Hepatitis B virus-associated hepatocellular carcinoma in South Africa: epidemiology and impact of HIV-1 co-infection and immune dysregulation

Maponga, Tongai Gibson (2016-12)

Thesis (PhD)--Stellenbosch University, 2016

Thesis

ENGLISH ABSTRACT : Co-infection with the human immunodeficiency virus (HIV) negatively impacts the natural progression of hepatitis B virus (HBV) infection, including causing rapid progression to liver fibrosis and hepatocellular carcinoma (HCC). In sub-Saharan Africa the overlap between high HIV and HBV prevalence may increase the incidence of HCC. The aim of this study was to investigate the effect of HIV co-infection on presentation of HCC among HBV-infected patients. Since HCC is thought to be driven by ongoing severe inflammation, the study also evaluated the association between the expression of markers of immune activation/exhaustion and liver inflammation in patients with chronic hepatitis B (CHB) to determine if the risk of hepatofibrosis is increased by exposure to gut microbial products and compared HIV-infected patients with HBV-infected and HIV-HBV co-infected patients. Ethical approval was obtained to conduct two sub-studies. The first sub-study (HCC Epidemiology Study) involved recruitment of patients diagnosed with HCC at oncology units of selected teaching hospitals in South Africa. A total of 107 HCC cases were recruited between December 2012 and October 2015. Demographic, laboratory and clinical data together with blood specimens were collected. Patients were tested for HBV, hepatitis C virus (HCV) and HIV. Molecular characterization of HBV and HCV was also performed. For the second sub-study (Liver Fibrosis and Immune Markers Study), 46 HBV/HIV co-infected; 47 HBV monoinfected; 39 HIV monoinfected and; 39 HIV-/HBV-uninfected controls were recruited following informed consent. All HIV-infected patients had been on highly active antiretroviral therapy (HAART) for ≥3 months. Liver stiffness measurements were taken using the Fibroscan 402. Cell-based immunomarkers of activation/exhaustion were measured using flow cytometry of fresh whole blood. Soluble serum/plasma immunomarkers were measured using ELISA and Luminex. HIV and HBV viral loads and genotyping of HBV were performed. Of 107 cases in the HCC Epidemiology study, 83 (78%) were male and 68/106 (64%, 95% CI: 59-77) were positive for HBsAg. HIV seropositivity was seen in 22/100 (22%, 95% CI: 14-30) of all HCC cases. Among HBsAg-positive HCC cases, 19/66 (29%, 95% CI: 18-40) were HIV-infected compared to only 3/34 (9%) among those that were HBsAg-negative, p=0.04. The proportion of females among the HBV/HIV co-infected HCC cases 6/18 (33%, 95% CI: 11-55) was significantly higher compared to those that were HBV-mono-infected 6/47 (13%, 95% CI: 3-23), p=0.005. HIV/HBV co-infected females presented younger, at mean age 36.8 years (95% CI: 32.2-41.5) compared to 50.5 years (95% CI: 30.2-70.8) in HBV-mono-infected women, p=0.09. Males continue to be disproportionally affected with HCC. There is a trend towards younger age at diagnosis of HCC among HIV-positive compared to HIV-negative women. The Liver Fibrosis and Immune Markers Study showed a high percentage of CD8+ T lymphocytes from co-infected subjects expressing HLA-DR/CD38 and PD-1 (p<0.05). Soluble CD14 and IP-10 were also significantly elevated in plasma of co-infected patients. Co-infected subjects exhibited delayed immune recovery with lower CD4/CD8 T cell ratio; CD4 cell counts and frequent HIV viremia compared to HIV mono-infected participants (p<0.05). The HBV mono-infected group had the highest proportion of participants with moderate/advanced liver fibrosis measured by Fibroscan, together with highest plasma concentrations of most of the cytokines measured. The results showed positive correlation between HIV and HBV viral replication and liver fibrosis. The results suggest that there is persistent T-lymphocyte dysregulation and delayed immune recovery in ART-experienced HBV/HIV co-infected patients. However this does not appear to be associated with severity of liver fibrosis in this cohort. HAART used in HIV is also effective against HBV and may therefore have led to control of viral replication leading to better fibrosis scores compared to the HBV mono-infected patients. Moderate/advanced liver fibrosis in HBV-mono-infection may well be an indicator of poor access to HBV screening and treatment.

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