Integrated hepatitis C treatment is associated with improved retention and success in outpatient treatment for opioid use disorder at a private clinic.

Background: Direct acting antiretrovirals (DAA) are effective for individuals who are infected with chronic hepatitis C virus (HCV), yet many people go without access to these lifesaving treatments. Materials and methods: We conducted a non-randomized study evaluating treatment data for patients in outpatient treatment for opioid use disorder (OUD) at a private clinic. Patients who were HCV-positive, had been in OUD treatment for at least 4 weeks, and engaged in integrated HCV treatment with DAA (co-located within their treatment for OUD) were compared to patients with HCV who only received OUD treatment. We evaluated HCV cure; OUD medication adherence, treatment utilization and retention; and illicit substance use for those engaged in treatment between 9/2016 and 1/2018. Results: Seventy-four patients completed integrated HCV-OUD treatment with DAA, with 87.8% achieving cure. Of the 66 who completed treatment and were subsequently evaluated for sustained viral response 98.5% were cured. Patients who received integrated HCV and OUD treatment in our clinic, stayed in OUD treatment longer, demonstrated higher OUD medication adherence, and used less opioids or cocaine compared to HCV-infected patients (n = 572) being treated only for OUD. Discussion: We have reported on a reproducible intervention that lends itself to outpatient OUD treatment. Analyses demonstrate the potential positive impact HCV treatment has on OUD recovery, including reduction in opioid and cocaine use and increased retention in care. Conclusion: Co-locating HCV treatment with existing OUD treatment is feasible, effective, and demonstrates positive outcomes for the treatment of both conditions.

Under one roof: identification, evaluation, and treatment of chronic hepatitis C in addiction care.

For over a decade, the vast majority of new hepatitis C virus (HCV) infections have been among young people who inject drugs (PWID). Well-characterized gaps in chronic HCV diagnosis, evaluation, and treatment have resulted in fewer than 5% of PWID receiving HCV treatment. While interferon-based treatment may have intentionally been foregone during part of this time in anticipation of improved oral therapies, the overall pattern points to deficiencies and treatment exclusions in the health care system. Treatment for HCV with all-oral, highly effective direct-acting antiviral medication for 12 weeks or less is now the standard of care, putting renewed focus on effective delivery of care. We describe here both the need for and process of chronic HCV care under the roof of addiction medicine.

Viral epitope-specific T cell responses induced in chronic, hepatitis C virus-infected patients.

BACKGROUND: Approximate 180 million people worldwide are infected with hepatitis C virus (HCV). Historically, vaccination has been the most effective strategy for controlling infections of such major health concern. Therapeutic vaccine strategies for HCV, however, have demonstrated negligible success. AIM: Demonstrate the ability of highly-conserved viral epitopes to overcome the immune dysfunction often associated with chronic HCV infections. METHODS: T cells from five chronic, HCV-infected patients were immunophenotyped by flow cytometry. The ex vivo T cell responses to highly-conserved viral epitopes were assessed by ELISpot assay and cytokine bead array analysis. RESULTS: Both HLA-DRB-1- and HLA-A2-restricted viral epitopes induced specific, TH1-type cytokine production by T cells derived from the patients. Induction occurred despite expression of cell-surface inhibitory molecules and the presence of regulatory T cells. CONCLUSION: These findings support the potential ability of a broad, multi-epitope-based therapeutic vaccine to elicit virus-specific immune responses in chronic hepatitis C virus-infected patients.

Adherence to Latent Tuberculosis Infection Treatment in a Population with a High Number of Refugee Children.

BACKGROUND: Refugee populations in the US have a higher reported prevalence of latent tuberculosis infection (LTBI). The objective of this study was to assess adherence to LTBI treatment in refugee and non-refugee children living in Rhode Island. METHODS: This was a retrospective review of LTBI patients seen in the Hasbro Pediatric Tuberculosis Clinic between August 2009 and September 2011. RESULTS: Of 120 patients with LTBI, 93% were foreign-born and 30% were refugees. Overall, 94 children (78.3%) completed therapy. Higher rates of treatment completion were seen among patients who were female, referred within the same hospital system, used an interpreter, and did not report side effects. Refugees attended more scheduled visits compared to non-refugees (p=0.019). CONCLUSIONS: Overall rates of completion of LTBI treatment were high in this population. Better adherence to clinic visits, likely due to the increased support and care coordination provided to the refugee children, improved treatment completion rates. [Full article available at http://rimed.org/rimedicaljournal-2017-02.asp].

HCV epitope, homologous to multiple human protein sequences, induces a regulatory T cell response in infected patients.

BACKGROUND & AIMS: Spontaneous resolution of hepatitis C virus (HCV) infection depends upon a broad T cell response to multiple viral epitopes. However, most patients fail to clear infections spontaneously and develop chronic disease. The elevated number and function of CD3(+)CD4(+)CD25(+)FoxP3(+) regulatory T cells (T(reg)) in HCV-infected patients suggest a role of Treg cells in impaired viral clearance. The factors contributing to increased Treg cell activity in chronic hepatitis C cases remain to be delineated. METHODS: Immunoinformatics tools were used to predict promiscuous, highly-conserved HLA-DRB1-restricted immunogenic consensus sequences (ICS), each composed of multiple T cell epitopes. These sequences were synthesized and added to cultures of peripheral blood mononuclear cells (PBMCs), derived from patients who resolved HCV infection spontaneously, patients with persistent infection, and non-infected individuals. The cells were collected and following 5days incubation, quantified and characterized by flow cytometry. RESULTS: One immunogenic consensus sequence (ICS), HCV_G1_p7_794, induced a marked increase in Treg cells in PBMC cultures derived from infected patients, but not in patients who spontaneously cleared HCV or in non-infected individuals. An analogous human peptide (p7_794), on the other hand, induced a significant increase in Treg cells among PBMCs derived from both HCV-infected and non-infected individuals. JanusMatrix analyses determined that HCV_G1_p7_794 is comprised of Treg cell epitopes that exhibit extensive cross-reactivity with the human proteome. CONCLUSIONS: A virus-encoded peptide (HCV_G1_p7_794) with extensive human homology activates cross-reactive CD3(+)CD4(+)CD25(+)FoxP3(+) natural Treg cells, which potentially contributes to immunosuppression and to the development of chronic hepatitis C.

Smarter vaccine design will circumvent regulatory T cell-mediated evasion in chronic HIV and HCV infection.

Despite years of research, vaccines against HIV and HCV are not yet available, due largely to effective viral immunoevasive mechanisms. A novel escape mechanism observed in viruses that cause chronic infection is suppression of viral-specific effector CD4(+) and CD8(+) T cells by stimulating regulatory T cells (Tregs) educated on host sequences during tolerance induction. Viral class II MHC epitopes that share a T cell receptor (TCR)-face with host epitopes may activate Tregs capable of suppressing protective responses. We designed an immunoinformatic algorithm, JanusMatrix, to identify such epitopes and discovered that among human-host viruses, chronic viruses appear more human-like than viruses that cause acute infection. Furthermore, an HCV epitope that activates Tregs in chronically infected patients, but not clearers, shares a TCR-face with numerous human sequences. To boost weak CD4(+) T cell responses associated with persistent infection, vaccines for HIV and HCV must circumvent potential Treg activation that can handicap efficacy. Epitope-driven approaches to vaccine design that involve careful consideration of the T cell subsets primed during immunization will advance HIV and HCV vaccine development.

Peptide-pulsed dendritic cells induce the hepatitis C viral epitope-specific responses of naïve human T cells.

Hepatitis C virus (HCV) is a major cause of liver disease. Spontaneous resolution of infection is associated with broad, MHC class I- (CD8(+)) and class II-restricted (CD4(+)) T cell responses to multiple viral epitopes. Only 20% of patients clear infection spontaneously, however, most develop chronic disease. The response to chemotherapy varies; therapeutic vaccination offers an additional treatment strategy. To date, therapeutic vaccines have demonstrated only limited success in clinical trials. Vector-mediated vaccination with multi-epitope-expressing DNA constructs provides an improved approach. Highly-conserved, HLA-A2-restricted HCV epitopes and HLA-DRB1-restricted immunogenic consensus sequences (ICS, each composed of multiple overlapping and highly conserved epitopes) were predicted using bioinformatics tools and synthesized as peptides. HLA binding activity was determined in competitive binding assays. Immunogenicity and the ability of each peptide to stimulate naïve human T cell recognition and IFN-γ production were assessed in cultures of total PBMCs and in co-cultures composed of peptide-pulsed dendritic cells (DCs) and purified T lymphocytes, cell populations derived from normal blood donors. Essentially all predicted HLA-A2-restricted epitopes and HLA-DRB1-restricted ICS exhibited HLA binding activity and the ability to elicit immune recognition and IFN-γ production by naïve human T cells. The ability of DCs pulsed with these highly-conserved HLA-A2- and -DRB1-restricted peptides to induce naïve human T cell reactivity and IFN-γ production ex vivo demonstrates the potential efficacy of a multi-epitope-based HCV vaccine targeted to dendritic cells.

Increasing hepatitis C prevalence and associated risk behaviors among incarcerated young adults.

This study sought to assess the rate of hepatitis C virus (HCV) infection and associated risk factors in young adults 18-28 years of age who were incarcerated in the Rhode Island Department of Corrections. The majority of participants reported injection drug use and engaged in high-risk behaviors such as needle sharing. Despite having these risk factors and believing themselves to be at risk, the majority of youths reported no prior HCV testing. Correctional facilities present a unique opportunity to detect HCV infection and provide risk reduction education to young adults, the population with the highest rates of new infections in the US. Seventy-two incarcerated individuals with a history of drug use were approached to participate in the study; 68 completed the screening and interview. The rate of HCV infection among adults <30 years of age and incarcerated at the Rhode Island Department of Corrections in 2011 was high (24%). In 1998, the rate of HCV among inmates <30 years of age at the same facility was only 11.4%. These data follow the same increase in HCV infection rates among young adults observed in non-incarcerated young adults across the nation. HCV is the leading cause of liver failure and hepatocellular carcinoma in the US. Despite a decline and leveling in HCV incidence nationwide, alarming increases in HCV rates among adolescents and young adults have been reported during the period between the years 1992 and 2005. This disquieting epidemic is attributable to injection drug use amongst young adults.

Divergent contributions of regulatory T cells to the pathogenesis of chronic hepatitis C.

Hepatitis C virus, a small single-stranded RNA virus, is a major cause of chronic liver disease. Resolution of primary hepatitis C virus infections depends upon the vigorous responses of CD4(+) and CD8(+) T cells to multiple viral epitopes. Although such broad CD4(+) and CD8(+) T-cell responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Purportedly, a variety of factors contribute to the diminished T-cell responses observed in chronic, virus-infected patients including the induction of and biological suppression by CD4(+)FoxP3(+) regulatory T cells. Indeed, a wealth of evidence suggests that regulatory T cells play diverse roles in the pathogenesis of chronic hepatitis C, impairing the effector T-cell response and viral clearance early during the course of infection and suppressing liver injury as the disease progresses. The factors that affect the generation and biological response of regulatory T cells in chronic, hepatitis C virus-infected patients is discussed.

The two-faced T cell epitope: examining the host-microbe interface with JanusMatrix.

Advances in the field of T cell immunology have contributed to the understanding that cross-reactivity is an intrinsic characteristic of the T cell receptor (TCR), and that each TCR can potentially interact with many different T cell epitopes. To better define the potential for TCR cross-reactivity between epitopes derived from the human genome, the human microbiome, and human pathogens, we developed a new immunoinformatics tool, JanusMatrix, that represents an extension of the validated T cell epitope mapping tool, EpiMatrix. Initial explorations, summarized in this synopsis, have uncovered what appear to be important differences in the TCR cross-reactivity of selected regulatory and effector T cell epitopes with other epitopes in the human genome, human microbiome, and selected human pathogens. In addition to exploring the T cell epitope relationships between human self, commensal and pathogen, JanusMatrix may also be useful to explore some aspects of heterologous immunity and to examine T cell epitope relatedness between pathogens to which humans are exposed (Dengue serotypes, or HCV and Influenza, for example). In Hand-Foot-Mouth disease (HFMD) for example, extensive enterovirus and human microbiome cross-reactivity (and limited cross-reactivity with the human genome) seemingly predicts immunodominance. In contrast, more extensive cross-reactivity with proteins contained in the human genome as compared to the human microbiome was observed for selected Treg epitopes. While it may be impossible to predict all immune response influences, the availability of sequence data from the human genome, the human microbiome, and an array of human pathogens and vaccines has made computationally-driven exploration of the effects of T cell epitope cross-reactivity now possible. This is the first description of JanusMatrix, an algorithm that assesses TCR cross-reactivity that may contribute to a means of predicting the phenotype of T cells responding to selected T cell epitopes. Whether used for explorations of T cell phenotype or for evaluating cross-conservation between related viral strains at the TCR face of viral epitopes, further JanusMatrix studies may contribute to developing safer, more effective vaccines.

Dendritic cells, regulatory T cells and the pathogenesis of chronic hepatitis C.

Hepatitis C virus (HCV) is a small, enveloped RNA virus and a major cause of chronic liver disease. Resolution of primary HCV infections depends upon the vigorous responses of CD4⁺ and CD8⁺ T cells to multiple viral epitopes. Although such broad-based responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Ostensibly, a variety of factors contribute to the diminished T cell responses observed in chronic, HCV-infected patients including impaired dendritic cell function and the induction of CD4⁺ FoxP3⁺ regulatory T cells. Overwhelming evidence suggests that the complex interaction of dendritic cells and regulatory T cells plays a critical role in the pathogenesis of chronic hepatitis C.

Transfusion-acquired Trypanosoma cruzi infection.

BACKGROUND: A 3(1/2)-year-old girl with Stage 4 neuroblastoma received multiple blood components and was subsequently diagnosed with Chagas disease, which is caused by Trypanosoma cruzi. STUDY DESIGN AND METHODS: All blood donors of the units that were transfused were requested to return to the collection facility for a blood sample to be tested for antibodies to T. cruzi. RESULTS: One first-time donor was found to be positive for the presence of T. cruzi antibodies. This donor was originally from Bolivia and immigrated to the United States 17 years previously. She had not returned to her native country since her emigration. CONCLUSIONS: This is the seventh reported case of Chagas disease transmission by blood transfusion in the United States and Canada. Although this would not be expected to occur in New England, it did, and this case demonstrates the significance of the immune status of patients as it relates to transfusion-acquired infections, the impact of geographic mobility in disease transmission, and the need for a licensed screening test for Chagas disease for the US blood supply.

Genital tract interleukin-8 but not interleukin-1beta or interleukin-6 concentration is associated with bacterial vaginosis and its clearance in HIV-infected and HIV-uninfected women.

Genital tract infections and cytokine perturbations are associated with increased HIV acquisition and transmission. We measured the relationship between bacterial vaginosis (BV) and concentrations of Interleukin-8 (IL-8), Interleukin-1beta (IL-1beta), and Interleukin-6 (IL-6) in cervicovaginal lavage (CVL) specimens collected longitudinally from 16 HIV-infected and 8 HIV-uninfected high-risk women. CVL samples were analyzed when women presented with BV, and at their next visit, after successful treatment, when BV was cleared. A subset of participants had cytokine levels evaluated at three consecutive clinic visits: before developing BV, at the time of BV diagnosis, and after clearing BV. Significantly higher IL-8, but not IL-1beta or IL-6 levels were present when women had active BV compared to when BV was absent. Trends in cytokine levels were similar for HIV-infected and HIV-uninfected women. BV in these women was associated with significantly higher concentrations of genital tract IL-8 which decreased 2.4 fold when BV was cleared.

Failure of serial human immunodeficiency virus type 1 DNA polymerase chain reactions to identify human immunodeficiency virus type 1 clade A/G.

The most commonly used test to screen for human immunodeficiency virus type 1 (HIV-1) infection in HIV-exposed infants in the United States is HIV-1 qualitative DNA polymerase chain reaction (PCR). However, the commercially available HIV-1 DNA PCR lack optimal sensitivity to detect non-subtype B subtypes of HIV-1. We report here HIV-1 infection in a West African infant that went undetected by serial HIV-1 DNA PCR tests.

Servicio de orientacion y deteccion de VIH vinculado a un programa comunitario antituberculoso en una poblacion de alto riesgo / Wide-spread HIV counseling and testing linked to a community based tuberculosis control program in a high-risk population

La finalidad del trabajo que aqui se describe fue evaluarel tamizaje comunitario para la deteccion de los casos de infeccion por VIH vinculado a un programa de lucha anticuberculosa en una poblacion de alto riesgo de ambas infecciones. De mayo de 1990 a agosto de 1992, trabajadores de salud comunitarios se comunicaron con adultos en domicilios y dispensarios de Cite Soleil, Haiti, para ofrecerles servicios institucionales de asesoramiento individual y de deteccion de VIH y de tuberculosis. A todas las personas que aceptaron la prueba se les dio asesoramiento posterior sobre VIH. Las que tenian tuberculosis activa recibieron tratamiento y a las que tenian enfermedad latente mas infeccion por VIH se les dio la oportunidad de participar en un ensayo clinico sobre quimioprofilaxis antituberculosa. La elevada prevalencia de infeccion por VIH en la poblacion examinada, al compararsela con otros grupos sometidos a tamizaje en la misma comunidad, indica que las personas en alto riesgo de infeccion por VIH buscaron selectivamente o aceptaron someterse a las pruebas de tamizaje ofrecidas en los dispensarios de tuberculosis. Asimismo, a muchas personas se les diagnostico tuberculosis activa en una fase mas temprana de la enfermedad de lo que hubiera sido posible sin un programa de tamizaje. En general, los resultados indican que cuando el tamizaje comunitario para la deteccion de VIH es parte de un programa de lucha antituberculosa, el resultado puede ser una mejor focalizacion de destinatarios para las pruebas de deteccion de ambas infecciones

Widespread HIV counseling and testing linked to a community-based tuberculosis control program in a high-risk population

The aim of the work reported here was to evaluate community-wide screening for HIV infection that was linked to a tuberculosis control program in a population at high risk for both infections. Between May 1990 and August 1992, adults in Cité Soleil, Haiti, were recruited by community health workers at their homes and in clinics for individual, clinic-based counseling and testing for HIV and tuberculosis. All of the screened subjects were offered post-test HIV counseling. Those with active tuberculosis received treatment, while those with latent tuberculosis and HIV infection were offered an opportunity to participate in a trial of antituberculosis chemoprophylaxis. The 10 611 individuals screened for HIV represented 10.0 percent of the adult population in Cité Soleil. HIV infection was detected in 1 629 (15.4 percent) and active tuberculosis in 242 (2.3 percent). Latent M. tuberculosis infection was found in 4 800 (67.5 percent) of 7 309 community residents who completed tuberculosis screening, 781 (16.3 percent) of whom were coinfected with HIV. The high prevalence of HIV infection found in this screened population, as compared to other groups undergoing HIV screening in the same community, suggests that people at high risk for HIV infection selectively sought or accepted tuberculosis clinic screening. Also, many people with active tuberculosis were identified earlier in the course of their disease than they would have been in the absence of a screening program. Overall, the results indicate that community-based screening for HIV infection within a tuberculosis control program can result in effective targeting of screening for both infections

Widespread HIV counseling and testing linked to a community-based tuberculosis control program in a high-risk population

The aim of the work reported here was to evaluate community-wide screening for HIV infection that was linked to a tuberculosis control program in a population at high risk for both infections. Between May 1990 and August 1992, adults in Cité Soleil, Haiti, were recruited by community health workers at their homes and in clinics for individual, clinic-based counseling and testing for HIV and tuberculosis. All of the screened subjects were offered post-test HIV counseling. Those with active tuberculosis received treatment, while those with latent tuberculosis and HIV infection were offered an opportunity to participate in a trial of antituberculosis chemoprophylaxis. The 10 611 individuals screened for HIV represented 10.0 percent of the adult population in Cité Soleil. HIV infection was detected in 1 629 (15.4 percent) and active tuberculosis in 242 (2.3 percent). Latent M. tuberculosis infection was found in 4 800 (67.5 percent) of 7 309 community residents who completed tuberculosis screening, 781 (16.3 percent) of whom were coinfected with HIV. The high prevalence of HIV infection found in this screened population, as compared to other groups undergoing HIV screening in the same community, suggests that people at high risk for HIV infection selectively sought or accepted tuberculosis clinic screening. Also, many people with active tuberculosis were identified earlier in the course of their disease than they would have been in the absence of a screening program. Overall, the results indicate that community-based screening for HIV infection within a tuberculosis control program can result in effective targeting of screening for both infections

This article will also be published in Spanish in the Bol. OSP. Vol. 120(5), 1996

Servicio de orientacion y deteccion de VIH vinculado a un programa comunitario antituberculoso en una poblacion de alto riesgo / Wide-spread HIV counseling and testing linked to a community based tuberculosis control program in a high-risk population

La finalidad del trabajo que aqui se describe fue evaluarel tamizaje comunitario para la deteccion de los casos de infeccion por VIH vinculado a un programa de lucha anticuberculosa en una poblacion de alto riesgo de ambas infecciones. De mayo de 1990 a agosto de 1992, trabajadores de salud comunitarios se comunicaron con adultos en domicilios y dispensarios de Cite Soleil, Haiti, para ofrecerles servicios institucionales de asesoramiento individual y de deteccion de VIH y de tuberculosis. A todas las personas que aceptaron la prueba se les dio asesoramiento posterior sobre VIH. Las que tenian tuberculosis activa recibieron tratamiento y a las que tenian enfermedad latente mas infeccion por VIH se les dio la oportunidad de participar en un ensayo clinico sobre quimioprofilaxis antituberculosa. La elevada prevalencia de infeccion por VIH en la poblacion examinada, al compararsela con otros grupos sometidos a tamizaje en la misma comunidad, indica que las personas en alto riesgo de infeccion por VIH buscaron selectivamente o aceptaron someterse a las pruebas de tamizaje ofrecidas en los dispensarios de tuberculosis. Asimismo, a muchas personas se les diagnostico tuberculosis activa en una fase mas temprana de la enfermedad de lo que hubiera sido posible sin un programa de tamizaje. En general, los resultados indican que cuando el tamizaje comunitario para la deteccion de VIH es parte de un programa de lucha antituberculosa, el resultado puede ser una mejor focalizacion de destinatarios para las pruebas de deteccion de ambas infecciones

Este articulo se publico en ingles en el Bull. PAHO. Vol. 30(1), 1996