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Optimising early infant diagnosis for HIV to prevent HIV-associated disease and mortality

3rd Pan-African Infectious Diseases Conference Gallagher Convention Centre, Midrand, Johannesburg Wednesday 8 May 2013. Optimising early infant diagnosis for HIV to prevent HIV-associated disease and mortality. Wolfgang Preiser.

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Optimising early infant diagnosis for HIV to prevent HIV-associated disease and mortality

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  1. 3rd Pan-African Infectious Diseases Conference Gallagher Convention Centre, Midrand, Johannesburg Wednesday 8 May 2013 Optimising early infant diagnosis for HIV to prevent HIV-associated disease and mortality Wolfgang Preiser Division of Medical VirologyStellenbosch University / National Health Laboratory Service Tygerberg

  2. 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

  3. Background: PMTCT in South Africa • 2002: provision of sdNVP after court order • 2004: HAART for pregnant women with ≤200 CD4+ cells/μl • 2008: dual prophylaxis with AZT and NVP from 28 weeks’gestation, NVP during labour and for babies within 72 hours of delivery • 2010: lifelong HAART if ≤ 350 CD4+ cells/μl; dual ART from 14 weeks onwards if > 350 CD4+ cells/μl (WHO option A) • Infant prophylaxis daily NVP for 6 weeks for all and continued if breastfeeding and mother not on HAART

  4. Resistance following PMTCT • > 95 % of pregnant women tested • PMTCT regimen: mother: ART or AZT from 34th week + sdNVP;baby: sdNVP plus AZT for 7 days • Transmission rate <5 % • Risk of maternal NVP resistance: 17.1 % • For comparison: sdNVP-only programmes~ 35.7 % (range 25 – 69 %) • Dual PMTCT only later introduced nationwide! van Zyl et al., J MedVirol2008

  5. 2010 Clinical Guidelines: PMTCT (Prevention of Mother-to- Child Transmission)

  6. 2010 Clinical Guidelines: PMTCT (Prevention of Mother-to- Child Transmission)

  7. 2010 Clinical Guidelines: PMTCT (Prevention of Mother-to- Child Transmission)

  8. HIV-exposed infants < 2 months tested by PCR, South Africa Year % HIV-exposed infants % infants tested by PCR tested positive 2008 36.6 9.6 2009 51.8 6.2 2010 59.8 4.4 2011 70.4 2.8 Barron et al., Bull World Health Organ 2013

  9. KwaZulu-Natal Experience • Retrospective analysis of infant HIV PCR results of infants from 2004 to 2012 • Significant decrease (p<0.0001) in proportion of 4 to 8 week old infants testing HIV PCR positive: from 27.5% in 2004 to 2.9% in 2012 • sdNVP (2005 to April 2008): - 48.7% • AZT from 28 weeks plus sdNVP / triple ART if <200 CD4+ cells/μl (May 2008 - April 2010): - 68.4% • AZT from 14 weeks plus sdNVP / triple ART if <350 CD4+cells/μl (May 2010 – Dec. 2012): -89.5% • 10-fold MTCT reduction from 2004 to 2012 Moodley et al., JAIDS ahead of print

  10. Tygerberg Experience • Revised PMTCT guidelines from April 2010: fast-tracked lifelong ART from CD4 count ≤350 cells/μl • Retrospective comparison of year cohorts of all pregnant women initiating HAART at Tygerberg Hospital between Jan 2008 and Dec 2010 • 250 women included and stratified by HAART initiation year • Year N CD4 count gestat. at HAART • 2008 82 155/μl 31 weeks • 2009 71 157/μl 30 weeks • 2010 97 208/μl 25 weeks Van Schalkwyk et al., JAIDS ahead of print

  11. Tygerberg Experience (cont.) • HIV transmission rates:2008 3/65 (4.6%)2009 4/57 (7.0%)2010 0/90 (0.0%) (p=0.021) • Positive impact of new PMTCT program evident • Women <8 weeks on HAART before delivery more likely to transmit than those ≥8 weeks • Longer duration of HAART before delivery associated with less transmission Van Schalkwyk et al., JAIDS ahead of print

  12. So is all fine and nothing to worry about? • HIV MTCT remains major cause of childhood morbidity and mortality • HIV-1 can be transmitted transplacentally, during delivery or through breastfeeding • Advances in PMTCT  majority of transmission now occurs in utero (transplacentally) • 5.7% – 7.5% of pregnancies in the absence of antenatal maternal ART Nielsen-Saines2012; Duri 2010; Johnson 2012

  13. PMTCT Cascade • HIV testing for pregnant women • ART for HIV-positive pregnant women • Retention in care, adherence • Postnatal care for mothers • Infant feeding support • Infant follow-up • Cotrimoxazole for HIV-exposed infants • Infant PCR testing at 6 weeks • Access to HAART for eligible infants • Adherence • 18-month infant HIV antibody testing Best Practices in PMTCT of HIV, SA

  14. Two priorities • Prevention of intra-uterine transmission • Earliest possible treatment of babies with intra-uterine infection

  15. Identify MTCT risk pregnancies • Risk of transplacental infection increased in pregnancies exposed to high maternal viraemia • Acute infection, late-stage infection, not on ART • Pregnancies with elevated transmission risk: • Unbooked (1st presentation when in active labour): Tygerberg prevalence 4.5% • Primary HIV infection during pregnancy • Poor adherence to ART Obimbo2009; Read 2012

  16. Prevention of intra-uterine transmission • Initiate ART early enough, preferably by 20 weeks gestation • Maintain high-level of adherence throughout • Currently high rates of loss to follow-up and poor adherence • Viraemia during pregnancy often remains undetected • Infrequent viral load monitoring • Post-partum adherence to maternal ART and infant NVP also important for preventing breastfeeding transmission Nachega et al. 2012, Centers for Disease Control and Prevention 2013, Van Schalkwyk et al. 2013

  17. How to further reduce MTCT • Improve antenatal ART to reduce transmission • Optimal gestational age for initiating ART: 20 to 24 weeks • Ensure good maternal adherence and retention in care • text-message adherence tools • novel low-cost event recorder adherence device (EVREC) • Diagnose incident infections • Monitor HIV viral load • throughout and close to delivery Horvath et al. 2012; Obimbo 2009; Read 2012

  18. Rapid / simple test devices (RTD) • Level 1 rapid test: • little or no equipment required • little or no laboratory experience needed Result: reactivenon- reactive Control bar Example: Determine Patient bar

  19. Diagnostic markers depend on situation 1000 107 Seroconversion CD4  / l HIV RNAcopies / ml antibodies detectable viral p24 antigen and viral genome (nucleic acid) detectable 500 104 window period viral eclipse 0 101 weeks years 2-3 years Infection time axis 19

  20. 4th generation tests detect p24 antigen in addition to HIV-specific antibodies Laboratory-based or point-of-care

  21. The HIV-infected infant • CHER study (2008): early initiation of ART (median 7 weeks) significant reduction in HIV-associated morbidity and mortality vs. ART initiation based on clinical or immunological parameters • However CHER did not identify in utero (transplacental) infection, known to be associated with rapid progression • In addition, early initiation of ART in the first few weeks of life may drastically reduce the latent HIV-1 reservoir in children Violari et al., N Engl J Med 2008; Persaud 2012

  22. How to improve management of infected infants • Testing of HIV-exposed infants younger than 4-6 weeks ("enhanced early infant diagnosis", WHO) • 76% of babies who test HIV PCR positive at 6 weeks (current standard of care) could already be diagnosed at birth • Subsequent early initiation of ART • Early initiation of ART reduces risk of HIV disease and death WHO 2012; Lilian et al., 2012; Violari et al., 2008

  23. Earliest possible treatment of infected babies • Only possible if diagnosed: "Enhanced early infant diagnosis" • 1st infant HIV test best in labour ward with results available before maternal discharge • Requires point-of-care diagnostic test for HIV-1 RNA, DNA or p24 antigen with a high analytic sensitivity Lilian et al., 2012

  24. Early infant diagnosis now • Dried blood spots (DBS) • Advantages: no need for venepuncture, easy to process, store and ship, once dried, very stable and non-infectious, can be used for nucleic acid and antibody tests

  25. The future: point-of-care testing? • SAMBA (simple amplification-based assay) • Liat(lab-in-a-tube) Lee et al., 2010; Tanriverdiet al. , 2010

  26. UNITAID. HIV/AIDS Diagnostics Market Landscape Semi-Annual Update October 2012. http://www.unitaid.eu

  27. Pilot study • Identify MTCT high-risk pregnancies • Test babies at the following timepoints: • within 4 hours of birth • at 1-2 weeks of age • at 6 weeks of age • at 10-14 weeks of age • Start infants on ART immediately after diagnosis • Follow for 12 months with clinical and laboratory monitoring • Results will inform modifications of current PMTCT programs to implement enhanced early diagnosis

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

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