Version May 2024
INTRODUCTION — Human pegivirus (HPgV-1), previously designated hepatitis G virus (HGV) and GB virus type C (GBV-C), is a single-stranded positive RNA virus belonging to the Flaviviridae family [1].
HPgV-1 was initially cloned from a surgeon (whose initials were GB, hence the term GB virus or GBV). Plasma from this patient transmitted hepatitis to tamarins. Three different GBV agents were isolated and designed GB virus types A, B, and C; the first two were probably tamarin agents [2]. The agent designated GBV-C is virtually identical to HGV. Because GBV-C/HGV infects human beings, it was renamed as human pegivirus type 1 (HPgV-1).
EPIDEMIOLOGY — HPgV-1 has a global distribution. It is estimated that one-sixth of the global population is seropositive for HPgV-1, and approximately 750 million people have had viremia [1]. In one meta-analysis of 35,468 volunteer blood donors, the global prevalence of HPgV-1 was 3.1 percent [3]. The pooled prevalence rates varied by continent, with rates of 1.7 percent in North America, 2.3 percent in Europe, 2.4 percent in Asia, and 9.1 percent in South America. Reported rates of viremia are higher in individuals with hepatitis C virus (HCV; 11 to 24 percent) and HIV (42 percent) [4,5].
TRANSMISSION — Infection is transmitted by transfusion of contaminated blood, through sexual contact, and via vertical transmission, similar to HCV and hepatitis B virus (HBV) [6,7]. Due to shared risk factors, co-infection with HIV-1 and/or HCV are high. (See 'Epidemiology' above.)
VIROLOGY
Composition and structure — HPgV-1 is a spherical enveloped virus approximately 50 nm in diameter [8]. HPgV-1 genome encodes a long open reading frame (ORF) that is translated into a single pre-polyprotein consisting of approximately 3000 amino acid residues. The coding region is flanked by long 5’ and 3’ untranslated regions (UTRs). The pre-polyprotein is cleaved into two structural proteins (envelope proteins E1 and E2) and six non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) by cellular signal peptidases and two viral proteases [9,10].
Genotypes — Based on genetic diversity, there are seven identified genotypes with varying global distribution. HPgV-1 genotypes 1 and 2 are prevalent in Africa [11]; genotype 2 is more prevalent in the United States and Europe [12,13]; genotype 3 is prevalent in Asia and South America [14,15]; genotype 4 and 5 in Southeast Asia [16]; genotype 6 has been reported in Indonesia [17]; and genotype 7 in China and Qatar [18].
NATURAL HISTORY AND CLINICAL IMPLICATIONS — HPgV-1 infection typically lasts for >6 months and is cleared spontaneously in more than 50 percent of infections within two years [19]. The exact role, if any, of HPgV-1 in producing disease in humans remains unclear [20]. HPgV viremia has been associated with an increased risk of lymphoma [21]. It may also have an impact on the disease course in patients with HIV or hepatitis C virus (HCV) coinfection. (See 'Impact on co-infections' below.)
Role in causing liver disease — The preponderance of evidence suggests that HPgV-1 does not cause hepatitis in humans [20,22]. In one report, approximately 75 percent of individuals positive for HPgV-1 RNA had normal serum aminotransferase levels [6]. While some studies suggested that HPgV-1 was associated with acute fulminant hepatitis [23,24], other reports have confirmed that the presence of HPgV-1 RNA in patients with fulminant hepatitis of unknown etiology was related to the administration of blood products after the onset of disease [25,26].
HPgV-1 RNA has been detected in patients with acute non-A to non-E viral hepatitis, in patients with chronic hepatitis of presumed viral etiology, in patients with cryptogenic cirrhosis, and in some patients with primary hepatocellular carcinoma. However, it is often difficult to tease out the direct role of HPgV-1 in these settings since coinfection with HCV is common [27]. There are no prospective studies that have documented histologically the progression from acute HPgV-1 infection through various stages of chronic liver disease, such as chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma. In patients with chronic non-A to non-E hepatitis or cryptogenic cirrhosis, there is no evidence that, if present, HPgV-1 is the cause of the disease, rather than being an innocent bystander [28,29].
Impact on co-infections
Patients with HIV co-infection
●Improved HIV outcomes — Accumulating evidence suggests a protective effect of HPgV-1 on patients co-infected with HIV [30-34]. In patients with HIV, HPgV-1 viremia has been associated with slower disease progression and lower mortality [32,35]. This was illustrated in a prospective cohort study of 271 men who were assessed for HPgV-1 viremia 12 to 18 months after HIV seroconversion and a subgroup of 138 patients who were evaluated again five to six years after HIV seroconversion [35]. At baseline, 231 men (85 percent) had evidence of current or previous infection. HPgV-1 status was not significantly associated with survival at 12 to 18 months following HIV seroconversion. However, patients with persistent HPgV-1 viremia five to six years after HIV seroconversion had significantly longer survival as compared with those without HPgV-1 RNA. The poorest outcomes occurred among the 9 percent of patients who lost HPgV-1 RNA between the two time points (relative hazard of death of 5.87 compared to those with persistent HPgV-1 RNA).
The protective effect of HPgV-1 may be related to maintenance of an intact T-helper 1 cytokine profile, the induction of HIV-inhibitory cytokines, and interference with HIV replication [36,37]. While the observations in these reports support further investigation into the mechanisms of interaction between HPgV-1 and HIV, the therapeutic implications remain unclear.
There is little information on the natural history of HIV and HPgV-1 co-infection in patients who are receiving antiretroviral therapy for HIV; but the available data suggest that the protective effect of HPgV-1 co-infection may be less apparent [38-40].
●No impact on vertical HIV transmission — HPgV-1 co-infection does not appear to mitigate or promote vertical transmission of HIV. In a retrospective cohort study of 186 pregnant persons with HIV, there were no differences in the rates of perinatal HIV transmission among the HPgV-1 RNA positive women and those without evidence of current or past HPgV-1 infection (28 versus 26 percent) [41].
Patients with HCV co-infection
●HCV and HPgV-1 co-infection – Coinfection with HPgV-1 does not appear to impact the clinical course or outcomes of HCV infection, HCV-related chronic liver disease, hepatic fibrosis, or transaminase levels. In one study of 189 patients with chronic HCV infection, 21 (11 percent) were positive for HPgV-1 RNA, and there was no significant difference in the course of the HCV infection and the response to interferon-alfa in patients with and without co-infection with HPgV-1 [42]. Interferon-alfa led to a decrease in HPgV-1 RNA titers that was not sustained after the cessation of therapy. Similar findings were noted in another study in which liver biopsies were performed [43]. Detailed histopathologic examination revealed no difference between the patients infected with HCV alone and the 15 percent who were co-infected with HPgV-1 [42]. Data on the effect of HPgV-1 infection on treatment of HCV with interferon-free therapies are lacking.
●HCV, HIV, and HPgV-1 co-infection – In patients with HCV/HIV coinfection, HPgV-1 viremia has been associated with a significant reduction in HCV-related liver morbidity. In a study of 158 HCV/HIV co-infected patients, in which 57 (26 percent) patients had HPgV-1 RNA and 94 (59 percent) had evidence of past exposure based upon results of antibody testing, active HPgV-1 was independently associated with a significant reduction in the risk of compensated and decompensated cirrhosis (HR 0.27, 95% CI 0.08-0.88) [34].
DIAGNOSTIC TESTS — Active infection is diagnosed by detecting its RNA in the serum by polymerase chain reaction. However, the sensitivity and specificity of this test are not known [2] and may significantly underestimate the true incidence of infection [44]. Appearance of antibodies to the major viral envelope glycoprotein (E2) are associated with the clearance of viremia [45]. There are no commercial assays available for either HPgV-1 antibodies or RNA.
NO ROLE FOR ROUTINE BLOOD DONOR SCREENING — Routine screening for HPgV-1 is not performed in blood donors. Whether donor blood should be screened for HPgV-1 and other viruses that have been discovered in human blood but are not known to cause disease is a contentious issue.
Arguments against donor screening include:
●The potential for high donor loss.
●The apparently very low incidence of posttransfusion hepatitis [46].
●The apparently mild disease when acute hepatitis does occur.
●The lack of proof that chronic liver disease occurs with HPgV-1 infection.
●The apparently very low disease burden due to HPgV-1.
●The difficulty in counseling otherwise healthy blood donors.
SUMMARY AND RECOMMENDATIONS
●Prevalence – Human pegivirus (HPgV-1), previously designated hepatitis G virus (HGV) and GB virus type C (GBV-C), has a global distribution. It is estimated that one-sixth of the world population is seropositive for HPgV-1, and approximately 750 million individuals have had viremia. (See 'Epidemiology' above.)
●Virology – HPgV-1 is a single-stranded positive RNA virus belonging to the Flaviviridae family. It is a spherical enveloped virus approximately 50 nm in diameter. Based on genetic diversity, there are seven identified genotypes with varying global distribution. (See 'Genotypes' above and 'Composition and structure' above.)
●Transmission – HPgV-1 is transmitted by transfusion of contaminated blood, through sexual contact, and via vertical transmission. Active infection is diagnosed by detecting its RNA in the serum by polymerase chain reaction. However, the sensitivity and specificity of this test are not known. (See 'Transmission' above and 'Diagnostic tests' above.)
●Natural history – HPgV-1 infection typically lasts for >6 months and is cleared spontaneously in more than 50 percent of infections within two years. Appearance of antibodies to the major viral envelope glycoprotein (E2) is associated with the clearance of viremia. (See 'Natural history and clinical implications' above.)
●Clinical significance
•The preponderance of evidence suggests that HPgV-1 does not cause hepatitis in humans. However, viremia has been associated with an increased risk of lymphoma. (See 'Role in causing liver disease' above.)
•In patients with HIV, HPgV-1 viremia has been associated with slower disease progression and lower mortality. (See 'Patients with HIV co-infection' above.)
•In patients with HIV/hepatitis C virus (HCV) coinfection, HPgV-1 viremia has been associated with a significant reduction in HCV-related liver morbidity. (See 'Patients with HCV co-infection' above.)
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