ABSTRACT
Approximately 20% of patients receiving liver transplants for end-stage hepatitis C rapidly develop severe allograph fibrosis within the first 24 months after transplant. Hepatitis C virus (HCV) variants were studied in 56 genotype-1-infected subjects with end-stage hepatitis C disease at the time before and 12 months after liver transplant, and post-transplant outcome was followed with serial liver biopsies. In 15 cases, pre-transplant HCV genetic diversity was studied in detail in liver (n=15), serum (n=15), peripheral blood mononuclear cells (n=13), and perihepatic lymph nodes (n=10). Our results revealed that pre-transplant HCV genetic diversity predicted the histological outcome of recurrent hepatitis C disease after transplant. Mild disease recurrence after transplant was significantly associated with higher genetic diversity and greater diversity changes between the pre- and post-transplant time points (p=0.004). Meanwhile, pre-transplant genetic differences between serum and liver were related to a higher likelihood of development of mild recurrent disease after transplant (p=0.039).
Subject(s)
DNA, Viral/genetics , Genetic Variation , Hepacivirus/classification , Hepacivirus/genetics , Hepatitis C, Chronic/virology , Liver Transplantation , RNA, Viral/genetics , Adolescent , Adult , Child , Female , Hepatitis C, Chronic/surgery , Humans , Leukocytes, Mononuclear/virology , Liver/virology , Lymph Nodes/virology , Male , Middle Aged , Prognosis , Recurrence , Serum/virology , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Hepatitis C virus (HCV) is hyperendemic in drug injectors, yet social structural and behavioral factors underlying transmission are not well established. METHODS: We conducted a case-control study of HCV seroconversion in drug injectors, focusing on transmission within networks. Incident case subjects (n=17) and seronegative control subjects (n=42) reported injection and sex partners and referred as many as 5 for interviewing and blood testing. We performed nucleotide sequencing of HCV isolates from infected individuals. RESULTS: Seventy-eight percent of recent injection partnerships involved behavior that could transmit HCV. Case subjects and control subjects were similar demographically and behaviorally. Case subjects, however, had more HCV-infected partners and consequently engaged in injection risk behavior with more infected partners. The injection network was mostly connected, dense, and cyclic, but the sexual network was highly fragmented. Although participants generally injected with partners of similar age, most HCV-uninfected participants recently had injected with infected partners. In at least 1 of 4 pairs of genetically linked infections, transmission appeared to be due to sharing of injection equipment other than syringes. Except for transmission pairs, network distance between incident case subjects and genetic distance between their HCV variants were uncorrelated. CONCLUSIONS: Without dramatic reductions in injection risk behaviors, shattering of cohesive injection networks, and/or broad coverage of an effective vaccine, HCV will likely remain hyperendemic in drug injectors.
Subject(s)
Endemic Diseases , Hepatitis C/epidemiology , Hepatitis C/transmission , Risk-Taking , Substance Abuse, Intravenous/virology , Adolescent , Adult , Case-Control Studies , Cohort Studies , Female , Genotype , Hepacivirus/classification , Hepacivirus/genetics , Hepatitis C/virology , Humans , Interviews as Topic , Male , Phylogeny , Prospective Studies , Sexual Behavior , Statistics as Topic , Substance Abuse, Intravenous/complications , Substance Abuse, Intravenous/psychology , Viral Envelope Proteins/genetics , Viral Proteins/geneticsABSTRACT
The role of viral factors in the pathogenesis of chronic hepatitis C is unknown. The objective of the present study was to characterize markers of hepatitis C virus (HCV) infection and replication in liver biopsy specimens obtained from 65 genotype 1-infected subjects, including 31 who were coinfected with human immunodeficiency virus (HIV), and to analyze associations between intrahepatic viral markers and hepatitis C disease severity. The percentages of liver cells harboring HCV genomes (%G) and replicative-intermediate RNAs (%RI) were evaluated using strand-specific in situ hybridization, while HCV core and NS3 antigens were assessed by immunocytochemistry. HIV-positive and HIV-negative subjects had similar mean grades and stages of liver disease and had similar indices of HCV infection and replication in liver, even though coinfected subjects had significantly shorter mean disease duration (P = 0.0003). Multivariate analysis showed that %G was not associated with grade or stage of liver disease (P = 0.5 and 0.4, respectively), while %RI was strongly associated with liver inflammation (P < 0.001), liver fibrosis (P < 0.001), and serum alanine aminotransferase levels (P = 0.01). NS3 antigen (but not core) was more frequently detected in HCV RI-positive versus RI-negative specimens (P = 0.028). These findings demonstrate a link between HCV proliferation and hepatitis C disease severity and suggest similar pathogenic mechanisms in HIV-positive and HIV-negative individuals.
