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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2016; 22(28): 6393-6401
Published online Jul 28, 2016. doi: 10.3748/wjg.v22.i28.6393
Hepatitis C virus: Promising discoveries and new treatments
Juliana Cristina Santiago Bastos, Marina Aiello Padilla, Leonardo Cardia Caserta, Clarice Weis Arns, Laboratory of Virology, Institute of Biology, State University of Campinas - UNICAMP, Campinas, SP 13083-970, Brazil
Noelle Miotto, Aline Gonzalez Vigani, Internal Medicine Department, Infectious Diseases division, FCM-UNICAMP, Campinas, SP 13083-970, Brazil
Author contributions: Bastos JCS, Padilla MA, Caserta LC, Miotto N, Vigani AG and Arns CW analyzed the literature and wrote the manuscript.
Conflict-of-interest statement: The authors have no conflict of interest to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Juliana Cristina Santiago Bastos, MsC, Laboratory of Virology, Institute of Biology, State University of Campinas - UNICAMP, P.O. Box: 6109, Campinas, SP 13083-970, Brazil. jusantiago_farmacia@yahoo.com.br
Telephone: +55-19-35216258 Fax: +55-19-35216185
Received: March 25, 2016
Peer-review started: March 27, 2016
First decision: May 12, 2016
Revised: June 7, 2016
Accepted: June 15, 2016
Article in press: June 15, 2016
Published online: July 28, 2016

Abstract

Despite advances in therapy, hepatitis C virus (HCV) infection remains an important global health issue. It is estimated that a significant part of the world population is chronically infected with the virus, and many of those affected may develop cirrhosis or liver cancer. The virus shows considerable variability, a characteristic that directly interferes with disease treatment. The response to treatment varies according to HCV genotype and subtype. The continuous generation of variants (quasispecies) allows the virus to escape control by antivirals. Historically, the combination of ribavirin and interferon therapy has represented the only treatment option for the disease. Currently, several new treatment options are emerging and are available to a large part of the affected population. In addition, the search for new substances with antiviral activity against HCV continues, promising future improvements in treatment. Researchers should consider the mutation capacity of the virus and the other variables that affect treatment success.

Key Words: Hepatitis C infection, Hepatitis C virus, Treatments, Antiviral research

Core tip: In recent years, new treatments for hepatitis C have been approved and represent a major advancement in this field. However, there are limitations that should be considered, and research for new treatments must continue. The objective of this review is to demonstrate the breakthroughs that have occurred and to discuss future developments.



INTRODUCTION

Hepatitis C virus (HCV) infection is an important cause of cirrhosis and hepatocellular carcinoma worldwide[1-3]. It is very dangerous due to the breakthrough of long-term asymptomatic HCV[4].

HCV is transmitted through exposure to infected blood and blood products. HCV infection can be spread through blood transfusion, injection drug use, sexual intercourse, surgery, and tattooing[2,5]. HCV infection is defined as the presence of HCV RNA and anti-HCV antibodies in the serum or plasma; a positive HCV antibody test indicates exposure to HCV and could represent a current or past infection. A positive HCV RNA test indicates a current HCV infection[2].

It is estimated that 130-150 million people globally have chronic hepatitis C infection, and a significant number of those who are chronically infected will develop liver cirrhosis or liver cancer. According to the World Health Organization, 350000 to 500000 people die each year from hepatitis C-related liver diseases. The most affected regions are Central and East Asia and North Africa, although the virus is found worldwide[6].

The natural history of HCV is influenced by a wide variety of factors. Host factors include age at infection, gender, race, obesity, steatosis, insulin resistance/diabetes, genetics, alanine aminotransferase levels and exercise. Viral factors include HCV RNA level, quasispecies/genotype, coinfection with hepatitis B virus and coinfection with human immunodeficiency virus. Environmental factors include alcohol use, cigarette use, cannabis use, caffeine consumption and herbal product use[1].

Approximately 15%-45% of infected persons spontaneously clear the virus within 6 mo of infection without any treatment, and the remaining 55%-85% of persons may progress to persistent chronic infection. It is estimated that the risk of developing cirrhosis of the liver within 20 years is 15%-30% in those with chronic HCV infection[6], and the risk of developing hepatocellular carcinoma is 1%-4% per year[1].

Acute HCV hepatitis in immunocompetent individuals is generally asymptomatic, but immunocompromised hosts (HIV infection) experience lymphoplasmatic portal inflammation, interface hepatitis, necroinflammatory lobular changes, moderately advanced fibrosis or rapid progression to fibrosis over a period of time[7].

Chronic hepatitis is defined as the persistence of infection for at least 6 mo after the onset of infection and is characterized by necroinflammation accompanied by a variable degree of fibrosis[7], end-stage liver disease and hepatocellular carcinoma[1].

The main extrahepatic manifestations in patients with HCV infection are immune- and inflammatory-related. Immune-related extrahepatic manifestations include mixed cryoglobulinemia, cryoglobulinemic vasculitis, B-cell NHL, Sicca syndrome, arthralgia/myalgia, autoantibody production (i.e., cryoglobulins, rheumatoid factor, and antinuclear, anticardiolipin, antithyroid and anti-smooth muscle antibodies), polyarthritis nodosa, monoclonal gammopathies, and immune thrombocytopenia. Inflammatory-related extrahepatic manifestations consist of type 2 diabetes mellitus, insulin resistance, glomerulonephritis, renal insufficiency, fatigue, cognitive impairment, depression, impaired quality of life, polyarthritis/fibromyalgia, and cardiovascular disorders (i.e., stroke and ischemic heart disease)[8]. Recent studies have suggested that HCV infection leads to increased risk of developing cardiovascular diseases and has been linked to increased risk of mortality caused by these diseases[9].

Several studies have considered the existence of occult HCV infection (viral RNA identified in hepatocytes but absent in serum). Although occult HCV infection is challenged by some researchers and is characterized by others as a milder condition than chronic hepatitis C, it is necessary to consider its existence because some studies have shown links between occult HCV infection and liver cirrhosis and hepatocellular carcinoma. In addition, due to the emergence of new treatment options, all possibilities should be considered, and special attention should be given to transfusion centers and patient risk groups[10,11].

HCV

HCV, classified in the family Flaviviridae, is an enveloped, single stranded positive sense RNA virus with a genome approximately 9600 nucleotides in length[12], encoding approximately 3000 amino acids[13]. Most of the genome is composed of a single open reading frame that encodes ten proteins: three structural proteins (core, E1, E2) and seven non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B)[13]. Most recently, an HCV protein named F was reported[14,15].

The most variable region of the genome is the region that codes the membrane glycoproteins E1 and E2[16]. Within the E2 gene, two hypervariable regions (HVR1 and HVR2) are described that show less sequence homology between isolates, with 50% identity[17]. Non-structural protein genes, such as the core gene, are some of the most conserved on the genome[12]. Within the 5’-NCR region, the most distant related isolates present 90% sequence identity[18,19].

The host immune system, large population sizes, short generation times and high replication rates are the factors that lead to the genetic variability of HCV[20]. Seven genetic lineages (genotypes 1 to 7) are recognized. These genotypes are subdivided into closely related sub-types differing from each other by 15% in nucleotide sequences[21]. Differences between the complete genomes occur at 31%-33% of nucleotide sites[22]. In Western countries, subtypes 1a, 1b and 3a are believed to cause the majority of HCV infections and are widely distributed[12].

For example, only 10%-20% of patients chronically infected with HCV genotype 1 show complete and permanent disappearance of the virus when treated with IFN-α alone, and 40%-50% experience successful treatment when treated with a combined therapy (INF-α/RBV). When patients infected with genotypes 2 or 3 are treated with monotherapy or combined therapy, higher successful treatment rates are observed (50% and 70%-80%, respectively)[23,24].

The mutation rate of HCV is estimated to be 2.5 × 10-5 mutations per nucleotide per genome replication[25], which is one of the highest rates for RNA viruses, including retroviruses[26]. Recombination also increases the genetic variability of HCV. Inter and intra genotypic recombinations have already been reported in various geographic locations, and the existence of intergenotypic recombination forms has also been reported[27,28]. Genotype 2 is considered to be present in most of the cases of recombinant forms, but other genotypes, except for genotype 4 and 7, also exhibit recombinant forms[29]. At the same time, the mutation rate may negatively affect the viability of viral populations. In a situation called lethal mutagenesis, a nucleotide sequence loses its information when the error rate transcends a tolerable limit[30].

Due to the high replication rate of HCV, an extensive number of variants are continuously produced during infection. These variants are closely related to each other but differ in nucleotide sequence, circulating as a complex population known as quasispecies. This population is able to rapidly adapt to a constantly changing environment[31,32]. This adaptation could lead to the coexistence of diverse variants in infected patients, creating an environment for intra and inter quasispecies interactions[33]. As a result of the continuous generation of variants, some of the variants may adapt to this changing environment and escape control by antiviral drugs[34]. Predominant and minor quasispecies can be transmitted in humans[35,36] and experimentally infected chimpanzees[37,38]. It is important to highlight that the HCV population fluctuates in patients during therapy, suggesting that HCV quasispecies may follow different evolution paths in different patients[39].

Host genetics are also indicated as a factor that could influence HCV evolution and treatment response[40]. For example, single nucleotide polymorphisms near the IL-28B gene appear to be associated with a low genetic variability in the NS3 coding region of the HCV genome[41].

EVOLUTION OF HCV TREATMENT

Since HCV treatment began in the early 1990s, treatment options have improved. Interferon alpha (IFN-α) was the first pan-genotypic option, with sustained virologic response (SVR) rates of 8%-21%[42]. Subsequently, the guanosine analogue ribavirin (RBV) was combined with IFN-α, which enhanced SVR rates to 40%. Then, pegylated IFN-α (PEG-IFN-α) associated with RBV improved SVR rates from 42% to 52%[43-45]. In 2011, the first wave of direct-acting antiviral agents (DAAs), NS3/4A protease inhibitors telaprevir (TVR) and boceprevir (BOC), became available. The association of these protease inhibitors with PEG-IFN-α/RBV improved SVR rates among patients with HCV genotype 1 infection. In treatment-naïve patients, the addition of TVR or BOC to PEG/RBV leads to an SVR increase of approximately 30%. Despite this improvement in SVR, these drugs were associated with serious adverse events (AEs) and low tolerance. More recently, a second wave of new DAAs allowed IFN-free, highly effective regimens. SVR can be achieved in more than 90% of treated patients via IFN-free regimens, with minimal AEs and high tolerability[46-49]. Unlike the nonspecific IFN-α-based and PEG-IFN-α-based therapies, DAAs target various proteins involved in HCV replication. In addition, most of these agents are specific to one or more genotypes. The classes of DAAs include NS3/4A protease inhibitors, NS5A inhibitors (nucleotides and non-nucleotide analogues), and NS5B polymerase inhibitors. During HCV replication, NS3/4A serine protease is required for self-cleavage, the NS5A region plays an important role in viral replication and assembly, and the NS5B region encodes RNA polymerase. Some of these drugs were initially combined with PEG-IFN-α and RBV, including the protease inhibitors TVR, BOC and simeprevir (SMV) and the NS5B polymerase inhibitor sofosbuvir (SOF). However, these regimens were still associated with PEG-IFN-α and RBV AEs and low tolerability[50-52].

All-oral treatment options followed this development, some associated with RBV and some not, including the combinations of SMV and SOF and SOF and NS5A inhibitor daclatasvir, the 3D regimen (paritaprevir/ritonavir/ombitasvir, co-administered with dasabuvir), and SOF plus ledipasvir. In recent years, more drugs have been designed, including grazoprevir, elbasvir, asunaprevir, beclabuvir, faldaprevir, and deleobuvir[52,53]. Drug options and their respective mechanisms and genotype sensitivity are shown in Table 1. The combined therapies increased SVR rates and tolerability and shortened treatment duration[52]. Treatment options for HCV infection, ranging from IFN-based regimens to new all-oral combinations, are presented in Table 2.

Table 1 Drugs for hepatitis C virus treatment.
Mechanism of actionDrugGenotype
Protease inhibitorTelaprevir1
Boceprevir1
Simeprevir1
Paritaprevir1, 4
Grazoprevir1, 4
Asunaprevir11
ABT-45011
Faldaprevir11
NS5A inhibitorsDaclatasvir1, 3
Ombitasvir1, 4
Ledipasvir1, 4, 5, 6
Elbasvir1, 4
Velpatasvir14
NS5B inhibitors
Nucleotide-analogueSofosbuvir1, 2, 3, 4, 5, 6
Non-nucleoside analogueDasabuvir1
Beclabuvir11
Table 2 Treatments for hepatitis C virus infection.
Ref.Treatment, wkGenotypeSVR (total, cirrhotic, non-cirrhotic)Previously treated
Patients included
Davis et al[53]IFN, 2413; NA; NAYes
IFN + RBV, 2430; NA; NA
IDEAL Study Team[54]PEG-IFN/RBV, 48139.8-40.9; 42.1-43.6; 20.7-23.6No
ADVANCE Study Team[48]TVR + PEG-IFN/RBV175; 62-81; 62No
REALIZE Study Team[49]TVR + PEG-IFN/RBV, 48163-64; 28-84; NAYes
SPRINT-2 Investigators[47]BOC + PEG-IFN/RBV, 28167; 70; 50No
BOC + PEG-IFN/RBV, 4868; 70; 50
RESPOND-2 Investigators[46]BOC + PEG-IFN/RBV, 36159; 35; 64Yes
BOC + PEG-IFN/RBV, 4866; 77; 66
PILLAR[55]SMP + PEG-IFN/RBV, 12180.5; NA; 80.5No
SMP + PEG-IFN/RBV, 2486.1; NA; 86.1
Gane et al[56]SOF + RBV, 122 or 3100; NA; 100No
SOF + PEG-IFN/RBV, 8100; NA; 100
COSMOS[57]SMP + SOF + RBV, 241NA; 93;79Yes
SMP + SOF, 24NA; 93; 100
SMP + SOF + RBV, 12NA; 93; 93
SMP + SOF, 12NA; 90; 94
OPTIMIST-1[58]SMP + SOF, 8183; NA; 83Yes
SMP + SOF, 1297; NA; 97
OPTIMIST-2[59]SMP + SOF, 12183; 83; NAYes
AI444040 Study group[60]DCV + SOF, 242 or 3100; NA; NANo
DCV + SOF + RBV, 2486; NA; NANo
DCV + SOF, 241100; NA; NAYes
DCV + SOF + RBV, 2495-100; NA; NA
ALLY-3 Study Team[61]DCV + SOF, 12386-91; 63; 96Yes
ION-2 Investigators[62]LDV + SOF, 12194; 86; 97Yes
LDV + SOF, 2499; 100; 99
LDV + SOF + RBV, 1296; 87; 100
LDV + SOF + RBV, 2499; 100; 99
ION-3 Investigators[63]LDV + SOF, 8194; NA; 94No
LDV + SOF + RBV, 893; NA; 93
LDV + SOF, 1295; NA; 95
MALACHITE-I/II[64]OBV + PTV/r + DSV + RBV, 12197-99; NA; 97-99Yes
PEARL-I[65]OBV + PTV/r491; NA; 91No
OBV + PTV/r + RBV100; NA; 100Yes
SAPPHIRE-II[66]ABT-450/r + OBV + DSV + RBV, 12196.3; NA; 93.6Yes
TURQUOISE-II[67]ABT-450/r + OBV + DSV + RBV, 12191.8; 91.8; NAYes
ABT-450/r + OBV + DSV + RBV, 2495.9; 95.9; NA
ASTRAL-2 and ASTRAL-3[68]SOF + VEL, 12299; 100; 99Yes
395; 93; 98
C-WORTHY[69]GZR + EBR, 12191-97; 91-97; NAYes
GZR + EBR + RBV, 1290-94; 90-94; NA
GZR + EBR, 1894-97; NA; NA
GZR + EBR + RBV, 1897-100; NA; NA
Everson et al[70]DCV + ASV + BCV, 12188.8-89.5; 71.4-100; 87.5-91.1No
DCV + ASV + BCV + RBV, 1285.7; 100; 85
SOUND-2[71]FDV + deleobuvir + RBV, 16159; NA; NANo
FDV + deleobuvir + RBV, 2859-69; NA; NA
FDV + deleobuvir + RBV, 4052; NA; NA
FDV + deleobuvir, 2839; NA; NA

Although HCV treatment has clearly improved since the introduction of DAAs, some challenges remain. Some populations remain difficult to treat, such as cirrhotic patients, prior non-responders, genotype 3-infected patients and patients with renal impairment[52,60]. In this group, the combination of grazoprevir and elbasvir appears to result in high SVR rates in the short-term[72]. Most of the DAAs have drug-to-drug interactions, requiring the substitution or suspension of some medications during HCV treatment[9]. The development of viral drug-induced resistance may compromise actual and future treatment options. Finally, some DAA regimens have significant cost barriers and are not fully available worldwide[52,73].

DAAs are currently too expensive for governments worldwide, especially in some low- and middle-income countries. Nevertheless, price decreases have already been announced for some of these drugs. As patents expire, high drug costs will be reduced, although this process will take several decades. This prospect offers some hope that universal access to the treatment might be possible and that DAAs will be optimally used to reduce HCV-related mortality and incidence in low- and middle-income countries[74,75].

ANTIVIRAL RESEARCH

Despite the progress of current DAAs in terms of SVR and treatment tolerability, difficult to treat populations and the emergence of resistant virus species indicate the continued need for research into new treatment options.

Some studies indicate that caffeine has the potential to improve liver function in patients chronically infected with HCV. Through in vitro research, it was possible to verify that caffeine may be an important new agent for anti-HCV therapies due to its efficient inhibition of HCV replication at non-toxic concentrations[76].

Many researchers use the bovine viral diarrhea virus (BVDV), another Flavivirus member, as a surrogate model in HCV studies because propagation in vitro is difficult, and HCV and BVDV share similarities with respect to replication cycle, biology, and genetic organization[77]. Many studies have sought new compounds with antiviral activity from natural products. For example, a study performed in Brazil[78] investigated the antiviral activity of several marine invertebrates and the microorganisms isolated from them. This study showed that an extract produced from the Bacillus genus, isolated from the sponge Petromica citrina, has potential antiviral activity and demonstrated an inhibition of 98% and a high selectivity index during viral adsorption. Another study performed in Brazil[79] described the antiviral activity, with 99% of inhibition and a selectivity index greater than 200 μmol/L, of compounds produced from Streptomyces chartreusis, a termite-associated bacterium.

Extracts from plants have also been investigated as potential producers of novel compounds that could be used to treat HCV. For example, one study[80] that screened Brazilian plant species described four compounds-a natural alkaloid isolated from Maytrenus ilicifolia and three other compounds from Peperomia blanda-that could drastically reduce RNA levels and viral protein levels during HCV replication.

In addition to the importance of screening, and due to the number of extracts that could be evaluated, others research studies have already identified molecules from natural sources belonging to different chemical families that have antiviral activity that affects different stages of the HCV life cycle[81]. Some active molecules cited in this review[81] include naringenin, extracted from grapefruit, quercetin, extracted from Embelia ribes, honokiol, extracted from Magnolia grandiflora; and others.

The polyphenols excoecariphenol D and corilagin, both isolated from the Chinese mangrove plant (Excoecaria agallocha), were shown to potentially inhibit HCV RNA replication in cells[82]. The monoterpene camphor, isolated from Ocimun basilicum, was identified as a potential virucidal, suggesting that the mechanism of action of this compound acts directly on the viral particle[83].

Another compound known as silymarin, a flavonoid extract from the milk thistle of Silybum marianum, showed promising antiviral activity, both in vitro and in vivo at different stages of HCV replication: entry of the HCV into the cell hosts, RNA and protein expression and in the secretion of infectious viral particles[84]. This compound has also been reported[85] to potently reduce HCV RNA levels in vivo when administered intravenously, and to dose-dependently inhibit the HCV 3a core gene[86].

CONCLUSION

In recent years, treatment for hepatitis C has made considerable advances, represented by an increase in SVR rates, reduction of treatment duration and reduction of AEs. However, despite these advances, the limitations of available treatments must be addressed. The difficult to treat populations and the emergence of resistant virus species indicate the continued need for research into new treatment options. Therefore, research must continue so that new substances with potential antiviral activity against this virus are identified and the limitations of existing treatments can be overcome. In addition to treatment, we must always consider the importance of prevention and the need for global pacts that will allow these treatments to be made available throughout the world.

Footnotes

Manuscript Source: Invited manuscript

Specialty Type: Gastroenterology and Hepatology

Country of Origin: Brazil

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P- Reviewer: Bare P, Lee SW, Rezaee-Zavareh MS S- Editor: Ma YJ L- Editor: A E- Editor: Wang CH

References
1.  Lingala S, Ghany MG. Natural History of Hepatitis C. Gastroenterol Clin North Am. 2015;44:717-734.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 153]  [Article Influence: 17.0]  [Reference Citation Analysis (0)]
2.  Taherkhani R, Farshadpour F. Epidemiology of hepatitis C virus in Iran. World J Gastroenterol. 2015;21:10790-10810.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 59]  [Cited by in F6Publishing: 65]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
3.  Bertino G, Ardiri A, Proiti M, Rigano G, Frazzetto E, Demma S, Ruggeri MI, Scuderi L, Malaguarnera G, Bertino N. Chronic hepatitis C: This and the new era of treatment. World J Hepatol. 2016;8:92-106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 57]  [Article Influence: 7.1]  [Reference Citation Analysis (0)]
4.  Madaliński K, Zakrzewska K, Kołakowska A, Godzik P. Epidemiology of HCV infection in Central and Eastern Europe. Przegl Epidemiol. 2015;69:459-464, 581-584.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29 Suppl 1:74-81.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 933]  [Cited by in F6Publishing: 1020]  [Article Influence: 68.0]  [Reference Citation Analysis (0)]
6.  World Health Organization. Hepatitis C, WHO fact sheet No. 164, updated July 2015.  Available from: http://www.who.int/mediacentre/factsheets/fs164_apr2014/en/.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Dhingra S, Ward SC, Thung SN. Liver pathology of hepatitis C, beyond grading and staging of the disease. World J Gastroenterol. 2016;22:1357-1366.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 16]  [Cited by in F6Publishing: 17]  [Article Influence: 2.1]  [Reference Citation Analysis (2)]
8.  Cacoub P, Comarmond C, Domont F, Savey L, Desbois AC, Saadoun D. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis. 2016;3:3-14.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 104]  [Article Influence: 13.0]  [Reference Citation Analysis (0)]
9.  Petta S, Maida M, Macaluso FS, Barbara M, Licata A, Craxì A, Cammà C. Hepatitis C Virus Infection Is Associated With Increased Cardiovascular Mortality: A Meta-Analysis of Observational Studies. Gastroenterology. 2016;150:145-155.e4; quiz e15-16.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 169]  [Cited by in F6Publishing: 176]  [Article Influence: 22.0]  [Reference Citation Analysis (0)]
10.  Rezaee-Zavareh MS, Hadi R, Karimi-Sari H, Hossein Khosravi M, Ajudani R, Dolatimehr F, Ramezani-Binabaj M, Miri SM, Alavian SM. Occult HCV Infection: The Current State of Knowledge. Iran Red Crescent Med J. 2015;17:e34181.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 25]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
11.  Rezaee Zavareh MS, Alavian SM. Occult Hepatitis C Infection Should Be More Noticed With New Treatment Strategies. Hepat Mon. 2015;15:e33462.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 4]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
12.  Simmonds P. Genetic diversity and evolution of hepatitis C virus--15 years on. J Gen Virol. 2004;85:3173-3188.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 622]  [Cited by in F6Publishing: 575]  [Article Influence: 28.8]  [Reference Citation Analysis (0)]
13.  Bartenschlager R, Penin F, Lohmann V, André P. Assembly of infectious hepatitis C virus particles. Trends Microbiol. 2011;19:95-103.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 320]  [Cited by in F6Publishing: 298]  [Article Influence: 21.3]  [Reference Citation Analysis (0)]
14.  Varaklioti A, Vassilaki N, Georgopoulou U, Mavromara P. Alternate translation occurs within the core coding region of the hepatitis C viral genome. J Biol Chem. 2002;277:17713-17721.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 108]  [Cited by in F6Publishing: 113]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
15.  Xu Z, Choi J, Lu W, Ou JH. Hepatitis C virus f protein is a short-lived protein associated with the endoplasmic reticulum. J Virol. 2003;77:1578-1583.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Argentini C, Genovese D, Dettori S, Rapicetta M. HCV genetic variability: from quasispecies evolution to genotype classification. Future Microbiol. 2009;4:359-373.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 33]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
17.  Le Guillou-Guillemette H, Vallet S, Gaudy-Graffin C, Payan C, Pivert A, Goudeau A, Lunel-Fabiani F. Genetic diversity of the hepatitis C virus: impact and issues in the antiviral therapy. World J Gastroenterol. 2007;13:2416-2426.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 63]  [Cited by in F6Publishing: 62]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
18.  Bukh J, Purcell RH, Miller RH. Sequence analysis of the 5’ noncoding region of hepatitis C virus. Proc Natl Acad Sci USA. 1992;89:4942-4946.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Piñeiro D, Martinez-Salas E. RNA structural elements of hepatitis C virus controlling viral RNA translation and the implications for viral pathogenesis. Viruses. 2012;4:2233-2250.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 25]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
20.  Domingo E, Holland JJ. RNA virus mutations and fitness for survival. Annu Rev Microbiol. 1997;51:151-178.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1104]  [Cited by in F6Publishing: 1012]  [Article Influence: 37.5]  [Reference Citation Analysis (0)]
21.  Smith DB, Bukh J, Kuiken C, Muerhoff AS, Rice CM, Stapleton JT, Simmonds P. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology. 2014;59:318-327.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 965]  [Cited by in F6Publishing: 924]  [Article Influence: 92.4]  [Reference Citation Analysis (0)]
22.  Simmonds P, Bukh J, Combet C, Deléage G, Enomoto N, Feinstone S, Halfon P, Inchauspé G, Kuiken C, Maertens G. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology. 2005;42:962-973.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1070]  [Cited by in F6Publishing: 1058]  [Article Influence: 55.7]  [Reference Citation Analysis (0)]
23.  Pawlotsky JM. The nature of interferon-alpha resistance in hepatitis C virus infection. Curr Opin Infect Dis. 2003;16:587-592.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 3]  [Reference Citation Analysis (0)]
24.  Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med. 2004;140:370-381.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Ribeiro RM, Li H, Wang S, Stoddard MB, Learn GH, Korber BT, Bhattacharya T, Guedj J, Parrish EH, Hahn BH. Quantifying the diversification of hepatitis C virus (HCV) during primary infection: estimates of the in vivo mutation rate. PLoS Pathog. 2012;8:e1002881.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 124]  [Cited by in F6Publishing: 115]  [Article Influence: 9.6]  [Reference Citation Analysis (0)]
26.  Kim T, Mudry RA, Rexrode CA, Pathak VK. Retroviral mutation rates and A-to-G hypermutations during different stages of retroviral replication. J Virol. 1996;70:7594-7602.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Yun Z, Lara C, Johansson B, Lorenzana de Rivera I, Sönnerborg A. Discrepancy of hepatitis C virus genotypes as determined by phylogenetic analysis of partial NS5 and core sequences. J Med Virol. 1996;49:155-160.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
28.  Kalinina O, Norder H, Mukomolov S, Magnius LO. A natural intergenotypic recombinant of hepatitis C virus identified in St. Petersburg. J Virol. 2002;76:4034-4043.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Morel V, Fournier C, François C, Brochot E, Helle F, Duverlie G, Castelain S. Genetic recombination of the hepatitis C virus: clinical implications. J Viral Hepat. 2011;18:77-83.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 56]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
30.  Domingo E, Gomez J. Quasispecies and its impact on viral hepatitis. Virus Res. 2007;127:131-150.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 88]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
31.  Biebricher CK, Eigen M. The error threshold. Virus Res. 2005;107:117-127.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
32.  Chambers TJ, Fan X, Droll DA, Hembrador E, Slater T, Nickells MW, Dustin LB, Dibisceglie AM. Quasispecies heterogeneity within the E1/E2 region as a pretreatment variable during pegylated interferon therapy of chronic hepatitis C virus infection. J Virol. 2005;79:3071-3083.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Echeverría N, Moratorio G, Cristina J, Moreno P. Hepatitis C virus genetic variability and evolution. World J Hepatol. 2015;7:831-845.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 68]  [Article Influence: 7.6]  [Reference Citation Analysis (1)]
34.  Pawlotsky JM. Hepatitis C virus population dynamics during infection. Curr Top Microbiol Immunol. 2006;299:261-284.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Cody SH, Nainan OV, Garfein RS, Meyers H, Bell BP, Shapiro CN, Meeks EL, Pitt H, Mouzin E, Alter MJ. Hepatitis C virus transmission from an anesthesiologist to a patient. Arch Intern Med. 2002;162:345-350.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Lin HJ, Seeff LB, Barbosa L, Hollinger FB. Occurrence of identical hypervariable region 1 sequences of hepatitis C virus in transfusion recipients and their respective blood donors: divergence over time. Hepatology. 2001;34:424-429.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 24]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
37.  Hijikata M, Mizuno K, Rikihisa T, Shimizu YK, Iwamoto A, Nakajima N, Yoshikura H. Selective transmission of hepatitis C virus in vivo and in vitro. Arch Virol. 1995;140:1623-1628.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Kojima M, Osuga T, Tsuda F, Tanaka T, Okamoto H. Influence of antibodies to the hypervariable region of E2/NS1 glycoprotein on the selective replication of hepatitis C virus in chimpanzees. Virology. 1994;204:665-672.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 53]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
39.  Cristina J, del Pilar Moreno M, Moratorio G. Hepatitis C virus genetic variability in patients undergoing antiviral therapy. Virus Res. 2007;127:185-194.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
40.  Valenti L, Pulixi E, La Spina S. IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity? Hepatol Int. 2012;6:356-359.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 4]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
41.  Aparicio E, Franco S, Parera M, Andrés C, Tural C, Clotet B, Martínez MA. Complexity and catalytic efficiency of hepatitis C virus (HCV) NS3 and NS4A protease quasispecies influence responsiveness to treatment with pegylated interferon plus ribavirin in HCV/HIV-coinfected patients. J Virol. 2011;85:5961-5969.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 17]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
42.  Lindsay KL. Therapy of hepatitis C: overview. Hepatology. 1997;26:71S-77S.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Brillanti S, Garson J, Foli M, Whitby K, Deaville R, Masci C, Miglioli M, Barbara L. A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C. Gastroenterology. 1994;107:812-817.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4847]  [Cited by in F6Publishing: 4689]  [Article Influence: 213.1]  [Reference Citation Analysis (0)]
46.  Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1287]  [Cited by in F6Publishing: 1288]  [Article Influence: 99.1]  [Reference Citation Analysis (0)]
47.  Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1948]  [Cited by in F6Publishing: 1951]  [Article Influence: 150.1]  [Reference Citation Analysis (0)]
48.  Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1866]  [Cited by in F6Publishing: 1835]  [Article Influence: 141.2]  [Reference Citation Analysis (0)]
49.  Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1205]  [Cited by in F6Publishing: 1194]  [Article Influence: 91.8]  [Reference Citation Analysis (0)]
50.  Banerjee D, Reddy KR. Review article: safety and tolerability of direct-acting anti-viral agents in the new era of hepatitis C therapy. Aliment Pharmacol Ther. 2016;43:674-696.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 111]  [Cited by in F6Publishing: 112]  [Article Influence: 14.0]  [Reference Citation Analysis (0)]
51.  Tamori A, Enomoto M, Kawada N. Recent Advances in Antiviral Therapy for Chronic Hepatitis C. Mediators Inflamm. 2016;2016:6841628.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 41]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
52.  Gutierrez JA, Lawitz EJ, Poordad F. Interferon-free, direct-acting antiviral therapy for chronic hepatitis C. J Viral Hepat. 2015;22:861-870.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 63]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
53.  Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, Shiffman ML, Zeuzem S, Craxi A, Ling MH. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1493-1499.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 894]  [Cited by in F6Publishing: 872]  [Article Influence: 58.1]  [Reference Citation Analysis (0)]
55.  Fried MW, Buti M, Dore GJ, Flisiak R, Ferenci P, Jacobson I, Marcellin P, Manns M, Nikitin I, Poordad F. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58:1918-1929.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 216]  [Cited by in F6Publishing: 239]  [Article Influence: 21.7]  [Reference Citation Analysis (0)]
56.  Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368:34-44.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 572]  [Cited by in F6Publishing: 603]  [Article Influence: 54.8]  [Reference Citation Analysis (0)]
57.  Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Corregidor A, DeJesus E, Pearlman B, Rabinovitz M, Gitlin N. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014;384:1756-1765.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 602]  [Cited by in F6Publishing: 665]  [Article Influence: 66.5]  [Reference Citation Analysis (0)]
58.  Kwo P, Gitlin N, Nahass R, Bernstein D, Rojter S, Schiff E, Davis M, Ruane PJ, Younes Z, Kalmeijer R. 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 treatment-experienced patients with chronic HCV genotype 1 infection without cirrhosis: OPTMIST-1 [abstract]. Vienna: Presented at the 50th Annual Meeting of the European Association for the Study of the Liver, April 22-26 2015; Abstract LP14.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Lawitz E, Matusow G, DeJesus E, Yoshida E, Felizarta F, Ghalib R, Godofsky E, Herring R, Poleynard G, Sheikh A. A phase 3, open-lable, single-arm study to evaluate the efficacy and safety of 12 weeks of simeprevir and sofosbuvironn treatment-naive or-experienced patients with chronic HCV genotype 1 infection and cirrhosis: OPTMIST-2 [abstract]. Vienna: Presented at the 50th Annual Meeting of the European Association for the Study of the Liver, April 22-26 2015; Abstract LP04.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211-221.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, Freilich BF, Younes ZH, Harlan W, Ghalib R. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61:1127-1135.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 504]  [Cited by in F6Publishing: 500]  [Article Influence: 55.6]  [Reference Citation Analysis (0)]
62.  Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, Nahass R, Ghalib R, Gitlin N, Herring R. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-1493.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1065]  [Cited by in F6Publishing: 1042]  [Article Influence: 104.2]  [Reference Citation Analysis (0)]
63.  Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, Shiffman ML, ESchiff E, Ghalib R, Ryan M. Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis. N Engl J Med. 2014;370:179-188.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 911]  [Cited by in F6Publishing: 906]  [Article Influence: 90.6]  [Reference Citation Analysis (0)]
64.  Dore GJ, Conway B, Luo Y, Janczewska E, Knysz B, Liu Y, Streinu-Cercel A, Caruntu FA, Curescu M, Skoien R. Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in genotype 1 HCV patients: The MALACHITE-I/II trials. J Hepatol. 2016;64:19-28.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 53]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
65.  Hézode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, Fleischer-Stepniewska K, Marcellin P, Hall C, Schnell G, Pilot-Matias T. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet. 2015;385:2502-2509.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 203]  [Cited by in F6Publishing: 191]  [Article Influence: 21.2]  [Reference Citation Analysis (0)]
66.  Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourlière M, Sulkowski MS, Wedemeyer H, Tam E, Desmond P. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:1604-1614.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 452]  [Cited by in F6Publishing: 477]  [Article Influence: 47.7]  [Reference Citation Analysis (0)]
67.  Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, Shiffman ML, Wedemeyer H, Berg T, Yoshida EM. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370:1973-1982.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 698]  [Cited by in F6Publishing: 731]  [Article Influence: 73.1]  [Reference Citation Analysis (0)]
68.  Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S, Lawitz E, Thompson A, Shiffman ML, Cooper C. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015;373:2608-2617.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 640]  [Cited by in F6Publishing: 625]  [Article Influence: 69.4]  [Reference Citation Analysis (0)]
69.  Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, Alric L, Bronowicki JP, Lester L, Sievert W. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015;385:1075-1086.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Everson GT, Sims KD, Thuluvath PJ, Lawitz E, Hassanein T, Rodriguez-Torres M, Desta T, Hawkins T, Levin JM, Hinestrosa F. Daclatasvir + asunaprevir + beclabuvir ± ribavirin for chronic HCV genotype 1-infected treatment-naive patients. Liver Int. 2016;36:189-197.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 23]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
71.  Zeuzem S, Soriano V, Asselah T, Gane EJ, Bronowicki JP, Angus P, Lohse AW, Stickel F, Müllhaupt B, Roberts S. Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis. Antimicrob Agents Chemother. 2015;59:1282-1291.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 10]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
72.  Sorbera MA, Friedman ML, Cope R. New and Emerging Evidence on the Use of Second-Generation Direct Acting Antivirals for the Treatment of Hepatitis C Virus in Renal Impairment. J Pharm Pract. 2016; Epub ahead of print.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
73.  Asselah T, Marcellin P. Optimal IFN-free therapy in treatment-naïve patients with HCV genotype 1 infection. Liver Int. 2015;35 Suppl 1:56-64.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 26]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
74.  Craxì L, Sacchini D, Refolo P, Minacori R, Daloiso V, Ricci G, Bruno R, Cammà C, Cicchetti A, Gasbarrini A. Prioritization of high-cost new drugs for HCV: making sustainability ethical. Eur Rev Med Pharmacol Sci. 2016;20:1044-1051.  [PubMed]  [DOI]  [Cited in This Article: ]
75.  Woode ME, Abu-Zaineh M, Perriëns J, Renaud F, Wiktor S, Moatti JP. Potential market size and impact of hepatitis C treatment in low- and middle-income countries. J Viral Hepat. 2016;23:522-534.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 14]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
76.  Batista MN, Carneiro BM, Braga AC, Rahal P. Caffeine inhibits hepatitis C virus replication in vitro. Arch Virol. 2015;160:399-407.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 32]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
77.  Finkielsztein LM, Moltrasio GY, Caputto ME, Castro EF, Cavallaro LV, Moglioni AG. What is known about the antiviral agents active against bovine viral diarrhea virus (BVDV)? Curr Med Chem. 2010;17:2933-2955.  [PubMed]  [DOI]  [Cited in This Article: ]
78.  Bastos JC, Kohn LK, Fantinatti-Garboggini F, Padilla MA, Flores EF, da Silva BP, de Menezes CB, Arns CW. Antiviral activity of Bacillus sp. isolated from the marine sponge Petromica citrina against bovine viral diarrhea virus, a surrogate model of the hepatitis C virus. Viruses. 2013;5:1219-1230.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 21]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
79.  Padilla MA, Rodrigues RA, Bastos JC, Martini MC, Barnabé AC, Kohn LK, Uetanabaro AP, Bomfim GF, Afonso RS, Fantinatti-Garboggini F. Actinobacteria from Termite Mounds Show Antiviral Activity against Bovine Viral Diarrhea Virus, a Surrogate Model for Hepatitis C Virus. Evid Based Complement Alternat Med. 2015;2015:745754.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 8]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
80.  Jardim AC, Igloi Z, Shimizu JF, Santos VA, Felippe LG, Mazzeu BF, Amako Y, Furlan M, Harris M, Rahal P. Natural compounds isolated from Brazilian plants are potent inhibitors of hepatitis C virus replication in vitro. Antiviral Res. 2015;115:39-47.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 25]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
81.  Calland N, Dubuisson J, Rouillé Y, Séron K. Hepatitis C virus and natural compounds: a new antiviral approach? Viruses. 2012;4:2197-2217.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 109]  [Cited by in F6Publishing: 97]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
82.  Li Y, Yu S, Liu D, Proksch P, Lin W. Inhibitory effects of polyphenols toward HCV from the mangrove plant Excoecaria agallocha L. Bioorg Med Chem Lett. 2012;22:1099-1102.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 31]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
83.  Kubiça TF, Alves SH, Weiblen R, Lovato LT. In vitro inhibition of the bovine viral diarrhoea virus by the essential oil of Ocimum basilicum (basil) and monoterpenes. Braz J Microbiol. 2014;45:209-214.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 24]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
84.  Wagoner J, Negash A, Kane OJ, Martinez LE, Nahmias Y, Bourne N, Owen DM, Grove J, Brimacombe C, McKeating JA. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology. 2010;51:1912-1921.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 157]  [Cited by in F6Publishing: 160]  [Article Influence: 11.4]  [Reference Citation Analysis (0)]
85.  Wagoner J, Morishima C, Graf TN, Oberlies NH, Teissier E, Pécheur EI, Tavis JE, Polyak SJ. Differential in vitro effects of intravenous versus oral formulations of silibinin on the HCV life cycle and inflammation. PLoS One. 2011;6:e16464.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 56]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
86.  Ashfaq UA, Javed T, Rehman S, Nawaz Z, Riazuddin S. Inhibition of HCV 3a core gene through Silymarin and its fractions. Virol J. 2011;8:153.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 17]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]