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Up Date Prevention of Mother to child Transmission of HIV and plan for CURE : A Global Challenge

Up Date Prevention of Mother to child Transmission of HIV and plan for CURE : A Global Challenge . Yvonne Bryson MD Distinguished Professor and Chief Global pediatric Infectious Disease David Geffen School of medicine at UCLA Mattel Children ’ s Hospital. Perinatal HIV-1 Infection.

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Up Date Prevention of Mother to child Transmission of HIV and plan for CURE : A Global Challenge

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  1. Up Date Prevention of Mother to child Transmission of HIV and plan for CURE : A Global Challenge Yvonne Bryson MD Distinguished Professor and Chief Global pediatric Infectious Disease David Geffen School of medicine at UCLA Mattel Children’s Hospital

  2. Perinatal HIV-1 Infection • The majority of pediatric HIV infection occurs from maternal-fetal transmission • Transmission rates vary by population and geographic area 13% Europe 40% Africa 25%-30% USA overall without treatment • Heterosexual transmission to women is now the most common route • As number of women HIV-infected increases perinatal infection will also increase

  3. PERINATAL HIV TRANSMISSION • Major advances • Increased knowledge of risk factors associated with transmission • Reduction of perinatal transmission by 67% by use of ZDV mother / infant (ACTG 076) • Shorten course ZDV in mother. Thai study 50% reduction. • Simple cheap regimens NEV in mother /infant IP & PP HIVNET 012 reduce transmission by 50% • Multi drug regimens reduce transmission to < 2% • Recent efficacy of 6week and 6 month NVP prophylaxis in infants reduces BFT PROMISE study • Post exposure prophylaxis high risk infants with two or three ARV reduces intrapartum transmission by 50% 040 NEJM 2012 • World wide implications

  4. Estimated AIDS Prevalence among Women in the United States and Perinatally Acquired AIDS Cases by Quarter-Year, 1985 - 1999 160 300 Heterosexual contact Pediatric cases IDU 140 250 120 200 100 Number of Cases Number of Cases (thousands) 80 150 60 100 40 50 20 0 0 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 Quarter-Year

  5. Global Challenges • Perinatal HIV transmission - major problem worldwide. • Approaches must be feasible, effective, and affordable. • Approaches may differ by country and population. • Development of an effective HIV vaccine is still the major hope and goal for the future. • Interim plans are focused on reduction of breast feeding transmission and child hood mortality in infants who are weaned.

  6. Perinatal HIV-1: What Do We Know Now? In Utero Intrapartum • HIV in fetal tissues • Early fetal loss • Virus/immunological patterns • Discordant twin • C-section/blood exposure • Ruptured membranes Breast Feeding Infected Live Born Infants • HIV in milk • Seroconverting mothers • Established inf. 14% • 30 - 50% positive virus birth • 50 - 70% negative virus birth - presumed intrapartum

  7. In Utero Transmission Maternal virus load cell-associated, cell-free  Neutralizing antibody  CD4 count / cell-mediated immunity  Virus phenotype / tropism  Placental breaks  Maternal-fetal transfusion  HIV or other infection of placenta  Fetal loss 

  8. Intrapartum Transmission Maternal virus load u - blood (cell-associated, cell-free) - cervicovaginal secretions Duration of ruptured membranes u Infant exposure to blood u - mucous membranes, swallowing Delivery mode-vaginal vs. c-section u Trauma u Maternal-fetal transfusion u Placenta - abruption u - chorioamnionitis - co-infections

  9. Breastfeeding Transmission • Breakdown of skin barrier • Intercurrent infections (mastitis) • Maternal plasma/milk viral load • Primary infection in mother • Mixed feedings • Early introduction of solids • Duration of breastfeeding

  10. HIV RNA levels in the plasma of transmitting and non-transmitting mothers at delivery (Dickover et al.) 1X106 1X105 Median HIV RNA copies / mL ZDV 1X104 No ZDV 1X103 1X102 N o n - t r a n s m i t t e r s T r a n s m i t t e r s

  11. Interruption of perinatalHIV transmission Intrauterine Intrapartum Post-partum vaccines antiretroviral therapy immune modulation vaccines antiretroviral therapy immune modulation C-section vaginal washing breast feeding 3 6 months Gestation Labour and Delivery 2 years

  12. Potential Approaches to Intervention of Vertical HIV-1 Transmission • Specific HIV immunoglobulin • HIVIG, monoclonals (Combinations) • Other - immune modulators • HIV-1 Vaccine • Maternal immunization • infant • Combinations of above Antiretrovirals Immune Based Therapy • during gestation • intrapartum • postpartum - infant BF mother (HAART) Local Approaches • vaginal washing • topical or oral treatment of infant • mode of delivery

  13. 076 Protocol Infusion Zidovudine or placebo Oral Oral Zidovudine or placebo Zidovudine or placebo Mother Infant Infection outcome 16 weeks 6 weeks Gestation Labour Post delivery

  14. RESULTS PACTG 076 PLACEBO ZDV • PERINATAL HIV 25% 8% TRANSMISSION P<.0001 (Conner et al, NEJM ‘94)

  15. HIVNET 012 STUDY %PERINATAL TRANSMISSION INFANT AGE DX ZDV NEV P VALUE AT BIRTH 10.4 8.2 .35 6-8 WEEKS 21.3 11.9 .0027 14-16 WEEKS 25.1 13.1 .0006 • EFFICACY OF NEV vs ZDV WAS 47% UP TO 16 WEEKS OF AGE

  16. Delivery Maternal Plasma HIV-1 RNA Levels at and Antiretroviral use during Pregnancy: Impact on Perinatal Transmission 51.4 27.8 60 17.2 11.3 29.4 None 50 0 20.4 20 12.5 Rates per 100 40 ZDV Mono (<4/94) 0 19 14.7 30 7.2 6.1 ZDV Mono (>4/94) 0 20 4.5 Multi-ART 2.6 1.8 0 0 10 HAART 2.4 1.7 0 0 0 0 >100000 >3000-40000 Undetectable (<400) Maternal Plasma HIV-1 RNA

  17. Perinatal guidelines vary by Resource/country • Effective, Affordable---- Moving Target • Short course NVP mother / infant ( problems NVP resistance in mother and infant -Doesn’t reduce in utero HIV • Use of other drugs Truvada/ ARV tail mother • ZDV plus mother/ infant NVP used in Thailand • Prevention of breast feeding transmission vs infant survival early weaning--- bottle feeding-- NVP as prophylaxis infant-HAART in breast feeding mother INFANT prophylaxis-- ZDV 6 weeks developed countries / NVP 6 weeks in infants breast feeding countries. Results of 040 –use of 2 /3 drugs in infant if mother not RX

  18. Problems with Universal HAART Solely for PMTCT in Developing Countries • Complexity – issues of difficulty in implementation and problems with adherence (and potential resistance) • Limited resources and cost – can’t provide ART to patients who need for own health • Limited formulary, with choice of regimens limited by toxicity (NVP toxicity with CD4 >250, lactic acidosis); need to use PI regimen (or triple NRTI?) • Mixed data on pregnancy outcome and HAART: preterm [Europe], LBW [Ivory Coast] • Maternal health (issues of start-stop HAART)

  19. -- Pattern of Infant Feeding and Postnatal MTCT-- Risk Factors for Postnatal MTCT

  20. MTCT Risk in Women Not Meeting WHO Criteria*for ART Who Receive Short-Course ARV ProphylaxisCote d’IvoireTrials Data, F. Dabis 6/05 Short AZT AZT+ AZT/3TC+HAART SD NVP SD NVP * Does not Meet WHO criteria if: WHO Stage 3 and CD4 >350 or Stage 1-2 and CD4 >200

  21. MTCT Risk in Women Meeting WHO Criteria* for ART Who Receive HAARTCote d’IvoireTrials Data, F. Dabis 6/05 2.4% Short AZTAZT+AZT/3TC+HAART SD NVPSD NVP * WHO Criteria for ART: WHO Stage 4 or Stage 3 and CD4<350 or Stage 1-2 and CD4<200

  22. Both Maternal and InfantARV Prophylaxis StrategiesPresume Early Weaning of the Infant to Avoid Continued HIV Exposure Post Prophylaxis: How Safe is Early Weaning?

  23. How to Optimize Infant SurvivalPost Weaning? Wendy Hammond/AED Linkages

  24. Breastfeeding Protects Against both Diarrhea Respiratory-Associated Mortality in 1st Year of Life WHO Collaborative Study Team, Lancet 2000 Pooled Odds Ratio for Mortality if Not Breastfeeding DD-diarrheal mortality RD- respiratory mortality

  25. PROMISE STUDY Promoting maternal and infant survival everywhere Over arching study proposed by IMPAACT network to answer important questions In PMTC and infant and maternal health Maternal HAART vs ZDV plus NVP ? MATERNAL HAART VS INFANT NVP FOR PREVENTION OF BREAST FEEDING TRANSMISSION Regimen for late presenters? Co trimoxazole in weaning babies vs enhanced hygeine Prevention of morbidity/mortality in infants Should mother stop HAART postpartum or post breast feeding if CD4Tcells >350

  26. PROMISE STUDY • APPROVED as PART OF IMPAACT NIH network of 67 clinical trial sites Globally Each country will participate in different parts depending if breast feeding or standard of HAART in mother now started 2010 • USA • AFRICA: 7 countries • India • Thailand • South America: Brazil, Argentina

  27. New challenges • Reduce in utero transmission further • Monitoring of HIV viral load – use of additional arv to reduce viral load asap- integrase inhibitor. Other tenofoviretc • identify seroconverting women in pregnancy and while breastfeeding - repeat rapid testing during gestation at delivery? Post partum • Newer point of care tests for P24 antigen • Identify women at highest risk of transmission?

  28. Challenge PMTC HIV developed/ resource poor countries • US and others: continued vigilance • HIV drug resistance • Identification monitoring of HIV + pregnant women • Support of Rx /prophylaxis in women and infants- follow up infants • Translation of science into practice • Politics • Need of a preventive vaccine/ Path to a CURE

  29. Assessment of functional CUREin HIV infected neonates • An ounce of prevention is worth a pound of CURE • Effective ARV prophylaxis given at the time of birth or during early breastfeeding can prevent HIV infection in HIV exposed neonates/infants • ARV prophylaxis during pregnancy can reduce both in utero and intrapartum MTCT of HIV

  30. CURE HIV? • Why neonates? • MTCT of HIV can occur in utero with the majority of transmission occurring from 28 weeks to delivery in live born infants – • 6- 8 % of infected infants of untreated HIV positive pregnant women These infants have HIV virus present at birth ( DNA PCR, RNA PCR and culture) • % of IP exposed infants also aquire HIV 0-4 weeks) BF 0-12 • It is unknown the level of integrated/vs.... unintegrated HIV DNA at birth or onset of infection • Early ARV treatment infected infants <3months seronegative normal immune status – reduced HIV reservoirs Persaud /Luzariaga

  31. 124LB Phase III Randomized Trial of the Safety and Efficacy of Three Neonatal Antiretroviral Regimens for the Prevention of Intrapartum HIV-1 Transmission NICHD HPTN 040/ PACTG 1043 Karin Nielsen-Saines*, D. Heather Watts, Valdilea G. Veloso, Yvonne J. Bryson, Esau C. Joao, Jose Henrique Pilotto, Glenda Gray, Gerhard Theron, James Bethel, Lynne Mofenson for the NICHD/HPTN 040 Study Group CROI 2011 Boston March, 2011

  32. In Utero and Intrapartum HIV Transmission % based on KM curves Statistical comparisons between single and multiple ARV arms : Hochberg’s modified Bonferroni approach

  33. Timing of HIV Infection for Infants Testing Positive After Birth by Study Treatment Arm (Intrapartum Only) HIV Transmission Rate Study week

  34. 040 VL of in-utero- and intrapartum-infected infants separated by treatment arm.

  35. The MISSISSIPPI baby CURE • Infant born of HIV + mother diagnosed at delivery in rural Mississippi • Infant HIV PCR done and started on ARVs at 30hr of age • 4 positive HIV DNA/RNA PCR, initial HIV RNA 19,000 at birth became negative by 20 days • Treated with HAART for 15 months Mother stopped RX • At 23 months tested by HIV DNA /RNA PCR negative

  36. Mississippi baby Cure • Pediatrician called Luzariaga at U Mass /Persaud • Negative antibody, negative HIV DNA/RNA PCR • Negative by ultrasensitive methods and latent CD4 Tcell replication competent assay • Now 30months old well and HIV negative off RX Fits definition for functional CURE

  37. Proposed Study: Early Intensive Treatment of High Risk HIV Exposed/Infected Infants to Assess a “functional HIV cure” • Hypothesis: Early at birth Intensive( multiple targeted including integrase inhibitor) ARV therapy/prophylaxis in HIV infected/exposed infants will significantly alter primary acute infection , reduce the latent viral reservoirs,preserve immune function and potentially result in cure or “functional cure”

  38. Nature medicine June 27 2013

  39. Step wise Pilot =Best shot • Start with current drugs now( Mississippi baby) • Then use most potent multi-class ARV including integrase inhibitor as early( at birth within 48 hours) and/or upon first evidence of HIV -- 18-24 infants • Step 2 next cohort add CCR5 inhibitor/ monoclonal antibody or additional integrase inhibitor as available • Goal to reduce HIV viral RNA rapidly and sustainably to <50cp/ml and reduce HIVDNA

  40. SUMMARY • Unique opportunity to assess earliest and most potent intervention in primary infection Proof of concept • Feasible high risk population similar to 040 which has completed enrollment of 1,700 infants whose mothers were not treated with ARV) prior to delivery and given ARV < 48 hrs • Even if does not result in CURE/potential functional cure will provide greater information on neonatal HIV pathogenesis

  41. Cure!

  42. NEVER UNDERESTIMATE THE POWER OF ONEor a few good people

  43. Elizabeth Glazer & Yvonne Bryson

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