Bimodal distribution and set point HBV DNA viral loads in chronic infection:retrospective analysis of cohorts from the UK and South Africa

CITATION: Downs, L. O. 2020. Bimodal distribution and set point HBV DNA viral loads in chronic infection : retrospective analysis of cohorts from the UK and South Africa. Wellcome Open Research, 14(5):113, doi: 10.12688/wellcomeopenres.15941.2.The original publication is available at: https://pubmed.ncbi.nlm.nih.govENGLISH ABSTRACT: Hepatitis B virus (HBV) viral load (VL) is used as a biomarker to assess risk of disease progression, and to determine eligibility for treatment. While there is a well recognised association between VL and the expression of the viral e-antigen protein, the distributions of VL at a population level are not well described. We here present cross-sectional, observational HBV VL data from two large population cohorts in the UK and in South Africa, demonstrating a consistent bimodal distribution. The right skewed distribution and low median viral loads are different from the left-skew and higher viraemia in seen in HIV and hepatitis C virus (HCV) cohorts in the same settings. Using longitudinal data, we present evidence for a stable 'set-point' VL in peripheral blood during chronic HBV infection. These results are important to underpin improved understanding of HBV biology, to inform approaches to viral sequencing, and to plan public health interventions.Publisher's versio

Bimodal distribution and set point HBV DNA viral loads in chronic infection:retrospective analysis of cohorts from the UK and South Africa

CITATION: Downs, L. O. 2020. Bimodal distribution and set point HBV DNA viral loads in chronic infection : retrospective analysis of cohorts from the UK and South Africa. Wellcome Open Research, 14(5):113, doi: 10.12688/wellcomeopenres.15941.2.The original publication is available at: https://pubmed.ncbi.nlm.nih.govENGLISH ABSTRACT: Hepatitis B virus (HBV) viral load (VL) is used as a biomarker to assess risk of disease progression, and to determine eligibility for treatment. While there is a well recognised association between VL and the expression of the viral e-antigen protein, the distributions of VL at a population level are not well described. We here present cross-sectional, observational HBV VL data from two large population cohorts in the UK and in South Africa, demonstrating a consistent bimodal distribution. The right skewed distribution and low median viral loads are different from the left-skew and higher viraemia in seen in HIV and hepatitis C virus (HCV) cohorts in the same settings. Using longitudinal data, we present evidence for a stable 'set-point' VL in peripheral blood during chronic HBV infection. These results are important to underpin improved understanding of HBV biology, to inform approaches to viral sequencing, and to plan public health interventions.Publisher's versio

Seroepidemiologic Survey of Crimean-Congo Hemorrhagic Fever Virus in Selected Risk Groups, South Africa

Crimean Congo hemorrhagic fever virus (CCHFV) is endemic in South Africa, but whether mild undiagnosed cases occur is unclear. In a seroepidemiologic survey, only 2 of 387 adults considered at risk because of occupational or recreational activities had evidence of previous infection. Seroprevalence in South Africa remains low within the groups investigated

Contamination with HIV antibody may be responsible for false positive results in specimens tested on automated platforms running HIV 4th generation assays in a region of high HIV prevalence

<div><p>Introduction</p><p>In South Africa where the prevalence of HIV infection is very high, 4^th generation HIV antibody/p24 antigen combo immunoassays are the tests of choice for laboratory based screening. Testing is usually performed in clinical pathology laboratories on automated analysers. To investigate the cause of false positive results on 4^th generation HIV testing platforms in public sector laboratories, the performance of two automated platforms was compared in a clinical pathology setting, firstly on routine diagnostic specimens and secondly on known sero-negative samples.</p><p>Methods</p><p>Firstly, 1181 routine diagnostic specimens were sequentially tested on Siemens and Roche automated 4^th generation platforms. HIV viral load, western blot and follow up testing were used to determine the true status of inconclusive specimens. Subsequently, known HIV seronegative samples from a single donor were repeatedly tested on both platforms and an analyser was tested for surface contamination with HIV positive serum to identify how suspected specimen contamination could be occurring.</p><p>Results</p><p>Serial testing of diagnostic specimens yielded 163 weakly positive or discordant results. Only 3 of 163 were conclusively shown to indicate true HIV infection. Specimen contamination with HIV antibody was suspected, based on the following evidence: the proportion of positive specimens increased on repeated passage through the analysers; viral loads were low or undetectable and western blots negative or indeterminate on problem specimens; screen negative, 2^nd test positive specimens tested positive when reanalysed on the screening assay; follow up specimens (where available) were negative. Similarly, an increasing number of known negative specimens became (repeatedly) sero-positive on serial passage through one of the analysers. Internal and external analyser surfaces were contaminated with HIV serum, evidence that sample splashes occur during testing.</p><p>Conclusions</p><p>Due to the extreme sensitivity of these assays, contamination with minute amounts of HIV antibody can cause a negative sample to test positive. Better contamination control measures are needed on analysers used in clinical pathology environments, especially in regions where HIV sero-prevalence is high.</p></div

Western blots of selected specimens: negative, positive and low positive controls are labelled N, P and LP respectively.

<p>Specimens of interest are labelled A to G. Specimens A, B and C were concordantly weakly positive on both serology assays and HIV viral loads were high. Their western blots were scored as positive (A) and indeterminate (B, C). Specimens D, E, F and G were also WB indeterminate, but RNA negative. A follow up specimen on D was antibody negative.</p

Determining sero-positivity at first and second testing episodes.

<p>The number of negative results decreased and the number of positive results increased on second testing on the Roche analyser at UN laboratory.</p

Study plan.

<p>(a) 1181 consecutive routine diagnostic samples (serum or plasma) tested on the Siemens HIV 4^th generation platform at the primary testing laboratories were re-tested on the Roche platform at the referral laboratory UN (using the same primary tube). Inconclusive specimens were further investigated with HIV viral load and western blot where specimen volume permitted. A subset of 26 specimens which were screen negative, second test positive was retested on the Siemens (initial screening assay) at the JE laboratory. (b) 210 known HIV antibody negative, NAT negative specimens from the same donor were tested on the Siemens and Roche platforms at JE and UN respectively. 105 specimens were tested on each analyser over a 10 day period and handled as normal clinical specimens. After the initial HIV serology test, the specimens were sent through the same analyser and tested for a second time.</p

S/CO values of false positive samples from Siemens analyser at JE laboratory.

<p>S/CO values of false positive samples from Siemens analyser at JE laboratory.</p

Barriers that prevent adults living with HBV infection from participating in clinical research: Experience from South Africa

High profile international goals have been set for the elimination of hepatitis B virus (HBV) infection as a public health threat by the year 2030. Developing and expanding equitable, accessible translational HBV research programmes that represent real-world populations are therefore an urgent priority for clinical and academic communities. We present experiences and insights by an expert interdisciplinary group focusing on barriers that impede adults living with HBV infection from participating in clinical studies. Our viewpoint describes barriers we have identified through working in a variety of settings across South Africa, including lack of education and awareness, experiences of stigma and discrimination, challenges for governance and data management, and a burden of complex morbidity. Through identifying these challenges, we propose solutions and interventions, highlight new approaches, and provide a framework for future research