High Rates of Sustained Virological Response Despite Premature Discontinuation of Directly Acting Antivirals in HCV-infected Patients Treated in a Real-life Setting

Massimiliano Fabbiani; Andrea Lombardi; Marta Colaneri; Paolo Del Poggio; Paolo Perini; Roberta D'Ambrosio; Elisabetta Degasperi; Clara Dibenedetto; Alessia Giorgini; Luisa Pasulo; Franco Maggiolo; Francesco Castelli; Paola Brambilla; Ombretta Spinelli; Tiziana Re; Ana Lleo; Mariagrazia Rumi; Caterina Uberti-Foppa; Alessandro Soria; Alessio Aghemo; Pietro Lampertico; Chiara Baiguera; Monica Schiavini; Stefano Fagiuoli; Raffaele Bruno

Disclosures

J Viral Hepat. 2021;28(3):558-568. 

In This Article

Abstract and Introduction

Abstract

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n = 168, 46%) and 3 (n = 59, 16.2%). DAA was discontinued a median of 1 (IQR 1–4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2 weeks before the planned schedule. In patients with F0–F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n = 2/4) vs. 99.1% (n = 109/110) for ≥4 weeks, p = 0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3% (n = 25/30) vs. 94.6% (n = 209/221) for ≥8 weeks, p = 0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0–F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials.

Introduction

Treatment of chronic hepatitis C (CHC) substantially changed in the last few years because of the widespread availability of directly acting antivirals (DAAs). These drugs, acting specifically on viral proteins involved in the replication process, lead to the eradication of hepatitis C virus (HCV) in nearly all treated patients, without relevant side effects. To date, the recommended treatment duration spans from 8 to 16 weeks based on the selected regimen, the HCV genotype, fibrosis stage and the therapeutic history of the patient.[1] These recommendations are derived from the large number of phase III trials conducted during the registration studies of DAAs. Of note, none of these was planned to have a duration below 8 weeks. A shorter treatment length, if effective, could be associated with several clear advantages: an increase in adherence, a potential reduction in the risk of adverse events, fewer interactions with concomitantly administered drugs, a decrease in costs and the potential to reach 'chaotic' clusters of patients where ultra-short treatment durations may provide a clinical benefit. Taken together, these elements could increase the number of patients treated and facilitate the global HCV eradication goal.[2]

Evidence supporting the feasibility of treatments with shorter duration is available in the literature. A Japanese modelling study, conducted on patients treated with daclatasvir (DCV) and asunaprevir, predicted that 100% and 98.5% of patients who had HCV-RNA <15 IU/ml at days 14 and 28 of treatment might have been cured with 6 and 8 weeks of therapy, respectively.[3] Interestingly, the predicted time to cure was not influenced by cirrhosis status nor age.

Other clinical studies have instead highlighted factors that can impact the response to short-duration DAA therapy. In the clinical trial NCT01805882, the administration of sofosbuvir (SOF), ledipasvir (LDV) and GS-9669, a non-nucleoside NS5B thumb site 3 inhibitor of HCV polymerase, or GS-9451, a HCV NS3/4A protease inhibitor, in a cohort of patients with HCV genotype 1 infection for 6 weeks resulted in significant sustained virological response (SVR) rates.[4] Unfortunately, a decrease in the cure rates was observed when the combination SOF+LDV+GS-9451 was administered for 6 weeks in a cohort of cirrhotic patients with HCV genotype 1 infection.[5] Indeed, SVR 12 weeks after the end of treatment (SVR12) was achieved in only 76% of those treated, suggesting that significant liver fibrosis could be an impediment to achieve SVR with shortened treatment duration.

Another factor influencing response rates is HCV genotype. Indeed, in the NCT02569710 phase IIa clinical trial, the three drugs combination of AL-335, an NS5B inhibitor, odalasvir and simeprevir (SIM) for 6 or 8 weeks, was highly efficacious against HCV genotype 1 reaching SVR12 rates of 100%.[6] Instead, the same combination was totally ineffective when given for 8 weeks in HCV genotype 3 infected patients.

Finally, the DAA employed can also impact the response rate. In the FOURward study, a four drugs regimen composed by DCV, asunaprevir, beclabuvir and SOF was administered in non-cirrhotic patients infected with HCV genotype 1 for 4 or 6 weeks. The SVR12 rates were disappointing being 29% and 57%, respectively.[7] Instead, in the C-SWIFT trial, treatment-naive patients with chronic HCV genotype 1 infection received elbasvir/grazoprevir (EBR/GZR) with SOF for 4–12 weeks. Here, SVR12 rates were higher, being 87% and 81% in non-cirrhotics and cirrhotics, respectively.[8]

Despite current European guidelines do not recommend regimens lasting less than 12 weeks in cirrhotic patients and less than 8 weeks in those with mild-to-severe liver fibrosis,[1] in routine clinical practice patients can prematurely discontinue the prescribed regimen for several reasons (i.e., low adherence, adverse events, hospitalization). However, there are no data about the effects of premature discontinuation of DAA regimens on reaching SVR12.

The aim of our study was to investigate SVR12 rates in patients who prematurely discontinued DAA regimens and to assess the shortest effective duration of DAA-based treatments able to lead to SVR and the factors influencing it. We identified, in a large cohort of patients with CHC treated with DAAs, those who prematurely withdrew (or discontinued) the assigned treatment. Then, we assessed the SVR rates in this subgroup and we stratified the results according to DAA regimen, HCV genotype, fibrosis stage and other relevant patient characteristics.

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