warfarin and Hepatitis-C

We report the case of 36-year-old woman who came to us with a history of recurrent miscarriages and who was later diagnosed as having primary antiphospholipid syndrome (PAPS) and chronic hepatitis C virus (HCV) infection. The patient was referred to us with generalised seizures; cranial MRI revealed multiple embolic infarcts in both frontal lobes and a focal cortical infarct in the left frontoparietal lobe. Her echocardiography showed mitral valve vegetation and insufficiency. The patient was put on oral anticoagulant therapy and during her 8-month follow-up period no thrombotic events occurred. We report this case because it was the first in which PAPS, valvular disease, a cerebral embolic event and HCV infection were coexistent in the same patient. We also review other cases in which there was valvular vegetation and a cerebral ischaemic event associated with PAPS.

Topics: Adult; Antibodies, Anticardiolipin; Anticoagulants; Anticonvulsants; Antiphospholipid Syndrome; Carbamazepine; Echocardiography, Doppler; Endocarditis; Epilepsy; Female; Hepatitis C; Humans; Intracranial Embolism; Magnetic Resonance Imaging; Mitral Valve Insufficiency; Warfarin

The potential inhibition of the major human cytochrome P450 (CYP) enzymes by faldaprevir was evaluated both in vitro and in clinical studies (healthy volunteers and hepatitis C virus [HCV] genotype 1-infected patients). In vitro studies indicated that faldaprevir inhibited CYP2B6, CYP2C9, and CYP3A, and was a weak-to-moderate inactivator of CYP3A4. Faldaprevir 240 mg twice daily in healthy volunteers demonstrated moderate inhibition of hepatic and intestinal CYP3A (oral midazolam: 2.96-fold increase in AUC(0-24 h)), weak inhibition of hepatic CYP3A (intravenous midazolam: 1.56-fold increase in AUC(0-24 h)), weak inhibition of CYP2C9 ([S]-warfarin: 1.29-fold increase in AUC(0-120 h)), and had no relevant effects on CYP1A2, CYP2B6, or CYP2D6. Faldaprevir 120 mg once daily in HCV-infected patients demonstrated weak inhibition of hepatic and intestinal CYP3A (oral midazolam: 1.52-fold increase in AUC(0-∞)), and had no relevant effects on CYP2C9 or CYP1A2. In vitro drug-drug interaction predictions based on inhibitor concentration ([I])/inhibition constant (Ki) ratios tended to overestimate clinical effects and a net-effect model provided a more accurate approach. These studies suggest that faldaprevir shows a dose-dependent inhibition of CYP3A and CYP2C9, and does not induce CYP isoforms.

Topics: Adolescent; Adult; Aminoisobutyric Acids; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Hepatitis C; Humans; In Vitro Techniques; Isoenzymes; Leucine; Male; Microsomes, Liver; Midazolam; Middle Aged; Oligopeptides; Proline; Protease Inhibitors; Quinolines; Thiazoles; Warfarin; Young Adult

Previous studies suggested that direct-acting antivirals (DAAs) against hepatitis C increased the blood coagulability of patients on warfarin. This study aims to descriptively investigate the effects of DAAs on the blood coagulability and liver function of patients on warfarin in Japan.. The Medical Information Database Network (MID-NET. For the 16 eligible patients, the mean values of both PT-INR and WSI (warfarin sensitivity index) defined as the value obtained by dividing the PT-INR by the warfarin daily dose slightly decreased at the date of completion of the DAA treatment in comparison with those at the date of initiation and subsequently increased at 12 weeks after treatment completion. In contrast, the warfarin daily dose increased at the date of completion of the DAA treatment, followed by a decrease at 12 weeks after its completion. Several laboratory tests related to the liver function also revealed a similar decrease at the end of the DAA treatment.. The analysis of MID-NET

Topics: Antiviral Agents; Hepatitis C; Hepatitis C, Chronic; Humans; Japan; Pharmaceutical Preparations; Warfarin

We previously reported an interaction with warfarin anticoagulation when initiating treatment with direct-acting antiviral agents for hepatitis C infection. A decreased warfarin sensitivity led to subtherapeutic anticoagulation. To study this interaction further, we expanded our research to include patients treated with the combination of elbasvir and grazoprevir concurrent with warfarin anticoagulation and investigated changes in warfarin sensitivity during and after treatment.. Using electronic health records of the Veterans Health Administration, patients starting treatment with elbasvir-grazoprevir for hepatitis C infection concurrent with warfarin anticoagulation were identified. Inclusion required stable warfarin anticoagulation prior to 12 weeks of treatment with elbasvir-grazoprevir. A warfarin sensitivity index (WSI) was calculated at the start of treatment, after 12 weeks after treatment, and at the end of treatment. The primary endpoint was the difference in WSI from pre- to end-treatment. The secondary endpoint was the WSI difference from before treatment to Changes in International Normalized Ratio, warfarin doses, and time in therapeutic range were measured.. In the final sample of 43 patients, the mean WSI decreased during treatment from 0.53 to 0.40, or 25.2%. After treatment, the mean WSI rose to 0.51. Although the mean weekly warfarin dose increased from 40.3 to 44.6 mg during treatment, the mean International Normalized Ratio decreased from 2.40 to 1.96, recovering to 2.59 after treatment. The time spent in therapeutic range decreased from 74.1% before treatment to 39.8% during treatment and back to 64.9% 12 weeks posttreatment.. When elbasvir-grazoprevir was added to stable warfarin anticoagulation, warfarin sensitivity decreased significantly during treatment and returned to baseline after treatment.

Topics: Anticoagulants; Antiviral Agents; Benzofurans; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Hepatitis C; Humans; Imidazoles; International Normalized Ratio; Male; Middle Aged; Quinoxalines; Retrospective Studies; Warfarin

The warfarin management strategy for a mechanical mitral valve patient initiated on a ritonavir-based hepatitis C treatment regimen is described. A 62-year-old male with a past medical history of hepatitis C genotype 1a and stable warfarin dose history was initiated on a concomitant Viekira Pak® (VP) regimen containing ritonavir. Prior to initiation of the VP for hepatitis C treatment, the patient was stable on a warfarin dose of 40 mg/wk for 5 months. During treatment with VP, the patient experienced a markedly decreased international normalized ratio (INR) and warfarin requirements ultimately increased 125% from baseline (90 mg/wk). Effective anticoagulation management throughout and surrounding the treatment period for hepatitis C involved frequent warfarin dose adjustments, including preemptive changes, close monitoring, and repeated use of enoxaparin to ensure adequate thrombotic prophylaxis. This is believed to be the first reported case describing the management of warfarin in a patient with hepatitis C who received VP and required a drastically increased weekly warfarin dose. The possible mechanisms suggestive of this interaction and similar case reports in the literature are discussed.

Topics: Anticoagulants; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Monitoring; Heart Valve Prosthesis; Hepatitis C; Humans; International Normalized Ratio; Macrocyclic Compounds; Male; Middle Aged; Mitral Valve; Ritonavir; Sulfonamides; Uracil; Warfarin

New regimens to treat hepatitis C virus infection have expanded the eligible patient population to include more patients receiving concurrent warfarin. The primary objective of this study was to assess whether a drug interaction occurs when these regimens are added to warfarin therapy.. This was a retrospective cohort design using a nationwide database of the Veterans Affairs Health System. Patients on warfarin therapy treated with sofosbuvir or ombitasvir, paritaprevir-ritonavir, and dasabuvir (OBV-PTV/r-DSV) from March 2014 through October 2015 were identified. The warfarin dose response was calculated using a warfarin sensitivity index (WSI) defined as the steady-state INR divided by the mean daily warfarin dose. The primary outcome was the change in WSI from hepatitis C treatment initiation to completion.. The final sample consisted of 271 patients. The WSI decreased 23% from a mean baseline value of 0.53 to 0.39 (decrease of 0.14; 95% CI = 0.11 to 0.16; P < 0.001). OBV-PTV/r-DSV produced a significantly greater decrease than any sofosbuvir regimen. Concurrent ribavirin accounted for an additional decrease in warfarin sensitivity of -0.09 (95% CI = -0.06 to -0.12; P < 0.001). The percentage of subtherapeutic INR results increased from 26% prior to hepatitis C treatment to 58% during treatment.. Results indicate a clinically significant reduction in warfarin dose-response when hepatitis C treatment regimens were added to warfarin. They were most profound with OBV-PTV/r-DSV. Ribavirin was associated with an additive effect. Clinicians should be aware of this potential drug interaction to closely monitor and minimize subtherapeutic levels of anticoagulation.

Topics: Aged; Anticoagulants; Antiviral Agents; Drug Interactions; Drug Therapy, Combination; Female; Hepatitis C; Humans; Male; Middle Aged; Retrospective Studies; Warfarin

SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 microM. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV.

Topics: Animals; Antiviral Agents; Cell Line; Cells, Cultured; Cyclophilin A; Cyclosporins; Dogs; Dose-Response Relationship, Drug; Enzyme Activation; Haplorhini; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Immunosuppressive Agents; Interleukin-2; Jurkat Cells; Leukocytes, Mononuclear; Mice; Molecular Structure; Rats; RNA, Viral; Virus Replication

Topics: Antibodies, Anticardiolipin; Anticoagulants; Cryoglobulinemia; Debridement; Enoxaparin; Hepatitis C; Humans; Male; Middle Aged; Necrosis; Penis; Plastic Surgery Procedures; Vasculitis, Leukocytoclastic, Cutaneous; Venous Thrombosis; Warfarin

The prevalence of anti-hepatitis virus C (HCV) antibody is much higher in hemodialysis (HD) patients than in the normal population. Recently, blood des-gamma-carboxy prothrombin (PIVKA-II) has been demonstrated as a sensitive marker for the early detection of hepatocellular carcinoma (HCC). In this study, we measured blood PIVKA-II in HD patients positive for anti-HCV antibody or hepatitis B virus surface (HBs) antigen to examine if HD therapy may affect the measurement of PIVKA-II.. Ninety-four stable HD patients who had anti-HCV antibodies (n = 86) or HBs antigen (n = 8) without any evidence of HCC were enrolled in the study (age: 60 +/- 11 years, duration of HD: 17 +/- 10 years, male/female = 63/31). Five patients had liver cirrhosis and another 5 patients received warfarin treatment. We simultaneously measured serum PIVKA-II and alpha-fetoprotein (AFP), and compared the association between these markers and HCV RNA titer and laboratory parameters.. Serum PIVKA-II became positive (> or = 40 mAU/ml) in only 5.6% (5/89) of patients without warfarin administration, ranging from 47 to 71 mAU/ml. Seventy out of 89 patients (78.7%) were below 20 mAU/ml. Serum PIVKA-II did not correlate with biochemical parameters including HCV RNA, while serum AFP was significantly correlated with serum AST (r = 0.21, p < 0.05), gamma-GTP (r = 0.21, p < 0.01) and platelet counts (r = -0.29, p < 0.01), respectively. In contrast, 5 patients receiving warfarin had an extremely high PIVKA-II value ranging from 1,930 to 19,900 mAU/ml. PIVKA-II was significantly and inversely correlated with the thrombotest value (r = -0.72, p = 0.01).. The positivity of blood PIVKA-II in HD patients with hepatitis viremia was identical to that in patients without renal failure. Warfarin treatment dramatically increased serum PIVKA-II more than 1,000 mAU/ml. These findings suggested that HD treatment itself did not affect the measurement of PIVKA-II, but vitamin K deficiency can readily influence the PIVKA-II level in dialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Alanine Transaminase; alpha-Fetoproteins; Anticoagulants; Aspartate Aminotransferases; Biomarkers; Female; gamma-Glutamyltransferase; Hepatitis C; Hepatitis C Antibodies; Humans; Incidence; Japan; Male; Middle Aged; Protein Precursors; Prothrombin; Renal Dialysis; RNA; Statistics as Topic; Treatment Outcome; Warfarin

To report a case of inhibition of the effect of warfarin during treatment with ribavirin.. A 61-year-old white man received combination treatment with interferon and ribavirin during 1 year for chronic hepatitis C. He was on permanent anticoagulant therapy with warfarin after a previous heart valve replacement. The dose of warfarin had to be increased by approximately 40% to maintain the desired level of anticoagulation.. Interferon has previously been reported to potentiate the effect of warfarin. This is the first case published in the English-language literature describing an inhibition of the effect of warfarin by the combination of interferon and ribavirin. A rechallenge with ribavirin demonstrated that the inhibition of warfarin could be reproduced. The mechanism for this interaction is unclear. The pharmacokinetics of ribavirin and the potential pathways for interaction are discussed.. During 4 weeks after starting or discontinuing treatment with ribavirin, prothrombin time may be affected in patients receiving warfarin for anticoagulation. It seems prudent to monitor warfarin therapy more frequently during those periods.

Topics: Anticoagulants; Antiviral Agents; Drug Interactions; Heart Valves; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Prothrombin Time; Recombinant Proteins; Ribavirin; Warfarin

The use of pharmacogenomics to individualize drug therapy offers the potential to improve drug effectiveness, reduce adverse side effects, and provide cost-effective pharmaceutical care. However, the combinations of disease, drug, and genetic test characteristics that will provide clinically useful and economically feasible therapeutic interventions have not been clearly elucidated. The purpose of this paper was to develop a framework for evaluating the potential cost-effectiveness of pharmacogenomic strategies that will help scientists better understand the strategic implications of their research, assist in the design of clinical trials, and provide a guide for health care providers making reimbursement decisions. We reviewed concepts of cost-effectiveness analysis and pharmacogenomics and identified 5 primary characteristics that will enhance the cost-effectiveness of pharmacogenomics: 1) there are severe clinical or economic consequence that are avoided through the use of pharmacogenomics, 2) monitoring drug response using current methods is difficult, 3) a well-established association between genotype and clinical phenotype exists, 4) there is a rapid and relatively inexpensive genetic test, and 5) the variant gene is relatively common. We used this framework to evaluate several examples of pharmacogenomics. We found that pharmacogenomics offers great potential to improve patients' health in a cost-effective manner. However, pharmacogenomics will not be applied to all currently marketed drugs, and careful evaluations are needed on a case-by-case basis before investing resources in research and development of pharmacogenomic-based therapeutics and making reimbursement decisions.

Topics: Anticholesteremic Agents; Anticoagulants; Antimetabolites, Antineoplastic; Cardiovascular Diseases; Carrier Proteins; Child; Cholesterol Ester Transfer Proteins; Cost-Benefit Analysis; Drug Therapy; Genotype; Glycoproteins; Hepatitis C; Humans; Interferons; Mercaptopurine; Methyltransferases; Pharmacogenetics; Pharmacology, Clinical; Phenotype; Pravastatin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Ribavirin; Warfarin

Topics: Blood Coagulation Disorders; Drug Synergism; Female; Hepatitis C; Humans; Interferons; Middle Aged; Warfarin