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Impact of Highly Active Antiretroviral Therapy on Chronic Hepatitis B Serological Markers among Senegalese HIV Co-infected Children

Impact of Highly Active Antiretroviral Therapy on Chronic Hepatitis B Serological Markers among Senegalese HIV Co-infected Children

Abou Ba, MD;1 Fatou K Ndiaye, MD;1 Yaay J Djeng;1 Cecile Cames, MD;2 Aminata Diack, MD;1 Ousmane N’diaye, MD1

1Centre Hospitalier National d’Enfants Albert Royer, BP: 25755-Fann, Dakar, Senegal; 2Institut de Recherche pour le Développement (IRD), UMI233 IRD, INSERM U1175, Université de Montpellier, Montpellier, France.

Corresponding author email: drabouba.ab@gmail.com

ABSTRACT

Background: Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) causes complex interactions.The aim of this study was to evaluate the seroprevalence and HBV evolution among HIV coinfected children receiving highly active antiretroviral therapy (HAART).

Methods: A descriptive cross-sectional study was carried out among 252 HIV infected children enrolled in the Hôpital d’enfants Albert Royer, Dakar, Senegal, from April 2013 to March 2015. Clinical characteristics, immuno-virological status, alanine aminotransferase (ALT) levels, and HBV serological marker were taken from the patients’ medical records.

Results: Overall, 7 children were HBsAg positive with a determinate prevalence rate of 2.8%. Median age at HIV diagnosis was 3.5 years (1.3-14.4 years). According to World Health Organization (WHO) staging, 40.1% of children were stage 4 and 25.8% were stage 3. Of the 7 HIV/HBV-co-infected children, 6 (86%) received lamivudine alone at initiation of treatment, and only one child received tenofovir associated with emtricitabine. Overall median HAART duration treatment including lamivudine alone or tenofovir+lamivudine (or emtricitabine) was 7.7 years (3.3-11.3). Only the two children (29%) receiving lamivudine during follow-up had high HBV DNA load despite having good immuno-virological status. Suppression of HBV DNA replication was achieved in 5 (71.4%) of 7 children.

Conclusion and Global Health Implication: HIV/HBV coinfection prevalence was low in our study. HBsAg and HBeAg loss were low while suppression of HBV DNA replication was still higher on tenofovir. Screening and monitoring HBV infection among all HIV infected children are required to direct treatment in order to improve children HBV/HIV coinfected outcome.

Key words: HBV infection • HIV infection • Children • antiretroviral therapy • Serological markers • Serprvalence • Immunology • Virology • Senegal

Copyright © 2019 Ba et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Ba et al. International Journal of Maternal and Child Health and AIDS (2019), Vol. 8, No. 2, 131-137

1. Introduction

1.1. Background of the Study

The global prevalence of hepatitis B virus (HBV) infection in people infected with human immunodeficiency virus (HIV) is 7.4% and about 1% of people infected with HB V (2. 7 million people) are also infected with HIV.1 In sub-Saharan Africa (SSA), HBV, and HIV infections are major global health problems, with over two-third of the total of 34 million people with HIV, and at least 8% of the population, chronically hepatitis B infected.2 Overall, between 40% to 60% of seropositive people are likely to be HBV infected and the prevalence estimation of chronic hepatitis B defined as persistence of hepatitis B surface antigen (HBsAg) for > 6 months among HIV infected is higher, between 15% to 20% reaching up to 34% of all the seropositive people, with higher

to 2015. The global prevalence of HIV infection remains stable with 0.5% in the general population.8 In Senegal, data are scarce in the pediatric HIV-HBV co-infectedchildren.

1.2. Objectives of the Study

The objective of this study was to investigate the prevalence of HBV infection in children with HIV infection, and to describe the HBV serological markers and HBV DNA among HIV-infected children and adolescent receiving highly active antiviral therapy (HAART).We hypothesized that there would be a significant association between HAART and evolution of chronic hepatitis B serological markers.

2. Methods

2.1. Study Setting

Full details of the rationale for the Maggsen ANRS Pediatric Cohort Study and methods are provided elsewhere.9 Briefly, the cohort included HIV-1-infected children aged two to < 16 years under active follow- up in two Senegalese HIV clinics from April 2013 to March 2015. Enrolled children were followed-up until March 2016. Children were seen every three months for a complete clinical assessment, and every six months for laboratory monitoring/fasting blood analyses. The present cross-sectional analysis uniquely included patients in the Albert Royer University Teaching Health Center (CHNEAR). This hospital is of the highest level with medical and surgical wards, and a large HIV infected children’s care and research unit for our country. Most children of all ages presenting with severe diseases are referred to CHNEAR by secondary or peripheral health facilities as well as by other hospitals of the same standing category (level III).

2.2. Data Collection and Analysis

Personal and clinical data as well as preliminary information regarding biological parameters include hepatitis b surface antigen (HBsAg), CD4+ lymphocyte counts, alanine amino transferase (ALAT), and plasma HIV RNA levels were extracted from the cohort medical records. Serological markers of HBV-infection (HBsAg), hepatitis B e antigen (HBeAg), anti-hepatitis B surface (HBs) antibody, and quantitative analysis of HBV-DNA were performed.

rates in West African and Southern African cohorts.

2,3

These viruses share common ways of transmission

in infants and children as a result of mother-to-child

transmission due to inadequate diagnosis of the

mother and, hence, absence of prophylaxis of blood-

borne viruses in pregnancy and the postpartum

period.
causes complex interactions. The impact of HBV on HIV natural history is less certain, although it is believed that HBV infection increases susceptibility to ART-related liver toxicity, impairs CD4 recovery, accelerates immunologic progression, and increases

the morbidity and mortality of HI V-infected patients. The natural history of HBV infection is modified by HIV infection. The course of chronic HBV is more aggressive, which can result in higher rates of chronic HB V, reduction of HBs Ag seroconversion, higher levels of HBV replication and often reactivation (HBeAg, and HBV DNA detection), accelerated cirrhosis, and increased likelihood of developing hepatocellular carcinoma, and decreased treatment response comparedwithpersonswithoutHIVcoinfection.4 Among HI V-infected patients, several different HB V serologicalpatternsmaybeencounteredbecauseof the patient’s immunosuppression and increased risk of exposure to HB V. 7 In Senegal, a country with a high chronic hepatitis B endemicity, 85% of people have been exposed to HBV, the prevalence of chronic hepatitis decreased from 17% to 11% between 1999

4-Coinfection with HI V and HB V viruses

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5,6

Clinical cases were presented and described using descriptive analysis. Median are presented with their minimum and maximum. Statistical analyses were performed using R studio version 3.5.0.10 Prevalence of Hepatitis B co-infection was expressed as a proportion. Ethics clearance for the MAGGSEN ANRS cohort protocol was given by the Ethics and Regulatory Committee and the Ministry of Health in Senegal. All parents or surrogate caretakers provided written informed consent.

3. Results

3.1. Sociodemographic Characterisitcs

From April 2013 to March 2015, a total of 220 HIV- infected children and adolescent were enrolled in the cohort study and 32 additional eligible children were considered so that the present analysis included 252 participants. Among these, 108 (42.9%) were boys. Median age at diagnosis was 9.5 years (6.5-12.5). They consisted of 87 urban, 140 suburban and 25 rural residents. According to WHO disease staging, 40% of children were stage 4 and 26% were at stage 3. Overall, the prevalence rate of HBV-HIV co- infection was 2.8% (n= 7, 4 boys and 3 girls). Baseline characteristics of 7 HBV-HIV co-infected children are summarized in Table 1.

3. 2. Biological and Chronic Hepatitis B Serological Markers at Last Follow Up

From the baseline CD4 count, median CD4 was 599 cell/mm3 (484-1393). Median ALT was 27UI/L (24-44). One out of three children who had HBeAg screening was positive at enrollment and two was negative. None had DNA HBV measurement at inclusion. Overall median H A ART duration treatment including lamivudine alone or tenofovir+lamivudine (or emtricitabine) was 7. 7 years (3. 3-11. 3). At any time of follow-up two children presented high ALT titer at 1. 5 normal limits, which spontaneously normalized. Lab tests at last follow-up are summarized in Table 2. Five of the HBsAg positive subjects had detectable HBe Ag a marker for HB V replication. Of them one was negative at inclusion. Five of 7 patients achieved undetectable load HBV titers at least once during follow-up after tenofovir-based treatment was initiated. Only two children receiving lamivudine at the

time of the study had HB V DN A replication with high viral load and positive to HBs Ag and HBe Ag. However, they had good immuno-virological status with CD4 levels above normal limits and DN A HI V undetectable. HBsAglossoccurredin1children(case1)(14.3%).Of the two children HBeAg negative at inclusion (case 1 and case 3), second (case 3) became HBeAg positive. Suppressed HB V DN A replication was achieved in 5 of the 7 children who received tenofovir associated with lamivudine or emtricitabine. The 2 children received lamivudine alone were replicative with high HBV DNA load> 200.000IU/mL.

4. Discussion

4.1. Discussion

This study found that chronic HBV seroprevalence among HI V infected children is low with less HBs Ag and HBe Ag loss and higher suppression of DN A HB V viral replication. This prevalence falls within the range of 1. 2 % to 6. 02% reported in the literature. 11, 12, 13 In Senegal, this study on pediatric HIV infection has remained the first one so far to our knowledge. This prevalence in HIV infected children is similar to those reported in children born to mothers HBV infected (3%).14 Moreover, it is much lower than the earlier HBsAg prevalence rates reported in Ivory Coast (12.1%) and Burkina Faso (28.2%) HIV infected children. 15, 16 This low prevalence in HI V infected children is surprising because HBV prevalence is higher in Senegalese general population (11%) and all children received first dose of HBV immunization at 6 week of age.8 Furthermore, most of transmission occurring during perinatal/neonatal period with a higher risk to develop chronic infection (80 to 90%). 8, 17, 18 Frequent HBe Ag positive with high HB V DN A levels in HI V-infected have been reported in prior studies. 15, 19, 20 In the literature, severe immune suppression, defined by higher mean HI V RN A and lower CD4%, was associated with higher detectable HB V DN A levels in children. These children were more likely to be HBsAg positive suggesting that children with more active HIV disease have less immune control of HB V. 18 This high rate of HB V persistence and viral HBV replication is classically reported secondary to formation of stable episomal cccDN A, and integrated HB V. Furthermore, in HB V

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HAART on Chronic Hepatitis B

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Table 1: Baseline characteristics of children in the study

Patients

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

Case 7

Sex

Male 15.7

Male 8.3

Female 18.7

Male 13.3

Female 4.4

Female 9.1

Male 8.7

Age at time of the study (years)

Age at HIV testing (years)

Residence WHOstaging HBeAg HBeAb

urban
4 negative negative 28

rural
4 unknow unknow 27 1352 75700

rural
4 negative unknow 24

urban
3 positive unknow 24

urban
2
unknow unknow
26
1334 undetectable

rural
4
unknow unknow
35
1393 undetectable

urban
1 unknow unknow 44

ALT (IU/L)
CD4 count (cells/μL)

526 undetectable

487 undetectable

484 226000

599 undetectable

HIV-1 RNA viral load

Age at ART initiation (years)

14.7 TDF+FTC+EFA No switch TDF+F TC+EFA

2.6 AZT+3TC+NVP 18.7
TDF+3 TC+LVP/R

8.11 AZT+3TC+EFA 16.7
TDF+F TC+EF V

9.5 ABC+3TC+EFA 16.11
TDF+F TC+EF V

1.3 AZT+3TC+NVP No switch
AZ T+3 TC+N VP

2.1 AZT+3TC+NVP 4.3
ABC+3 TC+LP V

3.4 AZT+3TC+NVP 5.5
TDF+F TC+EF V

ART regimen at initiation

Age at ART switch (years)

Current ART

regimen

WHO: World Health Organization, HBeAg: Hepatitis B e-antigen, HBeAb: Hepatitis B e antibodies, ALT: alanine aminotransferase, ART: antiretroviral therapy, TDF: tenofovir disoproxil fumarate, FTC: emtricitabine, EFA: efavirenz, 3TC : lamivudine , ABC : abacavir , NVP : nevirapine.

Table 2: Laboratory tests at last follow up clinical visit

HAART on Chronic Hepatitis B

Patients

 

Case 1

 

Case 2

 

Case 3

 

Case 4

 

Case 5

 

Case 6

 

Case 7

CD4 count (cells/μL)

HIV-1 RNA viral load (copies/mL)

HbsAg
HBeAg DNA-HBV (IU/ml) ALT

526 727 860
74 91 undetectable

135 239482

positive positive negative 25

1384 undetectable

positive positive 118298224 26

997 559 undetectable undetectable

positive positive positive positive 4246530 negative 68 26

negative positive negative negative negative negative 25 12

positive positive negative 22

infection, HBsAg is produced in large quantities and is generally considered to inhibit adaptive immunity and effective production of HBsAb, which is required for long term HB V control. 21, 22 Among HI V-infected patients, several different HB V serological patterns may be encountered because of the patient’s immunosuppression and increased risk of exposure to HBV. For example, presence of isolated antibody to hepatitis B core antigen (anti-HBc) and persistent chronic HBs antigenemia have been observed more often in HIV-infected patients because of impaired host immunity against HB V. 7 In study conducted in Ivory Coast, 26% of the sample tested showed an unusual pattern of HBe Ag/anti-HBe Ag positive/HB V DNA positive, indicating that development of anti- HBe Ag did not result in control of viral replication. 23 The WHO guideline recommends H A ART containing at least two drugs effective against HB V for all HI V- HB V co-infected patients irrespective of disease stage or CD4 count. 24 In HB V/HI V-coinfected adults, adolescents and children aged of 12 years or more, the nucleos(t)tide analogues (NAs) which have a high barrier to drug resistance (tenofovir or entecavir) are recommended.25 Due to the high prevalence of HB V-lamivudine resistance, HB V screening prior to initiation of ART is recommended to direct the selection of an appropriate optimal ART regimen for coinfected children. 15 In Senegal, current ART guidelines recommend zidovudine+lamivudine+nevirapine or efavirenz for children younger than 12 years, and tenofovir+lamivudine or emtricitabine+efavirenz for others older than 12 years old. While there are emerging data to suggest that antiretroviral regimens that contain drugs active against HB V infection (e. g. , tenofovir, emtricitabine, and lamivudine) may modify the natural history of HB V disease in HI V-

infected individuals by slowing disease progression and, in some patients, leading to seroconversion, additional long-term follow-up is needed to evaluate the effect of dual treatment. 21 However, Tenofovir-containing first-line H A ART, which has potent anti-HB V activity, is preferred for HIV-HBV coinfection because, it has been successful in achieving sustained HBV suppression in both treatment-naive and lamivudine- resistant HI V-HB V-co-infected individuals. 26 Early and effective tenofovir based ART, reduce risk of death among coinfected children underling the need for implementing universal HBV testing and prompt ART treatment. In this study, HBs Ag and HBe Ag loss and suppression HB V DN A replication were comparable with other results. In a systematic review and meta- analysis, Tenofovir was reported to have achieved high rates of suppression HB V DN A replication (85. 6%) at three years of treatment, and HBe Ag loss (86. 6% and 75. 0%) for HBe Ag positive and negative patients respectively.27 In a prospective study in China, lamivudine monotherapy-based c ART was efficient for HB V treatment when baseline HB V DN A <20. 000IU/ mL with HB V DN A suppression rate at 96. 8%, slightly lower than tenofovir (98. 0%). However, when DN A HB V was >20. 000IU/mL, tenofovir+lamivudine were associated with higher suppression rates (72.5%) than L AMI VUDINE alone (34. 5%). 28 Additionally, the small sample of children in our study did not allow us to analyze possible associations between the evolution of serological markers and the clinical and laboratory variables described. Although, tenofovir is associated with viral replication DN A HB V suppression.

4.2. Limitations

This study has some limitations. It was a cross- sectional study and conducted in just one hospital in

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  • Prevalence of HIV/HBV co-infection is low among Senegalese children

  • Screening and monitoring of HBV in HIV infected should be done systematically for choose HBV-active HIV ART [3TC and/or TDF]

  • Close monitoring should be performed in HIV/ HBV co-infected children.

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Dakar with a limited number of co-infected children. Data were sparse from the first visit to follow-up visits making it difficult to draw many conclusions about the effects of therapy delivered to the children. For further studies among chronic hepatitis b co-infected children, we recommend close monitoring of children’s immuno-virological status, liver enzyme and serological hepatitis b markers.

5. Conclusion and Global Health Implications

This study has demonstrated that overall seroprevalence of hepatitis b in HI V infected Senegalese children was low. HBsAg and HBeAg loss was low while suppression of HBV DNA replication was higher for children who received TENOFOVIR without liver toxicity was low demonstrating a positive evolution. There is therefore the need to ensure universal monitoring of HBV in HIV infected children as part of the national HIV program toward countrywide which would improve their quality of life.

Compliance with Ethical Standards

Conflicts of Interest: The authors declare that they have no conflicts of interest. Financial Disclosure: The authors declare that they have no financial disclosure. Funding/Support: Financial support of the MAGGSEN cohort study was provided by Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS)- France Ethics Approval: Ethics clearance for the MAGGSEN ANRS cohort protocol was given by the Ethics and Regulatory Committee and the Ministry of Health in Senegal. All parents or surrogate caretakers provided written informed consent. The cohort was registered with Clinical Trials. gov: NC T01771562.

acknowledge all the participating children and their caretakers. They sincerely thanks Siby Tidiane, MD (Bio 24) and Ousseynou Ndiaye, PhD (Centre régional de recherche et de formation à la prise en charge clinique - CRCF), Dakar, Senegal, in charge of the laboratory analyses.

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Acknowledgements: The authors Key Messages

gratefully

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