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A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8؉ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8 ؉ T cells during the acute and chronic stages of infection. Although HCV-specific CD8 ؉ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8 ؉ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCVspecific CD8؉ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the "death phase" of HCVspecific CD8؉ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.Hepatitis C virus (HCV) infects more than 150 million people worldwide (3, 61) and is a major cause of liver failure in the United States (41). Current treatments for chronic HCV infection cure only approximately 50% of persons infected with genotype 1 virus, the most prevalent genotype in the United States (49). In addition to limitations in efficacy, current antiviral therapy is prolonged and associated with disabling side effects, highlighting the need for improved therapeutic options.The adaptive T-cell immune response is important in mediating HCV clearance (10,14,19,36,42,55), yet the reason that a majority of infected patients develop only a weak, narrow, or nonpersistent adaptive response to acute infection is not well understood. Studies of some patients acutely infected with HCV show impairment of cytokine production and proliferation of HCV-specific CD8 ϩ T cells during the acute phase even though antigen-specific cells are present at a high frequency during this phase of infection (55). A period of "stunning" of HCV-specific CD8 ϩ T cells during the earliest time points has been observed (36). During the chronic phase of HCV infection, HCV-specific CD8 ϩ T cells also display significant functional deficits including impaired cytokine production and proliferative capacity (21, 62). Programmed death receptor 1 (PD-1) is an inhibitory receptor in the CD28 family that is expressed on antigen-specific T cells during acute and chronic viral infections (reviewed...

Suppression of hepatitis B virus (HBV) DNA to undetectable levels is an important goal for HIV/HBV-coinfected patients receiving anti-HBV-active antiretroviral therapy (ART), and current guidelines recommend that this outcome should be reached by one year of treatment. However, the proportion of patients that fail to achieve an undetectable HBV DNA at this time point and its determinants remain unknown in clinical practice. The objective of this study was to determine the incidence and risk factors for incomplete HBV suppression following one year of tenofovir-based ART. We performed a cohort study among tenofovir-treated HIV/HBV-coinfected patients. Patients had HBV viremia, initiated tenofovir-based ART, and had HBV DNA measured at one year of therapy. The primary outcome was incomplete HBV suppression (HBV DNA ≥2.6 log IU/mL) at one year. Logistic regression determined odds ratio (ORs) of incomplete HBV suppression for risk factors of interest. Among 133 patients, 54% (95% CI, 46%–63%) had incomplete HBV suppression at one year. Incomplete suppression was associated with higher baseline HBV DNA (OR, 1.46 per log IU/mL increase; 95% CI, 1.1–1.94) and detectable HIV viremia at one year (OR, 2.52; 95% CI, 1.19–5.32). Among 66 patients with suppressed HIV RNA at one year, 28 (42%) failed to achieve an undetectable HBV DNA. Failure to suppress HBV DNA by one year occurred in a sizeable proportion of tenofovir-treated HIV/HBV-coinfected patients. Higher HBV DNA and detectable HIV viremia were risk factors for incomplete HBV suppression.

Hepatitis B virus (HBV) is an important cause of end-stage liver disease and hepatocellular carcinoma. Effective treatment can delay or prevent these outcomes. The decision to treat is based on the activity of liver disease and HBV replication status, and the likelihood of a long-term benefit. Approved therapies include standard and pegylated interferon-alfa and nucleoside analogues: lamivudine, adefovir and entecavir. Current therapies do not eradicate HBV so long-term treatment is usually required. Development of drug resistance is a major concern with long-term treatment. Even with successful therapy, patients remain at risk for reactivation of viral replication and require lifelong monitoring.