Evolution of the serologic and virologic course of occult HBV infection in therapy experienced HIV co-infected patients.

We investigated how the natural course of occult hepatitis B virus (HBV) infection (OBI) may evolve during HIV co-infection and long term HBV-active HAART. From a cohort of 181 HIV infected patients who were consecutively recruited over a 5 year period, 28 HBV co-infected patients with sequential sera (n = 98) were identified. Iterative HBV serology and viral loads were determined before and during treatment. The viral HBsAg gene was then serially amplified, directly sequenced, and molecularly characterized. Persistent detection of anti-HBs did not result in a modification to the clinical course of OBI. In contrast, reactivation of chronic HBV infection, hepatic enzymatic flares and cases of HBV reinfection were evident among anti-HBs negative OBI patients, and this was a notable finding. Of the 14 chronic HBV infected patients, eight progressed to persistent OBI after initiation of HBV-active HAART, increasing the number of patients with OBI in the study. Long term HBV-active HAART was not found to have a notable impact on low level viremia during OBI. While the HBsAg gene sequences isolated from chronic HBV infection were genetically stable over time, OBI-associated variants (sP111R, sT127P, sY161F) were neither stable nor predominant during the course of infection. This study is the first of its kind from South Africa to show the occurrence of hepatic enzymatic flares, HBV reactivation, and reinfection in HAART-exposed HIV co-infected patients with OBI. Among the cases studied, there was further evidence that OBI-associated variants may not play a significant role in the pathogenesis of OBI.

Complete genome analysis of hepatitis B virus in human immunodeficiency virus infected and uninfected South Africans.

Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections are highly endemic in South Africa. Data on the complete genome sequences of HBV in HIV-positive patients in South Africa are scanty. This study characterized the complete HBV genome isolated from both HIV-positive and negative patients at the Dr George Mukhari Academic Hospital (DGMAH), Pretoria. Serum samples from nine (five HIV-positive and four HIV-negative) patients attending the DGMAH from 2007 to 2011 were serologically tested, amplified, and sequenced for complete genome. Phylogenetic tree was constructed using MEGA6.0. Mutations were analyzed by comparing the sequences with genotype-matched GenBank references. Eight patients were HBsAg positive, with only one from the HIV positive group being negative. Phylogenetic analysis of the complete genome sequences classified them into five genotypes; A1 (n = 4), A2 (n = 1), C1 (n = 2), D1 (n = 1), and D3 (n = 1). Deletions up to 35 nucleotides in length were identified in this study. No drug resistance mutations were identified in the P ORF, while the L217R mutation was identified in one subgenotype A2 sequence. The double (A1762T/G1764A) and triple (T1753C/A1762T/G1764A) mutations in the Basal core promoter were identified in four and two sequences, respectively. In the core region, mutation G1888A was identified in four of the subgenotype A1 sequences. In conclusion, this study has added to the limited South African data on HBV genotypes and mutations in HBV/HIV co-infected and HBV mono-infected patients, based on complete HBV genome analysis. Subgenotype A1 was predominant, and no drug-resistant mutants were detected in the study. J. Med. Virol. 88:1560-1566, 2016. © 2016 Wiley Periodicals, Inc.

Evidence for a change in the epidemiology of hepatitis B virus infection after nearly two decades of universal hepatitis B vaccination in South Africa.

The hepatitis B vaccine has been part of the South African Expanded Program on Immunization since April 1995 but its long-term impact remains unknown. This study tested 1,206 sera collected from patients aged 1-25 years from various health facilities across the country for HBV serological markers and HBV DNA. Based on the year the vaccine was introduced, samples were stratified by age into pre- and post-vaccine introduction populations, which were then compared for evidence of immunity and chronic carriage using the Chi-square test. Where HIV status was known, subset analyses were performed. Immunity to HBV infection increased from 13.0% in the pre- to 57.0% in the post-vaccine introduction population (P < 0.001). This decreased with increasing age within the post-vaccine introduction population (76.1% for 1-5 years, 50.0% for 6-10 years, and 46.3% for 11-16 years). In addition, HBV chronic carriage was significantly (P = 0.003) reduced in the post- (1.4%) compared to the pre-vaccine introduction population (4.2%). The difference in prevalence of active HBV infection in the serologically exposed pre- and post-vaccine introduction populations was not statistically significant. Subset analyses showed that evidence of immunity was significantly (P < 0.001) higher in the HIV negative compared to the HIV positive subset in both populations. Universal hepatitis B vaccination has been a remarkable success, with a significant increase in immunity to HBV infection. The observation that HBV chronic carriage increases as immunity wanes over time calls into question whether the time has come to consider a pre-adolescence vaccine booster dose policy.

Health Systems Determinants of Delivery and Uptake of Maternal Vaccines in Low- and Middle-Income Countries: A Qualitative Systematic Review.

Maternal vaccination is considered a key component of the antenatal care package for improving maternal and child health. Low- and middle-income countries (LMICs) fall short of global targets to prevent maternal and neonatal deaths, with a disproportionate burden of vaccine-preventable diseases. Strategies towards ending preventable maternal mortality necessitate a health systems approach to adequately respond to this burden. This review explores the health systems determinants of delivery and uptake of essential maternal vaccines in LMICs. We conducted a qualitative systematic review of articles on maternal vaccination in LMICs, published between 2009 and 2023 in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Thematic analysis was conducted to identify key themes in the literature, interpreted within a conceptual framing that explores the systems determinants influencing maternal vaccines. Our search yielded 1309 records, of which 54 were included, covering 34 LMICs. Most of the included studies were from South America (28/54) and included pregnant women as the primary study population (34/54). The studies explored influenza (25/54) and tetanus toxoid (20/54) vaccines predominantly. The findings suggest that systems hardware (lack of clear policy guidelines, ineffective cold-chain management, limited reporting and monitoring systems) are barriers to vaccine delivery. Systems software (healthcare provider recommendations, increased trust, higher levels of maternal education) are enablers to maternal vaccine uptake. Findings show that formulation, dissemination and communication of context-specific policies and guidelines on maternal vaccines should be a priority for decision-makers in LMICs.

Weak Adoption and Performance of Hepatitis B Birth-Dose Vaccination Programs in Africa: Time to Consider Systems Complexity?-A Scoping Review.

The persistent burden of chronic hepatitis B among ≤5-year-old children in Africa suggests missed opportunities for controlling mother-to-child transmission (MTCT) of the hepatitis B virus (HBV). This scoping review maps the evidence base on the risk of HBV MTCT, the status of HBV MTCT mitigation strategies including hepatitis B birth-dose vaccination, and the role of systems complexity on the suboptimal adoption and performance of hepatitis B birth-dose vaccination programs in Africa. Overall, 88 peer-reviewed and grey literature sources published between 2000-2022 were included in this review. The growing evidence base consistently argues for a heightened risk of HBV MTCT amidst the HIV co-epidemic in the region. Without universal HBV screening programs integrated within broader antenatal care services, current selective hepatitis B birth-dose vaccination is unlikely to effectively interrupt HBV MTCT. We underscore critical health systems-related barriers to universal adoption and optimal performance of hepatitis B birth-dose vaccination programs in the region. To better conceptualize the role of complexity and system-wide effects on the observed performance of the program, we propose an adapted systems-based logic model. Ultimately, exploring contextualized complex systems approaches to scaling-up universal hepatitis B birth-dose vaccination programs should form an integral part of the regional research agenda.

Expanding the reach of vaccinology training in Africa: leveraging the success of the Annual African Vaccinology Course.

Introduction: It is estimated that one in five African children lack access to recommended life-saving vaccines. This situation has been exacerbated by the COVID-19 pandemic which disrupted routine immunization services in several parts of the region. To better support recovery efforts and get immunization programmes back on track, policy makers, programme managers, immunization providers and academics need continuous upskilling. Unfortunately, the vaccinology training needed by these cadres remains limited and oftentimes inaccessible within our context. In addition, cadres should be continuously updated on advances in vaccinology so as to keep abreast with this rapidly evolving field. This calls for new and accessible approaches to training vaccinologists in Africa where the demand is high. Methods: The aim of this proof-of-concept study was to ascertain the training needs of alumni of the Annual African Vaccinology Course and assess the effectiveness of an online webinar series in meeting those needs. Results: We found that alumni from across Africa required refresher training to gain up-to-date information about new developments in vaccinology, leverage opportunities to reinforce and consolidate their knowledge, and exchange country-specific experiences with their counterparts. A prominent motivation for refresher training was the rapid developments and challenges brought on by the COVID-19 pandemic. Drawing on the expressed needs of our alumni, we developed a webinar training series. This series aimed to provide participants with training on current and emerging trends in vaccinology with a focus on the regional context. Online participation in the webinar series was found to be comparable to previous in-person training, reaching a diverse group of cadres, and allowing for participation of a richer global faculty due to fewer cost constraints. Further to this, a post-training survey indicated that generally, alumni training needs were successfully met. Discussion: The findings suggest that an online approach can be used to expand the reach of vaccinology training in Africa.

Interventions to Improve Knowledge, Attitudes, and Uptake of Recommended Vaccines during Pregnancy and Postpartum: A Scoping Review.

Tetanus, pertussis, influenza, and COVID-19 vaccines are recommended for the prevention of related morbidity and mortality during pregnancy and postpartum. Despite the established benefits of vaccination for prenatal and postnatal women, maternal vaccination is not universally included in routine antenatal programs, especially in low- and middle-income countries. Furthermore, the uptake of recommended vaccines among pregnant and postpartum women remains below optimum globally. This review aimed to map the evidence on interventions to improve knowledge, attitudes, and uptake of recommended vaccines among pregnant and postpartum women. We conducted a comprehensive and systematic search for relevant literature in PubMed, Scopus, Web of Science, EBSCOhost, and Google Scholar. Overall, 29 studies published between 2010 and 2023 were included in this review. The majority (n = 27) of these studies were from high-income countries. A total of 14 studies focused on the influenza vaccine, 6 on the Tdap vaccine, 8 on both influenza and Tdap vaccines, and only one study on the COVID-19 vaccine. Patient-centered interventions predominated the evidence base (66%), followed by provider-focused (7%), health system-focused (10%), and multilevel interventions (17%). Overall, the effect of these interventions on knowledge, attitudes, and uptake of maternal vaccines was variable.

Human Papillomavirus Vaccination in South Africa: Programmatic Challenges and Opportunities for Integration With Other Adolescent Health Services?

Compared to other regions of the world, sub-Saharan Africa has made limited progress in the implementation and performance of nationwide human papillomavirus (HPV) vaccination programmes. Without urgent intervention, this will serve to undermine cervical cancer elimination efforts in this region. The primary intent of this narrative review is to highlight the programmatic successes and challenges of the school-based HPV vaccination programme in South Africa since its inception in 2014, with the aim of contributing to the evidence base needed to accelerate implementation and improve programme performance in other sub-Saharan African countries. As of 2020, the proportion of adolescent girls aged 15 years who had received at least one dose of the HPV vaccine at any time between ages 9-14 years was 75%, while 61% had completed the full recommended two-dose schedule. This gives some indication of the reach of the South African HPV vaccination programme over the past 6 years. Despite this, vaccine coverage and dose completion rates have persistently followed a downward trend, slowing progress toward attaining global elimination targets. There is evidence suggesting that declining public demand for the HPV vaccine may be a result of weakening social mobilization over time, inadequate reminder and tracking systems, and vaccine hesitancy. Another concern is the disproportionate burden of HPV and HIV co-infections among adolescent girls and young women in South Africa, which predisposes them to early development of invasive cervical cancer. Moving forward, national policy makers and implementers will have to explore reforms to current age eligibility criteria and vaccine dose schedules, as well as implement strategies to support vaccine uptake among populations like out-of-school girls, girls attending private schools, and HIV positive young women. Additional opportunities to strengthen the South African HPV vaccination programme can be achieved by scaling up the co-delivery of other adolescent health services such as comprehensive sexual and reproductive health and rights education, deworming, and health screening. This calls for reinforcing implementation of the integrated school health policy and leveraging existing adolescent health programmes and initiatives in South Africa. Ultimately, establishing tailored, adolescent-centered, integrated health programmes will require guidance from further operational research.

Descriptive analysis of routine childhood immunisation timeliness in the Western Cape, South Africa.

Adherence to recommended age-specific immunisation schedules is critical in ensuring vaccine effectiveness against vaccine preventable diseases (VPDs). There is limited data on immunisation timeliness in sub-Saharan Africa. Therefore, this study assessed the timeliness of age-specific routine childhood immunisation within the Western Cape Province of South Africa. Participant records (N = 709) from a prospective health-facility based study conducted in Cape Town, SA in 2012-2016 were analysed. The outcome measure was receiving age-specific immunisations ≥4 weeks of that recommended for age as per the South African Expanded Programme on Immunisation (EPI-SA) schedule. Proportions, medians, inter-quartile ranges (IQR) and regression were used to obtain the prevalence, time-at-risk, and risk factors for delayed immunisation. A total of 652 /709 (91.9%) participants were eligible. Immunisation coverage declined with age from 94.9% (95% CI 92.9-96.4) at birth to 72.0% (95% CI 65.7-77.6) at 18 months. The highest delay in the uptake of vaccine doses was observed among the 3 rd dose of the DTP vaccine [163 (34.6% (95% CI 30.3-39.1)], while the lowest was seen among BCG [40 (6.5% (95% CI 4.7-8.8)]. The longest median time-at-risk of VPDs was among the 2 nd dose of the measles vaccine [12.9 (IQR 6.7-38.6) weeks] and the lowest was OPV birth dose [IQR 6.3 (5.3-9.1) weeks]. Low and upper-middle socio-economic quartiles were associated with delayed uptake of vaccine doses. Delayed vaccination increases the time of susceptibility to VPDs during infancy and childhood. There is a need to develop strategies aimed at mitigating factors associated with delay in uptake of routine childhood vaccines in the Western Cape. Mitigation strategies should provide vaccine education and mobile reminder systems. Education about timely vaccine uptake will aid in the provision of informed council from healthcare providers to caregivers. Multiple reminder systems could cater for low network coverage areas and caregivers with busy schedules.

Hepatitis B virus infection and hepatocellular carcinoma in sub-Saharan Africa: Implications for elimination of viral hepatitis by 2030?

Elimination of viral hepatitis in sub-Saharan Africa by 2030 is an ambitious feat. However, as stated by the World Health Organization, there are unprecedented opportunities to act and make significant contributions to the elimination target. With 60 million people chronically infected with hepatitis B virus (HBV) of whom 38800 are at risk of developing highly fatal hepatocellular carcinoma (HCC) every year, sub-Saharan Africa faces one of the greatest battles towards elimination of viral hepatitis. There is a need to examine progress in controlling the disproportionate burden of HBV-associated HCC in sub-Saharan Africa within the context of this elimination target. By scaling-up coverage of hepatitis B birth dose and early childhood vaccination, we can significantly reduce new cases of HCC by as much as 50% within the next three to five decades. Given the substantial reservoir of chronic HBV carriers however, projections show that HCC incidence and mortality rates in sub-Saharan Africa will double by 2040. This warrants urgent public health attention. The trends in the burden of HCC over the next two decades, will be determined to a large extent by progress in achieving early diagnosis and appropriate linkage to care for high-risk chronic HBV infected persons.

Characterization of National Immunization Programs in the Context of Public Health Emergencies: A Case Study of 13 Countries in the WHO Africa Region.

Multiple public health emergencies (PHEs) experienced annually in the World Health Organisation (WHO) Africa region affect the provision of health services, including immunization. However, there is limited information on the performance of national immunization programs (NIPs) in WHO Africa countries that experience PHEs. This study assessed PHEs (armed conflicts, disasters, and disease outbreaks) and the performance of NIPs using global and regional immunization targets outlined for the Decade of Vaccines. Thirteen beneficiary countries of PHE mitigation funds from the African Public Health Emergency Fund were used as case studies. Data on PHEs and immunization indicators between 2010 and 2019 in selected countries were extracted from different PHE databases and the WHO/UNICEF immunization database, respectively. The data were stratified by country and summarized using descriptive statistics. Mann-Whitney U test was done to determine the association between the frequency of PHEs and the performance of NIPs. There were 175 disease outbreaks, 288 armed conflicts, and 318 disasters in the examined countries between 2010 and 2019. The Democratic Republic of Congo had the highest total PHE count (n = 208), while Liberia had the lowest (n = 20). Only three of the 13 countries had a median coverage value for the third dose of the combined Diphtheria, Tetanus, and Pertussis vaccine (DTP3) that had attained the target for ≥90% immunization coverage. Higher counts of armed conflict and total PHEs were associated with not meeting immunization targets for national DTP3 coverage of ≥90% and Maternal and Neonatal Tetanus elimination, p < 0.01. It was clear that in the WHO Africa region, PHEs are prevalent, irrespective of a country's level of immunization maturity, and have the potential to derail the progress of NIPs in the absence of effective interventions. As we transition toward the Immunization Agenda 2030, we recommend that the WHO Africa region prioritizes interventions to mitigate the impacts of PHEs on NIPs.

Increasing hepatitis B vaccination coverage of healthcare workers - global lessons for South Africa.

Healthcare workers (HCWs) are at high risk of contracting hepatitis B (HB), a severe blood-borne vaccine-preventable disease, caused by HB virus (HBV) infection. Low HB vaccine (HepB) coverage has resulted in suboptimal protection and high HBV infection rates in South African HCWs. Studies from Africa have identified cost; unavailability/lack of access to HepB; and lack of awareness/knowledge of HB and HepB, as barriers to HCW uptake. Studies from Europe show little difference in HepB coverage between countries mandating versus recommending HepB. Providing easy and sustained access to free HepB to student HCWs, together with education about HB and HepB, are recommended to create demand for HepB. Only if this fails should mandatory vaccination be considered.

Developing vaccinology expertise for Africa: fifteen years and counting.

For 15 years, the Annual African Vaccinology Course (AAVC) hosted by the Vaccines for Africa Initiative, has been at the forefront of vaccinology training in Africa. The AAVC was developed in 2005 in response to the growing demand for vaccinology training in Africa. To date, 958 policy makers, immunization managers, public and private health practitioners, scientists, postgraduate and postdoctoral students have been trained. These participants are from 44 of the 54 African countries. The course content covers diverse topics such as considerations for new vaccine introduction, mathematical modelling, and emerging and re-emerging vaccine preventable diseases. As the landscape of vaccinology continues to evolve, the AAVC aims to expand the reach of vaccinology training using blended learning approaches which will incorporate online and face-to-face formats, while expanding access to this popular course. Ultimately, the AAVC endeavours to develop a big pool of vaccinology expertise in Africa and to strengthen regional ownership for immunization programmes.

Chronic hepatitis B-associated liver disease in the context of human immunodeficiency virus co-infection and underlying metabolic syndrome.

Globally, a shift in the epidemiology of chronic liver disease has been observed. This has been mainly driven by a marked decline in the prevalence of chronic hepatitis B virus infection (CHB), with the greatest burden restricted to the Western Pacific and sub-Saharan African regions. Amidst this is a growing burden of metabolic syndrome (MetS) worldwide. A disproportionate co-burden of human immunodeficiency virus (HIV) infection is also reported in sub-Saharan Africa, which poses a further risk of liver-related morbidity and mortality in the region. We reviewed the existing evidence base to improve current understanding of the effect of underlying MetS on the development and progression of chronic liver disease during CHB and HIV co-infection. While the mechanistic association between CHB and MetS remains poorly resolved, the evidence suggests that MetS may have an additive effect on the liver damage caused by CHB. Among HIV infected individuals, MetS-associated liver disease is emerging as an important cause of non-AIDS related morbidity and mortality despite antiretroviral therapy (ART). It is plausible that underlying MetS may lead to adverse outcomes among those with concomitant CHB and HIV co-infection. However, this remains to be explored through rigorous longitudinal studies, especially in sub-Saharan Africa. Ultimately, there is a need for a comprehensive package of care that integrates ART programs with routine screening for MetS and promotion of lifestyle modification to ensure an improved quality of life among CHB and HIV co-infected individuals.

Health systems constraints and facilitators of human papillomavirus immunization programmes in sub-Saharan Africa: a systematic review.

Given the vast investments made in national immunization programmes (NIPs) and the significance of NIPs to public health, it is important to understand what influences the optimal performance of NIPs. It has been established that well-performing NIPs require enabling health systems. However, systematic evidence on how the performance of health systems impacts on NIPs is lacking, especially from sub-Saharan Africa. We conducted a qualitative systematic review to synthesize the available evidence on health systems constraints and facilitators of NIPs in sub-Saharan Africa, using human papillomavirus immunization programmes as a proxy. Fifty-four articles published between 2008 and 2018 were found to be eligible. Data extraction was guided by an analytical model on the interface between NIPs and health systems. A cross-cutting thematic analysis of the extracted data was performed. This systematic review provides evidence necessary for informing ongoing health systems strengthening initiatives in sub-Saharan Africa. There is evidence to suggest that NIPs in sub-Saharan Africa have surmounted significant health systems constraints and have achieved notable public health success. This success can be attributed to strong political endorsement for vaccines, clear governance structures and effective collaboration with global partners. Despite this, significant health systems constraints persist in service delivery, vaccine communication, community engagement, the capacity of the health workforce and sustainable financing. These constraints could derail further progress if not addressed through health systems strengthening efforts. There is a need to expand the research agenda to include the comprehensive evaluation of health systems constraints and facilitators of NIPs within sub-Saharan Africa.

Impact of Lamivudine-Based Antiretroviral Treatment on Hepatitis B Viremia in HIV-Coinfected South Africans.

This prospective study investigated the impact of lamivudine-containing antiretroviral therapy (ART) on HIV-positive patients in South Africa with baseline hepatitis B virus (HBV) infection. Follow-up samples from 56 HBV/HIV co-infected patients, 25 with occult HBV infection (OBI) and 31 with chronic HBV infection (CHB), were available for analysis. HBV viral loads were quantified at 6, 12, 18, and 24 months post-ART initiation by the COBAS TaqMan HBV Test 48 assay, and the HBV polymerase gene was amplified with an in-house nested polymerase chain reaction assay. During 24 months of lamivudine-based ART, 6 of 8 (75%) OBI and 4 of 6 (67%) CHB patients achieved undetectable levels of HBV DNA, while 2 patients had persistent HBV DNA levels ≥ 2 × 105 despite lamivudine-based ART for 24 months. HIV viremia was undetectable in all patients at 12 months, suggesting high adherence to ART. Several lamivudine-associated HBV resistance mutations, including L180M, A181T, M204I, and M204V, were observed. Sequence analysis also revealed a rare genotype G infection. While resource-limited settings may use lamivudine-based ART because of availability and low cost, antivirals with dual therapy against HBV and HIV (e.g., lamivudine and tenofovir) should always be recommended with the regular monitoring of HBV viremia levels.

Assessment of humoral and cell-mediated immune responses to pertussis vaccination: a systematic review protocol.

INTRODUCTION: Globally, some studies show a resurgence of pertussis. The risks and benefits of using whole-cell pertussis (wP) or acellular pertussis (aP) vaccines in the control of the disease have been widely debated. Better control of pertussis will require improved understanding of the immune response to pertussis vaccines. Improved understanding and assessment of the immunity induced by pertussis vaccines is thus imperative. Several studies have documented different immunological outcomes to pertussis vaccination from an array of assays. We propose to conduct a systematic review of the different immunological assays and outcomes used in the assessment of the humoraland cell-mediated immune response following pertussis vaccination. METHODS AND ANALYSIS: The primary outcomes for consideration are quality and quantity of immune responses (humoral and cell-mediated) post-pertussis vaccination. Of interest as secondary outcomes are types of immunoassays used in assessing immune responses post-pertussis vaccination, types of biological samples used in assessing immune responses post-pertussis vaccination, as well as the types of antigens used to stimulate these samples during post-pertussis vaccination immune response assessments. Different electronic databases (including PubMed, Cochrane, EBSCO Host, Scopus and Web of Science) will be accessed for peer-reviewed published and grey literature evaluating immune responses to pertussis vaccines between 1990 and 2019. The quality of included articles will be assessed using standardised risk and quality assessment tools specific to the study design used in each article. Data extraction will be done using a data extraction form. The extracted data will be analysed using STATA V.14.0 and RevMan V.5.3 software. A subgroup analysis will be conducted based on the study population, type of vaccine (wP or aP) and type of immune response (cell-mediated or humoral). Guidelines for reporting systematic reviews in the revised 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement will be used in this study. ETHICS AND DISSEMINATION: Ethics approval is not required for this study as it is a systematic review. We will only make use of data already available in the public space. Findings will be reported via publication in a peer-reviewed journal and presented at scientific meetings and workshops. TRIAL REGISTRATION NUMBER: CRD42018102455.

A novel hepatitis B virus recombinant genotype D4/E identified in a South African population.

BACKGROUND: Genetic diversity is a characteristic trait of the hepatitis B virus (HBV) and has been associated with different clinical outcomes. In South Africa, HBV infection is a major public health concern. Most HBV infections are caused by genotype A strains. However rare cases of infection with HBV genotype D have been reported. The purpose of this study was to investigate the molecular characteristics of a rare HBV subgenotype D4 isolate. METHODS: The full-length genome of isolate ZADGM6964 was amplified in a one-step polymerase chain reaction. The amplified product was purified and cloned into a pGEM®-T Easy Vector System to investigate the genetic diversity of the viral quasi-populations. The primary isolate and clones were then directly sequenced and analysed using an array of bioinformatics software. RESULTS: Phylogenetic analysis showed that the primary isolate and cloned sequences formed a monophyletic cluster away from subgenotype D4 reference strains. Further recombination analysis revealed that isolate ZADGM6964 was in fact a D4/E recombinant strain with breakpoints identified within the X and overlapping pre-Core/Core open reading frames with a >70% bootstrap confidence level. The recombinant genotype D4/E was found to be unique from other D/E strains archived in the genetic database, GenBank. CONCLUSION: This study represents the first ever report on the isolation and molecular characterization of an HBV D4/E recombinant strain in South Africa. The findings provide evidence of further HBV genetic diversity in South Africa than has been previously reported.

Evidence of susceptibility to lamivudine-based HAART and genetic stability of hepatitis B virus (HBV) in HIV co-infected patients: A South African longitudinal HBV whole genome study.

BACKGROUND: Reports on the concomitant impact of HIV co-infection and long term highly active anti-retroviral therapy (HAART) on the genetic stability and molecular evolution of HBV are limited in sub-Saharan Africa. MATERIALS AND METHODS: This retrospective study investigated the molecular evolution of chronic HBV in HIV co-infected patients on lamivudine (3TC)-based HAART over a 5year period. Four HIV co-infected patients, consecutively recruited and followed-up, were screened for hepatitis B serological markers, and their viral loads determined. The HBV genome was amplified from longitudinal samples and characterized by Bayesian inference, mutational analysis, and identification of immune selection pressure. RESULTS: All patients exhibited persistent chronic HBV infection at baseline, as well as over the course of follow-up despite exposure to 3TC-based HAART. The polymerase gene in all isolates was relatively variable prior to HAART initiation at baseline and during the course of follow-up, although primary drug resistance mutations were not detected. All but one patient were infected with HBV subgenotype A1. The divergence rates between baseline and the last follow-up sequences ranged from 0 to 2.0×10(-3) substitutions per site per year (s/s/y). Positive selection pressure was evident within the surface and core genes. CONCLUSION: Despite persistent HBV infection in the HIV co-infected patients exposed to long term 3TC-based HAART, the molecular evolution of HBV over a 5year period was unremarkable. In addition, HBV exhibited minimal genetic variability overtime.