What is the first direct-acting antiviral (DAA) drug that can eradicate 90% of chronic Hepatitis C Virus (HCV)?

Ledipasvir-sofosbuvir is the First Direct-Acting Antiviral Drug That Can Eradicate 90% of Chronic HCV

Ledipasvir-sofosbuvir (option C) is the first direct-acting antiviral drug combination that can eradicate 90% or more of chronic Hepatitis C Virus (HCV) infections. This fixed-dose combination therapy represents a significant advancement in HCV treatment with sustained virological response (SVR) rates exceeding 90% across various patient populations.

Evolution of HCV Treatment

• The therapeutic landscape for chronic HCV infection has evolved rapidly since the approval of the first direct-acting antivirals (DAAs) in 2011, with telaprevir and boceprevir being the first-generation protease inhibitors 1
• These first-generation DAAs required combination with pegylated interferon-α (PEG-IFN) and ribavirin, achieving SVR rates of only 65-75% in genotype 1 patients 1, 2
• In 2014, newer DAAs were approved, including sofosbuvir (a nucleotide NS5B polymerase inhibitor), simeprevir (a second-wave protease inhibitor), and daclatasvir (an NS5A inhibitor) 1
• Ledipasvir-sofosbuvir became the first fixed-dose combination DAA therapy to achieve SVR rates consistently above 90% across patient populations 3, 4

Efficacy of Ledipasvir-sofosbuvir

• Clinical trials demonstrated that ledipasvir-sofosbuvir achieved SVR rates of 94-99% in treatment-naïve patients without cirrhosis after just 8-12 weeks of therapy 3
• In treatment-naïve patients with cirrhosis, ledipasvir-sofosbuvir achieved SVR rates of 94% after 12 weeks of treatment 3
• The combination of ledipasvir (NS5A inhibitor) and sofosbuvir (NS5B polymerase inhibitor) provides complementary mechanisms of action that effectively suppress HCV replication 5
• Unlike earlier treatments, ledipasvir-sofosbuvir does not require the addition of ribavirin in most cases, as studies showed no significant increase in SVR rates when ribavirin was added (93.9% vs 96.7%) 4

Advantages Over Previous Treatments

• Ledipasvir-sofosbuvir offers an interferon-free regimen, eliminating the significant side effects associated with interferon-based therapies 1
• Treatment duration is significantly shorter (8-12 weeks) compared to older regimens that required 24-48 weeks 1
• The fixed-dose combination has minimal side effects and fewer drug-drug interactions compared to first-generation protease inhibitors 1
• The high genetic barrier to resistance makes ledipasvir-sofosbuvir effective against various HCV genotypes, particularly genotype 1 1

Why Other Options Are Incorrect

• Ribavirin (option A) is not a direct-acting antiviral but rather a nucleoside analog with broad antiviral activity that was used in combination with interferon and later with DAAs; it cannot achieve 90% SVR rates on its own 1
• PEG-IFN-α 2a (option B) is an immunomodulator, not a direct-acting antiviral, and achieves only 40-50% SVR rates in genotype 1 patients when used with ribavirin 1
• Adefovir dipivoxil (option D) is primarily used for hepatitis B virus (HBV) treatment, not HCV 6

Clinical Considerations

• Ledipasvir-sofosbuvir is particularly effective for HCV genotype 1, which is historically the most difficult-to-treat genotype 3
• Treatment duration may need to be extended to 24 weeks in certain populations, such as treatment-experienced patients with cirrhosis 3
• Monitoring for potential HBV reactivation is necessary in patients with HBV/HCV coinfection during ledipasvir-sofosbuvir treatment 6
• HIV-coinfected patients show comparable response rates to HCV-monoinfected patients when treated with ledipasvir-sofosbuvir 7

In conclusion, ledipasvir-sofosbuvir represents a breakthrough in HCV treatment as the first direct-acting antiviral combination capable of eradicating over 90% of chronic HCV infections with a short treatment duration and favorable side effect profile.