Biomedical subjects

David L Thomas

Publications and source records attributed to David L Thomas.

88 records · Page 5Linked to original sources

PubMed2003

Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection.

Following an acute hepatitis B virus (HBV) infection, clearance or persistence is determined in part by the vigor and breadth of the host immune response. Since the human leukocyte antigen system (HLA) is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes are key determinants of viral clearance. HLA class I and II genes were molecularly typed in 194 Caucasian individuals with viral persistence and 342 matched controls who had cleared the virus. A single class I allele, A*0301 (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.30 to 0.72; P = 0.0005) was associated with viral clearance. The class II allele DRB1*1302 was also associated with clearance (OR, 0.42; 95% CI, 0.19 to 0.93; P = 0.03), but its significance decreased in a multivariate model that included other alleles associated with disease outcome as covariates. B*08 was associated with viral persistence both independently (OR, 1.59; 95% CI, 1.04 to 2.43; P = 0.03) and as part of the conserved Caucasian haplotype A*01-B*08-DRB1*03. The B*44-Cw*1601 (OR, 2.23; 95% CI, 1.13 to 4.42; P = 0.02) and B*44-Cw*0501 (OR, 1.99; 95% CI, 1.22 to 3.24; P = 0.006) haplotypes were also associated with viral persistence. Interestingly, both the B*08 haplotype and DR7, which forms a haplotype with B*44-Cw*1601, have been associated with nonresponse to the HBV vaccine. The associations with class I alleles are consistent with a previously implicated role for CD8-mediated cytolytic-T-cell response in determining the outcome of an acute HBV infection.

Adult↗

PubMed2003

The association of health-care use and hepatitis C virus infection in a random sample of urban slum community residents in southern India.

To determine whether health-care use was associated with prevalent hepatitis C virus (HCV) infection in Chennai, India, 1,947 adults from 30 slum communities were randomly selected to be interviewed about parenteral and sexual risks for HCV infection and to provide biological specimens for HCV and sexually transmitted infection (STI) testing. Prevalent HCV infection was detected in 2.4% of non-injection drug using (IDU) participants. Controlling for other associated factors, and excluding IDU, men who used informal health-care providers were five times as likely to be HCV infected as those who did not use informal providers (Adjusted Odds Ratio, AOR = 5.83; 95% confidence interval [CI]: 1.57, 21.6), a finding not detected in women. More research is needed to determine the extent to which HCV infection is associated with reuse of contaminated injection equipment in health-care settings in developing countries.

Adolescent↗

PubMed2002

HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS).

BACKGROUND: Although coinfection with HIV-1 and hepatitis B virus (HBV) is common, few long-term studies on liver-disease mortality in coinfected people have been undertaken. Our aim was to examine liver-related mortality among people at risk for HIV-1 and HBV infections. METHODS: We used data from a multicentre, prospective cohort study to classify 5293 men who had sex with men, according to their HIV-1 antibody status, ascertained semiannually, and their hepatitis-B surface antigen status (HBsAg), which we ascertained at baseline. Mortality rates were estimated in terms of person-years and Poisson regression methods were used to test for significance of relative risks. FINDINGS: 326 (6%) men were HBsAg positive, of whom 213 (65%) were HIV-1 positive. Of the 4967 HBsAg negative men, 2346 (47%) were infected with HIV-1. The liver-related mortality rate was 1.1/1000 person years, and was higher in men with HIV-1 and HBsAg (14.2/1000) than in those with only HIV-1 infection (1.7/1000, p<0.001) or only HBsAg (0.8/1000, p<0.001). In coinfected individuals, the liver-related mortality rate was highest with lower nadir CD4+ cell counts and was twice as high after 1996, when highly active antiretroviral therapy (HAART) was introduced. INTERPRETATION: Individuals coinfected with HIV-1 and HBV, especially those with low CD4+ nadir counts, are at increased risk for liver-related mortality, underscoring the importance of prevention, identification, and comprehensive management of hepatitis B in people infected with HIV-1.

Adult↗

PubMed2002

Hepatitis C and progression of HIV disease.

CONTEXT: Conflicting reports exist regarding the effect of hepatitis C virus (HCV) on the progression of human immunodeficiency virus (HIV) disease. OBJECTIVE: To assess the effect of HCV infection on clinical and immunologic progression of HIV disease and immunologic response to highly active antiretroviral therapy (HAART). DESIGN: Prospective cohort study. SETTING: University-based, urban HIV clinic in the United States. PATIENTS: There were 1955 patients enrolled between January 1995 and January 2001 who were eligible for analysis because of having at least 1 return visit to the clinic and being free of acquired immunodeficiency syndrome (AIDS) at enrollment. Median (interquartile range) length of follow-up was 2.19 (1.00-3.50) years for HCV-infected and 2.00 (1.00-3.00) years for HCV-uninfected patients. MAIN OUTCOME MEASURES: Progression to an AIDS-defining illness, survival, and progression to a CD4 cell count below 200/microL; CD4 cell count change following initiation of effective HAART (resulting in a viral load of <400 copies/mL recorded at > or = 75% of measurements). RESULTS: No difference was detected in the risk of acquiring an AIDS-defining illness (HCV-infected patients, 231 events [26.4%] and HCV-uninfected patients, 264 events [24.4%]; relative hazard [RH], 1.03; 95% confidence interval [CI], 0.86-1.23) or in the risk of death (HCV-infected patients, 153 deaths [17.5%] and HCV-uninfected patients, 168 deaths [15.5%]; RH, 1.05; 95% CI, 0.85 -1.30). Although an increased risk of death was detected in the subgroup of 429 HCV-infected patients with a baseline CD4 cell count of 50/microL through 200/microL (RH, 1.51; 95% CI, 1.01-2.27), after adjustment for exposure to HAART and its effectiveness in a multivariate Cox regression analysis, death was not independently associated with HCV infection in this subgroup (RH, 1.01; 95% CI, 0.65-1.56). Similarly, in those receiving effective HAART (n = 208), there was no difference in the increase in CD4 cell count or CD4 percentage during HAART in HCV-infected compared with HCV-uninfected patients. CONCLUSIONS: Among patients in this urban US cohort, we did not detect evidence that HCV infection substantially alters the risk of dying, developing AIDS, or responding immunologically to HAART, especially after accounting for differences in its administration and effectiveness.

Adult↗

PubMed2002

Prospective study of infective endocarditis among injection drug users.

To determine the effect of human immunodeficiency virus (HIV) infection and other factors on infective endocarditis (IE) among injection drug users (IDUs), the incidence of IE was determined according to HIV status in a cohort of IDUs. A nested case-control study assessed IE risk factors. IE incidence (117 cases) was higher among HIV-seropositive than HIV-seronegative IDUs (13.8 vs. 3.3 cases/1000 person-years) during 1988-1998. Multivariate analysis of HIV-infected case patients revealed an inverse association between IE and CD4 lymphocyte count (odds ratio [OR] for 200-499 cells/mm(3), 2.01; OR for <200 cells/mm(3), 3.61) and with alcohol intake (OR for 1-21 drinks/week, 0.43; OR for >21 drinks/week, 0.32). Women had an increased risk of IE (OR, 3.26), as did persons with increasing injection drug use frequency (OR for less than daily use, 3.15; OR for at least daily use, 6.07). This study confirms that IE is more common among IDUs with advanced HIV immunosuppression even after accounting for injection drug use behaviors.

Adult↗

PubMed2002

Needlestick transmission of hepatitis C.

Hepatitis C virus (HCV) transmission following a needlestick is an important threat to health care workers. We present the case of a 29-year-old medical intern who sustained a needlestick injury from a source patient known to be infected with both human immunodeficiency virus and HCV. The case patient subsequently developed acute HCV infection. The optimal strategy for diagnosing HCV infection after occupational exposures has not been defined. At a minimum, HCV antibody and alanine aminotransferase testing should be done within several days of exposure (to assess if the health care worker is already infected with HCV) and 6 months after percutaneous, mucosal, or nonintact skin exposure to blood or infectious body fluids from an HCV-infected patient. Currently, it is not possible to prevent HCV infection after exposure. However, recent data suggest that early treatment of acute HCV infection with interferon alpha may be highly effective in preventing chronic HCV infection. These data underscore the importance of identifying persons with acute HCV infection and promptly referring them to experienced clinicians who can provide updated counseling and treatment.

Accidents, Occupational↗

PubMed2002

Protection against persistence of hepatitis C.

BACKGROUND: Neither previous hepatitis C virus (HCV) infection nor vaccination with HCV-derived antigens protects against reinfection. However, HCV infection and vaccination in chimpanzees has been shown to reduce the magnitude and duration of viraemia with re-challenge. We aimed to establish whether similar immunity could be achieved in man. METHODS: From a study of injecting drug users, we identified 164 people who had no evidence of previous HCV infection and 98 individuals who had been previously, but were not currently, infected with HCV. We compared the incidence and persistence of HCV viraemia in these two groups over four consecutive 6-month periods. FINDINGS: Of participants without previous infection, the incidence of HCV infection was 21% (35/164). By contrast, people previously infected were half as likely to develop new viraemia (12% [12/98]), even after accounting for risk behaviour (hazard ratio, 0.45; 95% CI 0.23-0.88). Furthermore, in HIV-1-negative people, those previously infected were 12 times less likely than people infected for the first time to develop persistent infection (odds ratio 0.05, 95% CI 0.01-0.30), and median peak HCV RNA concentration was two logs lower. HCV persisted in six of six HIV-1-positive people, even in one man who had previously cleared HCV infection when he was HIV-1 negative. INTERPRETATION: There is an alarming frequency of HCV infection and persistence among injecting drug users. Our data suggest that immunity against viral persistence can be acquired, and that vaccines should be tested to reduce the burden of HCV-related liver disease.

Adult↗

PubMed2002

Translational and rotational forces on heart valve prostheses subjected ex vivo to a 4.7-T MR system.

PURPOSE: To assess the magnetic field interactions on 60 heart valve prostheses subjected to a 4.7 T MR system. It addresses the question of whether heart valves deemed safe at 1.5 T may pose safety hazards as patients are exposed to increased static magnetic fields. MATERIALS AND METHODS: Ex vivo testing was performed to evaluate translational and rotational forces on 60 heart valves using previously described techniques. RESULTS: Translational forces were detected on 58 heart valves ranging from 0.5 degrees to 7.5 degrees. Seven valves exhibited paramagnetic/weakly ferromagnetic behavior, and 51 valves exhibited diamagnetic behavior. Rotational forces were observed for 46 valves. CONCLUSIONS: Criteria previously used for safety assessment of heart valve prostheses and expressed in terms of magnetic forces suggest the forces observed in this study are compatible with the safe use of these valves in magnetic resonance (MR) systems with static fields up to 4.7 T.

Heart Valve Prosthesis↗

PubMed2002

Rapid simultaneous mapping of T2 and T2* by multiple acquisition of spin and gradient echoes using interleaved echo planar imaging (MASAGE-IEPI).

A new MRI sequence for the rapid simultaneous measurement of T2 and T2* is presented. The technique uses the multiple acquisition of spin and gradient echoes with interleaved echo planar imaging (MASAGE-IEPI). IEPI data sets are sampled during and between a pair of short and long echo time spin echoes, allowing the reconstruction of a set of images with different combinations of T2 and T2* weighting and the calculation of T2 and T2* maps. In the context of neuroimaging, these maps can provide information on cerebral hemodynamics and oxygenation status, either via the deoxyhemoglobin-based BOLD signal or by the effect of exogenous paramagnetic contrast agents. MASAGE-IEPI benefits from the inherent advantages of the IEPI approach, i.e., high time resolution and minimal image distortion, and also has good time efficiency due to the acquisition of multiple image data sets following each excitation pulse. The accuracy of the sequence for the measurement of T2 and T2* is verified on phantoms, and the technique is applied to monitor changing hemodynamics in the rat brain during episodes of hypoxia. Data for the generation of maps of T2 and T2* are acquired with a time resolution of 12 s to accurately define the rapidly changing time course. As increasing emphasis is placed on the role of T2 and T2* in the direct measurement of physiological parameters such as cerebral metabolic rate of oxygen consumption and blood vessel sizes, MASAGE-IEPI offers an efficient method for the measurement of these two important MRI parameters.

Animals↗

PubMed2002

Occult hepatitis B.

Worldwide, chronic hepatitis B virus (HBV) infection is the primary cause of cirrhosis and hepatocellular carcinoma and is one of the ten leading causes of death. Traditionally, people with chronic HBV infection have been identified with blood tests for HBV antigens and antibodies. Recently, another group of patients with chronic HBV infection has been identified by sensitive, molecular testing for HBV DNA. Members of this group are often referred to as having occult hepatitis B because they are HBV-DNA positive, but hepatitis B surface antigen negative. Occult hepatitis B occurs in a number of clinical settings. In this review, we examine occult hepatitis B in people co-infected with hepatitis C, in whom occult hepatitis B has been associated with advanced fibrosis and diminished response to interferon alpha. Although much more research is needed, existing reports justify a heightened awareness of the medical importance and means of testing for occult hepatitis B.

DNA, Viral↗

PubMed2002

Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections.

Hepatologists are frequently asked to evaluate human immunodeficiency virus (HIV)-infected patients with abnormal liver enzymes and to assess the causal role of medications, such as antiretroviral drugs. Recently, the use of HIV-1 specific non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine (NVP) and efavirenz (EFV), has been associated with severe hepatic injury. We prospectively studied the incidence of severe hepatotoxicity (grade 3 or 4 change in alanine or aspartate transaminase levels) among 568 patients receiving NNRTI-containing antiretroviral therapy, including 312 and 256 patients prescribed EFV and NVP, respectively. Hepatitis C virus (HCV) and hepatitis B virus (HBV) were detected in 43% and 7.7% of patients, respectively. Severe hepatotoxicity was observed in 15.6% of patients prescribed NVP and 8.0% of those prescribed EFV, but only 32% of NVP and 50% of EFV-associated episodes were detected during the first 12-weeks of therapy. The risk was significantly greater among persons with chronic viral hepatitis (69% of cases) and those prescribed concurrent protease inhibitors (PIs) (82% of cases). Nonetheless, 84% of patients with chronic HCV or HBV did not experience severe hepatotoxicity. Severe hepatotoxicity occurs throughout the course of NNRTI therapy and is more common among patients prescribed nevirapine, those coinfected with HCV or HBV, and those coadministered protease inhibitors.

Adult↗

PubMed2002

Peripheral blood count abnormalities among patients with hepatitis C in the United States.

An estimated 2.7 million people in the United States are infected with the hepatitis C virus (HCV), yet the influence of HCV infection on the peripheral blood count remains unknown. To investigate the prevalence of low peripheral blood counts among HCV-infected adults in the United States general population, we analyzed data collected in the third National Health and Nutrition Examination Survey (NHANES III). The study population consisted of 16,196 individuals age 18 or older who had peripheral blood counts and data on HCV infection. The lowest fifth percentile of each component of the peripheral blood was designated a priori as being low. HCV infection was assessed by antibody reactivity. HCV antibody-positive individuals were 3-fold more likely to have low neutrophil counts (HCV positive, 9% vs. HCV negative, 3%, P <.0001) and 2.6-fold more likely to have low platelet counts (HCV positive, 13% vs. HCV negative, 5%, P <.0001) independent of other evaluated factors. HCV infection was observed in more than 20% of persons with neutrophil counts below 1.0 x 10(9)/L or platelet counts less than 100 x 10(9)/L. No association was detected between anti-HCV status and anemia or other peripheral blood cell components. In conclusion, HCV-infected persons in the general population of the United States are more likely to have low neutrophil and platelet counts, and HCV testing should be considered for persons with unexplained neutrophil counts below 1.0 x 10(9)/L or platelet counts less than 100 x 10(9)/L. Alternate causes of anemia should be considered for HCV-infected persons with low red blood cell counts.

Erythrocyte Count↗

PubMed2002

Severity and correlates of liver disease in hepatitis C virus-infected injection drug users.

Between May 1996 and June 1998, 210 members of a cohort of 1,667 hepatitis C virus (HCV)-infected injection drug users (IDUs) were selected for liver biopsy procedure after stratification based on 2 consecutive serum alanine transaminase (ALT) levels. Liver histology, which could be fully evaluated for 207 subjects, was classified by using the modified Ishak scores. At the time of biopsy, the median age of subjects was 41.3 years and the median estimated duration of HCV infection was 20.7 years; 94% were African American; 78% men; 31% were human immunodeficiency virus (HIV) seropositive; and 76% had HCV genotype 1a or 1b. Total modified histologic activity index (MHAI) scores ranged from 0 to 9, and 26.6% had a total MHAI score of 5 or greater. Persons with a total MHAI score of 5 or greater were more likely to be HIV infected (P =.04). Higher fibrosis, indicated by Ishak modified fibrosis scores of 3 to 6, was present in 10.1% of subjects and was found more often in those older than 46 years of age (the highest quartile) (P <.01). Both fibrosis scores of 3 or greater and total scores of 5 or greater were associated with elevated ALT, aspartate transaminase (AST), and gamma-glutamyl transpeptidase (GGT) levels (P <.01). When serial values were considered, the results of liver enzyme testing could reduce the probability of an IDU having a fibrosis score of 3 or greater from 10% to 3%. In conclusion, these data indicate that severe liver disease is uncommon in this urban, HCV-infected IDU cohort, especially in younger persons and those with repeatedly normal liver enzymes.

Adult↗

PubMed2002

Hepatitis C and human immunodeficiency virus infection.

In the United States, an estimated 200,000 persons are infected with both hepatitis C virus (HCV) and human immunodeficiency virus (HIV). As the lives of HIV-infected persons have been prolonged by use of highly active antiretroviral therapy, liver disease has emerged as an important, and in some settings, the leading cause of morbidity and mortality. Human immunodeficiency virus infection appears to adversely affect all stages of hepatitis C infection, leading to increased viral persistence and accelerated progression of HCV-related liver disease. In turn, hepatitis C may affect the management of HIV infection, increasing the incidence of liver toxicity caused by antiretroviral medications. The medical management of hepatitis C in HIV-infected persons remains controversial, in part because of the complexity of both infections and potential drug interactions, but chiefly because there is so little published information. Nonetheless, the burden of liver disease is too high to delay management of HIV/HCV-coinfected persons while awaiting better data. Instead, the management of hepatitis C today must be based on data generated on persons without HIV and an understanding of both infections. Properly designed studies of therapy in HIV/HCV-coinfected persons are needed to help guide management of these patients in the future.

Disease Transmission, Infectious↗

PubMed2002

HLA-Cw*04 and hepatitis C virus persistence.

In studies of acute hepatitis C virus (HCV) infection, the early host immune response is one of the determinants of viral persistence. The class I human leukocyte antigens (HLA), which present foreign antigen to cytolytic T cells, are integral components of this response. We hypothesized that the highly polymorphic HLA genes affect the outcome of an HCV infection. To test this hypothesis, we molecularly typed 231 persons with well-documented clearance of an HCV infection and 444 matched persistently infected persons. HLA-A*1101 (odds ratio [OR], 0.49; 95% confidence interval [95% CI], 0.27 to 0.89), HLA-B*57 (OR, 0.62; 95% CI, 0.39 to 1.00), and HLA-Cw*0102 (OR, 0.43; 95% CI, 0.21 to 0.89) were associated with viral clearance, whereas HLA-A*2301 (OR, 1.78; 95% CI, 1.01 to 3.11) and HLA-Cw*04 (OR, 1.78; 95% CI, 1.21 to 2.59) were associated with viral persistence. HLA-Cw*04 is in strong linkage disequilibrium with HLA-B*53 and HLA-B*35, but only HLA-B*53 (OR, 1.70; 95% CI, 0.95 to 3.06) and the Cw*04-B*53 haplotype (OR, 1.76; 95% CI, 0.94 to 3.26) were weakly associated with viral persistence. HLA-B*53 has similar, but not necessarily identical, binding specificity to some HLA-B*35 subtypes (B*35-Px group). The association with the B*35-Px group was less strong than with HLA-B*53 alone. The association of HLA-Cw*04 with HCV persistence was codominant (two copies of the gene were more strongly associated with persistence than one copy). However, HLA-Cw*04 was not associated with HCV RNA levels among the persistently infected individuals. Since Cw*04 is a ligand for the killer immunoglobulin-like receptors on natural killer cells, these cells may be involved in recovery from HCV infection. Further investigation is needed to understand the relationship between class I alleles and HCV clearance.

Adult↗

PubMed2002

Peginterferon-alpha-2a (40kD) and ribavirin in patients with chronic hepatitis C: a phase II open-label study.

BACKGROUND AND AIMS: Addition of a 40kD polyethylene glycol moiety to interferon-alpha-2a [peginterferon-alpha-2a (40kD)] improves pharmacokinetic properties over those of standard interferon. We conducted a phase II study to assess the safety and initial efficacy of peginterferon-alpha-2a (40kD) plus ribavirin combination therapy in patients with chronic hepatitis C (CHC). METHODS: Twenty patients received open-label 180 microg peginterferon-alpha-2a (40kD) subcutaneously once weekly and oral ribavirin 1000 or 1200mg daily for patients weighing <75 or > or =75kg, respectively, for a period of 24 weeks. Patients with hepatitis C virus (HCV) genotype 1 and a virological response at week 24 received study drugs for an additional 24 weeks. RESULTS: A sustained virological response, defined as undetectable HCV RNA 24 (i.e. <100 copies/ml) weeks after completing the therapy, was achieved in 50% of patients in an intent-to-treat analysis (6/16 genotype 1 and 4/4 genotype non-1). Adverse events were similar to those reported with unmodified interferon plus ribavirin combination therapy. Anaemia led to ribavirin dose reduction in five patients. Neutropenia led to dose reduction in three patients treated with peginterferon-alpha-2a (40kD). CONCLUSIONS: The addition of ribavirin to a once-weekly peginterferon-alpha-2a (40kD) regimen should be investigated in larger clinical trials.

Adult↗