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David L Thomas

Publications and source records attributed to David L Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2006

Gene expression patterns that correlate with hepatitis C and early progression to fibrosis in liver transplant recipients.

BACKGROUND & AIMS: Liver transplant recipients infected with hepatitis C virus (HCV) develop recurrent hepatitis soon after transplantation and, in some cases, progress to fibrosis within the first 2 years. Our goals were to identify molecular processes influencing the liver disease progression and to find potential gene markers of early fibrosis. METHODS: We performed gene expression profiling on serial liver biopsy specimens obtained from 13 (11 infected and 2 uninfected) transplant recipients within the first year after transplantation at 0, 3, 6, and 12 months. The data were compared with clinical observations and with a gene expression database obtained for 55 nontransplant HCV-infected and uninfected liver samples. RESULTS: We identified several specific gene expression patterns. The first pattern was unique for the transplant recipients regardless of their infection status. The corresponding genes encoded stress response proteins and blood proteins involved in coagulation that were differentially expressed in response to posttransplantation graft recovery. The second pattern was specific to HCV-infected samples and included up-regulation of genes encoding components of the interferon-mediated antiviral response and immune system (antigen presentation, cytotoxic response). This up-regulation pattern was absent or suppressed in the patients who developed early fibrosis, indicating that the disease progression might result from an impaired liver response to infection. Finally, we identified gene expression patterns that were specific for 12-month biopsy specimens in all 4 HCV-infected patients who developed early fibrosis. CONCLUSIONS: The identified gene expression patterns may prove useful for diagnostic and prognostic applications in HCV-infected patients, including predicting early progression to fibrosis.

Adult↗
PubMed2006

Serum albumin as a prognostic indicator for HIV disease progression.

Low albumin levels have been associated with HIV progression. The objective of this analysis was to confirm this association and to further examine the effect of albumin before and after HIV seroconversion on disease progression. The association was first examined among individuals already infected with HIV at entry into a community-based cohort (n = 453) and further assessed among HIV seroconverters with albumin concentrations measured after (n = 219) and before seroconversion (n = 138). The prognostic effect of albumin on AIDS, AIDS mortality, and all-cause mortality was examined using Cox regression. Among 453 HIV-infected individuals, albumin <35 g/liter was associated with faster progression to AIDS [adjusted relative hazard (ARH), 1.8; 95% confidence interval (CI), 1.2-2.8], AIDS mortality (ARH, 2.2; 95% CI, 1.3-3.8), and all-cause mortality (ARH, 2.4; 95% CI, 1.6-3.5). Analyses restricted to HIV seroconverters were similar. Preseroconversion levels of albumin did not predict outcomes, but HIV seroconversion appeared to lower albumin levels. These data show that albumin <35 g/liter after HIV seroconversion is associated with faster HIV disease progression and suggest that low albumin levels are probably a consequence of HIV infection rather than merely reflective of some individuals inherently having low albumin levels.

Adolescent↗
PubMed2005

Options for treatment of hepatitis C in HIV-infected persons.

Irrespective of whether a patient has HIV infection, the optimal treatment for hepatitis C virus (HCV) infection is peginterferon alpha and ribavirin. In both HIV-infected and uninfected persons, sustained virologic response (SVR) rates are higher for genotype 2 and genotype 3 HCV infection and for patients with lower pre-treatment HCV RNA levels. HIV-infection does not alter either the reality that persons who fail to achieve a 2log(10) reduction in HCV RNA level after 12 weeks of therapy rarely achieve a SVR, or the theoretical benefits of maintenance therapy in those without viral responses. The same adverse treatment effects can occur in HIV-infected and uninfected persons, but treatment of HIV-infected persons is complicated by interactions between ribavirin and antiretroviral medications and effects of HCV treatment on the course of HIV. The optimal treatment doses and durations are not known for HIV-infected persons, who are also less likely to achieve a SVR. A final difference is that the benefits of HCV treatment breakthroughs are usually realized in patients without HIV years before those with HIV. Future research must focus both on improving outcomes with currently available medications and rapidly evaluating the safety and efficacy of forthcoming antiviral compounds in HIV/HCV coinfected persons.

Antiviral Agents↗
PubMed2005

High prevalence of alcohol use among hepatitis C virus antibody positive injection drug users in three US cities.

Injection drug users (IDUs) acquire the majority of new hepatitis C virus (HCV) infections and frequently use alcohol. Alcohol abuse accelerates liver disease among HCV-infected persons, can reduce the effectiveness of treatment for HCV infection and may be a contraindication for HCV treatment. HCV seropositive, HIV-negative IDUs aged 18-35 years in Baltimore, New York City and Seattle who were enrolled in a behavioral risk-reduction intervention trial underwent computerized self-interviews to assess baseline alcohol use and dependence and medical history. We measured problem alcohol use using the 10-item Alcohol Use Disorders Identification Test (AUDIT) scale. Of 598 participants, 84% responded "false" to: "it is safe for a person with HCV to drink alcohol". Problem drinking, defined as score > or =8 on AUDIT, was identified in 37%. Correlates of scoring > or =8 on AUDIT included homelessness, male gender, primarily injecting speedballs, having injected with used needles, prior alcohol treatment and depression. Although most HCV seropositive IDUs in our sample appear informed about their increased risk of liver disease from alcohol, two-fifths screened positive for problem alcohol use. These findings underscore the importance of referring HCV-positive persons to effective alcohol treatment programs to reduce future liver damage and improve eligibility for and effectiveness of treatment of HCV.

Adolescent↗
PubMed2005

Humoral immune response in acute hepatitis C virus infection.

BACKGROUND: There is little information on the timing, magnitude, specificity, and clinical relevance of the antibody response to acute hepatitis C virus (HCV) infection. We investigated the specificity, titer, and neutralizing potential of antibody responses to acute infection by examining 12 injection drug users before, during, and after infection. METHODS: Seroconversion was defined as incident detection of HCV-specific antibodies by using a commercially available enzyme-linked immuosorbent assay (ELISA). HCV protein-specific antibody responses were measured using recombinant antigens in an ELISA. For neutralization assays, plasma was incubated with human immunodeficiency virus (HIV)-HCV H77 or control HIV-murine leukemia virus (MLV) pseudotype virus and then allowed to infect Hep3B hepatoma cells. RESULTS: The mean time to HCV seroconversion was 6 weeks after the onset of viremia. Antibody responses to nonstructural proteins were detected before responses to the structural proteins, and antibodies to both were primarily restricted to the immunoglobulin G1 (IgG1) subclass. The maximum median end point titers for antibody responses to structural and nonstructural proteins were 1 : 600 and 1 : 6400, respectively. Antibodies that neutralized a retroviral pseudotype bearing HCV 1a envelope glycoproteins were detected at seroconversion in only 1 subject and at 6-8 months after seroconversion in 3 subjects. The delayed appearance of neutralizing antibodies was consistent with the late development of antibodies specific for the viral envelope glycoproteins, which are believed to mediate virus neutralization. CONCLUSION: The humoral immune response to acute HCV infection is of relatively low titer, is restricted primarily to the IgG1 subclass, and is delayed. A better understanding of why production of neutralizing antibody is delayed may improve efforts to prevent HCV infection.

Acute Disease↗
PubMed2005

Cellular immune selection with hepatitis C virus persistence in humans.

Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific cellular immune responses. To determine if immunologically driven sequence variation occurs with HCV persistence, we coordinately analyzed sequence evolution and CD8+ T cell responses to epitopes covering the entire HCV polyprotein in subjects who were followed prospectively from before infection to beyond the first year. There were no substitutions in T cell epitopes for a year after infection in a subject who cleared viremia. In contrast, in subjects with persistent viremia and detectable T cell responses, we observed substitutions in 69% of T cell epitopes, and every subject had a substitution in at least one epitope. In addition, amino acid substitutions occurred 13-fold more often within than outside T cell epitopes (P < 0.001, range 5-38). T lymphocyte recognition of 8 of 10 mutant peptides was markedly reduced compared with the initial sequence, indicating viral escape. Of 16 nonenvelope substitutions that occurred outside of known T cell epitopes, 8 represented conversion to consensus (P = 0.015). These findings reveal two distinct mechanisms of sequence evolution involved in HCV persistence: viral escape from CD8+ T cell responses and optimization of replicative capacity.

Amino Acid Substitution↗
PubMed2005

Divergent and convergent evolution after a common-source outbreak of hepatitis C virus.

The genomic sequences of viruses that are highly mutable and cause chronic infection tend to diverge over time. We report that these changes represent both immune-driven selection and, in the absence of immune pressure, reversion toward an ancestral consensus. Sequence changes in hepatitis C virus (HCV) structural and nonstructural genes were studied in a cohort of women accidentally infected with HCV in a rare common-source outbreak. We compared sequences present in serum obtained 18-22 yr after infection to sequences present in the shared inoculum and found that HCV evolved along a distinct path in each woman. Amino acid substitutions in known epitopes were directed away from consensus in persons having the HLA allele associated with that epitope (immune selection), and toward consensus in those lacking the allele (reversion). These data suggest that vaccines for genetically diverse viruses may be more effective if they represent consensus sequence, rather than a human isolate.

Alleles↗
PubMed2005

Prediction of hepatic fibrosis in HIV/HCV co-infected patients using serum fibrosis markers: the SHASTA index.

BACKGROUND/AIMS: To examine if serum fibrosis biomarkers could accurately identify the stage of liver disease amongst hepatitis C (HCV) and HIV co-infected patients. METHODS: One hundred and thirty seven HIV/HCV co-infected persons were randomly selected from the Johns Hopkins HIV Clinic cohort. Ninety five had complete testing for fibrosis markers in sera collected at the time of liver biopsy. Biopsies were scored according to Ishak modified histological activity index (F0 no fibrosis to F6 cirrhosis). Fibrosis was evaluated against alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST to platelet ratio (APRI), albumin, total bilirubin, hyaluronic acid (HA) and YKL-40. RESULTS: Sixty nine (73%) had no or minimal portal fibrosis (F0-2) and were compared with remaining subjects (F3-6). Fibrosis scores > or =F3 were found 27 times more often in persons with HA levels >86 ng/ml and 5.5 times more often in persons with HA levels 41-86 ng/ml. Less substantial associations were detected with levels of albumin <3.5 g/dl (OR 4.85) and AST >60 iu (OR 5.91). All 35 subjects who had favorable results of HA, albumin, and AST had minimal fibrosis (F0-2). CONCLUSIONS: Amongst HIV/HCV co-infected patients, serum testing for HA, albumin, and AST (SHASTA Index) was able to accurately stage mild and advanced fibrosis.

Adult↗
PubMed2005

Epidemiology and natural history of hepatitis C virus infection in injection drug users: implications for treatment.

Effective methods to diminish the burden of hepatitis C virus (HCV) infection among injection drug users (IDUs) require consideration of the epidemiology and natural history of both hepatitis C and drug use. Most HCV infections are due to injection drug use, and most IDUs have HCV infection. In addition, HCV infection often occurs with other medical problems, such as human immunodeficiency virus infection and depression, which may complicate its recognition and management. Infection with HCV can be fatal, but usually not until years later, and persons may be unaware of the infection, allowing an individual to infect many others. Effective treatment is available for HCV infection; however, the therapy is prolonged, involving both weekly injections and daily oral medication, and is typically associated with significant adverse effects, such as fatigue, depression, and, rarely, life-threatening complications. Although clearly some IDUs want their HCV infection to be treated, many are unwilling or unable to initiate or sustain treatment with currently available therapies, and IDUs who are treated require considerable, multidimensional support. Solutions to the problem of HCV infection among IDUs must account for these facts.

Delivery of Health Care↗
PubMed2005

Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus.

OBJECTIVE: To ascertain the prevalence and severity of hepatic steatosis among patients coinfected with HIV and hepatitis C virus (HCV) who had been taking antiretroviral therapy (ART); to investigate if steatosis is associated with more advanced liver disease, and to identify factors that might contribute to the process. METHODS: Steatosis was assessed among a randomly selected subset of HIV-HCV-coinfected patients who had received at least 2 years of ART in a cohort study at the Johns Hopkins University HIV clinic. Liver histology was evaluated by a single pathologist. The primary outcome measure was the hepatic steatosis grade, which was classified on a 5 point scale: 0, none; 1, steatosis involving < 5% of hepatocytes; 2, 5-29%; 3, 30-60%; 4 > 60%. RESULTS: Liver histology was assessed in 112 patients, 74% of whom were taking ART at the time of biopsy. The median cumulative exposure to nucleoside reverse transcriptase inhibitors and protease inhibitors was 5.8 and 3.7 years, respectively. No steatosis was detected in 60%; grades 2-4 steatosis was recognized in 18%. In multivariate analysis, steatosis was independently associated with Caucasian race, weight > 86 kg, hyperglycemia, and stavudine use. Patients with steatosis also were more likely to have greater hepatic fibrosis (P = 0.02) and necroinflammatory activity (P = 0.005). CONCLUSIONS: Steatosis was observed in 40% of HIV-HCV-coinfected patients with extensive ART exposure and was associated with more severe HCV-related liver disease. Metabolic abnormalities (excess weight and hyperglycemia) and stavudine use were modifiable risk factors for steatosis in this population.

Aged↗
PubMed2005

Prospective evaluation of community-acquired acute-phase hepatitis C virus infection.

BACKGROUND: More than two-thirds of hepatitis C virus (HCV) infections in Western countries are caused by injection drug use, but prospective clinical data regarding the most common mode of HCV acquisition are rare, in part because acute-phase HCV infection is usually asymptomatic. METHODS: To characterize acute-phase HCV infection, 179 HCV antibody-negative injection drug users were prospectively evaluated; 62 (34%) of these patients had seroconverted. Twenty of the participants who seroconverted had long-term follow-up with consistent monthly sampling before and after seroconversion, allowing detailed study. RESULTS: The first indication of HCV infection was the presence of HCV RNA in serum, which preceded elevation of alanine transaminase levels and total bilirubin levels to > or =2 times baseline in 45% and 77% of patients, respectively. No subjects had jaundice. The median time from initial viremia to seroconversion was 36 days (range, 32-46 days). In one instance, viremia was detected 434 days before seroconversion. However, in no other case was HCV RNA detected >63 days before seroconversion. In subjects with viral persistence, a stable level of HCV RNA in the blood was noted in some subjects within 60 days after the initial detection of viremia, but in others, it was not apparent until >1 year later. In subjects with long-term viral clearance, HCV became persistently undetectable as early as 94 and as late as 620 days after initial viremia. CONCLUSIONS: These data underscore the importance of nucleic acid screening of blood donations to prevent HCV transmission and of long-term follow-up to ascertain whether there is viral persistence, at least among injection drug users.

Acute Disease↗
PubMed2005

Hepatitis C virus coinfection and HIV load, CD4+ cell percentage, and clinical progression to AIDS or death among HIV-infected women: Women and Infants Transmission Study.

BACKGROUND: Despite previous study, it remains unclear whether hepatitis C virus (HCV) coinfection affects the progression of human immunodeficiency virus (HIV) type 1 infection. The Women and Infants Transmission Study provided an opportunity to assess this issue. METHODS: Longitudinal data on 652 HIV-1-infected women enrolled in the study before the availability of highly active antiretroviral therapy (HAART; 1989-1995) were analyzed. Random effects models were used to determine whether HCV coinfection was associated with different CD4+ cell percentages and HIV-1 RNA levels over time, and Cox proportional hazards models were used to compare the rates of clinical progression to acquired immunodeficiency syndrome (AIDS) or death. RESULTS: Of 652 women, 190 (29%) were HCV infected. During follow-up, 19% of women were exposed to HAART. After controlling for indicators of disease progression (CD4+ cell percentages and HIV-1 RNA levels determined closest to the time of delivery in pregnant women), ongoing drug use, receipt of antiretroviral therapy, and other important covariates, no differences were detected in the HIV-1 RNA levels, but the CD4+ cell percentages were slightly higher in HCV-infected women than in HCV-uninfected women. During follow-up, 48 women had progression to a first clinical AIDS-defining illness (ADI), and 26 died with no documented antecedent ADI. In multivariable analyses, HCV-infected participants did not have faster progression to a first class C AIDS-defining event or death (relative hazard, 0.75; 95% confidence interval, 0.37-1.53). CONCLUSIONS: In this cohort, the rate of clinical progression of HIV-1 infection was not greater for HCV-infected women.

Adult↗
PubMed2005

Association of CTLA4 polymorphism with regulatory T cell frequency.

A common single nucleotide polymorphism in CTLA4 has been linked with susceptibility and outcome in autoimmune and infectious diseases, respectively. Here, we show that this polymorphism is associated with the frequency of CD4(+)CD25(+) regulatory T cells in healthy human volunteers. We further show that, on a per cell basis, such regulatory T cells appear to be functionally indistinguishable across CTLA4 genotypes. These data implicate CTLA4 in regulatory T cell development, and provide a mechanism to account for the link between polymorphisms at this locus and the biological outcome of adaptive immune responses to self and to pathogens.

Antigens, CD↗
PubMed2005

The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection.

In the era of antiretroviral therapy (ART), liver disease has emerged as an important cause of death among persons with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. The objective of this study was to estimate the burden of liver disease and evaluate determinants of liver fibrosis and necroinflammatory activity among HIV/HCV coinfected patients receiving ART. We studied 112 randomly selected and 98 referred HCV-infected patients undergoing care in the Johns Hopkins University HIV clinic. Liver disease was characterized clinically and histologically. Of the 210 individuals studied--64% of whom had received ART within 2 years of liver disease assessment--33% had no fibrosis (F0), and 26% had bridging fibrosis or cirrhosis (> or =F3). The median necroinflammatory activity score was 3 (range, 0-9 of 18). ART was not associated with fibrosis; however, significantly less hepatic necroinflammatory activity was observed among persons who had received highly active antiretroviral therapy longer (P = .02) and more effectively (defined by HIV RNA suppression; P < .01). Twelve percent of individuals had previous ART-associated liver enzyme elevations (grades 3-4), but liver fibrosis was not more severe if the liver enzyme elevation resolved. On the other hand, liver fibrosis was more severe in persons with persistent liver enzyme elevations (grades 1-4). In conclusion, despite widespread exposure to ART and documented instances of ART-related hepatitis, we found no evidence that ART caused serious histological liver disease. Recognition of bridging fibrosis and cirrhosis in some but not most patients underscores the importance of identifying and treating liver disease in HIV/HCV coinfected persons.

Adult↗
PubMed2005

Comprehensive analyses of CD8+ T cell responses during longitudinal study of acute human hepatitis C.

We comprehensively studied the cellular immune response during acute human hepatitis C virus (HCV) infection by monthly prospective sampling of persons at high risk of infection. In 19 of 23 subjects, interferon-gamma-secreting T cells specific for 1 or more peptides spanning the entire HCV polyprotein were detected 1 to 3 months after infection. The median time to development of interferon gamma responses to HCV peptides was 33 days (range, 29-50 days), and these responses peaked between 180 and 360 days. Nineteen subjects had sufficient follow-up to determine outcome, with 15 (79%) developing persistent viremia and 4 (21%) clearing viremia spontaneously. Of those with progression to chronic infection and detectable T cell responses, all lost recognition of one or more antigens recognized during acute infection, and the median reduction in the magnitude of responses was 85%. Most significantly, despite ongoing viremia, those who had persistent infection did not develop new epitope specificities after the first 6 months of infection. In conclusion, in most individuals, the CD8+ T cell responses generated early in HCV infection decline in peripheral blood and are not replaced with new responses. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

Acute Disease↗
PubMed2005

Arterial spin labeling in small animals: methods and applications to experimental cerebral ischemia.

ASL enables noninvasive, quantitative monitoring of cerebral perfusion to be performed repeatedly over a period of hours. Thus, ASL is an attractive method for basic science studies of the time evolution and pathophysiology of diseases using animal models. In particular, ASL is valuable for basic science studies of evolving tissue status and viability in stroke using animal models of acute ischemia. This study describes both pulsed (PASL) and continuous ASL (CASL) studies of quantitative cerebral perfusion in rodent models of cerebral ischemia. Some technical factors pertinent to these studies are discussed, including a method for measuring arterial blood T(1) and double-echo PASL for measuring cerebral blood flow (CBF) and volume (CBV). Investigations of the CBF response to forebrain ischemia and reperfusion, and of regional variations in CBF and arterial transit time (ATT) are also discussed.

Animals↗
PubMed2005

Gradual changes in the apparent diffusion coefficient of water in selectively vulnerable brain regions following brief ischemia in the gerbil.

Although selective vulnerability and delayed neuronal death following global ischemia have been recognized in both the human and animal brain, the underlying mechanisms of cell damage are not fully understood. In this study we investigated the time-dependent changes of the apparent diffusion coefficient (ADC) of water and cerebral blood flow (CBF) in a classic animal model of selective vulnerability and delayed neuronal death, using magnetic resonance (MR) diffusion- and perfusion-weighted imaging. CBF was monitored using the noninvasive MR arterial spin labeling method called flow-sensitive alternating inversion recovery (FAIR). Bilateral common carotid occlusion was induced for 5 min, followed by 10 hr of reperfusion in a gerbil model. The most notable finding was that the lateral portion of the striatum in the basal ganglia exhibited a prolonged and gradual ADC decrease throughout the study following reperfusion. This pattern was not exhibited within the cortex. It is suggested that regions known to exhibit so-called delayed cell death progress to infarction via a gradual process that can be monitored by MR diffusion-weighted imaging (DWI).

Animals↗