Medicine, Dentistry & Health Sciences Collected Works - Research Publications
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ItemFactors Associated with Elevated ALT in an International HIV/HBV Co-Infected Cohort on Long-Term HAART(PUBLIC LIBRARY SCIENCE, 2011-11-01)BACKGROUND: Previous studies have demonstrated that hepatitis B virus (HBV) infection increases the risk for ALT elevations in HIV-HBV co-infected patients during the first year of HAART; however, there is limited data on the prevalence of ALT elevations with prolonged HAART in this patient group. METHODS/PRINCIPAL FINDINGS: To identify factors associated with ALT elevations in an HIV-HBV co-infected cohort receiving prolonged HAART, data from 143 co-infected patients on HAART enrolled in an international HIV-HBV co-infected cohort where ALT measurements were obtained every 6 months was analysed. A person-visit analysis was used to determine frequency of ALT elevation (≥ 2.5×ULN) at each visit. Factors associated with ALT elevation were determined using multivariate logistic regression with generalized estimating equations to account for correlated data. The median time on HAART at the end of follow-up was 5.6 years (range 0.4-13.3) years. During follow-up, median ALT was 36 U/L with 10.6% of person-visits classified as having ALT elevation. Most ALT elevations were grade 2 (86.5%), with only 13.5% of all ALT elevations grade 3 or higher. Univariate associations with ALT elevation (p<0.05) included history of AIDS, HBV DNA ≥ 2,000 IU/ml, HBeAg positive, study visit CD4 <200 cells/ml and nadir CD4 <200 cells/ml. In the multivariate analysis, only study visit CD4 <200 cells/ml (OR 2.07, 95%CI 1.04-4.11, p = 0.04) and HBeAg positive status (OR 2.22, 95%CI 1.03-4.79, p = 0.04) were independently associated with ALT elevation. CONCLUSIONS: In this HIV-HBV co-infected cohort, elevated ALT after >1 year of HAART was uncommon, and severe ALT elevations were rare. HIV-HBV co-infected patients on long-term HAART who are either HBeAg positive or have a CD4 count of <200 cells/ml are at increased risk for ALT elevations.
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ItemNo Preview AvailableViral Adaptation to Host Immune Responses Occurs in Chronic Hepatitis B Virus (HBV) Infection, and Adaptation Is Greatest in HBV e Antigen-Negative Disease(AMER SOC MICROBIOLOGY, 2012-01)Hepatitis B virus (HBV)-specific T-cell responses are important in the natural history of HBV infection. The number of known HBV-specific T-cell epitopes is limited, and it is not clear whether viral evolution occurs in chronic HBV infection. We aimed to identify novel HBV T-cell epitopes by examining the relationship between HBV sequence variation and the human leukocyte antigen (HLA) type in a large prospective clinic-based cohort of Asian patients with chronic HBV infection recruited in Australia and China (n = 119). High-resolution 4-digit HLA class I and II typing and full-length HBV sequencing were undertaken for treatment-naïve individuals (52% with genotype B, 48% with genotype C, 63% HBV e antigen [HBeAg] positive). Statistically significant associations between HLA types and HBV sequence variation were identified (n = 49) at 41 sites in the HBV genome. Using prediction programs, we determined scores for binding between peptides containing these polymorphisms and associated HLA types. Among the regions that could be tested, HLA binding was predicted for 14/18 (78%). We identified several HLA-associated polymorphisms involving likely known anchor residues that resulted in altered predicted binding scores. Some HLA-associated polymorphisms fell within known T-cell epitopes with matching HLA restriction. Enhanced viral adaptation (defined as the presence of the relevant HLA and the escaped amino acid) was independently associated with HBeAg-negative disease (P = 0.003). Thus, HBV appears to be under immune pressure in chronic HBV infection, particularly in HBeAg-negative disease.
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ItemNo Preview AvailableIn vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection(WILEY, 2012-08)The -1G mutant HBV is more prevalent in individuals co-infected with HIV/HBV than in individuals infected with HBV alone and in some cases is the dominant virus in circulation. This mutant is created by the deletion of a dGMP (-1G) from the guanine rich homopolymer sequence located at nts 2,085-2,090 (numbering from EcoRI site as position 1) in the HBV core gene. This deletion causes a frameshift generating a premature stop codon at (64) Asn in the HBV core gene (codon 93 in the precore gene), that truncates the precore protein, precursor of the secreted hepatitis B "e" antigen (HBeAg), and the core protein which forms the viral nucleocapsid. However, the replication phenotype of the -1G mutant HBV is unknown. An in vitro cell culture model in which hepatoma cells were transiently transfected with infectious cDNAs was used to show that the -1G mutant HBV is incapable of autonomous replication and, as expected, replication was restored to wild-type (wt) levels by supplying HBV core protein in trans. Although the -1G mutation had no deleterious effect on intracellular HBV-DNA levels, high levels of -1G mutant HBV relative to wt HBV reduced virus secretion and HBeAg secretion relative to empty vector controls. Importantly, the -1G mutant HBV also caused intracellular retention of truncated precore protein in the endoplasmic reticulum (ER) and Golgi apparatus. Together, these effects may be contributing to the increased pathology observed in the setting of HIV/HBV co-infection.
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ItemAssessment of HBV flare in a randomized clinical trial in HIV/HBV coinfected subjects initiating HBV-active antiretroviral therapy in Thailand(BIOMED CENTRAL LTD, 2012-03-09)BACKGROUND: Hepatic Flare (HF) after initiation of highly active antiretroviral therapy (HAART) in HIV-HBV coinfected individuals is well recognized but prospective data on predictors and subsequent outcome are limited. METHODS: The Tenofovir in HIV-HBV coinfection study was a randomized clinical trial of HBV-active HAART including lamivudine and/or tenofovir in antiretroviral naïve HIV-HBV individuals in Thailand. RESULTS: Early HF (EHF) was defined as ALT > 5 × ULN during the first 12 weeks. EHF was observed in 8 (22%) of individuals at a median of 56 days. 6/8 EHF cases were asymptomatic and resolved with HAART continuation, however one subject with underlying cirrhosis died following rapid hepatic decompensation. EHF was significantly associated with higher baseline ALT (79 IU/L vs 36 IU/L non-EHF, p = 0.008) and HBV DNA (9.9 log10 c/ml vs 8.4 log10 c/ml non EHF, p = 0.009), and subsequent serological change. HBeAg loss occurred in 75% of EHF cases versus 22% in non-EHF (p = 0.04), and HBsAg loss in 25% of EHF cases versus 4% of non-EHF (p = 0.053). CONCLUSION: EHF after HBV active HAART initiation was frequently observed in this population. Timing of EHF, association with elevated ALT and HBV DNA and high rate of seroconversion are all consistent with immune restoration as the likely underlying process. CLINICAL TRIAL NUMBER: NCT00192595.
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ItemNo Preview AvailableTLR2 AND TLR7/8 ACTIVATION PREDICT POST PARTUM HBV FLARES(ELSEVIER SCIENCE BV, 2012-04)
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ItemNo Preview AvailableClinical and virological predictors of hepatic flares in pregnant women with chronic hepatitis B(BMJ PUBLISHING GROUP, 2015-11)BACKGROUND: Unique immunological changes occur during pregnancy; the impact of which, on virological and biochemical markers of hepatitis B infection is not well established. Rapid changes in the immunological profile post partum and consequent rebound of the inflammatory response may result in hepatic flares. METHODS: Women with chronic hepatitis B were recruited during pregnancy into this observational study. Demographic and clinical data were collected together with virological and biochemical parameters at two time points during pregnancy (early and late) and two time points post partum (between 6 weeks and 12 weeks and at 12 months). Outcomes analysed included changes in HBV DNA, hepatitis B e antigen (HBeAg) status and flares of hepatitis. RESULTS: One hundred and twenty-six women were recruited. Twenty-seven women out of 108 with postpartum bloods (25%) met our definition of a postpartum flare (ALT range 38-1654). Using univariate analysis HBeAg status, younger age, gravida and parity were associated with a flare. On multivariate analysis HBeAg positivity at baseline fell just outside of statistical significance in predicting a postpartum flare (p=0.051). CONCLUSIONS: 25% of women with chronic hepatitis B will demonstrate increased liver inflammation in the postpartum period. This is usually asymptomatic and resolves spontaneously. This is more likely if the woman is HBeAg-positive at baseline (2.56 times the risk), although flares also commonly occur in HBeAg-negative women.
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ItemNo Preview AvailablePatterns and Causes of Suboptimal Response to Tenofovir-Based Therapy in Individuals Coinfected With HIV and Hepatitis B Virus(OXFORD UNIV PRESS INC, 2013-05-01)BACKGROUND: Tenofovir (TDF) is effective for treatment of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) infection; however, some individuals have ongoing HBV viremia, the reasons for which are unclear. We determined the patterns and factors associated with detectable HBV DNA in HIV-HBV-coinfected subjects on highly active antiretroviral therapy (HAART). METHODS: One hundred sixty-five HIV-HBV-coinfected individuals from the United States, Australia, and Thailand, the majority of whom were on HAART at study entry, were prospectively followed semiannually for a median of 2.8 years. Logistic regression was used to determine factors associated with detectable HBV DNA. RESULTS: Anti-HBV regimens were TDF/emtricitabine (57%), lamivudine or emtricitabine (19%), or TDF monotherapy (13%). During follow-up, HBV DNA was detected at 21% of study visits and was independently associated with hepatitis B e antigen (HBeAg), HAART <2 years, CD4 <200 cells/mm(3), detectable HIV RNA, reporting <95% adherence, and anti-HBV regimen. TDF/emtricitabine was less likely to be associated with detectable HBV than other regimens, including TDF monotherapy (odds ratio, 2.79; P = .02). In subjects on optimal anti-HBV therapy (TDF/emtricitabine) and with undetectable HIV RNA, HBeAg, CD4 <200 mm(3), and reporting <95% adherence remained associated with detectable HBV DNA. Three main patterns of HBV viremia were observed: persistent HBV viremia, viral rebound (>1 log from nadir), and viral blips. No TDF resistance was identified. CONCLUSIONS: Tenofovir/emtricitabine was superior to other anti-HBV regimens in long-term HBV suppression. HBV viremia on therapy was identified in 1 of 3 main patterns. Suboptimal adherence was associated with detectable HBV DNA during therapy, even when HIV was undetectable.