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

Tamandjou Tchuem, Cynthia Raissa (2019-12)

Thesis (PhD)--Stellenbosch University, 2019.

Thesis

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.

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