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Background: Injection drug use (IDU) leads to immune system dysfunction, thereby increasing the risk of opportunistic infection. There is a critical need to reveal the role of IDU in the immunopathogenesis of HIV infection., Methods: We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) derived from healthy control (HC) individuals, HIV-infected patients with IDU (HIV-IDU) and without IDU (HIV-nIDU). In addition, the Gene Set Enrichment Analysis (GSEA) was used to analyze the immunomodulatory effects of differential immune cells., Results: Seven types of cells were identified with specific expressions of maker genes. Specific subsets such as CD14 + monocytes, plasmacytoid dendritic cells (pDCs), plasma cells, and CD8 + T cells displayed a high degree of heterogeneity among HC, HIV-nIDU, and HIV-IDU. We identified signature genes for each subset in distinct groups, including CFP + CD14 + monocytes, PTPRCAP + pDCs, IGHD + plasma cells, and IFITM1 + CD8 + T cells from HIV-IDU, whereas these genes were not expressed in such cells from HIV-nIDU. Moreover, considerable heterogeneity in the function of these immune cells was observed across different groups, especially the elevated IFN-α/β signaling for CD14 + monocytes, histone H2A/2B and H3/4 pathway for pDCs, the creation of C4 and C2 activators for plasma cells, and drug metabolism cytochrome p450 for CD8 + T cells in HIV-IDU individuals., Conclusion: Our comprehensive analyses clarify the heterogeneous characteristics of the immune landscape between HIV-IDU and HIV-nIDU. These insights provide a deeper understanding of the IDU-mediated immunopathogenesis in HIV infection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Antiretroviral therapy has been effective in suppressing HIV viral load and enabling people living with HIV to experience longer, more conventional lives. However, as people living with HIV are living longer, they are developing aging-related diseases prematurely and are more susceptible to comorbidities that have been linked to chronic inflammation. Coincident with HIV infection and aging, drug abuse has also been independently associated with gut dysbiosis, microbial translocation, and inflammation. Here, we hypothesized that injection drug use would exacerbate HIV-induced immune activation and inflammation, thereby intensifying immune dysfunction. We recruited 50 individuals not using injection drugs (36/50 HIV+) and 47 people who inject drugs (PWID, 12/47 HIV+). All but 3 of the HIV+ subjects were on antiretroviral therapy. Plasma immune profiles were characterized by immunoproteomics, and cellular immunophenotypes were assessed using mass cytometry. The immune profiles of HIV+/PWID-, HIV-/PWID+, and HIV+/PWID+ were each significantly different from controls; however, few differences between these groups were detected, and only 3 inflammatory mediators and 2 immune cell populations demonstrated a combinatorial effect of injection drug use and HIV infection. In conclusion, a comprehensive analysis of inflammatory mediators and cell immunophenotypes revealed remarkably similar patterns of immune dysfunction in HIV-infected individuals and in people who inject drugs with and without HIV-1 infection., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: We performed a cross-sectional study of HIV-uninfected men and women who inject drugs from the ALIVE cohort to examine if black men and women who inject drugs have higher levels of CD4+ T cells expressing the integrin heterodimer α4β7 compared to white men and women., Materials and Methods: Flow cytometry was used to examine expression of α4β7 and other markers associated with different functional CD4+ T cell subsets in both men and women who inject drugs., Results: Higher levels of α4β7, CCR5, and CCR6 were observed on CD4+ T cells from black participants compared with white participants. In a multivariable model, α4β7 expression differed by race, but not sex, age, or other factors., Discussion: Black men and women express higher percentages of α4β7 expressing CD4+ T cells, which may play a role in HIV disease., Competing Interests: SM has received speaker fees from Gilead Sciences that was not related to this work. The authors have no other conflicts of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Health of HIV-infected people relies on early antiretroviral therapy, i.e. early diagnosis. We aimed to determine whether the characteristics at HIV diagnosis in two French medical centres changed over the last 20 years., Patients and Methods: All individuals diagnosed with HIV infection in Grenoble University Hospital (N=814) and Annecy Hospital (N=246) between 1997 and 2015 were included. We collected age, country of birth, mode of transmission, CD4T cell count, CD4/CD8 ratio, and HIV viral load., Results: Among the 1060 patients (mean age 37.4±11 years, 70.2% of men), 42.5% were men having sex with men (MSM); 65.2% were born in France, and 24.4% were born in Africa. Mean CD4T cell count at diagnosis was 396±288/mm 3 and was stable over the study period when considering all patients; when considering the MSM group, a significant increase over time was observed, with a mean increase of 7.3 CD4/mm 3 per year (P<0.001). A higher CD4 count at diagnosis was observed after 2005 (400±289 vs 468±271/mm 3 , P=0.005). The proportion of MSM patients with a CD4 count<200/mm 3 at diagnosis was lower after 2005 (14.7% after 2005 and 25.6% before, P=0.028) This was not observed in heterosexual patients (born in Africa or not)., Conclusion: In the MSM population, CD4 count at diagnosis is higher after 2005, suggesting that screening campaigns have become more efficient. This was not observed in other populations, who should be better targeted in future strategies., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

This study is aimed at assessing the willingness to participate in the HIV vaccine trials and the associated factors among people who inject drugs (PWIDs) in Tanzania. Information about the willingness to participate and the associated factors was collected using interviewer-administered questionnaires at the medication treatment for opioid use disorder (MOUD) clinic in Dar es Salaam. Data analysis was performed using the IBM SPSS Statistic 20. The mean age of respondents was 36.7, and the standard deviation (SD) was ±7.2. The majority of respondents (68%) had primary education, and a high proportion of them were single (61.5%). More than one-third (37.9%) shared needles and syringes. Most (87.3%) had more than three sexual partners, and almost half (51.4%) did not use condoms during sexual intercourse with nonregular partners. About 63% had knowledge of HIV transmission while 27% had heard about HIV vaccine trials. Generally, 76% of the respondents expressed willingness to participate in future HIV vaccine trials regardless of prior knowledge of HIV vaccine trials. Willingness to participate in HIV vaccine trials was not associated with education level, people living with, knowledge about HIV transmission, awareness of HIV vaccine trials, sharing of syringe/needles, and number of sexual partners. Only older age (OR = 1.6, 95%CI = 1.01, 2.6) and condom use (OR = 0.49, 95%CI = 0.26, 0.97) showed an association with willingness. However, after performing logistic regression with factors at p value ≤ 0.2 to ascertain the other factors on the effects of age, condom use, education level, and sharing of needles/syringes, the results were not statistically significant. Although participants reported a high willingness to participate in hypothetical HIV vaccine trials, no definitive conclusion can be drawn about the associated factors. Further studies with intensive educational programs are needed to investigate the factors on willingness to participate in actual HIV vaccine trials among PWIDs., Competing Interests: The authors declared that they have no conflict of interest., (Copyright © 2020 Masunga K. Iseselo et al.)

Objectives: Despite recommendations for vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) for all adults at increased risk of infection, several US states have reported increases in HAV and HBV infections among persons who inject drugs. We investigated hepatitis A and hepatitis B vaccination coverage among a sample of persons who reported injecting drugs and had evidence of hepatitis C virus (HCV) infection., Methods: We searched the Wisconsin Immunization Registry for the vaccination records of persons who underwent HCV testing at syringe services programs from January 1 through August 31, 2018, and were reported to the Wisconsin Division of Public Health as having positive HCV antibody test results and a history of injection drug use. We calculated the percentage of persons who were vaccinated according to national recommendations., Results: Of 215 persons reported, 204 (94.9%) had a client record in the Wisconsin Immunization Registry. Of these 204 persons, 66 (32.4%) had received ≥1 dose of hepatitis A vaccine, 46 (22.5%) had received 2 doses of hepatitis A vaccine, and 115 (56.4%) had received 3 doses of hepatitis B vaccine. Hepatitis B vaccine coverage decreased with increasing age, from 88.0% (22 of 25) among adults aged 20-24 to 30.3% (10 of 33) among adults aged 35-39., Conclusions: These findings suggest that most persons who inject drugs in Wisconsin are susceptible to HAV infection and that most persons aged ≥35 who inject drugs are susceptible to HBV infection. In addition to routine vaccination of children, targeted hepatitis vaccination programs should focus on adults who inject drugs to help prevent future infections.

Background: Women-specific factors exist that increases vulnerability to drug-related harms from injection drug use, including blood-borne viruses (BBVs), but gender-based differences in BBV prevalence have not been systematically examined., Methods: We conducted meta-analyses to estimate country, regional, and global prevalence of serologically confirmed human immunodeficiency virus (HIV), hepatitis C virus (HCV; based on detection of anti-HCV antibody), and hepatitis B virus (HBV; based on detection of HBV surface antigen) in people who inject drugs (PWID), by gender. Gender-based differences in the BBV prevalence (calculated as the risk among women relative to the risk among men) were regressed on country-level prevalence and inequality measures (Gender inequality index, Human development index, Gini coefficient, and high, low or middle income of the country)., Results: Gender-based differences varied by countries and regions. HIV prevalence was higher among women than men in sub-Saharan Africa (relative risk [RR], 2.8; 95% confidence interval [CI], 1.8-4.4) and South Asia (RR, 1.7; 95% CI, 1.1-2.7); anti-HCV was lower among women in the Middle East and North Africa (RR, 0.6; 95% CI, .5-.7) and East and Southeast Asia (RR, 0.8; 95% CI, .7-.9). Gender-based differences varied with country-levels of the BBV prevalence in the general population, human development, and income distribution., Conclusion: HIV was more prevalent in women who inject drugs as compared to their male counterparts in some countries, but there is variation between and within regions. In countries where women are at higher risks, there is a need to develop gender-sensitive harm-reduction services for the particularly marginalized population of women who inject drugs., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

HTLV-2/HIV-1-coinfected patients and HIV-infected patients with natural HIV-1 control show an immune capacity that allows some control of viral infections. These two groups of patients have showed an immune capacity that allows them to have some control over viral infections, very strong control of HIV-1 replication in the case of HIV-1 controllers. The purpose of this retrospective cross-sectional study was to compare viral and immunologic parameters between three cohorts of Caucasian adult HIV-1-infected patients, including HIV-1 controllers (29 patients), HTLV-2/HIV-1 chronic progressors (56 patients), and HIV-1 chronic progressors (101 patients), followed in two different tertiary University Hospitals in Spain. Demographic parameters, nadir CD4 T cell count, CD4 and CD8 T cell counts and percentage, anti-HCV antibodies, HCV RNA load, HCV genotype, HIV-1 RNA loads, and anti-HTLV-2 antibodies were analyzed. HIV-1 controllers and HTLV-2/HIV-1 chronic progressors were younger and with shorter time since HIV-1 diagnosis compared to HIV-1 chronic progressors. HIV-1 controllers and HTLV-2/HIV-1 chronic progressors had significantly higher CD8 T cell percentage (p = 0.002 and p = 0.016, respectively) and lower levels of HCV RNA loads (0.015 and 0.007, respectively) compared to that of HIV-1 chronic progressors. Multivariate analyses showed that gender and HTLV-2 infection were independently associated to HCV RNA load, while only HTLV-2 infection was independently associated to CD8 T cell percentage. The implication of HTLV-2 infection in the control of HIV-1 and HCV infections is worth being further analyze., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: HIV-exposed seronegative people who inject drugs (HESN-PWID) have been shown to have increased natural killer (NK) cell and myeloid activation when compared with control donors., Methods: We investigated potential mechanisms maintaining NK activation by conducting quantitative proteome comparisons of NK cells from HESN-PWID subjects and control donors. Proteins upregulated in NK cells were measured in the plasma of HESN-PWID subjects by ELISA and further investigated for their ability to induce innate immune activation in vitro., Results: The NK cell proteome comparison showed markedly higher levels of interferon-stimulated proteins and S100 proteins, including S100A14. Consistent with these results, we observed significantly higher levels of S100A14 in the plasma of HESN-PWID subjects compared with controls (P = 0.033, n = 25). In vitro, the addition of recombinant S100A14 protein significantly activated NK cells in a peripheral blood mononuclear cell mixture (P = 0.011, n = 9), but not purified NK cells alone. Treatment of purified monocytes with recombinant S100A14 protein induced secretion of TNF-alpha and led to significantly higher NK CD69 activation (P = 0.0156, n = 7) in a co-culture through a TLR4-dependent interaction., Conclusions: Our study identified S100A14 as a novel protein increased within NK cells and plasma of HESN-PWID subjects with the capacity to sustain NK activation through TLR4-dependent activation of myeloid cells.

Background and Aims: Harm reduction strategies have been shown to decrease the incidence of human immunodeficiency virus (HIV) infection in people who inject drugs (PWID), but the results have been inconsistent when it comes to prevention of hepatitis C virus (HCV) infection. We aimed to examine the rate of HCV seroconversion among people who use drugs (PWUD) followed at a mobile harm reduction unit (MHRU) to evaluate if a low-threshold methadone substitution program (LTMSP) is associated with a low HCV seroconversion rate and subsequently identify barriers for elimination., Materials and Methods: A cohort of PWUD have been followed at a MRHU in Madrid between 2013 and 2016. Individuals who were negative for HCV antibodies at baseline and who had at least one retest for HCV antibodies were eligible. Kaplan-Meier methods were employed to estimate the global incidence density., Results: During the study period, 946 PWUD were screened for HCV at least once. At baseline 127 PWUD were negative for HCV antibodies and had at least one follow-up HCV antibodies test. The baseline HCV prevalence was 33%. After a median 0.89 (IQR 0.3-1.5) years of follow-up and 135 person-years of risk for HCV infection, 28 subjects seroconverted. The incidence density for HCV seroconversion for this sample was 20.7 cases (95% CI: 14.3-29.7) per 100 person-years. Injecting drugs in the last year was strongly associated to HCV seroconversion (AHR 15.5, 95%CI 4.3-55.8, p < 0.001). Methadone status was not associated to HCV seroconversion., Conclusions: A high incidence of HCV infection was found among PWUD at a MHRU in Madrid. In this setting opiate substitutive treatment (OST) as a LTMSP does not appear to protect against HCV seroconversion., Competing Interests: The authors have declared that no competing interests exist.

AIDS is a major cause of preventable mortality in HIV-infected people who inject drugs (HIV-PWID). An observational study was conducted to examine trends in AIDS mortality and related factors among HIV-infected individuals who died between 2000 and 2015 at an urban hospital. Overall HIV-mortality was 6.5% (413/6307) with no changes over time (p 0.76). AIDS mortality dropped in HIV-PWID (p 0.02) although it represented 26.4% at the end of study period. Age (per one-year increase) [odds ratio (OR) 0.95], third study period (2010-2015) (OR 0.54), HIV-PWID on opioid agonist therapy (OAT) (OR 0.39), and HIV RNA suppression (OR 0.15) were associated with AIDS mortality. OAT was reported in 58.3% (161/276) and RNA suppression in 30.9% (85/276) of HIV-PWID. OAT non-retention was due to drop-outs [85.2% (98/115)] and rejection [14.8% (17/115)] in HIV-PWID. Therefore, additional strategies are required to improve OAT retention and HIV RNA suppression to continue reducing AIDS mortality.

People who inject drugs (PWID) are commonly exposed to hepatitis B virus (HBV) and hepatitis D virus (HDV). We evaluated the prevalence of HDV viremia among hepatitis B surface antigen (HBsAg)-positive PWID (n = 73) using a new quantitative microarray antibody capture (Q-MAC) assay, HDV western blot, and HDV RNA. HDV Q-MAC performed well in this cohort: anti-HDV, 100% sensitivity and specificity; HDV viremia, 61.5% sensitivity and 100% specificity. Hepatitis D viremia was present in 35.6% of HBsAg-positive participants and was more common in those with resolved compared to chronic hepatitis C (5.1% vs 0.6%; adjusted odds ratio, 9.80; P < .0001).

Background & Aims: Natural killer (NK) cell function is regulated by inhibitory and activating receptors including killer cell immunoglobulin-like receptors (KIRs). Here, we analyzed the impact of different KIR/KIR-ligand genotypes on the outcome of hepatitis C virus (HCV) infection in people who inject drugs (PWID)., Methods: KIR/KIR-ligand genotypes associated with spontaneous clearance of HCV infection were identified in a cohort of PWID from Germany (n=266) and further validated in a second anti-HCV positive cohort of PWID recruited in North America (n=342). NK cells of PWID and healthy donors were functionally characterized according to their KIR/KIR-ligand genotype by flow cytometry., Results: Multivariate logistic regression analysis revealed that KIR3DL1/HLA-Bw4 80(T) was associated with spontaneous clearance of HCV infection in PWID, which was confirmed in the PWID cohort from North America. Compared with PWID with detectable HCV RNA, the frequency of individuals with multiple HLA-Bw4 alleles was significantly higher in anti-HCV positive PWID with resolved HCV infection (29.7% vs. 15.2%; p=0.0229) and in anti-HCV seronegative PWID (39.2%; p=0.0006). KIR3DL1 + NK cells from HLA-Bw4 80(T)-positive PWID showed superior functionality compared to HLA-Bw4 80(I)-positive PWID. This differential impact was not observed in healthy donors; however, the HLA-Bw4 copy number strongly correlated with the functionality of KIR3DL1 + NK cells., Conclusions: HLA-Bw4-80(T) and multiple HLA-Bw4 copies in combination with KIR3DL1 are associated with protection against chronic hepatitis C in PWID by distinct mechanisms. Better licensing of KIR3DL1 + NK cells in the presence of multiple HLA-Bw4 copies is beneficial prior to seroconversion whereas HLA-Bw4 80(T) may be beneficial during acute hepatitis C. Lay summary: Natural killer (NK) cells are part of the innate immune system and are regulated by a complex network of activating and inhibiting receptors. The regulating receptor-ligand pairs of an individual are genetically determined. Here, we identified a particular set of ligand and receptor genes that are associated with better functionality of NK cells and better outcome upon exposure to HCV in a high-risk group., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Research indicates that hepatitis C antibody (anti-HCV) prevalence is higher among Australian Aboriginal and Torres Strait Islander (Aboriginal) than non-Aboriginal people who inject drugs (PWID). We examined trends in demographic and drug use characteristics and anti-HCV prevalence among Australian Needle and Syringe Program Survey (ANSPS) respondents by Aboriginal status from 1996 to 2015., Methods: The ANSPS survey involved collecting demographic, behavioural data and a dried blood spot for anti-HCV testing. We used logistic regression to determine demographic and behavioural factors associated with testing anti-HCV positive in the following time-periods (1996-2000, 2001-2005, 2006-2010, 2011-2015) among Aboriginal and non-Aboriginal PWID respondents., Results: Overall, there were 16,948 PWID, with 11% identifying as Aboriginal. The proportion of Aboriginal respondents increased from 7% in 1996-2000 to 16% in 2011-2015. Overall anti-HCV prevalence was significantly higher among Aboriginal (60%) than non-Aboriginal PWID (52%, p<0.01). Receptive syringe sharing (RSS) declined among non-Aboriginal PWID (p<0.001) over time, however among Aboriginal PWID, RSS remained stable (p=0.619). Factors independently associated with testing positive for anti-HCV among Aboriginal PWID in 2011-2015 were 16 or more years since first injection (adjusted odds ratio [AOR] 6.04, p<0.001), history of incarceration (AOR: 1.74, p=0.010) and currently or previously on opioid substitution therapy (AOR: 1.89, p=0.003). Compared to 1996-2000, testing anti-HCV positive was significantly associated with the time-periods: 2001-2005 (unadjusted odds ratio [OR]: 1.39, p<0.001), 2006-2010 (OR: 1.38, p<0.001) and 2011-2015 (OR: 1.25, p<0.001) among non-Aboriginal PWID; however this increase did not occur among Aboriginal PWID., Conclusion: The proportion of Aboriginal PWID attending Needle Syringe Programs appears to have increased. Overall, the prevalence of anti-HCV has remained higher among Aboriginal than non-Aboriginal PWID. Coupling increased access to NSPs with new interferon-free HCV treatments and culturally appropriate education and counselling services could influence new HCV infections among Aboriginal PWID., (Copyright © 2017 Elsevier B.V. All rights reserved.)

High levels of immune activation are reported for people who inject drugs. Studies of the relationship between injection behaviors and immune activation have yielded mixed results, in part due to lack of control for hepatitis C virus in analyses. This study, of 48 HIV-seronegative people who inject drugs, examines this relationship controlling for hepatitis C virus viremia. Frequency of injection was positively related to markers of immune activation (soluble CD14, %CD8CD38HLADR T cells), as was duration of injection (high-specificity C-reactive protein and D-dimer). Sharing injection equipment was not related to markers studied. Findings suggest that efforts to encourage injection cessation or reduction in frequency can have positive health benefits through reducing immune activation.

Background:  Chronic inflammation, as defined by persistent immune activation, is associated with adverse clinical outcomes. People who inject drugs (PWID) have evidence of persistent immune activation. Here, in a cohort of PWID with or without hepatitis C virus (HCV) infection, we sought to dissect out the contribution of chronic HCV infection (common in PWID) from the effects of injection drug use itself., Methods:  Four groups of study volunteers were recruited: group 1 comprised active PWID; group 2, individuals who ceased injecting drugs 1-2 months before recruitment; group 3, individuals who ceased injecting drugs 3-4 months before recruitment; and group 4, healthy volunteers. Soluble and cell-associated markers of immune activation were quantified., Results:  HCV-viremic PWID have elevated levels of immune activation when compared to healthy volunteers. Cessation of injection drug use results in a decline in immune activation in the absence of HCV viremia, while HCV-viremic individuals who previously were PWID continue to harbor elevated levels of immune activation, as defined by increased levels of soluble CD14 and tumor necrosis factor α and by the presence of CD38 + HLA-DR + CD4 + and CD8 + T cells., Conclusions:  Immune activation, a well-defined surrogate of poor clinical outcome that is elevated in PWID, can regress to normal levels in former injection drug users who are HCV aviremic. Therefore, enhanced harm-reduction efforts should incorporate aggressive treatment of HCV infection., Clinical Trials Registration:  NCT01831284., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Injection drug use is a growing major public health concern. Injection drug users (IDUs) have a higher incidence of co-morbidities including HIV, Hepatitis, and other infections. An effective humoral response is critical for optimal homeostasis and protection from infection; however, the impact of injection heroin use on humoral immunity is poorly understood. We hypothesized that IDUs have altered B cell and antibody profiles., Methods and Findings: A comprehensive systems biology-based cross-sectional assessment of 130 peripheral blood B cell flow cytometry- and plasma- based features was performed on HIV-/Hepatitis C-, active heroin IDUs who participated in a syringe exchange program (n = 19) and healthy control subjects (n = 19). The IDU group had substantial polydrug use, with 89% reporting cocaine injection within the preceding month. IDUs exhibited a significant, 2-fold increase in total B cells compared to healthy subjects, which was associated with increased activated B cell subsets. Although plasma total IgG titers were similar between groups, IDUs had significantly higher IgG3 and IgG4, suggestive of chronic B cell activation. Total IgM was also increased in IDUs, as well as HIV Envelope-specific IgM, suggestive of increased HIV exposure. IDUs exhibited numerous features suggestive of systemic inflammation, including significantly increased plasma sCD40L, TNF-α, TGF-α, IL-8, and ceramide metabolites. Machine learning multivariate analysis distilled a set of 10 features that classified samples based on group with absolute accuracy., Conclusions: These results demonstrate broad alterations in the steady-state humoral profile of IDUs that are associated with increased systemic inflammation. Such dysregulation may impact the ability of IDUs to generate optimal responses to vaccination and infection, or lead to increased risk for inflammation-related co-morbidities, and should be considered when developing immune-based interventions for this growing population.

Objectives: To examine the relationship between benzodiazepine (BZD) use and HCV seroconversion in 2 linked prospective cohorts of persons who inject drugs (PWID)., Methods: We examined prospective cohorts of 440 PWID (baseline BZD users: n = 102; 23.2%) from the AIDS Care Cohort to Evaluate Access to Survival Services (ACCESS) and the Vancouver Injection Drug Users Study (VIDUS) cohorts, followed-up from 1996 to 2013 in Vancouver, Canada., Results: At baseline, the prevalence of HCV was higher among those who used BZD (80.5% vs 61.5%; P < .001). After adjustment, BZD use remained independently associated with increased rates of HCV seroconversion (adjusted rate ratio = 1.67; 95% confidence interval = 1.05, 2.66)., Conclusions: BZD use is independently associated with HCV seroconversion in a population of PWID.

Purpose of Review: The majority of hepatitis C virus (HCV) infections in the United Kingdom and many developing countries were acquired through injecting. New clinical guidance suggests that HCV treatment should be offered to people with a transmission risk - such as people who inject drugs (PWID) - irrespective of severity of liver disease. We consider the strength of the evidence base and potential problems in evaluating HCV treatment as prevention among PWID., Recent Findings: There is good theoretical evidence from dynamic models that HCV treatment for PWID could reduce HCV chronic prevalence and incidence among PWID. Economic evaluations from high-income settings have suggested HCV treatment for PWID is cost-effective, and that in many settings HCV treatment of PWID could be more cost-effective than treating those at an equivalent stage with no ongoing transmission risk. Epidemiological studies of older interferon treatments have suggested that PWID can achieve similar treatment outcomes to other patient groups treated for chronic HCV. Impact and cost-effectiveness of HCV treatment is driven by the potential 'prevention benefit' of treating PWID. Model projections suggest that more future infections, end stage liver disease, and HCV-related deaths will be averted than lost through reinfection of PWID treated successfully for HCV. However, there is to date no empirical evidence from trials or observational studies that test the model projections and 'prevention benefit' hypothesis. In part this is because of uncertainty in the evidence base but also there is unlikely to have been a change in HCV prevalence due to HCV treatment because PWID HCV treatment rates historically in most sites have been low, and any scale-up and switch to the new direct acting antiviral has not yet occurred. There are a number of key uncertainties in the data available on PWID that need to be improved and addressed to evaluate treatment as prevention. These include estimates of the prevalence of PWID, measurements of HCV chronic prevalence and incidence among PWID, and how to interpret reinfection rates as potential outcome measures., Summary: Eliminating HCV through scaling up treatment is a theoretical possibility. But empirical data are required to demonstrate that HCV treatment can reduce HCV transmission, which will require an improved evidence base and analytic framework for measuring PWID and HCV prevalence.

Background: Meaningful reductions in Hepatitis C Virus (HCV) transmission rates among persons who inject drugs (PWID) require a comprehensive prevention approach, including access to harm reduction measures and to healthcare-related interventions, such as HCV screening, testing and antiviral treatment. Little is known, however, about the role of visiting a primary care physician (PCP) in relation to HCV infection risk among PWID, when integrated within a combined prevention approach. This study assessed the association between PCP visiting and HCV seroconversion among PWID attending needle exchange programs (NEP)., Methods: A prospective cohort study, HEPCO, was conducted among active PWID in Montréal (2004-2013). Interviews scheduled at 3- or 6-month intervals included completion of an interviewer-administered questionnaire, and collection of blood samples for HCV antibody testing. HCV-seronegative participants who reported NEP attendance at baseline and had at least one follow-up visit were eligible for this study. HCV incidence was calculated using the person-time method. Time-varying Cox regression modeling was conducted to evaluate the relationship between self-reported recent PCP visiting and HCV incidence., Results: At baseline assessment, of 226 participants (80.5% male; median age: 30.6 years), 37.2% reported having recently visited a PCP. During 449.6 person-years of follow-up, 79 participants seroconverted to HCV [incidence rate: 17.6 per 100 person-years, 95% confidence interval (CI): 14.0-21.8]. Covariate-adjusted analyses indicated that visiting a PCP was associated with a lower risk of HCV infection [Adjusted Hazard Ratio: 0.54, 95% CI: 0.31-0.93]. Other independent predictors of HCV infection included unstable housing, cocaine injection and prescription opioid injection., Conclusion: Among PWID attending NEP, visiting a PCP was associated with a lower risk of HCV infection. Yet, only a minority of participants reported PCP visiting. Efforts to intensify engagement with PCP among PWID could potentially contribute to lower HCV transmission when integrated within a combined approach to prevention., (Copyright © 2015 Elsevier B.V. All rights reserved.)

People who inject drugs are vulnerable to several infections. To the best of our knowledge, this is the first case report of a simultaneous diagnosis of leptospirosis and acute infection or recurrence of occult hepatitis C in an HIV-infected drug user. We report a case of a 47-year-old Caucasian man with HIV infection, on antiretroviral therapy, and with a history of hepatitis C (positive anti-hepatitis C virus (HCV) and HCV RNA persistently negative) who was admitted with febrile acute hepatitis. He was a former injecting drug user, on opioid substitution therapy, who relapsed to injection drug use 3 weeks prior to admission. Work up revealed positive HCV RNA and Leptospira DNA in his urine. Four weeks later he had an undetectable HCV load, and also at 6 months of follow-up. This case highlights the presence of two concomitant infectious aetiologies of acute hepatitis in an HIV-infected drug user., (2015 BMJ Publishing Group Ltd.)

Background: Our study aims were to assess hepatitis A virus (HAV) and hepatitis B virus (HBV) susceptibility and infection among young persons who inject drugs (PWID) who may have been vaccinated as children and to evaluate self-report of HAV and HBV vaccination., Methods: We recruited PWID aged 18-40 years-old in San Diego during 2009 and 2010 and collected demographic, socioeconomic, health, and behavioral factors. Participants were asked if they had been vaccinated against HAV and HBV, and serum samples were collected for HAV and HBV serologic testing., Results: Of 519 participants, 365 (72%) were male, 252 (49%) were white non-Hispanic, 38 (7%) were Black non-Hispanic, 138 (27%) were White Hispanic, and 22 (4%) were born outside the U. S. Of the total participants, 245 (47%) had surface hepatitis B antibody (anti-HBs) titers <10mIU/ml (i.e., HBV susceptible) and 325 (63%) had no detectable HAV antibodies (HAV susceptible). Hepatitis B surface antigen was detected in 7 (1%) of total participants; and 135 (26%) were anti-HCV-antibody positive. Compared to serologic findings, self-report of HBV and HAV vaccination was 71% and 41% sensitive, and 58% and 73% specific, respectively., Conclusion: HAV and HBV antibodies in half or more of this young PWID population did not have levels indicative of protection, and about a quarter had HCV infection, putting them at risk for complications resulting from co-infection with HAV or HBV. Programs serving this population should vaccinate PWIDs against HAV and HBV and not rely on self-report of vaccination., (Published by Elsevier Ltd.)

Background & Aims: HCV seroprevalence surveys in longstanding injecting drug users (IDUs) reveal a small minority who remain seronegative, with some exhibiting HCV-specific cellular immunity. This study aimed to characterise this immunity, assess associations with risk behaviours and protection against infection., Methods: A nested case-control series from a prospective cohort of seronegative IDUs was selected with incident cases (IN; n = 28) matched by demographics and risk behaviour to exposed uninfected (EU) subjects (n = 28). Samples were assayed for natural killer (NK) cell phenotypes and function, HCV-specific IFNγ in ELISpot, and HCV-specific CD4 T effector responses. IL28B and HLA-C/KIR2DL3 genotypes were tested., Results: Numbers of activated (CD69(+)) NK cells in the mature CD56(dim)CD16(+) subset, and cytotoxic (NKp30(+)) cells in the CD56(bright)CD16(+) subset were higher in the EU subjects (p = 0.040, p = 0.038 respectively). EU subjects had higher frequencies of interferon gamma (IFNγ) producing NK cells, and lower frequencies of CD107a expression (p = 0.003, p = 0.015 respectively). By contrast, the frequency, magnitude, and breadth of HCV-specific CD4 and CD8 T cell responses did not differ, nor did IL28B, HLA-C, or KIR2DL3 allele frequencies., Conclusions: Sustained NK cell activation contributes to protection against HCV infection. HCV-specific cellular immunity is prevalent in EU subjects but does not appear to be protective., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: CD8+ T cells are an essential component of successful adaptive immune responses against hepatitis C virus (HCV). A major obstacle to vaccine design against HCV is its inherent viral sequence diversity. Here, we test the hypothesis that different sequence variants of an immunodominant CD8+ T cell epitope, all binding with high affinity to HLA class I, target different T cell receptor repertoires and thereby influence the quality of the CD8+ T cell response. The impacts of sequence differences in the HLA-A*02-restricted HCV NS31406-1415 epitope on in vitro priming of naive CD8+ T cells from seronegative donors and cross-reactivity of primed T cells with other epitope variants were characterized. Although the six epitope variants tested were all high-affinity binders to HLA-A*02:01, substantial differences in priming and cross-reactivity of CD8+ T cells were observed. The variant associated with the most reproducible priming and induction of T cells with broad cross-reactivity was a genotype 1b variant (KLSALGLNAV) that is more common in HCV isolates collected in Asia but is rare in sequences from Europe and North America. The superior immunogenicity and cross-reactivity of this relatively rare epitope variant were confirmed by using HCV-specific memory CD8+ T cells from people who inject drugs, who are frequently exposed to HCV. Collectively, the data suggest that sequence differences at the epitope level between HCV isolates substantially impact CD8+ T cell priming and the degree of cross-reactivity with other epitope variants., Importance: The results have important implications for vaccine design against highly variable pathogens and suggest that evidence-based selection of the vaccine antigen sequence may improve immunogenicity and T cell cross-reactivity. Cross-reactive CD8+ T cells are likely beneficial for immune control of transmitted viruses carrying epitope variants and for prevention of immune escape during acute infection. To this end, rare epitope variants and potentially even altered epitope sequences associated with priming of broadly cross-reactive T cell receptors should be considered for vaccine design and need further testing., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objectives: Guidelines recommend hepatitis C virus (HCV) screening for all people living with HIV (PLWH). Understanding HCV testing practices may improve compliance with guidelines and can help identify areas for future intervention., Methods: We evaluated HCV screening and unnecessary repeat HCV testing in 8,590 PLWH initiating care at 12 U.S. HIV clinics between 2006 and 2010, with follow-up through 2011. Multivariable logistic regression examined the association between patient factors and the outcomes: HCV screening (≥1 HCV antibody tests during the study period) and unnecessary repeat HCV testing (≥1 HCV antibody tests in patients with a prior positive test result)., Results: Overall, 82% of patients were screened for HCV, 18% of those screened were HCV antibody-positive, and 40% of HCV antibody-positive patients had unnecessary repeat HCV testing. The likelihood of being screened for HCV increased as the number of outpatient visits rose (adjusted odds ratio 1.02, 95% confidence interval 1.01-1.03). Compared to men who have sex with men (MSM), patients with injection drug use (IDU) were less likely to be screened for HCV (0.63, 0.52-0.78); while individuals with Medicaid were more likely to be screened than those with private insurance (1.30, 1.04-1.62). Patients with heterosexual (1.78, 1.20-2.65) and IDU (1.58, 1.06-2.34) risk compared to MSM, and those with higher numbers of outpatient (1.03, 1.01-1.04) and inpatient (1.09, 1.01-1.19) visits were at greatest risk of unnecessary HCV testing., Conclusions: Additional efforts to improve compliance with HCV testing guidelines are needed. Leveraging health information technology may increase HCV screening and reduce unnecessary testing.

The aim of this study is to explore the prevalence of hepatitis C virus (HCV) infection among injection drug users (IDUs) with and without human immunodeficiency virus (HIV) infection in southern Taiwan. For 562 IDUs (265 anti-HIV negative, 297 anti-HIV positive), we analyzed liver function, anti-HIV antibody, anti-HCV antibody, HCV viral loads, and hepatitis B surface antigen (HBsAg). HIV RNA viral loads and CD4 cell count for anti-HIV-seropositive IDUs and the HCV genotype for HCV RNA-seropositive IDUs were measured. The seroprevalence rates of anti-HIV, anti-HCV, and HBsAg were 52.8%, 91.3%, and 15.3%, respectively. All the anti-HIV-seropositive IDUs were positive for HIV RNA. Anti-HCV seropositivity was the most important factor associated with HIV infection (odds ratio [OR], 25.06; 95% confidence intervals [CI], 8.97-74.9), followed by male gender (OR, 6.12; 95% CI, 4.05-9.39) and HBsAg seropositivity (OR, 1.90; 95% CI, 1.11-3.34). Among IDUs positive for anti-HCV, 80.7% had detectable HCV RNA. HCV viremia after HCV exposure was strongly related to HIV infection (OR, 6.262; 95% CI, 1.515-18.28), but negatively correlated to HBsAg seropositivity (OR, 0.161; 95% CI, 0.082-0.317). HCV genotype 6 was the most prevalent genotype among all IDUs (41.0%), followed by genotypes 1 (32.3%), 3 (12.8%), and 2 (5.6%). In conclusion, about half IDUs were infected with HIV and >90% with HCV infection. Male and seropositivity for HBsAg and anti-HCV were factors related to HIV infection among our IDUs. HIV was positively correlated, whereas hepatitis B co-infection was negatively correlated with HCV viremia among IDUs with HCV exposure. Different HCV molecular epidemiology was noted among IDUs.

Background: Across Europe, illicit drug-related mortality has not declined despite ever increasing prevention measures. The cause of these deaths has traditionally been associated with overdose. Previous findings have revealed the appearance of non-lethal opioid concentrations, leading us to investigate a further cause of death. The symptoms of heroin intoxication with asphyxia and/or cardiovascular involvement resemble anaphylaxis, and therefore it has been speculated that such deaths might be caused by an allergic reaction. The study´s aims were to investigate levels of allergic mediators in long-term injecting drug users (IDU) compared to healthy controls and to determine if oral opioid substitution therapy (OST) resulted in similar allergic symptoms to those reported by IDU after intravenous (IV) heroin use., Methods: We quantified the concentrations of histamine, diamine oxidase (DAO), tryptase and lipoprotein-associated phospholipase A2 (LpPLA2) at baseline and 1 h after administration of Substitol®retard (482 ± 220 mg) in 56 patients at a withdrawal centre (Austria) and compared them with healthy controls (n = 103). Questionnaires and face-to-face interviews were used to assess allergic symptoms and side effects in IDU. Descriptive statistical analyses of quantitative data were performed by using SPSS., Results: Baseline histamine, tryptase and LpPLA2 were significantly elevated in IDU compared to the healthy control group, while DAO decreased. Blood levels showed no significant change after oral substitution uptake. Self-reported allergic symptoms and side effects after IV heroin use were reported in 55 cases (98.2%), minimal symptoms were documented after OST (12.5%, 7/56)., Conclusions: This study revealed that baseline histamine concentrations were elevated in chronic IDU, although only relatively small changes in tryptase plasma levels occurred. After IV heroin application the reported allergic symptoms were mostly mild and did not lead to clinically relevant side effects. The substitution substance was clearly better tolerated than IV administered heroin. Elevated levels of allergic mediators such as histamine in IDUs may place them at greater risk of severe or fatal anaphylaxis when exposed to heroin; however, this requires further investigation.

Background: It remains unclear whether the natural course of human immunodeficiency virus (HIV) differs in subjects infected through injecting drug use (IDU) and no data have been published from low- or middle-income countries. We addressed this question in an urban cohort in Indonesia, which is experiencing a rapidly growing HIV epidemic strongly driven by IDU., Methods: All antiretroviral treatment (ART) naïve HIV-positive patients who had at least two subsequent CD4 cell counts available before starting ART were included in this study. We examined the association between IDU and CD4 cell decline using a linear mixed model, with adjustment for possible confounders such as HIV viral load and hepatitis C antibodies., Results: Among 284 HIV-positive ART naïve patients, the majority were male (56%) with a history of IDU (79% among men). People with a history of IDU had a statistically significant faster decline in CD4 cells (p<0.001). Based on our data, patients with a history of IDU would have an average 33% decline in CD4 cells after one year without ART, compared with a 22% decline among non-users. At two years, the decline would average 66 and 40%, respectively. No other factor was significantly associated with CD4 cell decline., Conclusions: We show that a history of IDU is associated with a more rapid CD4 cell natural decline among HIV-positive individuals in Indonesia. These findings have implications for monitoring ART naïve patients with a history of IDU and for starting ART in this group.

Background: Illegal drug use and HIV are independent risk factors for tuberculosis (TB) among injecting drug users (IDU). Estonia and Latvia have experienced high rates of TB as well as IDU and HIV outbreaks. There is a lack of knowledge about TB among IDUs in these countries. The purpose of the current study was to estimate the prevalence and risk factors of Mycobacterium tuberculosis (MTB) infection among IDUs in Estonia and Latvia., Methods: Participants for this cross-sectional study were recruited from syringe exchange programmes using respondent-driven sampling. For assessing infection with MTB interferon-gamma release assay (IGRA) was used., Results: The study included 375 participants from Estonia and 313 from Latvia. The prevalence of IGRA-positivity among IDUs was 7.7% in Estonia and 25.6% in Latvia. HIV-prevalence was 62% in Estonia and 23% in Latvia. In both countries, IGRA-positivity rates did not differ between HIV-positive and HIV-negative participants. IGRA-positivity was independently associated with a prior diagnosis of TB in Estonia and with imprisonment (ever within a lifetime) and preceding contact with a TB patient in Latvia., Conclusion: Our findings indicate there is an urgent need for a more vigorous approach in providing IDUs with TB screening services., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Effective health care models to scale up combination antiretroviral therapy (ART) are needed in rural southwestern China. We aimed to evaluate the ART treatment outcomes and their associations with patients' demographic characteristics and pre-treatment clinical features in a scaled-up provincial ART program serving eight heavily HIV-affected prefectures in Yunnan Province. We abstracted information from a computerized database for adults initiating ART between July 2007 and September 2008. Survival functions of mortality and treatment failure were calculated by age group, gender, transmission mode, and baseline CD4 count. Multivariable Cox regression analyses were conducted to find independent associations of various demographic and baseline clinical features with outcome variables. Of the 1967 patients in the mortality analysis, there were 110 deaths, of which 16 were coded as accidents or suicides. Adjusted hazard ratios (AHR) associated with mortality were greater for patients with baseline CD4 counts <100 cells/µl vs. patients with CD4 counts ≥200 cells/µl, for male vs. female, for single vs. married, and for those acquired HIV through injection drug use (IDU) vs. other modes of transmission. Successful treatment was 81.3% at six months after treatment started. Immunologic treatment failure was associated with baseline CD4 counts but not with demographic characteristics. Overall loss to follow-up rate was 2.1%. Collaboration between clinics and community networks are distinctive features of Yunnan's model for scaling up ART across a diverse, poor, and rural population. This study finds that the strategy can succeed even if 40% of the patients have a history of IDU.

Death in anaphylactic shock cannot be diagnosed by autopsy alone. Morphological diagnosis of anaphylactic death by counting mast cells in the lung and airways have failed to give consistent results. Previously it has been observed that eosinophils seem to accumulate in the spleen in anaphylaxis. The purpose of this study was to investigate if it is possible to safely diagnose anaphylactic deaths by counting eosinophils, mast cells, and basophils in the spleen. In 43 forensic autopsy cases specific antibodies to mast cells, eosinophil-, and basophil granulocytes were used on sections from lung and splenic tissue. The cells were counted in 20 × 40 fields in a Leica photo-microscope. Presumed deaths in anaphylaxis were compared with sudden deaths after intravenous injection of opiates, and sudden cardiac deaths (control group). The main result was that significant (p < 0.05) increases of both eosinophil granulocytes (mean 26.6 ± 17.8/SD/)and mast cells (3.2 ± 2.0/SD/) versus controls (eosinophils mean 7.0 ± 10.5 and mast cells mean 0.9 ± 1.1) were seen in splenic tissue in anaphylactic deaths. Comparing cases with high and low concentrations of mast cell tryptase in serum showed a similar increase in eosinophils and mast cells in the spleen in cases with elevated tryptase, but not in the lung. The numbers of pulmonary mast cells and eosinophils were not different in anaphylactic deaths compared with controls. It is concluded that by quantifying eosinophil granulocytes and mast cells in the spleen in combination with tryptase measurements in serum it is possible to diagnose anaphylaxis with a high degree of certainty.

Background: TLR3 recognizes dsRNA and triggers immune responses against RNA and DNA viruses. A polymorphism in TLR3, rs3775291 (Leu412Phe), has been associated with the increased susceptibility to enteroviral myocarditis, protection against tick-borne encephalitis virus and HIV-1 infection. We investigated Caucasian intravenous drug users (IDUs) and blood donors in order to evaluate the associations between TLR3 genotypes and susceptibility to HIV infection., Materials and Methods: A total of 345 Caucasian IDUs were recruited, 50% of them were HIV positive, 89% HCV and 77% HBV positive. Based on their history of needle sharing, 20 of the HIV negative IDUs were classified as highly exposed HIV seronegatives (HESNs), 68 as non-HESNs and 85 as unexposed. The control group consisting of 497 blood donors tested negative for all three viruses. TLR3 rs3775291 were determined by using TaqMan Allelic Discrimination Assay., Results: The TLR3 rs3775291 T allele frequency was similar among the HIV negative and HIV positive IDUs and blood donors - 36%, 31% and 34%, respectively. The frequency of persons possessing at least one TLR3 rs3775291 T allele was significantly higher in HESNs compared with blood donors and HIV positive IDUs (80% vs. 55%; p=0.037 and 80% vs. 53%; p=0.031, respectively). In the univariate analysis, persons who possessed at least one T allele had reduced odds of being HIV seropositive (OR=0.29, 95% CI=0.09-0.90). This association remained significant (OR=0.25, 95% CI=0.07-0.87) after the adjustment for other co-variates (HCV, HBV serostatus and duration of intravenous drug use)., Conclusions: The TLR3 rs3775291 T allele has a protective effect against HIV infection among HESNs IDUs., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Unlabelled: Hepatitis C virus reinfection and spontaneous clearance of reinfection were examined in a highly characterised cohort of 188 people who inject drugs over a five-year period. Nine confirmed reinfections and 17 possible reinfections were identified (confirmed reinfections were those genetically distinct from the previous infection and possible reinfections were used to define instances where genetic differences between infections could not be assessed due to lack of availability of hepatitis C virus sequence data). The incidence of confirmed reinfection was 28.8 per 100 person-years (PY), 95%CI: 15.0-55.4; the combined incidence of confirmed and possible reinfection was 24.6 per 100 PY (95%CI: 16.8-36.1). The hazard of hepatitis C reinfection was approximately double that of primary hepatitis C infection; it did not reach statistical significance in confirmed reinfections alone (hazard ratio [HR]: 2.45, 95%CI: 0.87-6.86, p=0.089), but did in confirmed and possible hepatitis C reinfections combined (HR: 1.93, 95%CI: 1.01-3.69, p=0.047) and after adjustment for the number of recent injecting partners and duration of injecting. In multivariable analysis, shorter duration of injection (HR: 0.91; 95%CI: 0.83-0.98; p=0.019) and multiple recent injecting partners (HR: 3.12; 95%CI: 1.08-9.00, p=0.035) were independent predictors of possible and confirmed reinfection. Time to spontaneous clearance was shorter in confirmed reinfection (HR: 5.34, 95%CI: 1.67-17.03, p=0.005) and confirmed and possible reinfection (HR: 3.10, 95%CI: 1.10-8.76, p-value=0.033) than primary infection. Nonetheless, 50% of confirmed reinfections and 41% of confirmed or possible reinfections did not spontaneously clear., Conclusions: Hepatitis C reinfection and spontaneous clearance of hepatitis C reinfection were observed at high rates, suggesting partial acquired natural immunity to hepatitis C virus. Public health campaigns about the risks of hepatitis C reinfection are required.

Co-infection of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) with human immunodeficiency virus (HIV) has an adverse effect on liver disease progression. This study investigated the prevalence of HBV and/or HCV co-infection in HIV-infected patients in Central China. A total of 978 HIV-infected patients from Hunan Province were enrolled. HBV serum markers, anti-hepatitis-C-virus antibody (anti-HCV), HBV DNA, and HBV genotypes were analyzed. The prevalence of hepatitis B surface antigen (HBsAg) and anti-HCV in HIV-infected patients was 19.4 % and 62.4 %, respectively. The prevalence of anti-HCV in HIV-positive intravenous drug users was 93.6 %. Among HBsAg-positive patients, 88.1 % were found to have at least one HBV serum marker. The rates of HIV mono-infection, HBV/HIV dual infection, HCV/HIV dual infection, and HBV/HCV/HIV triple infection were 30.4 %, 7.2 %, 50.2 %, and 12.2 %, respectively. Antibody to HBsAg (Anti-HBs) was more common in anti-HCV-positive than anti-HCV-negative patients (53.3 % vs 40.2 %, P = 0.000), but isolated hepatitis B core antibody (anti-HBc) was more common in anti-HCV-negative than anti-HCV-positive patients (24.2 % vs 12.3 %, P = 0.000). Hepatitis B e antigen (HBeAg) and sexual transmission were independent risk factors for active HBV replication. Intravenous drug use and male sex were independent risk factors, but old age and presence of HBeAg were independent protective factors for anti-HCV. Co-infection of HBV and/or HCV with HIV infection is common in central China. HCV status is associated with anti-HBs and isolated anti-HBc in co-infected patients.

Background: Up to 90% HIV-1 positive intravenous drug users (IDUs) are co-infected with HCV. Although best recognized for its function as a major co-receptor for cell entry of HIV, CC chemokine receptor 5 (CCR5) has also been implicated in the pathogenesis of HCV infection. Here, we investigated whether CCR5 haplotypes influence HIV-1 and HCV seropositivity among 373 Caucasian IDUs from Estonia., Methods: Of these IDUs, 56% and 44% were HIV and HCV seropositive, respectively, and 47% were coinfected. 500 blood donors seronegative for HIV and HCV were also evaluated. CCR5 haplotypes (HHA to HHG*2) were derived after genotyping nine CCR2-CCR5 polymorphisms. The association between CCR5 haplotypes with HIV and/or HCV seropositivity was determined using logistic regression analysis. Co-variates included in the models were length of intravenous drug use, HBV serostatus and copy number of CCL3L1, the gene encoding the most potent HIV-suppressive chemokine and ligand for CCR5., Results: Compared to IDUs seronegative for both HCV and HIV (HCV-/HIV-), IDUs who were HCV+/HIV- and HCV+/HIV+were 92% and 82%, respectively, less likely to possess the CCR5-HHG*1 haplotype, after controlling for co-variates (P(adjusted) = 1.89 × 10(-4) and 0.003, respectively). This association was mostly due to subjects bearing the CCR5 HHE and HHG*1 haplotype pairs. Approximately 25% and<10% of HCV-/HIV- IDUs and HCV-/HIV- blood donors, respectively, possessed the HHE/HHG*1 genotype., Conclusions: Our findings suggest that HHG*1-bearing CCR5 genotypes influence HCV seropositivity in a group of Caucasian IDUs.

Studies of hepatitis C virus (HCV) infection amongst injecting drug users (IDUs) have suggested that this population can be separated into two risk groups (naive and experienced) with different injecting risk behaviours. Understanding the differences between these two groups and how they interact could lead to a better allocation of prevention measures designed to reduce the burden of HCV in this population. In this paper we develop a deterministic, compartmental mathematical model for the spread of HCV in an IDU population that has been separated into two groups (naive and experienced) by time since onset of injection. We will first describe the model. After deriving the system of governing equations, we will examine the basic reproductive number R₀, the existence and uniqueness of equilibrium solutions and the global stability of the disease free equilibrium (DFE) solution. The model behaviour is determined by the basic reproductive number, with R₀ = 1 a critical threshold for endemic HCV prevalence. We will show that when R₀ ≤ 1, and HCV is initially present in the population, the system will tend towards the globally asymptotically stable DFE where HCV has been eliminated from the population. We also show that when R₀ > 1 there exists a unique non-zero equilibrium solution. Then we estimate the value of R₀ from epidemiological data for Glasgow and verify our theoretical results using simulations with realistic parameter values. The numerical results suggest that if R₀ > 1 and the disease is initially present then the system will tend to the unique endemic equilibrium.

Background: Detection of hepatitis C virus (HCV) reinfection and intercalation (ie, 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 injection drug users 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; 3 demonstrated viral intercalation, and 1 was not classifiable as either. Estimated incidence of first reinfection was 5.4 per 100 person-years (95% confidence interval, 2.0-14.5). Six (75%) participants, including 3 of 4 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 4 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.

During the course of human immunodeficiency virus type 1 (HIV-1) disease, the virus has been shown to effectively escape the immune response with the subsequent establishment of latent viral reservoirs in specific cell populations within the peripheral blood (PB) and associated lymphoid tissues, bone marrow (BM), brain, and potentially other end organs. HIV-1, along with hepatitis B and C viruses (HBV and HCV), are known to share similar routes of transmission, including intravenous drug use, blood transfusions, sexual intercourse, and perinatal exposure. Substance abuse, including the use of opioids and cocaine, is a significant risk factor for exposure to HIV-1 and the development of acquired immune deficiency syndrome, as well as HBV and HCV exposure, infection, and disease. Thus, coinfection with HIV-1 and HBV or HCV is common and may be impacted by chronic substance abuse during the course of disease. HIV- 1 impacts the natural course of HBV and HCV infection by accelerating the progression of HBV/HCV-associated liver disease toward end-stage cirrhosis and quantitative depletion of the CD4+ T-cell compartment. HBV or HCV coinfection with HIV-1 is also associated with increased mortality when compared to either infection alone. This review focuses on the impact of substance abuse and coinfection with HBV and HCV in the PB, BM, and brain on the HIV-1 pathogenic process as it relates to viral pathogenesis, disease progression, and the associated immune response during the course of this complex interplay. The impact of HIV-1 and substance abuse on hepatitis virus-induced disease is also a focal point.

A cohort of injection drug users (IDU) have been identified who despite a long history of IDU and sharing of injecting equipment remain seronegative and aviraemic for hepatitis C virus (HCV). They have been termed HCV exposed uninfected (EU). The study of potential innate or adaptive immune mechanisms of resistance to HCV infection in this group is of interest. The aim of this study was to determine the levels of a broad range of cytokines in serum of exposed, uninfected individuals to ascertain whether there is a specific cytokine profile associated with apparent resistance to HCV. Sera from 22 EU individuals were analysed for a range of cytokines and chemokines, and compared to 16 treatment-naive chronic HCV cases (HCV Ab+ RNA+), 16 individuals with spontaneous resolution of HCV (HCV-Ab+ and HCV-RNA-) and 10 healthy unexposed controls. EU subjects had strikingly higher levels of both IL-6 (on average more than 100-fold, P = 0.001) and IL-8 (on average more than 10-fold, P < 0.001) than the comparison groups. Additionally higher levels of tumour necrosis factor-alpha (TNF-α; on average up to threefold, P = 0.02) were seen in EU individuals. The levels of interferon-alpha (IFN-α) were upregulated in all HCV exposed groups in comparison to healthy controls (P = 0.013). Adaptive immune cytokine levels were no different between the groups. Cytokine profiling demonstrated raised levels of pro-inflammatory innate immune cytokines and chemokines in EU IDU, in particular interleukin-6 and interleukin-8. These findings suggest innate immune activation may be the key to prevention of infection in this cohort., (© 2012 Blackwell Publishing Ltd.)

Objective: HIV-1-infected active drug users (ADU) obtain smaller clinical benefits with antiretroviral therapy (HAART) compared to non-ADU subjects with sexually-transmitted HIV-1 infection. Therefore treatment strategies are required to address the specific issues arising in this challenging scenario. We describe the effectiveness of HAART provided in a drug abuse outpatient treatment facility through a comprehensive integrated care that includes medical, drug dependence, and psychosocial support., Methods: We included all consecutive HIV-1-infected ADU admitted for drug dependency treatment and who started their first HAART. A comparator arm consisted of a control group of sexually transmitted HIV-1-infected subjects attended in a reference hospital under standard care. The strategy did not include directly observed treatment., Results: A total of 71 ADU and 48 matched subjects infected through sexual transmission were included. ADU had lower baseline CD4+ T-cell counts (196 vs 279 cells/μL, P=.001), and more advanced CDC stages (P=.001). The estimated probabilities of patients with virological response ( < 50 copies/mL) at weeks 48 and 96 were 92.9% (95%-CI: 87.1%-99.1%) and 87.3% (95%-CI: 78.7%-95.2% for ADU, and 93.7%(95%-CI: 84.1%-99.8%) and 87.5% (95%-CI: 77.5%-97.3%) for sexually-infected subjects (P= .1325 and .241). Kaplan-Meier estimates of time to loss of virological response did not show differences between groups (log rank test, P=.965)., Conclusions: An integrated multidisciplinary care of HIV-1-infected antiretroviral naïve ADU provided in a drug abuse treatment center obtains high rates of virological suppression, similar to those observed in a comparison group of sexually-transmitted HIV-1-infected subjects. This strategy should be further evaluated in public health programs and assessed in randomized trials.

Objective: There is considerable recent interest in immunostimulation caused by opiates, but, although there is intense interest in this process within the central nervous system particularly in connection with the pathways underlying chronic pain, few studies set out to define the course of clinical markers of this process in the systemic circulation or over the temporal span of the life course., Methods: For this reason, we have compared clinical pathology results from 1747 opiate substance use disorder with 6450 non-substance use disorder patients taken from our clinical pathology database. All continuous data were transformed to their natural logarithm to improve normality assumptions., Results: Globulins, erythrocyte sedimentation rate, white cell count, lymphocytes, monocytes, and platelets were all high in substance use disorder (P ≤ 0.01). These variables, C-reactive protein, high-sensitivity C-reactive protein, and neutrophils were all high at multiple regression when corrected for age (P < 0.0001) in both sexes (P ≤ 0.01). There were significant interactions between age and addictive status for C-reactive protein, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, globulins, white cell count, and lymphocytes and monocytes (P < 0.01)., Conclusions: These results are consistent with immunostimulation affecting soluble and cellular elements of the blood both in relative terms and after correction for age. They are consistent with other data showing diffuse and generalized immunostimulation like the high-risk polyclonal immunosenescent gammopathy seen in the very elderly known as "inflamm-aging" that carries an uncommonly poor prognosis for longevity. As such, it merits further detailed investigation.

Background: Injection drug users (IDUs) face numerous obstacles to receiving optimal HIV care, and have been shown to underutilize antiretroviral therapy (ART). We sought to estimate the degree to which providers of HIV care defer initiation of ART because of injection drug use and to identify clinic and provider-level factors associated with resistance to prescribing ART to IDUs., Methods: We administered an Internet-based survey to 662 regular prescribers of ART in the United States and Canada. Questionnaire items assessed characteristics of providers' personal demographics and training, site of clinical practice and attitudes about drug use. Respondents then rated whether they would likely prescribe or defer ART for hypothetical patients in a series of scenarios involving varying levels of drug use and HIV disease stage., Results: Survey responses were received from 43% of providers invited by email and direct mail, and 8.5% of providers invited by direct mail only. Overall, 24.2% of providers reported that they would defer ART for an HIV-infected patient with a CD4+ cell count of 200 cells/mm3 if the patient actively injected drugs, and 52.4% would defer ART if the patient injected daily. Physicians were more likely than non-physician providers to defer ART if a patient injected drugs (adjusted odds ratio 2.6, 95% CI 1.4-4.9). Other predictors of deferring ART for active IDUs were having fewer years of experience in HIV care, regularly caring for fewer than 20 HIV-infected patients, and working at a clinic serving a population with low prevalence of injection drug use. Likelihood of deferring ART was directly proportional to both CD4+ cell count and increased frequency of injecting., Conclusions: Many providers of HIV care defer initiation of antiretroviral therapy for patients who inject drugs, even in the setting of advanced immunologic suppression. Providers with more experience of treating HIV, those in high injection drug use prevalence areas and non-physician providers may be more willing to prescribe ART despite on-going injection drug use. Because of limitations, including low response rate and use of a convenience sample, these findings may not be generalizable to all HIV care providers in North America.

Retroviral coinfections with HIV-1 and HTLV-1 or with HIV-1 and HTLV-2 occur with variable frequencies throughout the world with the highest prevalence in large metropolitan areas in the Americas, Europe, and Africa. The recognition that retroviral coinfections exist dates back to the discovery of HIV-1 over 25 years ago. Despite the large body of published information regarding the biological and clinical significance of retroviral coinfections, controversy throughout several decades of research was fueled by several flawed epidemiologic studies and anecdotal reports that were not always supported with ample statistical and scientific evidence. However, the growing consensus obtained from recent systematic and well-devised research provides support for at least three conclusions: (1) HIV-1 and HTLV-1 coinfections are often seen in the context of patients with high CD4(+) T cell counts presenting with lymphoma or neurological complications; (2) HIV-1 and HTLV-2 coinfections have been linked in some cases to a "long term nonprogressor" phenotype; and (3) differential function and/or overexpression of the HTLV-1 and HTLV-2 Tax proteins likely play a pivotal role in the clinical and immunologic manifestations of HIV/HTLV-1 and -2 coinfections. This review will recount the chronology of work regarding retroviral coinfections from 1983 through the present.

Unlabelled: CD56(pos) natural killer (NK)/natural T (NT) cells are important innate effectors providing the first line of defense against viral infection. Enhanced NK activity has been shown to protect from human immunodeficiency virus-1 infection. However, the role played by these innate effectors in protection against or development of hepatitis C virus (HCV) infection is unknown. We characterized CD56(pos) populations in 11 injection drug users (IDUs) who remained uninfected despite being repeatedly exposed to HCV. NK profiles in exposed but uninfected (EU) individuals were compared with preinfection samples (median 90 days prior to HCV seroconversion) collected from 14 IDUs who were exposed and subsequently became infected (EI) and unexposed normal control subjects (n = 8). Flow cytometric analysis of CD56(pos) populations demonstrated that EUs had a higher proportion of CD56(low) mature (P = 0.0011) NK cells compared with EI subjects. Bead-isolated NKs ( > 90% purity) from EUs had significantly higher interleukin-2 (IL-2)-induced cytolytic activity against the NK-sensitive cell line K562 at an effector-to-target ratio of 10:1 (P < 0.0001). NKp30, a natural cytotoxicity receptor involved in NK activation, is highest on NK/NT cells in EUs relative to infected subjects. Using the JFH-1 infection system, we demonstrated that NKp30(high) cells in the absence of exogenous stimulation significantly reduce infection of hepatocytes., Conclusion: CD56(pos) populations in EUs are enriched for effector NKs displaying enhanced IL-2-induced cytolytic activity and higher levels of the natural cytotoxicity receptor NKp30-activating receptor. In addition, NKp30(high) cells are more effective in preventing infection of Huh-7.5 cells than their NKp30(low/neg) counterparts. These data support the hypothesis that NK cells contribute to anti-HCV defense in vivo in the earliest stages of infection, providing innate protection from HCV acquisition.

Background: Increased natural killer (NK) activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected individuals. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1) has also been observed in a subset of HIV-1 exposed, uninfected individuals. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intravenous drug users (EU-IDU) remains to be elucidated., Objective: We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU individuals and 15 control, uninfected donors from Philadelphia., Design: We assessed the activation status of NK cells and dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU individuals., Results: As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU individuals compared with control uninfected donors (P = 0.0056, n = 13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU individuals. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared with control uninfected donors (P = 0.0011, n = 12). When stimulated in vitro, both PDCs and NK cells from EU-IDU individuals maintained strong effector cell function and did not exhibit signs of exhaustion., Conclusion: Increased maturation of PDCs is associated with heightened NK activation in EU-IDU individuals suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.

Objective: The purpose of this paper is to highlight disparities between injection drug users (IDUs) and those who had never been IDUs from the Nutrition for Healthy Living (NFHL) cohort. Although IDUs were enrolled in the cohort throughout its duration, few analyses have sought to highlight findings specific to them., Methods: NFHL, a prospective, longitudinal cohort conducted from 1995-2005, included 881 human immunodeficiency virus (HIV) -infected men and women over the age of 18. Subjects were seen every 6 months; body composition and dietary and laboratory data were collected. Individuals were classified as current IDUs, past IDUs, and never-IDUs. The classification of ever-IDU combined current and past users., Results: In NFHL, a higher proportion of ever-IDUs were women, African American, had a high school education or less, smoked, and were housing insecure and food insecure compared to never-IDUs. Ever-IDUs had lower total, soluble, and insoluble fiber and individual micronutrient intakes. A higher proportion of ever-IDUs had hepatitis C and HIV-related symptoms, used highly active antiretroviral therapy (HAART) less, and had a CD4 count <500 cells/mm3, than never-IDUs, at the study endpoint., Conclusions: The course of HIV infection in past and current IDUs appears to be unique and requires more investigation. Physiologic and sociodemographic characteristics of IDUs contribute to poor disease management and nutritional status. Classic manifestations of HIV persist in IDUs in the HAART era.

Aim: Injecting drug users are a high-risk population for hepatitis B (HBV), but are difficult to engage in vaccination programmes. This study examines the completion rates of a HBV vaccination schedule and seroconversion in a group of patients in methadone maintenance treatment., Methods: Patients at a public methadone maintenance programme in Sydney, Australia, were screened for viral hepatitis (hepatitis A, B and C) and offered a rapid HBV vaccination schedule (0, 1 and 2 months). Hepatitis B surface antibody (antiHBs) was retested on completion of the vaccination schedule., Results: A total of 143 patients [71.3% male, mean age 33.1 (standard deviation +/- 8.3)] enrolled in the project. Forty-nine per cent of patients were HAV antibody (Ab) positive, 81.1% hepatitis C virus (HCV) antibody (Ab) positive and 38.9% antiHBs positive. Exposure to multiple hepatitis viruses was common, with 24.5% testing positive for all three viruses. Seventy-three (83%) of the 88 antiHBs negative patients completed the vaccination schedule. Post-vaccination serology indicated a seroconversion rate of 75.4% (55 of 73) of completors, or 62.5% of eligible participants (55 of 88)., Conclusion: While there was a high rate of completion of the rapid vaccination schedule in this population, a moderate seroconversion rate was achieved. Further work is required to identify an optimal vaccination schedule in opioid substitution patients.