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Hepatitis C
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Rebecca Pierce-Williams, Neil Silverman, Raja Dhanekula, Jonathan M. Fenkel, Danielle Tholey
Historically, treatment consisted of pegylated interferon (PEG-IFN), ribavirin and protease inhibitors. Ribavirin is contraindicated in pregnancy due to teratogenicity concerns. Treatment has changed dramatically since 2011 with the development of DAAs.For any genotype, in a treatment-naïve patient without cirrhosis, the preferred therapy is either 8 weeks of glecaprevir/pibrentasvir or 12 weeks of sofosbuvir/velpatasvir.Treatments are associated with few and mild side effects (headache, nausea, fatigue, insomnia).Ongoing research into HCV treatment (ledipasvir/sofosbuvir) during pregnancy is promising, as many women could be cured while receiving prenatal care.Until treatment in pregnancy is approved, women should be referred to a hepatologist in the postpartum treatment for antiviral therapy and long-term follow-up.
Anti-Infective Agents
Published in Radhwan Nidal Al-Zidan, Drugs in Pregnancy, 2020
Risk Summary: The reproduction studies in animals have shown no evidence of fetal harm or impaired fertility. The pregnancy experience in humans is adequate to exhibit that the embryo-fetal risk is nonexistent or very low. However, Ledipasvir is contraindicated during pregnancy if taken in combination with Ribavirin and peginterferon alfa.
R
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Antivirals: atazanavir darunavir, fosamprenavir, saquinavir and tipranavir and possibly nevirapine increase concentration of rifabutin – halve or reduce dose of rifabutin; efavirenz reduces the concentration of rifabutin – increase dose of rifabutin; concentration of both drugs reduced with etravirine; indinavir increases rifabutin concentration – avoid; concentration of indinavir reduced – increase indinavir dose; concentration of elvitegravir reduced and active metabolite of rifabutin increased – reduce dose of rifabutin; concentration of rilpivirine reduced – increase rilpivirine dose to 50 mg once daily; ritonavir increases the concentration of rifabutin resulting in increased risk of uveitis – reduce rifabutin dose; concentration of saquinavir reduced and concentration of rifabutin increased – reduce rifabutin dose; concentration of daclatasvir and simeprevir possibly reduced – avoid; avoid with ledipasvir, sofosbuvir and telaprevir.
Development and validation of a versatile HPLC-DAD method for simultaneous determination of the antiviral drugs daclatasvir, ledipasvir, sofosbuvir and ribavirin in presence of seven potential impurities. Application to assay of dosage forms and dissolution studies
Published in Drug Development and Industrial Pharmacy, 2019
Mostafa M. Baker, Sherif F. Hammad, Tarek S. Belal
Hepatitis C virus (HCV) infection is a major worldwide health menace which should be efficiently combated. Being one of the most affected nations by HCV, Egypt is on its ambitious way to making history and completely eradicate HCV infection hopefully by the end of the next decade. Treatment of HCV infection has significantly changed during the last few years. Novel direct-acting antivirals (DAAs) are now the standard of care for the management of HCV infection for their excellent survival rate and tolerability. Sofosbuvir (SOF) is a nucleotide analog polymerase inhibitor of nonstructural protein (NS-5B) and it is the most essential DAA used in combination with drugs for the treatment of HCV infection. The fixed-dose combination of sofosbuvir (SOF) and ledipasvir (LED) is approved for the treatment of chronic HCV infection worldwide. LED/SOF combination exhibits a favorable drug-drug interaction profile and can be administered with various medications that may be used by HCV-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Other important HCV antiviral drugs commonly co-administered with SOF include daclatasvir (DAC) and ribavirin (RIB) [1–3]. Chemical structures of the four drugs under analysis in this study are shown in Figure 1.
Bioactivation of cyclopropyl rings by P450: an observation encountered during the optimisation of a series of hepatitis C virus NS5B inhibitors
Published in Xenobiotica, 2018
Xiaoliang Zhuo, Ying-Zi Wang, Kap-Sun Yeung, Juliang Zhu, Xiaohua Stella Huang, Kyle E. Parcella, Kyle J. Eastman, John F. Kadow, Nicholas A. Meanwell, Yue-Zhong Shu, Benjamin M. Johnson
Interestingly, cyclopropane rings have been integrated into non-nucleoside, direct-acting antiviral agents against key functional proteins of the hepatitis C virus (HCV) that are essential in the viral life cycle (De Clercq, 2007). For example, BMS-605339, a potent inhibitor of the non-structural protein 3/4 A (NS3/4 A) protease, which catalyses proteolysis of a viral polyprotein to individual functional proteins, features two cyclopropyl rings – one in the acylsulfonamide P1' position and the other in the P1 amino acid. The superior antiviral potency of BMS-605339 compared to the corresponding carboxylic acid derivative is attributed to the optimal van der Waals interaction between the cyclopropylacylsulfonamide moiety and key residues within the hydrophobic S1' pocket of the enzyme as evident based on a cocrystal structure (Scola et al., 2014). Ledipasvir, an inhibitor of non-structural protein 5 A (NS5A), which plays an important role in viral RNA replication, represents another example where the introduction of a spiro-cyclopropyl moiety into the C3-position of a pyrrolidine ring improved antiviral potency (EC50 in cell based assays), plasma protein-adjusted EC50 and PK properties (Link et al., 2014).
Timing of treatment initiation of direct-acting antivirals for HIV/HCV coinfected and HCV monoinfected patients
Published in AIDS Care, 2018
Donald P. Rice, Michelle A. Ordoveza, Ann M. Palmer, George Y. Wu, Lisa M. Chirch
The longest mean time to treatment was found in patients with private insurance and those denied the initial regimen prescribed for them. The differences for both of these factors were highly significant in univariate and multivariate analyses. These findings reflect the rules that Connecticut Medicare and Medicaid have adopted to provide DAA therapy for patients with HCV regardless of genotype, choice of regimen, or fibrosis level (Connecticut Department of Social Services, n.d.-a). Denial of an initial regimen prescription was uncommon (6.3% of cases) but contributed to delay in therapy. This represents a remediable source of delay that could become less frequent as insurance payers cease to advocate interferon-based regimens. Unrestricted access to DAA regimens is likely to have a positive impact in controlling the HCV epidemic, though the degree of that impact is beyond the scope of this study. Our study also found that ledipasvir/sofosbuvir was associated with more rapid initiation of therapy suggesting that simplified prescribing with multigenotypic regimens may facilitate more rapid initiation of treatment.