ARCH GASTROENTEROHEPATOLOGY 2001; 20 ( No 1 – 2 )
GB virus-C
/ Hepatitis G Virus: A hepatitis virus or not, is the dilemma finally solved?
GBV-C/Hepatitis G Virus: Virus hepatitisa ili ne, da li je dilema kona~no re{ena?
Institute for Infectious and Tropical Disease, Clinical Center of Serbia, Belgrade, Serbia, Yugoslavia.
( accepted March 3rd, 2001 )
Address correspondence to: Professor Neda Svirtlih, MD, PhD,
Institute for Infectious and Tropical Disease
Clinical Center of Serbia,
Bul JA 16, YU-11000 Belgrade,
Serbia, Yugoslavia
FAX: + 381 11 684 272,
E-mail: [email protected]
Abbreviations used in this article: AIDS, acquired immunodeficiency syndrome; anti E2 antibody, antibody to the second envelope protein; bDNA, branched-chain DNA; GBV-A, GB virus A; GBV-B, GB virus B; GBV-C, GB virus C; GBV-C/HGV, GB virus C/ hepatitis G virus; ELISA, enzyme-linked immunoabsorbent assay; FHF, fulminant hepatic failure; IDU, intravenous drug user; IFN-a, interferon-alpha; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HGV, hepatitis G virus; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; HVR, hypervariable region; non A-E hepatitis, non A, B, C, D, E hepatitis; ORF, open reading frame; PCR, polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; TAH, transfusion-associated hepatitis. UTR, untraslated region
GB virus-C, or Hepatitis G virus is a new human virus identified in 1995-1996. It is classified as a member of the Flaviviridae family. The virus is similar, but not identical to hepatitis C virus. The virus contains a postitive-stranded RNA , which encodes a nucleocapsid and two putative envelope glycoproteins. The main route of transmission is parenteral, less frequently are sexual or perinatal. The virus is characterized by a long-time persistence in humans with currently unknown mechanisms. It can replicate in many different cells and tissues, but the primary site of its replication is still unrecognized. The GB virus C/hepatitis G virus is spread worldwide with higher prevalence rate than hepatitis C virus. According to reported data, there are no conclusive evidences for causal link between this virus and either acute or chronic liver disease. Without confirmations that this virus has features of classical hepatotropic virus, GB virus-C/ hepatitis G virus cannot be accepted as a “hepatitis” virus.
Key words: GBV-C/HGV, hepatitis.
GB virus C /Hepatitis G je virus koji je zarazan za ljude. Otkriven je tokom 1995 i 1996 godine. Svrstan je u familiju Flaviviridae. Po svojoj strukturi je sli~an hepatitis C virusu. Sastoji se od pozitivnog lanca RNA iz koga nastaju protein jezgra i dva glikoproteina omota~a. Naj~e{}e se prenosi parenteralno, re|e seksualno ili perinatalno. Virus mo`e dugo da se odr`ava u organizmu za sada jo{ uvek neutvrdjenim mehanizmima. Dokazano je da se razmno`ava u razli~itim }elijama i tkivima iako primarno mesto njegovog razmno`avanja jo{ nije defnitivno utvr|eno. Virus je ra{iren u celom svetu i prevalenca mu je ve}a od hepatitis C virusa. Iz publikovanih podataka, nema ubedljivih dokaza o uzro~noj vezi ovog virusa i akutne ili hroni~ne bolesti jetre. Kako nije dokazano da poseduje osobine koje imaju klasi~ni hepatotropni virusi, za GBV-C/HGV ne mo`e da se tvrdi da je virus koji uzrokuje hepatitis kao ni da se naziva virusom hepatitisa.
Klju~ne re~i: GBV-C/HGV, hepatitis.
During 1995 and 1996, two independent groups of investigators identified and partially characterized three new RNA viruses related to hepatitis C virus (HCV). The source of viral isolates was the serum from the patient GB (34-old surgeon GB who contracted hepatitis). The isolation of these viruses was possible because of the ability of the agent, namely “GB agent”, to infect and passage in monkeys over the years.
Chronologically, in 1995 the Virus Discovery Group at Abbott Labs identified two RNA viruses from tamarine: GB virus-A (GBV-A) and GB virus-B (GBV-B) (1). After isolation of these viruses, they identified several novel genome sequences from human sera of twelve patients, including four with hepatitis (2,3). The limited nucleotide sequence identity between GBV-A, GBV-B and hepatitis C virus (HCV), suggested that it was a novel virus, tentatively named “GB virus C” (GBV-C). Moreover, they presumed that GBV-C virus could be responsible for some cases of non A-E (non A,B,C,D,E) hepatitis.
At the same time, another group at Genlabs Technologies identified and determined the complete sequences of a viral genome, which they termed Hepatitis G Virus (HGV) (4). They used the serum from the patient with chronic HCV hepatitis and identified several unique sequences of a genome that did not belong to HCV. From these sequences a polymerase chain reaction (PCR) method was used to amplify overlapped clones for the entire viral genome. They also confirmed that the isolated virus was transfusion-transmissible. The polyprotein sequence identities between of the virus they have discovered and other three viruses: GBV-A, GBV-B and HCV, were 43.8%, 28.4% and 26.8%, respectively. Finally, they confirmed that HGV was 85.5% identical in nucleotide sequence and 100% identical in amino acid sequence to the corresponding portion of GBV-C that had been characterized by Abbott group.
Based on genome and amino acid sequence comparisons, it was concluded that GBV-C and HGV were variants of the same virus. Since a nomenclature of this novel virus is not decided definitely, three terms are equally in use, e.g., GBV-C, HGV and GBV-C/HGV.
From that time, numerous investigators become extensively engaged to determine the significance of this new virus. They evaluated its molecular characteristics, routes of transmission, pathogenicity and finally, clinical implications in the liver disease.
Classification and viral characteristics
Virus GBV-C/HGV is classified as a member of hepacivirus genus within the Flaviviridea family (5). Like HCV, GBV-C/HGV contains a positive-sense single strand RNA genome, approximately 9.4 Kb in length, with a long open reading frame (ORF). This ORF encodes a single polyprotein with 2873 amino acids (2,4). Investigations based on analyses of amino acid sequences, revealed that the predicted GBV-C/HGV polyprotein contains two putative envelope proteins (E1 and E2), a trypsin-like serine protease, and RNA-dependent RNA polymerase. One difference between this virus and HCV is in a limited homology between the amino terminus of GBV-C/HGV polyprotein and HCV core protein. In different isolates, the putative core GBV-C/HGV protein appeared truncated or even absent. It raised very interesting questions about the structure of the virus that could be a precedent in currently identified RNA viruses. Thus, these data enabled speculations that the biophysical structure of GBV-C/HGV could be different from HCV or other flaviviruses, perhaps producing particles without nucleocapsid (6). Also, some investigators considered that GBV-C/HGV for its complete organization and effectiveness, could utilize a cellular protein or a protein from another coexisting virus such a HCV, by analogy to hepatitis D virus. This problem was solved after first characterization of GBV-C/ HGV particle types in 1998 (7). The investigators indicated that GBV-C/HGV virus was consisted of extremely low-density virion (1.07-1.09 g/ml), and a nucleocapsid of 1.18 mg/ml. Evaluation of the buoyant density of GBV-C/HGV enabled characterization of particles consistent with nucelocapsid. Additionally, electron microscopy analysis demonstrated an apparent nucleocapsid within an envelope protein (8). Finally, current data about GBV-C/HGV genomic structure indicate that its genome, besides coding for structural proteins of the viral core and envelope (core, E1, E2), also codes for a number of nonstructural proteins that are important during viral replication (NS2-NS5).
Sequence analysis of the main terminal 5’-untranslated region (5’-UTR) showed a certain degree of heterogeneity among different isolates. This domain of GBV-C/HGV is relatively lengthy and does not share a significant primary or secondary structure with the same domain of HCV. Construction of phylogenetic trees for putative RNA helicase and RNA-dependent polymerase of the Flaviviridae, confirmed that HCV was closely related to GBV-B, but GBV-C was more nearer to GBV-A (9).
Based on the study of 44 sequences around the world, the existence of three groups (not completely characterized as genotypes), were initially proposed. They correlated with their geographic origin: group 1 (West African), 2 (North American, US, European), and 3 (Asian, mainly Japanese) (10,11). The first two groups include two subgroups, designated as a and b. Further analyses identified many other isolates that are deposited in GenBank database and utilize for ratification and confirmation of eventually new viral variants (12,13,14,15,16). Very recently, novel viral variants were discovered and named as group 4 and 5 (South African) (17,18). The significance in differences of viral groups is mainly in their use for epidemiological studies. Also, it is under extensive investigations if any specific viral group type could be important in pathogenesis of the liver disease.
Structural comparison of the 5’UTR domain between GBV-C/HGV and HCV suggests that these two viruses may have separate evolutionary pathways. Moreover, phylogenetic analysis of GBV-C and GBV-A suggests that these viruses may have a common ancestor (19). Mechanism of co-speciation could be involved in virus evolution over a period of 35 million years (20).
Similarly to HCV, several genome variations were found in NS3 region of the GBV-C genome, designated as quasispecies (20,21). The study of heterogeneity of GBV-C/HGV in comparison with HCV, showed that the mean genetic distance among former viral strains was significantly lower (22). Recent analyzes of the extent of diversity using different genome regions, suggested that in one persistently infected individual, it could differ from each other at 0.23%- 0.84% of nucleotide position and at 0.42%-0. 61% of amino acid position (23). Moreover, similar mutation patterns were demonstrated among GBV-C/HGV, HCV and human pseudogenes, but not in human immunodeficiency virus (HIV) (24). It means that nucleotide analogues as effective therapy in HIV infection used against HCV and GBV-C/HGV infections, could have side effects on the normal cells of humans.
Viral diagnosis and its significance
Ribonucleic acid of GBV-C/HGV was first isolated by PCR amplification method. (1,2,3,4). More sensitive method with reverse transcription (RT-PCR) and bDNA (branched-chained DNA) methods are currently in use in most laboratories. Both methods enable discovering the presence of the virus in sera, different body fluids and tissues. Discovering the viral RNA allows to analyze and follow-up the duration and outcome of GBV-C/HGV infection. That is of particular interest for the viral persistence. Also, these methods can be used for detection of very small amounts of the virus after liver transplantation or grafts re-infection (25,26,27,28). Also, detection of viral RNA and its sequence analysis are important for evaluation of the viral tropism (29). Detection of positive or negative strands of viral RNA (as well as other intermediates in viral replication), or in situ hybridization, can help to determinate the primary site of the viral replication (30,31,32). Furthermore, by quantitation of GBV-C/HGV RNA, it is possible to evaluate final effects of antiviral therapy (33,34,35). Sequences analyses of some genome regions that express clustering between individuals (family members, mother and child or among spouses, etc.), may help to confirm a source of infection that is usable in epidemiological studies for the viral transmission (36,37). In spite of all advantages of these diagnostic methods, problems of their standardization and commercial production for GBV-C/HGV are still unresolved (38,39).
After discovering of GBV-C/HGV RNA, an assay for detection of antibody to the second envelope protein (anti E2 antibody) of GBV-C/HGV was developed (40). Recombinant GBV-C/HGV envelope protein E2 was used as antigen in an enzyme-linked immunoabsorbent assay (ELISA). It was noticed that the clearance of viremia in selected group of patients was followed by the appearance of anti E2 antibody. Other studies using simultaneous viral markers (anti E2 and RNA), demonstrated that the existence of anti E2 antibody and viral RNA were mutually exclusive. All these findings confirmed these antibodies as the evidence for successful immune response (41,42,43,44,45). Also, it was demonstrated that the immunity to GBV-C/ HGV infection is long lasting and at last, these anti E2 antibodies if presented in pre-transplantation sera, were shown as protective against graft re-infection (46,47). Anti E2 antibodies are currently available for commercial use.
Epidemiology
Transmission
Virus GBV-C/HGV was initially discovered as transfusion-transmissible virus, potentially causing transfusion-associated hepatitis (TAH) (1,4). After that time, numerous studies were done to investigate the presence of the virus in sera of different individuals. They revealed particular groups at increase risk for viral transmission: patients with history of transfusion of whole blood or blood products (e.g., coagulation factors concentrates, plasma, immunoglobulins etc.); intravenous drug users (IDUs); patients maintenance on hemodialysis; patients with history of tattoo, acupuncture, etc. (49,50,51,52). Investigators reported that detection of GBV-C/ HGV in commercial blood donors was approximately in a half of them and also, that transmission of the virus was more frequent in patients who received non virus-inactivated blood products (53,54). It was also noticed that same routes of transmission of blood-borne viruses, such as HCV, HIV and Hepatitis B Virus (HBV), enabled their common infection with GBV-C/HGV. Moreover, it was reported that transmission of HGB-C/HGV was more frequent among patients with these co-infections (50,54,55).
Discovering the persistence of the virus in individuals without data of exposure to blood or blood products indicated the possibility for other routes of viral transmission. Viral infection, especially with the same strain among sexual partners and from mothers to their children, give rise of possibility of sexual and vertical transmission. Investigating the presence of the virus in couples demonstrated that sexual/close contacts with steady partners decreased the frequency of infection. As well, investigation among prostitutes confirmed that a number of sexual intercourse and age of prostitutes increased the chance for infection (56,57,58,59). Taken together, many authors agree that although sexual contact with infected partner is a risk for infection with GBV-C/HGB, it has lower importance that parenteral transmission (60). On contrary, perinatal transmission seems significantly high in generally (33,3%-80%) (36,61,62,63,64,65,66). It is more frequent than perinatal infection of HCV (2.8%-4.2%) (36). According to investigations, perinatal transmission is stressed as particularly hazardous for babies whose mothers have high viral load, are anti HCV or/and anti HIV positive as former drug users (36,67). In this type of transmission, intrauterine or birth canal infection seem more important than the infection by breast-feeding because it was not possible to detect the virus in breast milk (68). However, the majority of infants born from virus-positive mothers are already viral positive, so it is not advisable to discourage mothers from breast-feeding.
Finally, some unknown horizontal routes of GBV-C/HGV infection may also exist. One of them is its transmission among family members (37,70).
Prevalence
The prevalence of GBV-C/ HGV depends on several factors, mostly on exposure to parenteral infection. Other important factors are co-infection with another blood-borne viruses (HCV, HBV, HIV, etc.), sexual or close contacts with infected individuals, and maternal infectivity.
Geographically observed, GBV-C/GHB RNA has been detected in healthy population in 1-7% in the United States (4,71,72). Interestingly, a high prevalence rate (6%) was detected in children and younger adults without any known risk factor (73). In children co-infected with HCV, the prevalence rate was estimated in 11%. Oppositely to US, in Japanese children the prevalence rate of GBV-C/HGV was found in 0.5% (63). In Western countries, according to summarized data from 1999, the prevalence of GBV-C/HGV has been estimated approximately in 1-10% (74). Separately reported data from France, Germany, Spain, Italy, Czech, Greece, Norwegian and Scotland, confirmed GBV-C/HGV RNA prevalence rate in blood donors in 4.2%, 1.9-3%, 0.5-9,7%, 1.2-3%, 2.15%, 10%, 2.5%, and 2.25%, respectively (51,59,75,76,77,78,79,80.81,82). Authors from Japan reported the prevalence rate in 0.5-1.7% (45,63,83,84,85). Reports from Japan, but also from other geographic regions, presented higher prevalence of GBV-CHGV in patients simultaneously infected with HCV and HIV, particularly in HCV endemic areas (45). In other countries from Asia, the prevalence of GBV-C/HGV RNA was detected in Taiwan, India, Saudi Arabia and China in 3%; 4%, 0.5-2% and 1% respectively (52,54,86,87). The prevalence of 5.85% was reported from Brazil (37). The prevalence in high-risk groups was reported in patients maintenance on hemodialysis, patients with thalasemia and/or hemophilia, i.v. drug abusers and prostitutes in 3.9-57.5%, 19.7-37.6%, 19.3-54%, and 13-24.8%, respectively (48,51,54,58,80,84,86,87,88,89). Frequent infection of GBV-C/HGV in these groups of patients explains their exposure to multiple transfusions, common co-infections with other viruses and close contacts with infected individuals (90,91). For example, the investigation of GBV-C/HGV RNA in virus non-inactivated plasma, determined the presence of the virus in 9% of samples (53). It is interesting that in patients with extrahepatic malignancies and without history of transfusion, the prevalence of the virus was found in a higher rate than in general population (12.5% vs 4.5%) (92).
Analyzing reported prevalence rate of GBV-C/HGV worldwide, it must be mentioned that results are very overlapping. Existed differences mostly depend on techniques that were used in PCR technology (e.g., type of primers), or problems in method standardization between laboratories. Also, determination of antibodies to envelope protein (E2), was not done in all studies. Authors who investigated both viral markers (RNA and antibodies), mostly concluded that the antibody prevalence was significantly higher than the prevalence of the virus (80% vs 20%) as the confirmation that the majority of individuals can resolve the infection. It also demonstrates that the infection with this virus is more frequent than if it is presented only by RNA prevalence.
The evident epidemiological conclusion of GBV-C/HGV infection worldwide is about its generally high frequency. With some exeptionals, the prevalence of GBV-C/HGV is even higher than HCV. From that point of view, recommended measures for prevention of HCV infection, may be also useful to prevent routes of GBV-C/HGV transmission.
Pathogenesis
At this time, the pathogenesis in GBV-C/HGV is under extensive research. Of particular interest are attempts to explain two mechanisms in GBV-C/HGV that are basic in pathogenesis: the viral persistence and its hepatotropism.
Majority of the authors agrees that GBV-C/HGV has ability to replicate in the host for many years producing chronic viral infection (93,94) For example, the rate of persistent infection via natural infection after blood transfusion is approximately 10-30% (95,96). It was reported that de novo infection after liver transplantation was 46.2% and re-infection of the graft was 85.7%, that presumed even higher persistence in such cases (97). Follow-up of infants born from virus positive mothers discovered viral RNA after 12 and 24 months in 91% and 57% (98). In other study of children with HCV co-infection receiving blood transfusion in perinatal period, viral RNA was found in 7.6% after 12-17 years (99).
In contrast to HCV, humoral immune response to GBV-C/HGV expressed as the presence of anti E2 antibodies, is effective. Viral RNA never reappeared after its clearance following by detectable antibodies (44,46).
It is also confirmed that GBV-C/HGV characterizes genome stability and absence of the hypervariable region (HVR) in the E2 domains (22,46). It is generally accepted that the host’s immune response is not able to “pressure” the virus to produce novel mutations in that domain that allow virus to continue to multiple. Although, some viral quasipecies were discovered from different tissues, they reflect heterogeneity from other domains, mostly non-structural (NS3) (20,100). It could not be excluded that these quasispecies may have some influences on clinical course or therapy outcome. However, the existence of “escape” mutants and antigen drifts that evade the immune response in pathogeneity of this virus similar to HCV does not seem reliable.
Many other factors may be candidates to contribute in viral persistence but they are not sufficiently examined. For example, investigation of the human leukocyte antigen (HLA) in GBV-C/HGV infection demonstrated some linkages of the virus and particular haplotypes (e.g., HLA DQ7, DR15 and DR8) (101). Additionally, there are very strong suggestions that the virus replicates in lymphocytes, Kupffer cells and endothelial cells (102,103,104). If the virus damages these cells, it may impair their functional efficiencies of antigen presenting, cellular killing and other important mechanisms in immune response (102,103,104). Fortunately, successful transmission of the virus to monkeys and novel culture and cellular systems that are under development, will be useful to study the relation between the virus, host, and their interaction in the future (105,106,107).
The issue about the viral capability to replicate in hepatocytes is also very contradictory. After discovering the viral RNA in sera, many investigators looked for its negative sense (minus-RNA) in the liver and other tissues in order to locate the primarily site of viral replication. Some of them had shown that the virus primarily replicated in the liver, but majority excluded such finding (27,30,31,108,109,110). Evidences against the viral replication in the liver came from simultaneous findings of viral RNA in sera in higher amounts than in the liver. Detectable of viral RNA in the liver is often explained by contamination with circulating virus from sera (32,34). Recent arguments against primarily viral replication in the liver were evidences of negative sense of viral RNA founded in spleen and bone marrow. These findings were so convincing that GBV-C/HGV was described as primarily lymphotropic virus (111,112).
More recent reports of viral tropism are still opposite and controversial. One is the report with viral replicate intermediates detected by in situ hybridization in cytoplasm of hepatocytes in 67% (113). In the other, CD4+ cells were successfully infected with full length of viral RNA (107). It seems according to all data that the GBV-C/HGV is not definitely confirmed as a primarily hepatotropic virus, although it can replicate in small amounts in the liver. Although evidence of viral replication in lymphocytes is intriguing, it is already known for other hepatotropic viruses. It may resemble to cytomegalovirus or Ebstein-Barr virus but it is also not in concordance with clinical manifestation of GBV-C/HGV infection.
Clinical characteristics
Acute hepatitis
It is generally accepted that clinical manifestations of GBV-C/HGV infection are very mild or even absent. Most of patients with GBV-C/HGV have no any sign of acute or chronic hepatitis, although they are infected for years.
Investigations of the role of GBV-C/HGV in TAH confirmed its incidence in idiopathic, non-A-E hepatitis, in 3.1- 29.1% ( (72,80,95,114,115). These different findings can be explained by frequent simultaneous co-infections with HCV and HBV in connection with their different geographical distributions. Of important is to mention that in all studies, the incidence of GBV-C/HGV in non A-E TAH was significantly higher than its prevalence rate in blood donors. At the same time, in the majority of non A-E TAH, the incidence of GBV-C/HGV was lower than in TAH associated with other hepatitis viruses. From all these epidemiological data, it is under the question whether GBV-C/HGV has any causal role in TAH.
Clinically, idiopathic TAH with detectable GBV-C/HGV RNA was described as mild disease, without jaundice and with normal or slightly elevated aminotransferases (72,95,115,116,117). Also, in almost all patients, clinical sings were absent, although the virus continued to replicate in some cases (72). Following the appearance of viral RNA in sera, authors concluded that the incubation period for GBV-C/HGV infection was between 1-20 weeks after blood transfusion (95,118). It was also noticed that the presence of GBV-C/HGV did not worsen the course of acute HCV hepatitis (72). As exception from these findings, more severe clinical form in GBV-C/HGV positive idiopathic TAH was described in Italy (80). Finally, a large retrospective collaborative study of morbidity and mortality in non-A-C TAH was done and reported in the last issue of Hepatology, February 2001 (119). In this report, the authors strictly excluded the GBV-C/HGV as the responsible etiological factor in TAH and its eventual consequences, even in anti HCV-negative cases.
The role of the GBV-C/HGV in fulminant hepatic failure (FHF) is also controversial. In FHF viral RNA was detected in 16-38,8% (120,121). Some investigators used different primers for the RNA detection and reported a lower incidence (4% -10%) (123). Additionally, particular mutations were found in FHF and it gave the explanation of this serious disease in the possibility of these variants for different tropism and patogenicity (123). Other investigators did not confirm the influence of these mutations and moreover, they found the same viral mutations in healthy individuals (124). Earlier report from Japanese authors about the significant role of GBV-C/HGV in FHF was not confirmed. Detection a high prevalence rate of the virus in patients with FHF underlying liver transplantation had arguments in use of intensive supportive measures with multiple blood transfusions and blood products infected with the virus (117,122,125,126).
Taken together, it is not most likely for the reliable causal relation between acute hepatitis, including FHF, and GBV-C/HGV infection.
Chronic hepatitis
In spite that GBV-C/HGV can persist, the existence of chronic hepatitis caused by this virus is also obscure. From the etiological point of view, numerous attempts to detect HGV-C/HGV RNA in various chronic liver diseases had been done. From these data, the prevalence rate of the virus did not show convinced differences between groups of chronic hepatitis of known etiology (viral hepatitis B, alcoholic hepatitis, autoimmune hepatitis), and between these groups and cryptogenic liver disease. The exception from these findings was only found in co-infection with HCV. As illustration, in cryptogenic liver disease, the prevalence of GBV-C/GBV was detected in 8-25.4% (4,87,95,127,128). The investigation of multiple clinical, biochemical and histological data could not confirm the significant role of the virus in this liver disease (90,95,127,129). Further, detection of GBV-C/HGV in chronic hepatitis B, alcohol liver disease, autoimmune hepatitis was confirmed in 8-10%, 2-10% and 8%, respectively (4,87,95).
Special attention was given to investigate the presence of GBV-C/HGV in chronic HCV hepatitis. The estimated prevalence rate was detected in 5-26.5% (35,50,90,93,130,131,132). The mean prevalence rate was approximately 20%, but prevalence rate of 5% and 51% was also reported (35,133). However, investigations of significant influence of GBV-C/HGV on clinical and biochemical characteristics, HCV RNA viral load and response to interferon-alpha (IFN-a) therapy, could not been confirmed (35,90,93,95,127,130,132,133).
Histological evaluations of chronic hepatitis with detectable GBV-C/HGV mostly showed a hall mark of steatosis with mild portal inflammatory lesions, some fibrous enlargement of portal tracts and thin fibrous septa (130,134,135,136). In comparison with chronic HCV hepatitis, no particular features were noticed. Recently, an interesting exception from earlier studies was observed that suggested the important histological influence of GBV-C/HGV in HCV chronic hepatitis (137). Significantly more severe bile duct damage, perivenular fibrosis, pericellular fibrosis and irregular regeneration of hepatocytes were seen in GBV-C/HGV-positive patients in comparison with patients without this virus.
Most authors that evaluated IFN-atherapy concluded that GBV-C/HGV was sensitive to this antiviral treatment (33,35,130). Moreover, they also reported that effects of therapy in HCV positive patients was not dependent on the presence of GBV-C/HGV. The effect of IFN therapy strictly depended on pre-treatment viral load (138). Unfortunately, a low rate of sustained response was noticed. Recent data raise the possibility that positive selection may act over GBV-C/HGV genome during interferon therapy, and contribute to the persistence with this virus (100). This finding is important and needs further confirmations.
Numerous studies from transplantation units reported that the presence of GBV-C/HGV did not correlate with severity of the post-transplantation liver disease or graft survival (25,26,28).
Similar findings were reported in evaluation of the correlation between hepatocellular carcinoma (HCC) and the presence of GBV-C/HGV. Investigations of viral RNA in sera of patients with HCC and chronic liver diseases of different etiology, as well as detection of its nucleid acids in the liver tissue, did not find any association between GBV-C/HGV and HCC (139,140,141).
Significant attention was given to investigate the role of GBV-C/HGV in the liver disease of children. The report from the United Kingdom in 1997, indicates negative causative relationships between the presence of GBV-C/HGV and specific chronic liver disease in children (142). Moreover, the virus did not produce any effect on clinical course of HCV and given IFN therapy. In another study investigators also did not confirm any clinical, histological or virological differences among two groups of children (with and without HCV co-infection), except in children with malignancies (143). Therefore this virus was not considered as important aetiological agent in paediatric liver diseases (36,143). It must be mentioned that it was found that the majority of HGV infected children had active viral infection wheather or not co-infected with HCV, (98,143). Unfortunately, there is the report of negative experience with serious side effects to applied IFN-atherapy in 12-old girl co-infected with HCV that required emergent discontinue of the therapy (144).
While co-infection with HCV in HIV infection is verified as opportunistic infection, investigations in patients with GBV-C/HGV and HIV infection showed completely opposite findings. Namely, in both infections, patients had higher number of CD4+ counts and higher survival rate of AIDS than patients with HIV infection alone (57,145,146). Until now, there is no convincing explanation for these phenomena. Moreover, current antiviral drugs used in HIV infection is not effective for GBV-C/HGV, as it is true for IFN-a(147).
Conclusion
According to reported and summarized data, there is no strong evidence for causal link between GBV-C/HGV infection and the liver disease. Almost all clinical studies failed to confirm its specific disease association. Moreover, there is no significant evidence that GBV-C/HGV is even a primarily hepatotropic virus. GBV-C/HGV is obvious a human flavivirus and can persist in humans, but this virus has no complete criteria to be accepted and called a “ hepatitis “ virus.
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