Introduction
HIV and hepatitis B virus (HBV) remain major public health concerns worldwide, with about 36.9 and 350 million people living respectively with HIV and chronic HBV (CHB) infections worldwide [
1,
2]. While 70% of the global HIV burden is found in sub-Saharan Africa (SSA), HBV is ubiquitous within the Asian (15%) and African populations (8–40%) [
2], thus indicating a high risk of HIV/HBV co-presence within the African populations. Of note, HIV/HBV co-infection is characterized by a synergistic interaction between both viruses leading on one hand, to a rapid progression to AIDS defining event(s), and on the other hand, to an earlier development of hepatocellular carcinoma as compared to HBV mono-infected individuals [
3]. Also, the probability of acquiring CHB is significantly higher in the frame of HIV infection, and this event becomes more worrisome for children at early age (80–90% of infants aged below 1 year and 30–50% of children aged 1–4 years) infected with HBV end-up developing CHB infection [
4,
5]. Thus, in order to support the global effort of eliminating viral hepatitis, strategies toward integrated prevention and care for HIV/HBV would be essential, especially for paediatric populations for whom the risk of CHB is the highest [
2,
3].
The common routes of HBV transmission among children are perinatal and horizontal during early childhood [
6,
7]. Of note, perinatal transmission was more frequent in Asia (from mother-to-child) while the horizontal was more in SSA (horizontally from infected household members or unsafe materials during early age) in year 1990 [
8,
9]. Of relevance, “children detected positive for hepatitis B surface antigen (HBsAg) and envelope antigen (HBeAg) are highly contagious; over 85–90% of them are potential CHB carriers and liver cancer patients at adulthood, a condition that would be worsening in the context of co-infection with HIV [
10‐
12]. In this context, ensuring an effective implementation of a preventive package would be helpful, starting from universal screening of HBV among pregnant women attending their first antenatal care (ANC), a systematic vaccination against HBV all pregnant women having a negative HBsAg result, providing HBV antibodies at birth to all vertically-exposed babies, and a universal vaccination of new-borns [
13]. However, response to anti-HBV vaccine might vary according to age and HIV status, thereby indicating high vulnerability to HBV among children living with HIV (CLHIV) as we previously reported within a similar target population in Cameroon [
13]. Thus, assessing the burden of HBV in CLHIV in Cameroon would help in understanding the current epidemiologic context and in designing interventions for greater protectiveness at country-level.
Even though Cameroon is experiencing declining trends of both HIV among adults and adolescents aged 15–49 years (from 4.3 to 3.4%) and HBV (12.2 to 8.1%), the country is still experiencing a generalized epidemic of both infections, suggesting consistent risks of paediatric infections and the need for evidence-based strategic interventions to support an integrated care [
14,
15]. Though data on HBV/HIV coinfection in children remain largely uncovered in several SSA countries, our previous findings from Cameroon indicate a poor immunological response to HBV-vaccine in the population of CLHIV, hence suggesting risks of HBV-infection in spite of vaccination [
13]. Additionally, HBV/HIV prevalence remains high in several African countries (5–40%), with 17.5% coinfection among pregnant women in Cameroon [
7,
16‐
18] where the screening of HBV in new born babies is not yet systematically done. Furthermore, antiretroviral therapy (ART), for both children and adults living in SSA, usually entails molecules with anti-HBV activities (lamivudine [3TC], emtricitabine [FTC], tenofovir [TDF]), with limited evidence on its effects on HBV pathogenesis in the frame of co-infection with HIV in children [
16,
17]. Thus, understanding factors sustaining risks of HBV transmission to CLHIV is crucial for designing integrated but impactful strategies against HBV for CLHIV in SSA [
16,
17].
Integrating HBV service delivery with HIV care requires the use of simple, affordable and rapid diagnostic tests (RDTs) for HBV screening in SSA settings [
7,
13]. Of note, in spite of their high sensitivity and specificity, reference diagnostic assays remain costly, require sophisticated platforms and are time consuming [
13]. In this frame, RDTs are highly encouraged and are widely used for HBV screening, but without a prior assessment of the diagnostic accuracy for ensuring clinical validation of result delivered locally [
13]. Thus, assessing the performance of commonly used HBV RDTs in routine practice would prompt the rollout of HBV/HIV service integration and support the global effort toward elimination, especially in children known to have a higher risk of vulnerability to infection and rapid disease progression if co-infected.
The objectives of our study were to evaluate the prevalence of HBV in the population of CLHIV, determine factors associated with HBV-infection in these children, and assess the diagnostic performance of two RDTs routinely used for HBV detection.
Discussion
In RLS with a high burden of HIV and HBV, evidence favouring an easy integrated care of HIV/HBV are necessary to scale-up interventions towards meeting the global target of eliminating both HIV and HBV by 2030, especially for children who are generally among the most vulnerable [
7,
13]. Achieving these goals require an understanding of the epidemiological burden, the risk factors involved, and knowledge on reliable HBV RDTs.
From our study participants, the sex distribution was similar (54.2% female, ratio F/M of 5/4),similar to a distribution found in a previous study in the same setting [
13]. Though some studies found men to be slightly higher in proportion [
21‐
23], the reported distribution between girls and boys in our study is within the range of birth rate proportions in the country. This therefore ensures a possible representativeness of our findings to the target population of CLHIV in Cameroon [
24]. With a mean age of 8.7 years old, our findings are concordant with previous reports (mean age of 7.3 ± 3.6 years in Nigeria) in 201 6[
21], thus ensuring comparability. However, age distribution was different from a previous study, due to differences in the primary aims and eligibility conditions (mean age of 26.6 and min-max: 6- 59 months) [
13].
HBV-positivity was relative moderate (2.4%), and was similar to previous findings from the target populations in Cameroon (4.3%) [
13], and in other countries (2% in Ethiopia [
22], 1.6% in Democratic republic of Congo [
25], 1.2% in Tanzania [
26], 2.2% in Malawi [
27], 3.3% in Thailand [
28]). Compared to the highly endemic HBV among adult populations [
15] or pregnant women (17, 5%) [
18], the relatively moderate pediatric HBV prevalence is probably due to the wide paediatric coverage of anti-HBV vaccination in Cameroon [
29]. This moderate prevalence of HBV in children could be partly attributed to maternal ART containing essentially TENLAM-E (77.1%), a regimen known to have molecules with antiviral activity (tenofovir and lamivudine) against HBV infection [
7].
Regarding risk factors of HBV infection among these children, age 10–15 years appears with a higher (5%) but non-significant risk (
p = 0.78) of HBV acquisition compared to younger ones (0%), as confirmed by previous studies [
21,
22,
30]. Though non-significant, the presence of HBV only among in older children with advanced age, in a context of no reported sexual activity, suggests elow risk of HBV mother-to-child transmission and underscores the possibility of horizontal transmission of HBV(unsafe environment). Also, this may reflect the inability to achieve HBsAg clearance due to impaired immunity [
31,
32]. Most importantly, the, hypothesis of low HBV prevalence or ART-tailoring HBV-infection seems to be the most prominent, owing to the fact that co-infected mothers with positive HBeAg, HBsAg and HBV DNA transmitted HBV to their children in Burkina-Faso [
32].
Infants who experienced a vaginal delivery vs. Caesarean section are more at risk of HBV acquisition, as previously reported in China (RR = 2.20, 95% CI 1.02–4.74,
p = 0.04) [
33]. Of relevance, the two cases of positive HBV are from mothers with unknown HBsAg status during pregnancy, another factor significantly associated with HBV-positivity in CLHIV (
p = 0.0097), due to no preventive or prophylactic measure undertaken against HBV during delivery. This calls for a systematic HBV testing of each pregnant woman with unknown HBV status in the labour room and the use of anti-HBV serum for infants born to HBsAg-positive mothers, as currently practised not only the USA [
34].
Children from mothers receiving ART consisting of TENLAM-E appeared to have a slightly lower risk of HBV acquisition. Though not significant, this difference may reflect the ability of the aforementioned regimen (containing tenofovir and lamivudine) to control HBV; this observation merits further assessment in larger studies. Of note, feeding option and antiseptic bath did not have any effect on the risk of HBV acquisition, thus suggesting the effectiveness of protective breastfeeding demonstrated in the prevention of mother to child transmission [
35‐
38], pending confirmatory findings on HBV as the amniotic fluid may contain HBV DNA [
39]. HBV-positivity was also in the frame of no anti-HBV vaccination, supporting the benefit of universal vaccination of children [
40], for ensuring a consistent decline of HBV (i.e. 88.5% decline with HBV vaccine coverage in USA) [
41].
Regarding the diagnostic performance of the two HBV RDTs, DiaSpot®rapid test has excellent intrinsic performance (100% sensitivity, 100% specificity) and extrinsic performance (100% PPV and 100% NPV). However, the HBV 5 in 1 kit revealed poorer intrinsic performance (50% sensitivity, 97.8% specificity) and extrinsic performance (50% PPV and 97.8% NPV). These observations are highly concordant with previous findings on pooled analysis of HBV 5 in 1 kit showing sensitivity and specificity lower than the World Health Organisation (WHO) prequalified RDTs among people living with HIV (pooled sensitivity and specificity of 72.3 and 99.8% respectively) [
42‐
47]. Thus, in a context of limited resources, Diaspot test should be prioritised for HBV testing on an individual living with HIV-infection [
48]. The observed difference in sensitivities of both RDTs could be due to the fact that HBV variants are not effectively recognized by the antibodies coated on the test kit, leading to loss of or weakened epitope binding affinity [
49].
The relative low-rate of HBV could also be due to events of occult HBV infection, generally characterised by a negative HBsAg and positive HBV DNA. This suggests further studies using molecular diagnostic platforms [
4,
50]. Of note, vaccine-escape mutants within the ‘a’ determinant of the S genes are not genuinely recognized by conventional diagnostic tests as the wild type particles [
50]. More so, hypothesis of occult hepatitis B in HIV-positive persons exposed to tenofovir- or lamivudine-containing ART regimens should be taken into consideration while explaining this low HBsAg prevalence and the reduced clinical sensitivity of the kit HBV-5 in 1[
42]. A wider sampling and the use molecular assays would be more informative.
Study limitations
Knowledge on the effective routes of HBV transmission, either vertical or horizontal, could not be delineated in the current study. Also, a thorough performance of both rapid tests under evaluation requires a higher sample size, which in our study was hindered by limited availability of financial resources. Further studies covering these epidemiological and diagnostic aspects would be relevant.
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