Introduction
Daclatasvir is an oral direct-acting antiviral agent that specifically inhibits the hepatitis C virus (HCV) nonstructural protein 5A (NS5A). It was approved by the FDA in 2015 as part of combination therapy for the treatment of chronic hepatitis C virus infection. Daclatasvir represents a significant advancement in HCV treatment, offering high cure rates with improved tolerability compared to older interferon-based regimens.
Mechanism of Action
Daclatasvir is a first-in-class HCV NS5A replication complex inhibitor. It binds to domain 1 of the NS5A protein, disrupting its multiple functions in the viral replication cycle. Specifically, daclatasvir inhibits both RNA replication and the assembly of HCV virions. The drug exhibits picomolar potency against HCV and demonstrates activity against multiple HCV genotypes, though with varying potency across different genotypes.
Indications
Daclatasvir is indicated in combination with sofosbuvir for the treatment of chronic HCV genotype 1 or 3 infection in adults. The combination is also used off-label for other HCV genotypes based on clinical evidence. It may be used with or without ribavirin depending on patient factors such as cirrhosis status and previous treatment experience.
Dosage and Administration
The recommended dosage is 60 mg taken orally once daily with or without food. Daclatasvir should be used in combination with other antiviral agents, typically sofosbuvir 400 mg once daily.
Special Populations:- Hepatic impairment: No dose adjustment needed for mild, moderate, or severe hepatic impairment
- Renal impairment: No dose adjustment needed for any degree of renal impairment
- Elderly patients: No dose adjustment required
- Pediatric patients: Safety and efficacy not established
Pharmacokinetics
Absorption: Median Tmax is 2 hours post-dose. Administration with a high-fat meal decreases Cmax by 28% and AUC by 23%, but this is not clinically significant. Distribution: Protein binding is approximately 99%. Apparent volume of distribution is 47 L. Metabolism: Primarily metabolized by CYP3A4. Daclatasvir is also a substrate of P-glycoprotein (P-gp) and organic cation transporter (OCT) 1. Elimination: Mean elimination half-life is 12-15 hours. Approximately 88% of the dose is excreted in feces and 6.6% in urine.Contraindications
- Hypersensitivity to daclatasvir or any component of the formulation
- Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort, carbamazepine, phenytoin) due to significantly reduced daclatasvir concentrations
Warnings and Precautions
- Risk of hepatitis B virus reactivation: Screen all patients for current or previous HBV infection before initiation
- Use with amiodarone: Serious symptomatic bradycardia may occur when coadministered with sofosbuvir and amiodarone
- Pregnancy: No human data; use during pregnancy only if potential benefit justifies potential risk
- Lactation: Not recommended during breastfeeding
- Post-treatment monitoring: Monitor HCV RNA levels after completion of therapy to confirm sustained virologic response
Drug Interactions
Significant interactions:- Strong CYP3A inducers: Contraindicated (reduce daclatasvir exposure by >90%)
- Moderate CYP3A inducers: Consider alternative or adjust daclatasvir dose to 90 mg daily
- Strong CYP3A inhibitors: Adjust daclatasvir dose to 30 mg daily
- Moderate CYP3A inhibitors: Adjust daclatasvir dose to 30 mg daily
- Notable interactions: Carbamazepine, phenytoin, rifampin, ketoconazole, clarithromycin, ritonavir, dabigatran, digoxin
Adverse Effects
Common adverse reactions (≥10%):- Fatigue (14-18%)
- Headache (14%)
- Nausea (8-12%)
- Bradycardia when used with amiodarone
- Hepatitis B reactivation
- Increased bilirubin (10%)
- Increased lipase (3%)
Monitoring Parameters
- HCV RNA levels at baseline, during treatment (week 4 optional), at end of treatment, and 12-24 weeks post-treatment
- Liver function tests (ALT, AST, bilirubin) at baseline and as clinically indicated
- HBV DNA and serology in patients with current or previous HBV infection
- Heart rate in patients taking amiodarone concomitantly
- Pregnancy testing in women of childbearing potential
Patient Education
- Take exactly as prescribed, typically one 60 mg tablet daily
- May be taken with or without food
- Complete the full course of therapy even if feeling better
- Report any symptoms of slow heart rate (dizziness, lightheadedness, fatigue) immediately
- Use effective contraception during treatment and for some time after completion
- Inform all healthcare providers about all medications being taken, including over-the-counter drugs and herbal supplements
- Attend all scheduled follow-up appointments and laboratory tests
References
1. FDA Prescribing Information: Daklinza (daclatasvir) tablets. 2015. 2. Wyles DL, Ruane PJ, Sulkowski MS, et al. Daclatasvir plus sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):714-725. 3. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61(4):1127-1135. 4. American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA). HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. 2023. 5. European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol. 2018;69(2):461-511.