REtrieval And cure of Chronic Hepatitis C (REACH): Results of micro-elimination in the Utrecht province.

BACKGROUND: The Netherlands is one of the six European countries considered on track to eliminate hepatitis C virus by 2030. To achieve this goal, continuous efforts have to be put into designing efficient case-finding strategies, including the retrieval of previously diagnosed hepatitis C virus-infected who are lost to follow-up. AIMS: To trace and treat all lost to follow-up hepatitis C virus patients in the Utrecht region and create an efficient retrieval strategy that can be used in future (national) retrieval initiatives. METHODS: Positive hepatitis C virus diagnostic tests (anti-hepatitis C virus IgG or hepatitis C virus-RNA) from the laboratory of all four hospitals and one central laboratory for primary care diagnostics in the province of Utrecht from 2001 to 2015 were linked to clinical records. Untreated patients with available contact information were deemed eligible for retrieval and invited for reevaluation with (virology) blood tests, fibroscan measurement and possible direct-acting antiviral therapy. MAIN RESULTS: After screening all hepatitis C virus diagnostics, 1913 chronic hepatitis C virus-infected were identified of which 14.1% (n = 269) were invited back into care. Overall, 17.4% was traced with the highest yield (28.3%) in those who lived in the Utrecht province. Through renewed patient assessments, 42 chronic hepatitis C virus infections were re-identified (76% with a history of intravenous drug use, 24% with Metavir F3-F4). Until now, 59% has either scheduled or initiated direct-acting antiviral therapy. CONCLUSION: The retrieval of previously diagnosed hepatitis C virus patients through screening of laboratory diagnostics from the past is feasible and should be pursued for further control and reduction of hepatitis C virus infection. Retrieval is most successful when performed regionally. LAY SUMMARY: To completely eliminate chronic hepatitis C virus (HCV) infection and prevent complications, undiagnosed and also previously diagnosed but lost to follow-up (LFU) HCV patients have to be brought (back) into care for therapy. Retrieval of LFU HCV patients through screening of laboratory diagnostics from the past is feasible and most successful when performed regionally.

Resistance-associated polymorphisms in Dutch hepatitis C genotype 1a patients with and without HIV infection.

UNLABELLED:  Background and aim. Resistance-associated variants (RAVs) on the NS3 region of the hepatitis C virus (HCV) may be relevant for antiviral therapy, but data in human immunodeficiency virus (HIV) coinfected patients are scarce. We assessed frequencies of NS3 RAVs in patients infected with HCV genotype 1a with or without HIV coinfection. MATERIAL AND METHODS: HCV NS3 amino acids 1-181 were sequenced by the Sanger method and analyzed for RAVs. RAVs and their distribution between HCV genotype 1a clade I and II viruses were compared between HIV-infected versus HIV-uninfected patients. RESULTS: 148 samples were available (n = 68 HIV and n = 80 non-HIV). Relative frequency of clade I and clade II was significantly different between HIV (85% and 15%) and non-HIV groups (49% and 51%). Overall, HIV infected patients exhibited significantly lower prevalence of RAVs than HIV-uninfected patients (62% vs. 79%, p = 0.03). However, Q80K prevalence was significantly higher in HIV-infected subjects (50% vs. 24%, p = 0.001), whereas prevalence of S122D/G/N/S (2% vs. 16%, p = 0.002) and N174G/N/S (10% vs. 55%, p < 0.0001) polymorphisms were significantly lower. Q80K was found exclusively in clade I viruses. S122 (3% vs. 22%, p=0.001) and N174 (13% vs. 75%, p<0.0001) polymorphisms had significantly lower prevalence in clade I than clade II viruses. CONCLUSIONS: In the Netherlands, prevalence of clade I viruses and Q80K was significantly higher in HCV genotype 1a infected patients with HIV coinfection than in those without HIV coinfection. Prevalence of N174 and S122 polymorphisms was significantly higher in clade II than clade I viruses.

Immunogenicity of Influenza Vaccines: Evidence for Differential Effect of Secondary Vaccination on Humoral and Cellular Immunity.

While currently used influenza vaccines are designed to induce neutralizing antibodies, little is known on T cell responses induced by these vaccines. The 2009 pandemic provided us with the opportunity to evaluate the immune response to vaccination in a unique setting. We evaluated both antibody and T cell responses in a cohort of public health care workers (18-52 years) during two consecutive influenza seasons from 2009 to 2011 and compared the MF59-adjuvanted pandemic vaccine with the unadjuvanted seasonal subunit vaccine that included the pandemic strain [The study was registered in the Netherlands Trial Register (NTR2070)]. Antibody responses were determined in serum by a hemagglutination inhibition assay. Vaccine-specific T cell responses were evaluated by detecting IFN-γ producing peripheral blood mononuclear cells using whole influenza virus or vaccine-specific peptide pools as stimulating antigens. Mixed effects regression models were used to correct the data for influenza-specific pre-existing immunity due to previous infections or vaccinations and for age and sex. We show that one dose of the pandemic vaccine induced antibody responses sufficient for providing seroprotection and that the vaccine induced T cell responses. A second dose further increased antibody responses but not T cell responses. Nonetheless, both could be boosted by the seasonal vaccine in the subsequent season. Furthermore, we show that the seasonal vaccine alone is capable of inducing vaccine-specific T cell responses, despite the fact that the vaccine did not contain an adjuvant. In addition, residual antibody levels remained detectable for over 15 months, while T cell levels in the blood had contracted to baseline levels by that time. Hereby, we show that pandemic as well as seasonal vaccines induce both humoral and cellular responses, however, with a different profile of induction and waning, which has its implications for future vaccine design.

The hepatitis C virus nonstructural protein 3 Q80K polymorphism is frequently detected and transmitted among HIV-infected MSM in the Netherlands.

OBJECTIVES: The Q80K polymorphism is a naturally occurring resistance-associated variant in the hepatitis C virus (HCV) nonstructural protein 3 (NS3) region and is likely transmissible between hosts. This study describes the Q80K origin and prevalence among HCV risk groups in the Netherlands and examines whether Q80K is linked to specific transmission networks. DESIGN AND METHODS: Stored blood samples from HCV genotype 1a-infected patients were used for PCR and sequencing to reconstruct the NS3 maximum likelihood phylogeny. The most recent common ancestor was estimated with a coalescent-based model within a Bayesian statistical framework. RESULTS: Study participants (n = 150) were either MSM (39%), people who inject drugs (17%), or patients with other (15%) or unknown/unreported (29%) risk behavior. Overall 45% was coinfected with HIV. Q80K was present in 36% (95% confidence interval 28-44%) of patients throughout the sample collection period (2000-2015) and was most prevalent in MSM (52%, 95% confidence interval 38-65%). Five MSM-specific transmission clusters were identified, of which three exclusively contained sequences with Q80K. The HCV-1a most recent common ancestor in the Netherlands was estimated in 1914 (95% higher posterior density 1879-1944) and Q80K originated in 1957 (95% higher posterior density 1942-1970) within HCV-1a clade I. All Q80K lineages could be traced back to this single origin. CONCLUSION: Q80K is a highly stable and transmissible resistance-associated variant and was present in a large part of Dutch HIV-coinfected MSM. The introduction and expansion of Q80K variants in this key population suggest a founder effect, potentially jeopardizing future treatment with simeprevir.

Acute influenza virus-associated encephalitis and encephalopathy in adults: a challenging diagnosis.

Background: Acute influenza-associated encephalopathy/encephalitis (IAE) in adults is a rare but well-known complication of influenza virus infection. The diagnosis is difficult to make due to the absence of distinctive clinical symptoms and validated diagnostic criteria. We present an illustrative case and a case review on acute IAE in adults. Methods: We performed a Medline search of the English literature using the terms influenz*, encephal* and adult, and constructed a database of detailed descriptions of patients with influenza virus infection with influenza-like symptoms at the onset of neurological symptoms. Results: A total of 44 patients were included. Confusion and seizures were the most prevalent neurological symptoms, present in 12 (27 %) and 10 (23 %) patients, respectively. Magnetic resonance imaging (MRI) was performed in 21 patients and anomalies were found in 13 (62 %), with lesions located throughout the brain. Influenza virus RNA was detected in cerebrospinal fluid (CSF) in 5 (16 %) of 32 patients. Eight (18 %) of the forty-four patients died. The benefits of antiviral and immunomodulatory therapy have not been well studied. Discussion: Our results show that many different neurological symptoms can be present in patients with acute onset IAE. Therefore, the diagnosis should be considered in patients with fever and neurological symptoms, especially during the influenza season. Laboratory diagnosis consists of demonstration of influenza virus RNA in brain tissue, CSF or respiratory samples, and demonstration of intrathecal antibody production against influenza virus. The presence of brain lesions in MRI and influenza virus in CSF appear to be of prognostic value.