Ignite Creation Date:
2024-05-05 @ 11:54 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00164060
Status:
TERMINATED
Last Update Posted:
2013-12-05
First Post:
2005-09-13
Brief Title:
Associations Outcomes and Genomics of GB Virus C Hepatitis C Virus and Human Immunodeficiency Virus Infection
Sponsor:
Bayside Health
Organization:
Bayside Health
Study Overview
Official Title:
Associations Outcomes and Genomics of GB Virus C Hepatitis C Virus and Human Immunodeficiency Virus Infection
Status:
TERMINATED
Status Verified Date:
2005-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to examine the effect of GB virus C GBV-C on the natural history of chronic hepatitis C virus HCV infection in subjects co-infected with HIV and HCV The other aspect of the study is to assess the effect of GBV-C on the severity of liver disease due to chronic hepatitis C in subjects co-infected with HIV and HCV This will be done by determining the point prevalence of co-infection retrospectively then following that cohort prospectively In addition further individuals will be recruited in a prospective manner
Detailed Description:
Background and Research Plan
GBV-C and hepatitis G virus HGV are both RNA viruses from the Flaviviridae family Molecular characterization of these viruses has shown them to be virtually identical to each other 12 GBV-C was first isolated in 1995 from an archival blood sample obtained in the 1960s from a surgeon with acute non A-E hepatitis 3 GBV-C has a 29 amino acid sequence homology with Hepatitis C Virus HCV another flavivirus 4 However GBV-C in contrast to HCV is not hepatotropic as the virus neither replicates primarily in hepatocytes nor causes acute or chronic hepatitis Indeed GBV-C does not cause any specific disease nor does it represent a substantial health risk in humans Nevertheless GBV-C infection is relatively common with a 2 prevalence rate in healthy blood donors the majority of whom clear the virus and develop antibodies to the envelope glycoprotein E2
HIV infection has a particularly high rate of co-infection with GBV-C Studies suggest that co-infection leads to a beneficial effect on the course of HIV 567 with co-infection associated with a significantly lower mortality rate among HIV-infected subjects compared to those not infected with GBV-C The mechanism of the beneficial effect of GBV-C on the course of HIV infection is obscure
Among new cases of non-A non-B hepatitis in the United States 18 percent are positive for GBV-C and 80 of these patients are also infected with HCV Amongst patients with HCV 10-20 have GBV-C RNA in their serum 4 In another report 189 patients with chronic HCV infection were evaluated 21 11 were positive for GBV-C RNA 8 The course of the HCV infection and the response to interferon-alfa were not affected by co-infection with GBV-C Interferon-alfa led to a decrease in GBV-C RNA titers that was not sustained after the cessation of therapy Similar findings were noted in another study in which liver biopsies were performed 9 Detailed histopathologic examination revealed no difference between the patients infected with HCV alone and the 15 percent who were co-infected with GBV-C There have been no studies to date looking at the effect GBV-C HCV and HIV have on each other
Our previous studies into HIV and GBV-C have suggested that co-infection is common Active GBV-C infection is frequently observed in persons involved in high-risk sexual activity and with HIV infection Homosexual intercourse appears to be a more effective means of transmission of GBV-C GBV-C has the same epidemiology and transmission as HIV and underlines the intimate association between GBV-C and HIV 10
MethodsExperimental Design
Stored sera is available from people who have attended the Hepatitis and HIV clinics at the Alfred Hospital Sera is available back to approximately 1990 and has been stored at minus 20ºC and as such is suitable for GBV-C detection particularly RNA by PCR Of the sera stored by the HIV clinic 203 patients are known to be co-infected with HCV who are currently still alive Once ethics committee approval is obtained we propose to contact these groups of people and see if they would participate in this study Once consent is obtained we plan to perform the following
A Stored sera will be retrospectively examined for the point prevalence of infection with HCV GBV-C and HIV These individuals will then be followed up in a prospective manner assessing the progression of liver disease and other factors as outlined in Tables 1 to 4
B New subjects attending the Alfred Hospital Hepatitis or HIV clinics will be recruited and followed prospectively also as outlined in Tables 1 to 4
C An age and sex matched control group infected with HCV alone will be identified via the Alfred Hospital Hepatitis clinic This clinic has a large cohort of well-characterized HCV infected subjects that extends back to 1989
The inclusion and exclusion criteria for the study are as follows
Inclusion criteria
1 Sera available and appropriate for testing Including serial sera over a period of time retrospective analysis
2 HIV serology positive
3 Unequivocal HCV antibody positive or HCV RNA positive
Exclusion criteria
1 Those without sera available
2 Those unwilling to give informed consent
3 Persons with Hepatitis B Virus infection as defined by the presence of Hepatitis B surface antigen andor Hepatitis B Virus DNA positive
Where possible information will also be obtained about these people by interview examining the medical records or discussion with their General Practitioners Subjects will also be encouraged to attend the hospital in person where a clinical exam can be performed If insufficient sera is stored further blood will be drawn at this time and examined for HCV HIV and GBV-C related parameters as outlined in the tables below A study specific questionnaire will be generated in which subjects will be asked to complete a confidential questionnaire that contains information related to demographic and behavioral factors that may contribute to the acquisition of GBV-C HCV or HIV infection or various combinations of the above Demographic variables will include age sex country of birth and occupation Information relevant to HIV infection including the use of HAART and the presence or absence of AIDS defining syndromes will be obtained The questionnaire will attempt to identify the approximate time of acquisition of both HCV and HIV In addition the extent of liver disease will be assessed alcohol consumption will be quantified and information will be gathered on previous treatment with Interferon and Ribavirin
The main outcomes of this study will be liver related morbidity such as chronic hepatitis cirrhosis or hepatocellular cancer and overall patient survival The detailed information contained in the following tables will be obtained from interview medical records and clinical examination
Table 1 GBV-C
1 Testing sera for GBV-C RNA and E2 antibodies to GBV-C
2 Performing testing at one-year intervals if sera is available
Table 2 HIV
1 CD4 count buffy coat in HIV positive
2 HIV viral load
3 Use of highly active antiretroviral therapy HAART and other retroviral treatment andor change in treatment
4 Complications of HIVAIDS and AIDS defining illnesses
Table 3 Liver disease HCV
1 HCV viral load and genotype
2 Child-Pugh classification based on levels of bilirubin albumin and clotting profiles and the presence of ascites and encephalopathy
3 Complications of liver disease ascites encephalopathy variceal bleeding and hepatocellular carcinoma
4 ALT and AST levels as well as ASTALT ratio
5 Alpha Feto Protein AFP level
6 Liver histology at biopsy with assessment of inflammation grade stage of fibrosis and severity of hepatic steatosis
7 Liver ultrasound results
8 Results of endoscopy ie features of portal hypertension
Table 4 Survival Data
1 Has patient died
2 Date of death
3 Cause of death
Results will be statistically examined by univariate and multivariate analysis in terms of clinical outcomes with respect to chronic hepatitis C liver disease between GBV-C positive and negative groups in the HIV co-infected cohort compared with the HCV infected cohort alone See following Table 5
Table 5 Study Design
Study Group No1 HCV ve HIV ve GBV-C RNAve Study Group No2 HCV ve HIV ve GBV-C RNA-ve Control Group HCV ve alone
References relevant to this project from literature search
1 Linnen J Wages J Zhang-Keck Z et al Molecular cloning and disease association of hepatitis G virus A new transfusion transmissible agent Science 1996 271505-8
2 Alter HJ The cloning and clinical implications of HGV and HGBV-C N Engl J Med 1996 3341536-7
3 Simons JN Leary TP Dawson GJ et al Isolation of novel virus-like sequences associated with Human hepatitis Nat Med 19951564-9
4 Di Bisceglie AM Hepatitis G virus infection A work in progress Ann Intern Med 1996 125772
5 Tillman HL Heiken H Knapik-Botor A et al Infection with GB virus C and reduced mortality among HIV-infected patients N Engl J Med 2001 345715-24
6 Xiang J Wunschmann S Diekema DJ et al Effect of coinfection with GB virus C on survival among patients with HIV infection N Engl J Med 2001345707-14
7 Lefrere JJ Roudot-Thoraval F Morand-Joubert L et al Carriage of GB virus Chepatitis G virus RNA is associated with a slower immunologic virologic and clinical progression of human Immunodeficiency virus disease in coinfected persons J Infect Dis 1999 179783-9
8 Tanaka E Alter HJ Nakatsuji Y et al Effect of hepatitis G virus infection on chronic hepatitis C Ann Intern Med 1996125740-3
9 Bralet MP Roudot-Thoraval F Pawlotsky JM et al Histopathologic impact of GB virus C infection on chronic hepatitis C Gastroenterology 1997112188-92
10 Berzsenyi MD Bowden SD Bailey MJ et al Sexual and blood-borne transmission of GB virus C and its association with Human Immunodeficiency Virus In press
GBV-C and hepatitis G virus HGV are both RNA viruses from the Flaviviridae family Molecular characterization of these viruses has shown them to be virtually identical to each other 12 GBV-C was first isolated in 1995 from an archival blood sample obtained in the 1960s from a surgeon with acute non A-E hepatitis 3 GBV-C has a 29 amino acid sequence homology with Hepatitis C Virus HCV another flavivirus 4 However GBV-C in contrast to HCV is not hepatotropic as the virus neither replicates primarily in hepatocytes nor causes acute or chronic hepatitis Indeed GBV-C does not cause any specific disease nor does it represent a substantial health risk in humans Nevertheless GBV-C infection is relatively common with a 2 prevalence rate in healthy blood donors the majority of whom clear the virus and develop antibodies to the envelope glycoprotein E2
HIV infection has a particularly high rate of co-infection with GBV-C Studies suggest that co-infection leads to a beneficial effect on the course of HIV 567 with co-infection associated with a significantly lower mortality rate among HIV-infected subjects compared to those not infected with GBV-C The mechanism of the beneficial effect of GBV-C on the course of HIV infection is obscure
Among new cases of non-A non-B hepatitis in the United States 18 percent are positive for GBV-C and 80 of these patients are also infected with HCV Amongst patients with HCV 10-20 have GBV-C RNA in their serum 4 In another report 189 patients with chronic HCV infection were evaluated 21 11 were positive for GBV-C RNA 8 The course of the HCV infection and the response to interferon-alfa were not affected by co-infection with GBV-C Interferon-alfa led to a decrease in GBV-C RNA titers that was not sustained after the cessation of therapy Similar findings were noted in another study in which liver biopsies were performed 9 Detailed histopathologic examination revealed no difference between the patients infected with HCV alone and the 15 percent who were co-infected with GBV-C There have been no studies to date looking at the effect GBV-C HCV and HIV have on each other
Our previous studies into HIV and GBV-C have suggested that co-infection is common Active GBV-C infection is frequently observed in persons involved in high-risk sexual activity and with HIV infection Homosexual intercourse appears to be a more effective means of transmission of GBV-C GBV-C has the same epidemiology and transmission as HIV and underlines the intimate association between GBV-C and HIV 10
MethodsExperimental Design
Stored sera is available from people who have attended the Hepatitis and HIV clinics at the Alfred Hospital Sera is available back to approximately 1990 and has been stored at minus 20ºC and as such is suitable for GBV-C detection particularly RNA by PCR Of the sera stored by the HIV clinic 203 patients are known to be co-infected with HCV who are currently still alive Once ethics committee approval is obtained we propose to contact these groups of people and see if they would participate in this study Once consent is obtained we plan to perform the following
A Stored sera will be retrospectively examined for the point prevalence of infection with HCV GBV-C and HIV These individuals will then be followed up in a prospective manner assessing the progression of liver disease and other factors as outlined in Tables 1 to 4
B New subjects attending the Alfred Hospital Hepatitis or HIV clinics will be recruited and followed prospectively also as outlined in Tables 1 to 4
C An age and sex matched control group infected with HCV alone will be identified via the Alfred Hospital Hepatitis clinic This clinic has a large cohort of well-characterized HCV infected subjects that extends back to 1989
The inclusion and exclusion criteria for the study are as follows
Inclusion criteria
1 Sera available and appropriate for testing Including serial sera over a period of time retrospective analysis
2 HIV serology positive
3 Unequivocal HCV antibody positive or HCV RNA positive
Exclusion criteria
1 Those without sera available
2 Those unwilling to give informed consent
3 Persons with Hepatitis B Virus infection as defined by the presence of Hepatitis B surface antigen andor Hepatitis B Virus DNA positive
Where possible information will also be obtained about these people by interview examining the medical records or discussion with their General Practitioners Subjects will also be encouraged to attend the hospital in person where a clinical exam can be performed If insufficient sera is stored further blood will be drawn at this time and examined for HCV HIV and GBV-C related parameters as outlined in the tables below A study specific questionnaire will be generated in which subjects will be asked to complete a confidential questionnaire that contains information related to demographic and behavioral factors that may contribute to the acquisition of GBV-C HCV or HIV infection or various combinations of the above Demographic variables will include age sex country of birth and occupation Information relevant to HIV infection including the use of HAART and the presence or absence of AIDS defining syndromes will be obtained The questionnaire will attempt to identify the approximate time of acquisition of both HCV and HIV In addition the extent of liver disease will be assessed alcohol consumption will be quantified and information will be gathered on previous treatment with Interferon and Ribavirin
The main outcomes of this study will be liver related morbidity such as chronic hepatitis cirrhosis or hepatocellular cancer and overall patient survival The detailed information contained in the following tables will be obtained from interview medical records and clinical examination
Table 1 GBV-C
1 Testing sera for GBV-C RNA and E2 antibodies to GBV-C
2 Performing testing at one-year intervals if sera is available
Table 2 HIV
1 CD4 count buffy coat in HIV positive
2 HIV viral load
3 Use of highly active antiretroviral therapy HAART and other retroviral treatment andor change in treatment
4 Complications of HIVAIDS and AIDS defining illnesses
Table 3 Liver disease HCV
1 HCV viral load and genotype
2 Child-Pugh classification based on levels of bilirubin albumin and clotting profiles and the presence of ascites and encephalopathy
3 Complications of liver disease ascites encephalopathy variceal bleeding and hepatocellular carcinoma
4 ALT and AST levels as well as ASTALT ratio
5 Alpha Feto Protein AFP level
6 Liver histology at biopsy with assessment of inflammation grade stage of fibrosis and severity of hepatic steatosis
7 Liver ultrasound results
8 Results of endoscopy ie features of portal hypertension
Table 4 Survival Data
1 Has patient died
2 Date of death
3 Cause of death
Results will be statistically examined by univariate and multivariate analysis in terms of clinical outcomes with respect to chronic hepatitis C liver disease between GBV-C positive and negative groups in the HIV co-infected cohort compared with the HCV infected cohort alone See following Table 5
Table 5 Study Design
Study Group No1 HCV ve HIV ve GBV-C RNAve Study Group No2 HCV ve HIV ve GBV-C RNA-ve Control Group HCV ve alone
References relevant to this project from literature search
1 Linnen J Wages J Zhang-Keck Z et al Molecular cloning and disease association of hepatitis G virus A new transfusion transmissible agent Science 1996 271505-8
2 Alter HJ The cloning and clinical implications of HGV and HGBV-C N Engl J Med 1996 3341536-7
3 Simons JN Leary TP Dawson GJ et al Isolation of novel virus-like sequences associated with Human hepatitis Nat Med 19951564-9
4 Di Bisceglie AM Hepatitis G virus infection A work in progress Ann Intern Med 1996 125772
5 Tillman HL Heiken H Knapik-Botor A et al Infection with GB virus C and reduced mortality among HIV-infected patients N Engl J Med 2001 345715-24
6 Xiang J Wunschmann S Diekema DJ et al Effect of coinfection with GB virus C on survival among patients with HIV infection N Engl J Med 2001345707-14
7 Lefrere JJ Roudot-Thoraval F Morand-Joubert L et al Carriage of GB virus Chepatitis G virus RNA is associated with a slower immunologic virologic and clinical progression of human Immunodeficiency virus disease in coinfected persons J Infect Dis 1999 179783-9
8 Tanaka E Alter HJ Nakatsuji Y et al Effect of hepatitis G virus infection on chronic hepatitis C Ann Intern Med 1996125740-3
9 Bralet MP Roudot-Thoraval F Pawlotsky JM et al Histopathologic impact of GB virus C infection on chronic hepatitis C Gastroenterology 1997112188-92
10 Berzsenyi MD Bowden SD Bailey MJ et al Sexual and blood-borne transmission of GB virus C and its association with Human Immunodeficiency Virus In press
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None