Breakthroughs in hepatitis C research: from discovery to cure

Abstract

In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.

Fig. 1. Major breakthroughs in HCV history.

Breakthroughs are separated into basic and translational (part a) and clinical (part b) research, and research that formed part of major awards is indicated. DAA, direct-acting antiviral agent; HCV, hepatitis C virus; IFN, interferon-α; NANBH, non-A, non-B hepatitis; NS5A, nonstructural protein 5A; Peg-IFN, pegylated interferon-α; PI, protease inhibitor; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virological response; VEL, velpatasvir; VOX, voxilaprevir. Additional refs^,.

Fig. 2. Impact of different measures on the incidence of post-transfusion NANBH.

Development of the risk for post-transfusion non-A, non-B hepatitis (NANBH) over time. Over the years, various measures have been taken to reduce the risk of post-transfusion hepatitis. This included the exclusion of paid blood donors, screening for alanine aminotransferase (ALT) levels as well as hepatitis B virus (HBV) infection, and ultimately testing donors for anti-hepatitis C virus (HCV) antibodies and HCV RNA. AIDS, acquired immunodeficiency syndrome; HBsAg, hepatitis B surface antigen. Adapted with permission from ref., H. J. Alter.

Fig. 3. Organization of the HCV genome.

Illustration of the hepatitis C virus (HCV) genome, which contains only a single open reading frame encoding one polyprotein of about 3,000 amino acids. The structural proteins, which include the core or capsid (C) protein and envelope (E1 and E2) proteins, can be found in the N-terminal region. The C-terminal region contains the nonstructural (NS) proteins that are required at various steps of viral replication. NTR, N-terminal region; NS2, NS3, NS4B, NS5A, NS5B, nonstructural proteins 2, 3, 4B, 5A, 5B, respectively; p7, ion channel; 4A, nonstructural protein 4A. Adapted from ref., Springer Nature Limited.

Fig. 4. HCV life cycle.

Entry of hepatitis C virus (HCV) into hepatocytes is a complex and yet not completely understood process that involves several different host proteins, including CD81, scavenger receptor B type 1 (SRB1), claudin 1 as well as occludin. After endocytosis, the viral envelope fuses with the endosome membrane. This is followed by uncoating of the viral RNA, which is then translated into the polyprotein by host enzymes. Viral proteases are required (for example, nonstructural proteins NS3 and NS4) to process the HCV polyprotein into the various structural and nonstructural viral proteins. The NS5B polymerase assisted by the NS3 helicase is required for the production of HCV RNA positive replicates. For the final step of viral assembly and release, it is assumed that the NS5A protein has a central role. ER, endoplasmic reticulum; LDLR, low-density lipoprotein receptor; miR, microRNA. Adapted from ref., Springer Nature Limited.

Fig. 5. Evolution of HCV therapy.

There has been a continuous increase in sustained virological response rates over time, starting with only 6–19% when using the first interferon-α (IFN) monotherapies to cure rates of >98% in the era of direct-acting antiviral agents (DAAs)^,,,,,,,,,. HCV, hepatitis C virus; Peg-IFN, pegylated interferon-α; PI, protease inhibitor; RBV, ribavirin.

Fig. 6. Cascade of care.

Overview of the various steps required to cure patients with hepatitis C virus (HCV) infection. It becomes obvious that an increase in sustained virological response has only a minor efficacy on the overall proportion of patients with HCV infection who are cured: 1–2% for patients treated with interferon-α (IFN) monotherapy, and 8% for patients treated with modern direct-acting antiviral agents. For a substantial change, other parts of the cascade need to be markedly improved.