Science Spotlight

The battle of the liver vs. Hepatitis C virus: Cure edition

From the Jerome Laboratory, Vaccine and Infectious Disease Division

    Hepatitis C virus (HCV) causes inflammation of the liver. Severity of symptoms causes by viral replication range from acute mild illness to lifelong liver damage. Modern medicine has allowed for the possibility of clearing infection through organ transplantation and/or drug therapy. HCV is considered cured when serum levels of HCV RNA are below detectable levels 12 to 24 weeks after treatment completion, another term for this is sustained virologic response (SVR). In 2011 the US Food and Drug Administration approved a new generation of drugs for Hepatitis C virus (HCV) treatment called direct-acting antiviral (DAAs). These drugs target the replication machinery of HCV and, in combination with other treatments, are able to cure chronic HCV. With DAAs the fraction of patients achieving SVR is in excess of 90%, which is similar to SVR rates seen in liver transplant patients. To put this in perspective, the previous treatment option, an interferon-ribavarin regimen, has only a 50% cure rate. With the increase in DAAs use and thus more people being cured of HCV, a better understanding of the post SVR liver landscape needs to be investigated. In order to better understand the liver landscape after SVR treatment regardless of how SVR was acheieved, researchers from the Vaccine and Infectious Disease Division at Fred Hutch analyzed liver samples from HCV transplant patients at various time points after SVR. Understanding the histologic features of the liver after SVR is a high priority because liver biopsies are common proactive for post- HCV paitents either after DAAs or liver- transplants. This work was published in the Journal of Clinical Gastroenterology and Hepatology.

Example of H&E stained liver biopsy from a cured patient. Examples of necroinflammatroy can be seen in the enlarged section. Figure provided by Dr. Cook.

The study was composed of 170 allograft biopsies from 36 individual patients. Of the 170 samples 65 were collected after patients reached SVR, the rest (pre-SVR) were used for comarison. Paitents were treated with drug therapy and received a liver transplant. Most paitents received interferon/ ribavirin, some got DAAs and some spontaneously cleared the virus. Despite being post-SVR – where no viral RNA can be detected - 69% of samples displayed histopathological features consistent with recurrent HCV as documented by necroinflammatory activity and fibrosis (see figure). This suggests that ‘cured’ patients may have persistent features of active HCV hepatitis even in the absence of the virus. To understand how long this pathology persists after SVR, tissues were categorized based on time since SRV , out to 5 years later. At all time points HCV-like pathology was documented in the majority of samples. For a small number of patients both pre and post-SRV samples existed, in these biopsies the HCV grade was compared and approximately 50% of samples had a grade equal to or higher than the pre-SVR sample.

    To further understand the results, the group used PCR of viral RNA to determine if the liver biopsies had detectable RNA that would suggest replicating virus and thus a reason for the histological appearance of active infection. Of the 32 biopsies tested, 89% were positive by PCR pre-SRV and only 1 was positive after being cured. The one positive sample had levels just above the limit of detection. Taken together these data suggest that HCV-type necroinflammatroy liver damage continues in the absence of replicating virus regardless of treatment methods. Dr. Cook stated, “Thus, it appears that an on-going HCV infection is not necessary for the maintenance of the HCV-associated liver inflammation, fibrosis, and cirrhosis. Unfortunately, this on-going inflammation seen in the biopsy could lead to lab-related mis-interpretation of liver biopsies as recurrent HCV as well as clinically with ongoing pathology in the livers of post-transplant patients.” This information raises many further questions for HCV researchers and pathologists alike. In Dr. Cook’s words, “Could there be extremely low levels of HCV present in the liver causing the ongoing inflammation? Has the work done to date been sufficient to understand what is happening in non-transplant cases? Why does the inflammatory reaction persist in the transplant?  Does that tell us that in some ways the inflammatory causes are persistent or a demonstration of a dysfunctional immune response?”

Whitcomb E, Choi W-T, Jerome KR, Cook L, Landis C,Ahn J, Te HS, Esfeh J, Hanouneh IA, Rayhill SC, Gibson W, Plesec T, Koo J, Wang HL, Hart J, Pai RK, Westerhoff M. 2017. Biopsies from Allograft Liver Contain Histologic Features of Hepatitis C Virus Infection Following Virus Eradication. Clin Gastroenterol Hepatol.