Hepatitis C virus is treated with all-oral medications. These pills, called antiviral medications , are usually taken once per day. These antiviral medications are extremely good at attacking the virus and preventing it from multiplying.
The goal of hepatitis C virus (HCV) treatment has evolved. Just a few years ago the goal was to slow the progression of the disease. Today the goal is to obtain a sustained virological response (SVR) i.e. undetectable HCV RNA 12-24 months after treatment. SVR is considered a cure and has been associated with decreases in all-cause mortality, liver-related death, the need for liver transplantation, hepatocellular carcinoma rates, and liver-related complications.
FDA approved, fully oral, direct-acting antiviral (DAA) treatment regimens can yield nearly 100% SVR for most patient populations. DAAs are molecules that target specific nonstructural proteins of the virus and results in disruption of viral replication and infection. There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target. The four classes are nonstructural proteins 3/4A (NS3/4A) protease inhibitors (PIs), NS5B nucleoside polymerase inhibitors (NPIs), NS5B non-nucleoside polymerase inhibitors (NNPIs), and NS5A inhibitors.
Current guidelines strongly recommend treatment "for all patients with chronic HCV infection, except those with a short life expectancy that cannot be remediated by HCV therapy, liver transplantation, or another directed therapy. Patients with a short life expectancy owing to liver disease should be managed in consultation with an expert (AASLD 2017)."
CLASSES OF DIRECT-ACTING ANTIVIRALS
The main targets of the direct-acting antiviral (DAA) agents are the HCV-encoded proteins that are vital to the replication of the virus. The life cycle of the hepatitis C virus (HCV) can be divided into several stages, including:
RNA translation and protein processing – After cell entry, the viral RNA is translated through host machinery into a polyprotein, which is cleaved during and after translation by both host and viral-encoded proteases into 10 mature viral proteins, including several nonstructural (NS) proteins. One of the viral proteases involved in this post-translational processing is a heterodimeric complex of the NS3 and NS4A proteins (NS3/NS4A). NS3 possesses proteolytic activity and NS4 is a membrane protein that acts as a cofactor.
Synthesis and assembly of viral RNA – Synthesis of new viral RNA occurs in a highly structured replication complex that consists of NS3, NS4A, NS4B, NS5A, and NS5B. NS5B is an RNA-dependent RNA polymerase that is essential for viral replication. NS5A has a presumptive role in the organization of the replication complex and in regulating replication. It is also involved in the assembly of the viral particle that is released from the host cell.
Direct-acting antivirals are inhibitors of the NS3/4A protease, the NS5A protein, and the NS5B polymerase.
NS3/4A protease inhibitors — Contemporary NS3/4A protease inhibitors include:
- Glecaprevir – a potent, pangenotypic protease inhibitor that is only available in combination with the NS5A inhibitor pibrentasvir.
- Voxilaprevir – a potent, pangenotypic protease inhibitor that is only available in combination with the NS5B inhibitor sofosbuvir and the NS5A inhibitor velpatasvir.
- Grazoprevir – a protease inhibitor that is only available in combination with the NS5A inhibitor elbasvir.
There is a recommended, interferon and ribavirin free, oral dosed, combination DAA regimen for nearly all patients. DAA therapy is short duration (8-12 weeks), well tolerated and powerfully effective treatment but it must be patient-specific to achieve an optimum outcome.
Some factors that influence the selection of an appropriate drug regimen may include:
FDA approved DAAs are designed to act at critical points in the HCV lifecycle. After entering the host cell viral RNA is translated to produce one long inactive polyprotein chain of ten viral proteins. Both host and viral proteases are necessary to cleave the long chain into ten functional viral proteins. The virus cannot replicate if the long chain polyprotein is not cleaved or the proteins are not free to carry out their respective functions.
There are three classes of approved DAAs.
Recommended drug combinations Treatment Naive Patients without cirrhosis |
|
Recommended Regimen |
Approved genotypes |
| Elbasvir/Grazoprevir | 1b, 4 |
| Sofosbuvir/ledipasvir | 1, 4, 5, 6 |
| Sofosbuvir/velpatasvir | 1,2,3,4,5,6 |
| Sofosbuvir/velpatasvir/voxilaprevir | 1,2,3,4,5,6 |
| Glecaprevir/pibrentasvir | 1,2,3,4,5,6 |
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Reference
Bhattacharya, D., Aronsohn, A., Price, J., Lo Re, V., & AASLD-IDSA HCV Guidance Panel (2023). Hepatitis C Guidance 2023 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, ciad319. Advance online publication. https://doi.org/10.1093/cid/ciad319