David L Thomas

Johns Hopkins Medicine, Baltimore, Maryland, United States

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Publications (185)1887.14 Total impact

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    ABSTRACT: Genetic polymorphisms within the interferon lambda (IFN-) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls generation of the IFN-4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability. We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach. Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r(2)=0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p=0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p=0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep C (p=0.03) and week 20 in HALT-C (p=0.03), as well as for spontaneous HCV clearance (p=0.048). IFNL4-ΔG/TT is the primary IFN- region polymorphism for impaired HCV clearance. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 07/2015; DOI:10.1016/j.jhep.2015.06.035 · 10.40 Impact Factor
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    ABSTRACT: Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. A case-cohort study (n=470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) clinical trial (1571 HIV treatment-naïve adults who initiated cART; CD4+ T cell count <300 cells/mm; nine countries) was conducted. A subcohort of 30 participants/country was randomly selected; additional cases were added from the main cohort. Cases (n=236 [random subcohort-36; main cohort-200]) had clinical progression (incident WHO Stage 3/4 event or death) within 96 weeks following cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4+ T-cell count was 167 cells/mm. In multivariate analysis, highest quartile CRP concentration (adjusted hazards ratio [aHR] 2.53, 95%CI 1.02-6.28) and CD4+ T-cell activation (aHR 5.18, 95CI 1.09-24.47) were associated with primary outcomes, compared to lowest quartiles. sCD14 had a trend towards association with clinical failure (aHR 2.24, 95%CI 0.96-5.21). Measuring CRP and CD4+ T-cell activation may identify patients with CD4+ T cell counts < 300 cells/mm at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 05/2015; DOI:10.1097/QAI.0000000000000696 · 4.39 Impact Factor
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    ABSTRACT: Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from [Formula: see text] infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e.g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replication and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.
    PLoS Computational Biology 11/2014; 10(11):e1003934. DOI:10.1371/journal.pcbi.1003934 · 4.83 Impact Factor
  • Clinical Infectious Diseases 09/2014; 59 Suppl 2(suppl 2):S61-2. DOI:10.1093/cid/ciu440 · 9.42 Impact Factor
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    ABSTRACT: IMPORTANCE New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). OBJECTIVE To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS An International Antiviral Society–USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. RESULTS Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. CONCLUSIONS AND RELEVANCE After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.
    JAMA The Journal of the American Medical Association 07/2014; 312(4):410-25. DOI:10.1001/jama.2014.8722 · 30.39 Impact Factor
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    ABSTRACT: Background & Aims: The contribution of humoral immune responses to spontaneous control of Hepatitis C virus (HCV) infection remains unclear. We assessed nAb responses during acute HCV infection to determine whether infection outcome is associated with the neutralizing antibody (nAb) response, specifically its timing or breadth (neutralization of multiple genotype-matched variants). Methods: A representative genotype 1 HCV pseudoparticle (HCVpp) library, consisting of 19 genetically-distinct genotype 1 HCVpp that comprise the natural variability of genotype 1 E1E2 sequences, was used to assess anti-genotype 1 nAb responses during acute infection in at-risk persons followed prospectively. Neutralization of individual library HCVpp by the last viremic plasma sample obtained before clearance was compared to either one-year post-initial viremia or clearance time-matched specimens obtained from subjects developing persistent infection. Results: In persistently infected persons nAb responses were delayed then progressively broadened whereas in persons who controlled viremia broader responses were detected early and contracted after clearance of viremia. Surprisingly, the breadth of anti-genotype 1 nAb responses was not dependent upon subjects' infection genotype. Also, individual library HCVpp neutralization sensitivity was not associated with any known E2 sequence determinants. Interestingly, two single nucleotide polymorphisms in the HLA-DQ locus were associated with nAb breadth. Conclusions: Taken together, these data demonstrate that control of HCV infection is associated with more rapid development of a broad nAb response, independent of the infection viral genotype, providing further evidence for the role of nAb in controlling HCV infection and the potential benefit of generating broad anti-HCV nAb responses by vaccination. (Hepatology 2014;).
    Hepatology 06/2014; 59(6). DOI:10.1002/hep.27013 · 11.19 Impact Factor
  • David L Thomas
    New England Journal of Medicine 03/2014; 370(12):1162-3. DOI:10.1056/NEJMe1401440 · 54.42 Impact Factor
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    ABSTRACT: The prevalence of hepatitis C viral (HCV) infection in sub-Saharan Africa remains unclear. We tested 1000 individuals from Rakai Uganda with the Ortho v3.0 HCV ELISA. All serologically positive samples were tested for HCV RNA. 7.6%(76/1000) subjects were HCV antibody positive, none were confirmed by detection of HCV RNA.
    Clinical Infectious Diseases 09/2013; DOI:10.1093/cid/cit602 · 9.42 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) predominantly infects hepatocytes, but many hepatocytes are not infected; studies have shown that HCV antigens cluster within the liver. We investigated spatial distribution and determinants of HCV replication in human liver samples. We analyzed liver samples from 4 patients with chronic HCV infection (genotype 1, Metavir scores 0-1) to estimate the proportion of infected hepatocytes and amount of HCV viral RNA (vRNA) per cell. Single-cell laser capture microdissection was used to capture approximately >1000 hepatocytes in grids, to preserve geometric relationships. HCV vRNA and IFITM3 mRNA (the transcript of an interferon-stimulated gene) were measured in the same hepatocytes by quantitative PCR and assembled to identify areas of high and low HCV replication. Patients' serum levels of HCV RNA ranged from 6.87 to 7.40 log10 IU/mL; the proportion of HCV-infected hepatocytes per person ranged from 21% to 45% and the level of vRNA ranged from 1 to 50 IU/hepatocyte. Infection was not random; we identified clustering of HCV-positive hepatocytes using infected-neighbor analysis (P<.0005) and distance to the k(th) nearest neighbor compared with random distributions, obtained by bootstrap simulations (P<0.02). Hepatocytes that expressed IFITM3 did not appear to cluster and were largely HCV-negative. We used single-cell laser capture and high-resolution analysis to show that in human liver, HCV infects hepatocytes in non-random clusters, whereas expression of antiviral molecules is scattered among hepatocytes. These findings show that quantitative single-cell RNA measurements can be used to estimate the abundance of HCV vRNA per infected human hepatocyte, and are consistent with cell-cell propagation of infection in the absence of clustered IFITM3.
    Gastroenterology 08/2013; 145(6). DOI:10.1053/j.gastro.2013.08.034 · 13.93 Impact Factor
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    ABSTRACT: To confirm previously-identified polymorphisms in HAVCR1 that were associated with persistent hepatitis C virus (HCV) infection in individuals of African and of European descent, we studied 165 African-descent and 635 European-descent subjects. Since the association only confirmed in African-descent subjects (rs6880859, OR 2.42, P=0.01), we then used 379 African-descent subjects (142 with spontaneous HCV clearance) to fine map HAVCR1. rs111511318 was strongly associated with HCV persistence after adjusting for IL28B and HLA (adjusted P=8.8 x 10(-4)) as was one 81 kilobase haplotype (adjusted P=0.0006). The HAVCR1 genomic region is an independent genetic determinant of HCV persistence in African-descent subjects.
    The Journal of Infectious Diseases 08/2013; 209(3). DOI:10.1093/infdis/jit444 · 5.78 Impact Factor
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    ABSTRACT: Interferon lambda 4 protein can be generated in IFNL4-ΔG carriers, but not IFNL4-TT homozygotes. We studied 890 anti-hepatitis C virus (HCV) positive participants in the Women's Interagency HIV Study. Among African Americans (n=555), HCV was more often cleared for those with genotype IFNL4-TT/TT (32.6%; odds ratio (OR), 3.59; p=3.3x10(-5)) than IFNL4-TT/ΔG (11.3%; OR, 0.95; p=0.86) or IFNL4-ΔG/ΔG (11.9%; referent). Pooling these data with published results in African Americans (n=1,678), ORs were: IFNL4-TT/TT, 3.84 (p=8.6x10(-14)); IFNL4-TT/ΔG, 1.44 (p=0.03); area under the curve was 0.64 for IFNL4-ΔG genotype and 0.61 for rs12979860 ('IL28B'). IFNL4-ΔG is strongly associated with impaired spontaneous HCV clearance.
    The Journal of Infectious Diseases 08/2013; 209(3). DOI:10.1093/infdis/jit433 · 5.78 Impact Factor
  • Andrea L. Cox · David L. Thomas
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    ABSTRACT: Most people who inject drugs (PWID) are infected with hepatitis C virus (HCV), and PWID have the highest risk of HCV infection of any risk group. The incidence of HCV infection is 5%-25% per year, demonstrating continued need for HCV infection prevention in PWID. Existing data in chimpanzees and PWID suggest that protective immunity against persistent HCV infection is achievable. Due to the high incidence of infection, PWID are both the most likely to benefit from a vaccine and a population in which vaccine efficacy could be tested. Challenges to testing a vaccine in PWID are significant. However, the first HCV vaccine trial in at-risk HCV-uninfected PWID was initiated in 2012. The results will likely guide future vaccine development and strategies for vaccination of this and other high-risk populations.
    Clinical Infectious Diseases 07/2013; 57(suppl 2):S46-S50. DOI:10.1093/cid/cit329 · 9.42 Impact Factor
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    ABSTRACT: Abstract Several epidemiological studies have suggested that hepatitis C virus (HCV) infection is associated with the presence of obstructive lung disease (OLD). However, there is a strong link between HCV infection and tobacco abuse, a major risk factor for the development of OLD. In this study we analyzed clinical, laboratory and spirometric data from 1068 study participants to assess whether HCV infection, viremia, or HCV-associated end organ damage were associated with OLD. Demographics, risk behavior, serologic status for HCV and HIV, and spirometric measurements were collected from a cross-sectional analysis of the Acquired Immunodeficiency Syndrome (AIDS) Linked to the IntraVenous Experience (ALIVE) study, an observational cohort of IDUs followed in Baltimore, MD since 1988. Of 1,068 participants, 890 (83%) were HCV positive and 174 (16%) met spirometric criteria for OLD. Factors independently associated with OLD were age and BMI. HCV infection, viral load and HCV-associated end organ damage were similar in participants with and without OLD. In summary, there was no independent association between markers of HCV exposure, chronicity, viremia, or HCV-associated end-organ damage with OLD. Our findings support the strong correlation between HCV status, injection drug use, and smoking. These data suggest that HCV may not be a sole contributor to the increased prevalence of OLD described in previous studies of HCV-infected individuals.
    COPD Journal of Chronic Obstructive Pulmonary Disease 07/2013; 11(1). DOI:10.3109/15412555.2013.800854 · 2.62 Impact Factor
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    ABSTRACT: Chronic infection with hepatitis C virus (HCV) is a major global health problem-there are approximately 120-130 million chronic infections worldwide. Since discovery of HCV 24 y ago, there has been a relentless effort to develop successful antiviral therapies. Studies of interferon-α(IFN)-based therapies have helped define treatment parameters, and these treatment strategies have cured a substantial percentage of patients. However, IFN must be injected, and there are problems with tolerability, adherence, and incomplete response in a large percentage of patients. New drug candidates designed to target the virus or the host have recently been introduced at an unprecedented pace. In phase I-III studies, these agents have exceeded expectations and achieved rates of response previously not thought possible. We are therefore entering a new era of therapy for HCV infection and interferon independence.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 07/2013; 12(5). DOI:10.1016/j.cgh.2013.06.024 · 6.53 Impact Factor
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    David L Thomas
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    ABSTRACT: We are entering an important new chapter in the story of hepatitis C virus (HCV) infection. There are clear challenges and opportunities. On the one hand, new HCV infections are still occurring, and an estimated 185 million people are or have previously been infected worldwide. Most HCV-infected persons are unaware of their status yet are at risk for life-threatening diseases such as cirrhosis and hepatocellular carcinoma (HCC), whose incidences are predicted to rise in the coming decade. On the other hand, new HCV infections can be prevented, and those that have already occurred can be detected and treated-viral eradication is even possible. How the story ends will largely be determined by the extent to which these rapidly advancing opportunities overcome the growing challenges and by the vigor of the public health response.
    Nature medicine 07/2013; 19(7):850-8. DOI:10.1038/nm.3184 · 28.05 Impact Factor
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    ABSTRACT: 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. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse.
    Annals of internal medicine 02/2013; DOI:10.7326/0003-4819-158-9-201305070-00604 · 16.10 Impact Factor
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    ABSTRACT: Chinese translation Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood. To evaluate the host genetic basis for spontaneous resolution of HCV infection. 2-stage, genome-wide association study. 13 international multicenter study sites. 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence). Frequencies of 792 721 single nucleotide polymorphisms (SNPs). Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10-30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10-16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015). Epigenetic effects were not studied. IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection. Office of AIDS Research, National Institutes of Health, and Frederick National Laboratory for Cancer Research.
    Annals of internal medicine 02/2013; 158(4):235-45. DOI:10.7326/0003-4819-158-4-201302190-00003 · 16.10 Impact Factor
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    ABSTRACT: 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 double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
    Nature Genetics 01/2013; 45(2). DOI:10.1038/ng.2521 · 29.65 Impact Factor
  • Hepatology 12/2012; 56(6):1520-1521. · 11.19 Impact Factor

Publication Stats

18k Citations
1,887.14 Total Impact Points

Institutions

  • 1999–2014
    • Johns Hopkins Medicine
      • • Division of Infectious Diseases
      • • Department of Epidemiology
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 1996–2014
    • Johns Hopkins University
      • • Division of Infectious Diseases
      • • Department of Medicine
      • • Department of Epidemiology
      Baltimore, Maryland, United States
  • 2013
    • State University of New York Downstate Medical Center
      Brooklyn, New York, United States
  • 1999–2013
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, Maryland, United States
  • 2012
    • Emory University
      Atlanta, Georgia, United States
  • 2011
    • National Institutes of Health
      • Branch of Liver Diseases Branch (LDB)
      Bethesda, MD, United States
  • 2007
    • Third Military Medical University
      • Southwest Hospital
      Ch’ung-ch’ing-shih, Chongqing Shi, China
    • National Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      Maryland, United States
  • 2005
    • University of New South Wales
      • School of Medical Sciences
      Kensington, New South Wales, Australia
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 2004
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
    • Medical University of South Carolina
      • Department of Microbiology and Immunology (College of Medicine)
      Charleston, SC, United States
  • 2000
    • Southwest Foundation For Biomedical Research
      San Antonio, Texas, United States
    • New York Academy of Medicine
      New York, New York, United States