Cure rates above 90% have been reported in most Phase III clinical trials using distinct all-oral direct-acting antivirals (DAAs) in chronic hepatitis C patients. Preliminary results in real-world patients have confirmed this, although efficacy tends to be lower.
Methods
All consecutive chronic hepatitis C patients treated with all-oral DAA regimens at three hepatitis clinics in Spain were retrospectively examined. Host and viral factors were tested as predictors of treatment failure.
Results
A total of 363 chronic hepatitis C patients had completed a course of all-oral DAA therapy outside clinical trials up to the end of 2015. All but 14 (4%) patients achieved sustained virological response. There were 10 failures that occurred after 12 weeks of sofosbuvir-ledipasvir, despite 5 of them being on ribavirin. All failures but one were relapses. The only patient with viral breakthrough selected NS5B L159F and NS5A Y93H. In multivariate analyses, only advanced liver fibrosis (Metavir F3–F4) and HIV coinfection were significantly associated with treatment failure. A trend towards lower response was seen for HCV genotype 4.
Conclusions
Treatment failures outside clinical trials are roughly seen in 4% of chronic hepatitis C patients who complete a course of all-oral DAA therapy, resembling what is seen in registration trials. In our series, outcomes were not significantly influenced by ribavirin addition, IL28B polymorphisms, HCV genotype, high baseline HCV RNA or prior interferon failure. However, advanced liver fibrosis and HIV coinfection were significantly associated with treatment failure. Our findings support that there is still room for individualization of current DAA therapy.
References
1.
Del BelloD., ChaA., SorberaM.Real-world sustained virologic response rates of sofosbuvir-containing regimens in patients coinfected with hepatitis C and HIV.Clin Infect Dis2016; 62: 1497–1504.
2.
ZhuG., ZouZ-L, ZhengJ-NSystematic review and network meta-analysis of randomized controlled trials -comparative effectiveness and safety of DAA for treatment-naive hepatitis C genotype 1.Medicine (Baltimore)2016; 95: e3004.
3.
SorianoV., LabargaP., de MendozaC.New hepatitis C therapies for special patient populations.Expert Opin Pharmacother2016; 17: 217–229.
4.
JensenD., O'LearyJ., PockrosP.Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: real world experience.Hepatology2014; 60Suppl S1: 219A.
5.
DieterichD., BaconB., FlammS.Evaluation of sofosbuvir and simeprevir –based regimens in the TRIO network: academic and community treatment of a real world, heterogeneous population.Hepatology2014; 60Suppl S1: 220A.
6.
AfdhalN., BaconB., DieterichD.Failure with all-oral DAA regimens: academic and community treatment of a real world population from the TRIO network.66th Annual Meeting of the American Association for the Study of Liver Diseases. 13–17 November 2015, San Francisco, CA, USA. Abstract LB17.
7.
BackusL.I., BelperioP.S., ShahoumianT.A., LoomisT.P., MoleL.A.Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S. Veterans.Aliment Pharmacol Ther2015; 42: 559–573.
8.
SulkowskiM.S., VargasH.E., Di BisceglieA.M.Effectiveness of simeprevir plus sofosbuvir, with or without ribavirin, in real-world patients with HCV genotype 1 infection.Gastroenterology2016; 150: 419–429.
9.
SorianoV., VispoE., PovedaE., LabargaP., BarreiroP.Treatment failure with new hepatitis C drugs.Expert Opin Pharmacother2012; 13: 313–323.
10.
ButiM., Riveiro-BarcielaM., EstebanR.Management of direct antiviral agent failures.J Hepatol2015; 63: 1511–1522.
11.
KowdleyK.V., GordonS.C., ReddyK.R.Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.N Engl J Med2014; 370: 1879–1888.
12.
KwoP., GitlinN., NahassR.A Phase 3 randomized open-label study to evaluate the efficacy and safety of 8 and 12 weeks of simeprevir plus sofosbuvir in treatment-naïve and –experienced patients with chronic HCV genotype 1 infection without cirrhosis: OPTIMIST-1.J Hepatol2015; 62Suppl 2: 270.
13.
LawitzE., PoordadF.F., PongP.S.Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label Phase 2 trial.Lancet2014; 383: 515–523.
14.
Benítez-GutiérrezL., BarreiroP., LabargaP.Prevention and management of treatment failure to new oral hepatitis C drugs.Expert Opin Pharmacother2016; 17: 1215–1223.
15.
LontokE., HarringtonP., HoweA.Hepatitis C virus drug resistance-associated substitutions: state of the art summary.Hepatology2015; 62: 1623–1632.
16.
ZiolM., Handra-LucaA., KettanehA.Non-invasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C.Hepatology2005; 41: 48–54.
17.
CastéraL., VergniolJ., FoucherJ.Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.Gastroenterology2005; 128: 343–350.
18.
de LédinghenV., DouvinC., KettanehA.Diagnosis of hepatic fibrosis and cirrhosis by transient elastography in HIV/hepatitis C virus-coinfected patients.J Acquir Immune Defic Syndr2006; 41: 175–179.
19.
RallónN.I., NaggieS., BenitoJ.M.Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients.AIDS2010; 24: F23–F29.
20.
DeeksE.D.Cobas AmpliPrep/Cobas Taqman HCV quantitative test version 2.0: an in vitro test for hepatitis C virus RNA quantification.Mol Diagn Ther2015; 19: 1–7.
21.
VerbeeckJ., StanleyM., CelisM.Evaluation of Versant hepatitis C virus genotype assay (LiPA) 2.0.J Clin Microbiol2008; 46: 1901–1906.
22.
EASL.Recommendations on treatment of hepatitis C 2015.J Hepatol2015; 63: 199–236.
23.
BackusL.I., BalpeiroP.S., ShahoumianT.Effectiveness of ledipasvir/sofosbuvir in treatment naive genotype 1 patients treated in routine medical practice.Hepatology2015; 62Suppl S1: 255A.
24.
TerraultN., ZeuzemS., Di BisceglieA.Treatment outcomes with 8, 12 and 24 weeks regimens of ledipasvir/ sofosbuvir for the treatment of hepatitis C infection. Analysis of a multicentre prospective observational study (TARGET).Hepatology2015; 62Suppl S1: 256A.
25.
ZayedN., GamalH., ElmakhzangyH.Therapeutic outcome of 6198 interferon-naive Egyptian patients with chronic hepatitis C: a real-life experience and lessons in DAAs’ era.J Viral Hepat; 23: 506–511.
26.
EsmatG., El RazikyM., GomaaA.High virologic response rate in Egyptian HCV genotype 4 patients treated with ravidasvir (PPI-668) and sofosbuvir: results of a large multicenter Phase 3 registrational trial.Hepatology2015; 62Suppl S1: 1381A.
AhmadT., YinP., SaffitzJ.Cardiac dysfunction associated with a nucleotide polymerase inhibitor for treatment of hepatitis C.Hepatology2015; 62: 409–416.
29.
DysonJ.K., HutchinsonJ., HarrisonL.Liver toxicity associated with sofosbuvir, an NS5A inhibitor and ribavirin use.J Hepatol2016; 64: 234–238.
30.
StineJ.G., IntagliataN., ShahN.L.Hepatic decompensation likely attributable to simeprevir in patients with advanced cirrhosis.Dig Dis Sci2015; 60: 1031–1035.
31.
SorianoV., BarreiroP., de MendozaC., PeñaJ.M.Hepatic decompensation with sofosbuvir plus simeprevir in a patient with Child-Pugh B compensated cirrhosis.Antivir Ther2016; 21: 91–92.
32.
ShibataS., UmemuraT., KomatsuM., TanakaE.Severe hepatotoxicity associated with asunaprevir and daclatasvir in chronic hepatitis C.Hepatology2016; 63: 2063–2064.
33.
Marchan-LopezA., DominguezL., Kessler-SaizP., Jarrin-EstupiñanE.Liver failure in HIV-HCV coinfection treated with sofosbuvir, ledipasvir and antiretroviral therapy.J Hepatol2016; 64: 752–753.
34.
HelmersR.A., BymeT.J., WesseliusL.J.Serious pulmonary toxicity secondary to novel hepatitis C antiviral therapy in a liver transplant recipient.Mayo Clin Proc2015; 90: 1294–1297.
35.
RenardS., BorentainP., SalaunE.Severe pulmonary arterial hypertension in patients treated for hepatitis C with sofosbuvir.Chest2016; 149: e69–e73.
36.
BanerjeeD., ReddyK.Safety and tolerability of direct-acting antiviral agents in the new era of hepatitis C therapy.Aliment Pharmacol Ther2016; 43: 674–696.
37.
WelkerM-W, LuhneS., LangeC.Lactic acidosis in patients with hepatitis C virus related cirrhosis and combined ribavirin/sofosbuvir treatment.J Hepatol2016; 64: 790–799.
38.
HoofnagleJ.H.Hepatic decompensation during direct-acting antiviral therapy of chronic hepatitis C.J Hepatol2016; 64: 763–765.
39.
SorianoV., BarreiroP., de MendozaC.Hypoglycemia in a diabetic patient during hepatitis C therapy.Hepatology2016; 63: 2065–2066.
40.
De MonteA., CourjonJ., AntyR.Direct-acting antiviral treatment with HCV: reactivation of hepatitis B virus coinfection as a further challenge.J Clin Virol2016; 78: 27–30.
