Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network

Abstract

BackgroundFew data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure.AimTo evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage.MethodsData on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers.ResultsAmong 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5–14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3–12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications.ConclusionsFailure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.

Advanced liver disease outcomes after hepatitis C eradication by human immunodeficiency virus infection in PITER cohort

“…After successful DAA treatment, preliminary data have shown an improvement in Child-Pugh class (observed in 85% of coinfected and in 65.9% of monoinfected patients, with no significant difference between the two groups), suggesting that viral eradication helps liver function recovery in the majority of patients with liver cirrhosis (data not shown). As previously reported, HCV cured after DAA therapy induce a reduction of the risk of HCC occurrence compared with non-responders; however, a residual risk still persists even after viral eradication [23][24][25][26]. In particular, regarding the HCC occurrence following viral eradication, the cumulative incidence was 2.2% in coinfected and 3.9% in monoinfected patients, significantly lower compared to the cumulative incidence of HCC (13.8%) reported in patients who experienced treatment failure in the PITER cohort [23].…”

“…As previously reported, HCV cured after DAA therapy induce a reduction of the risk of HCC occurrence compared with non-responders; however, a residual risk still persists even after viral eradication [23][24][25][26]. In particular, regarding the HCC occurrence following viral eradication, the cumulative incidence was 2.2% in coinfected and 3.9% in monoinfected patients, significantly lower compared to the cumulative incidence of HCC (13.8%) reported in patients who experienced treatment failure in the PITER cohort [23]. However, careful follow-up is important not only in patients with virological failure or with known risk factors (i.e., decompensation of liver cirrhosis prior to antiviral treatment or a "cured" HCC), but also in patients with F4 fibrosis stage/liver cirrhosis prior to viral eradication.…”

Efficacy and safety of direct‐acting antivirals for hepatitis C in the elderly: A systematic review and meta‐analysis

“…In fact, we identified several studies that specifically focus on elderly populations while others reported age‐specific subgroup analyses. While most of the studies reported comparable efficacy of DAAs in the elderly compared to younger patients, some raised concerns that higher rates of treatment failure may specifically affect subgroups with other negative predictive factors, including cirrhosis and HCV genotypes 3 and 4 . Moreover, some studies also reported higher rates of SAEs and treatment discontinuation in the elderly .…”

“…While most of the studies reported comparable efficacy of DAAs in the elderly compared to younger patients, some raised concerns that higher rates of treatment failure may specifically affect subgroups with other negative predictive factors, including cirrhosis 24 and HCV genotypes 3 and 4. [25][26][27] Moreover, some studies also reported higher rates of SAEs and treatment discontinuation in the elderly. 18,[28][29][30] These findings have raised concerns whether a 'treat all' strategy is justified given the lack of a comprehensive risk-benefit analysis in this particular patient population.…”

Rescue therapy for chronic hepatitis C virus infection after repeated treatment failures: Impact on disease progression and risk of hepatocellular carcinoma

“…Kondili et al . suggested that CTP class deterioration and impairment of hepatic function after repeated treatment failures could be improved by successful retreatment in a significant number of retreated patients …”