No abstract

Hepatitis C virus (HCV) infection is the main cause of non-A, non-B hepatitis. 1-5 HCV consists of a heterogeneous mix of isolates defined by genotype, each of which is further classified into subtypes. 6,7 A number of factors have been considered in terms of their potential to predict the outcome of the disease. These include age of infection, viral typesubtype, quasispecies, viral load, and mode of infection. [8][9][10][11][12][13] Clinical heterogeneity in disease progression may reflect viral heterogeneity and variations in host response. 14-17 The human leukocyte antigen (HLA) has been shown to influence host response to infection. [18][19][20][21][22] Although HLA class II genes have shown associations with viral clearance or persistence of the HCV these findings are not uniform. [23][24][25][26][27][28] In addition, direct comparisons between studies is often difficult because of heterogeneity of ethnic background, viral genotype, phenotype frequencies of individual alleles between populations, gender, and duration of disease. To avoid heterogeneity of risk factors and confounding variables in viral type/subtype we studied a unique cohort of individuals all infected by anti-D contaminated from a single source of HCV 1b. The patients were of similar ethnogeographic background and had an absence of competing risk factors for liver disease.The present study is a follow-up investigation of the well-documented series of Irish women who were inadvertently infected with HCV as a result of receiving contaminated anti-D immunoglobulin (from a single source) in 1977 to 1978. [29][30][31] The contaminating HCV 1b was derived from a single infected donor. [30][31][32][33] The homogeneity of this group allows one to examine variation in host response to HCV infection without the potentially confounding influence of factors such as gender, specific HCV genotype, age range, and general health status. The purpose of the present study was to address whether particular HLA class II alleles are associated with clearance or persistence of HCV type 1b. PATIENTS AND METHODSThe study group consisted of 156 female individuals all of whom were iatrogenically infected between May 1977 and November 1978 with HCV type 1b from a single source. All 156 cases tested positive for antibodies to HCV (by recombinant immunoblot assay; Chiron Corporation, Emeryville, CA) and 46% (n ϭ 72) were positive for HCV RNA by qualitative reverse transcriptase-polymerase chain reaction (RT-PCR) using the Roche AMPLICOR test (F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland). The HCV status of the 84 patients who tested negative on initial qualitative HCV RT-PCR screening was confirmed by retesting within an 18-month period. The HCV genotype of the 72 virus-positive individuals was confirmed to be HCV 1b by reverse line probe assay (Inno-Lipa HCV II, INNOGENETICS N.V., Zwijndrecht, Belgium).Investigations were performed with informed consent and complied with a standardized protocol in compliance with standard of care and in accordance hospital eth...

The aim of this study was to investigate the relationship between human leukocyte antigen (HLA) class II genes and the natural fluctuations in hepatitis C viral load in a homogeneous patient population. The study group consisted of 57 viremic (hepatitis C virus [HCV] 1b) women for whom HLA class II DRB1 and DQB1 haplotyping, virologic, histologic, and biochemical markers of disease activity were available. All patients were infected with HCV 1b from the same source of hepatitis C-contaminated anti-D immunoglobulin during the period from May 1977 to November 1978. The mean slope of change of viral load was 0.34 (SD ؎ 0.73) log 10 viral copies/mL/year, which is significantly different from zero, P < 10 ؊9 . Analysis of the relationship between the slope of change of viral load and HLA class II haplotype indicated a significantly different slope of change of viral load between the alleles of (1) DRB1*15 and DRB1*0701, and (2) DQB1*0602 and DQB1*0201, P c ‫؍‬ .036 and P c ‫؍‬ .026 after Bonferroni correction for multiple comparisons, respectively. Significant differences for grade and stage of disease at liver biopsy were observed for DQB1*0501 and DQB1*0201 alleles; P ‫؍‬ .019, r s ‫؍‬ .64, and P ‫؍‬ .047, r s ‫؍‬ .57, respectively. In addition, significant differences in stage of disease were found to exist between DRB1*13 and DRB1*0701, P ‫؍‬ .031, r s ‫؍‬ ؊.71. The rate of disease progression in chronic hepatitis C is variable and influenced by both viral and host-related factors. Relevant virus-related factors might include size of inoculum, quasispecies diversity, and genotype. Transfusion-associated infection has a more rapid progression to active liver disease than needle stick-associated infection. 1,2 This is presumably related to the smaller viral burden at exposure for the latter case. Hepatitis C viral production is estimated to reach 10 10 to 10 13 virions/day with a short half-life of several hours. [3][4][5][6] The magnitude of the serum viral load has relevance for the success of antiviral therapy. Serum viremia at or below the threshold of 6.3 log 10 viral copies/mL is a good prognostic indicator of likely response to either interferon monotherapy or interferon and ribavirin combination therapy. 7-9 Similar to the human immunodeficiency virus (HIV), the high turnover rates and error-prone replication exhibited by the hepatitis C virus (HCV) provides a mechanism for the generation of immune escape and antiviral therapy-resistant mutants. [10][11][12][13] Host factors that influence disease progression in individuals infected with HCV include age at exposure, excessive alcohol consumption, and the presence of competing causes for liver disease such as the hepatitis B virus and hepatitis A virus superinfection. Individuals infected with HCV who are greater than 50 years of age have a more severe disease and higher mortality rate than younger individuals. 14,15 The genetic background of the host as assessed by human leukocyteassociated antigen (HLA) typing has shown some associations with clearance of ...

No abstract

No abstract

No abstract

A large cohort of rhesus-negative women in Ireland were inadvertently infected with hepatitis C virus following exposure to contaminated anti-D immunoglobulin in 1977-8. This major iatrogenic episode was discovered in 1994. We studied 36 women who had been infected after their first pregnancy, and compared them to an age- and parity-matched control group of rhesus-positive women. The presence of hepatitis C antibody was confirmed in all 36 by enzyme-linked immunosorbent assay and by recombinant immunoblot assay, while 26 (72%) of the cohort were HCV-RNA-positive (type 1b) on PCR testing. In the 20 years post-infection, all members of the study group had at least one pregnancy, and mean parity was 3.5. They had a total of 100 pregnancies and 85 of these went to term. There were four premature births, one being a twin pregnancy, and 11 spontaneous miscarriages. One miscarriage occurred in the pregnancy following HCV infection. There were two neonatal deaths due to severe congenital abnormalities in the PCR-positive women. Of the children born to HCV-RNA positive mothers, only one (2.3%) tested positive for the virus. Significant portal fibrosis on liver biopsy was confined to HCV-RNA-positive mothers apart from one single exception in the antibody-positive HCV-RNA-negative group. Comparison with the control group showed no increase in spontaneous miscarriage rate, and no significant difference in obstetric complications; birth weights were similar for the two groups.

Hepatitis C virus (HCV) infection is the main cause of parenteral non-A, non-B hepatitis. 1-5 HCV consists of a heterogeneous mix of isolates defined by genotype, each of which is further classified into subtypes. A number of factors have been identified as important in predicting the outcome of disease progression. These include age at infection, viral type/subtype, viral load, quasispecies, and mode of infection. [6][7][8][9][10] Clinical heterogeneity in disease progression may reflect either viral heterogeneity or variations in host response. However, the fluctuations in viral load during the natural history of hepatitis C infection are poorly understood. The purpose of the present study was to determine if viral load remains at a steady state or is in dynamic flux during the course of an HCV infection. To avoid heterogeneity of risk factors and confounding variables in viral type/subtype, we studied a unique cohort of individuals all infected by anti-D/ blood product from a single source of HCV 1b. The sole source of the infectious agent was identified as HCV 1b-contaminated anti-D immunoglobulin. The contaminating HCV 1b was derived from a single donor. [11][12][13] The patients were of similar ethnogeographic background and had an absence of other risk factors for liver disease.Serum HCV RNA can be quantitated by a range of different technologies (reverse transcription-polymerase chain reaction [RT-PCR], RT-PCR coupled to different signal amplification systems such as colorimetric assays, and the branched chain technology). [14][15][16][17][18][19][20] The level of sensitivity achieved by the more recent versions of these technologies has improved qualitative assessment of HCV serum status. Clinically relevant sensitivities of 100 viral genomes per mL of serum are now readily achievable.The work reported here used the Roche Monitor system for amplification of the HCV. The high degree of reproducible quantification of viral load and a uniform linear range of amplification between the different versions of the Roche HCV Monitor assays for HCV of genotype 1b provide a means in which quantifications over several generations of assays are suitable for longitudinal studies. In addition, amplification of HCV genotype 1b by the Monitor system does not suffer from the reported difficulties associated with other genotypes. 21