Peer support for people living with hepatitis B virus-A foundation for treatment expansion.

Chronic hepatitis B infection (CHB) affects 300 million people worldwide and is being targeted by the United Nations 2030 Sustainable Development Goals (SDGs) and the World Health Organisation (WHO), working towards elimination of hepatitis B virus (HBV) as a public health threat. In this piece, we explore the evidence and potential impact of peer support to enhance and promote interventions for people living with CHB. Peer support workers (PSWs) are those with lived experience of an infection, condition or situation who work to provide support for others, aiming to improve education, prevention, treatment and other clinical interventions and to reduce the physical, psychological and social impacts of disease. Peer support has been shown to be a valuable tool for improving health outcomes for people living with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), but to date has not been widely available for communities affected by HBV. HBV disproportionately affects vulnerable and marginalised populations, who could benefit from PSWs to help them navigate complicated systems and provide advocacy, tackle stigma, improve education and representation, and optimise access to treatment and continuity of care. The scale up of peer support must provide structured and supportive career pathways for PSWs, account for social and cultural needs of different communities, adapt to differing healthcare systems and provide flexibility in approaches to care. Investment in peer support for people living with CHB could increase diagnosis, improve retention in care, and support design and roll out of interventions that can contribute to global elimination goals.

Under-representation of the WHO African region in clinical trials of interventions against hepatitis B virus infection.

The WHO African region bears a disproportionate burden of morbidity and mortality related to chronic hepatitis B virus (HBV) infection and accounts for an estimated 70% of new HBV infections worldwide. We investigated the extent to which HBV clinical trials represented populations in this region by searching the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for interventional clinical trials published in English between database inception and May 29, 2023, using the search term "Hepatitis B". We identified 1804 unique clinical trials, of which 18 (1·0%) recorded involvement of the WHO African region. There is no evidence that the number of HBV clinical trials in this region has improved over time. The diversity of new interventions and industry sponsorship in the WHO African region were low, with trials of HBV comparing poorly with those of other endemic infectious diseases (eg, malaria, HIV, and SARS-CoV-2). HBV research and clinical trial investigations have neglected the WHO African region, leading to profound health inequities. HBV clinical trials are urgently needed to evaluate the efficacy of newly discovered therapeutics and to ensure that interventions can be equitably distributed and deployed as they become available.

Development and evaluation of a simple treatment eligibility score (HEPSANET) to decentralise hepatitis B care in Africa: a cross-sectional study.

BACKGROUND: Hepatitis B virus (HBV) elimination requires expanding and decentralising HBV care services. However, peripheral health facilities lack access to diagnostic tools to assess eligibility for antiviral therapy. Through the Hepatitis B in Africa Collaborative Network (HEPSANET), we aimed to develop and evaluate a score using tests generally available at lower-level facilities, to simplify the evaluation of antiviral therapy eligibility in people living with HBV. METHODS: We surveyed the availability of clinical and laboratory parameters across different health-care levels in sub-Saharan Africa. We used data from the HEPSANET dataset, the largest cross-sectional dataset of treatment-naive people living with HBV in sub-Saharan Africa, to derive and validate the score. Participants from this dataset were included in the analysis if they were aged 18 years or older and had liver fibrosis stages determined by a liver stiffness measurement or liver histopathology. Participants with co-infections or metabolic disorders were excluded. We allocated participants to the derivation and validation sets by geographical site. In the derivation set, we used stepwise logistic regression to identify the best performing parameters for identifying participants that met the 2017 European Association for the Study of the Liver (EASL) criteria. Regression coefficients were converted into integer points to construct simplified algorithms for different health-care levels. In the validation set, we estimated the area under the receiver operating characteristic, sensitivity, and specificity of the simplified algorithm for identifying antiviral therapy eligibility defined by the 2017 EASL criteria. FINDINGS: At 11 sites from eight countries that returned surveys, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count were generally available at district hospital levels, and hepatitis B e antigen and point-of-care HBV DNA tests were available only at regional and provincial hospital levels or above. Among 2895 participants included from the HEPSANET database (1740 [60·1%] male, 1155 [39·9%] female), 409 (14·1%) met EASL antiviral therapy eligibility criteria. In the derivation set, the optimal district-level hospital score was: ALT (IU/L), less than 40 (0 points), 40-79 (+1), 80 or greater (+2); AST (IU/L), less than 40 (0), 40-79 (+1), 80 or greater (+2); and platelet counts (109/L), less than 100 (+2), 100-149 (+1), 150 or greater (0). When combined with family history and clinical data for decompensated cirrhosis that do not require any biological tests, a cut-off of 2 points or more had a sensitivity and specificity of 82% (95% CI 76-86) and 95% (93-96) to identify treatment-eligible individuals in the derivation set, and 78% (71-85) and 87% (86-89) in the validation set, respectively. INTERPRETATION: Using a score incorporating platelet counts, AST, and ALT, the majority of people living with HBV requiring antiviral therapy can be identified. Our findings suggest that clinical staging can be decentralised down to district hospital level in sub-Saharan Africa. FUNDING: European Association for the Study of the Liver Foundation, John C Martin Foundation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

An Oxford Nanopore Technology-Based Hepatitis B Virus Sequencing Protocol Suitable For Genomic Surveillance Within Clinical Diagnostic Settings.

Chronic hepatitis B virus (HBV) infection remains a significant public health concern, particularly in Africa, where there is a substantial burden. HBV is an enveloped virus, with isolates being classified into ten phylogenetically distinct genotypes (A - J) determined based on full-genome sequence data or reverse hybridization-based diagnostic tests. In practice, limitations are noted in that diagnostic sequencing, generally using Sanger sequencing, tends to focus only on the S-gene, yielding little or no information on intra-patient HBV genetic diversity with very low-frequency variants and reverse hybridization detects only known genotype-specific mutations. To resolve these limitations, we developed an Oxford Nanopore Technology (ONT)-based HBV genotyping protocol suitable for clinical virology, yielding complete HBV genome sequences and extensive data on intra-patient HBV diversity. Specifically, the protocol involves tiling-based PCR amplification of HBV sequences, library preparation using the ONT Rapid Barcoding Kit, ONT GridION sequencing, genotyping using Genome Detective software, recombination analysis using jpHMM and RDP5 software, and drug resistance profiling using Geno2pheno software. We prove the utility of our protocol by efficiently generating and characterizing high-quality near full-length HBV genomes from 148 left-over diagnostic Hepatitis B patient samples obtained in the Western Cape province of South Africa, providing valuable insights into the genetic diversity and epidemiology of HBV in this region of the world.

Hepatitis B in Africa Collaborative Network: cohort profile and analysis of baseline data.

Approximately 80 million people live with chronic hepatitis B virus (HBV) infection in the WHO Africa Region. The natural history of HBV infection in this population is poorly characterised, and may differ from patterns observed elsewhere due to differences in prevailing genotypes, environmental exposures, co-infections, and host genetics. Existing research is largely drawn from small, single-centre cohorts, with limited follow-up time. The Hepatitis B in Africa Collaborative Network (HEPSANET) was established in 2022 to harmonise the process of ongoing data collection, analysis, and dissemination from 13 collaborating HBV cohorts in eight African countries. Research priorities for the next 5 years were agreed upon through a modified Delphi survey prior to baseline data analysis being conducted. Baseline data on 4,173 participants with chronic HBV mono-infection were collected, of whom 38.3% were women and the median age was 34 years (interquartile range 28-42). In total, 81.3% of cases were identified through testing of asymptomatic individuals. HBeAg-positivity was seen in 9.6% of participants. Follow-up of HEPSANET participants will generate evidence to improve the diagnosis and management of HBV in this region.

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.

The forgotten people: Hepatitis B virus (HBV) infection as a priority for the inclusion health agenda.

Hepatitis B virus (HBV) infection represents a significant global health threat, accounting for 300 million chronic infections and up to 1 million deaths each year. HBV disproportionately affects people who are under-served by health systems due to social exclusion, and can further amplify inequities through its impact on physical and mental health, relationship with stigma and discrimination, and economic costs. The 'inclusion health' agenda focuses on excluded and vulnerable populations, who often experience barriers to accessing healthcare, and are under-represented by research, resources, interventions, advocacy, and policy. In this article, we assimilate evidence to establish HBV on the inclusion health agenda, and consider how this view can inform provision of better approaches to diagnosis, treatment, and prevention. We suggest approaches to redress the unmet need for HBV interventions among excluded populations as an imperative to progress the global goal for the elimination of viral hepatitis as a public health threat.

Systematic review and individual-patient-data meta-analysis of non-invasive fibrosis markers for chronic hepatitis B in Africa.

In sub-Saharan Africa, simple biomarkers of liver fibrosis are needed to scale-up hepatitis B treatment. We conducted an individual participant data meta-analysis of 3,548 chronic hepatitis B patients living in eight sub-Saharan African countries to assess the World Health Organization-recommended aspartate aminotransferase-to-platelet ratio index and two other fibrosis biomarkers using a Bayesian bivariate model. Transient elastography was used as a reference test with liver stiffness measurement thresholds at 7.9 and 12.2kPa indicating significant fibrosis and cirrhosis, respectively. At the World Health Organization-recommended cirrhosis threshold (>2.0), aspartate aminotransferase-to-platelet ratio index had sensitivity (95% credible interval) of only 16.5% (12.5-20.5). We identified an optimised aspartate aminotransferase-to-platelet ratio index rule-in threshold (>0.65) for liver stiffness measurement >12.2kPa with sensitivity and specificity of 56.2% (50.5-62.2) and 90.0% (89.0-91.0), and an optimised rule-out threshold (<0.36) with sensitivity and specificity of 80.6% (76.1-85.1) and 64.3% (62.8-65.8). Here we show that the World Health Organization-recommended aspartate aminotransferase-to-platelet ratio index threshold is inappropriately high in sub-Saharan Africa; improved rule-in and rule-out thresholds can optimise treatment recommendations in this setting.

Persistent Severe Acute Respiratory Syndrome Coronavirus 2 Infection With accumulation of mutations in a patient with poorly controlled Human Immunodeficiency Virus infection.

A 22-year-old woman with uncontrolled advanced human immunodeficiency virus (HIV) infection was persistently infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) beta variant for 9 months, the virus accumulating >20 additional mutations. Antiretroviral therapy suppressed HIV and cleared SARS-CoV-2 within 6 to 9 weeks. Increased vigilance is warranted to benefit affected individuals and prevent the emergence of novel SARS-CoV-2 variants.

A tale of two waves: characteristics and outcomes of COVID-19 admissions during the Omicron-driven fourth wave in Cape Town, South Africa, and implications for the future.

Objectives: The aim of this study was to describe the pattern of admissions during the fourth wave of COVID-19 in order to inform future public health policies. Methods: This was a retrospective descriptive study of an early cohort of all adult patients with SARS-CoV-2 infection admitted to a tertiary hospital in Cape Town, South Africa, at the start of the country's fourth wave. This was compared with an early cohort from the first wave at the same institution. Results: In total, 121 SARS-CoV-2-positive admissions from the fourth wave were included. Thirty-one (25.6%) patients had COVID-19 pneumonia, while 90 (74.4%) had incidental SARS-CoV-2 infection. (In the first wave all 116 patients had COVID-19 pneumonia.) Thirty-two (26.4%) patients self-reported complete or partial COVID-19 vaccination, of whom 12 (37.5%) were admitted with COVID-19 pneumonia. Compared with the first wave, there were fewer intensive- or high-care admissions (18/121 [14.9%] vs 42/116 [36.2%]; p < 0.001) and mortality was lower (12/121 [9.9%] vs 31/116 [26.7%]; p = 0.001). Conclusion: Admissions to the COVID-19 wards during the fourth wave primarily included patients with incidental SARS-CoV-2 infection. There was a reduction in the need for critical care and in-hospital mortality. This changing epidemiology of COVID-19 admissions may be attributed to a combination of natural and/or vaccination-acquired immunity.

RETRACTED: Gradual emergence followed by exponential spread of the SARS-CoV-2 Omicron variant in Africa.

The geographic and evolutionary origins of the SARS-CoV-2 Omicron variant (BA.1), which was first detected mid-November 2021 in Southern Africa, remain unknown. We tested 13,097 COVID-19 patients sampled between mid-2021 to early 2022 from 22 African countries for BA.1 by real-time RT-PCR. By November-December 2021, BA.1 had replaced the Delta variant in all African sub-regions following a South-North gradient, with a peak Rt of 4.1. Polymerase chain reaction and near-full genome sequencing data revealed genetically diverse Omicron ancestors already existed across Africa by August 2021. Mutations, altering viral tropism, replication and immune escape, gradually accumulated in the spike gene. Omicron ancestors were therefore present in several African countries months before Omicron dominated transmission. These data also indicate that travel bans are ineffective in the face of undetected and widespread infection.

Relative Hypercoagulopathy of the SARS-CoV-2 Beta and Delta Variants when Compared to the Less Severe Omicron Variants Is Related to TEG Parameters, the Extent of Fibrin Amyloid Microclots, and the Severity of Clinical Illness.

Earlier variants of SARS-CoV-2 have been associated with hypercoagulability and an extensive formation of fibrin amyloid microclots, which are considered to contribute to the pathology of the coronavirus 2019 disease (COVID-19). The newer omicron variants appear to be far more transmissible, but less virulent, even when taking immunity acquired from previous infections or vaccination into account. We here show that while the clotting parameters associated with omicron variants are significantly raised over those of healthy, matched controls, they are raised to levels significantly lower than those seen with more severe variants such as beta and delta. We also observed that individuals infected with omicron variants manifested less extensive microclot formation in platelet-poor plasma compared with those harboring the more virulent variants. The measurement of clotting effects between the different variants acts as a kind of "internal control" that demonstrates the relationship between the extent of coagulopathies and the virulence of the variant of interest. This adds to the evidence that microclots may play an important role in reflecting the severity of symptoms observed in COVID-19.

Hepatitis B Virus Research in South Africa.

Despite being vaccine-preventable, hepatitis B virus (HBV) infection remains the seventh leading cause of mortality in the world. In South Africa (SA), over 1.9 million people are chronically infected with HBV, and 70% of all Black chronic carriers are infected with HBV subgenotype A1. The virus remains a significant burden on public health in SA despite the introduction of an infant immunization program implemented in 1995 and the availability of effective treatment for chronic HBV infection. In addition, the high prevalence of HIV infection amplifies HBV replication, predisposes patients to chronicity, and complicates management of the infection. HBV research has made significant progress leading to better understanding of HBV epidemiology and management challenges in the SA context. This has led to recent revision of the national HBV infection management guidelines. Research on developing new vaccines and therapies is underway and progress has been made with designing potentially curative gene therapies against HBV. This review summarizes research carried out in SA on HBV molecular biology, epidemiology, treatment, and vaccination strategies.

Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa.

Three lineages (BA.1, BA.2 and BA.3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern predominantly drove South Africa's fourth Coronavirus Disease 2019 (COVID-19) wave. We have now identified two new lineages, BA.4 and BA.5, responsible for a fifth wave of infections. The spike proteins of BA.4 and BA.5 are identical, and similar to BA.2 except for the addition of 69-70 deletion (present in the Alpha variant and the BA.1 lineage), L452R (present in the Delta variant), F486V and the wild-type amino acid at Q493. The two lineages differ only outside of the spike region. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure, on the background of variants not possessing this feature. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa by the first week of April 2022. Using a multinomial logistic regression model, we estimated growth advantages for BA.4 and BA.5 of 0.08 (95% confidence interval (CI): 0.08-0.09) and 0.10 (95% CI: 0.09-0.11) per day, respectively, over BA.2 in South Africa. The continued discovery of genetically diverse Omicron lineages points to the hypothesis that a discrete reservoir, such as human chronic infections and/or animal hosts, is potentially contributing to further evolution and dispersal of the virus.

Immuno-Thrombotic Complications of COVID-19: Implications for Timing of Surgery and Anticoagulation.

Early in the coronavirus disease 2019 (COVID-19) pandemic, global governing bodies prioritized transmissibility-based precautions and hospital capacity as the foundation for delay of elective procedures. As elective surgical volumes increased, convalescent COVID-19 patients faced increased postoperative morbidity and mortality and clinicians had limited evidence for stratifying individual risk in this population. Clear evidence now demonstrates that those recovering from COVID-19 have increased postoperative morbidity and mortality. These data-in conjunction with the recent American Society of Anesthesiologists guidelines-offer the evidence necessary to expand the early pandemic guidelines and guide the surgeon's preoperative risk assessment. Here, we argue elective surgeries should still be delayed on a personalized basis to maximize postoperative outcomes. We outline a framework for stratifying the individual COVID-19 patient's fitness for surgery based on the symptoms and severity of acute or convalescent COVID-19 illness, coagulopathy assessment, and acuity of the surgical procedure. Although the most common manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is COVID-19 pneumonitis, every system in the body is potentially afflicted by an endotheliitis. This endothelial derangement most often manifests as a hypercoagulable state on admission with associated occult and symptomatic venous and arterial thromboembolisms. The delicate balance between hyper and hypocoagulable states is defined by the local immune-thrombotic crosstalk that results commonly in a hemostatic derangement known as fibrinolytic shutdown. In tandem, the hemostatic derangements that occur during acute COVID-19 infection affect not only the timing of surgical procedures, but also the incidence of postoperative hemostatic complications related to COVID-19-associated coagulopathy (CAC). Traditional methods of thromboprophylaxis and treatment of thromboses after surgery require a tailored approach guided by an understanding of the pathophysiologic underpinnings of the COVID-19 patient. Likewise, a prolonged period of risk for developing hemostatic complications following hospitalization due to COVID-19 has resulted in guidelines from differing societies that recommend varying periods of delay following SARS-CoV-2 infection. In conclusion, we propose the perioperative, personalized assessment of COVID-19 patients' CAC using viscoelastic hemostatic assays and fluorescent microclot analysis.

Emergence and phenotypic characterization of the global SARS-CoV-2 C.1.2 lineage.

Global genomic surveillance of SARS-CoV-2 has identified variants associated with increased transmissibility, neutralization resistance and disease severity. Here we report the emergence of the PANGO lineage C.1.2, detected at low prevalence in South Africa and eleven other countries. The initial C.1.2 detection is associated with a high substitution rate, and includes changes within the spike protein that have been associated with increased transmissibility or reduced neutralization sensitivity in SARS-CoV-2 variants of concern or variants of interest. Like Beta and Delta, C.1.2 shows significantly reduced neutralization sensitivity to plasma from vaccinees and individuals infected with the ancestral D614G virus. In contrast, convalescent donors infected with either Beta or Delta show high plasma neutralization against C.1.2. These functional data suggest that vaccine efficacy against C.1.2 will be equivalent to Beta and Delta, and that prior infection with either Beta or Delta will likely offer protection against C.1.2.

Assessing the clinical severity of the Omicron variant in the Western Cape Province, South Africa, using the diagnostic PCR proxy marker of RdRp target delay to distinguish between Omicron and Delta infections - a survival analysis.

BACKGROUND: At present, it is unclear whether the extent of reduced risk of severe disease seen with SARS-Cov-2 Omicron variant infection is caused by a decrease in variant virulence or by higher levels of population immunity. METHODS: RdRp target delay (RTD) in the Seegene AllplexTM 2019-nCoV PCR assay is a proxy marker for the Delta variant. The absence of this proxy marker in the transition period was used to identify suspected Omicron infections. Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the Seegene AllplexTM assay from November 1 to December 14, 2021 in the Western Cape Province, South Africa, in the public sector. Adjustments were made for vaccination status and prior diagnosis of infection. RESULTS: A total of 150 cases with RTD and 1486 cases without RTD were included. Cases without RTD had a lower hazard of admission (adjusted hazard ratio [aHR], 0.56; 95% confidence interval [CI], 0.34-0.91). Complete vaccination was protective against admission, with an aHR of 0.45 (95% CI, 0.26-0.77). CONCLUSION: Omicron has resulted in a lower risk of hospital admission compared with contemporaneous Delta infection, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant remains a challenge to accurately assessing variant virulence.