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2.  HIV Incidence Determination in the United States: A Multiassay Approach 
The Journal of Infectious Diseases  2012;207(2):232-239.
Background. Accurate testing algorithms are needed for estimating human immunodeficiency virus (HIV) incidence from cross-sectional surveys.
Methods. We developed a multiassay algorithm (MAA) for HIV incidence that includes the BED capture enzyme immunoassay (BED-CEIA), an antibody avidity assay, HIV load, and CD4+ T-cell count. We analyzed 1782 samples from 709 individuals in the United States who had a known duration of HIV infection (range, 0 to >8 years). Logistic regression with cubic splines was used to compare the performance of the MAA to the BED-CEIA and to determine the window period of the MAA. We compared the annual incidence estimated with the MAA to the annual incidence based on HIV seroconversion in a longitudinal cohort.
Results. The MAA had a window period of 141 days (95% confidence interval [CI], 94–150) and a very low false-recent misclassification rate (only 0.4% of 1474 samples from subjects infected for >1 year were misclassified as indicative of recent infection). In a cohort study, annual incidence based on HIV seroconversion was 1.04% (95% CI, .70%–1.55%). The incidence estimate obtained using the MAA was essentially identical: 0.97% (95% CI, .51%–1.71%).
Conclusions. The MAA is as sensitive for detecting recent HIV infection as the BED-CEIA and has a very low rate of false-recent misclassification. It provides a powerful tool for cross-sectional HIV incidence determination.
doi:10.1093/infdis/jis659
PMCID: PMC3532826  PMID: 23129760
HIV; incidence testing; United States; epidemiology
3.  Longitudinal changes in engagement in care and viral suppression for HIV-infected injection drug users 
AIDS (London, England)  2013;27(16):2559-2566.
Objective
To examine temporal trends and predictors of linkage to HIV care, longitudinal retention in care and viral suppression among injection drug users (IDUs) infected with HIV.
Design
Community-based, prospective cohort study
Methods
We prospectively studied 790 HIV-infected IDUs participating in the AIDS Linked to the Intravenous Experience (ALIVE) study from 1998 through 2011. IDUs were considered linked to care if they attended any HIV care visit during follow-up and retained in care if they reported HIV clinic attendance at every semiannual study visit. We used logistic regression to identify predictors of poor retention in care and failure to achieve sustained viral suppression in response to ART.
Results
Of 790 HIV-infected IDUs studied, 740 (93.6%) were ever linked to care. The majority of IDUs (76.7%) received ART at some point during observation and of these, most (85.4%) achieved viral suppression. However, over a median of 8.7 years of follow-up, only 241 (30.5%) IDUs were continuously retained with no 6-month lapses in HIV care and only 63 (10.2%) had sustained viral suppression at every study visit after first receiving ART. Suboptimal engagement in care was associated with poor access to medical care, active drug use, and incarceration.
Conclusion
Compared with national estimates of retention in care and virologic suppression in the United States, IDUs are substantially less likely to remain fully engaged in HIV care. Strategies to optimize HIV care should acknowledge the elevated risk of poor engagement in care among IDUs.
doi:10.1097/QAD.0b013e328363bff2
PMCID: PMC3795966  PMID: 23770493
antiretroviral therapy; drug users; human immunodeficiency virus; primary care; retention in care
4.  Limited Uptake of Hepatitis C Treatment among Injection Drug Users 
Journal of community health  2008;33(3):126-133.
We characterized HCV treatment knowledge, experience and barriers in a cohort of community-based injection drug users (IDUs) in Baltimore, MD. In 2005, a questionnaire on HCV treatment knowledge, experience and barriers was administered to HCV-infected IDUs. Self-reported treatment was confirmed from medical records. Of 597 participants, 71% were male, 95% African-American, 31% HIV co-infected and 94% were infected with HCV genotype 1; 70% were aware that treatment was available, but only 22% understood that HCV could be cured. Of 418 who had heard of treatment, 86 (21%) reported an evaluation by a provider that included a discussion of treatment of whom 30 refused treatment, 20 deferred and 36 reported initiating treatment (6% overall). The most common reasons for refusal were related to treatment-related perceptions and a low perceived need of treatment. Compared to those who had discussed treatment with their provider, those who had not were more likely to be injecting drugs, less likely to have health insurance, and less knowledgeable about treatment. Low HCV treatment effectiveness was observed in this IDU population. Comprehensive integrated care strategies that incorporate education, case-management and peer support are needed to improve care and treatment of HCV-infected IDUs.
doi:10.1007/s10900-007-9083-3
PMCID: PMC3800027  PMID: 18165889
Hepatitis C virus; Injection drug use; Antiviral therapy; Health care access
5.  A variant upstream of IFNL3 (IL28B) creating a novel interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus 
Nature genetics  2013;45(2):164-171.
SUMMARY
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
doi:10.1038/ng.2521
PMCID: PMC3793390  PMID: 23291588
6.  Laser Captured Hepatocytes Show Association of BCHE Loss and Fibrosis Progression in Hepatitis C Infected Drug Users 
Hepatology (Baltimore, Md.)  2012;56(2):544-554.
Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV-infected subjects with pre-cirrhotic liver fibrosis (Ishak fibrosis 3–5) were matched for age, race, and gender to five HCV-infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in pre-cirrhotic fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross-sectionally in an expanded cohort of 143 HCV-infected individuals. In a longitudinal study, serum BCHE activity were already decreased at study inception in 19 fibrosis progressors compared to 20 fibrosis non-progressors (p<0.05). Non-progressors also had decreased BCHE activity over time compared to initial values, but these evolved a median (range) 8.6 (7.8–11.4) years after the study period inception(p<0.05). Laser captured portal tracts were enriched for immune related genes when compared to hepatocytes but pre-cirrhotic livers lost this enrichment.
Conclusion
Overall, we found that chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV-related fibrosis among injection drug users.
doi:10.1002/hep.25655
PMCID: PMC3388175  PMID: 22331678
butyrylcholinesterase; Hepacivirus; chronic HCV infection; laser capture microdissection; portal tract
7.  HIV, Age, and the Severity of Hepatitis C Virus–Related Liver Disease 
Annals of internal medicine  2013;158(9):658-666.
Background
Persons with HIV infection have been reported to develop age-related diseases at younger ages than those without HIV. Whether this finding is related to HIV infection or failure to control for other risk factors is unknown.
Objective
To investigate whether persons with HIV infection develop hepatitis C virus (HCV)–related liver disease at younger ages than similar persons without HIV.
Design
Comparison of the severity of liver fibrosis by age among persons who have HCV with and without HIV followed concurrently in the same protocol.
Setting
Observational cohort from Baltimore, Maryland, participating in the ALIVE (AIDS Linked to the IntraVenous Experience) study.
Participants
1176 current and former injection drug users with antibodies to HCV.
Measurements
Liver fibrosis assessed semiannually from 2006 to 2011 by elastography (FibroScan, Echosens, Paris, France) and using previously validated thresholds for clinically significant fibrosis and cirrhosis; concurrent assessment of medical history, alcohol and illicit drug use, HCV RNA levels, hepatitis B virus surface antigen level, body mass index, and (for those with HIV) CD4+ lymphocyte count and HIV RNA levels.
Results
Among 1176 participants with antibodies to HCV, the median age was 49 years and 34% were coinfected with HIV and HCV. Participants contributed 5634 valid liver fibrosis measurements. The prevalence of clinically significant fibrosis without cirrhosis (12.9% vs. 9.5%) and of cirrhosis (19.5% vs. 11.0%) was greater in persons coinfected with HIV and HCV than in those with only HCV (P < 0.001). Increasing age and HIV infection were independently associated with liver fibrosis, as were daily alcohol use, chronic hepatitis B virus infection, body mass index greater than 25 kg/m2, and greater plasma HCV RNA levels. When these factors were kept constant, persons with HIV had liver fibrosis measurements equal to those of persons without HIV, who were, on average, 9.2 years older.
Limitation
The process of liver fibrosis began before the study in most persons.
Conclusion
In this cohort, persons who have HCV with HIV have liver fibrosis stages similar to those without HIV who are nearly a decade older.
doi:10.7326/0003-4819-158-9-201305070-00604
PMCID: PMC3708651  PMID: 23440167
8.  Stability of liver fibrosis among HCV-infected injection drug users 
Antiviral therapy  2012;17(5):813-821.
Background
There are few published data characterizing patterns of liver stiffness measurements (LSMs) among HCV-infected persons and their potential impact on clinical decisions (for example, deferring treatment and hepatocellular carcinoma surveillance).
Methods
A total of 591 HCV-infected injection drug users (IDUs) in a community-based cohort had four LSMs. We used semi-parametric latent class growth modelling to identify patterns, which then became a gold standard against which we characterized validity of information from the initial measurements.
Results
Median age was 49, 68% were male, 92% African-American and 33% HIV-coinfected. The median LSM at visit 1 was 6.7 kPa (IQR 5.3–8.8). Over a median 1.75 years, LSM measures were stable; median change between visits was 0 kPa (IQR -1.4–1.7). Only 3% had evidence of fibrosis progression. Other groups included stable patterns of 1) no fibrosis (59%), 2) moderate fibrosis (21%), 3) severe fibrosis (7%) and 4) cirrhosis (9%). Individuals with fibrosis progression were more likely to be HIV-infected than those with stable low fibrosis (P<0.001). The diagnostic accuracy of the first LSM for identification of need for cancer surveillance (cirrhosis ≥12.3 kPa) was high (positive predictive value = 97%). Although no single low LSM had high negative predictive value for significant fibrosis (metavir <2), individuals with two or more low results rarely had progression.
Conclusions
These data underscore the stability of liver fibrosis in a cohort of predominantly African-American HCV-infected persons over 1.75 years, support using LSMs to monitor untreated persons at risk for progression and assess need for hepatocellular carcinoma surveillance.
doi:10.3851/IMP2085
PMCID: PMC3699312  PMID: 22418880
9.  Genetic Polymorphism in IL28B Is Associated With Spontaneous Clearance of Hepatitis C Virus Genotype 4 Infection in an Egyptian Cohort 
The Journal of Infectious Diseases  2011;204(9):1391-1394.
Single-nucleotide polymorphisms (SNPs) around IL28B are associated with spontaneous hepatitis C virus (HCV) clearance of genotypes 1 and 3 in white and African-American populations. This study investigated whether the IL28B SNP (rs12979860) is associated with spontaneous clearance of HCV, principally genotype 4, in 162 Egyptians (80 with clearance). The protective C allele was more common in those with spontaneous clearance (76.3% vs 57.9%; P = .0006). Individuals with clearance were 3.4 (95% confidence interval, 1.8–6.5) times more likely to have C/C genotype. Thus, IL28B plays a role in spontaneous clearance of HCV genotype 4 in North Africa.
doi:10.1093/infdis/jir536
PMCID: PMC3182308  PMID: 21933876
10.  CXCL9 and CXCL10 Chemokines as Predictors of Liver Fibrosis in a Cohort of Primarily African-American Injection Drug Users With Chronic Hepatitis C 
The Journal of Infectious Diseases  2011;204(6):832-836.
CXCL9 (monokine induced by IFN γ [Mig]) and CXCL10 (interferon [IFN] γ−inducible protein 10 [IP-10]) have been associated with hepatic fibrosis in predominantly white hepatitis C virus (HCV)–infected patients. We investigated their potential as noninvasive markers of hepatic fibrosis and fibrosis progression in African-American patients. Peripheral chemokine levels were measured in 115 HCV-infected patients within 4 months of liver biopsy; patients underwent a second biopsy after 3–5 years. CXCL10 levels appeared to be higher in patients with advanced fibrosis on the contemporaneous biopsy and were significantly higher in patients with advanced fibrosis compared with those with minimal fibrosis on the later biopsy (P = .0045). Therefore, CXCL10 has potential as a marker of fibrosis progression in African-American HCV-infected patients.
doi:10.1093/infdis/jir424
PMCID: PMC3156920  PMID: 21849280
11.  Protective interleukin-28B genotype affects hepatitis C virus clearance, but does not contribute to HIV-1 control in a cohort of African–American elite controllers/suppressors 
AIDS (London, England)  2011;25(3):385-387.
We tested the hypothesis that a single nucleotide polymorphism (SNP) located near the interleukin-28B gene is associated with the control of hepatitis C virus and HIV-1 replication in elite controllers/suppressors. We show here that the protective genotype is not overrepresented in elite controllers/suppressors compared with HIV-1-seronegative patients and HIV-1-infected patients with viral loads more than 10 000 copies/ml. Thus, it appears that this SNP is not associated with the elite control of HIV-1 infection.
doi:10.1097/QAD.0b013e328341b86a
PMCID: PMC3158988  PMID: 21099664
12.  KIR2DL2 Enhances Protective and Detrimental HLA Class I-Mediated Immunity in Chronic Viral Infection 
PLoS Pathogens  2011;7(10):e1002270.
Killer cell immunoglobulin-like receptors (KIRs) influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection.
Author Summary
Hepatitis C virus (HCV) and human T-cell leukemia virus (HTLV-I) infect millions of people worldwide. Some HCV-infected individuals spontaneously clear the virus and many HTLV-1-infected people remain asymptomatic; however, in both cases the infection can lead to serious illness such as cancer. The factors which determine outcome are still elusive. We have found that a gene that encodes a receptor (KIR2DL2) enhances both protective and detrimental HLA class I-mediated immunity to HCV and HTLV-1. Strikingly, although KIRs are primarily associated with innate immunity, our observations suggest that they also have a major impact on the efficiency of the adaptive immune response. This work helps to explain why one individual infected with a virus remains healthy but another, infected with the same virus develops disease; it also helps to explain why particular HLA class I molecules do not always protect or cause susceptibility as expected. Interestingly, the impact of the KIR is entirely context dependent: if an HLA class I molecule is protective then protection is enhanced, but in the context of a detrimental HLA then susceptibility is enhanced. This study reveals a novel role for inhibitory KIRs in adaptive immunity.
doi:10.1371/journal.ppat.1002270
PMCID: PMC3192839  PMID: 22022261
13.  Temporal trends in HAART initiation among injection drug users in Baltimore, MD, 1996–2008 
Background
We characterized temporal trends in HAART initiation (1996–2008) among treatment eligible persons in a community-based cohort of current and former injection drug users (IDUs) in Baltimore.
Methods
The AIDS Linked to the IntraVenous Experience (ALIVE) cohort has been following HIV positive IDUs since 1988. HAART eligibility was defined as the first visit after January 1, 1996 where CD4 was <350 cells/µl. Temporal trends and predictors of HAART initiation were examined using chi-square tests for trend and lognormal survival models.
Results
The median age of 582 HAART-eligible IDUs was 41; 75% were male, 97% African American and 60% active injectors. 345 initiated HAART over 1803 person-years (19.2 per 100 person-years, 95% CI, 17.2–21.3); there was no significant temporal trend in HAART initiation. Independent predictors of delayed initiation included heavy injection and higher CD4 count; prior AIDS diagnosis, usual source of care and health insurance were predictors of more rapid initiation. The delay between eligibility and initiation decreased among those becoming eligible most recently (2003–07) compared with those in earlier calendar periods (1996–2003); however, a substantial number initiated HAART in recent calendar years either after substantial delay or not at all.
Conclusions
We failed to observe substantial improvement in HAART initiation among current and former IDUs over 12 years; heavy drug injection remains the major barrier to HAART initiation and consistent HIV care. The fact that many IDUs initiate HAART after significant delay or not at all raises concern that disparities in HIV care for IDUs remain at a time of simplified antiretroviral regimens and increasing adoption of earlier treatment.
doi:10.1086/652867
PMCID: PMC2874101  PMID: 20450418
HIV/AIDS; injection drug users; highly active antiretroviral therapy; temporal trends
14.  Progression of Biopsy-Measured Liver Fibrosis in Untreated Patients with Hepatitis C Infection: Non-Markov Multistate Model Analysis 
PLoS ONE  2011;6(5):e20104.
Background
Fibrosis stages from liver biopsies reflect liver damage from hepatitis C infection, but analysis is challenging due to their ordered but non-numeric nature, infrequent measurement, misclassification, and unknown infection times.
Methods
We used a non-Markov multistate model, accounting for misclassification, with multiple imputation of unknown infection times, applied to 1062 participants of whom 159 had multiple biopsies. Odds ratios (OR) quantified the estimated effects of covariates on progression risk at any given time.
Results
Models estimated that progression risk decreased the more time participants had already spent in the current stage, African American race was protective (OR 0.75, 95% confidence interval 0.60 to 0.95, p = 0.018), and older current age increased risk (OR 1.33 per decade, 95% confidence interval 1.15 to 1.54, p = 0.0002). When controlled for current age, older age at infection did not appear to increase risk (OR 0.92 per decade, 95% confidence interval 0.47 to 1.79, p = 0.80). There was a suggestion that co-infection with human immunodeficiency virus increased risk of progression in the era of highly active antiretroviral treatment beginning in 1996 (OR 2.1, 95% confidence interval 0.97 to 4.4, p = 0.059). Other examined risk factors may influence progression risk, but evidence for or against this was weak due to wide confidence intervals. The main results were essentially unchanged using different assumed misclassification rates or imputation of age of infection.
Discussion
The analysis avoided problems inherent in simpler methods, supported the previously suspected protective effect of African American race, and suggested that current age rather than age of infection increases risk. Decreasing risk of progression with longer time already spent in a stage was also previously found for post-transplant progression. This could reflect varying disease activity, with recent progression indicating active disease and high risk, while longer time already spent in a stage indicates quiescent disease and low risk.
doi:10.1371/journal.pone.0020104
PMCID: PMC3103523  PMID: 21637766
15.  Prevalence and risk factors for unrecognized obstructive lung disease among urban drug users 
Background
Obstructive lung disease (OLD) is frequently unrecognized and undertreated. Urban drug users are at higher risk for OLD due to race, behavioral, and socioeconomic characteristics, yet little data exist on prevalence and risk factors associated with unrecognized OLD in this population.
Objective
The objective of this study is to determine the prevalence of unrecognized OLD in an urban population and identify the characteristics associated with lack of physician-diagnosed OLD.
Design
Cross-sectional analysis from the Acquired Immunodeficiency Syndrome Linked to the Intravenous Experience (ALIVE) study, an observational study of current and former injection drug users in Baltimore, Maryland, USA.
Participants
All participants with spirometry-defined airflow obstruction were stratified by the presence or absence of physician diagnosis of OLD.
Main measures
Using cross-sectional demographic, clinical, and spirometric measurements, multivariable regression models were generated to identify factors independently associated with unrecognized OLD.
Key results
Of the 1083 participants evaluated in the ALIVE lung substudy, 176 (16.3%) met spirometric criteria for OLD. Of those, only 88 (50%) had a physician diagnosis of OLD. The prevalence of unrecognized OLD decreased as severity of airflow obstruction increased. Factors independently associated with unrecognized OLD were absence of respiratory symptoms (prevalence ratio [PR], 1.70; 95% confidence interval [CI]: 1.29–2.23; P < 0.01) and less severe dyspnea (PR, 0.83; 95% CI: 0.72–0.96, per point increase in dyspnea scale; P = 0.01). In the subset of human immunodeficiency virus (HIV)–infected participants, the use of antiretroviral therapy (ART) was independently associated with an increased prevalence of unrecognized OLD (PR, 1.93; 95% CI: 1.05–3.56; P = 0.03).
Conclusions
In a cohort of current and former urban drug users, OLD is substantially underrecognized and associated with lack of respiratory symptoms. Relying on the presence of respiratory symptoms as a trigger to perform spirometry may result in a substantial underdiagnosis of OLD in this population. HIV-infected individuals receiving ART are a population particularly vulnerable to unrecognized OLD.
doi:10.2147/COPD.S15968
PMCID: PMC3048084  PMID: 21407821
obstructive lung disease; human immunodeficiency virus infection; COPD; asthma; spirometry
16.  Acceleration of Hepatitis C Virus Envelope Evolution in Humans Is Consistent with Progressive Humoral Immune Selection during the Transition from Acute to Chronic Infection▿  
Journal of Virology  2010;84(10):5067-5077.
During the transition from acute to chronic infection in individuals persistently infected with hepatitis C virus (HCV), cellular responses initiate within the first 6 months of primary infection and collapse thereafter, whereas humoral responses activate later during the chronic phase. Whether and how this deviation of immune responses specifically influences HCV evolution are unknown. To determine the pattern of HCV evolution during this critical period, we conducted extensive sequence analysis on annual clonal hemigenomic sequences for up to 3 years in six well-characterized subjects, using statistical methods that accounted for repeated measures. Significantly different evolutionary rates were observed in envelope versus nonenvelope genes, with an increasing rate of nonsynonymous change (dN) in envelope genes and a stable dN in nonenvelope genes (P = 0.006). The ratio of the envelope to nonenvelope nonsynonymous rate increased from 2 in year 1 to 5 in years 2 and 3. Centripetal changes (reversions toward matching of the worldwide subtype 1a consensus sequence) were frequently observed during the 3-year transition from acute infection to chronicity, even in the presence of neutralizing antibody (NAb) pressure. Remarkably, sequences of hypervariable region 1 (HVR1) remained stable for up to 21 months in the absence of NAb pressure in one subject, followed by rapid changes that were temporally associated with the detection of NAb responses, which strongly suggests that HVR1 evolution is shaped by NAb pressure. These data provide the first systematic estimates of HCV evolutionary rates in multiple genes during early infection in vivo and provide additional evidence for deterministic, rather than random, evolution of HCV.
doi:10.1128/JVI.02265-09
PMCID: PMC2863818  PMID: 20200239
17.  Non-structured treatment interruptions (NTIs) among injection drug users in Baltimore, MD 
Background
We characterized patterns of highly active antiretroviral therapy (HAART) use and predictors of non-structured treatment interruptions (NTIs) among injection drug users (IDUs) in Baltimore, MD.
Methods
335 IDUs who initiated HAART from 1996-2006 were studied. NTIs were defined as any subsequent six-month interval where HAART was not reported. Predictors of the first NTI and subsequent restart of HAART were examined using Cox regression.
Results
260 (78%) reported ≥1 NTI. Of 215 with ≥1 follow-up visit after the NTI, 44 (20%) never restarted HAART, 62 (29%) restarted and remained on HAART and 109 (51%) reported multiple NTIs. NTIs were less likely among those who initiated HAART in later calendar years and hada recent outpatient visit and more likely among women, persons with detectable HIV RNA at the prior visit and those who reported injecting daily. Among those with NTIs, interuptions occurred earlier in persons who were younger, did not have a prior AIDS diagnosis and were actively injecting; NTIs lasted longer in persons who had higher HIV RNA levels, were incarcerated and drinking alcohol. A recent outpatient visit and not actively injecting were associated with restarting HAART.
Conclusions
NTIs were common in this population and occurred most frequently in the setting of active drug use and disruption of health care. Effective linkages between primary care for HIV and substance abuse treatment may improve HAART outcomes in this population.
doi:10.1097/QAI.0b013e318198a800
PMCID: PMC2782439  PMID: 19214124
Highly active antiretroviral therapy; injection drug users; treatment interruptions
18.  High Programmed Death-1 levels on HCV specific T cells during acute infection are associated with viral persistence and require preservation of cognate antigen during chronic infection1 
HCV is an important human pathogen that represents a model for chronic infection since the majority of infected individuals fail to clear the infection despite generation of virus-specific T cell responses during the period of acute infection. While viral sequence evolution at targeted MHC class I restricted epitopes represents one mechanism for immune escape in HCV, many targeted epitopes remain intact under circumstances of viral persistence. In order to explore alternative mechanisms of HCV immune evasion, we analyzed patterns of expression of a major inhibitory receptor on T cells, programmed death-1 (PD-1), from the time of initial infection and correlated these with HCV RNA levels, outcome of infection, and sequence escape within the targeted epitope. We show that the level of PD-1 expression in early HCV infection is significantly higher on HCV-specific T cells from those who progress to chronic HCV infection compared to those who clear infection. This correlation is independent of HCV RNA levels, compatible with the notion that high PD-1 expression on HCV-specific CD8 T cells during acute infection inhibits viral clearance. Viral escape during persistent infection is associated with reduction in PD-1 levels on the surface of HCV specific T cells, supporting the necessity of ongoing antigenic stimulation of T cells for maintenance of PD-1 expression. These results support the idea that PD-1 expression on T cells specific for nonescaped epitopes contributes to viral persistence and suggest that PD-1 blockade may alter the outcome of HCV infection.
PMCID: PMC2773824  PMID: 19050238
CD8+ T cells; HCV infection; Programmed Death-1; Viral Escape
19.  Interaction between RANTES promoter variant and CCR5Δ32 favors recovery from hepatitis B 
Recovery from acute hepatitis B virus (HBV) infection occurs in 95% of adult-acquired infections. A 32-base pair deletion in CCR5 (CCR5Δ32), which encodes for a nonfunctional receptor, increases the likelihood of recovery. Using 181 subjects with persistent HBV infection and 316 who had recovered, we tested the hypothesis that an epistatic interaction between functional polymorphisms in RANTES (a CCR5 ligand) and CCR5 impacts recovery. Specific models designed to assess individual contributions of compound genotypes demonstrated that the only combination associated with recovery from an HBV infection was RANTES -403A with CCR5Δ32 (OR 0.36, P= 0.02). Since the phenotypic consequence of -403A is reported to be higher levels of RANTES, we propose a model where excess RANTES in combination with low CCR5 favor recovery from an HBV infection, which will require validation through functional testing. “This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org.”
PMCID: PMC2650505  PMID: 19017985
Viral infection; chemokines; human
20.  Long-term effectiveness of diagnosing and treating latent tuberculosis infection in a cohort of HIV-infected and at risk injection drug users 
Introduction
Between 1990 and 1998, tuberculin skin testing (TST) and isoniazid preventive therapy (IPT) was provided to injection drug users participating in the AIDS Linked to the Intravenous Experiences (ALIVE) cohort.
Methods
A registry match was conducted with the ALIVE cohort database and the Maryland State Department of Health and Mental Hygiene tuberculosis registry.
Results
Of 2,010 participants, 1,753(74%) had a TST placed and read; 536(31%) were positive. TST positivity was 16% in HIV-positives;39% in HIV-negatives(p<0.01). Overall, 299(56%) TST reactors started IPT; 165(55%) completed six months. Three tuberculosis cases were diagnosed among HIV-negatives (IR=0.16/1,000PYs); 19 among HIV-positives (1.94/1000PYs; IRR=12.3(3.61−64.70). Within the entire cohort, tuberculosis rates were 0.8/1000PYs for those not receiving IPT, 0.48/1000PYs for those receiving any IPT, 0.29/1000PYs for those completing at least 30 days and 0/1000PYs for completers. Ten cases of tuberculosis occurred in HIV-infected individuals with negative TSTs.
Discussion
IPT was associated with protection against tuberculosis, but uptake was modest. While it is likely that tuberculosis incidence would have increased, especially in HIV-positive subjects, if the IPT program had not occurred, more significant declines in tuberculosis incidence in this population will require improved methods for ensuring uptake and completion of IPT and preventing disease in TST-negative individuals.
doi:10.1097/QAI.0b013e31818d5c1c
PMCID: PMC2637943  PMID: 18989223
tuberculosis; latent tuberculosis infection; HIV
21.  Assessment of Liver Fibrosis by Transient Elastography in Persons with Hepatitis C Virus Infection or HIV–Hepatitis C Virus Coinfection 
Background
Transient elastography is a novel, noninvasive method for staging liver fibrosis. We compared elastography with histologic methods among hepatitis C virus (HCV)–infected and human immunodeficiency virus (HIV)–HCV-coinfected participants in an urban, predominantly black study population.
Methods
Participants recruited from the AIDS Linked to the Intravenous Experience and the Johns Hopkins HIV Clinical Cohort studies underwent elastography to determine liver stiffness measurements. Liver biopsy specimens were staged F0–F4 in accordance with the Metavir score. Diagnostic accuracy and determination of liver stiffness cutoff values, compared with histologic methods, were determined by receiver operating characteristic analysis. Logistic regression methods identified parameters associated with discordant classification status.
Results
Of 192 participants, 139 (72%) were coinfected with HIV and HCV, 121 (63%) had insignificant fibrosis, and 48 (25%) had cirrhosis. Overall, the area-under-the-curve receiver operating characteristic was 0.87 for detection of both significant fibrosis (95% confidence interval, 0.82–0.92) and cirrhosis (95% confidence interval, 0.81–0.93). With use of cutoff values of ≥9.3 kPa for fibrosis and ≥12.3 kPa for cirrhosis, 79%–83% of participants were correctly classified by liver stiffness measurement (compared with histologic methods); accuracy appeared to be higher among HIV-uninfected participants than among HIV-infected participants. Most discordance occurred when liver stiffness measurements indicated liver disease and histologic examination did not (in 16% of participants); the patients with these discordant results were more likely to have attributes that increased the odds of significant fibrosis, such as elevated serum fibrosis markers or HIV-related immunosuppression, compared with persons in whom low fibrosis was predicted by both examination of a biopsy specimen and elastography.
Conclusions
For most HCV-infected persons, fibrosis stage predicted by elastography is similar to that predicted by examination of a biopsy specimen. Elastography-based measurement of liver stiffness holds promise to expand liver disease screening and monitoring, particularly among injection drug users.
doi:10.1086/597350
PMCID: PMC2715996  PMID: 19236273
22.  Human Immunodeficiency Virus-related Microbial Translocation and Progression of Hepatitis C 
Gastroenterology  2008;135(1):226-233.
Background & Aims
HIV-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation.
Methods
We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized.
Results
HIV-related CD4+ lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS binding protein, soluble CD14, fucose-binding lectin (AAL) reactive to IgG specific for the alpha galactose epitope, and suppressed levels of endotoxin-core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), e.g. LPS, odds ratio 19.0 (p = 0.002), AAL, odds ratio 27.8 (p<0.0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis.
Conclusions
Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.
doi:10.1053/j.gastro.2008.03.022
PMCID: PMC2644903  PMID: 18457674
23.  Isoniazid Preventive Therapy, Hepatitis C Virus Infection, and Hepatotoxicity among Injection Drug Users Infected with Mycobacterium tuberculosis 
Treatment of latent Mycobacterium tuberculosis infection with isoniazid can cause hepatotoxicity, but the risk of isoniazid-associated hepatotoxicity among persons coinfected with hepatitis C virus (HCV) is unknown. We conducted a prospective study among 146 injection drug users with M. tuberculosis infection and normal baseline hepatic transaminase values who were treated with isoniazid. Of 146 participants, 138 (95%) were HCV-seropositive. Thirty-seven participants (25%) were human immunodeficiency virus (HIV)—seropositive. Thirty-two (22%; 95% confidence interval [CI], 16%–30%) of 146 participants developed transaminase value elevations to >3 times the upper limit of normal. Transaminase value elevation was associated with concurrent alcohol use but not with race, age, presence of hepatitis B surface antigen, HIV-1 infection, or current injection drug use. Isoniazid was withdrawn from 11 participants (8%; 95% CI, 4%–13%). Of 8 deaths during follow-up, none were attributed to isoniazid-associated hepatotoxicity. The risk of transaminase value elevation and drug discontinuation for HCV-infected persons receiving isoniazid was within the range reported for populations with lower HCV prevalence.
doi:10.1086/323896
PMCID: PMC2650436  PMID: 11641824
24.  Immunoglobulin Allotypes Influence IgG Antibody Responses to Hepatitis C Virus Envelope Proteins E1 and E2 
Human immunology  2008;69(3):158-164.
Immunoglobulin (Ig) GM and KM allotypes—genetic markers of γ and κ chains, respectively—are associated with the outcome of hepatitis C virus (HCV) infection, but the underlying mechanisms are not well understood. We hypothesized that GM and KM allotypes could contribute to the outcome of HCV infection by influencing the levels of IgG antibodies to the HCV glycoproteins E1E2. We serologically allotyped 100 African Americans with persistent HCV infection for GM and KM markers and measured anti-E1E2 antibodies. Subjects with the GM 1,17 5,13 phenotype had significantly higher levels of anti-E1E2 antibodies than the subjects who lacked this phenotype (p = 0.008). Likewise, subjects with the KM 1-carrying phenotypes had higher levels of anti-E1E2 antibodies than the subjects who lacked these phenotypes (p = 0.041). Median titers were fourfold higher in persons expressing both GM 1,17 5,13 and KM 1-carrying phenotypes compared to those who lacked these phenotypes (p = 0.011). Interactive effects of these GM-KM phenotypes were previously found to be highly significantly associated with spontaneous HCV clearance. Results presented here show that Ig allotypes contribute to the inter-individual differences in humoral immunity to the HCV epitopes, a finding that may provide a mechanistic explanation for their involvement in the outcome of HCV infection.
doi:10.1016/j.humimm.2008.01.019
PMCID: PMC2364665  PMID: 18396207
Immunoglobulin; GM and KM allotypes; IgG antibodies; Proteins E1 and E2; Hepatitis C virus; Humoral immunity
25.  Progression of Fibrosis during Chronic Hepatitis C Is Associated with Rapid Virus Evolution▿  
Journal of Virology  2007;81(12):6513-6522.
Hepatic fibrosis is the primary mediator of disease due to chronic infection with hepatitis C virus (HCV). HCV exists as a quasispecies in each infected individual, and longitudinal viral sequence changes may reveal viral dynamics and the selection pressures applied by the host immune system. Thus, we hypothesized that patterns of sequence change might reveal the immunopathogenesis of fibrosis progression. We tested this hypothesis by studying individuals enrolled in a prospective study of chronic HCV-related hepatic fibrosis with little or no fibrosis at first biopsy (stage 0 or 1) and a second planned liver biopsy sample obtained 4 years later. Serum was obtained from five individuals with fast progression (FP; defined as a >2-stage change between visits) and 10 carefully matched individuals with slow progression (SP; defined as a <2-stage change between visits). We sequenced multiple cloned hemigenomic cDNAs from each person spanning six genes (core through NS3). Phylogenetic analysis revealed temporal shifts in phylogenetic clustering over time, suggesting frequent quasispecies replacement rather than simple diversification. In addition, mixed infections were detected in three subjects, with coexistence in two subjects (one FP, one SP) of subtypes 1a and 1b throughout the 4-year biopsy interval. Subjects with FP had a higher rate of evolution than subjects with SP, with a preponderance of synonymous changes, suggesting purifying selection, except in hypervariable region 1, where positive selection pressure is frequently detected. Thus, in a small but carefully matched cohort we found evidence for rapid neutral evolution of HCV in persons with rapid progression of hepatic fibrosis, suggesting higher turnover of infected cells.
doi:10.1128/JVI.02276-06
PMCID: PMC1900109  PMID: 17329332

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