A study of the prevalence of Hepatitis B virus infection in the infants of HIV-positive mothers participating in P1041 in South Africa

Thesis (MScMedSc)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Despite the decreased rate of HBV horizontal transmission in South Africa (SA) due to the HB vaccine, the risk of perinatal transmission remains of concern, especially in HIV/HBV co-infected women. Loss of HBV immune control, resulting in higher HBV replication and thus increasing the risk of transmission is described in HIV/HBV co-infected women. Chronic hepatitis is a well-recognized risk factor for hepatocellular carcinoma (HCC). The presence of specific HBV mutations has been reported in chronic and HCC patients and is used in algorithms for the prediction of HCC in CHB patients in Asia. While these mutations are extensively described in male patients, little is known regarding the antenatal and paediatric populations. This study aimed to determine the prevalence of HBV infection in HIV-exposed infants and to investigate the presence of HCC-related mutations in pregnant women and HIV-exposed children in SA. Residual samples of infants born to HIV-infected mothers were collected from the P1041 study previously conducted in SA. HBV markers (HBsAg, anti-HBs and anti-HBc) were tested on the Architect (Abbott). HBsAg positive samples were tested for HBV DNA to determine HBV viral loads. HBV strains were characterised by sequencing of the HBsAg gene and genotypes were determined by phylogenetic analysis using HepSEQ (www.hepseq.org.uk). For the HCC-related mutations investigation, samples and data were collected from three HBV-related studies: the NHLS Paediatric Study, an Antenatal Study and the current study. Pre-S, basal core promoter (BCP) and pre-core data was collected from all samples. Multiple alignments were formed and the nucleotide sequences of these extracts were translated into protein sequences. These protein sequences were compared manually to the HBV reference genes to identify HCC-related mutations. Of 850 HIV-exposed infants tested, three infants were positive for both HBsAg and HBV DNA. Two samples show evidence of past, but cleared HBV infection. Sequence analysis showed that the infants were infected with a subgenotype A1. At follow up, only one infant and mother were able to be traced and contacted. The infant was HIV-infected and had been on an ART regimen, including lamivudine for two years. HBV testing showed that the infant was HBsAg positive and had an undetectable viral load. Core sequence analysis showed clustering between mother and infant sequences. Transmission of mutant HBV previously associated with HCC prompted the question of what the prevalence of mutations in the antenatal and paediatric population is. In this investigation of HCC-related mutations study, a higher prevalence of combined pre-S, BCP and pre-core mutations was found in HIV-infected as compared to HIV-uninfected women. This study shows that vertical transmission is occurring in HIV-exposed infants in SA despite HB vaccination. Data described in this study suggests the importance of HB vaccination closer to the time of birth in SA. Moreover, data on the higher prevalence of HCC-related mutations in HIV-infected pregnant women provide a background for further longitudinal studies to confirm these findings and their implications in SA.AFRIKAANSE OPSOMMING: As gevolg van die beskikbaarheid van die Hepatitis B virus (HBV) entstof , het horisontale transmissie van die virus drasties in Suid-Afrika (SA) verminder. Ten spyte hiervan, is daar steeds ‘n hoë risiko van perinatale transmissie van swanger vroue na hulle babas, dit word veral gesien met MIV/HBV positiewe vroue. Dit is wyd beskryf dat vroue wat mede-besmet is met MIV/HBV gewoonlik beheer verloor oor hulle immuunstelsel, wat lei tot ‘n hoër mate van HBV replikasie en dus ‘n hoër risiko van virus oordrag. Kroniese hepatitis is wel bekend as ‘n hoë risiko faktor vir HCC. Die teenwoordigheid van spesifieke HBV mutasies in kroniese en HCC pasiënte word alreeds in Asië gebruik in sekere algoritmes en formules om infeksie aan te dui en te voorspel. Hierdie mutasies is omvattend beskryf in manlike pasiënte, maar baie min is bekend in voorgeboorte en pediatriese gevalle. In hierdie studie het ons die teenwoordigheid van HCC-verwante mutasies in swanger vroue en MIV-blootgestelde kinders in Suid-Afrika ondersoek. Monsters is verkry van babas gebore van MIV-positiewe moeders van die P1041 studie wat voorheen in SA gedoen is. Die HBV merkers (HbsAg, teen-HBs en teen-HBc) was op die Architect (Abbott) getoets. HBsAg positiewe monsters was getoets vir HBV DNA om die virale lading te bepaal. Die verskeidenheid HBV stamme was gekarakteriseer deur die virus se nukleïensuur volgordes te bepaal. Die verskillende genotipes is bepaal deur filogenetiese analises te doen met behulp van die HepSEQ (www.hepseq.org.uk) program. Vir die HCC-verwante mutasie studie is monsters en data vergelyk met 3 HBV-verwante studies: die NHLS pediatriese studie, ‘n voorgeboorte studie en hierdie spesifieke studie. Voor-S, basale kern promoter en voor-kern data was van alle monsters bekom. ‘n Veelvoudige belyning was gedoen met die nukleïensuur volgordes van die verskeie DNA ekstrakte, wat daarna vertaal is in proteïen volgordes. Hierdie proteïenvolgordes translasie was by hand vergelyk met verwysings gene om die relatiewe HCC mutasies te probeer identifiseer. Van die 850 blootgestelde MIV babas wat getoets is, het 3 positief getoets vir beide HbsAg en HBV DNA. Twee monsters het bewys van verlede , maar vrygestelde HBV infeksie. Data analise bewys dat die babas met subtipe A1 besmet was. Ons kon slegs een moeder en baba paar opvolg en kontak vir verdere toetse. Die baba was MIV-positief en was op antiretrovirale behandeling , insluitend lamivudine, vir ten minste 2 jaar. HBV toetse het gewys dat die baba HbsAg positief is en ‘n onopspoorbare virale lading gehad het. Kern nukleïensuur volgorde analise het groepering getoon tussen die ma en baba se virus monsters . Die transmissie van die mutante HBV wat geassosieer is met HCC het gelei tot die vraag wat die voorkomssyfer is van hierdie spesifieke mutasies in die voorgeboorte en pediatriese populasies in SA. In hierdie studie het ons ‘n hoër gekombineerde voorkomssyfer gevind van die voor-S, basale kern promoter en voor-kern mutasies in MIV-positiewe vroue, in vergelyking met MIV-negatiewe vroue. Hierdie studie bewys dus dat vertikale transmissie van HBV in blootgestelde MIV babas steeds plaasvind, ten spyte van HBV inenting. Die data wat in hierdie studie beskryf was dui daarop dat die belangrikheid van HBV inenting nader aan die tyd van die geboorte in SA gegee moet word.As gevolg van die hoë voorkomssyfer van HCC-verwante mutasies in swanger vroue, is daar verdere longitudinale studies nodig om hierdie bevindinge en hul implikasies in SA te bevestig

Hepatitis B virus mother-to-child transmission in Namibia: transmission dynamics and possibilities for elimination

Thesis (PhD)--Stellenbosch University, 2019.ENGLISH ABSTRACT: Introduction: Hepatitis B virus (HBV) remains endemic in sub-Saharan Africa (SSA). While the roll-out of pediatric HBV immunization from six weeks of age has had an impact on horizontal transmission of the virus, mother-to-child transmission (MTCT) has been identified as the driver of the current HBV epidemic in the region. Given the high likelihood of developing chronic HBV infection (CHB) if the infection is acquired during infancy, preventing HBV MTCT in SSA is vital. Where MTCT occurs, it is essential to identify the HBV-infected children for appropriate management, especially in the context of HIV. Current antiretroviral therapy (ART) for the management of HIV infection includes tenofovir for children ≥ 10 years old. Children below the age of 10 years are treated with lamivudine. However, many of the HIV/HBV co-infected children are left on lamivudine treatment for more than ten years and are at risk of developing HBV drug resistance and uncontrolled HBV infection. Uncontrolled HBV infection is a known factor for increased risk of severe liver damage. Aim: This research project aimed to (1) assess the molecular character of HBV and the liver health of HIV/HBV co-infected children who have been on long-term lamivudine treatment, (2) to determine the feasibility of a screen-treat-vaccinate intervention to prevent HBV MTCT, and (3) to measure the costs and health outcomes of combined prophylactic measures against HBV MTCT, in Namibia. Methodology: Three sub-studies were conducted as part of this research project, to answer each of its aims. The first sub-study involved HIV/HBV co-infected children and adolescents below the age of 18 years old, and who have been exposed to lamivudine. Venous blood samples were collected from these children for HBV serological testing (HBsAg, HBeAg, anti-HBe and anti-HBc total) using Murex ELISA assays. Dried blood spots (DBS) samples were used for HBV DNA levels measurement and genotyping. HBV DNA measurements were completed using the automated AmpliPrep/COBAS TaqMan HBV test V2.0. Genotyping and mutation analyses were performed using online tools. Liver health was assessed through AST platelet ratio index (APRI). An APRI score > 0.5 was considered a sign of liver fibrosis. Mothers attending with these children and adolescents were also enrolled in the study, to determine the role of HBV MTCT in these pediatric HBV infections. DBS were collected from these mothers for HBV molecular characterization as well. The second sub-study focused on pregnant women attending antenatal clinics (ANCs) in Windhoek. These women were recruited following informed consent and screened for HBV using the Alere DetermineTM HBsAg rapid test. HBsAg positive pregnant women were tested for further HBV serological markers (HBeAg, anti-HBe, anti-HBc IgM), and HBV viral loads were measured to determine the risk of MTCT. Positive mothers at high risk of MTCT were reviewed for antiviral prophylaxis and offered treatment where necessary. HBV-exposed babies were immunized as per Namibian guidelines, and followed-up to determine the rate of MTCT. The feasibility of offering routine antenatal HBV rapid testing was assessed quantitatively and qualitatively. The former involved determining the diagnostic accuracy of the rapid test used for HBsAg screening, and the latter focused on the perceptions of this antenatal care service by healthcare workers (HCWs). In the third sub-study, the costs and health outcomes of four interventions against HBV MTCT were assessed through a cost-effectiveness analysis. The interventions included: (1) universal birth dose (BD) vaccination, (2) BD vaccination and HBIG, (3) BD vaccination, HBIG, and maternal antiviral prophylaxis informed by sequential HBV viral load testing, and (4) BD vaccination, HBIG, and maternal antiviral prophylaxis informed by sequential HBeAg testing. All resources including consumables, HCW’s time, building space and facilities (and their quantity) were measured and valued to determine the unit costs of HBsAg screening at the ANCs, providing antenatal treatment and administering pediatric immunoprophylaxis. Health outcomes were measured in terms of the number of pediatric HBV infections averted. The incremental cost-effectiveness ratios (ICERs) of these interventions were calculated and were used to compare each intervention to the previous less expensive one. Results: Fifteen HIV/HBV co-infected children/adolescents and six mothers attending with the children were enrolled in the first sub-study. Ten serum samples obtained from Windhoek were further tested for HBV serological markers; seven were HBeAg positive/anti-HBe negative (7/10; 70%), three were HBeAg negative (3/10; 30%), and all were reactive for anti-HBc (total) (10/10; 100%). Among HBeAg negatives, one was anti-HBe negative and two were anti-HBe positive. Eight of the fifteen children (8/15; 53.3%) were HBV DNA positive. The viral strains were grouped with genotype E (6/8; 75%) and genotype D3 (2/8; 25%) and harbored lamivudine drug-associated resistance variants and immune escape mutants. Liver health was assessed in nine children: five with detectable levels of HBV DNA and four with undetectable levels of HBV DNA. An abnormal APRI score of 0.713, was detected in one HBV DNA positive child (1/9; 11.1%). In the second sub-study an HBsAg seroprevalence of 5.4% was observed among 515 (28/515) pregnant women enrolled at ANCs in Windhoek. Three pregnant women (3/28; 10.7%) were positive for HBeAg; of whom one was HIV/HBV co-infected and the other two were HBV mono-infected. The two (2/28; 7.14%) HBV mono-infected/HBeAg-positive patients presented with viral load > 105 IU/ml, the study cut-off for antenatal treatment to prevent HBV MTCT; one received antiviral prophylaxis with tenofovir, the other was offered prophylaxis but did not receive it. Postpartum, 25 of the 28 HBV-exposed babies (25/28; 89.3%) were traced and followed-up to determine their HBV status and the rate of HBV MTCT. Fourteen (14/25; 56%) were males, and eleven were females (11/25; 44%). All babies had been vaccinated against HBV at birth, and 15 (15/25; 60%) had received hepatitis B immunoglobulin (HBIG). The 25 babies were tested for HBsAg at a median age of seven weeks (Range: 5.57 weeks – 20.29 weeks). All were non-reactive for HBsAg, including both babies born to the highly viremic women. With regards to the feasibility of HBV rapid testing as part of antenatal care services, the DetermineTM HBsAg rapid test had a 100% diagnostic sensitivity and specificity. HCWs found the test simple to use and showed a preference for rapid testing over laboratory testing for routine antenatal screening of HBV. They believed that this method would improve early diagnosis and treatment of HBV of pregnant women. In the cost-effectiveness analysis conducted in the third sub-study, a preventive strategy with universal BD vaccination alone was the cheapest option but was less effective. Adding HBIG to BD vaccination, and providing maternal antiviral prophylaxis was the most effective and the most costly strategy. The strategy that includes antiviral prophylaxis with sequential HBeAg testing added to BD vaccination and HBIG had an ICER of US$6 262.42 per infection averted, in comparison to the strategy including BD vaccination and HBIG only. The BD vaccination and HBIG strategy had an ICER of US$4 550.34/ pediatric HBV infection averted, in comparison to BD vaccination alone. These ICERs were highly sensitive to the prevalence of highly infectious pregnant women, the cost of the HBeAg test, and the effectiveness of each strategy for preventing MTCT in highly infectious pregnant women. Conclusion: Results from this research project reemphasized the issue of pediatric CHB, especially in HIV/HBV co-infected children. The data described in this study also showed that elimination of MTCT of HBV in Namibia is achievable, through routine antenatal HBsAg screening, treating pregnant women at high risk of MTCT, and providing HBV vaccination from birth. Screening using rapid testing was found cheap, and a feasible alternative for detecting HBV infection in pregnant women. The costs and health benefits of implementing antenatal antiviral prophylaxis and HBIG presented in the study provide background data for further assessment of the value for money of these interventions in SSA, and to explore alternatives excluding HBIG for HBV PMTCT.AFRIKAANSE OPSOMMING: Inleiding: Die Hepatitis B virus (HBV) bly endemies in Afrika suid van die Sahara (SSA). Terwyl die uitrol van pediatriese HBV-immunisasie vanaf ses weke 'n impak gehad het op die horisontale oordrag van die virus, is moeder-tot-kind-oordrag (MTCT) geïdentifiseer as die belangrikste dryfveer van die huidige HBV-epidemie in die streek. Gegewe die hoë waarskynlikheid om chroniese HBV-infeksie (CHB) te ontwikkel indien die infeksie gedurende die kinderjare verwerf word, is die voorkoming van HBV MTCT in SSA noodsaaklik. Waar MTCT plaasgevind het, is dit noodsaaklik om die HBV-geïnfekteerde kinders te identifiseer en voortaan te monitor vir gepaste hantering, veral in die konteks van MIV infeksies. Huidige antiretrovirale terapie (ART) vir die behandeling van MIV-infeksie sluit tenofovir vir kinders ≥ 10 jaar in. Kinders onder die ouderdom van 10 jaar word behandel met lamivudien. Baie van die kinders met MIV/HBV ko-infeksie is egter al meer as tien jaar aan lamivudienbehandeling blootgestel en loop die risiko om HBV-middelweerstand en ongekontroleerde HBV-infeksie te ontwikkel. Ongekontroleerde HBV infeksie is 'n bekende faktor vir verhoogde risiko van ernstige lewerskade. Doelwitte: Hierdie navorsingsprojek het ten doel om (1) die molekulêre eienskappe van HBV en die lewergesondheid van MIV/HBV mede-besmette kinders te beoordeel wat op langtermyn lamivudienbehandeling was, (2) om die lewensvatbaarheid van 'n sifting-behandeling-inenting ingreep om HBV MTCT te voorkom, te bepaal en (3) om die koste en gesondheidsuitkomste van gekombineerde profilaktiese maatreëls teen HBV MTCT in Namibië te meet.Metodiek: Drie substudies is uitgevoer om elkeen van die studiedoelwitte aan te spreek. Die eerste substudie het kinders en adolessente met MIV/HBV ko-infeksie onder die ouderdom van 18 jaar, en wat aan lamivudien blootgestel is, ingesluit. Veneuse bloedmonsters is van hierdie kinders versamel vir HBV serologiese toetsing (HBsAg, HBeAg, anti-HBe en totale anti-HBc) deur die Murex ELISA toetse. Gedroogde bloedvlek (DBS) monsters is gebruik om HBV DNA vlakke te meet en die virus te genotpieer. HBV DNA-metings is voltooi met behulp van die geoutomatiseerde AmpliPrep / COBAS TaqMan HBV toets V2.0. Genotipering en mutasie analises is uitgevoer met behulp van aanlyn-metodes. Lewer gesondheid is geassesseer deur die AST bloedplaatjie verhouding indeks (APRI) te gebruik. 'n APRI-telling> 0.5 is beskou as 'n teken van lewerfibrose. Betrokke moeders is ook in die studie ingeskryf om die rol van HBV MTCT in die pediatriese HBV-infeksies te bepaal. DBS is ingesamel uit hierdie moeders vir HBV molekulêre karakterisering. Die tweede substudie het gefokus op swanger vroue wat voorgeboorteklinieke (ANC’s) in Windhoek bygewoon het. Hierdie vroue is gewerf na ingeligte toestemming en gesif vir HBV met behulp van die Alere Determine TM HBsAg vinnige toets. HBsAg positiewe swanger vroue is verder getoets vir HBV serologiese merkers (HBeAg, anti-HBe, anti-HBc IgM) en HBV virale ladings is gemeet om die risiko van MTCT te bepaal. Positiewe moeders met 'n hoë risiko van MTCT is oorweeg vir antivirale profilakse en behandeling is aangebied waar nodig. HBV-blootgestelde babas is geïmmuniseer volgens Namibiese riglyne, en gevolg om die tempo van MTCT te bepaal. Die uitvoerbaarheid van die aanbied van roetine voorgeboortelike HBV vinnige toetsing is kwantitatief en kwalitatief geassesseer. Eersgenoemde behels die bepaling van die diagnostiese akkuraatheid van die vinnige toets wat gebruik word vir HBsAg-screening, en laasgenoemde het gefokus op die persepsies van hierdie voorgeboortesorgdiens deur gesondheidswerkers (HCWs). In die derde substudie is die koste en gesondheidsuitkomste van vier intervensies teen HBV MTCT geassesseer deur 'n koste-effektiwiteitsanalise. Die intervensies sluit in: (1) BD-inenting, (2) BD-inenting en HBIG, (3) BD-inenting, HBIG en antivirale profylaksis van die moeder wat ingelig word deur sekwensiële HBV virale ladingstoetsing en (4) BD-inenting, HBIG, en antivirale profylaxe van die moeder geïnformeer deur sekwensiële HBeAg toetsing. Alle hulpbronne, insluitend verbruiksgoedere, HCW se tyd, gebouruimte en fasiliteite (en hul hoeveelheid) is gemeet en gewaardeer om die eenheidskoste van HBsAg-screening by die ANC te bepaal, wat voorgeboortelike behandeling en die administrasie van pediatriese immunoprofielaksis verskaf. Gesondheidsuitkomste is gemeet in terme van die aantal pediatriese HBV-infeksies afgewend. Die inkrementele koste-effektiwiteitsverhoudings (ICER's) van hierdie intervensies is bereken en is gebruik om elke intervensie met die vorige goedkoper een te vergelyk. Resultate: Vyftien MIV/HBV mede-besmette kinders/adolessente en ses moeders was in die eerste substudie ingeskryf. Tien serummonsters wat van Windhoek verkry is, is verder getoets vir HBV serologiese merkers; sewe was HBeAg positief/anti-HBe negatief (7/10, 70%), drie was HBeAg negatief (3/10; 30%) en almal was reaktief vir anti-HBc (totaal) (10/10; 100%). Onder HBeAg negatiewe, was een anti-HBe negatief en twee was anti-HBe positief. Ag van die vyftien kinders (8/15; 53,3%) was HBV DNA positief. Die virusstamme is gegroepeer met genotipe E (6/8; 75%) en genotipe D3 (2/8; 25%) en bevat lamivudien-middel-verwante weerstandsvariante en immuun-ontwyk-mutante. Lewer gesondheid is in nege kinders geassesseer: vyf met waarneembare vlakke van HBV DNA en vier met onopspoorbare vlakke van HBV DNA. 'n Abnormale APRI-telling van 0.713 is opgespoor in een HBV DNA positiewe kind (1/9, 11.1%). In die tweede substudie is ' n HBsAg seroprevalensie van 5,4% waargeneem onder 515 (28/515) swanger vroue wat by ANC's in Windhoek ingeskryf is. Drie swanger vroue (3/28; 10.7%) was positief vir HBeAg; van wie een MIV/HBV ko-infeksieen die ander twee slegs HBVinfeksie gehad het.. Die twee (2/28, 7.14%) HBV mono-geïnfekteerde/HBeAg-positiewe pasiënte het 'n viruslading> 105 IE / ml, die studie afgesny vir voorgeboortelike behandeling om HBV MTCT te voorkom; een het antivirale profilakse met tenofovir ontvang, die ander is profilakse aangebied, maar het dit nie ontvang nie. Postpartum, 25 van die 28 HBV-blootgestelde babas (25/28, 89.3%) is opgevolg om hul HBV status en die tempo van HBV MTCT te bepaal. Veertien (14/25, 56%) was mans, en elf was vroue (11/25; 44%). Alle babas is teen geboorte teen HBV ingeënt en 15 (15/25, 60%) het hepatitis B immunoglobulien (HBIG) ontvang. Die 25 babas is getoets vir HBsAg op mediane ouderdom van sewe weke (Bereik: 5.57 weke – 20.29 weke). Almal was nie-reaktief vir HBsAg, insluitende albei babas wat gebore is aan die hoogs viremiese vroue. Met betrekking tot die haalbaarheid van HBV vinnige toetsing as deel van voorgeboortesorgdienste, het die Determine TM HBsAg vinnige toets 'n 100% diagnostiese sensitiwiteit en spesifisiteit gehad. HCWs het die toets maklik gevind om te gebruik en het 'n voorkeur getoon vir vinnige toetse oor laboratoriumtoetse vir roetine-voorgeboortelike screening van HBV. Hulle het geglo dat hierdie metode vroeë diagnose en behandeling van HBV van swanger vroue sal verbeter. In die koste-effektiwiteitsanalise wat in die derde substudie gedoen is, was 'n voorkomende strategie met universele BD-inenting alleen die goedkoopste opsie, maar was minder effektief. Die toevoeging van HBIG tot BD-inenting, en die voorsiening van moeder se antivirale profylaksis was die mees effektiewe en die duurste strategie. Die strategie wat antivirale profilakse sluit met sekwensiële HbeAg toets bygevoeg BD inenting en HBIG het 'n ICER van $6 per infeksie afwyk, in vergelyking met die strategie, insluitende BD-inenting en slegs HBIG. Die BD-inenting en HBIG-strategie het 'n ICER van US$ 4 550.34/pediatriese HBV-infeksie afgeneem, in vergelyking met BD-inenting alleen. Hierdie ICER's was hoogs sensitief vir die voorkoms van hoogs aansteeklike swanger vroue, die koste van die HBeAg-toets en die effektiwiteit van elke strategie om MTCT te voorkom in hoogs aansteeklike swanger vroue. Slotsom: Resultate van hierdie navorsingsprojek het die kwessie en ernstigheid van pediatriese CHB infeksie herbeklemtoon, veral in MIV/HBV mede-besmette kinders. Die data wat in hierdie studie beskryf is, het ook getoon dat die eliminasie van MTCT van HBV in Namibië bereik kan word deur roetine-voorgeboortelike HBsAg-sifting, behandeling van swanger vroue met hoë risiko van MTCT en die verskaffing van HBV-inenting vanaf geboorte. Sifting-toetsingmet behulp van vinnige toetsing is goedkoop en 'n haalbare alternatief vir die opsporing van HBV infeksie in swanger vroue. Die koste en gesondheidsvoordele van die implementering van voorgeboortelike antivirale profilakse en HBIG wat in die studie beskryf word, verskaf data vir verdere assessering van die waarde vir geld van hierdie intervensies in SSA en om alternatiewe te ondersoek wat HBIG vir HBV PMTCT uitgesluit het.Doctora

Viral hepatitis associated hepatocellular carcinoma on the African continent, the past, present, and future: a systematic review

Abstract Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in Africa. In Africa, the major causes of HCC include chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV). Knowledge of the changes in the incidence of viral hepatitis-associated HCC over time and the factors responsible for such changes is key in informing policies for the prevention of viral hepatitis-associated HCC in Africa. Aim The study aimed to systematically summarize the changes in the prevalence of viral hepatitis among HCC patients and the overall effect of the prevalence of viral hepatitis on the incidence of HCC over the past four decades in Africa (1980–2019). Methods A literature search was conducted in MEDLINE (PubMed), Google Scholar, Science Direct, Scopus, Web of Science, and African wide web for articles published on viral hepatitis-associated HCC in Africa from 1980 to 2019. The abstracts of the articles were screened for eligibility and those meeting the inclusion criteria were retrieved and reviewed. Results A total of 272 studies were included in the analysis. Viral hepatitis-related HCC incidence changed by 1.17% (95% confidence interval (CI): 0.63–1.71, p < 0.001), 0.82% (95% CI: 0.45–1.18, p < 0.001), and 3.34% (95% CI: 2.44–4.25, p < 0.001) for every 1% change in the prevalence of HBV, HCV, and hepatitis D virus (HDV) respectively, per decade. The incidence of HBV-related HCC decreased by − 0.50% (95% CI: − 0.74 – − 0.25, p < 0.001) over the last 40 years, while HCV-related HCC increased. Conclusion Overall, the incidence of viral hepatitis-associated HCC has not declined, mainly due to no decline in the prevalence of HCV, HDV, and the high number of chronic hepatitis B carriers on the African continent. There is an urgent need for the allocation of resources for the implementation of treatment and preventive programs for HBV, HCV, HDV, and HCC in Africa. This systematic review is registered with PROSPERO®, number CRD42020169723

Hepatitis B virus drug resistance mutations in HIV/HBV co-infected children in Windhoek, Namibia

CITATION: Tchuem, C. R. T., et al. 2020. Hepatitis B virus drug resistance mutations in HIV/HBV co-infected children in Windhoek, Namibia. PLoS ONE, 15(9):e0238839, doi:10.1371/journal.pone.0238839.The original publication is available at https://journals.plos.org/plosone/Publication of this article was funded by the Stellenbosch University Open Access FundENGLISH ABSTRACT: In patients who are HIV infected, hepatitis B virus (HBV) infection is an important co-morbidity. However, antiretroviral options for HIV/HBV co-infected children are limited and, at the time of this study, only included lamivudine. These children may remain on this regimen for many years until late adolescence. They are at high risk of developing HBV drug resistance and uncontrolled HBV disease. The aim of this study was to characterize HBV infection in HIV/HBV co-infected children. Known HIV-infected/HBsAg-positive children, previously exposed to lamivudine monotherapy against HBV, and their mothers were recruited at the Katutura Hospital paediatric HIV clinic in Windhoek, Namibia. Dried blood spot and serum samples were collected for HBV characterization and serological testing, respectively. Fifteen children and six mothers participated in the study. Eight of the 15 children (53.3%) tested HBV DNA positive; all eight children were on lamivudine-based ART. Lamivudine-associated resistance variants, together with immune escape mutants in the surface gene, were identified in all eight children. Resistance mutations included rtL80I, rtV173L, rtL180M, rtM204I/V and the overlapping sE164D, sW182*, sI195M and sW196LS variants. HBV strains belonged to genotypes E (6/8, 75%) and D3 (2/8, 25%). Further analysis of the HBV core promoter region revealed mutations associated with reduced expression of HBeAg protein and hepatocarcinogenesis. All six mothers, on HBV-active ART containing tenofovir and lamivudine, tested HBV DNA negative. This study confirms the importance of screening HIV-infected children for HBV and ensuring equity of drug access to effective HBV treatment if co-infected.https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238839Publisher's versio

Evidence of co and triple infections of Hepatitis B and C amongst HIV infected pregnant women in Buea, Cameroon

CITATION: Ikomey, G. M. et al. 2016. Evidence of co and triple infections of Hepatitis B and C amongst HIV infected pregnant women in Buea, Cameroon. Science Journal of Public Health, 4(2):127-131, doi:10.11648/j.sjph.20160402.17.The original publication is available at http://www.sciencepublishinggroup.com/journal/index?journalid=251Little epidermiological data is available on the prevalence of HIV, Hepatitis B and C, Co-and or triple infection during pregnancy in Cameroon as well as many other resource limited settings. HIV and Hepatitis B and C are major public health concerns world wide. Our study aimed at assessing the seroprevalence of Hepatitis B and C amongst HIV infected pregnant women in Buea, located in the Southwest region of Cameroon. A Cross-sectional study on consented pregnant women were conducted from March 2015 to August 2015. HIV-1 infections were detected using the national HIV-1 test algorithms. Hepatitis B surface antigen (HBsAg), anti-HBe and anti- Hepatitis C (anti-HCV) were detected using Enzyme linked Immunosorbent Assays (ELISAs). Of the 1230 recruited pregnant women, 97/1230 (7.8%) (95% CI: 3.5, 29.0%) were confirmed HIV-1 positive. HIV/HBV co-infection were observed in 14/97 (14.4%) (95% CI: 39.8, 100%), whilst 11/97 (11.3 %; 95% CI: 27.5, 100%) were HIV/HCV co-infections. Two HIV-infected pregnant women (8/97(8.2%; 95% CI: 0.1, 17.2%)) were HIV/HBV/HCV triple-infected. Anti-HBc was detected in all HBV-infected pregnant women (14/14; (100.0%)) (95.0% CI: 39.8, 100.0%). Seropositivity for HIV-1 was higher (37%) amongst subjects aged between 32-37 years, whilst none was found above 40. From our results we conclude that Co- and triple infections of HIV, Hepatitis B and C were present amongst pregnant women in Buea. Epidemiological data generated from this study are limited due to the existence of triple infected. It will therefore serve as a guide to the government policies to reinforce screening, treatment and prevention strategies, through its Mother–to-Child–transmission (pMTCT) Programme nationwide.http://article.sciencepublishinggroup.com/html/10.11648.j.sjph.20160402.17.htmlPublisher's versio

Vaccine effectiveness and duration of protection of COVID-19 mRNA vaccines against Delta and Omicron BA.1 symptomatic and severe COVID-19 outcomes in adults aged 50 years and over in France

International audienceThe emergence of SARS-CoV-2 variants calls for continuous monitoring of vaccine effectiveness (VE). We estimated the absolute effectiveness of complete 2-dose primary vaccination and booster vaccination with COVID-19 mRNA vaccines, and the duration of protection against Delta and Omicron BA.1 symptomatic infection and severe outcomes. French residents aged !50 years, who presented with SARS-CoV-2-like symptoms and tested for SARS-CoV-2 between June 6, 2021 and February 10, 2022 were included. A test-negative study was conducted to estimate VE against symptomatic infection, using conditional logistic regression models. Cox proportional hazard regressions were performed to assess additional protection against severe COVID-19 outcomes (any hospitalization, and intensive care units [ICU] admission or in-hospital death). In total, 273 732 cases and 735 919 controls were included. VE against symptomatic infection after 2-doses vaccination was 86% (95% CI: 75-92%) for Delta and 70% (58-79%) for Omicron, 7-30 days post vaccination. Protection waned over time, reaching 60% (57-63%) against Delta and 20% (16.-24%) for Omicron BA.1 > 120 days after vaccination. The booster dose fully restored protection against symtpomatic Delta infection (95% [81-99%]) but only partially against symptomatic Omicron BA.1 infection (63% [59-67%]). VE against Delta-related severe outcomes was above 95% with 2 doses, and persisted for at least four months. Protection against any Omicron BA.1-hospitalization was 92% (65%-99%) at 8-30 days, and 82% (67%-91%) > 120 days from the second dose. Against BA.1 ICU admission or in-patient death, VE stood at 98% (0-100%) at 8-30 days, and was 90% (40-99%) > 120 days from the second dose. Protection confered by mRNA vaccines against severe disease caused by either Delta or Omicron BA.1 appeared high and sustained over time. Protection against symptomatic diseases after 2 doses decreased rapidly, especially against Omicron BA.1. A booster dose restored high protection against Delta but only a partial one against Omicron BA.1

Estimating the risk of incident SARS-CoV-2 infection among healthcare workers in quarantine hospitals: the Egyptian example

International audienceIn response to the COVID-19 epidemic, Egypt established a unique care model based on quarantine hospitals where only externally-referred confirmed COVID-19 patients were admitted, and healthcare workers resided continuously over 1- to 2-week working shifts. Using a mathematical model accounting for the false-negative rates of RT-PCR tests, we computed the incidence rate of SARS-CoV-2 infection among HCWs, while unveiling the proportion of infections remaining undiagnosed despite routine testing. We relied on longitudinal data, including results of routine RT-PCR tests, collected within three Egyptian quarantine hospitals. We estimated an incidence rate (per 100 person-day, PD) of 1.05 (95% CrI 0.58–1.65) at Hospital 1, 1.92 (95% CrI 0.93–3.28) at Hospital 2 and 7.62 (95% CrI 3.47–13.70) at Hospital 3. We found that the risk for an HCW to be infected during a working shift lay within the range of risk levels previously documented in standard healthcare settings for Hospitals 1–2, whereas it was > threefold higher for Hospital 3. This large variation suggests that HCWs from quarantine hospitals may face a high occupational risk of infection, but that, with sufficient infection control measures, this risk can be brought down to levels similar to those observed in standard healthcare settings