Primary Hepatitis C Virus Infection Research Articles

Early-Onset Liver Fibrosis Due to Primary Hepatitis C Virus Infection Is Higher Over Time in HIV-Infected Men

To the Editor—We were pleased to read the recent report by Vogel et al [1] of their study undertaken in response to our findings of rapid onset fibrosis during primary hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)–infected men [2]. Their study, plus the recent publication of the liver biopsy results of Bottieau et al [3], seems to cement that this unexpected outcome is a true consequence of primary HCV infection in HIV-infected men. We disagree, however, that their results using transient elastography demonstrate a sharp decrease in the fibrosis progression rate (FPR) to a clinically unimportant level soon after the primary HCV infection period has waned.

Reply to Fierer et al

To the Editor—We are thankful for the comments made by Fierer et al, which enrich the current discussion on the natural course of acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)–infected individuals [1]. However, we do feel that the authors may have over-interpreted our data when stating that we demonstrated a “sharp decrease in the fibrosis progresssion rate (FPR) to a clinically unimportant level soon after the primary HCV infection period has waned.” This statement is not correct. We showed that the calculated FPR using a linear model most likely overestimates fibrosis progression in the setting of acute HCV infection, for which only short follow-up times are available. We are happy to see that Fierer et al agree with this interpretation and no longer calculate FPRs when reporting the outcome of liver biopsies of acute HCV infections. Indeed, concordant to the current consensus statement on acute HCV infections in HIV-infected individuals, we recommended that every HIV-infected patient should be advised to consider early treatment of acute HCV infection if spontaneous clearance does not occur [2]. We fully agree that further follow-up in patients withholding treatment is warranted to detect advancing liver fibrosis early and avoid the development of significant fibrosis and/or cirrhosis and ultimately end-stage liver disease [3].

Spontaneous clearance of primary acute hepatitis C virus infection correlated with high initial viral RNA level and rapid HVR1 evolution

The aim of this study is to determine whether early viral dynamics and evolution predict outcome of primary acute hepatitis C virus (HCV) infection. HCV- and human immunodeficiency virus-negative injection drug users were enrolled prospectively and followed monthly to identify acute HCV infection using RNA detection. Subjects with more than 1 month between HCV-RNA-negative and -positive visits were excluded to ensure stringent acute infection. Differences in medians of log-transformed viral RNA levels and evolutionary rates in each gene of a 5'-hemigenomic amplicon were assessed using Mann-Whitney's rank-sum test. Correlation coefficient was calculated using Spearman's rank order. Initial viremia level was 50-fold higher in subjects with spontaneous clearance (compared with persistence) of primary acute HCV infection (median, 7.1 versus 5.4 log(10) IU/mL; P = 0.002). Initial viremia level in subjects with interleukin (IL)28B-C allele at rs12979860 and clearance was higher than that in subjects with IL28B-T allele and persistence (P = 0.001). Evolutionary rates in the hypervariable region 1 (HVR1) region of the E2 gene were significantly higher in self-resolvers than those in persistence subjects during early infection, whereas other genes or regions had comparable rates. All major substitutions in HVR1 in persistence subjects were convergent changes, whereas over the same time interval clearance subjects displayed divergent evolution, indicating different immune responses between the two groups. Spontaneous clearance of acute HCV infection is predicted by high initial viremia as well as favorable IL28B genotype and is associated with rapid envelope-sequence evolution. This linkage of host genetics, viral dynamics, and evolution provides new directions for mechanistic studies. (HEPATOLOGY 2012;55:1684-1691).

Hepatitis C virus-specific cellular immune responses in individuals with no evidence of infection

The detection of hepatitis C virus (HCV)-specific T cell responses in HCV-uninfected, presumably unexposed, subjects could be due to an underestimation of the frequency of spontaneously resolving infections, as most acute HCV infections are clinically silent. To address this hypothesis, HCV-specific cellular immune responses were characterized, in individuals negative for an HCV PCR assay and humoral response, with (n = 32) or without (n = 33) risk of exposure to HCV. Uninfected volunteers (n = 20) with a chronically HCV-infected partner were included as positive controls for potential exposure to HCV and HCV infection, respectively. HCV-specific T cell responses in freshly isolated peripheral blood mononuclear cells were studied ex vivo by ELISPOT and CFSE-based proliferation assays using panels of HCV Core and NS3-derived peptides. A pool of unrelated peptides was used as a negative control, and a peptide mix of human cytomegalovirus, Epstein-Bar virus and Influenza virus as a positive control. Overall, 20% of presumably HCV-uninfected subject tested had detectable T-cell responses to the virus, a rate much higher than previous estimates of HCV prevalence in developed countries. This result would be consistent with unapparent primary HCV infections that either cleared spontaneously or remained undetected by conventional serological assays.

Spontaneous Control of Primary Hepatitis C Virus Infection and Immunity Against Persistent Reinfection

We followed patients with ongoing hepatitis C virus (HCV) exposure following control of an initial HCV infection to determine whether primary control conferred protection against future persistent infections. Twenty-two active injection drug users (IDU) who had cleared a primary hepatitis C viremia for at least 60 days were monitored monthly. Reinfection was defined as the detection of a new HCV infection. Protection was assessed based on the magnitude and duration of viremia following reinfection and generation of T-cell and neutralizing antibody (nAb) responses. Reinfection occurred in 11 IDU (50%) who previously spontaneously controlled primary HCV infection. Although viral clearance occurs in approximately 25% of patients with primary infections, spontaneous viral clearance was observed in 83% of reinfected patients. The duration and maximum level of viremia during subsequent episodes of reinfection were significantly decreased compared with those of the primary infection in the same subjects. In contrast to chronic infection, reinfection was associated with a significant increase in the breadth of T-cell responses. During acute infection, nAbs against heterologous viral pseudoparticles were detected in 60% of reinfected subjects; cross-reactive nAbs are rarely detected in patients who progress to chronic infection. HCV reinfection is associated with a reduction in the magnitude and duration of viremia (compared with the initial infection), broadened cellular immune responses, and generation of cross-reactive humoral responses. These findings are consistent with development of adaptive immunity that is not sterilizing but protects against chronic disease.

Hepatitis C infection: recent insights relevant to transfusion safety

Hepatitis C virus (HCV) infects over 100 million persons worldwide, and is hence one of the most prevalent and clinically significant blood‐borne pathogens. The introduction of HCV antibody screening in the early 1990s led to detection of large numbers of infected donors and dramatic increases in blood safety. The seroprevalence of HCV in blood donors varies, ranging from rates as low as 0·01% in South Africa to ~0·5% in most developed countries, to > 5% in focal endemic areas such as Egypt. Studies of HCV in infected donors and recipients were instrumental in the discovery of HCV, and have yielded ongoing insights into HCV epidemiology, natural history and pathogenesis. Recent examples include detailed characterization of the dynamics of acute HCV infection based on studies of plasma donor panels, and important contributions to understanding viral and host factors influencing HCV transmission and disease outcome based on linked donor‐recipient cohort studies. The addition of nucleic acid testing (NAT) for HCV RNA to routine HCV antibody screening of donors in 1999 further reduced the risk of transfusion‐transmitted HCV. Mini‐pool (MP)‐NAT screening has led to detection of well over 500 donors in the viraemic, preseroconversion phase of primary HCV infection, as well as to discrimination of seropositive donors into those with resolved and chronic infections. Studies of donors with acute, chronic/persistent and resolved HCV infections have further contributed to our understanding of viral and host genetic and immunological determinants of spontaneous clearance of HCV and short‐ and long‐term disease outcomes. This review will highlight these past scientific contributions, and present the results of a recent survey of the yield of HCV MP‐NAT screening and estimated residual risks of MP‐NAT screened transfusions in different regions of the world. Finally, the review will discuss available evidence for the infectivity of very low‐level viraemia that may be missed by MP‐NAT, information that is pivotal to modelling the residual risk of MP‐NAT screened blood transfusions, and which will guide further strategies to reduce risk by further enhancing screening or implementation of pathogen‐inactivation technologies.

Hepatitis C virus infection in HIV-infected patients

The hepatitis C virus (HCV) is a spherical enveloped RNA virus of the Flaviviridae family, classified within the Hepacivirus genus. Since its discovery in 1989, HCV has been recognized as a major cause of chronic hepatitis and hepatic fibrosis that progresses in some patients to cirrhosis and hepatocellular carcinoma. In the United States, approximately 4 million people have been infected with HCV, and 10,000 HCVrelated deaths occur each year. Due to shared routes of transmission, HCV and HIV co-infection are common, affecting approximately one third of all HIV-infected persons in the United States. In addition, HIV co-infection is associated with higher HCV RNA viral load and a more rapid progression of HCV-related liver disease, leading to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons because the incidence of infection is increased and the natural history of HCV infection is accelerated in co-infected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed among HIV/HCV co-infected individuals.

Distinguishing acute from chronic and resolved hepatitis C virus (HCV) infections by measurement of anti-HCV immunoglobulin G avidity index.

An assay to measure avidity index (AI) was developed to diagnose incident hepatitis C virus (HCV) infections. The assay demonstrated an AI value statistically significantly lower in primary HCV infections than in chronic infections. When the assay was applied to past resolved infections, the difference in AI values was not as significant as the difference between incident and chronic infections. Lower AI values obtained in past resolved infections may be directly related to lower levels of immunoglobulin G anti-HCV in past resolved infections than in either new infections or chronic infections.

Chronic hepatitis B and other correlates of spontaneous clearance of hepatitis C virus among HIV-infected people with hemophilia

To identify correlates of spontaneous hepatitis C virus (HCV) clearance among people with human immunodeficiency virus (HIV) co-infection. Baseline (2001-2004) analysis of a cohort study of people with hemophilia. Detailed questionnaire data were used to identify dates of primary HCV and HIV infections and to categorize sex; race; alcohol use; interferon treatment; hepatitis B virus (HBV) status; and HIV/AIDS history, treatment and current status. Spontaneous HCV clearance was defined as nondetection of HCV RNA by polymerase chain reaction assay in paired annual plasma, excluding those treated with interferon. Chi-squared, Fisher exact test, and logistic regression were used to identify correlates of clearance. Among 478 HIV-infected participants, 61 (12.8%) had cleared HCV. Among the 31 participants with chronic HBV (as well as HIV), 16 (51.6%) had cleared HCV. With chronic HBV, HCV clearance was increased 11.2-fold (95% confidence interval, 5.1-24.8), after adjusting for sex, race, and hemophilia severity. Excluding the participants with chronic HBV, the prevalence of HCV clearance was 10.1%; and it was significantly reduced among males (9.7%, P = 0.05), blacks (1.6%, P = 0.01), and participants with severe hemophilia (8.2%, P = 0.02). HCV clearance was not associated with HIV RNA detection in plasma, CD4 cell count, anti-HIV therapy, AIDS history, ages at or years of HIV or HCV infection, or alcohol consumption. HCV clearance is unambiguously and markedly increased with chronic HBV infection among HIV co-infected people.

Correlates of Spontaneous Clearance of Hepatitis C Virus among HIV-Infected Persons with Hemophilia.

Up to the late 1980s, hepatitis C virus (HCV) infected the majority of people with hemophilia (PWH) in the United States (US), via contaminated plasma clotting factor therapy. Approximately two-thirds of the HCV-infected PWH in the US also were infected with human immunodeficiency virus (HIV). The Second Multicenter Hemophilia Cohort Study (MHCS-II) investigated complications of HCV and HIV infections in people with hemophilia. From 2001 - 2005, data and specimens were collected from 2561 anti-HCV positive participants, including 763 who were co-infected with HIV. These data were analyzed for correlates of spontaneous HCV clearance.Results. Of the 763 HIV-positive, anti-HCV-positive participants, 285 were eliminated from the analysis because they had received interferon treatment to clear HCV, lacked HCV treatment data, or lacked sufficient specimens to determine HCV clearance status. Of the remaining 478 interferon-untreated participants, 61 (12.8%) had cleared HCV RNA from plasma. HCV had cleared in 8.6% of the 116 who were never infected with hepatitis B virus (HBV), 11.6% of 207 with resolved HBV infection, and 8.9% of 124 with missing HBV status (P≥ 0.41). In contrast, HCV had cleared in 16 (51.6%) of the 31 participants with chronic HBV surface antigen (HBsAg) in serum. Adjusted for gender and race, HCV clearance was increased 7.4-fold (95% CI 3.7 - 15.0) for those with chronic HBsAg. In the HBsAg negative group, HCV clearance was significantly lower among participants of African ancestry (1.6%, p=0.01) and was significantly lower in PWH with severe compared to mild or moderate coagulopathy (8.2% vs 15.9%, p=0.02). Clearance was unrelated to type of initial clotting factor replacement therapy, year of birth, year of primary HCV infection, age at primary HCV infection, age at HIV infection, and year of enrollment in the cohort. HCV clearance occurred in 2 (12.5%) of the 14 participants in whom primary HCV infection occurred after or within one year of HIV infection, compared to 9.1% when HCV infection occurred more than one year before HIV (p=0.65). HCV clearance was unrelated to CD4 count at cohort enrollment, history of immunologically or clinically defined AIDS, and detection of HIV RNA in plasma at cohort enrollment. HCV clearance tended to be higher among the 231 participants on HAART (12.6%) than in those on less intensive (9.1%), anomalous (6.7%) or no anti-HIV therapy (6.5%, Ptrend=0.07), although when restricted to non-African ancestry males, HIV therapy was not associated with clearance (Ptrend=0.26).Conclusion. Unlike in HIV-negative people with hemophilia, HCV clearance in the current study was unrelated to age at or year of primary HCV infection. We were unable to evaluate repeated exposure to and likely re-infection with HCV, although the lower clearance in patients with severe hemophilia, who would have been treated, and thus exposed more frequently, supports the hypothesis of lower clearance with re-infection. While reduced overall, spontaneous HCV clearance was markedly increased by the presence of chronic HBsAg carriage. These findings will increase our understanding of interactions between these viruses and may lead to improved approaches to treatment of co-infected patients.

Morphologic Features of Hepatitis C Recurrence in Patients After Orthotopic Liver Transplantation-Preliminary Analysis of our Case Observations

Introduction Hepatitis C virus (HCV) recurrence is almost universal in patients after liver transplantation. The diagnosis of reinfection is more difficult than that of a primary process, as shown by our pathomorphologic analysis of cases of HCV recurrence. Material During 5.5 years, 240 liver biopsies included 54 obtained from liver transplant recipients with primary HCV infections, among whom 26 (56.5%) had clinical signs and symptoms of hepatitis. Nineteen patients from this population underwent 30 liver biopsies. In addition, seven biopsies were performed in five patients without clinical signs of reinfection. Results In 44.2% of patients with HCV recurrence and 15% without reinfection, the intensity of the primary process in the native livers was assessed as high. Reinfection was found in all patients with liver carcinoma and 67% with hepatocyte dysplasia. Histologic signs of infection were estimated as minimal ( n = 4), mild ( n = 19), or moderate ( n = 4). In five patients with reinfections and one without recurrence, histologic manifestations of acute rejection were also observed. In conclusion, HCV was the indication for liver transplantation in 22.4% cases. Clinical manifestation of recurrence was found in 56.5% of the patients, who tended to be older than those without disease recurrence. Upon microscopy, lobular lesions predominated over the portal changes. Factors predisposing to HCV recurrence were coexistence of other liver disorders, a high intensity of the inflammatory process, hepatocyte dysplasia, and/or hepatocellular carcinoma in the native liver and acute rejection episodes.

A critical role for the chimpanzee model in the study of hepatitis C.

Chimpanzees remain the only recognized animal model for the study of hepatitis C virus (HCV). Studies performed in chimpanzees played a critical role in the discovery of HCV and are continuing to play an essential role in defining the natural history of this important human pathogen. In the absence of a reproducible cell culture system, the infectivity titer of HCV challenge pools can be determined only in chimpanzees. Recent studies in chimpanzees have provided new insight into the nature of host immune responses-particularly the intrahepatic responses-following primary and secondary experimental HCV infections. The immunogenicity and efficacy of vaccine candidates against HCV can be tested only in chimpanzees. Finally, it would not have been possible to demonstrate the infectivity of infectious clones of HCV without chimpanzees. Chimpanzees became infected when RNA transcripts from molecular clones were inoculated directly into the liver. The infection generated by such transfection did not differ significantly from that observed in animals infected intravenously with wild-type HCV. The RNA inoculated into chimpanzees originated from a single sequence, and the animals therefore had a monoclonal HCV infection. Monoclonal infection simplifies studies of HCV, because virus interaction with the host is not confounded by the quasispecies invariably present in a natural infection. It furthermore permits true homologous challenge in studies of protective immunity and in testing the efficacy of vaccine candidates. Finally, this in vivo transfection system has made it possible to test for the first time the importance of genetic elements for HCV infectivity.

Conserved hierarchy of helper T cell responses in a chimpanzee during primary and secondary hepatitis C virus infections.

Control of hepatitis C virus (HCV) infection could be influenced by the timing and magnitude of CD4+ T cell responses against individual epitopes. We characterized CD4+ T cells targeting seven Pan troglodytes (Patr) class II-restricted epitopes during primary and secondary HCV infections of a chimpanzee. All Patr-DR-restricted HCV epitopes bound multiple human HLA-DR molecules, indicating the potential for overlap in epitopes targeted by both species. Some human MHC class II molecules efficiently stimulated IL-2 production by chimpanzee virus-specific T cell clones. Moreover, one conserved epitope designated NS3(1248) (GYKVLVLNPSV) overlapped a helper epitope that is presented by multiple HLA-DR molecules in humans who spontaneously resolved HCV infection. Resolution of primary infection in the chimpanzee was associated with an initial wave of CD4+ T cells targeting a limited set of dominant epitopes including NS3(1248.) A second wave of low-frequency CD4+ T cells targeting other subdominant epitopes appeared in blood several weeks later after virus replication was mostly contained. During a second infection 7 years later, CD4+ T cells against all epitopes appeared in blood sooner and at higher frequencies but the pattern of dominance was conserved. In summary, primary HCV infection in this individual was characterized by T cell populations targeting two groups of MHC class II-restricted epitopes that differed in frequency and kinetics of appearance in blood. The hierarchial nature of the CD4+ T cell response, if broadly applicable to other HCV-infected chimpanzees and humans, could be a factor governing the outcome of HCV infection.

Immunoglobulin G antibody avidity assay for serodiagnosis of hepatitis C virus infection.

It has been reported that the avidity of specific IgG antibody is lower in primary viral infection than in chronic viral infection. However, few studies have been reported on the IgG avidity in hepatitis C virus (HCV) infection. In the present study, 36 patients with antibody to HCV (anti-HCV) were examined for IgG avidity by an enzyme immunoassay with or without urea elution. The avidity index was significantly low in patients with primary HCV infection (7.7 +/- 6.8%, mean +/- SD), compared with patients with chronic HCV infection (77.0 +/- 21.8%) and individuals with past HCV infection (44.5 +/- 12.6%). Temporal changes of IgG avidity were examined in six patients with primary HCV infection. The avidity index was low in the acute phase of the infection and then increased with time. These results suggest that the avidity assay for IgG anti-HCV is a useful method for distinguishing primary HCV infection from chronic or past HCV infection.

Impact of aging on the development of hepatocellular carcinoma in patients with posttransfusion chronic hepatitis C.

Hepatitis C virus (HCV) infection is a heterogeneous disease, the natural history of which remains controversial. There is solid evidence that chronic HCV infection is responsible for the occurrence of hepatocellular carcinoma (HCC). The aim of the current cohort study was to determine the rate of the development of HCC from the time of primary HCV infection and to assess the risk factors for the development of HCC in chronic posttransfusion hepatitis C patients. Four hundred sixty-nine patients with clinically compensated HCV, who had undergone a single blood transfusion comprised the current study cohort. Patients with other risk factors for chronic liver disease were excluded. All patients were referred to the liver center at the National Nagasaki Medical Center between December 1980 and December 1998 and were followed prospectively until the end of the analysis (June 2000). Follow-up data were obtained for 445 patients. The mean duration from HCV infection to the end of the observation was 28 years. Fifty-two patients (11.1%) progressed to HCC. The mean duration from the time of blood transfusion to the diagnosis of HCC was 31 years. Multivariate Cox regression analyses revealed age, fibrosis, duration from HCV infection to study entry, and alcohol consumption to be the independent factors affecting the development of HCC. The risk of developing HCC in patients age > or = 56 years was increased 7.8-fold compared with that in patients age < 56 years. The mean age of patients at the time of HCC diagnosis was 65 years (range, 58-79 years). At the time of diagnosis, 92% of the 52 HCC patients were age > 60 years and 38 of the HCC patients (73%) were in their 60s. There was a significantly negative correlation between the duration from HCV infection to the development of HCC and the age of the patient at the time of infection (correlation coefficient = 0.702; P < 0.0001; Y = 61.1-0.82X), indicating that the age of patients, rather than the duration of HCV infection, is more significant for HCC development in patients with posttransfusion HCV. Moreover, these data may contribute to the design of an optimal follow-up schedule for patients with posttransfusion HCV.

Hepatitis C virus infection in HIV-infected patients

The hepatitis C virus (HCV) is a spherical enveloped RNA virus of the Flaviviridae family, classified within the Hepacivirus genus. Since its discovery in 1989, HCV has been recognized as a major cause of chronic hepatitis and hepatic fibrosis that progresses in some patients to cirrhosis and hepatocellular carcinoma. In the United States, approximately 4 million people have been infected with HCV, and 10,000 HCV-related deaths occur each year. Due to shared routes of transmission, HCV and HIV co-infection are common, affecting approximately one third of all HIV-infected persons in the United States. In addition, HIV co-infection is associated with higher HCV RNA viral load and a more rapid progression of HCV-related liver disease, leading to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons because the incidence of infection is increased and the natural history of HCV infection is accelerated in co-infected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed among HIV/HCV co-infected individuals.

Insights into the epidemiology, natural history and pathogenesis of hepatitis C virus infection from studies of infected donors and blood product recipients

Studies of patients with post-transfusion non-A, non-B hepatitis and their implicated donors were critical to the discovery of hepatitis C virus (HCV) and to the development and progressive enhancement of HCV immunoassays for donor screening and diagnostic applications. Post-transfusion HCV cases have also been used to define the time course of viral and immunological markers following acute infection. Even more precise data on the timing and characteristics of viremia and immune responses during primary HCV infection have been derived from studies of serial samples from source plasma donors who were identified while in the process of infection and seroconversion. Such data have been critical to the derivation of estimates for the viremic, pre-seroconversion window period, and hence projections of the yield of addition of nucleic acid amplification technology (NAT) or HCV core antigen enzyme immunoassays (Ag-EIAs) to antibody screening in donor and diagnostic settings. In addition to these implications for screening and diagnosis, studies of HCV in the blood donor and blood product recipient settings have yielded substantial insights into the epidemiology, pathogenesis and prognosis of HCV infection. In the future, prospective studies of blood and plasma donors detected in the primary phase of HCV infection by NAT screening, will be important for defining viral and host genetic and immunological determinants of clearance of acute viremia, as well as for investigating the benefits of early treatment. Thus, the findings from studies of HCV among donors and blood product recipients have yielded and should continue to provide important insights into HCV pathogenesis leading to novel diagnostic, therapeutic and vaccination strategies.

Viral clearance in hepatitis C (1b) infection: Relationship with human leukocyte antigen class II in a homogeneous population

The aim of this study was to investigate the possibility of a significant relationship between human leukocyte antigen (HLA) class II and the clearance of hepatitis C virus (HCV). The study group consisted of 156 Irish women who iatrogenically received HCV 1b-contaminated Anti-D immunoglobulin between May 1977 and November 1978. Thus, the study population was homogeneous in terms of gender, source of infection, and ethnicity. On Screening in 1994, all individuals were anti-HCV antibody positive by recombinant immunoblot assay, while 46% (n = 72) of the group were HCV-positive by reverse transcriptase-polymerase chain reaction (RT-PCR). HLA DRB1 and DQB1 status was molecularly defined by high resolution reverse line probe hybridization methodology. Clearance of HCV 1b was found to be associated with DRB1*01. However, this association was lost after Bonferroni correction for multiple comparisons. Extended haplotype analysis between specific DRB1 and DQB1 allelic combinations identified a significant reduction in the frequency of DQB1*0501 in the presence of DRB1*0701 in the persistently infected individuals in the study group (P <.05). No associations with either viral clearance or persistence were found at the DQB1 locus. Our results suggest that HLA DRB1*01 appears to contribute to the spontaneous resolution of a primary HCV infection in the Irish population. The presence of DRB1*0701 in the absence of DQB1*0501 possibly reflects an influence of this allele in persistence of HCV infection. Defined and homogeneous patient populations offer the best opportunity to illuminate previously disguised immunogenetic factors important in the clearance of HCV 1b.

Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus.

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Owing to shared routes of transmission, HCV and human immunodeficiency virus (HIV) coinfection are common, affecting approximately one-third of all HIV-infected persons in the United States. In addition, HIV coinfection is associated with higher HCV RNA level and a more rapid progression of HCV-related liver disease, which leads to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons, because the incidence of infection is increased and the natural history of HCV infection is accelerated in coinfected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed for HIV-HCV-coinfected individuals.

Low Levels of Hepatitis C Virus RNA in Serum, Plasma, and Peripheral Blood Mononuclear Cells of Injecting Drug Users During Long Antibody-Undetectable Periods Before Seroconversion

Screening of antibodies to hepatitis C virus (HCV) is widely used for monitoring the prevalence of HCV infections and to assess HCV infectivity. Among HCV-infected individuals in the general population, the interval between the detection of HCV RNA and the development of HCV antibodies is usually 5 to 6 weeks, but in rare cases, seroconversion may be prolonged up to 6 to 9 months. In this study, we tested for the presence of HCV RNA during the antibody-undetectable period of 19 drug-injecting HCV seroconverters to gain insight into the antibody-negative carrier status in this population. HCV seroconversion status was determined by testing the first and last serum samples obtained from each subject, using third-generation antibody screening and confirmation assays. Serial samples were tested for HCV-specific antibodies to establish the moment of seroconversion and HCV RNA by single reverse transcriptase-polymerase chain reaction (RT-PCR) and branched DNA assay (bDNA) in serum. Plasma and peripheral blood mononuclear cells (PBMCs) were independently collected and tested for HCV RNA. HCV RNA-positivity was confirmed by Southern blot hybridization and sequencing of serial samples. The 19 HCV seroconverters had a mean follow-up of 5 years (range, 1 to 8 years). Of the 19, 4 were human immunodeficiency virus (HIV)-infected before HCV seroconversion. HCV RNA was detected in serum before seroconversion in 12 (63.2%) of the 19 HCV seroconverters, independent of HIV status. In 7 of these 12, the antibody-undetectable period was relatively short (2 to 10 months). The other 5, who were all HIV-negative before HCV seroconversion, had intermittent low levels of HCV RNA before seroconversion for a period of more than 12 months, with a mean of 40.8 months (range, 13 to 94 months). In all 5 individuals, independent repeats of the experiments confirmed the presence of HCV RNA in serum, and in 3 of these individuals, HCV-positivity was confirmed in independently collected plasma and PBMC samples. Low levels of HCV RNA may be present during prolonged antibody-undetectable periods before seroconversion in a number of injecting drug users. Independent of HIV status, their immune system appears to be unable to respond to these low HCV RNA levels and was sometimes only activated after reinfections with distinct HCV genotypes. These results indicate that primary HCV infection may not always elicit the rapid emergence of HCV antibodies and suggests that persistent low levels of HCV RNA (regardless of the genotype) may not elicit at all or delay antibody responses for prolonged periods of time.