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Background & AimsParitaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients.MethodsMechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction.ResultsCoadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a <2-fold change in mean Cmax and AUC for most medications and the DAAs, indicating minimal to modest interactions. Carbamazepine decreased PTV, ritonavir, and DSV exposures substantially, while gemfibrozil increased DSV exposures substantially. Although coadministration with ethinyl estradiol-containing contraceptives resulted in elevated alanine aminotransferase levels, coadministration with a progestin-only contraceptive did not.ConclusionsThe majority of medications can be coadministered with the 3D regimen of OBV, PTV/r, and DSV without dose adjustment, or with clinical monitoring or dose adjustment. Although no dose adjustment is necessary for the 3D regimen when coadministered with 17 of the 20 medications, coadministration with gemfibrozil, carbamazepine, or ethinyl estradiol-containing contraceptives is contraindicated. Paritaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients. Mechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction. Coadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a <2-fold change in mean Cmax and AUC for most medications and the DAAs, indicating minimal to modest interactions. Carbamazepine decreased PTV, ritonavir, and DSV exposures substantially, while gemfibrozil increased DSV exposures substantially. Although coadministration with ethinyl estradiol-containing contraceptives resulted in elevated alanine aminotransferase levels, coadministration with a progestin-only contraceptive did not. The majority of medications can be coadministered with the 3D regimen of OBV, PTV/r, and DSV without dose adjustment, or with clinical monitoring or dose adjustment. Although no dose adjustment is necessary for the 3D regimen when coadministered with 17 of the 20 medications, coadministration with gemfibrozil, carbamazepine, or ethinyl estradiol-containing contraceptives is contraindicated.

Abstract licence: CC BY-NC-ND

The treatment for chronic hepatitis C has been revolutionized with the development of direct-acting antiviral agents. Several regimens have been approved and are currently used in clinical practice, treating a wide range of patient populations infected with hepatitis C. The interferon-free combination of paritaprevir/ritonavir-ombitasvir and dasabuvir (PrOD or the three-drug [3D] regimen) with or without ribavirin is indicated for the treatment of chronic hepatitis C in both treatment-naïve and experienced patients infected with genotype 1, including those coinfected with HIV and patients post-liver transplantation. More recently, paritaprevir/ritonavir-ombitasvir (PrO, or 2D regimen) has been approved in hepatitis C virus patients infected with genotype 4. This review will summarize pharmacokinetic and clinical efficacy data for the 3D regimen in an attempt to help the clinicians delineate its place in the ever-increasing direct-acting antiviral armamentarium for the treatment of chronic hepatitis C.

Abstract licence: CC BY-NC

Although ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) therapy is highly effective for chronic hepatitis C (CHC), clinicians frequently encounter transient hyperbilirubinemia, which can be misidentified as hepatotoxicity. This study investigated the role of SLCO1B1 (OATP1B1) and SLCO1B3 (OATP1B3) genetic polymorphisms in predicting bilirubin spikes and distinguishing transporter-mediated interference from hepatocellular injury. In this prospective study of 65 patients with HCV genotype 1, genotyping for OATP1B1 (c.388A&gt;G, c.521T&gt;C) and OATP1B3 (c.334T&gt;G, c.699G&gt;A) was performed using PCR-RFLP and capillary electrophoresis (QIAxcel Advanced System). Clinical and biochemical parameters were monitored over a 12-week treatment period. Hyperbilirubinemia (total bilirubin &gt;1.1 mg/dL) developed in 18.5% of the cohort, typically within the first month. A distinct ‘AST-dominant’ biochemical signature, elevated bilirubin and AST paired with stable ALT, was identified, suggesting transporter-specific interference rather than hepatocyte damage. Statistical analysis pinpointed the OATP1B3 c.699G&gt;A (rs7311358) variant as the sole genetic driver (p = 0.007). Carriers of the c.699G&gt;A allele faced a 6.3-fold higher risk of developing hyperbilirubinemia (OR: 6.30, 95% CI: 1.48–26.80, p = 0.032), while no significant associations were found for OATP1B1 variants. We conclude that OATP1B3 c.699G&gt;A is a potent predictor of OPrD-induced hyperbilirubinemia. Identifying this genotype pre-treatment allows clinicians to anticipate transient, benign bilirubin elevations and prevent unnecessary drug discontinuation, thereby mitigating therapeutic inertia and ensuring treatment continuity for CHC patients.

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Background/Aims: Chronic hepatitis C virus (HCV) infection constitutes a substantial healthcare concern in Türkiye. The clinical application of direct-acting antiviral medications (DAAs) has transformed its management. The goal is to assess the efficacy and safety of DAAs in the real-world setting in Turkish patients with chronic HCV. Materials and Methods: Thirty-seven centers from Türkiye recorded 1807 patients to the database. Patients aged >18 years were enrolled to the study. Their demographics, clinical information, DAAs used, efficacy, and safety information were evaluated. Efficacy and safety results were reported for patients with 12-week post-treatment (SVR12) data. Results: Among the patients, 919 (50.9%) were female with a mean of age 56 ± 15 years (range:18-97 years) and 238 (13%) were cirrhotic. Liver biopsy was performed in 296 patients. Mean histologic activity index score was 7.68 and fibrosis score was 2.58. Baseline mean viral load was 4.11×106 copies/mL. Patients received the following treatments: Paritaprevir+Ritonavir+Ombitasvir+Dasabuvir (PrOD):706, Ledipasvir+Sofosbuvir:490, Sofosbuvir+Ribavirin:176, PrOD+Ribavirin:175, Ledipasvir+Sofosbuvir+Ribavirin:156, PrO+Ribavirin:32, and PrO:10. Response at the end of treatment was 99.2% (1454/1465) and SVR12 was 97.8% (1289/1318). The DAAs were generally well tolerated. Ten and 13 patients discontinued therapy because of drug-related and unrelated adverse side effects, respectively. Conclusion: This real-world study demonstrated that DAA treatment for HCV is both safe and highly effective. In two-thirds of the patients, the hepatic inflammation is moderate to severe, and fibrosis is moderate to advanced in half of them. Patients' characteristics suggest that HCV infection is often not diagnosed or treated until patients present with moderate-to-severe stage, indicating that diagnostic and therapeutic approaches should be used more effectively.

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Over the last several years, many advances have been made in the treatment of chronic hepatitis C virus (HCV) infection with the development of direct-acting antivirals. Paritaprevir/ritonavir/ombitasvir with dasabuvir (PrOD) is a novel combination of a nonstructural (NS) 3/4A protein inhibitor boosted by ritonavir, an NS5A protein inhibitor, and an NS5B nonnucleoside polymerase inhibitor. This review aims to discuss the pharmacology, efficacy, safety, drug interactions, and viral drug resistance of PrOD in the treatment of HCV genotype 1 infections. Phase I, II, and III human and animal studies that describe the pharmacology, pharmacokinetics, efficacy, and safety of PrOD for HCV were identified and included. Studies that evaluated patients without cirrhosis (n=2,249) and with cirrhosis (n=422) demonstrated that PrOD for 12 or 24 weeks was effective at achieving sustained virologic response rates (>90%) in patients with genotype 1a or 1b HCV infection. Although indicated for the treatment of HCV genotype 1 infection, PrOD is also recommended for the treatment of HCV in patients coinfected with HIV. Additionally, promising data exist for the use of PrOD in liver-transplant recipients. The most common adverse drug events associated with PrOD included nausea, pruritus, insomnia, diarrhea, asthenia, dry skin, vomiting, and anemia. The high efficacy rates seen coupled with a favorable side effect profile seen with PrOD with or without ribavirin have led to its addition as a recommended treatment regimen for HCV genotype 1 infection.

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