Browsing by Author "Hairwadzi, H N"

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    CTLA4 gene polymorphisms in autoimmune hepatitis (AIH) : gene and clinical disease correlations in South African patients
    (2007) Marais, Surita; Hairwadzi, H N; Meissner, P N; Corrigall, A V; Spearman, W
    Also available online. Includes bibliographical references (leaves 76-85).
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    HBV genotypes at the Groote Schuur Hospital Liver Clinic, Cape Town : genotype and subgenotype prevalence and the influence of ethnicity on treatment outcomes during long term clinical follow-up of patience with chronic HBV infection.
    (2008) Nderu, Michelle W; Hairwadzi, H N; Smuts, H
    In the developing world, hepatitis B virus (HBV) is an important cause of acute and chronic liver disease. Two billion people worldwide are infected with the virus and an estimated 350 million who have failed to clear the virus have chronic infection. In Africa, HBV is endemic with 98% of the inhabitants being infected with the virus at some point in their lives. Of these 10% fail to clear the virus. The emergence of HBV-HIV coinfected cases in sub-Saharan Africa adds a new dimension in the management of this disease and highlights the need to understand the pathogenesis and treatment of HBV. HBV genotype A and D have been shown to be present in southern Africa with genotype A generally being the predominant genotype documented in South Africa. This is based on studies carried out in the Gauteng and Kwa-Zulu Natal regions. There is very little prevalence data from the W estem Cape and other provinces and there is no data on the pre-dominant HBV genotype seen in this region. This study investigates the predominant HBV genotype and subgenotypes seen at the Groote Schuur Liver Clinic, Cape Town and the possible correlations between the HBV genotype, race and disease severity. In addition early work investigating the possible presence of lamivudine resistant strains in lamivudine na'ive patients are reported. This is important as the increase in incidence of lamivudine use in HBV-HIV co-infected patients may have potential implications in lamivudine treatment management programmes. 169 chronic HBV patients from all races and age groups were recruited into the study. The HBV DNA levels, HBeAg and HBsAg status were determined as part of their standard management at the Liver Clinic. Two methods were used in combination to identify the HBV genotype of the patient using the conserved S-gene on the HBV genome. The detection of lamivudine resistant mutations on the YMDD motif was determined using nucleotide sequence analysis. The possible correlations between race, HBV genotype, interferon-a (IFN-a) treatment, virological and biochemical parameters were analysed. In this study, 73% of the patients were identified as genotype D, 27% as genotype A with one patient being genotype B2. The subgenotypes D3 and D4 were also identified in the xiii cohort. Although genotype D predominates in the Mixed race this did not reach statistical significance in this study. The genotype B2 patient was an immigrant from Taiwan, in keeping with published data from Asia. The Caucasians were older compared to the other races while the non-Caucasoids presented at an older age and with more severe disease. The Asians showed the best response to IFN-a treatment while the Black Africans had significantly lower ALB levels at presentation compared to the other races. As noted in published literature, high ALT and low HBV DNA levels correlated with a better response to IFN-a treatment. No lamivudine resistant strains were found in the lamivudine nai"ve patients but one YVDD mutation was found in a patient who was on lamivudine therapy. This study shows that genotype D and its subgenotype, D3, is the predominant genotype seen in this urban clinical cohort of patients. The unexpected presence of subgenotype D4 is documented. This interesting observation may be explained by the historically well documented population migration from the Indian and Asian Pacific islands into the Cape Town region. No lamivudine resistant strains present with in the lamivudine nai"ve patients in the clinic indicates that these strains are not yet circulating as there have been reports of the presence of these resistant strains in lamivudine nai"ve patients in South Africa. Gene polymorphisms and socio-economic factors may explain the racial difference with respect to age at HBV diagnosis. The success of IFN-a treatment may be related to the varied genetics of the population.
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    An investigation of genome-wide promoter region cytosine-phosphate-guanine (CpG) Island methylation profiles in patients with chronic hepatitis B virus infection
    (2014) Kgatle, Mankgopo Magdeline; Hairwadzi, H N; Ramesar, Raj
    Hepatitis B virus (HBV) is oncogenic and a major cause of hepatocellular carcinoma (HCC) in the developing world. It integrates parts of its genome such as the HBx gene, core and surface antigens into the human genome. The integrated viral DNA disrupts gene function resulting in physiological changes that cause liver disease. The viral inserts are inactivated through methylation. This is a protective innate response driven by human DNA methyltransferases triggered by the presence of viral DNA inserts. This thesis investigates the hypothesis that during the innate response to methylate integrated HBV DNA, there is unintended methylation of genomic DNA around the intercalated viral DNA that could be adjacent host promoter Cytosine-phosphateGuanine (CpG) islands. This would activate or silence genes including tumour suppressors and result in the clinical disease phenotypes of hepatic inflammation, fibrosis and HCC that characterise chronic HBV infection. Genome-wide microarray analysis was used to investigate for the presence of promoter CpG island methylation in a cohort of patients with liver disease due to HBV infection, HCC, autoimmune hepatitis which is a non-viral liver disease and normal cases with no liver disease. The study identified hypermethylation in promoter regions, transcription start sites, gene exons and introns. Only sites in the promoter region and within 100bp upstream of a transcription start site were analysed for this thesis presentation. Using an extended cohort of patients with chronic HBV infection and normal controls, bisulfite DNA sequencing was used to validate and confirm the presence of DNA methylation in a selection of some of genes identified. HBV infected patients were shown to have hypermethylation in the promoter CpG island regions of several genes that regulate hepatic metabolism, tumour suppression, ribonucleic acid splicing, vitamin D receptor binding, protein ubiquitination and the cell cycle. Many of these genes have transcriptional binding factors that are known to be affected by the transcriptional transactivator HBx protein, suggesting that HBx protein is important in the pathogenesis of liver disease. Amongst the most hypermethylated core promoter regions identified were those for cyclin kinases genes such as Cyclin D3 (CCND3). CCND3 gene is important in liver regeneration and wound healing and its abnormal function has been linked to the development of liver fibrosis and HCC. Increased methylation of CCND3 gene was associated with HBV e antigen positive status and genotype D, supporting the hypothesis that increased methylation is associated with host and viral factors. Methylation induced alteration in the function of the identified gene promoters would affect cellular signalling with effects on cell growth, differentiation, proliferation and apoptosis. These changes would explain the development of hepatic inflammation, apoptosis, fibrosis and malignant transformation seen in chronic HBV infection. Further investigation of these genes will provide new insights on mechanisms of HBV induced liver disease and the development of new molecular diagnostic tools or therapeutic interventions.
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    South African guideline for the management of chronic hepatitis B: 2013
    (2013) Spearman, C W N; Sonderup, Mark W; Botha, J F; van der Merwe, S W; Song, E; Kassianides, C; Newton, K A; Hairwadzi, H N
    Hepatitis B remains a significant yet preventable health issue in South Africa. The introduction of the hepatitis B vaccine into the country some 18 years ago has demonstrated benefit, but the exposure to, and prevalence of chronic HBsAg positivity remain unacceptably high. Those with chronic hepatitis B virus infection have an elevated risk of developing cirrhosis with end-stage liver disease and a markedly elevated risk of hepatocellular carcinoma, independent of the presence of cirrhosis. The challenge in South Africa remains prevention through the universal vaccination coverage of all children and the identification of those with chronic hepatitis B virus infection. Over the last decade our understanding of hepatitis B and its behaviour and natural history in those with chronic infection has significantly improved. This understanding is key to identifying those who warrant further evaluation and therapy. A number of global societies have updated their guidelines in recent years. This document draws on these guidelines and serves to contextualise, for South Africa, practice guidelines for the management of chronic hepatitis B.