pibrentasvir (ABT-530) / AbbVie - LARVOL DELTA

Sustained Virologic Response and Kidney Transplant Outcomes After a Short-Course of a Direct-Acting Antiviral and Ezetimibe in Recipients of Kidneys from HCV-Infected Deceased Donors (WTC 2025) - "A short-course of glecapravir-pibrentasvir and ezetimibe before and after transplantation in recipients of HCV-infected kidneys was highly successful in achieving SVR and resulted in comparable short-term kidney transplant outcomes. This strategy should be widely adopted to safely expand the use of HCV-infected kidneys for transplantation."

Cardiovascular • Diabetes • Hepatitis C • Metabolic Disorders • Transplant Rejection • Transplantation

The Genotypes/Subtypes and Antiviral Drug Resistance of the Hepatitis C Virus from Patients in a Tertiary Care Hospital in Nepal. (PubMed, Viruses) - "Resistant mutations against sofosbuvir, pibrentasvir, velpatasvir, daclatasvir, and dasabuvir were found at 25%, 18%, 16%, 16%, and 2%, respectively, mostly on subtype 3a. The predominant HCV genotype/subtype in our patient group was 3a, and resistance mutations against direct-acting antivirals were found in most untreated patients."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Analysis of the susceptibility of refractory hepatitis C virus resistant to nonstructural 5A inhibitors. (PubMed, Sci Rep) - "Compared with the WT, the Q24K/L28M/R30Q/A92K RASs was 36,000-fold resistant to daclatasvir, 440,000-fold resistant to ledipasvir, 6300-fold resistant to velpatasvir, 3100-fold resistant to elbasvir, and 1.8-fold resistant to pibrentasvir. Furthermore, a combination of pibrentasvir and sofosbuvir showed therapeutic efficacy against these RASs. Combination regimens may eradicate HCV with NS5A Q24K/L28M/R30E/A92K RASs."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Extended 6-month stability data in blister packs demonstrated for hepatitis C medications (BSG 2024) - "Quantitative The stability of in-date originally packed sofosbuvir 400mg/velpatasvir 100mg (S/V) and glecaprevir 100mg/pibrentasvir 40mg (G/P) tablets were assessed in BP at room temperature, monthly over six months for:Tablet weightUltraviolet-visible spectroscopy (measuring absorbance to determine active-ingredient concentration variations)Infra-red spectroscopy (to observe composition variations)Control measurements were obtained of both S/V and G/P.Qualitative We surveyed HCV operation delivery networks (ODN) on BP use.View this table:View inline View popup 48 Table 1 Changes of S/V and G/P in BP over six months compared to controlQuantitativeData reported as mean ± standard deviation with *p<0.05, **p<0.01, ***p<0.001Qualitative: 11 responses were received, but 2 ODN responded twice. Composition variances were observed, but all below 10% and not related to the actives; these could be due to water absorbance, excipient changes and/or machine/operator..."

Hepatitis C • Hepatology • Infectious Disease • Inflammation

Preclinical Pharmacokinetic Assessment of a Hepatitis C Virus Long-Acting Injectable Formulation (CROI 2024) - "Background: Eight weeks of daily, oral glecaprevir (G) and pibrentasvir (P) cures 98% of people with chronic Hepatitis C Virus (HCV) infection. Preclinical data for a novel G/P LAI demonstrate sustained therapeutic concentrations in rats over a period of 13 weeks, exceeding the 8-week human target duration. Parenteral administration did not adversely affect hepatic penetration in comparison to the oral route. Further work is required to optimise drug ratios and confirm safety through GLP toxicology assessments to support first-in-human evaluation."

PK/PD data • Preclinical • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Development of a long-acting injectable formulation for the treatment of hepatitis C (ACS-Sp 2024) - "Long-acting injectable SDN formulations of two antiviral drugs, glecaprevir (GLE) and pibrentasvir (PIB), have been developed both as single formulations and fixed dose combinations (FDC), using emulsion-templated spray drying (ETSD)...In vivo pharmacokinetic studies of GLE and PIB formulations, and a FDC of 1:1 GLE:PIB have been when re-dispersed in water for injection showed a prolonged release over a period of 3 months for the FDC and the single PIB formulation. The SDN formulation comprising solely of GLE saw the API release quicker over the course of 1 month, whilst within the FDC the release profile of GLE was comparable to PIB in terms of release duration. The data presented demonstrates the feasibility of a long-acting injectable formulations of GLE and PIB, which the offers the potential opportunity to treat hepatitis C using a single injection at the point of diagnosis."

Hepatitis C • Hepatology • Infectious Disease • Inflammation

VIDEO: ‘Unique’ protocol expands transplant pool to include HCV-infected donors (Healio) - "In this video, Norah Terrault, MD, MPH, FAASLD, spoke with Healio about a presentation from The Liver Meeting on 'The Toronto Protocol,' an ultra-short course of glecaprevir/pibrentasvir with ezetimibe."

Video

Chemoprophylactic Assessment of Combined Intranasal SARS-CoV-2 Polymerase and Exonuclease Inhibition in Syrian Golden Hamsters. (PubMed, Viruses) - "Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. Overall, prevention of transmission was observed in most animals treated with RDV, while other agents reduced the viral load following contact transmission. No benefit of combining FVP or RDV with PIB was observed."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Design of Redispersible High-Drug-Load Amorphous Formulations: Impact of Ionic vs Nonionic Surfactants on Processing and Performance. (PubMed, Mol Pharm) - "Preparation of 90% drug-load amorphous nanoparticles (ANPs) of <300 nm diameter using solvent/antisolvent nanoprecipitation, organic solvent removal, and spray drying was demonstrated previously on model compound ABT-530 with Copovidone and sodium dodecyl sulfate (anionic)...Characterization of ANPs by dynamic light scattering, filtrate potency assay, scanning electron microscopy, and differential scanning calorimetry revealed differences in surface properties of nanoparticles afforded by surfactants. This work demonstrates the importance of understanding the impact of the stabilizing agents on nanoparticle behavior when designing a high-drug-load amorphous formulation for poorly water-soluble compounds as well as the impact on redispersion."

Journal

Atovaquone and Pibrentasvir Inhibit the SARS-CoV-2 Endoribonuclease and Restrict Infection In Vitro but Not In Vivo. (PubMed, Viruses) - "Furthermore, atovaquone, but not pibrentasvir, is observed to modulate HCoV-OC43 dsRNA and infection in a manner consistent with nsp15 inhibition. Although neither pibrentasvir nor atovaquone translate to clinical efficacy in a murine prophylaxis model of SARS-CoV-2 infection, atovaquone may serve as a basis for the design of future nsp15 inhibitors."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Preemptive antiviral therapy in lung transplantation from hepatitis C donors results in a rapid and sustained virologic response. (PubMed, JTCVS Open) - "Recipients of hepatitis C virus nucleic acid test positive donor lungs underwent preemptive direct-acting antiviral therapy with glecaprevir 300 mg/pibrentasvir 120 mg for 8 weeks from January 1, 2019, to December 31, 2020. Preemptive direct-acting antiviral therapy results in rapid viral clearance and sustained virologic response at 12 months. Preemptive direct-acting antiviral may partially prevent hepatitis C virus transmission."

Clinical • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Transplantation

Implications of 3D conformations on protein binding and crystal polymorphism of NS5A inhibitors ombitasvir and pibrentasvir (ACS-Fall 2023) - "In contrast for pibrentasvir, the cis/cis conformers were the most abundant, low-energy minima conformers. The degree of conformational flexibility and/or the ability to adopt different conformations translate into drug development implications, ranging from difficulty of crystallizability to intricate crystal form landscape, such that ombitasvir and pibrentasvir embody some of the key challenges in contemporary solid-state chemistry."

Hepatitis C • Hepatology • Infectious Disease • Inflammation

A Simplified Algorithm for the Management of Hepatitis C Infection. (PubMed, Gastroenterol Hepatol (N Y)) - "The pretreatment evaluation uses platelet-based stratification to initially assess fibrosis, and the pan-genotypic regimens glecaprevir/pibrentasvir or sofosbuvir/velpatasvir are recommended for treatment. This algorithm provides guidance for management of uncomplicated cases of HCV by frontline HCPs and indicates when referral to an HCV specialist is warranted. The algorithm was created to enable more HCPs to screen for and manage HCV infection, and thus contribute to its elimination."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatitis C • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Oncology • Solid Tumor

Unique Quality by Design Approach for Developing HPLC and LC-MS Method for Estimation of Process and Degradation Impurities in Pibrentasvir, Antiviral Agent for Hepatitis C. (PubMed, ACS Omega) - "During the stress study, degrading impurities were identified by the LC-MS technique and the mechanism pathway. A QbD-based experimental design (DoE) approach was used to establish the robustness of the method."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Prospects for Long-Acting Treatments for Hepatitis C. (PubMed, Clin Infect Dis) - "One such tool could be long-acting parenteral formulations of HCV treatments, which may allow PLWHC to be diagnosed and cured in a single encounter. Although existing highly effective oral medications might be formulated as long-acting parenteral treatments, pharmacological, regulatory, patent, and medical challenges have to be overcome; this requires the concerted efforts of PLWHC, researchers, funding agencies, industry, the World Health Organization, and other stakeholders."

Journal • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Expanded Experience With Ultra-Short Duration Pangenotypic Direct Acting Anti-Viral (DAA) to Prevent Virus Transmission From Hepatitis C Viremic Donors to Hepatitis C Negative Kidney Transplants (KIDNEY WEEK 2022) - "Ezetimibe (EZ), has been shown to restrict HCV entry in hepatocytes in a humanized mouse model...All 5 patients with HCV transmission achieved SVR with 12 weeks of Glecapravir/Pibrentasvir therapy. Conclusion Our data suggests that 7-days ultra-short duration pan-genotypic SOF/VEL prophylaxis was safe and largely effective in preventing donor-derived HCV transmission and has the potential of resulting in significant cost-savings by avoiding longer DAA therapy in a large majority of D+/R- KT. The addition of EZ did not appear to provide any additional benefit in preventing HCV viral transmission."

Hepatitis C • Hepatology • Infectious Disease • Inflammation • Liver Failure • Transplantation

A Hepatitis C (HCV) Infection Treatment Dilemma (ACG 2022) - "Carbamazepine (CBZ) is contraindicated with all available DAAs...An initial plan for daclatasvir (DAC)-sofosbuvir (SOF)-ribavirin (RBV) was proposed, but DAC is no longer available in the US...Given worsening liver condition, shared decision-making was performed, and patient completed 16 weeks of Glecaprevir (GLE)/pibrentasvir (PIB) + SOF 400mg with 4 weeks of ezetimibe 10mg stopping when the viral load was undetectable. Patient was instructed to start the ezetimibe with the GLE/PIB + SOF but was hesitant to take it due to adverse reaction to statins in the past...HCV relies on cell-to-cell transmission, so we chose to add ezetimibe 10mg daily until HCV not detected. There is a need for larger studies to determine the applicability of this case study to other patients."

Anemia • Fibrosis • Hematological Disorders • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Neuralgia • Pain • Thrombocytopenia

Design of a Re-dispersible High Drug Load Amorphous Formulation. (PubMed, J Pharm Sci) - "Utilizing ABT-530 as model compound, a controlled solvent-antisolvent precipitation method resulted in a dilute suspension that contained drug-rich (90% (w/w)) amorphous nanoparticles (ANP)...A systematic evaluation of formulation properties and process variables resulted in the generation of dry powder composed of 1 - 8 µm agglomerates of nanoparticles which in contact with water regenerated the colloidal suspension having particle size comparable to primary particles. Thus, this work demonstrates an approach to designing a re-dispersible high drug load ANP based powder formulation (≥90% w/w) that could be used in preparation of a high drug load solid dosage form."

Journal

Pan-genotypic direct-acting antivirals for patients with hepatitis C virus infection and chronic kidney disease stage 4 or 5. (PubMed, Hepatol Int) - "The use of prophylactic or preemptive pan-genotypic DAAs in HCV-negative recipients who receive HCV-positive kidneys has shown promise in shortening KT waiting time, achieving excellent on-treatment efficacy and safety, and maintaining post-KT patient and graft survival. HCV elimination is highly feasible through multifaceted interventions, including mass screening, treatment scale-up, universal precautions, and post-SVR reinfection surveillance."

Journal • Review • Chronic Kidney Disease • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Nephrology • Renal Disease • Transplantation

Combination glecaprevir, pibrentasvir with ezetimibe prevents HCV in transplantation (Healio) - '"We have an availability of safe, well-tolerated and highly effective hepatitis C therapies with direct acting antiviral agents,' Bashar Aqel, MD...'Use of HCV viremic grafts has been associated with a reduced wait time, good graft and patient survival, and very favorable cost effectiveness...Glecaprevir/pibrentasvir is a highly effective, pangenotypic [direct acting antiviral agent] with confirmed safety in patients with kidney disease and minimal drug-to-drug interaction.'"

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Infrequent hepatitis C genotypes/subtypes in patients treated with DAA-based regimens: successes and failures (EASL-ILC 2022) - "One cirrhotic genotype 1d patient failed 2 one-DAA-based regimens (telaprevir (TPV)/pegylated interferon (pegIFN)/Ribavirin (RBV); sofosbuvir (SOF)/pegIFN/RBV) was successfully retreated with SOF/ledipasvir (LDV). One cirrhotic genotype 1 k patient failed 4 DAA-based regimens (SOF/simeprevir (SIM); SOF/LDV 24/48 weeks; SOF/LDV/RBV). In a subgroup analysis of patients treated with a 2-last generation DAA (SOF/velpatasvir (VEL), SOF/VEL/RBV, glecaprevir (GLE)/pibrentasvir (PIB)), 50 patients were identified...A genotype 3b patient failed SOF/VEL for 12 weeks and was successfully retreated with SOF/VEL/ voxilaprevir (VOX) for 12 weeks... Our real-world data show that in patients with infrequent HCV genotypes/subtypes treated with 2 last-generation DAA the SVR rate is 90%. Although the data are limited, these results support the possibility of initially treating them with 2 lastgeneration DAA. More data are needed to determine optimal treatment regimen by genotype/subtype..."

Clinical • Fibrosis • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Liver Cirrhosis • Transplantation

Establishing a protocol for management and DAA treatment of HCV during pregnancy: adherence to a co-located care protocol (EASL-ILC 2022) - "Initial DAA ordered was ledipasvir/sofosbuvir for 7 (42%), ledipasvir/velpatasvir for 7 (42%) and gleceprevir/pibrentasvir for 2 (12%). Pregnancy offers an important opportunity to link women with HCV to treatment-the majority were diagnosed initially during routine screening during pregnancy. Cholestasis of pregnancy was a prevalent complication. HCV treatment during pregnancy is feasible and will likely offer benefits to maternal and child health, however significant challenges remain to ensure adherence through the vulnerable postpartum period."

Clinical • Cholestasis • Hepatitis C • Hepatology • Infectious Disease

Real-life effectiveness and safety of sofosbuvir/velpatasvir in difficult to treat hepatitis C patients (EASL-ILC 2022) - "70.3% have failed prior DAA treatment (Daclatasvir + asunaprevir n = 16, sofosbuvir+ribavirin n = 3, sofosbuvir + ledipasvir n = 2, glencaprevir+ pibrentasvir n = 3, boceprevir n = 1) Naïve patients received SOF/VEL for 12 weeks and the patientswith prior DAA failure received SOF/VEL for 24 weeks, ribavirin was added in 78.4% of treatment schedules. SOF/VEL is an effective and safe retreatment for difficult to treat HCV population in a real-life setting."

Clinical • Fibrosis • Gastrointestinal Cancer • Hepatitis C • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Oncology • Solid Tumor

Eliminating Hepatitis C Positive Status from Kidney Donor Profile Index (KDPI) Calculations Results in Improved Transplant Rates and Outcomes in an Elderly Veteran Population (ATC 2022) - "HCV NAT (+) recipients were treated with once daily Mayvret(glecaprevir 300mg/pibrentasvir 120mg) started at least 30 minutes pre-operatively and continued for 8 weeks. HCV NAT (+) status increases KDPI calculations by almost 20% points and are not truly reflective of actual donor risk. HCV NAT (+) donors were younger with a lower recalculated KDPI, which correlated to improved graft function and minimal complications in an elderly veteran population. Therefore, eliminating HCV status from KDPI calculations may result in increased utilization with excellent outcomes."

Clinical • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Transplantation

Outcomes Following Renal Transplant with Hepatitis C Viremic Donors in an Elderly Veteran Population with Preemptive Mayvret Therapy (ATC 2022) - "HCV NAT (+) recipients were treated with once-daily Mayvret (Glecaprevir 300mg/Pibrentasvir 120mg) started at least 30 minutes pre-operatively and continued for 8 weeks. Low to no copays allowed for preemptive antiviral initiation in the veteran population. Additionally, differences in KDPI are not truly reflective of actual donor risk as HCV increases KDPI calculation. However, HCV NAT (+) transplants with a pre-emptive treatment protocol results in improved graft function with minimal to no complications in an elderly veteran population."

Clinical • Diabetes • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Metabolic Disorders • Transplantation