Immune profiling in Puerto Rican injection drug users with and without HIV-1 infection.

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.

Racial differences in α4ß7 expression on CD4+ T cells of HIV-negative men and women who inject drugs.

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 α4ß7 compared to white men and women. MATERIALS AND METHODS: Flow cytometry was used to examine expression of α4ß7 and other markers associated with different functional CD4+ T cell subsets in both men and women who inject drugs. RESULTS: Higher levels of α4ß7, CCR5, and CCR6 were observed on CD4+ T cells from black participants compared with white participants. In a multivariable model, α4ß7 expression differed by race, but not sex, age, or other factors. DISCUSSION: Black men and women express higher percentages of α4ß7 expressing CD4+ T cells, which may play a role in HIV disease.

Willingness to Participate in Hypothetical HIV Vaccine Trial and Associated Factors among People Who Inject Drugs in Dar es Salaam, Tanzania.

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.

Immune profile at HIV infection diagnosis: Evolution in the French Alps area over the last 20 years.

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/mm3 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/mm3 per year (P<0.001). A higher CD4 count at diagnosis was observed after 2005 (400±289 vs 468±271/mm3, P=0.005). The proportion of MSM patients with a CD4 count<200/mm3 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.

Hepatitis A and Hepatitis B Vaccination Coverage Among Persons Who Inject Drugs and Have Evidence of Hepatitis C Infection.

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.

A Global Meta-analysis of the Prevalence of HIV, Hepatitis C Virus, and Hepatitis B Virus Among People Who Inject Drugs-Do Gender-Based Differences Vary by Country-Level Indicators?

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.

High CD8 T cell percentage and HCV replication control are common features in HIV-1 controllers and HTLV-2-co-infected patients with a history of injection drug use.

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.

S100A14 Is Increased in Activated NK Cells and Plasma of HIV-Exposed Seronegative People Who Inject Drugs and Promotes Monocyte-NK Crosstalk.

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.

HCV seroconversion in a cohort of people who use drugs followed in a mobile harm reduction unit in Madrid: Breaking barriers for HCV elimination.

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.

Hepatitis D Viremia Among Injection Drug Users in San Francisco.

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).

Trends in AIDS Mortality, Retention in Opioid Agonist Therapy, and HIV RNA Suppression in HIV-Infected People Who Injected Drugs from 2000 to 2015.

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.

Trends in hepatitis C antibody prevalence among Aboriginal and Torres Strait Islander people attending Australian Needle and Syringe Programs, 1996-2015.

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.

HLA-Bw4 80(T) and multiple HLA-Bw4 copies combined with KIR3DL1 associate with spontaneous clearance of HCV infection in people who inject drugs.

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.

Brief Report: The Relationship Between Injection Drug Use Risk Behaviors and Markers of Immune Activation.

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.

Chronic Hepatitis C Virus Infection and the Proinflammatory Effects of Injection Drug Use.

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.

Humoral Dysregulation Associated with Increased Systemic Inflammation among Injection Heroin Users.

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.

Benzodiazepine Use and Hepatitis C Seroconversion in a Cohort of Persons Who Inject Drugs.

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.

Hepatitis C virus treatment as prevention in people who inject drugs: testing the evidence.

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.