Hepatitis C Treatment: current and future perspectives

Munir, Sadaf; Saleem, Sana; Idrees, Muhammad; Tariq, Aaliyah; Butt, Sadia; Rauff, Bisma; Hussain, Abrar; Badar, Sadaf; Naudhani, Mahrukh; Fatima, Zareen; Ali, M. Tanseer; Ali, Liaqat; Akram, Mohd.; Aftab, Mahwish; Khubaib, Bushra; Awan, Zunaira

doi:10.1186/1743-422x-7-296

Cited by 90 publications

(58 citation statements)

References 47 publications

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“…Treatment for HCVinfected patients often consists of a combination of pegylated alpha interferon (Peg-IFN-␣) and ribavirin (RBV), which produces serious side effects and incomplete antiviral efficacy in many patients. Only ϳ50% of the patients infected with HCV GT1 achieve a sustained viral response (SVR) upon treatment, although higher rates (ϳ80%) have been reported for patients infected with GT2 and GT3 (11)(12)(13). The new direct-acting antiviral agents (DAAs) telaprevir and boceprevir are NS3 protease inhibitors being used in combination with Peg-IFN-␣ and RBV that increase SVR rates and shorten the treatment duration for patients infected with GT1 only (14).…”

mentioning

confidence: 99%

Potency and Resistance Analysis of Hepatitis C Virus NS5B Polymerase Inhibitor BMS-791325 on All Major Genotypes

Liu

Tuttle

Gao

et al. 2014

Antimicrob Agents Chemother

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BMS-791325 is a hepatitis C virus (HCV) inhibitor binding to the thumb domain of the NS5B RNA-dependent RNA polymerase. BMS-791325 is well characterized in genotype 1 (GT1) and exhibits good inhibitory activity (50% effective concentration [EC 50 ], <10 nM) against hybrid replicons containing patient NS5B sequences from GT3a, -4a, and -5a while potency against GT2 is significantly reduced (J. A. Lemm et al., Antimicrob. Agents Chemother. 58:3485-3495, 2014, doi:http://dx.doi.org/10.1128/AAC.02495-13). BMS-791325 potency against GT6a hybrid replicons is more variable, with two of three hybrid clones having EC 50 s similar to that for GT1 while a third patient clone was ϳ10 times less susceptible to BMS-791325. To characterize the resistance profile of BMS-791325 beyond GT1, curing studies were performed across GT1a and -3a to -6a and demonstrated that GT1a has the highest resistance barrier versus BMS-791325 while GT6a has the lowest. Selection of GT3 to -6 NS5B chimeric replicon cells at different concentrations of BMS-791325 revealed substitutions in the thumb domain of NS5B at residues 494 and 495 that conferred different levels of resistance to BMS-791325 but remained susceptible to NS5A or NS3 protease inhibitors. In addition, we demonstrate that the reduced potency of BMS-791325 against one GT6a patient is due to an A494 polymorphism present in ϳ21% of sequences in the European HCV database. The results from this report suggest that BMS-791325 is a candidate for combination treatment of HCV GT3 to -6 chronic infections, and the resistance profiles identified will provide useful information for future clinical development.

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confidence: 99%

Potency and Resistance Analysis of Hepatitis C Virus NS5B Polymerase Inhibitor BMS-791325 on All Major Genotypes

Liu

Tuttle

Gao

et al. 2014

Antimicrob Agents Chemother

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“…Hepatitis C virus (HCV), a positive-strand RNA virus of the Flaviviridae family, is a leading cause of liver disease and hepatocellular carcinoma (35,59). The HCV genome encodes a single polyprotein that is cleaved by cellular and viral proteases into at least 10 individual proteins (40,48).…”

mentioning

confidence: 99%

Distinct Functions of NS5A in Hepatitis C Virus RNA Replication Uncovered by Studies with the NS5A Inhibitor BMS-790052

Fridell

Qiu

Valera

et al. 2011

J Virol

133

118

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BMS-790052, targeting nonstructural protein 5A (NS5A), is the most potent hepatitis C virus (HCV) inhibitor described to date. It is highly effective against genotype 1 replicons and also displays robust genotype 1 anti-HCV activity in the clinic (M. Gao et al., Nature 465:96-100, 2010). BMS-790052 inhibits genotype 2a JFH1 replicon cells and cell culture infectious virus with 50% effective concentrations (EC 50 s) of 46.8 and 16.1 pM, respectively. Resistance selection studies with the JFH1 replicon and virus systems identified druginduced mutations within the N-terminal region of NS5A. F28S, L31M, C92R, and Y93H were the major resistance mutations identified; the impact of these mutations on inhibitor sensitivity between the replicon and virus was very similar. The C92R and Y93H mutations negatively impacted fitness of the JFH1 virus. Secondsite replacements at NS5A residue 30 (K30E/Q) restored efficient replication of the C92R viral variant, thus demonstrating a genetic interaction between NS5A residues 30 and 92. By using a trans-complementation assay with JFH1 replicons encoding inhibitor-sensitive and inhibitor-resistant NS5A proteins, we provide genetic evidence that NS5A performs the following two distinct functions in HCV RNA replication: a cis-acting function that likely occurs as part of the HCV replication complex and a trans-acting function that may occur outside the replication complex. The cis-acting function is likely performed by basally phosphorylated NS5A, while the trans-acting function likely requires hyperphosphorylation. Our data indicate that BMS-790052 blocks the cis-acting function of NS5A. Since BMS-790052 also impairs JFH1 NS5A hyperphosphorylation, it likely also blocks the trans-acting function.Hepatitis C virus (HCV), a positive-strand RNA virus of the Flaviviridae family, is a leading cause of liver disease and hepatocellular carcinoma (35, 59). The HCV genome encodes a single polyprotein that is cleaved by cellular and viral proteases into at least 10 individual proteins (40, 48). Nonstructural protein 3 (NS3), NS4A, NS4B, NS5A, and NS5B are sufficient for HCV RNA replication in cell culture (6, 30). NS3-4A is the primary viral protease, and NS5B is an RNAdependent RNA polymerase (4,5,14). NS4B, a hydrophobic protein with multiple trans-membrane domains, induces an endoplasmic reticulum-derived membranous web that harbors the HCV replication complex (10, 32). NS5A is also essential for HCV RNA replication, but its precise roles in this process are poorly understood (21, 33).NS5A is an RNA binding protein that interacts with other HCV nonstructural proteins and is capable of altering NS5B polymerase activity in vitro (9,20,41,46,47). NS5A also interacts with a variety of cellular proteins and is potentially involved in modulating multiple aspects of the cellular environment (33, 43). In addition to its role(s) in RNA replication, NS5A is also required for viral assembly (3, 50). NS5A is a modular protein with an N-terminal amphipathic ␣-helix membrane anchor (amino acids [aa] 5 t...

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“…There are about 175 million HCV patients worldwide that constitute 3% of world's population. The main route of HCV transmission is parental; however 90% intravenous drug users are at highest risk [31]. It is associated with cirrhosis, hepatocellular carcinoma, and liver failure.…”

Section: Discussionmentioning

confidence: 99%

Food Supplement for Therapy of HCV

Younes¹

2013

J Antivir Antiretrovir

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Hepatitis C is a progressing global health problem. The expense of the exciting regimen for treatment is not available for many patients. Herbal medicines have been used as complementary therapy in the treatment of liver diseases for a long time. Fifty one patients with hepatitis C have been seen in our outpatient clinic, with twelve patients as control. Patients were interviewed to obtain detailed clinical data before and after treatment. The herbal medicines used in the treatment of HCV are Milk Thistle, Phyllanthus, Garlic, Cinnamon, Parsley, Black seed and AKHY-J-25 (mixture of herbs). Every patient received single oral capsule of herbal preparations powder, in early morning on an empty stomach with two cups of water and simple breakfast after two hours, from three months to two years, and twelve patients as control received placebo. The results showed 20% of patients had no detectable HCV RNA in serum at 24 week treatment, 72.6% showed clinical and biochemical improvement with decline of HCV RNA to lower limit and 7.4% showed clinical and biochemical improvement without change in level of HCV RNA.

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Hepatitis C Treatment: current and future perspectives

Cited by 90 publications

References 47 publications

Potency and Resistance Analysis of Hepatitis C Virus NS5B Polymerase Inhibitor BMS-791325 on All Major Genotypes

Potency and Resistance Analysis of Hepatitis C Virus NS5B Polymerase Inhibitor BMS-791325 on All Major Genotypes

Distinct Functions of NS5A in Hepatitis C Virus RNA Replication Uncovered by Studies with the NS5A Inhibitor BMS-790052

Food Supplement for Therapy of HCV

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