Harvoni - Drug Monograph

Introduction

Harvoni (ledipasvir/sofosbuvir) is a fixed-dose combination antiviral medication developed by Gilead Sciences for the treatment of chronic hepatitis C virus (HCV) infection. Approved by the FDA in October 2014, it represents a significant advancement in HCV therapy, offering high cure rates with all-oral, interferon-free regimens. Harvoni combines an NS5A inhibitor (ledipasvir) with a nucleotide analog NS5B polymerase inhibitor (sofosbuvir) to target multiple stages of the HCV lifecycle.

Mechanism of Action

Harvoni exerts its antiviral effect through two complementary mechanisms:

• Ledipasvir: Inhibits HCV NS5A protein, which is essential for viral RNA replication and virion assembly
• Sofosbuvir: A nucleotide analog inhibitor of HCV NS5B RNA-dependent RNA polymerase, which serves as the catalytic subunit for viral RNA replication

This dual mechanism provides potent suppression of HCV replication across multiple genotypes, particularly genotype 1, which accounts for approximately 75% of HCV infections in the United States.

Indications

Harvoni is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults and pediatric patients 3 years of age and older. Specific indications include:

• Treatment of HCV genotype 1, 4, 5, or 6 infection
• Treatment of HCV/human immunodeficiency virus (HIV-1) coinfection
• Treatment of patients with compensated cirrhosis
• Treatment of patients undergoing liver transplantation to prevent HCV recurrence

Dosage and Administration

• Treatment-naïve without cirrhosis: 12 weeks
• Treatment-naïve with cirrhosis: 24 weeks
• Treatment-experienced without cirrhosis: 12 weeks
• Treatment-experienced with cirrhosis: 24 weeks

• Renal impairment: No dosage adjustment required
• Hepatic impairment: No dosage adjustment required for mild, moderate, or severe hepatic impairment
• Pediatric dosing (≥3 years): Based on weight and formulation (tablets or pellets)

Pharmacokinetics

Contraindications

• Hypersensitivity to ledipasvir, sofosbuvir, or any component of the formulation
• Coadministration with strong P-glycoprotein inducers (e.g., rifampin, St. John's wort) due to significantly decreased concentrations of ledipasvir and sofosbuvir

Warnings and Precautions

Drug Interactions

• Antacids: Separate administration by 4 hours
• H2-receptor antagonists: Administer simultaneously or separated by 12 hours
• Proton pump inhibitors: Administer with food simultaneously
• P-gp inducers: Contraindicated (rifampin, St. John's wort)
• Anticonvulsants (carbamazepine, phenytoin): Not recommended
• HIV medications: Use with caution with tipranavir/ritonavir

Adverse Effects

• Fatigue
• Headache
• Nausea

• Hepatitis B reactivation
• Symptomatic bradycardia when coadministered with amiodarone
• Severe skin reactions (rare)

Monitoring Parameters

• HCV genotype confirmation
• HBV coinfection screening
• Liver function tests (ALT, AST, bilirubin)
• Renal function assessment
• Pregnancy testing in women of childbearing potential

• HCV RNA levels at week 4, end of treatment, and 12 weeks post-treatment (SVR12)
• Liver function tests
• Monitoring for signs/symptoms of HBV reactivation
• Cardiac monitoring if coadministered with amiodarone

• SVR12 assessment to confirm cure
• Ongoing monitoring for liver-related complications in patients with advanced fibrosis

Patient Education

• Take Harvoni exactly as prescribed, once daily with or without food
• Do not stop treatment without consulting your healthcare provider
• Inform all healthcare providers about all medications you're taking, including over-the-counter drugs and herbal supplements
• Report any signs of hepatitis B reactivation (fatigue, weakness, loss of appetite, nausea, vomiting, jaundice)
• Use effective contraception during treatment
• Attend all scheduled follow-up appointments and laboratory tests
• Understand that achieving SVR12 (undetectable HCV RNA 12 weeks after completing therapy) is considered a cure

References

1. FDA Prescribing Information: Harvoni (ledipasvir/sofosbuvir). October 2014. 2. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898. 3. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888. 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. Naggie S, Cooper C, Saag M, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373(8):705-713.