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1.
Haematologica ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488561

RESUMO

Peripheral T-cell lymphoma comprises a heterogeneous group of mature non-Hodgkin lymphomas. Their diagnosis is challenging, with up to 30% of cases remaining unclassifiable and referred to as "not otherwise specified". We developed a reverse transcriptase-multiplex ligation-dependent probe amplification gene expression profiling assay to differentiate the main T-cell lymphoma entities and to study the heterogeneity of the "not specified" category. The test evaluates the expression of 20 genes, including 17 markers relevant to T-cell immunology and lymphoma biopathology, one EBV-related transcript, and variants of RHOA (G17V) and IDH2 (R172K/T). By unsupervised hierarchical clustering, our assay accurately identified 21/21 ALK-positive anaplastic large cell lymphomas, 16/16 extranodal NK/T-cell lymphomas, 6/6 hepatosplenic T-cell lymphomas, and 13/13 adult T-cell leukemia/lymphomas. ALK-negative anaplastic lymphomas (n=34) segregated into one cytotoxic cluster (n=10) and one non-cytotoxic cluster expressing Th2 markers (n=24) and enriched in DUSP22-rearranged cases. The 63 TFH-derived lymphomas divided in two subgroups according to a predominant TFH (n=50) or an enrichment in Th2 (n=13) signatures. We next developed a support vector machine predictor which attributed a molecular class to 27/77 not specified T-cell lymphomas: 17 TFH, 5 cytotoxic ALK-negative anaplastic, and 5 NK/T-cell lymphomas. Among the remaining cases, we identified two cell-of-origin subgroups corresponding to cytotoxic/Th1 (n=19) and Th2 (n=24) signatures. A reproducibility test on 40 cases yielded a 90% concordance between 3 independent laboratories. This study demonstrates the applicability of a simple gene expression assay for the classification of peripheral T-cell lymphomas. Its applicability to routinely-fixed samples makes it an attractive adjunct in diagnostic practice.

2.
J Virol ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511383

RESUMO

Several studies support a role for specific Killer Immunoglobulin-like Receptor (KIR)/HLA combinations in protection from HIV infection and slower time to AIDS. NK cells acquire effector functions through education, a process that requires the interaction of inhibitory Natural Killer (NK) cell receptors with their major histocompatibility complex (MHC) class I (or HLA-I) ligands. HLA-C allotypes are ligands for the inhibitory KIRs (iKIRs) KIR2DL1, KIR2DL2 and KIR2DL3 whereas the ligand for KIR3DL1 is HLA-Bw4. HIV infection reduces the expression of cell surface HLA-A, B and C on infected CD4 T cells (iCD4). Here, we investigated whether education through iKIR/HLA interactions influenced NK responses to autologous iCD4. Enriched NK cells were stimulated with autologous iCD4 or uninfected CD4 cells as controls. The capacity of NK cells to produce CCL4, IFN-γ and/or CD107a by single positive (sp) KIR2DL1, KIR2DL2, KIR2DL3 and KIR3DL1 NK cells was assessed by flow cytometry. Overall, we observed that NK cell education potency was directly related to the frequency of each spiKIR+ NK cell's ability to respond to the reduction of their cognate HLA-ligand on autologous iCD4 as measured by the frequency of spiKIR+ NK cells producing CCL4, IFN-γ and/or CD107a. Both NK cell education and HIV mediated changes in HLA expression influenced NK responses to iCD4 cells.IMPORTANCE Epidemiological studies show that natural killer (NK) cells have anti-HIV activity able to reduce the risk of HIV infection and/or slow HIV disease progression. How NK cells contribute to these outcomes is not fully characterized. We used primary NK and autologous HIV-infected cells to examine the role of education through four inhibitory Killer Immunoglobulin Receptors (iKIRs) from persons having HLA types able to educate, versus not, NK cells bearing one of these iKIRS. HIV-infected cells activated NK cells through missing-self mechanisms due HIV Nef and Vpu mediated downmodulation of cell surface HLA expression. A higher frequency of educated than uneducated NK cells expressing each of these iKIRs responded to autologous HIV+ cells by producing CCL4, IFN-γ and CD107a. As NK cells were from HIV uninfected individuals, they model the consequences of healthy NK/HIV+ cell interactions occurring in the HIV eclipse phase when new infections are susceptible to extinction.

3.
J Viral Hepat ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31433888

RESUMO

Hepatitis C virus (HCV) acquisition remains high in key risk environments including injection drug use and sex between men. However, few studies examine the independent contribution of sexual behaviour to HCV acquisition among people who inject drugs (PWID). We estimated HCV incidence and examined sexual behaviour as a time-varying predictor of HCV acquisition in a prospective cohort study of PWID in Montreal (2004-2017). Initially, HCV-negative participants completed behavioural questionnaires and HCV antibody testing (6 months until 2011, 3 months thereafter). A time-updating exposure variable (no sex, opposite-sex partner only, ≥1 same-sex partner) was generated for the previous 6/3 months. Time to HCV seroconversion was examined using Cox regression analysis, adjusted for age, unstable housing and incarceration (both past 3 months), and daily, heroin, cocaine and prescription opioid injecting (all past month). Among 440 PWID (baseline: median age 33 years, 18.9% female, 1.4% HIV-positive), 156 participants seroconverted during follow-up (overall incidence rate: 11.9/100 person-years [PY]). Incidence was lowest in the no sex group (8.70 and 2.91 cases/100 PY in males and females, respectively) and highest in the ≥1 same-sex partner group (24.14 and 21.97 cases/100 PY in males and females, respectively). Among males, HCV risk was 47% lower in those reporting no sex compared to ≥1 same-sex partner (adjusted hazard ratio: 0.53, 95% confidence interval: 0.28, 0.99). In this cohort of PWID, reporting recent same-sex partners was associated with greater risk of HCV acquisition among males, necessitating targeted harm reduction strategies that consider the complex interplay of sexual and injecting risk behaviours.

4.
Presse Med ; 2019 Aug 22.
Artigo em Francês | MEDLINE | ID: mdl-31447335

RESUMO

Chronic lymphoproliferative disorders should be classified according to the revised 2016 WHO classification. Biopsies are not mandatory for all chronic lymphoproliferative disorders as blood or bone marrow cytologroachical approach can be sufficient for some lymphoma entities. Diagnostic is based on a multidiscplinary approach taking into account clinical presentation, histopathological, cytological, immunophenotypical features (immunohistochemistry and Flow cytometry) and molecular pattern (translocation by FISH, Mutations landscape by NGS, and genomic abnormalities by CGH array). An important heterogeneity of clinical presentation and prognosis arises within the same lymphoma subtype. Clinical evolution is characterized by relapses, cytological progression and transformation into diffuse large B cell lymphoma, aggressive lymphoma or high-grade lymphomas.

5.
Clin Infect Dis ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31300820

RESUMO

BACKGROUND: In many settings, recent or prior injection drug use remain barriers to accessing direct-acting antiviral treatment (DAA) for hepatitis C virus (HCV) infection. We examined longitudinal patterns of drug and alcohol use and injection equipment sharing among people with recent injecting drug use or receiving opioid agonist treatment (OAT) during and following DAA-based treatment. METHODS: SIMPLIFY and D3FEAT are phase IV clinical trials evaluating the efficacy of DAA among people with past six-month injecting drug use or receiving OAT through a network of 25 international sites. Enrolled in 2016-2017, participants received sofosbuvir/velpatasvir (SIMPLIFY) or paritepravir/ritonavir/dasabuvir/ombitasvir±ribavirin (D3FEAT) for 12 weeks. Additionally, they completed a behavioural questionnaire before, during and after treatment, up to two years following treatment initiation. The impact of time in HCV treatment and follow-up on longitudinally measured behavioural outcomes was estimated using generalized estimating equations analyses. RESULTS: At screening, of 190 participants (mean age: 47; 74% male), 62% reported any past-month injecting (47% opioids, 39% stimulants), 16% past-month injection equipment sharing and 61% current OAT. Median alcohol use was 2 (AUDIT-C test, range 1-12). During follow-up, opioid injecting (OR: 0.95, 95%CI: 0.92-0.99) and sharing (0.87; 95%CI: 0.80-0.94) decreased, whereas no significant changes were observed for stimulant injecting (OR: 0.98, 95%CI: 0.94-1.02) or alcohol use (OR: 0.99; 95%CI: 0.95-1.04). No increasing patterns were noted for any outcome considered. CONCLUSION: Injecting drug use and risk behaviours remained stable or decreased during and following DAA-based HCV treatment. Findings further support expanding HCV treatment to all, irrespective of injection drug use.

6.
Int J Drug Policy ; 72: 1-10, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31345644

RESUMO

There have been major strides towards the World Health Organization goal to eliminate hepatitis C virus (HCV) infection as a global public health threat. The availability of simple, well-tolerated direct-acting antiviral therapies for HCV infection that can achieve a cure in >95% of people has provided an important tool to help achieve the global elimination targets. Encouragingly, therapy is highly effective among people receiving opioid agonist therapy and people who have recently injected drugs. Moving forward, major challenges include ensuring that new infections are prevented from occurring and that people who are living with HCV are tested, linked to care, treated, receive appropriate follow-up, and have equitable access to care. This editorial highlights key themes and articles in a special issue focusing on the elimination of HCV among people who inject drugs. An overarching consideration flowing from this work is how to ensure equitable access to HCV treatment and care for all. This special issue maps the field in relation to: HCV prevention; the cascade of HCV care; strategies to enhance testing, linkage to care, and treatment uptake; and HCV treatment and reinfection. In addition, papers draw attention to the 'risk environments' and socio-ecological determinants of HCV acquisition, barriers to HCV care, the importance of messaging around the side-effects of new direct-acting antiviral therapies, the positive transformative potential of treatment and cure, and the key role of community-based drug user organizations in the HCV response. While this special issue highlights some successful efforts towards HCV elimination among people who inject drugs, it also highlights the relative lack of attention to settings in which resources enabling elimination are scarce, and where elimination hopes and potentials are less clear, such as in many low and middle income countries. Strengthening capacity in areas of the world where resources are more limited will be a critical step towards ensuring equity for all so that global HCV elimination among PWID can be achieved.

7.
J Virol ; 93(18)2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31270222

RESUMO

HIV-exposed seronegative KIR3DS1 homozygotes have a reduced risk of HIV infection. HLA-F is the ligand for the activating NK cell receptor (NKR) KIR3DS1. HLA-F is expressed on HIV-infected CD4 T cells. Coculture of sorted, HIV-infected CD4- (siCD4-) T cells with NK cells activated a higher frequency of KIR3DS1+ than KIR3DS1- NK cells from KIR3DS1 homozygotes to elicit anti-HIV functions such as CCL4, gamma interferon (IFN-γ), and CD107a expression. This was the case whether KIR3DS1+/- NK cells were analyzed inclusively or exclusively by gating out NK cells coexpressing the NKRs, KIR2DL1/L2/L3, 3DL2, KIR2DS1/S2/S3/S5, NKG2A, and ILT2. Blocking the interaction of HLA-F on siCD4- cells with KIR3DS1 on exclusively gated KIR3DS1+ NK cells with KIR3DS1-Fc chimeric protein or an HLA-F-specific monoclonal antibody reduced the frequency of activated KIR3DS1+ cells compared to that under control conditions. KIR3DS1+ NK cell activation by HIV-infected CD4+ cells may underlie the reduced risk of KIR3DS1 homozygotes to HIV infection.IMPORTANCE This study investigated a mechanism that may underly epidemiological studies showing that carriage of the KIR3DS1 homozygous genotype is more frequent among HIV-exposed seronegative subjects than among HIV-susceptible individuals. Carriage of this genotype is associated with a reduced risk of HIV infection. The protective mechanism involves the interaction of HLA-F on CD4+ cells infected with replication-competent HIV with the activating NK receptor, KIR3DS1. This interaction leads to the activation of KIR3DS1+ NK cells for secretion of cytokines and chemokines with anti-HIV activity. Among these is CCL4, which binds and blocks CCR5, the coreceptor for HIV entry of HIV into new target cells. In the setting of an exposure to HIV, incoming HIV-infected cells expressing HLA-F rapidly activate KIR3DS1+ NK cells to elicit anti-HIV activity. Exclusive gating strategies and blocking experiments support the notion that the HLA-F/KIR3DS1 interaction is sufficient to activate NK cell functions.

8.
J Exp Med ; 216(8): 1777-1790, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31213488

RESUMO

Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.

9.
CMAJ ; 191(17): E462-E468, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036608

RESUMO

BACKGROUND: Opioid agonist treatment is considered important in preventing acquisition of hepatitis C virus (HCV) among people who inject drugs; however, the role of dosage in opioid agonist treatment is unclear. We investigated the joint association of prescribed dosage of opioid agonist treatment and patient-perceived dosage adequacy with risk of HCV infection among people who inject drugs. METHODS: We followed prospectively people who inject drugs at risk of acquiring HCV infection (who were RNA negative and HCV-antibody negative or positive) in Montréal, Canada (2004-2017). At 6-month, then 3-month intervals, participants were tested for HCV antibodies or RNA, and completed an interviewer-administered behavioural questionnaire, reporting the following: current exposure to opioid agonist treatment (yes/no), prescribed dosage either high (methadone ≥ 60 mg/d or buprenorphine ≥ 16 mg/d) or low, and perceived dosage adequacy (adequate/inadequate). We then assigned participants to 1 of 5 exposure categories: no opioid agonist treatment, high dosage of opioid agonist treatment perceived to be adequate, high dosage perceived to be inadequate, low dosage perceived to be adequate or low dosage perceived to be inadequate. To estimate associations between categories of opioid agonist treatment dosage and incident HCV infection, we conducted Cox regression analyses, adjusting for multiple confounding factors. RESULTS: Of 513 participants (median age 35.0 yr, 77.6% male), 168 acquired HCV over 1422.6 person-years of follow-up (incidence 11.8/100 person-years, 95% confidence interval [CI] 10.1-13.7). We observed a gradient in the relative risks of HCV infection across categories of opioid agonist treatment dosage. Compared with people who inject drugs not receiving opioid agonist treatment, adjusted hazard ratios were 0.43 (95% CI 0.23-0.84) for those receiving high dosages perceived to be adequate, 0.61 (95% CI 0.25-1.50) for those receiving high dosages perceived to be inadequate, 1.22 (95% CI 0.74-2.00) for those receiving low dosages perceived to be adequate and 1.94 (95% CI 1.11-3.39) for those receiving low dosages perceived to be inadequate. INTERPRETATION: Risk of HCV infection varies considerably according to dosage of opioid agonist treatment and patient-perceived adequacy, with associations indicating both protective and harmful effects relative to no exposure to opioid agonist treatment.

10.
Addict Behav ; 96: 175-182, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31108263

RESUMO

BACKGROUND: High-risk injection behaviors are associated with high prevalence of mental health problems among people who inject drugs (PWID). However, whether the use of mental health services is associated with lower risk of sharing injection material remains undetermined. This study aims to examine the association between mental health service utilisation and receptive sharing risk, and determine the potential modifying effect of psychological distress on this association. METHODS: Participants answered an interviewer-administered questionnaire at 3-month intervals gathering information on sociodemographic characteristics, substance use and related behaviors, services utilisation and significant mental health markers. Relationship between the use of mental health services and receptive sharing was modeled using the generalized estimating equation (GEE), controlling for age at baseline, gender, and other potential confounders. Psychological distress was estimated using the Kessler Psychological Distress Scale (K10). Effect modification was investigated by adding an interaction term in the univariate GEE analysis. RESULTS: 358 participants contributed to 2537 visits (median age 40.3, 82% male). Mental health service utilisation was reported in 631 visits (25%), receptive sharing in 321 visits (13%) and severe psychological distress in 359 visits (14%). In multivariate GEE analyses, a significant association was identified between receptive sharing and the use of mental health services (aOR = 0.69; 95% CI = 0.50-0.94). We found no evidence of effect modification by psychological distress. CONCLUSION: Among PWID, mental health service utilisation was associated with lower likelihood of receptive sharing, regardless of level of psychological distress. These findings should be taken into account when designing harm reduction strategies for this population.

11.
Addiction ; 114(8): 1495-1503, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30957310

RESUMO

BACKGROUND AND AIMS: For most people who inject drugs (PWID), drug injecting follows a dynamic process characterized by transitions in and out of injecting. The objective of this investigation was to examine injecting cessation episodes of 1-3-month duration as predictors of hepatitis C virus (HCV) acquisition. DESIGN: Cohort study. SETTING: Montréal, Canada. PARTICIPANTS: A total of 372 HCV-uninfected (HCV RNA-negative, HCV antibody-positive or -negative) PWID (mean age = 39.3 years, 82% male, 45% HCV antibody-positive) enrolled between March 2011 and June 2016. MEASUREMENTS: At 3-month intervals, participants completed an interviewer-administered questionnaire and were tested for HCV particles (HCV RNA). At each visit, participants indicated whether they injected in each of the past 3 months (defined as three consecutive 30-day periods). Injecting cessation patterns were evaluated on a categorical scale: persistent injecting (no injecting cessation in the past 3 months), sporadic injecting cessation (injecting cessation in 1 of 3 or 2 of 3 months) and short injecting cessation (injecting cessation in 3 of 3 months). Their association with HCV infection risk was examined using Cox regression analyses with time-dependent covariates, including age, gender, incarceration, opioid agonist treatment and other addiction treatments. FINDINGS: At baseline, 61, 26 and 13% of participants reported persistent injecting, sporadic injecting cessation and short injecting cessation, respectively. HCV incidence was 7.5 per 100 person-years [95% confidence interval (CI) = 5.9-9.5; 916 person-years of follow-up]. In adjusted Cox models, sporadic injecting cessation and short injecting cessation were associated with lower risks of incident HCV infection compared to persistent injecting (adjusted hazard ratios = 0.56, 95% CI = 0.30-1.04 and 0.24, 95% CI = 0.09-0.61), respectively. CONCLUSION: Short and sporadic injecting cessation episodes were common among a cohort of people who inject drugs in Montréal, Canada. Injecting cessation episodes appear to be protective against hepatitis C virus acquisition, particularly when maintained for at least 3 months.

12.
Int J Drug Policy ; 72: 11-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31003825

RESUMO

As direct-acting antiviral (DAA) therapy costs fall and eligibility criteria are relaxed, people who inject drugs (PWID) will increasingly become eligible for HCV treatment. Yet eligibility does not necessarily equate to access. Amidst efforts to expand treatment uptake in this population, we seek to synthesise and clarify the conceptual underpinnings of access to health care for PWID, with a view to informing research and practice. Integrating dominant frameworks of health service utilisation, care seeking processes, and ecological perspectives on health promotion, we present a comprehensive theoretical framework to understand, investigate and intervene upon barriers and facilitators to HCV care for PWID. Built upon the concept of Candidacy, the framework describes access to care as a continually negotiated product of the alignment between individuals, health professionals, and health systems. Individuals must identify themselves as candidates for services and then work to stake this claim; health professionals serve as gatekeepers, adjudicating asserted candidacies within the context of localised operating conditions; and repeated interactions build experiential knowledge and patient-practitioner relationships, influencing identification and assertion of candidacy over time. These processes occur within a complex social ecology of interdependent individual, service, system, and policy factors, on which other established theories provide guidance. There is a pressing need for a deliberate and nuanced theory of health care access to complement efforts to document the HCV 'cascade of care' among PWID. We offer this framework as an organising device for observational research, intervention, and implementation science to expand access to HCV care in this vulnerable population. Using practical examples from the HCV literature, we demonstrate its utility for specifying research questions and intervention targets across multiple levels of influence; describing and testing plausible effect mechanisms; and identifying potential threats to validity or barriers to research translation.

13.
Int J Drug Policy ; 72: 69-76, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31010749

RESUMO

BACKGROUND: Multiple barriers for accessing hepatitis C virus (HCV) treatment were identified during the interferon-based (IFN) treatment era for people who inject drugs (PWID). Whether these barriers persist since the introduction of IFN-free direct-acting antiviral (DAA) agents in Canada remains to be documented. This study examined temporal trends in HCV treatment initiation and associated factors during the transition from INF-based to all-oral DAA regimens. METHODS: The study population was drawn from a prospective cohort of PWID in Montreal, Canada. At three-month/one-year intervals between 2011 and 2017, participants with chronic HCV infection completed an interviewer-administered questionnaire on socio-demographic characteristics, drug use and health service utilisation, including HCV treatment. Time-updated Cox multivariate regression models, stratified by DAA + INF (2011-2013) and all-oral DAA (2014-2017) availability periods, were conducted to examine associations between time to HCV treatment initiation and associated barriers and facilitators. RESULTS: Of 308 participants (85% male, median age 42 [IQR: 33, 50]), 80 (26%) initiated HCV treatment during 915 person-years (PY). Incidence rates increased from 1.6 /100 PY (95%CI:0.9-2.6) in 2011 to 12.7 (10.6-15.1) in 2017 (p-trend = 0.0012). In multivariate analyses, visiting a primary care physician (2011-2013: aHR = 3.63[1.21-10.9]; 2014-2017: 2.52[1.10-5.77]) and frequent injection (0.23[0.05-0.99] and 0.49[0.24-0.99]) were consistently associated with treatment initiation. Participants aged >40 (2.27[1.24-4.13]), receiving opioid agonist therapy (OAT) (2.17[1.19-3.94]), and reporting prior HCV treatment (3.00[1.75-5.15]) were more likely to initiate treatment in the all-oral DAA period. CONCLUSION: Treatment initiation increased between 2011 and 2017, but still remains low among PWID. Primary care visiting was a key facilitator regardless of the period, while engagement in OAT and health services, indicated by prior HCV treatment, increased the likelihood of treatment initiation in the DAA era. These findings suggest that access to health services is essential but not enough to scale up treatment in this population.

14.
Clin Infect Dis ; 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30816419

RESUMO

BACKGROUND: While opioid agonist therapy (OAT) reduces the risk of HCV acquisition among people who inject drugs (PWID), protective effects may be attenuated in females compared to males. This study assessed sex disparities in HCV incidence among PWID exposed to OAT and factors independently associated with decreased protective efficacy. METHODS: Inc3 pools biological and behavioural data from prospective observational studies examining incident HIV and HCV. Independent predictors were identified using Cox regression models with random effects after accounting for the clustering effect of study sites. Unadjusted and adjusted hazard ratios (aHR) and 95% Confidence Intervals are presented in sex-specific analyses. RESULTS: Among 701 participants exposed to OAT observed over 3,003 visits and 1,427 person-years observation (PYO), HCV incidence was 16.5 PYO (95%CI 13.1-20.7) in females and 7.6 PYO (95%CI 6.0-9.5) in males (F:M aHR 1.80, 95%CI 1.37-2.22, p<0.001). Factors associated with HCV acquisition among females exposed to OAT included non-white race (aHR 1.79, 95%CI 1.25-2.56, p=0.001), recent unstable housing (aHR 4.00, 95%CI 3.62-4.41, p<0.001), recent daily or more frequent injection (aHR 1.45, 95%CI 1.01-2.08, p=0.042) and recent receptive syringe sharing (aHR 1.43, 95%CI 1.33-1.53, p<0.001). CONCLUSIONS: Female PWID exposed to OAT are twice as likely as their male counterparts to acquire HCV. While there is a need for better understanding of sex differences in immune function and opioid pharmacokinetic and pharmacodynamic parameters, structural and behavioural interventions that target women, including affordable housing and safe injection self-efficacy, are required to bolster the efficacy of OAT in preventing HCV transmission.

15.
Infect Genet Evol ; 71: 36-41, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30853512

RESUMO

Transfer of hepatitis C virus (HCV) infection from a donor to a new recipient is associated with a bottleneck of genetic diversity in the transmitted viral variants. Existing data suggests that one, or very few, variants emerge from this bottleneck to establish the infection (transmitted founder [T/F] variants). In HCV, very few T/F variants have been characterized due to the challenges of obtaining early infection samples and of high throughput viral genome sequencing. This study used a large, acute HCV, deep-sequenced dataset from first viremia samples collected in nine prospective cohorts across four countries, to estimate the prevalence of single T/F viruses, and to identify host and virus-related factors associated with infections initiated by a single T/F variant. The short reads generated by Illumina sequencing were used to reconstruct viral haplotypes with two haplotype reconstruction algorithms. The haplotypes were examined for random mutations (Poisson distribution) and a star-like phylogeny to identify T/F viruses. The findings were cross-validated by haplotype reconstructions across three regions of the genome (Core-E2, NS3, NS5A) to minimize the possibility of spurious overestimation of single T/F variants. Of 190 acute infection samples examined, 54 were very early acute infections (HCV antibody negative, RNA positive), and single transmitted founders were identified in 14 (26%, 95% CI: 16-39%) after cross validation across multiple regions of the genome with two haplotype reconstruction algorithms. The presence of a single T/F virus was not associated with any host or virus-related factors, notably viral genotype or spontaneous clearance. In conclusion, approximately one in four new HCV infections originates from a single T/F virus. Resolution of genomic sequences of single T/F variants is the first step in exploring unique properties of these variants in the infection of host hepatocytes.

16.
Int J Drug Policy ; 66: 87-93, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30743093

RESUMO

It is estimated that 6.1 million people with recent injecting drug use (PWID) are living with hepatitis C virus (HCV). Although HCV-related morbidity and mortality among PWID continues to increase, the advent of direct acting antiviral (DAA) HCV regimens with cure rates >95% provides an opportunity to reverse the rising burden of disease. Additionally, given evidence that opioid substitution therapy and high-coverage needle and syringe programs can reduce HCV incidence by up to 80%, there is an opportunity to reduce HCV transmission with increased coverage of harm reduction services. However, there are significant patient, provider, health system, structural, and societal barriers that impede access to HCV prevention and care for PWID. The International Network on Hepatitis in Substance Users (INHSU), in collaboration with the Australasian Society for HIV, Viral Hepatitis, Sexual Health Medicine (ASHM), Harm Reduction International, the Canadian Network on Hepatitis C, Canadian Research Initiative in Substance Misuse, the National Viral Hepatitis Roundtable, Médecins du Monde and CATIE, held a roundtable discussion prior to the Harm Reduction Conference in Montreal, Canada on 13th May 2017 to discuss how to improve HCV prevention and care for PWID. Over 100 international researchers, practitioners, policy makers, advocates, and affected community members came together to discuss shared priorities for action, develop actionable next steps and to create partnerships to enable application of priorities. This paper highlights the key priority areas identified by participants including: enhancing global coverage of harm reduction services; addressing punitive drug policies; ensuring access to affordable HCV diagnostics and treatment; improving the evidence-base for HCV prevention, testing, linkage to care and treatment; implementing integrated HCV programs; advancing peer-based models of HCV care; and tackling social determinants of health inequalities for PWID. This paper also highlights the recommended actions for each priority identified by the participants from this roundtable.

17.
J Leukoc Biol ; 105(3): 551-563, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30698860

RESUMO

The engagement of activating NK receptors (aNKR) stimulates NK cell activity, provided that interactions between inhibitory NK receptors (iNKR) with their HLA ligands do not override them. Abs bound to target cells can also activate NK cells by engaging the CD16 aNKR. NK cell education status is an important factor for Ab-dependent NK cell activation (ADNKA) of some NK cell subsets. However, whether NK cell education also influences Ab-dependent cellular cytotoxicity (ADCC) levels is not fully known. ADCC-GranToxiLux (GTL) assays measured ADCC activity as the frequency of granzyme B positive (%GzB+ ) target cells. Target cells were anti-HIV Immunoglobulin G (HIVIG)-opsonized CEM-NKr.CCR5 (CEM) cells. Lymphocytes and sorted single positive (SP) NKG2A+ , KIR2DL1+ , KIR2DL3+ , and KIR3DL1+ NK cells, to self- and nonself HLA, were used as effectors in ADCC-GTL assays to examine how education status influenced ADCC activity. ADNKA activity was assessed by stimulating lymphocytes with HIVIG-opsonized CEMs and measuring the frequency of NK cell populations defined by their expression of iNKRs, along with IFN-γ, CCL4, and CD107a functions. ADCC: the %GzB+ CEM cells generated by self- versus nonself HLA-specific SPiNKR did not differ. ADNKA: More NK cells educated through KIR2DL1 and KIR3DL1, but not KIR2DL3, responded to ADNKA than their uneducated counterparts. CD16 engagement induced ADCC and ADNKA activity. With the proviso that groups' sizes were small, our results support the notion that NK cell education does not influence ADCC levels but does contribute to ADNKA activity.

18.
J Viral Hepat ; 26(4): 476-484, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30578702

RESUMO

Interactions between the host immune system and the viral variants determine persistence of hepatitis C virus (HCV) infection after the acute phase of infection. This study describes the genetic variability of within-host HCV viral variants in acute infection and correlates it with host- and virus-related traits and infection outcome. Next generation sequence data (Illumina, MiSeq platform) of viral genomes from 116 incident acute infections (within 180 days of infection) were analysed to determine all the single nucleotide polymorphism (SNP) frequencies above a threshold of 0.1%. The variability of the SNPs for the full open reading frame of the genome as well as for each protein coding region were compared using mean standardized Shannon entropy (SE) values calculated separately for synonymous and nonsynonymous mutations. The envelope glycoproteins regions (E1 and E2) had the highest SE values (indicating greater variability) followed by the NS5B region. Nonsynonymous mutations rather than synonymous mutations were the main contributors to genomic variability in acute infection. The mean difference of Shannon entropy was also compared between subjects after categorizing the samples according to host and virus-related traits. Host IFNL3 allele CC polymorphism at rs12979860 (vs others) and viral genotype 1a (vs 3a) were associated with higher genomic variability across the viral open reading frame. Time since infection, host gender or continent of origin was not associated with the viral genomic variability. Viral genomic variability did not predict spontaneous clearance.

20.
J Clin Invest ; 2018 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-30521495

RESUMO

ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in two primary-antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal-zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients' blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centres and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target ROCK, the patients' lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in patients' cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signalling, and confining B lymphocytes and myelocytes within their dedicated functional environment.

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