Frequent Longitudinal Sampling of Hepatitis C Virus Infection in Injection Drug Users Reveals Intermittently Detectable Viremia and Reinfection
ABSTRACT Background. Detection of hepatitis C virus (HCV) reinfection and intercalation (i.e., intermittent recurrent bouts of viremia with homologous virus interspersed with aviremic periods) requires extensive and frequent evaluation and viral sequencing.Methods. HCV infection outcomes were studied prospectively in active IDU with recurrent HCV RNA positive tests after serial negative results. HCV viremia and viral sequences (Core/E1) were assessed from monthly blood samples.Results. Viral clearance, reinfection and intercalating infection were all detected. Among 44 participants with apparently resolved HCV (26 incident HCV clearers and 18 enrolled with already resolved infection), 36 (82%) remained persistently HCV RNA negative, but 8 demonstrated intermittent recurrent viremia. Four of these (50%) had confirmed reinfection with a heterologous virus; three demonstrated viral intercalation, and one was not classifiable as either. Estimated incidence of first reinfection was 5.4/100 PY; (95% CI, 2.0, 14.5). Six (75%) participants, including three of four of those with reinfection, demonstrated sustained viral clearance for a median of 26 months since last HCV RNA test.Conclusions. These results show that frequent monitoring and viral sequencing are required to correctly assess HCV outcomes and estimate incidence of reinfection (which was previously overestimated). Sustained clearance may take many months and occur after episodes of reinfection and viral intercalation. Three of four subjects who had confirmed reinfection showed evidence of long term clearance. Viral intercalation occurs with significant frequency. Further studies of these events, especially immunological are needed to inform HCV clinical care and vaccine development.
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ABSTRACT: Hepatitis C virus (HCV) infection is still a serious global health burden. Despite improved therapeutic options, a preventative vaccine would be desirable especially in undeveloped countries. Traditionally, highly conserved epitopes are targets for antibody-based prophylactic vaccines. In HCV-infected patients, however, neutralizing antibodies are primarily directed against hypervariable region I (HVRI) in the envelope protein E2. HVRI is the most variable region of HCV, and this heterogeneity contributes to viral persistence and has thus far prevented the development of an effective HVRI-based vaccine. The primary goal of an antibody-based HCV vaccine should therefore be the induction of cross-reactive HVRI antibodies. In this study we approached this problem by presenting selected cross-reactive HVRI variants in a highly symmetric repeated array on capsid-like particles (CLPs). SplitCore CLPs, a novel particulate antigen presentation system derived from the HBV core protein, were used to deliberately manipulate the orientation of HVRI and therefore enable the presentation of conserved parts of HVRI. These HVRI-CLPs induced high titers of cross-reactive antibodies, including neutralizing antibodies. The combination of only four HVRI CLPs was sufficient to induce antibodies cross-reactive with 81 of 326 (24.8%) naturally occurring HVRI peptides. Most importantly, HVRI CLPs with AS03 as an adjuvant induced antibodies with a 10-fold increase in neutralizing capability. These antibodies were able to neutralize infectious HCVcc isolates and 4 of 19 (21%) patient-derived HCVpp isolates. Taken together, these results demonstrate that the induction of at least partially cross-neutralizing antibodies is possible. This approach might be useful for the development of a prophylactic HCV vaccine and should also be adaptable to other highly variable viruses.PLoS ONE 07/2014; 9(7):e102235. DOI:10.1371/journal.pone.0102235 · 3.53 Impact Factor
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ABSTRACT: The US faces at least two distinct epidemics of hepatitis C virus infection (HCV), and due largely to revised screening recommendations and novel therapeutic agents, corresponding opportunities. As only 49%-75% of HCV-infected persons in the US are aware of their infection, any chance of addressing HCV in the US is dependent upon screening to identify undiagnosed infections. Most HCV in the US consists of longstanding infections among persons born during 1945-1965 who are suffering escalating rates of liver-related morbidity and mortality. Mathematical modeling supports aggressive action to reach and treat these persons to minimize the subsequent burden of advanced liver disease on patients and the health care system. Incident infection is primarily among persons who inject drugs, less than 10% of whom have been treated for HCV. Expanded screening and treatment of active persons who inject drugs raises the prospect of utilizing "treatment as prevention" to stem the tide of incident HCV infections in this population. HIV-positive men who have sex with men (MSM) represent a population at risk for sexually transmitted HCV who may also benefit from adjusted screening guidelines to identify both acute and chronic infections. Prisoners also represent a critical population for aggressive screening and treatment. Finally, the two-stage testing algorithm for HCV diagnosis is problematic and difficult for patients and providers to navigate. While emerging therapeutics raise the prospect of reducing HCV-related morbidity and mortality, as well as eliminating new infections, major barriers remain with regard to identifying infections, improving access to treatment, and ensuring payer coverage of costly new therapeutic regimens.Hepatic Medicine: Evidence and Research 07/2014; 6:79-87. DOI:10.2147/HMER.S40940
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ABSTRACT: Hepatitis C virus (HCV) remains a global problem, despite advances in treatment. The low cost and high benefit of vaccines have made them the backbone of modern public health strategies, and the fight against HCV will not be won without an effective vaccine. Achievement of this goal will benefit from a robust understanding of virus-host interactions and protective immunity in HCV infection. In this review, we summarize recent findings on HCV-specific antibody responses associated with chronic and spontaneously resolving human infection. In addition, we discuss specific epitopes within HCV's envelope glycoproteins that are targeted by neutralizing antibodies. Understanding what prompts or prevents a successful immune response leading to viral clearance or persistence is essential to designing a successful vaccine.Frontiers in Immunology 11/2014; 5:550. DOI:10.3389/fimmu.2014.00550