Camilla S. Graham

Influence of Human Immunodeficiency Virus Infection on the Course of Hepatitis C Virus Infection: A Meta-Analysis

Studies have shown that rates of liver disease are higher in persons who are coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) than they are in persons with HCV alone, but estimates of risk vary widely and are based on data for dissimilar patient populations. We performed a meta-analysis to quantify the effect of HIV coinfection on progressive liver disease in persons with HCV. Eight studies were identified that included outcomes of histological cirrhosis or decompensated liver disease. These studies yielded a combined adjusted relative risk (RR) of 2.92 (95% confidence interval [CI], 1.70-5.01). Of note, studies that examined decompensated liver disease had a combined RR of 6.14 (95% CI, 2.86-13.20), whereas studies that examined histological cirrhosis had a pooled RR of 2.07 (95% CI, 1.40-3.07). There is a significantly elevated RR of severe liver disease in persons who are coinfected with HIV and HCV. This has important implications for timely diagnosis and consideration of treatment in coinfected persons.

Pegylated interferon α therapy in acute hepatitis C: Relation to hepatitis C virus–specific T cell response kinetics

Pegylated interferon α (PEG IFN‐α) improves sustained virological response rates in chronic hepatitis C, but neither its role in acute hepatitis C nor the biologic basis for its action has been defined. This prospective study assessed the efficacy of PEG IFN‐α treatment in acute hepatitis C in relation to the kinetics of hepatitis C virus (HCV)‐specific CD4+ T cell responses during therapy and follow‐up. Forty subjects with proven acute hepatitis C who received either PEG IFN‐α plus ribavirin (n = 20) or PEG IFN‐α monotherapy (n = 20) for 24 weeks in addition to 14 untreated subjects with acute hepatitis C were prospectively followed. Serum HCV RNA, HCV‐specific CD4+ T cell responses, and cytokine production were measured before and during therapy and at follow‐up and correlated to the outcome. The sustained virological response rate was 85% with PEG IFN‐α/ribavirin combination and 80% with PEG IFN‐α monotherapy. Five untreated subjects had spontaneous recovery. The frequency, magnitude, and breadth of HCV‐specific CD4+ T helper 1 responses were significantly higher in treated subjects compared with untreated subjects with self‐limited disease or subjects with chronic evolution. The CD4+ T cell responses were maintained in subjects with sustained virological responses and self‐limited disease but fluctuated in those who developed chronic infection. In conclusion, PEG IFN‐α therapy in acute hepatitis induces high rates of sustained virological response and prevents choronicity, probably through efficient early stimulation of multispecific HCV‐specific CD4+ T helper 1 responses. (HEPATOLOGY 2004;39:1721–1731.)

HIV infection does not affect the performance of noninvasive markers of fibrosis for the diagnosis of hepatitis C virus-related liver disease.

Background:Noninvasive markers of hepatic fibrosis hold great promise to stage liver fibrosis and to monitor disease progression. To date, few studies have assessed the performance of the currently available markers of hepatic fibrosis in HIV-infected cohorts. The aim of the current study was to compare the diagnostic performance and characteristics of a number of noninvasive markers of hepatic fibrosis in populations of hepatitis C virus (HCV)-infected patients with and without HIV infection. Methods:A sample of 97 subjects (40 HCV/HIV-coinfected, 57 HCV-infected) undergoing liver biopsy as part of an ongoing prospective cohort study was evaluated. Liver biopsies were assessed by a single hepatopathologist and scored according to Ishak criteria. Noninvasive markers of fibrosis studied included international normalized ratio, platelet count, aspartate aminotransferase (AST)/alanine aminotransferase ratio, AST platelet ratio index (APRI), Forns index, procollagen III N peptide, hyaluronic acid, and YKL-40. Results:The correlations between fibrosis markers with the stage of fibrosis and the diagnostic performance of each of the tests were similar in the groups with and without HIV infection. Although a trend to improved diagnostic performance in the HCV/HIV-coinfected group was observed, this may be related to the small sample size. Conclusions:The diagnostic performance of the evaluated noninvasive markers of liver fibrosis is equivalent in HCV/HIV-coinfected and HCV-infected subjects. These tests may be of value for the clinical evaluation of HCV/HIV-coinfected patients and warrant further study.

Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor beta that can suppress HCV-specific T-cell responses.

ABSTRACT Hepatitis C virus (HCV)-specific T-cell responses are rarely detected in peripheral blood, especially in the presence of human immunodeficiency virus (HIV) coinfection. Based on recent evidence that T-regulatory cells may be increased in chronic HCV, we hypothesized that functional blockade of regulatory cells could raise HCV-specific responses and might be differentially regulated in the setting of HIV coinfection. Three groups of subjects were studied: HCV monoinfected, HCV-HIV coinfected, and healthy controls. Frequencies of peripheral T cells specific for peptides derived from HCV core, HIV type 1 p24, and recall antigens were analyzed by gamma interferon (IFN-γ) enzyme-linked immunospot assay. HCV-specific T-cell responses were very weak in groups with HCV and HCV-HIV infections. Addition of blocking antibodies against transforming growth factor β1 (TGF-β1), -2, and -3 and interleukin-10 specifically increased the HCV-specific T-cell responses in both infected groups; however, this increase was attenuated in the group with HCV-HIV coinfection compared to HCV infection alone. No increase in recall antigen- or HIV-specific responses was observed. Flow cytometric sorter analysis demonstrated that regulatory-associated cytokines were produced by HCV-specific CD3+CD8+CD25− cells. Enhancement of the IFN-γ effect was observed for both CD4 and CD8 T cells and was mediated primarily by TGF-β1, -2, and -3 neutralization. In conclusion, blockade of TGF-β secretion could enhance peripheral HCV-specific T-cell responses even in the presence of HIV coinfection.

Cellular Immune Responses in Seronegative Sexual Contacts of Acute Hepatitis C Patients

ABSTRACT Acute hepatitis C virus (HCV) is typically defined as new viremia and antibody seroconversion. Rates and immunologic correlates of hepatitis C clearance have therefore been based on clearance of viremia only in individuals who initially had an antibody response. We sought to characterize the immunological correlates of clearance in patients with acute hepatitis C and their sexual contacts. We prospectively determined CD4+ and CD8+ cytotoxic T-lymphocyte responses in index patients with acute HCV and their sexual contacts who developed acute infection, either with or without spontaneous clearance, as well as those contacts who never developed viremia. Responses were measured using proliferation and ELISpot assays for CD4+ and CD8+ responses. We demonstrate in this prospective study that cellular immune responses can develop in exposed but persistently aviremic and antibody-negative individuals as well as those individuals with spontaneous clearance of acute HCV. These findings lend further credence to the importance of cellular immune responses in recovery from HCV and suggest that low exposure to HCV may lead to development of HCV-specific immune responses without ongoing HCV replication. This finding has important implications for HCV vaccine and therapeutic development.

Kinetics of Intrahepatic Hepatitis C Virus (HCV)-Specific CD4+ T Cell Responses in HCV and Schistosoma mansoni Coinfection: Relation to Progression of Liver Fibrosis

The kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4(+) T cell responses and their role in progression of fibrosis have not previously been characterized. Subjects with HCV/Schistosoma mansoni coinfection have a more rapid progression of HCV liver fibrosis than do those with HCV infection alone. The present prospective longitudinal study compared the liver histology, HCV-specific intrahepatic and peripheral CD4(+) T cell proliferative responses, and cytokines (enzyme-linked immunospot) in 48 subjects with unresolved acute HCV infection with or without S. mansoni coinfection, at 6-10 months after acute infection and at the end of follow-up (96+/-8.7 months), and the findings were correlated to the rate of progression of fibrosis per year. Coinfected subjects had significant worsening of fibrosis, compared with subjects with HCV infection alone. At baseline, subjects with HCV infection alone had stronger multispecific intrahepatic HCV-specific CD4(+) T helper 1 responses than did coinfected subjects, who had either no responses or weak, narrowly focused responses, and, over time, these T cell responses were maintained only in the liver. The rate of progression of fibrosis and virus load inversely correlated with intrahepatic HCV-specific CD4(+) T cell response. The present prospective analysis indicates that enhancement of progression of liver fibrosis is associated with failure to develop early, multispecific, HCV-specific CD4(+) Th1 responses, suggesting that novel therapeutic approaches inducing strong cellular immune responses might limit subsequent liver damage in individuals with chronic hepatitis C.

Health-Related Quality of Life of Patients with HIV Disease: Impact of Hepatitis C Coinfection

Health-related quality of life (HRQOL) is diminished in patients infected with both hepatitis C virus (HCV) and human immunodeficiency virus (HIV), but the effect of HIV/HCV coinfection on HRQOL is unknown. We compared the HRQOL of urban HIV/HCV coinfected patients with that of patients infected with either HCV or HIV alone. We then compared the 3 groups with a US population sample, adjusting for demographic characteristics. HRQOL for the group of HIV/HCV coinfected patients was statistically similar to that of HRQOL in patients with either HCV or HIV alone, but the 3 groups had a significantly decreased HRQOL than did the adjusted US population. Using multivariate techniques, we determined that age, unemployment, injection drug use, and depression were associated with impaired HRQOL. These findings underscore the importance of a multidisciplinary approach to the treatment of these patient populations.

Comparison of HCV-specific intrahepatic CD4+ T cells in HIV/HCV versus HCV.

Persons with human immunodeficiency virus (HIV) and hepatits C virus (HCV) coinfection are at increased risk for progression to cirrhosis compared with persons with HCV alone, but the reasons for this are unclear. In chronic HCV, the mechanism of liver injury is presumed to be due to HCV‐specific T cell destruction of hepatocytes, so it is paradoxical that immunosuppressed hosts have higher rates of fibrosis progression. We examined intrahepatic cellular immune responses to HCV antigens to determine whether there were qualitative or quantitative differences in subjects with and without HIV. Expanded, CD4‐enriched, liver‐infiltrating lymphocytes from 18 subjects with chronic HCV and 12 subjects with HIV/HCV were cultured in the presence of HCV core protein, nonstructural proteins NS3 and NS5, and recall antigens tetanus toxoid and Candida. Secretion of interferon γ (IFN‐γ), tumor necrosis factor α (TNF‐α), and interleukin (IL) 10 was determined using enzyme‐linked immunosorbent spot assay. There were no significant differences in liver biopsy grade or stage for HIV/HCV versus HCV groups. There were no significant differences between groups in the secretion of IFN‐γ or TNF‐α in response to HCV or recall antigens. However, there was a significant increase in IL‐10 secretion in response to NS3 and NS5 in subjects with HCV compared with HIV and HCV coinfection. In conclusion, subjects with coinfection have an alteration of intrahepatic HCV‐specific IL‐10 cytokine response that may have implications for HCV‐related disease progression. (HEPATOLOGY 2004;40:125–132.)

Imported Fasciola hepatica Infection in the United States and Treatment with Triclabendazole

Infection with Fasciola hepatica, a liver trematode, is not frequently reported in the United States. We describe 2 patients, both originally from Cape Verde, who illustrate the spectrum of clinical presentations of F. hepatica as well as the means of treating infection with this parasite. Patient 1 had extensive disease and underwent multiple diagnostic procedures before the correct diagnosis was reached. Patient 2, who had few symptoms, had fascioliasis diagnosed by a noninvasive evaluation. Both patients were treated with triclabendazole without experiencing significant side effects. Fascioliasis that has been imported to the United States may elude prompt or accurate diagnosis. Obtaining a detailed travel history and recognizing the clinical presentation early in the course of infection may permit timely and noninvasive identification of infection. Triclabendazole is now the recommended drug for treating for fascioliasis because of its efficacy, safety, and ease of use.

CD8+ Cell Responses to Hepatitis C Virus (HCV) in the Liver of Persons with HCV-HIV Coinfection versus HCV Monoinfection

OBJECTIVE Cellular immune responses are difficult to detect in the peripheral blood of persons with chronic hepatitis C virus (HCV) infection. We sought to determine whether T cell responses were present in the liver of patients with human immunodeficiency virus (HIV) and HCV coinfection. METHODS T cells were expanded from liver-biopsy samples from 10 patients coinfected with HIV and HCV (median CD4(+) cell count, 456 cells/mm(3)) and 8 patients infected with HCV alone. CD8(+) cell responses were detected by use of a modified enzyme-linked immunospot (ELISpot) assay with recombinant vaccinia virus, and CD4(+) cell responses were detected by use of ELISpot with recombinant HCV proteins core, nonstructural (NS) 3, and NS5. RESULTS Intrahepatic CD8(+) cell responses to HCV were detected in 7 of 10 patients coinfected with HCV and HIV (median frequency, 638 spot-forming cells [sfc]/1 x 10(6) cells) and were similar to those observed in patients singly infected with HCV (7/8; median, 647 sfc/1 x 10(6) cells). Intrahepatic HCV-specific CD4(+) cell responses were also comparable in both groups and correlated with the intrahepatic CD8(+) cell responses (r=0.59; P=.03). CONCLUSION HCV-specific CD8(+) cell responses are present in the liver of persons with chronic HCV infection even when they are coinfected with HIV; these correlate with intrahepatic HCV-specific CD4(+) cell responses.