Treatment of HCV Infection by Targeting MicroRNA Janssen, Harry L.A; Reesink, Hendrik W; Lawitz, Eric J ...
The New England journal of medicine,
05/2013, Volume:
368, Issue:
18
Journal Article
Peer reviewed
Open access
In this phase 2 trial, an antisense oligonucleotide was tested in the treatment of chronic hepatitis C virus infection. The oligonucleotide was designed to bind to and sequester a microRNA required ...for HCV replication.
Approximately 170 million persons worldwide are chronically infected with the hepatitis C virus (HCV).
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Chronic HCV infection is a major cause of liver cirrhosis, liver failure, and hepatocellular carcinoma and is the leading indication for liver transplantation in many Western countries.
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Sustained eradication of HCV infection has been associated with a reduced risk of liver-related morbidity and all-cause mortality.
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Despite the recent registration of protease inhibitors for the treatment of chronic HCV genotype 1 infection, current therapeutic regimens remain dependent on the administration of pegylated interferon and ribavirin for 24 to 48 weeks.
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Thus, anti-HCV therapy continues to . . .
In patients with HCV genotypes 2 and 3, sofosbuvir plus ribavirin was administered for 12 weeks in patients with genotype 2 and for 24 weeks in those with genotype 3. Rates of sustained virologic ...response were 93% in patients with genotype 2 and 85% in those with genotype 3.
Of the six main genotypes of the hepatitis C virus (HCV), genotypes 2 and 3 account for approximately 30% of chronic infections worldwide.
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Although these two genotypes have historically been grouped together in treatment guidelines and clinical trials,
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accumulating evidence suggests that there are important clinical differences between them.
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,
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HCV genotype 3 infection is associated with a higher incidence of hepatic steatosis, more rapid progression of fibrosis, and possibly a greater risk of hepatocellular carcinoma than is HCV genotype 2 infection.
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Moreover, patients with HCV genotype 3 infection are less responsive to peginterferon-based treatment than are patients . . .
Summary Background miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect ...of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes. Methods In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18–65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-α based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using the SAS procedure Proc Plan. The first cohort received one subcutaneous injection of 2 mg/kg RG-101 or placebo; the second cohort received one subcutaneous injection of 4 mg/kg or placebo. Patients were followed up for 8 weeks (all patients) and up to 76 weeks (patients with no viral rebound and excluding those who were randomised to the placebo group) after randomisation. The primary objective was safety and tolerability of RG-101. This trial was registered with EudraCT, number 2013-002978-49. Findings Between June 4, 2014, and Oct 27, 2014, we enrolled 32 patients with chronic HCV genotype 1 (n=16), 3 (n=10), or 4 (n=6) infections. In the first cohort, 14 patients were randomly assigned to receive 2 mg/kg RG-101 and two patients were randomly assigned to receive placebo, and in the second cohort, 14 patients were randomly assigned to receive 4 mg/kg RG-101 and two patients were randomly assigned to receive placebo. Overall, 26 of the 28 patients dosed with RG-101 reported at least one treatment-related adverse event. At week 4, the median viral load reduction from baseline was 4·42 (IQR 3·23–5·00) and 5·07 (4·19–5·35) log10 IU/mL in patients dosed with 2 mg/kg RG-101 or 4 mg/kg RG-101. Three patients had undetectable HCV RNA levels 76 weeks after a single dose of RG-101. Viral rebound at or before week 12 was associated with the appearance of resistance associated substitutions in miR-122 binding regions in the 5′ UTR of the HCV genome. Interpretation This study showed that one administration of 2 mg/kg or 4 mg/kg RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated anti-miR-122 oligonucleotide, was well tolerated and resulted in substantial viral load reduction in all treated patients within 4 weeks, and sustained virological response in three patients for 76 weeks. Funding Regulus Therapeutics, Inc.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long‐term therapy may be required. We investigated whether adding on pegylated interferon (Peg‐IFN) to ETV therapy enhances ...serological response rates. In this global investigator‐initiated, open‐label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg‐IFN add‐on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add‐on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg‐IFN add‐on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6‐14.0; P = 0.004). Eleven (13%) of the add‐on‐treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add‐on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg‐IFN add‐on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. Conclusion: Although the primary endpoint was not reached, 24 weeks of Peg‐IFN add‐on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add‐on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg‐IFN add‐on therapy may facilitate the discontinuation of nucleos(t)ide analogs. (Hepatology 2015;61:1512–1522)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In patients with chronic infection with HCV genotype 1 and undetectable HCV at weeks 4 and 12 of treatment, a 24-week regimen that included telaprevir, peginterferon, and ribavirin was not inferior ...to a 48-week regimen.
Chronic infection with hepatitis C virus (HCV) represents a serious health issue for nearly 200 million infected persons worldwide.
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Achievement of a sustained virologic response may be associated with improved long-term clinical outcomes, including increased survival.
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In patients infected with HCV genotype 1, 48 weeks of treatment with peginterferon alfa and ribavirin results in a rate of sustained virologic response of 40 to 50%.
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Telaprevir administered in combination with peginterferon and ribavirin has led to high rates of sustained virologic response in phase 2 and phase 3 trials involving patients with HCV genotype 1 infection, who have not . . .
Telaprevir (VX‐950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype 1 patients. Using a ...highly sensitive sequencing assay that detects minor populations of viral variants (≥5%), mutations were identified that conferred low‐level (V36M/A, T54A, or R155K/T) or high‐level (A156V/T and 36/155) resistance to telaprevir in vitro. We report a detailed kinetic analysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon–alpha‐2a (PEG‐IFN–alpha‐2a) for 14 days. In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given telaprevir alone or with telaprevir/PEG‐IFN–alpha‐2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients. Conclusion: These studies suggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild‐type virus, which uncovers pre‐existing telaprevir‐resistant variants. In patients given telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of telaprevir and PEG‐IFN–alpha‐2a inhibited both wild‐type and resistant variants. In the present study, every patient who began PEG‐IFN–alpha‐2a and ribavirin after the 14‐day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that telaprevir‐resistant variants are sensitive to PEG‐IFN–alpha‐2a and ribavirin. (HEPATOLOGY 2007.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background. Treatment of patients with chronic hepatitis B (CHB) with nucleos(t)ide analogues (NAs) suppresses hepatitis B virus (HBV) DNA production but does not affect the synthesis of the RNA ...pregenome or HBV messenger RNA. Whether HBV RNA–containing particles continue to be secreted into the bloodstream remains controversial. Methods. We developed a sensitive polymerase chain reaction (PCR) assay to quantify the HBV RNA load in a supernatant of NA-treated HepG2-2.2.15 cells and in plasma specimens from 20 patients with CHB who were receiving NA therapy and 86 patients treated with pegylated interferon alfa (Peg-IFN) and adefovir. Results. Treatment of HepG2-2.2.15 cells with NAs for 9 days reduced HBV DNA levels (by 1.98 log10 copies/mL), whereas HBV RNA levels increased (by 0.47 log10 copies/mL; P < .05). During long-term NA treatment of patients with CHB, HBV RNA levels remained higher than HBV DNA levels. Peg-IFN–based treatment induced a stronger decrease in the HBV RNA load than NA monotherapy, and this decline was more pronounced in responders than in nonresponders. In HBV e antigen–negative patients, a lower baseline plasma HBV RNA level was independently associated with response to Peg-IFN and adefovir (odds ratio, 0.44; P = .019). Immunoprecipitation with HBV core antigen–specific antibodies after removal of the HBV surface antigen envelope demonstrated the association of plasma HBV RNA with virions. Conclusions. HBV RNA is present in virions in plasma specimens from patients with CHB. HBV RNA levels vary significantly from those of established viral markers during antiviral treatment, which highlights its potential as an independent marker in the evaluation of patients with CHB.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Tissue resident memory T cells (T
) have been identified in various tissues, however human liver T
to date remain unidentified. T
can be recognized by CD69 and/or CD103 expression and may play a role ...in the pathology of chronic hepatitis B (CHB) and hepatitis C virus infection (CHC). Liver and paired blood mononuclear cells from 17 patients (including 4 CHB and 6 CHC patients) were isolated and CD8+ T cells were comprehensively analysed by flowcytometry, immunohistochemistry and qPCR. The majority of intrahepatic CD8+ T cells expressed CD69, a marker used to identify T
, of which a subset co-expressed CD103. CD69 + CD8+ T cells expressed low levels of S1PR1 and KLF2 and a large proportion (>90%) was CXCR6+, resembling liver T
in mice and liver resident NK cells in human. Cytotoxic proteins were only expressed in a small fraction of liver CD69 + CD8+ T cells in patients without viral hepatitis, however, in livers from CHB patients more CD69 + CD8+ T cells were granzyme B+. In CHC patients, less intrahepatic CD69 + CD8+ T cells were Hobit+ as compared to CHB and control patients. Intrahepatic CD69 + CD8+ T cells likely T
which have a reduced cytolytic potential. In patients with chronic viral hepatitis T
have a distinct phenotype.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background & Aim Interferon (IFN) negatively impacts patients’ well-being and patient-reported outcomes (PROs). Our aim was to assess PROs during treatment with an IFN-free regimen sofosbuvir (SOF) + ...ribavirin (RBV). Methods Four PRO questionnaires Short Form-36 (SF-36), Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity Index: Specific Health Problem (WPAI:SHP) were administered at baseline, end-of-treatment and post-treatment to 334 HCV genotype 2 and 3 patients (naïve or treatment-experienced) enrolled in the VALENCE study. Of these, 250 genotype 3 patients were treated for 24 weeks while 73 genotype 2 and 11 genotype 3 patients received 12 weeks of treatment. Results Baseline PRO scores were similar between the two arms of the study. Throughout and after treatment, patients receiving 12 or 24 weeks had similar FACIT-F, CLDQ-HCV, SF-36 and WPAI:SHP scores (all p >0.05). Compared to their own baseline scores, patients receiving SOF + RBV experienced modest declines in some aspects of SF-36, CLDQ-HCV, fatigue and WPAI:SHP scores ( p = 0.04 to <0.0001). By follow-up week 12, all PRO scores returned to the pre-treatment levels ( p >0.05). In patients achieving SVR-12 (regardless of the regimen), significant improvements were noted in general health ( p = 0.0004), CLDQ-HCV ( p <0.0001), fatigue ( p = 0.005), emotional well-being ( p <0.0001) and physical component summary score of SF-36 ( p = 0.0022). In multivariate analysis, baseline depression, fatigue, insomnia, cirrhosis, and treatment-related adverse events were the most consistent predictors of PRO impairment (all p <0.05). Conclusions PROs are minimally impacted by SOF + RBV regimens. An additional 12 weeks of treatment does not substantially add to the PRO burden.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In this randomized trial of patients infected with hepatitis C virus genotype 1 in whom a sustained virologic response was not achieved after initial therapy, patients retreated with peginterferon ...alfa-2a and ribavirin combined with telaprevir were more likely to have a sustained response than patients retreated with peginterferon alfa-2a and ribavirin alone.
Patients retreated with peginterferon alfa-2a and ribavirin combined with telaprevir were more likely to have a sustained response than patients retreated with peginterferon alfa-2a and ribavirin alone.
Worldwide, an estimated 170 million people have chronic hepatitis C virus (HCV) infection, and in many of these people, cirrhosis and complications of end-stage liver disease will develop.
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Chronic HCV infection is the leading cause of liver disease and is the leading indication for liver transplantation in the United States and Europe.
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Currently available treatment for HCV infection necessitates peginterferon alfa injections combined with oral ribavirin for 24 or 48 weeks (depending on the HCV genotype).
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Overall, in 40 to 50% of patients infected with HCV genotype 1 who have not previously been treated, the currently available treatment results . . .
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