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  1. Science & Research (Biologics)

Diagnosis and Pathogenesis of Hepatitis Viruses That Impact the Safety of Blood and Related Products

David R. McGivern, PhD

Office of Blood Research and Review
Division of Emerging and Transfusion Transmitted Diseases
Laboratory of Emerging Pathogens



David McGivern joined CBER in 2018 as a Principal Investigator (tenure-tracked) in the Office of Blood Research and Review. Prior to joining FDA he worked at the University of North Carolina as an assistant professor in the Department of Medicine, Division of Infectious Diseases, where he began a research program in hepatitis viruses. Dr. McGivern received his PhD from the University of East Anglia, UK and completed postdoctoral training at the University of Dundee (UK) and the University of Texas Medical Branch at Galveston.

General Overview

Our laboratory focuses on transfusion-transmissible viruses that cause acute and chronic hepatitis: hepatitis E virus (HEV) and hepatitis C virus (HCV).

HEV is an important cause of water-borne acute hepatitis in developing countries with poor sanitation infrastructure. Worldwide, outbreaks of HEV are associated with approximately 70,000 deaths and 3,000 stillbirths per year. In the US and other developed nations, outbreaks of HEV are rare. However, sporadic HEV infections are associated with either travel to countries where HEV is endemic or consumption of undercooked pork or venison products. Most infections with foodborne HEV strains have no symptoms and infected individuals can feel well enough to donate blood. When immune-suppressed persons (e.g., organ transplant recipients) receive blood products containing HEV, the virus can establish chronic infection and cause progressive liver disease. For this reason, HEV is a threat to blood safety. Transfusion transmission of HEV has been well documented in some European countries, such as Germany, where testing of blood donors showed as many as 1 in 1,300 were HEV positive. In the US, HEV is less common than Europe, but probable cases of transfusion transmission have been identified.

This laboratory is developing reference reagents to facilitate evaluation of tests to detect HEV in blood. We are evaluating 1) novel biomarkers of HEV infection to improve detection in blood; 2) new animal models as surrogates to study markers of infection and pathogenesis in immune competent and immune suppressed individuals with acute vs chronic HEV infection.

HCV is a bloodborne virus transmitted by unsafe injection practices, such as sharing needles, and less frequently by sexual contact. HCV can also be transmitted by blood transfusion. In developed countries such as the US, screening blood donations for HCV has substantially reduced the risk of transfusion transmission. Following exposure to HCV, most individuals fail to clear the virus and develop a lifelong infection. Approximately 2.4 million people in the US and 71 million people worldwide are living with chronic hepatitis C, which increases their risk of developing liver disease. Disease progression is slow, variable, and can be symptom-free for decades. During this time the infection causes progressive liver damage that can lead to cirrhosis and in some cases, liver cancer. Our research combines animal models of chronic hepatitis C and the study of clinical samples to understand why HCV-associated disease progresses faster in some individuals.

Recently developed antiviral therapies are well tolerated and can eliminate HCV from an infected person. However, HCV will likely remain a problem for decades because many people do not know they are chronically infected with HCV until they develop end-stage liver disease. Additionally, there is no vaccine for HCV and people who are cured lack protective immunity and are at risk for re-infection. In the last few years, there have been increases in HCV infections in the US associated with the opioid epidemic and injection drug use. Continued testing of blood donations for HCV is essential to ensure blood safety.

Our research into replication and pathogenesis caused by HCV and HEV will support evaluation of improved diagnostics and identification of biomarkers to support disease management. This research program will maintain the expertise needed by the Office of Blood Research and Review to support regulatory review of assays and devices for detecting hepatitis viruses and other virus infections in blood products.

Scientific Overview

Our research on viral hepatitis has three goals:

Compared to HEV, chronic HCV infection is common in the US. However, disease outcomes are extremely variable. Therefore, we will collaborate with clinical investigators at NIH in studies of human liver biopsy specimens to understand molecular mechanisms underlying differences in disease progression (e.g., in older vs. younger persons).

  1. Establish reference reagents to standardize HEV detection assays among laboratories. We are optimizing production of HEV in cell culture to generate reference reagents. These reference reagents will be characterized and compared to the World Health Organization international reference panel for HEV, which includes strains of HEV genotypes 1-4 isolated from donors. We will also generate reference reagents for the other clinically relevant HEV genotypes and rarer genotypes with zoonotic potential. These reagents will facilitate the evaluation of NAT assays for detecting HEV in blood products.
  2. Determine the prevalence and impact of hepatitis viruses in the US. The prevalence of HEV in the US, and more broadly in the Americas, is poorly characterized. We will evaluate sensitive assays to detect HEV and immune responses to HEV infection in blood. In collaborative studies, we will use these assays to determine the prevalence of HEV in blood donors and the prevalence and potential impact of HEV infection in persons with comorbidities that could result in worse disease outcomes (e.g., persons on immunosuppressive therapy or with chronic liver disease).
  3. Study hepatitis virus transmission and pathogenesis. HCV and HEV are both positive strand RNA viruses that infect hepatocytes, causing a wide range of disease outcomes. Historically, understanding the molecular mechanisms controlling disease progression has been hampered by the lack of appropriate animal models for both infections.

    HCV replicates only in humans and chimpanzees. Recently, a rat ortholog of HCV has been discovered that can replicate and establish chronic infection in rodents, causing progressive liver disease. This model provides an opportunity to understand the factors contributing to disease during chronic hepatitis C.

    HEV can infect a wider range of hosts, including rhesus macaques, rabbits and gerbils. We will explore small animal models in order to understand mechanisms of disease during both acute and persistent HEV infection. Identifying factors that control whether acute HEV infection is cleared will enable us to determine which patients are most at risk for developing persistent infection and progressive liver disease. These models might also serve as a platform for studies of transfusion transmission of HEV and evaluation of pathogen reduction technologies designed to eliminate HEV infectivity in blood and related products.


  1. PLoS Pathog 2023 Sep 13;19(9):e1011664
    Distinct disease features of acute and persistent genotype 3 hepatitis E virus infection in immunocompetent and immunosuppressed Mongolian gerbils.
    Subramaniam S, Fares-Gusmao R, Sato S, Cullen JM, Takeda K, Farci P, McGivern DR
  2. J Clin Virol 2022 Dec;157:105325
    Development and characterization of secondary standards for nucleic acid amplification technology (NAAT) assays for detection of hepatitis E virus.
    Fares-Gusmao R, Jiang Z, Subramaniam S, Visser BJ, Scott A, Ishida Y, Saito T, Baylis SA, McGivern DR, HEV Standard Calibration Study Group
  3. Proc Natl Acad Sci U S A 2021 Apr 27;118(17):e2019633118
    Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis.
    Nishimura N, De Battista D, McGivern DR, Engle RE, Tice A, Fares-Gusmao R, Kabat J, Pomerenke A, Nguyen H, Sato S, Bock KW, Moore IN, Kleiner DE, Zamboni F, Alter HJ, Govindarajan S, Farci P
  4. who.int WHO/BS.2020.2402
    Collaborative study for the establishment of a WHO international standard for SARS-CoV-2 RNA.
    Bentley E, Mee ET, Routley S, Mate R, Fritzsche M, Hurley M, Duff YL, Anderson R, Hockley J, Rigsby P, Page M, Rose N, Mattiuzzo G, Collaborative Study Group
  5. Open Forum Infect Dis 2019 May;6(5):ofz175
    Prevalence and impact of hepatitis E virus infection among persons with chronic hepatitis B living in the US and Canada.
    McGivern DR, Lin HHS, Wang J, Benzine T, Janssen HJA, Khalili M, Lisker-Melman M, Fontana RJ, Belle SH, Fried MW



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