Oral DAA Research Articles

Su1061 Pearl-IV: a 12-Week Regimen of ABT-450/r/ABT-267 and ABT-333, With or Without Ribavirin Achieves Svr12 Rates≥90% in Treatment-Naïve Adults Infected With Hepatitis C Virus Genotype 1A

Background: The HCV-PRO is a validated disease-specific patient reported outcome (PRO) instrument. This analysis reports on HCV-infected patient response in a trial of oral DAA therapy and assesses psychometric properties of the French-translated HCV-PRO. Method: French Genotype 1 patients in the multinational AVIATOR trial of interferon-free DAA therapy responded to theHCV-PRO, SF-36v.2, and EQ-5D 5L+VAS. HCV-PROwas translated under Harmonization standards. Approved French-language SF-36 and EQ-5Dwere included for psychometric comparison. Analyses of response were performed at Baseline, week 8 (Wk8), End of Treatment (EOT), and 24 week follow-up (PTW24), and included change from baseline. Internal consistency/reliability of HCV-PRO items and total score were evaluated using Cronbach's alpha. Convergent validity was assessed through Pearson's correlation (0.5-0.9=moderate-strong) to SF-36 MCS/PCS and EQ-5D VAS. Discriminant validity was assessed by dichotomizing HCV-PRO score on EQ-5D Anxiety/Depression and Pain/Discomfort dimensions (none versus some). Results: Demographics (N=58): 48% female, 88% white, 45% ≥50 years of age, 45% Genotype 1a, 86% IL28B non-CC. Clinical response (SVR24) was 93.1%. All PRO scores were minimally changed during treatment (Wk8, EOT). Mean HCV-PRO score at PTW24 was improved (p<0.03) over baseline. Cronbach's alpha for HCV-PRO items and total scores were 0.44-0.95. HCV-PRO total score exhibited moderateto-high correlation with SF-36 MCS/PCS and EQ-5D VAS total scores (r=0.54-0.87). HCVPRO scores were lower in patients with anxiety/depression or pain/discomfort (p<0.01). Conclusion: The French-translated HCV-PRO is a valid, responsive, disease-specific instrument. HCV-PRO score changed minimally during oral DAA treatment and improved over baseline after therapy.

Su1058 Early Stopping Rules for Faldaprevir Plus Pegylated Interferon α-2A and Ribavirin in Treatment-Naïve Patients: Exploratory Study of Pooled Data From Phase III Trials

Background: The HCV-PRO is a validated disease-specific patient reported outcome (PRO) instrument. This analysis reports on HCV-infected patient response in a trial of oral DAA therapy and assesses psychometric properties of the French-translated HCV-PRO. Method: French Genotype 1 patients in the multinational AVIATOR trial of interferon-free DAA therapy responded to theHCV-PRO, SF-36v.2, and EQ-5D 5L+VAS. HCV-PROwas translated under Harmonization standards. Approved French-language SF-36 and EQ-5Dwere included for psychometric comparison. Analyses of response were performed at Baseline, week 8 (Wk8), End of Treatment (EOT), and 24 week follow-up (PTW24), and included change from baseline. Internal consistency/reliability of HCV-PRO items and total score were evaluated using Cronbach's alpha. Convergent validity was assessed through Pearson's correlation (0.5-0.9=moderate-strong) to SF-36 MCS/PCS and EQ-5D VAS. Discriminant validity was assessed by dichotomizing HCV-PRO score on EQ-5D Anxiety/Depression and Pain/Discomfort dimensions (none versus some). Results: Demographics (N=58): 48% female, 88% white, 45% ≥50 years of age, 45% Genotype 1a, 86% IL28B non-CC. Clinical response (SVR24) was 93.1%. All PRO scores were minimally changed during treatment (Wk8, EOT). Mean HCV-PRO score at PTW24 was improved (p<0.03) over baseline. Cronbach's alpha for HCV-PRO items and total scores were 0.44-0.95. HCV-PRO total score exhibited moderateto-high correlation with SF-36 MCS/PCS and EQ-5D VAS total scores (r=0.54-0.87). HCVPRO scores were lower in patients with anxiety/depression or pain/discomfort (p<0.01). Conclusion: The French-translated HCV-PRO is a valid, responsive, disease-specific instrument. HCV-PRO score changed minimally during oral DAA treatment and improved over baseline after therapy.

P723 FALDAPREVIR PLUS PEGYLATED INTERFERON/RIBAVIRIN DID NOT INCREASE ANAEMIA COMPARED WITH PEGYLATED INTERFERON/RIBAVIRIN IN HCV GENOTYPE-1, TREATMENT-NAIVE PATIENTS: POOLED ANALYSIS OF PHASE III STUDIES

Background: The HCV-PRO is a validated disease-specific patient reported outcome (PRO) instrument. This analysis reports on HCV-infected patient response in a trial of oral DAA therapy and assesses psychometric properties of the French-translated HCV-PRO. Method: French Genotype 1 patients in the multinational AVIATOR trial of interferon-free DAA therapy responded to theHCV-PRO, SF-36v.2, and EQ-5D 5L+VAS. HCV-PROwas translated under Harmonization standards. Approved French-language SF-36 and EQ-5Dwere included for psychometric comparison. Analyses of response were performed at Baseline, week 8 (Wk8), End of Treatment (EOT), and 24 week follow-up (PTW24), and included change from baseline. Internal consistency/reliability of HCV-PRO items and total score were evaluated using Cronbach's alpha. Convergent validity was assessed through Pearson's correlation (0.5-0.9=moderate-strong) to SF-36 MCS/PCS and EQ-5D VAS. Discriminant validity was assessed by dichotomizing HCV-PRO score on EQ-5D Anxiety/Depression and Pain/Discomfort dimensions (none versus some). Results: Demographics (N=58): 48% female, 88% white, 45% ≥50 years of age, 45% Genotype 1a, 86% IL28B non-CC. Clinical response (SVR24) was 93.1%. All PRO scores were minimally changed during treatment (Wk8, EOT). Mean HCV-PRO score at PTW24 was improved (p<0.03) over baseline. Cronbach's alpha for HCV-PRO items and total scores were 0.44-0.95. HCV-PRO total score exhibited moderateto-high correlation with SF-36 MCS/PCS and EQ-5D VAS total scores (r=0.54-0.87). HCVPRO scores were lower in patients with anxiety/depression or pain/discomfort (p<0.01). Conclusion: The French-translated HCV-PRO is a valid, responsive, disease-specific instrument. HCV-PRO score changed minimally during oral DAA treatment and improved over baseline after therapy.

Virus de l’hépatite C

The treatment of hepatitis C virus (HCV) infection markedly progressed these two last decades. Since 15 years, the combination of pegylated interferon α and ribavirin led to a sustained virologic response (SVR) which corresponds to a complete recovery in around 45% of patients with HCV genotype 1, 65% with HCV genotype 4, 70% with HCV genotype 3 and around 85% with HCV genotype 2. A better understanding of the HCV life-cycle recently resulted in the development of several potential direct-acting antiviral drugs (DAA) targeting viral proteins (NS3/4A protease inhibitors, NS5B nucleosidic and non nucleosidic polymerase inhibitors, NS5A replication complex inhibitors). A lot of data has been reported with the combinations of pegylated interferon α/ribavirin and the first generation oral DAA, Telaprevir and Boceprevir. These regimens have demonstrated a high level of antiviral efficacy (75% of SVR) and an acceptable safety profile. After this first major step, the combination of the second generation DAA with pegylated interferon α/ribavirin will impact antiviral potency (75 to 90% of SVR) and tolerance and will reduce the duration of therapies and the pill burden. The next step, which is an actual revolution, will be the oral combination of new DAA which is likely to become the standard of care for chronic HCV after 2015. Most studies have been conducted in small numbers of "easy-to-treat" patients with short post-treatment period with outstanding results but we are now waiting for confirming these results in more difficult-to-treat patients (experienced genotype 3-infected or genotype 1-infected patients who failed to first generation protease inhibitors, cirrhotic, HIV co-infected patients, allograft recipients or candidates to transplantation).

Oral antiviral therapies for chronic hepatitis C infection.

The treatment of hepatitis C virus (HCV) infection with pegylated interferon alpha and ribavirin leads to a sustained virologic response in around 50% of patients with HCV genotype 1, 65% with HCV genotype 4, 75% with HCV genotype 3 and around 80% with HCV genotype 2. A better understanding of the HCV lifecycle has resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins [NS3/4A protease inhibitors, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase inhibitors, NS5A replication complex inhibitors]. This review summarizes the main clinical data for the combinations of oral DAAs. DAAs, either in combination with pegylated interferon alpha or in interferon-free regimens, have demonstrated a high level of antiviral efficacy and a generally well-tolerated safety profile in treatment-naïve patients and in prior nonresponders to pegylated interferon alpha/ribavirin. Oral combination of new DAAs is likely to become the standard of care for chronic HCV in treatment-naïve or treatment-experienced patients. However, most studies so far have included small numbers of 'easy-to-treat' patients with short post-treatment periods for defining the sustained virologic response. Extension of the number of treated patients (including 'difficult-to-treat' patients, i.e. patients infected with genotype 3, who failed to respond to first-generation protease inhibitors or with cirrhosis as well as immunocompromised patients) and of the post-treatment follow up in a real-life setting could significantly worsen the rate of recovery. In these 'difficult-to-treat' patients, the rate of virologic cure with new DAAs could be lower than expected and consequently interferons may be still necessary in combination with the new drugs.

15 LANDSCAPE OF SOMATIC MUTATION IN HEPATOCELLULAR CARCINOMA

viral breakthrough, 1 before week 12; HCV variants associated with asunaprevir and daclatasvir resistance were identified. Serious adverse events included 1 patient with hyperbilirubinemia and gastroenteritis, 3 with pyrexia and 1 hypochondriasis. Conclusions: The dual oral DAA combination of daclatasvir and asunaprevir, without peg-alfa/RBV, may offer a needed therapeutic alternative to peg-alfa/RBV-containing regimens for many patients, including some difficult-to-treat groups.

Telaprevir for the treatment of hepatitis C

Introduction: More than 180 million people worldwide are infected with the chronic hepatitis C virus (HCV), a major cause of liver cirrhosis, and its life-threatening complications including liver failure, portal hypertension and hepatocellular carcinoma. For patients infected with HCV genotype 1, the chances of a sustained virologic response (SVR) with the previous standard of care treatment (Peg-IFN-α + ribavirin) are only 40 – 50%. Neither drug targets a specific HCV protein, and treatment is not only compromised by insufficient SVR rates but also associated with several side effects. With a better understanding of the HCV life-cycle, and of the structural features of HCV proteins, several promising direct antiviral drugs (DAAs) have entered clinical development.Areas covered: This review summarizes the clinical development of telaprevir and discusses the possible role of telaprevir in combination with Peg-IFN-α and ribavirin as a new standard treatment against HCV infection, as well as any possible challenges in the future.Expert opinion: Triple therapy, with telaprevir in combination with Peg-IFN-α + ribavirin, is the new standard for chronic hepatitis C treatment in genotype 1-infected patients. At present, there are several next-generation DAAs in clinical development in combination with Peg-IFN-α. The future, however, may also include new treatment strategies, such as oral DAA combinations.