Dasabuvir

Non-Nucleoside Binding Site Characterization (Palm I Allosteric Site)

This compound binds to an allosteric site on the HCV NS5B polymerase. patsnap.comnih.govresearchgate.netpatsnap.com Specifically, it targets the palm domain of the enzyme, and is referred to as a non-nucleoside NS5B-palm polymerase inhibitor. drugbank.comdrugcentral.org This binding site is known as the palm I allosteric inhibitory site. nih.gov Resistance mapping studies have indicated that this compound targets this site. drugbank.comdrugcentral.org The palm I site is located within the palm domain of the polymerase and partially overlaps with the palm II site. nih.govasm.org Resistant variants selected by this compound, such as C316Y, M414T, Y448C, Y448H, and S556G, are consistent with binding to the palm I site. nih.gov In silico modeling suggests that this compound binds near the active site, extending from the β-hairpin loop in the thumb domain. nih.gov

Conformational Changes Induced by this compound Binding

Binding of this compound to the NS5B polymerase outside its active site induces a conformational change in the enzyme. drugbank.compatsnap.comnih.govresearchgate.net This allosteric modulation renders the polymerase nonfunctional or unable to elongate viral RNA. drugbank.compatsnap.comnih.govresearchgate.net The induced conformational change prevents the enzyme from effectively carrying out its role in RNA synthesis. drugbank.compatsnap.comnih.govresearchgate.net In silico studies have confirmed that the NS5B-dasabuvir complex is stable and that this compound binding can influence loops involved in the elongation process. nih.gov

Inhibition of Viral RNA Synthesis and Replication

By binding to the allosteric site and inducing conformational changes, this compound effectively inhibits the RNA-dependent RNA polymerase activity of NS5B. drugbank.comwikipedia.orgpatsnap.comdrugcentral.orgcancer.govnih.gov This inhibition prevents the synthesis of new viral RNA molecules, thereby stopping the replication of the HCV genome. drugbank.comwikipedia.orgpatsnap.comcancer.gov The cessation of viral RNA synthesis leads to a reduction in the viral load. patsnap.com

Genotype-Specific Potency against Hepatitis C Virus (Genotype 1a and 1b)

This compound demonstrates highly potent and selective activity against Hepatitis C virus genotype 1, specifically genotypes 1a and 1b. drugbank.comwikipedia.orgnih.govmedchemexpress.comresearchgate.nettga.gov.auresearchgate.netmedchemexpress.comrxabbvie.comtga.gov.aueuropa.eu Its use is largely limited to genotype 1 infections because the binding sites for non-nucleoside inhibitors like this compound are not well conserved across all HCV genotypes, leading to lower potential for cross-genotypic activity. drugbank.comnih.gov Studies have shown significantly lower potency against polymerases from other HCV genotypes, such as 2a, 2b, 3a, and 4a, often more than 200 times less potent compared to genotype 1. tga.gov.autga.gov.au

Comparative Analysis of Inhibitory Concentrations (IC50 and EC50) in Replicon Systems and Enzymatic Assays

The inhibitory activity of this compound has been quantified through both enzymatic assays using recombinant NS5B polymerase and cell-based replicon assays that measure inhibition of viral RNA replication in cell culture.

In biochemical assays, this compound inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates with 50% inhibitory concentration (IC50) values typically ranging between 2.2 and 10.7 nM. nih.govtga.gov.auresearchgate.netmedchemexpress.comrxabbvie.comtga.gov.au The mean IC50 value against a panel of genotype 1a and 1b polymerases was reported as 4.2 nM. tga.gov.autga.gov.aueuropa.eu this compound demonstrated significant selectivity, being at least 7,000-fold more potent against HCV genotype 1 polymerases compared to human/mammalian polymerases. nih.govmedchemexpress.commedchemexpress.com

In HCV subgenomic replicon systems, this compound inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 nM and 1.8 nM, respectively. drugbank.comnih.govmedchemexpress.comtga.gov.aumedchemexpress.comrxabbvie.comtga.gov.aueuropa.euresearchgate.net The activity was retained against a panel of chimeric subgenomic replicons containing NS5B genes from genotype 1 clinical isolates, with EC50s ranging between 0.15 and 8.57 nM. nih.gov The mean EC50 against replicons from treatment-naïve genotype 1a isolates was 0.77 nM (range 0.4 to 2.1 nM), and against genotype 1b isolates was 0.46 nM (range 0.2 to 2 nM). tga.gov.autga.gov.aueuropa.eueuropa.eutga.gov.au

It has been observed that the inhibitory potency of this compound in replicon assays is reduced in the presence of human plasma. A 12- to 13-fold decrease in activity was noted with 40% human plasma, resulting in EC50s of 99 nM for genotype 1a (H77) and 21 nM for genotype 1b (Con1) replicons. nih.govmedchemexpress.comtga.gov.aumedchemexpress.comtga.gov.aueuropa.euresearchgate.net

The M1 metabolite of this compound has also shown antiviral activity, although with lower potency (30-40% less) than the parent compound against genotype 1a and 1b laboratory strains in the replicon assay. tga.gov.autga.gov.au

Table 1: Inhibitory Concentrations of this compound against HCV Genotype 1

Table 2: Selectivity of this compound

Assessment of Selectivity against Human and Mammalian Polymerases

This compound demonstrates a high degree of selectivity for inhibiting HCV genotype 1 polymerases over a range of human and mammalian polymerases. Studies have shown that this compound is at least 7,000-fold more selective for inhibiting HCV genotype 1 polymerases compared to human/mammalian polymerases. nih.govnih.govmedchemexpress.comselleckchem.comglpbio.com This selectivity was assessed against various human and mammalian DNA-dependent DNA polymerases (including polymerases alpha, beta, and gamma) and DNA-dependent RNA polymerases (such as RNA polymerases II and III), as well as one RNA-dependent DNA polymerase (polymerase gamma-RT function). nih.gov

The inhibitory activity of this compound on recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates has been measured with 50% inhibitory concentration (IC50) values typically ranging between 2.2 and 10.7 nM. nih.govnih.govmedchemexpress.comglpbio.com In contrast, the activity against human and mammalian polymerases is significantly lower, contributing to its favorable selectivity profile. nih.gov

Evaluation of this compound Activity against Other Flaviviruses

Studies have evaluated the activity of this compound against other medically important flaviviruses, including Zika virus (ZIKV), West Nile virus (WNV), and tick-borne encephalitis virus (TBEV). mdpi.comresearchgate.netcornell.edunih.gov In in vitro assays using Vero cells, this compound has demonstrated antiviral effects against these flaviviruses at micromolar concentrations. mdpi.comresearchgate.netcornell.edunih.govresearchgate.net

Specifically, this compound exhibited inhibitory effects on the replication of ZIKV (strains MR-766 and Paraiba_01), WNV (strains 13-104 and Eg101), and TBEV (strain Hypr) in Vero cells. mdpi.comresearchgate.netcornell.edunih.gov The 50% effective concentration (EC50) values for this compound against these flaviviruses in Vero cells ranged from 9.09 µM (TBEV) to 10.85 µM (WNV 13-104). mdpi.comresearchgate.netcornell.edu

This compound also showed anti-ZIKV effects in human astrocytes and a slight effect in neuroblastoma cells, indicating potential cell-type-dependent activity. nih.gov

Analogous Mechanisms of Action in Related Viral Polymerases

This compound functions as a non-nucleoside inhibitor that targets the palm domain of the HCV NS5B polymerase, inducing a conformational change that prevents viral RNA elongation. drugbank.comnih.gov Considering the structural similarities between the RNA-dependent RNA polymerases of HCV and other viruses within the Flaviviridae family, it is hypothesized that the mechanism of action of this compound against these related viral polymerases could be analogous. mdpi.com

While this compound is known to interact with HCV polymerase, the exact binding sites and detailed mechanisms of inhibition for other flaviviruses may vary. mdpi.com The binding sites for non-nucleoside NS5B inhibitors like this compound are reported to be poorly conserved across different HCV genotypes, which contributes to its genotype 1 restriction. drugbank.comnih.gov The extent of conservation of these binding sites in the polymerases of other flaviviruses would influence the analogous nature of this compound's mechanism of action. Despite the structural similarities, the micromolar concentrations required for activity against other flaviviruses, compared to the nanomolar activity against HCV, suggest potential differences in the interaction or binding affinity with the respective polymerases. nih.govmdpi.comresearchgate.netcornell.edunih.gov

Absolute Bioavailability Research

Studies have investigated the extent to which this compound is absorbed into the systemic circulation after oral administration. The absolute bioavailability of this compound has been estimated to be approximately 70%. drugbank.comnih.govfda.gov This indicates that a significant portion of the administered dose reaches the bloodstream. Food intake has been shown to increase the exposure (AUC) of this compound. amazonaws.comtga.gov.aueuropa.eu Administration with a moderate-fat meal resulted in a notable increase in this compound AUC and Cmax. europa.eu

Plasma Protein Binding Characteristics

This compound demonstrates high binding to human plasma proteins. It is reported to be greater than 99.5% bound to plasma proteins over a range of concentrations. drugbank.comnih.govamazonaws.comtga.gov.au This extensive protein binding is a significant factor influencing its distribution and elimination. Plasma protein binding of this compound is not substantially altered in patients with renal or hepatic impairment. tga.gov.au

Volume of Distribution Studies

The volume of distribution provides insight into how this compound is distributed between plasma and other body tissues. The volume of distribution of this compound at steady state is reported to be approximately 149 liters. drugbank.comnih.govamazonaws.com Following intravenous administration, the volume of distribution is approximately 400 L. europa.eu The blood to plasma concentration ratio in humans is between 0.5 and 0.7, suggesting preferential distribution in the plasma compartment of whole blood. tga.gov.aueuropa.eu

Here is a table summarizing key absorption and distribution data:

Interactive Data Table: Absorption and Distribution of this compound

Primary Cytochrome P450 Enzymes Involved (CYP2C8, CYP3A)

This compound is predominantly metabolized by cytochrome P450 (CYP) 2C8. drugbank.comnih.govtga.gov.aufda.govnih.govresearchgate.nethep-druginteractions.orgnih.gov CYP3A also contributes to its metabolism, albeit to a lesser extent. drugbank.comnih.govtga.gov.aunih.govresearchgate.nethep-druginteractions.org This metabolic profile is crucial for understanding potential drug-drug interactions. Strong inhibitors of CYP2C8 can significantly increase this compound exposure, while strong CYP3A inhibitors have a lesser effect. nih.gov Conversely, CYP3A inducers can decrease this compound exposure. nih.gov

Identification and Antiviral Activity of this compound Metabolites (e.g., M1)

Following administration, unchanged this compound is the major component of drug-related radioactivity in plasma, accounting for approximately 60%. tga.gov.au Several metabolites have been identified in plasma, with the most abundant being metabolite M1. tga.gov.auresearchgate.nettga.gov.au M1 represents a significant portion of drug-related radioactivity (around 21% of AUC) in circulation. tga.gov.auresearchgate.nettga.gov.au

Here is a table summarizing key metabolism data:

Interactive Data Table: Metabolism of this compound

Major Routes of Elimination (Fecal vs. Renal)

Studies indicate that this compound is predominantly eliminated from the body through the feces. Following a single oral dose of [14C]this compound, a mean of 94.4% of the administered radioactivity was recovered in feces. nih.govresearchgate.net In contrast, renal excretion plays a minimal role, with only about 2% of the dose eliminated in the urine. drugbank.comnih.govresearchgate.nettga.gov.au This suggests that hepatic metabolism and subsequent biliary excretion are the primary pathways for this compound clearance. dovepress.com Analysis of excreta revealed that a significant portion of the radioactivity in feces (26.2%) was attributed to the parent compound, while only a negligible amount (0.03%) of the parent compound was found in urine, further supporting metabolism as the major elimination pathway. drugbank.com

Table 1: Major Elimination Routes of this compound

Half-Life Determination and Implications for Dosing Frequency in Research Settings

The elimination half-life of this compound has been determined to be approximately 5.5 to 6 hours. drugbank.comtga.gov.audovepress.commims.com Some research indicates a terminal half-life of approximately 5-8 hours. nih.gov This relatively short half-life supports a twice-daily dosing regimen in clinical research and therapeutic settings to maintain adequate drug concentrations for inhibiting viral replication. nih.gov The M1 metabolite of this compound, which retains antiviral activity, has a half-life similar to that of the parent compound. nih.gov

Table 2: this compound Half-Life

Impact of Hepatic Impairment on this compound Exposure

Hepatic impairment has a notable impact on this compound pharmacokinetics, particularly in severe cases. Studies have shown that in subjects with mild or moderate hepatic impairment (Child-Pugh A or B), this compound exposures are minimally affected, with differences in AUC values generally less than 35% compared to individuals with normal hepatic function. tga.gov.autga.gov.aunih.gov However, in subjects with severe hepatic impairment (Child-Pugh C), this compound AUC values were significantly increased, showing a rise of approximately 320% to 325%. tga.gov.aunih.govdovepress.com This substantial increase in exposure in severe hepatic impairment highlights the importance of hepatic function in this compound clearance.

Table 3: Impact of Hepatic Impairment on this compound Exposure (AUC)

Impact of Renal Impairment on this compound Pharmacokinetics

Unlike hepatic impairment, renal impairment does not appear to appreciably alter the pharmacokinetics of this compound. Studies have shown that this compound pharmacokinetic parameters are similar between healthy subjects and those with mild, moderate, or severe renal impairment, including individuals on dialysis. nih.goveuropa.eu Population pharmacokinetic analyses have indicated that creatinine clearance is not a statistically significant predictor of this compound AUC values. researcher.life This is consistent with the minimal renal excretion of this compound. dovepress.com

Influence of Ethnicity on Pharmacokinetic Parameters

Research has investigated the potential influence of ethnicity on this compound pharmacokinetics. Population pharmacokinetic analyses from Phase 3 clinical studies indicated that Asian subjects had approximately 29% to 39% higher this compound exposures (AUC) compared to non-Asian subjects. tga.gov.autga.gov.aueuropa.eu However, other studies suggest that this compound exposures in Asian subjects are comparable with Caucasian subjects. nih.gov While some analyses identified Asian race as a significant covariate for this compound AUC, the magnitude of the effect on drug exposure was considered modest and not clinically significant in some contexts. researcher.lifenih.gov

Correlation between this compound Exposure and Early Viral RNA Decline

Research has explored the relationship between this compound exposure and the early decline in plasma HCV RNA. In studies involving this compound as part of a multi-DAA regimen, a rapid decline in plasma HCV RNA is observed. For instance, in one study of treatment-naive, non-cirrhotic patients with HCV genotype 1a receiving a regimen including this compound, the mean baseline plasma HCV RNA was 6.7 log10 IU/mL and decreased by -4.1 log10 IU/mL by Day 7 nih.govnih.gov.

However, some analyses have suggested that this compound exposure may not be a significant predictor of sustained virologic response (SVR) in genotype 1a patients when used in combination with other DAAs europa.eu. A simulation study using a semi-mechanistic model of viral dynamics also did not show a significant difference in SVR when the exposures of all components, including this compound, were reduced by 50% europa.eu.

Early viral kinetics, specifically the rate of plasma HCV RNA decline, have been investigated for their potential to predict treatment outcomes or resistance. While some studies have suggested that early viral kinetics can predict DAA resistance, others have not consistently found that viral kinetics during DAA therapy predict SVR nih.govviralhepatitisjournal.org. One study reported that early plasma HCV RNA kinetics predicted treatment responses, but others described detectable plasma HCV RNA levels at the end of therapy in patients who ultimately achieved SVR nih.gov.

Intrahepatic Viral Kinetics in Response to this compound-Containing Regimens

Studies utilizing techniques like fine needle aspiration (FNA) have allowed for the investigation of HCV RNA kinetics within the liver tissue itself, providing a more direct measure of the antiviral effect at the site of infection oup.comoup.comnih.gov.

In a substudy involving HCV genotype 1a-infected individuals coinfected with suppressed HIV receiving a this compound-containing regimen, early events in both liver and plasma were examined. The study found that at baseline, the mean percentage of HCV-infected cells in the liver was 25.2%, which correlated with plasma HCV RNA levels nih.govnih.gov. By Day 7 of treatment, the mean percentage of HCV-infected cells in the liver had significantly decreased to 1.0%, indicating rapid clearance of HCV infection from the liver nih.govnih.gov. DAAs, including this compound, were detectable in the liver tissue at this time point nih.gov.

This rapid decline in infected hepatocytes suggests a strong antiviral effect of the this compound-containing regimen directly within the liver. Based on these findings, researchers extrapolated that HCV eradication in these participants could potentially occur within a relatively short timeframe, estimated to be around 50–63 days of treatment nih.gov. This aligns with the high SVR rates observed in clinical trials of this compound-containing regimens nih.govinfeksiyon.orgplos.orgresearchgate.net.

Comparisons between plasma and intrahepatic viral kinetics have shown that baseline HCV RNA levels were higher and declined more rapidly in plasma than in the liver during the initial phase of treatment oup.comnih.gov. However, the coadministration of ribavirin did not appear to significantly impact the rate of HCV RNA decline in either plasma or liver during the first two weeks of treatment in one study oup.comnih.govnih.gov.

The rapid reduction in infected hepatocytes observed with this compound-containing regimens highlights the potent direct antiviral activity of these therapies at the primary site of HCV replication nih.gov.

Data Table: Early Viral Load Decline

Note: OBV = Ombitasvir, PTV = Paritaprevir, r = Ritonavir, DSV = this compound, RBV = Ribavirin.

Identification of Key Amino Acid Variants in NS5B (e.g., C316Y, S556G, M414T, Y448C/H)

Several key amino acid substitutions in NS5B have been identified through in vitro selection and analysis of treatment-failure isolates that confer resistance to this compound. Prominent among these are substitutions at positions C316, M414, Y448, and S556 nih.gov.

In genotype 1a replicons, S556G was frequently selected at lower this compound concentrations, while C316Y, Y448C, and Y448H were more prevalent at higher concentrations nih.gov. Other variants observed in genotype 1a included M414T nih.gov.

For genotype 1b, common selected variants included C316Y and M414T nih.gov. Substitutions at positions S368, N411, A553, and S556 have also been observed in genotype 1b nih.gov.

Specific RASs identified in NS5B that are associated with this compound resistance include C316Y, S556G, M414T, and Y448C/H nih.gov. Other relevant substitutions include C316N, M414I/V, N411S, Y448C/H, A553T/V, G554S, S556G/R, G558R, D559G/N, and Y561H, depending on the HCV genotype and subtype nih.govtga.gov.au.

Impact of Resistance Mutations on this compound Inhibitory Potency (Fold-Change in EC50/IC50)

The impact of these RASs on this compound's inhibitory potency is typically measured by the fold-change in EC50 (half-maximal effective concentration) or IC50 (half-maximal inhibitory concentration) compared to wild-type virus or enzyme natap.org. A higher fold-change indicates a greater reduction in susceptibility.

Studies have shown varying levels of resistance conferred by different single RASs. For genotype 1a, C316Y and Y448C/H have been reported to confer very high levels of resistance, with fold-changes exceeding 900-fold nih.gov. S556G in genotype 1a resulted in a lower fold-change, typically around 30-fold oup.com. M414T in genotype 1a showed fold-changes around 32-fold oup.com.

In genotype 1b, C316Y and C316N conferred lower levels of resistance compared to genotype 1a C316Y nih.govoup.com. M414T in genotype 1b showed fold-changes around 26-fold oup.com. S556G in genotype 1b conferred approximately 11-fold resistance nih.govoup.com. Some substitutions in genotype 1b, such as S368T and N411S, have shown high fold-changes in resistance nih.gov.

The following table summarizes representative fold-changes in EC50 for selected NS5B RASs in HCV genotype 1:

Combinations of RASs can lead to higher levels of resistance than single substitutions oup.com.

Genetic Barrier to Resistance Across HCV Genotypes

The genetic barrier to resistance refers to the number of nucleotide mutations required for resistance to emerge elsevier.es. For this compound, the genetic barrier is considered to be relatively low, meaning that resistance can potentially arise through a single nucleotide substitution natap.org. This is in contrast to some other classes of antivirals, like nucleoside inhibitors, which often have a higher genetic barrier natap.orgnih.gov.

The low genetic barrier for this compound is attributed to the fact that key resistance-associated amino acid changes can result from a single nucleotide change in the viral RNA sequence egms.de. This facilitates the rapid selection and emergence of resistant variants under drug pressure nih.gov. The emergence of resistance mutations in NS5B can occur via transition or transversion substitutions; transitions generally have a lower energy barrier and occur more frequently nih.gov.

Analysis of this compound-NS5B Binding Pocket Alterations due to Mutations

Computational studies have analyzed the binding pose of this compound within the palm I allosteric site of NS5B and how mutations alter this binding pocket nih.govresearchgate.netsemanticscholar.org. This compound is predicted to bind to the palm I site, extending towards the active site and interacting with residues in the β-hairpin loop (residues L443 to I454) of the thumb domain, as well as residues near the active site in the palm domain nih.govresearchgate.net.

RAS positions, including 316, 414, 448, and 556, are located within or near the this compound binding pocket, and substitutions at these positions can directly impact the shape and properties of the pocket nih.gov. Mutations can cause steric clashes, alter the local environment, or change the flexibility of the binding site, thereby reducing the affinity of this compound for NS5B semanticscholar.org.

For example, computational analysis suggests that mutations can lead to changes in this compound's conformation within the binding pocket semanticscholar.org. Alterations in the binding pocket due to RASs can disrupt key interactions between this compound and NS5B residues that are essential for potent inhibition nih.govsemanticscholar.org.

Changes in Binding Energy and Hydrogen Bonding Interactions

Computational studies can also quantify the impact of RASs on the binding affinity between this compound and NS5B by calculating changes in binding energy semanticscholar.org. A decrease in binding energy (making the value less negative) indicates reduced affinity, consistent with resistance.

Molecular docking and simulation studies have shown that mutations can lead to changes in hydrogen bonding and other non-covalent interactions between this compound and the NS5B protein nih.govsemanticscholar.orgjapsonline.com. This compound has been shown to form hydrogen bonds with residues such as S288, N291, D318, I447, and Y448 in the NS5B binding pocket nih.govresearchgate.net.

Some mutations have been computationally predicted to decrease binding energy, which can be associated with altered hydrogen bonding patterns, including increased or decreased interactions with specific residues or the formation of new hydrogen bonds semanticscholar.org. Conversely, some mutations might increase binding energy, potentially due to decreased interactions with key residues semanticscholar.org. For instance, a computational study indicated that mutations like C316N, C451S, and N411S can decrease binding energy, while M414V, A553V, and C445F might increase it, supported by observed changes in hydrogen bonding and pi-pi interactions semanticscholar.org.

These computational insights help to explain the molecular basis for this compound resistance conferred by specific RASs and can inform the design of new inhibitors aimed at overcoming these resistance mechanisms semanticscholar.org.

Baseline Polymorphisms and Their Clinical Significance

Baseline polymorphisms in the NS5B region associated with this compound resistance have been observed in treatment-naïve patients mdpi.comoup.com. The prevalence of baseline NS5B RASs can vary depending on the HCV genotype and subtype. In genotype 1b (GT1b), baseline NS5B RASs have shown a prevalence of 14.8% in one study mdpi.com. Specifically, the C316N polymorphism is relatively common in GT1b, with reported baseline prevalences ranging from approximately 10% to 36% asm.orgmdpi.com. The S556G variant is also observed in GT1b, with a prevalence of around 11% asm.org.

In genotype 1a (GT1a), baseline NS5B RASs appear to be less common nih.gov. The S556G variant has been reported as the most prevalent baseline NS5B variant in GT1a in some studies asm.org.

Studies have investigated the impact of these baseline polymorphisms on treatment outcome with this compound-containing regimens. In the AVIATOR study, baseline NS5B polymorphisms, including C316N in GT1b and S556G in both GT1a and GT1b, were prevalent, but they did not have a significant impact on the likelihood of achieving SVR when this compound was used in combination with other DAAs asm.orgnih.gov. Similarly, a pooled analysis of Phase 2b and 3 clinical trials indicated that baseline NS5B substitutions/polymorphisms had little impact on SVR rates in GT1a- and GT1b-infected subjects treated with recommended this compound-containing regimens tga.gov.auabbvie.com.

However, the presence of specific baseline NS5B RASs, such as C316N and S556G in GT1b, has been shown to confer reduced susceptibility to this compound in vitro asm.orgoup.com. A combination of C316N and S556G in GT1b can result in a 38-fold reduction in susceptibility to this compound oup.com.

Development of Resistance During and After this compound-Containing Therapies

The development of resistance during or after treatment with this compound-containing regimens is a key factor in treatment failure dovepress.com. In clinical trials evaluating this compound in combination with other DAAs (such as paritaprevir and ombitasvir, with or without ribavirin), virologic failure rates were low, but resistance-associated substitutions were frequently observed in patients who failed therapy nih.govasm.orgnih.govfda.govelsevier.es.

In GT1a patients who experienced virologic failure, treatment-emergent NS5B RASs included S556G asm.orgnih.govmdpi.comdovepress.com. Other variants selected in vitro or identified in clinical trials conferring resistance to this compound include substitutions at amino acid positions C316, S368, A395, N411, M414, E446 (GT1a only), Y448, A553, G554, S556, or D559 tga.gov.autga.gov.au. The C316Y, M414T, Y448H, and S556G variants have been noted to have higher replication efficiency rates, potentially contributing to resistance dovepress.comnih.gov.

In GT1b patients who failed treatment, treatment-emergent NS5B RASs included S556G mdpi.com. The predominant variants selected in genotype 1b replicon resistance selection were C316Y and M414T asm.org.

The persistence of these treatment-emergent RASs after treatment failure has been assessed. In GT1a-infected subjects in Phase 2b trials, this compound treatment-emergent variants like M414T, G554S, S556G, G558R, or D559G/N in NS5B were observed tga.gov.au. Due to the high SVR rates in GT1b, trends in the persistence of treatment-emergent variants in this genotype could not be established tga.gov.au. The long-term clinical impact of the emergence or persistence of virus containing this compound-resistance-associated substitutions is not fully known tga.gov.au.

Phase 3 and Phase 3b Study Designs

Phase 3 and 3b studies involving this compound have typically been multicenter trials, often open-label, evaluating the efficacy and safety of this compound in combination with other DAAs, with or without ribavirin (RBV). These studies have enrolled both treatment-naive and treatment-experienced patients with chronic HCV genotype 1 infection, including those with compensated cirrhosis. elsevier.esdovepress.comahdbonline.comresearchgate.net

For instance, the TOPAZ-III study (M14-225) was a Phase 3b, open-label, multicenter trial conducted in Brazil to evaluate a this compound-containing regimen in genotype 1-infected patients with advanced hepatic fibrosis (METAVIR F3-F4). elsevier.es This study included both treatment-naive and interferon-experienced patients. elsevier.esresearchgate.net Similarly, the SAPPHIRE-I and SAPPHIRE-II trials were Phase III studies that assessed this compound-based therapy in treatment-naive and treatment-experienced non-cirrhotic patients with genotype 1 HCV, respectively. nih.govdovepress.com PEARL-II and PEARL-III studies evaluated this compound in combination with other DAAs in genotype 1b patients without cirrhosis. dovepress.comahdbonline.com TURQUOISE-II was an open-label randomized clinical trial that enrolled treatment-naive or treatment-experienced patients with genotype 1a or 1b and compensated cirrhosis. ahdbonline.com GEODE-II was a Phase 3, open-label, multicenter study that evaluated a this compound-containing regimen with low-dose ribavirin in genotype 1a-infected patients without cirrhosis. nih.gov

Study designs have varied in duration, with treatment periods typically ranging from 12 to 24 weeks, and follow-up periods extending to 12 or 24 weeks post-treatment to assess sustained virologic response (SVR). elsevier.esdovepress.comnih.govtga.gov.au Some studies, like TOPAZ-II, have included longer-term follow-up periods (e.g., five years post-treatment) to evaluate the long-term impact of SVR on liver disease progression. abbvie.comabbvie.com While some studies were open-label, the assessment of HCV RNA as an objective laboratory measurement was considered unlikely to introduce bias in efficacy reporting. elsevier.es

Real-World Effectiveness Studies and Patient-Reported Outcomes

Beyond controlled clinical trials, real-world effectiveness studies have provided valuable insights into the performance of this compound-based regimens in broader patient populations encountered in routine clinical practice. elsevier.esinfeksiyon.org These observational studies often include patients with a wider range of comorbidities and characteristics than those typically enrolled in pivotal trials. plos.org

For example, the AMBER study assessed the real-world effectiveness and safety of a this compound-containing regimen in patients with chronic hepatitis C, including individuals with advanced liver disease and those who had not responded to previous therapies. infeksiyon.org Another real-world study in Southern Brazil evaluated the SVR rates among compensated chronic hepatitis C patients treated with various DAA therapies, including a this compound-containing regimen. elsevier.es These studies have generally shown high effectiveness rates consistent with those observed in Phase 3 trials. infeksiyon.orgplos.org

While the provided search results mention patient-reported outcomes in the context of real-world studies, detailed findings on specific patient-reported outcomes related to this compound were not extensively available in the snippets.

Sustained Virologic Response (SVR) Rates across Patient Subgroups

Sustained virologic response, typically defined as undetectable HCV RNA at 12 weeks (SVR12) or 24 weeks (SVR24) after the completion of treatment, is the key measure of treatment success. abbvie.cominfeksiyon.org this compound-based regimens have demonstrated high SVR rates across various patient subgroups with HCV genotype 1 infection. nih.govnih.gov

The SVR12 and SVR24 rates are highly concordant, with SVR12 being a strong predictor of SVR24. tga.gov.auabbvie.com

Here is a summary of SVR12 rates in selected subgroups based on the search results:

Analysis of Virologic Failure and Post-Treatment Relapse

Despite high SVR rates, a small percentage of patients treated with this compound-based regimens may experience virologic failure, either during treatment (breakthrough) or after completing therapy (relapse). abbvie.comnatap.org In Phase 3 trials, the rate of on-treatment virologic failure was low, around 0.2-0.8%. dovepress.comabbvie.comnatap.orgabbvie.com Post-treatment relapse rates were also low, typically ranging from 1.5% to 2.7%. dovepress.comabbvie.comnatap.orgabbvie.com

Analysis of virologic failure has focused on identifying the presence of resistance-associated substitutions (RASs) in the HCV genome. elsevier.esdovepress.comtga.gov.auabbvie.comfda.gov Treatment-emergent RASs have been detected in patients who experienced virologic failure with this compound-based regimens. elsevier.esdovepress.comtga.gov.auabbvie.comfda.gov These substitutions can occur in the NS3, NS5A, and NS5B regions, corresponding to the targets of the combined DAA therapy. elsevier.esdovepress.comtga.gov.auabbvie.comfda.gov

In patients who experienced virologic failure with this compound-containing regimens, NS5B substitutions, including those at positions C316Y, M414T/V, Y448H/C, G554S, S556G, and D559G, have been associated with reduced susceptibility to this compound in vitro. nih.govmdpi.com Analysis of patients who failed this compound-based therapy has shown the emergence of NS5B substitutions, such as M414I and C316N. abbvie.com The presence of RASs at the time of virologic failure is common. elsevier.esdovepress.comtga.gov.auabbvie.comfda.govmdpi.comoup.com

Virologic failure was more prevalent in genotype 1a patients compared to 1b in some studies, potentially linked to resistance patterns. nih.gov Factors associated with treatment failure can include prior treatment experience, presence of cirrhosis, and pre-existing RASs. oup.com

Treatment-Naive versus Treatment-Experienced Patients

Clinical trials have investigated the efficacy of this compound-containing regimens in both patients who have not received prior HCV treatment (treatment-naive) and those who have failed previous therapies, particularly interferon-based regimens (treatment-experienced). Studies such as MALACHITE-I and MALACHITE-II compared the all-oral combination of ombitasvir/paritaprevir/ritonavir and this compound ± ribavirin (OBV/PTV/r+DSV±RBV) with telaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) in non-cirrhotic, chronic HCV GT1-infected patients. nih.gov

In MALACHITE-I, which included treatment-naive patients, SVR12 rates with OBV/PTV/r+DSV+RBV were 97% for genotype 1a and 99% for genotype 1b. nih.gov For genotype 1b, the regimen without ribavirin also showed a high SVR12 rate of 98%. nih.gov In contrast, the TPV+PegIFN/RBV regimen resulted in lower SVR12 rates (82% for genotype 1a and 78% for genotype 1b). nih.gov

MALACHITE-II focused on treatment-experienced patients (failure to prior PegIFN/RBV therapy). The OBV/PTV/r+DSV+RBV regimen achieved an SVR12 rate of 99%, significantly higher than the 66% observed with TPV+PegIFN/RBV. nih.gov

These studies demonstrate that this compound, as part of the 3D regimen, provides high SVR rates in both treatment-naive and treatment-experienced patients with chronic HCV genotype 1 infection.

Patients with Compensated Cirrhosis and Advanced Fibrosis

The efficacy of this compound-containing regimens has also been evaluated in patients with more advanced liver disease, specifically those with compensated cirrhosis (Child-Pugh A) and advanced fibrosis (METAVIR F3/4).

The TURQUOISE-II trial enrolled treatment-naive or treatment-experienced patients with HCV genotype 1a or 1b and compensated cirrhosis (Child-Pugh A). ahdbonline.com Treatment with ombitasvir, paritaprevir, and ritonavir plus this compound, with ribavirin, for 12 or 24 weeks resulted in high SVR rates. ahdbonline.com

Another real-world study in Romania including patients with F2, F3, and F4 fibrosis (compensated cirrhosis) infected with HCV genotype 1b reported an efficacy rate of over 99% with OBV/PTV/r combined with this compound, with or without ribavirin. researchgate.net

Research has also investigated the regimen in patients with non-compensated cirrhosis (Child-Pugh B or C), though it is generally recommended to be avoided in this population due to potential risks of hepatic decompensation. ejgm.co.uk However, one study in patients with HCV GT1b and non-compensated cirrhosis showed a 100% SVR rate in those treated with the 3D therapy, including those who discontinued early for safety reasons. ejgm.co.uk

Patients with Severe Renal Impairment and End-Stage Renal Disease (ESRD)

The efficacy and safety of this compound-containing regimens have been evaluated in patients with chronic kidney disease (CKD), including those with severe renal impairment (eGFR <30 mL/min/1.73 m²) and ESRD, including those on hemodialysis.

An open-label study (RUBY-II) evaluated the efficacy and safety of OBV/PTV/r with or without this compound in adults with HCV genotype 1a or 4 infection and severe renal impairment or ESRD. clinicaltrialsregister.eu

A real-life cohort study in the Czech Republic evaluated the PrOD regimen in 23 patients with HCV GT1 (21 GT1b, 2 GT1a), including 4 with CKD4 and 19 on maintenance hemodialysis. karger.com Six patients had compensated liver cirrhosis, and three were liver transplant recipients. karger.com All 23 patients completed the 12-week treatment and achieved an SVR12 rate of 100%. karger.com

These findings indicate that this compound, as part of the 3D regimen, is highly effective in achieving SVR in patients with severe renal impairment and ESRD infected with HCV genotype 1, particularly genotype 1b.

Research in Patients Coinfected with HIV-1

Clinical research has also focused on the efficacy of this compound-containing regimens in patients coinfected with both HCV genotype 1 and HIV-1.

The TURQUOISE-I trial evaluated OBV/PTV/r plus DSV treatment in patients with HIV-1/HCV genotype 1 coinfection, with or without cirrhosis. oup.com Part 1a of this phase 2 trial reported SVR12 rates of 94% and 91% after 12 or 24 weeks of treatment, respectively. oup.com Excluding nonvirologic failures, the SVR12 rate was 98% for genotype 1. oup.com

A real-life study of PrOD ± ribavirin in HIV/HCV-coinfected patients with GT1 in routine clinical practice in Spain reported that 172 out of 182 patients (94%) attained SVR. tandfonline.com The SVR rates by mITT analysis were 97% for genotype 1a and 98% for genotype 1b. tandfonline.comtandfonline.com In this study, 98% of patients with cirrhosis achieved SVR. tandfonline.comtandfonline.com

A comprehensive analysis of the effectiveness of OBV/PTV/r, this compound for HCV in HIV/HCV coinfected subjects, including clinical trials and observational studies, found a pooled estimated SVR12 rate of 96.3% for genotype 1. nih.gov Subgroup analysis showed SVR12 rates of 96.8% for treatment-naive and 98.9% for treatment-experienced patients with genotype 1. nih.gov Patients with cirrhosis had a pooled SVR12 rate of 97.8%, while those without cirrhosis had a rate of 96.7%. nih.gov

These studies demonstrate high SVR rates with this compound-containing regimens in HIV-1 coinfected patients with HCV genotype 1.

Post-Liver Transplant Patients

Recurrent HCV infection after liver transplantation significantly impacts graft and patient survival. Clinical research has investigated the use of this compound-containing regimens in this specific population.

The CORAL-I study, a multicenter phase III study, evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and this compound with ribavirin for 24 weeks in HCV genotype 1-infected liver transplant recipients who were at least 12 months post-transplant. europa.euoatext.com This study found the therapy to be both safe and effective, with SVR rates of 97% in genotype 1. oatext.com

A real-world study (AMBER-CEE) assessed the efficacy and safety of OBV/PTV/r/+DSV±RBV in the treatment of post-transplant recurrence of HCV genotype 1 infection. researchgate.netannalsoftransplantation.com This study included 35 liver transplant recipients with recurrent HCV genotype 1 infection, the majority of whom were genotype 1b-infected and treatment-experienced. researchgate.netannalsoftransplantation.com SVR12 was achieved by all patients (35/35, 100%), irrespective of prior treatment history or degree of fibrosis. researchgate.netannalsoftransplantation.com

A single-center real-world study in Spain reported a 100% SVR rate at 12 weeks post-treatment with oral ombitasvir combined with ritonavir-paritaprevir plus this compound and ribavirin for 24 weeks in 22 liver graft recipients transplanted due to cirrhosis caused by genotype 1 HCV with post-transplantation viral recurrence and scant fibrosis. oatext.com

These studies indicate that this compound, as part of the 3D regimen, is highly effective in achieving SVR in post-liver transplant patients with recurrent HCV genotype 1 infection.