Articles: Background
Articles: Background
Articles: Background
Summary
Lancet 2015; 385: 2502–09 Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-
Published Online containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for
March 31, 2015 effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an
http://dx.doi.org/10.1016/
S0140-6736(15)60159-3
NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus
paritaprevir plus ritonavir), given with or without ribavirin.
See Comment page 2443
Department of Hepatology and
Gastroenterology, Hôpital Henri
Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were
Mondor, AP-HP, Université Paris- recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain,
Est, Inserm, Créteil, France Turkey, and the USA. Eligible participants were aged 18–70 years with non-cirrhotic, chronic HCV genotype 4
(Prof C Hézode MD); Centre de
infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10 000 IU/mL.
Recherche sur l’Inflammation
(CRI), Inserm UMR, Université Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation
Paris Diderot, Service lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without
d’Hépatologie, AP-HP Hôpital weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated
Beaujon, Clichy, France
interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained
(Prof T Asselah MD); Division of
Gastroenterology and virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention
Hepatology, University of to treat. This study is registered with ClinicalTrials.gov, number NCT01685203.
Pennsylvania, Philadelphia, PA,
USA (Prof K R Reddy MD);
Findings Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were
Southern California Liver Centers
and Southern California Research infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study
Center, Coronado, CA, USA medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and
(Prof T Hassanein MD); 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received
Hepatology Unit, Hospital
the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6–100])
Universitario La Fe, Universidad
de Valencia and Ciberehd, in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3–97·5]) in the ribavirin-free regimen. No
Valencia, Spain statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference
(M Berenguer MD); Department −9·16% [95% CI −19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI
of Infectious Disease, Liver
Diseases and Acquired Immune
92·7–100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%)
Deficiencies, Wroclaw Medical of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The
University, Wroclaw, Poland most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of
(K Fleischer-Stepniewska MD); 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications,
Service d’Hépatologie, AP-HP
Hôpital Beaujon, Clichy, France
including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for
(Prof P Marcellin MD); AbbVie Inc, haemoglobin less than 100 g/L or anaemia.
North Chicago, IL, USA
(C Hall MS, G Schnell PhD, Interpretation An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin
T Pilot-Matias PhD,
N Mobashery MD, R Redman MD,
achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well
R A Vilchez MD); and Groupe tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and
Hospitalier Cochin-Saint Vincent previously treated patients with HCV genotype 4 infection.
De Paul, Université Paris
Descartes, Inserm, Institut
Pasteur, Paris, France
Funding AbbVie.
(Prof S Pol MD)
Correspondence to: Introduction (genotypes 1–7) and 67 subtypes have been identified;4
Dr Christophe Hézode, Service Chronic hepatitis C virus (HCV) infection is a global their prevalence rates differ by geographical region.
d’Hépatologie et de health problem, with 130–150 million people infected Globally, HCV genotype 4 accounts for roughly 13% of
Gastroentérologie, Hôpital
Henri Mondor, 94010 Créteil Cedex,
worldwide.1 The infection is a common cause of all HCV infections.5 HCV genotype 4 is common in the
France chronic progressive liver disease (eg, cirrhosis)2 and Middle East, north Africa, and sub-Saharan Africa and is
[email protected] hepatocellular carcinoma.3 At least seven HCV genotypes responsible for more than 90% of HCV infections in
Data are n (%), n, or mean (SD). BMI=body-mass index. HCV=hepatitis C virus. NA=not applicable. OBV=ombitasvir. pegIFN plus RBV=pegylated interferon plus ribavirin.
PTV=paritaprevir. RBV=ribavirin. *The Versant HCV Genotype Inno-LiPA assay (version 2.0) was used at baseline to determine HCV genotype; however, the LiPA assay was
unable to accurately identify subtypes.22 †Viral subtypes were determined by phylogenetic analyses of NS5B (a 329 nucleotide region)23 and full-length NS3/4A and NS5A
nucleotide sequences. Baseline samples from three patients were not available for analysis. ‡No cirrhosis or little fibrous expansion into portal areas. §Fibrous expansion in
most portal areas with some portal-to-portal bridging. ¶Marked fibrous expansion, including portal-to-portal and portal-to-central bridging.
ribavirin dose modification for adverse events unrelated Any serious adverse event 1 (2%) 0 0
to anaemia (one [2%] of 42 for anxiety, palpitations, and Any adverse event leading to study 0 0 0
drug discontinuation
insomnia and one [2%] for erythema).
Adverse events (>10% of patients
In all treatment groups, alanine aminotransferase in any group)
(ALT) and AST concentrations improved from baseline Asthenia 11 (25%) 10 (24%) 16 (33%)
beginning at week 1 and continued through the last Diarrhoea 2 (5%) 6 (14%) 3 (6%)
protocol-specified laboratory assessment at post Fatigue 3 (7%) 5 (12%) 9 (18%)
treatment week 4 (appendix). One patient had an
Headache 13 (30%) 14 (33%) 14 (29%)
asymptomatic AST elevation at one visit (table 3), which
Insomnia 2 (5%) 4 (10%) 8 (16%)
resolved spontaneously with continued dosing. No
Irritability 3 (7%) 6 (14%) 2 (4%)
concomitant elevations greater than grade 2 were noted
Myalgia 0 0 5 (10%)
for ALT levels or bilirubin concentrations. Three
Nasopharyngitis 2 (5%) 2 (5%) 6 (12%)
treatment-experienced patients had grade 3 bilirubin
Nausea 4 (9%) 7 (17%) 6 (12%)
concentrations; ALT and international normalised ratio
Pruritus 2 (5%) 1 (2%) 5 (10%)
of these patients were normal. Three patients with
hyperbilirubinaemia had a bilirubin elevation at a single OBV=ombitasvir. PTV=paritaprevir. RBV=ribavirin.
visit, which decreased or normalised with continued
Table 2: Treatment-emergent adverse events
treatment. These bilirubin elevations were mainly
indirect and probably related to the combined effects of
ribavirin-associated hemolysis and paritaprevir on the Treatment-naive patients Treatment-experienced
bilirubin transporter OATP-1. No concomitant ALT or patients (OBV plus PTV plus
AST elevations were observed. ritonavir with RBV)
OBV plus PTV OBV plus PTV plus
Discussion plus ritonavir ritonavir with RBV
HCV genotype 4 infections account for a large proportion ALT >5 × ULN and ≥2 × baseline 0 0 0
of the worldwide HCV epidemic.24 In this study of an AST >5 × ULN and ≥2 × baseline 1/43 (2%) 0 0
all-oral, interferon-free, 12-week regimen of ombitasvir Alkaline phosphatase >5 × ULN 0 0 0
plus paritaprevir plus ritonavir with or without ribavirin, Total bilirubin, grade 3 0 0 3/49 (6%)
high SVR12 rates were achieved in HCV genotype 4-infected Haemoglobin, g/L
treatment-naive and treatment-experienced patients <100 1/43 (2%) 1/42 (2%) 1/49 (2%)
without cirrhosis. Although no difference between the <80–65 0 1/42 (2%) 0
ribavirin-containing and ribavirin-free regimens was
Data are n/N (%). OBV=ombitasvir. PTV=paritaprevir. RBV=ribavirin. ALT=alanine aminotransferase. ULN=upper limit
noted, the 100% (42/42) SVR12 rate recorded with the
of normal. AST=aspartate aminotransferase.
ribavirin-containing regimen in treatment-naive and
treatment-experienced patients suggests that this Table 3: Post baseline laboratory abnormalities
multitargeted regimen provides the highest certainty of
achieving sustained virological response in patients genotype 4-infected patients, but this regimen had
infected with diverse HCV genotype 4 subtypes (panel). major limitations, including suboptimum response
The addition of ribavirin to the two-direct-acting antiviral rates,25 large side-effects, high treatment discontinuation
drug regimen could be an important consideration for rates, and prolonged treatment durations. Combination
physicians when treating patients with HCV genotype 4 therapy with pegylated interferon plus ribavirin and a
because subtyping is not a common clinical procedure, direct-acting antiviral drug has increased the efficacy of
and genotype 4 is a heterogeneous genotype with pegylated interferon plus ribavirin-based regimens in
multiple subtypes.4 Unfortunately, we do not know the genotype 4-infected patients; however, the adverse
susceptibility of all subtypes to direct-acting antiviral effects of these currently recommended regimens
drugs, and larger clinical studies are necessary to fully suggest that effective pegylated interferon-free regimens
understand the role of ribavirin in this regimen. with more favourable tolerability would be beneficial.
In the past, combination pegylated interferon plus The treatment in this trial showed SVR12 rates greater
ribavirin was recommended for treatment of HCV than or similar to those reported with combinations of
Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp and Dohme, and 11 Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir,
Roche, and a consultant for Boehringer-Ingelheim. TA has been a clinical ombitasvir, and dasabuvir achieves 97% and 100% sustained
investigator, speaker, and consultant for AbbVie, Boehringer-Ingelheim, virologic response with or without ribavirin in treatment-
Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck experienced patients with HCV genotype 1b infection.
Sharp and Dohme, and Roche. KF-S has been a clinical investigator and Gastroenterology 2014; 147: 359–65.
speaker for Bristol-Myers Squibb and Roche. PM has received grants 12 Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and
from Roche, Gilead, Bristol-Myers Squibb, Novartis, Janssen, Merck dasabuvir with or without ribavirin for HCV. N Engl J Med 2014;
370: 1983–92.
Sharp and Dohme, and Alios BioPharma; is an investigator for Roche,
Gilead, Bristol-Myers Squibb, Vertex, Novartis, Janssen, Merck Sharp and 13 Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir
for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med
Dohme, Boehringer-Ingelheim, AbbVie, Pfizer, and Alios BioPharma;
2014; 370: 1879–88.
is a speaker for Roche, Gilead, Bristol-Myers Squibb, Novartis, Janssen,
14 Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with
and Merck Sharp and Dohme; and is a consultant for Roche, Gilead,
ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med
Bristol-Myers Squibb, Vertex, Novartis, Janssen, Merck Sharp and 2014; 370: 1604–14.
Dohme, AbbVie, Alios BioPharma, Idenix, and Akron. MB has been a
15 Benhamou Y, Moussalli J, Ratziu V, et al. Telaprevir activity in
speaker for Bristol-Myers Squibb, Janssen, Gilead, Roche, Merck Sharp treatment-naive patients infected hepatitis C virus genotype 4:
and Dohme, Novartis, and AbbVie; and has been a board member for a randomized trial. J Infect Dis 2013; 208: 1000–07.
Bristol-Myers Squibb, Janssen, Merck Sharp and Dohme, Novartis, and 16 DeGoey DA, Randolph JT, Liu D, et al. Discovery of ABT-267,
AbbVie. KRR has served as an ad-hoc advisor to Gilead, Bristol-Myers a pan-genotypic inhibitor of HCV NS5A. J Med Chem 2014;
Squibb, AbbVie, Merck, Genentech-Roche, Vertex, and Janssen; and has 57: 2047–57.
received research support from Gilead, Bristol-Myers Squibb, AbbVie, 17 Pilot-Matias T, Tripathi R, Cohen D, et al. In vitro and in vivo
Merck, Vertex, and Janssen. TH has received research grants from antiviral activity and resistance profile of the hepatitis C virus
AbbVie, Boehringer-Ingelheim, Bristol-Myers Squibb, Eisai, Gilead NS3/4A protease inhibitor ABT-450. Antimicrob Agents Chemother
Sciences, Idenix, Ikaria, Janssen, La Jolla Pharmaceuticals, Merck, 2015; 59: 988–97.
Mochida, NGM BioPharmaceuticals, Roche, Ocera, Sundise, Salix, 18 Krishnan P, Beyer J, Mistry N, et al. In vitro and in vivo antiviral
Taigen, Takeda, Tobria, Vertex, and Vital Therapies; serves on advisory activity and resistance profile of ombitasvir, an inhibitor of HCV
boards for AbbVie and Bristol-Myers Squibb; and is a speaker for Baxter, NS5A. Antimicrob Agents Chemother 2014; 59: 979–87.
Bristol-Myers Squibb, Gilead, and Salix. SP has been a speaker for 19 Menon RM, Klein CE, Lawal AA, et al. Pharmacokinetics and
GlaxoSmithKline, Bristol-Myers Squibb, Boehringer-Ingelheim, Janssen, tolerability of the HCV protease inhibitor ABT-450 following single
Gilead, Roche, Merck Sharp and Dohme, Sanofi, Novartis, Vertex, and ascending doses in healthy adult volunteers with and without
AbbVie; has been a board member for GlaxoSmithKline, Bristol-Myers ritonavir (HEP DART 2009 abstract 57). Glob Antiviral J 2009;
Squibb, Boehringer-Ingelheim, Janssen, Gilead, Roche, Merck Sharp and 5: 53.
Dohme, Sanofi, Novartis, Vertex, and AbbVie; and received grants from 20 Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with
Bristol-Myers Squibb, Gilead, Roche, and Merck Sharp and Dohme. ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med
2014; 370: 1594–603.
Acknowledgments 21 Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and
We thank Kerstin Krauss, Charles Meyer, Ingrid Facey, Cordula Ubrig, dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med
Christina Giannoulis, Christine Collins, Rakesh Tripathi, Jill Beyer, 2014; 370: 1973–82.
Thomas Reisch, and Preethi Krishnan of AbbVie for assistance provided 22 Di Lello FA, Neukam K, Parra-Sanchez M, et al. Hepatitis C virus
in the preparation and operation of the study. This study was funded by genotype 4 in Southern and Central Spain does not originate from
AbbVie Inc. Editorial and medical writing support was provided by recent foreign migration waves. J Med Virol 2013; 85: 1734–40.
Jillian Gee, Complete Publication Solutions (Horsham, PA, USA), which 23 Koletzki D, Dumont S, Vermeiren H, Fevery B, De Smet P,
was funded by AbbVie. Stuyver LJ. Development and evaluation of an automated
hepatitis C virus NS5B sequence-based subtyping assay.
References Clin Chem Lab Med 2010; 48: 1095–102.
1 World Health Organization. Hepatitis C. WHO fact sheet 164, 2014. 24 Kamal SM. Improving outcome in patients with hepatitis C virus
http://www.who.int/mediacentre/factsheets/fs164/en/ (accessed genotype 4. Am J Gastroenterol 2007; 102: 2582–88.
March 20, 2015).
25 Esmat G, El Raziky M, El Kassas M, Hassany M, Gamil ME. The
2 Freeman AJ, Dore GJ, Law MG, et al. Estimating progression to future for the treatment of genotype 4 chronic hepatitis C. Liver Int
cirrhosis in chronic hepatitis C virus infection. Hepatology 2001; 2012; 32: 146–50.
34: 809–16.
26 Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously
3 Abdel-Hamid M, El-Daly M, Molnegren V, et al. Genetic diversity in untreated chronic hepatitis C infection. N Engl J Med 2013;
hepatitis C virus in Egypt and possible association with 368: 1878–87.
hepatocellular carcinoma. J Gen Virol 2007; 88: 1526–31.
27 Bronowicki JP, Ratziu V, Gadano A, et al. Randomized trial of
4 Smith DB, Bukh J, Kuiken C, et al. Expanded classification of asunaprevir plus peginterferon alfa and ribavirin for previously
hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria untreated genotype 1 or 4 chronic hepatitis C. J Hepatol 2014;
and genotype assignment web resource. Hepatology 2014; 59: 318–27. 61: 1220–27.
5 Gower E, Estes CC, Hindman, Razavi-Shearer K, Razavi H. Global 28 Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir plus
epidemiology and genotype distribution of the hepatitis C virus peginterferon alfa and ribavirin for treatment-naive chronic
infection. J Hepatol 2014; 61: S45–47. hepatitis C genotype 1 or 4 infection: a randomised study. Gut 2014;
6 American Association for the Study of Liver Diseases and the published online July 30. DOI:10.1136/gutjnl-2014-307498.
Infectious Diseases Society of America. Recommendations for 29 Esmat GE, Shiha G, Omar RF, et al. Sofosbuvir plus ribavirin in the
testing, managing, and treating hepatitis C, 2014. http://www. treatment of Egyptian patients with chronic genotype 4 HCV
HCVguidelines.org (accessed March 20, 2015). infection. Hepatology 2014; 60: 662A–3A.
7 Brok J, Gluud LL, Gluud C. Ribavirin monotherapy for chronic 30 Kapoor R, Kohli A, Sidharthan S, et al. All oral treatment for
hepatitis C. Cochrane Database Syst Rev 2009; 4: CD005527. genotype 4 chronic hepatitis C infection with sofosbuvir and
8 European Association for the Study of the Liver. EASL ledipasvir: interim results from the NIAID SYNERGY trial.
recommendations on treatment of hepatitis C, 2014. http://www. Hepatology 2014; 60: Abs 321.
easl.eu/assets/application/files/easl_recommendations_hcv_2014_ 31 Asselah T, De Muynck S, Broet P, et al. IL28B polymorphism is
full.pdf (accessed March 20, 2015). associated with treatment response in patients with genotype 4
9 Schinazi R, Halfon P, Marcellin P, Asselah T. HCV direct-acting chronic hepatitis C. J Hepatol 2012; 56: 527–32.
antiviral agents: the best interferon-free combinations. Liver Int 32 Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir
2014; 34: 69–78. for HCV genotype 1 infection. N Engl J Med 2013; 369: 630–39.
10 Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for
untreated HCV genotype 1 infection. N Engl J Med 2014; 370: 1889–98.