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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.

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

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  1. 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

  2. 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….

  3. 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

  4. 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)

  5. 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)

  6. … 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. U.K. guidelines

  22. 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?

  23. Acknowledgements Dr. Monique Andersson TongaiMaponga NafiisahChotun Prof Richard S. Tedder Dr. SamreenIjaz Funding: Harry Crossley Poliomyelitis Research NHLS K-funding Foundation (PRF)

  24. Thank you, baiedankie, enkosikakhulu, vielen Dank!

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