Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase

BACKGROUND: Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct- acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES: To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS: We searched for all published and unpublished trials in The Cochrane Hepato- Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS ; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA: Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co- interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health- related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non- serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS: We included a total of 138 trials randomising a total of 25, 232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13, 466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%) ; OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6% ; OR 0.93, 95% CI 0.75 to 1.15 , 15, 817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C- related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79 ; 5 trials, very low- quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73 ; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS: The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long- term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.

Direct-acting antivirals for chronic hepatitis C

RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic.

Hepatitis C virus (HCV) infection is a serious problem worldwide, but no effective drugs are currently available. Through screening of our privileged structure library, quinoxalin-2(1H)-one derivative N-(7-(cyclohexyl(methyl)amino)-3-oxo-3,4-dihydroquinoxalin-6-ylcarbamothioyl)benzamide (compound 1) was identified as potent HCV inhibitor in vitro. Subsequently, a structure–activity relationship analysis was carried out that showed N-(7-(cyclohexyl(methyl)amino)-3-oxo-3,4-dihydroquinoxalin-6-ylcarbamothioyl)furan-2-carboxamide (compound 11, EC50 = 1.8 μM, SI = 9.6), 6-(cyclohexyl(methyl)amino)-7-(4-phenylthiazol-2-ylamino)quinoxalin-2(1H)-one (compound 33, EC50 = 1.67 μM, SI = 37.4), 2-(cyclohexyl(methyl)amino)-3-(4-phenylthiazol-2-ylamino)-7,8,9,10-tetrahydro-5H-pyrido[1,2-a]quinoxalin-6(6aH)-one (compound 60, EC50 = 1.19 μM, SI = 9.27), 8-(cyclohexyl(methyl)amino)-7-(4-phenylthiazol-2-ylamino)pyrrolo[1,2-a]quinoxalin-4(5H)-one (compound 65, EC50 = 1.82 μM, SI = 9.9), and 6-(diethylamino)-7-(4-phenylthiaz...

Quinoxalin-2(1H)-one derivatives as inhibitors against hepatitis C virus.

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)61650-5/pdf

New hcv therapies on the horizon

https://www.journal-of-hepatology.eu/article/S0168-8278(10)60033-5/pdf

31 safety and antiviral activity of the hcv non-nucleoside polymerase inhibitor vx-222 in treatment-naive genotype 1 hcv-infected patients

92 safety, tolerability and antiviral activity of vch-916, a novel non-nucleoside hcv polymerase inhibitor in patients with chronic hcv genotype-1 infection

940 safety, tolerability and pharmacokinetics of the hcv polymerase inhibitor vch-222 following single dose administration in healthy volunteers and antiviral activity in hcv-infected individuals

854 results of a safety, tolerability and pharmacokinetic phase i study of vch-916, a novel polymerase inhibitor for hcv, following single ascending doses in healthy volunteers

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31 safety and antiviral activity of the hcv non-nucleoside polymerase inhibitor vx-222 in treatment-naive genotype 1 hcv-infected patients

92 safety, tolerability and antiviral activity of vch-916, a novel non-nucleoside hcv polymerase inhibitor in patients with chronic hcv genotype-1 infection

940 safety, tolerability and pharmacokinetics of the hcv polymerase inhibitor vch-222 following single dose administration in healthy volunteers and antiviral activity in hcv-infected individuals

854 results of a safety, tolerability and pharmacokinetic phase i study of vch-916, a novel polymerase inhibitor for hcv, following single ascending doses in healthy volunteers