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3rd Pan-African Infectious Diseases Conference Gallagher Convention Centre, Midrand, Johannesburg Tuesday 7 May 2013. HBV -HIV co-infection in pregnancy: implications for HBV immunisation?. Wolfgang Preiser.

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hbv hiv co infection in pregnancy implications for hbv immunisation

3rd Pan-African Infectious Diseases Conference

Gallagher Convention Centre, Midrand, Johannesburg

Tuesday 7 May 2013

HBV-HIV co-infection in pregnancy: implications for HBV immunisation?

Wolfgang Preiser

Division of Medical VirologyStellenbosch University / National Health Laboratory Service Tygerberg

slide2

Background

  • South Africa introduced HBV vaccine into EPI in April 1995
  • Vaccine administered at 6, 10 and 14 weeks of age, predicated on studies showing:
    • few infected pregnant women are highly infectious (i.e. HBeAg-positive) and consequently ...
    • ... HBV transmission occurs predominantly horizontally during early childhood
    • In contrast E and SE Asia: many HBeAg-positive, HBV transmission vertical (perinatal)
  • These studies were conducted under circumstances very different from today….
slide3

HIV seroprevalence in pregnant women in South Africa: 1990 – 2011

HIV seroprevalence / %

countrywide

National Dept. ofHealth, RSA: 2011 National Antenatal Sentinel HIV & Syphilis Prevalence Survey

slide4

Background

  • HIV-HBV co-infected patients:
    • more likely to be HBeAg-positive
    • higher HBV viral loads
    • less likely to clear infection
    • more likely to reactivate
  • than mono-infected patients
  • HIV-induced immune paresis may increase HBV infectivity in pregnant women
  • Lamivudine (3TC), until recently part of 1st line ART in SA, also active against HBV
    • 1stline ART = monotherapy against HBV
    • 3TC monotherapy induces emergence of resistant HBV (YMDD mutant)
slide5

Could this mean trouble?

  • Yes! Because:
  • HBV infection in HIV-infected pregnant women could be upregulated
  • Maternal co-infection might thus increase the risk of vertical HBV transmission which …
  • … might not be noticed for many years:
    • Symptomatic infection rare at young age but
    • most infected children remain chronically infected and
    • are thus at risk for long-term HBV sequelae (e.g. hepatocellular carcinoma)
slide6

… and possibly even more trouble

  • Drug-induced mutations in polymerase gene might affect overlapping surface gene reading frame

LAM RESISTANCE F158Y E164D 195M/6L/*

ADF RESISTANCE 172*

hepatitis B surface antigen

1 227

Terminal Protein

Spacer

Polymerase / Reverse transcriptase

RNAase H

aa 1 183 349 692 845

5

231

G F A B C D E

...YMDD..

aa 1 LAM RESISTANCE 166 173,(180) 204 344

ADF RESISTANCE (80) 181

slide7

Study aims

  • to determine the prevalence and character of HBV infection in HIV-infected pregnant women:
    • attending Tygerberg Hospital, a large tertiary hospital in Cape Town,
    • participating in the annual HIV antenatal survey in the Western Cape, compared to HIV-uninfected matched controls;
  • to determine whether vertical transmission of HBV is occurring in HIV-exposed infants

Andersson et al., J Acquir Immune DeficSyndr, August 2012;T. Maponga, MSc thesis March 2012; Andersson et al., submitted;

N. Chotun, MSc thesis October 2012

slide8

Study 1:Materials and methods

  • Retrospective cross-sectional study
  • Samples from HIV-positive pregnant women
  • Collected between July 2008 and October 2009
  • Data: age, parity, CD4 count, ART, route of delivery, birth outcome, infant birth weight
  • HBsAg, anti-HBc, HBeAg and anti-HBe tested on AxSYM (Abbott)
  • Confirmation of HBsAg low-positive samples by neutralisation using Murex GE 34/36 assay
  • HBV viral load by in-house real-time PCR (HPA)
  • Sequencing of HBsAg gene and analysis using DNASTAR

Andersson et al., J Acquir Immune DeficSyndr, August 2012

slide9

Study 1:Results

  • 1661 HIV-positive women delivered at TBH between July 2008 – Oct 2009
  • 202 women included in the study:
    • median age 28 years (IQR 24-32)
    • median CD4 count 198 cells/ul (IQR 117-329)
    • 47.5% (96/202) on ART
  • 5.9% (12/202) samples confirmed HBsAg positive
  • 5/12 cases HBeAg positive, 7/12 anti-HBe positive
  • 6/10 cases HBV viral load >104 IU/ml
  • Mostly HBV genotype A
  • No significant surface antigen or polymerase mutations detected

Andersson et al., JAIDS, August 2012

slide10

Study 1:Discussion and conclusions

  • Strengths: clinical + virological data
  • Limitations: small sample size; bias
  • No significant association between CD4 count and HBsAg status (P = 0.36), HBV viral load (P = 0.34) or HBeAg (P = 0.21) status
  • 7/12 HBsAg positives on ART, 5/12 unbooked
  • Maternal HBeAg positivity likely associated with increased risk of vertical transmission leading to persistent infection in the infant
  • High maternal HBV viral load likely associated with increased risk of MTCT

Andersson et al., J Acquir Immune DeficSyndr, August 2012

slide11

Study 2:Materials and methods

  • Retrospective, cross-sectional, unlinked anonymous study
  • Residual samples
  • Pregnant women from the Western Cape 2008 National HIV and Syphilis Antenatal Survey
  • HIV-infected women age- and race-matched to HIV-uninfected women
  • Samples tested for markers of HBV infection, incl. HBV viral load and genotype
  • HBsAg phenotype determined by Luminex
  • Samples from HIV-infected women tested for antiretroviral drug residues by mass spectrometry

T. Maponga, MSc thesis March 2012; Andersson et al., submitted

slide12

Study 2:Results

  • All 1543 HIV-infected women age- and race-matched to randomly selected HIV-uninfected women
  • Median age (26.8 and 26 years), parity and education similar in both groups
  • Significant association between HBsAg positivity and lower educational grade (p=0.03), but not between HBsAg status and age (p=0.52) or parity (p=0.27)

T. Maponga, MSc thesis March 2012; Andersson et al., submitted

slide13

Study 2:Results

  • HBV viral loads >105 in 21% (11/53) of HIV-coinfected and in 11% (5/45) of HIV-uninfected women
  • mean HBV viral loads in
  • HBeAg positive HBeAg negative
slide14

Study 2:Results

  • 92.7% (64/69) genotype A, 7.3% (5/69) genotype D
  • 3/50 HIV-HBV co-infected samples (1.5 %) antiretroviral drug residues: 2 x lamivudine + nevirapine, 1 x lamivudine + lopinavir
  • Sub-samples: anti-HBc in absence of detectable HBsAg positive in 68/159 (42.2%) of HIV-infected vs. 42/153 (27.5%) of HIV-uninfected women

T. Maponga, MSc thesis March 2012; Andersson et al., submitted

slide15

Study 2:Discussion and conclusions

  • Little difference in HBsAg prevalence in HIV-infected vs. HIV-uninfected women
    • as shown elsewhere in South Africa, Côte d’Ivoire, Malawi and Tanzania
  • Evidence of loss of HBV control in HIV-coinfected women: trend toward higher HBV viral loads
  • Higher proportion than expected of all HBV-infected mothers HBeAg-seropositive (17.5%)
    • contrast with Oshitani et al. (1995) who found significant difference in HBeAg prevalence in HIV-infected (25%) vs. HIV-uninfected women (12.3%)

T. Maponga, MSc thesis March 2012; Andersson et al., submitted

slide16

Study 3:Materials and methods

  • 1000 HIV-exposed infants
  • Residual routine HIV PCR samples
  • Median age 46 days (range 0 – 540), 48.7% male
  • 6.1% HIV-infected
  • HBsAg, anti-HBc (Abbott AxSYM), HBsAg confirm. (Murex), HBeAg, anti-HBe (DiaSorin)
  • HBV viral load (in-house real-time PCR), sequencing and sequence analysis
  • HBsAg and/or HBV DNA positives considered true positives:
    • mother-infant pairs followed up through clinics
    • blood samples taken from mother and baby

N. Chotun, MSc thesis October 2012

slide17

Study 3:Results

  • At screening:
  • 4 male HIV-uninfected infants found HBV-infected:
    • 3 HBsAg positive and HBV-DNA positive
    • 1 positive for HBV-DNA only (occult infection)
    • HBV viral loads: 2 high (104 and 107 IU/ml), 2 low (102IU/ml)
  • All 4 had been vaccinated against HBV

N. Chotun, MSc thesis October 2012

slide18

Study 3:Results

  • At follow-up:
  • 2 infants positive for all tested HBV markers and with high viral loads >108 IU/ml
  • 1 infant with low viral load had cleared the infection, now negative for all tested markers
  • 1 infant with occult HBV infection lost to follow-up
  • Four mothers:
  • All positive for HBsAg and HBeAg
  • 3 high (107 IU/ml) and 1 low viral load (103 IU/ml)
  • All CD4 counts >350/μl
  • None on tenofovir or lamivudine

N. Chotun, MSc thesis October 2012

slide19

Study 3:Results

  • 2 infant, 4 maternal HBV DNA positive samples sequenced at follow-up
  • All subgenotype A1
  • No drug resistance mutations
  • 2 transmission events proven

N. Chotun, MSc thesis October 2012

slide20

Study 3:Discussion and conclusions

  • Again shown persistently infected highly infectious mothers
  • Shown vertical transmission of HBV
  • More studies needed to determine exposure and rate of transmission and infection in HIV-unexposed and HIV-infected infants
  • Screen pregnant women at booking for HBsAg?
    • Using rapid test?
  • Administer HBV vaccine within 24 hours of delivery?
    • What about HBIg?

N. Chotun, MSc thesis October 2012

slide22

Open questions

  • Should routine infant immunisationagainst HBV be modified (e.g. 1stdose at birth)?
  • What is the prevalence of HBV infection in HIV-infected children (many of whom were born before ART rollout and pre-tenofovir)?
  • Is there evidence of vertical transmission of HBV in HIV-exposed children in other parts of sub-Saharan Africa with higher HBV prevalences?
slide23

Acknowledgements

Dr. Monique Andersson

TongaiMaponga

NafiisahChotun

Prof Richard S. Tedder

Dr. SamreenIjaz

Funding:

Harry Crossley Poliomyelitis Research NHLS K-funding Foundation (PRF)