: In patients with advanced liver cirrhosis due to chronic hepatitis C virus (HCV) infection antiviral therapy with peginterferon and ribavirin is feasible in selected cases only due to potentially life-threatening side effects. However, predictive factors associated with hepatic decompensation during antiviral therapy are poorly defined. METHODS: In a retrospective cohort study, 68 patients with HCV-associated liver cirrhosis (mean MELD score 9.18 ± 2.72) were treated with peginterferon and ribavirin. Clinical events indicating hepatic decompensation (onset of ascites, hepatic encephalopathy, upper gastrointestinal bleeding, hospitalization) as well as laboratory data were recorded at baseline and during a follow up period of 72 weeks after initiation of antiviral therapy. To monitor long term sequelae of end stage liver disease an extended follow up for HCC development, transplantation and death was applied (240 weeks, ± SD 136 weeks). RESULTS: Eighteen patients (26.5%) achieved a sustained virologic response. During the observational period a hepatic decompensation was observed in 36.8%. Patients with hepatic decompensation had higher MELD scores (10.84 vs. 8.23, p<0.001) and higher mean bilirubin levels (26.74 vs. 14.63 µmol/l, p<0.001), as well as lower serum albumin levels (38.2 vs. 41.1 g/l, p=0.015), mean platelets (102.64 vs. 138.95/nl, p=0.014) and mean leukocytes (4.02 vs. 5.68/nl, p=0.002) at baseline as compared to those without decompensation. In the multivariate analysis the MELD score remained independently associated with hepatic decompensation (OR 1.56, 1.18-2.07; p=0.002). When the patients were grouped according to their baseline MELD scores, hepatic decompensation occurred in 22%, 59%, and 83% of patients with MELD scores of 6-9, 10-13, and >14, respectively. Baseline MELD score was significantly associated with the risk for transplantation/death (p<0.001). CONCLUSIONS: Our data suggest that the baseline MELD score predicts the risk of hepatic decompensation during antiviral therapy and thus contributes to decision making when antiviral therapy is discussed in HCV patients with advanced liver cirrhosis.

Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients.

The preeminent mode of action of the broad-spectrum antiviral nucleoside ribavirin in the therapy of chronic hepatitis C is currently unresolved. Particularly under contest are possible mutagenic effects of ribavirin that may lead to viral extinction by lethal mutagenesis of the hepatitis C virus (HCV) genome. We applied ultradeep sequencing to determine ribavirin-induced sequence changes in the HCV coding region (nucleotides [nt] 330 to 9351) of patients treated with 6-week ribavirin monotherapy (n = 6) in comparison to placebo (n = 6). Baseline HCV RNA levels maximally declined on average by -0.8 or -0.1 log10 IU/ml in ribavirin- versus placebo-treated patients. No general increase in rates of nucleotide substitutions in ribavirin-treated patients was observed. However, more HCV genome positions with high G-to-A and C-to-U transition rates were detected between baseline and treatment week 6 in ribavirin-treated patients in comparison to placebo-treated patients (rate of 0.0041 transitions per base pair versus rate of 0.0022 transitions per base pair; P = 0.049). Similarly, the sensitive detection of low-frequency minority variants by statistical filtering indicated significantly more positions with G-to-A and C-to-U transitions in ribavirin-treated patients than in placebo-treated patients (rate of 0.0331 transitions versus rate of 0.0186 transitions per G/C-containing position at baseline; P = 0.018). In contrast, non-ribavirin-associated A-to-G and U-to-C transitions were not enriched in the ribavirin group (P = 0.152). We conclude that ribavirin exerts a mutagenic effect on the virus in patients with chronic hepatitis C by facilitating G-to-A and C-to-U nucleotide transitions.

Prediction of minimal residual viremia in HCV type 1 infected patients receiving interferon-based therapy.

INTRODUCTION: Complete suppression of viral replication is crucial in chronic HCV treatment in order to prevent relapse and resistance development. We wanted to find out which factors influence the period from being already HCV RNA negative by bDNA assay (< 615 IU/mL) to become undetectable by the more sensitive TMA test (< 5.3 IU/mL). MATERIAL AND METHODS: Evaluated were 433 HCV type 1-infected patients. All of them received 1.5 ug/kg Peg-IFNα-2b plus ribavirin for 18-48 weeks. bDNA was performed weekly during the first 8 weeks and thereafter at weeks 12, 24, and 48. Patients who became bDNA undetectable were additionally analysed by TMA. RESULTS: Of the 309 patients with on-treatment response (< 615 IU/mL), 289 also reached undetectable HCV RNA levels by TMA. Multivariate analysis revealed that viremia ≤ 400,000 IU/mL (p = 0.001), fast initial virologic decline (p = 0.004) and absence of fibrosis (p = 0.035) were independent predictors of an accelerated on-treatment response by TMA assay in already bDNA negative patients. bDNA negative patients becoming HCV RNA undetectable by TMA within the following 3 weeks had a frequency of relapse of 21%, whereas those showing TMA negativity after 3 weeks relapsed in 38% (p = 0.001). In RVR patients (bDNA < 615 IU/mL at week 4) the corresponding relapse rates were 15.3% vs. 37.5%, respectively (p = 0.003). CONCLUSION: Early viral kinetics, baseline viremia and fibrosis stage are important tools to predict persistent minimal viremia during interferon-based therapy. The data have implications for designing a more refined treatment strategy in HCV infection, even in the setting of protease inhibitor-based triple treatment.

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.

Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C.

UNLABELLED: Earlier studies have suggested neurocognitive impairment in patients with chronic hepatitis C virus (HCV) infection even before liver cirrhosis has developed. Since these deficits might be reversible after successful antiviral therapy, we analyzed the long-term course of neurocognitive parameters in HCV patients with and without successful virus elimination by an interferon-based antiviral treatment. In a multicenter study including 168 HCV patients receiving antiviral therapy (peginterferon alpha-2b and ribavirin) we performed a long-term follow-up of neurocognitive performance before and after treatment. Neurocognitive function was psychometrically assessed using the computer-aided TAP (Test Battery of Attentional Performance). When tested at least 12 months after termination of antiviral treatment, patients with sustained virologic response (SVR) had improved significantly as compared to their pretreatment performance in three of five TAP subtasks (vigilance, P < 0.001; shared attention: optical task, P < 0.001; working memory, P < 0.001). Patients who failed to eradicate the virus, however, showed no significant long-term changes in neurocognitive performance in all five subtasks assessed (0.194 < P < 0.804). In the posttreatment evaluation, neurocognitive function was significantly better in responders to the antiviral therapy as compared to nonresponders. CONCLUSION: Successful eradication of HCV leads to a significant improvement of relevant aspects of attentional and neurocognitive performance, indicating that the neurocognitive impairment caused by chronic HCV infection is potentially reversible. This therefore suggests an added therapeutic benefit of antiviral treatment in HCV infection. Improvement of neurocognitive function may be an additional treatment indication in patients with HCV. (HEPATOLOGY 2013;58:497-504).

Importance of minimal residual viremia for relapse prediction in patients with chronic hepatitis C genotype 1 infection.

This study demonstrates that a more precise prediction of the individual relapse risk in chronic hepatitis C virus genotype 1 infection can be obtained by kinetics of minimal residual viremia at weeks 4, 8, and 12 in combination with levels of baseline viremia. These data may also help to further individualize new protease inhibitor-based triple therapy regimens.

Improved responses to pegylated interferon alfa-2b and ribavirin by individualizing treatment for 24-72 weeks.

BACKGROUND & AIMS: Guidelines recommend that patients with chronic hepatitis C virus (HCV) infection be treated with pegylated interferon and ribavirin for 24, 48, or 72 weeks, based on their virologic response to treatment. We investigated the effects of treating patients for individualized durations. METHODS: We treated 398 treatment-naïve patients who had HCV genotype 1 infections with pegylated interferon alfa-2b and ribavirin for 24, 30, 36, 42, 48, 60, or 72 weeks (mean of 39 weeks, termed individualized therapy); the duration of therapy was determined based on baseline viral load and the time point at which HCV RNA levels became undetectable (measured at weeks 4, 6, 8, 12, 24, and 30). Results were compared with those of 225 patients who received standard treatment for 48 weeks (mean of 38 weeks). RESULTS: Rates of sustained virologic response (SVR) were 55% among patients who received individualized treatment and 48% among those who received standard treatment (P < .0001 for noninferiority). SVR rates, according to the time point at which HCV RNA levels became undetectable, did not differ significantly between groups. Patients with a rapid virologic response (undetectable levels of HCV RNA at week 4) who were treated for 24 to 30 weeks achieved high rates of SVR (86%-88%). Rates of SVR increased among slow responders who first tested negative for HCV RNA at week 24 and were treated for 60 to 72 weeks compared with those treated for 48 weeks (60%-68% vs 43%-44%). The CC polymorphism at IL28B rs129797860 was associated with an increased rate of SVR compared with the CT/TT polymorphism (P < .0001) at baseline but not among patients who had undetectable levels of HCV RNA following treatment. CONCLUSIONS: Individualizing treatment of patients with chronic HCV genotype 1 infections for 24 to 72 weeks results in high rates of SVR among rapid responders and increases SVR among slow responders.

Randomized trial of peginterferon alfa-2b and ribavirin for 48 or 72 weeks in patients with hepatitis C virus genotype 1 and slow virologic response.

UNLABELLED: The benefit of extending treatment duration with peginterferon (PEG-IFN) and ribavirin (RBV) from 48 weeks to 72 weeks for patients with chronic hepatitis C genotype 1 infection has not been well established. In this prospective, international, open-label, randomized, multicenter study, 1,428 treatment-naïve patients from 133 centers were treated with PEG-IFN alfa-2b (1.5 µg/kg/week) plus RBV (800-1,400 mg/day). Patients with detectable hepatitis C virus (HCV) RNA and a ≥2-log(10) drop in HCV RNA levels at week 12 (slow responders) were randomized 1:1 to receive 48 weeks (n = 86) or 72 weeks (n = 73) of treatment. Sustained virologic response (SVR) rates were 43% in slow responders treated for 48 weeks and 48% in slow responders treated for 72 weeks (P = 0.644). Relapse rates were similar in slow responders treated for 48 or 72 weeks (47% versus 33%, P = 0.169). The safety profile was similar in both treatment arms; serious adverse events leading to discontinuation of treatment were observed in 3.5% of slow responders treated for 48 weeks and 8.2% of those treated for 72 weeks. Among slow responders with a <2-log drop in HCV RNA at week 8, SVR was 39% in the 72-week arm and 19% in the 48-week arm. CONCLUSION: These data suggest that 48 weeks of therapy with PEG-IFN alfa-2b plus RBV (800-1,400 mg/day) should remain a standard-of-care treatment for treatment-naïve G1 slow responders.

Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients.

UNLABELLED: Individualized treatment on the basis of early viral kinetics has been discussed to optimize antiviral therapy in chronic hepatitis C virus (HCV) infection. Individually tailored reduction in treatment duration in HCV type 1-infected patients represents one possible strategy. Four hundred thirty-three patients were randomly assigned to receive either 1.5 microg/kg peginterferon alfa-2b weekly plus 800-1,400 mg ribavirin daily for 48 weeks (n = 225, group A) or an individually tailored treatment duration (18-48 weeks; n = 208, group B). In the latter group, treatment duration was calculated using the time required to induce HCV RNA negativity (branched DNA [bDNA] assay; sensitivity limit, 615 IU/mL) multiplied by the factor 6. All bDNA negative samples were retested with the more sensitive transcription-mediated amplification (TMA) assay (sensitivity limit, 5.3 IU/mL). Sustained virologic response (SVR) rates were significantly lower in group B (34.6% versus 48.0% [P = 0.005]) due to higher relapse rates (32.7% versus 14.2% [P< 0.0005]). Important predictors of response were the levels of baseline viremia as well as the time to TMA negativity on treatment. Taking the simultaneous presence of low baseline viral load (<800,000 IU/mL) and a negative TMA test within the first 4 weeks as predictors for treatment response, SVR rates were comparable between both treatment schedules with an SVR probability of >80% obtained in patients treated for only 18 or 24 weeks. CONCLUSION: The individualized treatment strategy according to time to bDNA negativity failed to provide comparable efficacy compared with the standard of care. The inferiority of the individualized protocol may be explained by the use of a less sensitive HCV RNA assay, and also by underestimation of the importance of baseline viremia.