Hepatitis Caused by Other Viruses

Discovery of Novel Hepatitis Viruses

During the long search for the cause of transfusion-associated non-A, non-B hepatitis (see Chapter 80 ), candidate hepatitis viruses were discovered, primarily in individual or small numbers of patients with an acute clinical hepatitis and negative testing for all known viruses. Viral discovery programs with more advanced sequencing technology such as metagenomics continue with the hope of isolating pathogens in individuals with acute hepatitis syndromes who test negative for hepatitis A to E (non–A-E hepatitis). Although a number of viruses have been identified, a causal link with liver disease has been hard to demonstrate in most instances.

Gbv-C/human Pegivirus

The GB agent (GBV) and HGV were discovered and later shown to be 2 isolates of the same virus. A 35-year-old surgeon with the initials GB developed an acute icteric hepatitis. When his serum was serially inoculated into healthy tamarins, they too developed hepatitis. Analysis of the tamarins infected with derivations of the GB serum led to the identification of 2 distinct viruses, labeled GBV-type A (GBV-A) and GBV-type B (GBV-B) . Neither GBV-A or GBV-B infect humans, but a third virus, closely related to the GB agents, was subsequently identified by the same investigators from a human sample and was classified as GBV-C . At approximately the same time, another group independently identified a virus from the serum of a patient with cryptogenic non–A-E hepatitis, which they named HGV. Subsequent studies revealed 96% homology between the genomes of HGV and GBV-C, indicating that they were actually 2 strains of the same virus. Because large epidemiologic studies have not demonstrated any association between infection with GBV-C/HGV and acute or chronic hepatitis, the use of the term “hepatitis G virus” has been questioned. More recently, even the name GBV has been challenged. GBV-A and -B infect only new-world primates and a more recently discovered related virus called GBV-D infects only bats. In fact, even the index patient (“GB”) was subsequently shown to be infected with HCV as the cause of his liver disease. As such, in 2011, a new nomenclature was adopted that preserved the name GBV only for the original GBV-B strain and called the other related viruses Pegivirus to indicate that they cause persistent (Pe) infection and originate from the historically named G or GB viruses. They are all in the class of GBV-C, which is now known as HPgV. Notably, despite some structural similarities with HCV, HPgV should no longer be classified as a hepatitis virus. Although HPgV is detected in many patients with non - A-to-E acute and chronic hepatitis and may persist for years, it does not appear to cause liver (or any other) disease, even in immunocompromised persons. ^{, ,} HPgV infection has been established in Old World monkeys, including cynomolgus macaques. ^, Interestingly, following acute inoculation and progression to chronicity of HPgV infection, very little sequence evolution was seen supporting the nonpathogenicity of this viral family. It is primarily if not exclusively lymphotrophic, and for persons with HIV infection, coinfection with HPgV is associated with a milder course of HIV-related disease and a better response to antiretroviral therapy, ^, possibly through direct competition for the same cell-type or through induction of cytokines.

Because HPgV infection is not associated with clinical liver disease, no treatments have targeted HPgV specifically. In HIV-HCV-HPgV coinfected persons, peginterferon and ribavirin treatment led to sustained HPgV clearance in 31% of patients, with no observable subsequent effect on the course of HCV or HIV infection. In patients coinfected with HPgV and HCV who were treated with interferon and ribavirin, HPgV RNA disappeared from serum during therapy but reappeared in all patients following discontinuation of therapy. ^, Importantly, no effect of HPgV infection on the response to treatment of HCV or HBV infection was observed. ^, Neither the effect of HCV DAAs on HPgV replication nor the effect of HPgV on the response to DAAs has been reported.

Tt Virus Infection

TTV was first identified in 1977, by the use of representational difference analysis in a patient (with the initials TT) in Japan who had acute post-transfusion non–A-G hepatitis. TTV is also referred to as the transfusion-transmitted and Torque-Teno virus.