There are four current classes of DAAs, which are defined by their mechanism of action and therapeutic target: nonstructural protein (NS) 3/4A protease inhibitors, NS5B nucleoside polymerase inhibitors, NS5B non-nucleoside polymerase inhibitors, and NS5A inhibitors. The main targets of the DAAs are the HCV-encoded proteins that are vital to the replication of the virus (Figure 49–1).
The safety profiles of all the combination regimens (see Table 49–7) are generally excellent, with adverse events of mild severity and very low rates of discontinuation due to adverse events in clinical trials in the absence of concurrent ribavirin use.
The NS5A protein plays a role in both viral replication and the assembly of HCV; however the exact mechanism of action of the HCV NS5A inhibitors remains unclear.
Daclatasvir is used in combination with sofosbuvir for treatment of HCV genotypes 1, 2, and 3. It may be taken with or without food and does not require adjustment for renal or hepatic impairment. Exposure of daclatasvir was similar between healthy and HCV-infected subjects. Protein binding is ~99%. It is metabolized via CYP3A and excreted primarily in the feces. Terminal elimination half-life is 12–15 hours.
Daclatasvir is generally well tolerated. The most common adverse effects in patients receiving daclatasvir/sofosbuvir were headache and fatigue, usually mild or moderate in severity. Serious symptomatic bradycardia has been reported in patients receiving daclatasvir with sofosbuvir and amiodarone.
Daclatasvir is primarily metabolized through CYP3A metabolism and should not be given with strong inducers of this enzyme. In addition, dose adjustment is required when co-administered with strong CYP3A inhibitors or moderate CYP3A inducers. Daclatasvir is an inhibitor of P-glycoprotein transporter (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP).
Elbasvir has in vitro activity against most major HCV genotypes, as well as some viral variants resistant to earlier NS5A inhibitors. It is only available as a fixed-dose combination with grazoprevir, recommended for treatment of HCV genotypes 1 and 4 (see Table 49–7).
The presence of baseline NS5A resistance-associated variants (RAVs) significantly reduced rates of SVR at 12 weeks using elbasvir/grazoprevir regimen in patients with genotype 1a. Since 10–15% of patients without prior exposure will have NS5A RAVs, baseline testing should be considered prior initiation of therapy.
Absorption is not food-dependent. Peak concentrations after ingestion occur at a median of 3 hours. Elbasvir is extensively bound to plasma proteins (>99.9%), partially eliminated by oxidative metabolism, and primarily excreted in the feces. Elbasvir/ grazoprevir should not be administered to patients with moderate or severe hepatic impairment or in conjunction with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) inhibitors, strong inducers or inhibitors of CYP3A, or efavirenz.
The most commonly reported side effects during therapy with elbasvir/grazoprevir were fatigue, headache, and nausea. Elevations in serum aminotransferases may occur.