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Prevention of Mother-to-Child HIV Transmission: State of the Art

Prevention of Mother-to-Child HIV Transmission: State of the Art. Lynne M. Mofenson, M.D. Pediatric, Adolescent and Maternal AIDS Branch National Institute of Child Health and Human Development National Institutes of Health Department of Health and Human Services. Overview.

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Prevention of Mother-to-Child HIV Transmission: State of the Art

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  1. Prevention of Mother-to-Child HIV Transmission:State of the Art Lynne M. Mofenson, M.D. Pediatric, Adolescent and Maternal AIDS Branch National Institute of Child Health and Human Development National Institutes of Health Department of Health and Human Services

  2. Overview • Current trends in MTCT in U.S. • Results of initial short-course ARV prophylaxis trials. • Results of newer trials to enhance efficacy of short-course ARV prophylaxis. • Ongoing trials to reduce breastfeeding transmission. • Issues related to NVP resistance. • Challenges in PMTCT globally.

  3. Perinatal Transmission in the U.S.

  4. Perinatal HIV Transmission: United States • In the U.S., ~6,000-7,000 HIV-infected women give birth annually. • Prior to 1994, ~25% of their infants became infected. • Following results of PACTG 076, transmission rates dropped to 5-8%. • With current recommendations for use of HAART and elective C/S for women with HIV RNA >1,000 and for avoidance of breastfeeding, transmission has decreased to <2% for women identified early in pregnancy.

  5. Mother to Child HIV Transmission in the U.S. Over Time

  6. Perinatal Transmission Global Picture

  7. Perinatal HIV Transmission: Global • Globally, >2 million HIV-infected women give birth annually, most in resource-poor countries, where regimens used in US are too complex and expensive to use. • Transmission rates in breastfeeding women without antiretroviral prophylaxis are between 30-40%. • About 2,000 children become infected daily; in 2003, an estimated 700,000 infants were newly infected with HIV.

  8. Initial Phase of Perinatal Trials Short-Course AZT Short-Course Combination Single-Dose NVP

  9. First Phase of Perinatal Clinical TrialsPost-PACTG 076 • Following PACTG 076, recognition of the need to develop shorter, less expensive regimens more applicable to resource-limited settings. • Studies first focused on modifications of AZT-alone prophylactic regimens. • Studies also explored whether short-course combination regimens might have improved efficacy. • Studies asked if similar efficacy to combination could be achieved with alternative drugs that were less expensive and could be used in very simple regimens.

  10. Initial Perinatal Trials Focused on Prevention of In Utero and Intrapartum Transmission AP IP PP(baby, mother or both) 14 wks 28 wks 36 wks 3d to 1 wk 6 wks 076 NonBF NonBF Thai (Harvard) NonBF Thai (Harvard) NonBF Thai (Harvard), BMS IvC (ANRS), PETRA, Thai (Harvard) BF/NonBF Thai (CDC), IvC (CDC) NonBF/BF PETRA, 012, SAINT BF PETRA BF PP: Minimal duration? Is it needed? AP: Minimum duration? Is it needed? IP: Work alone?

  11. Initial Perinatal HIV Clinical TrialsEfficacy of Regimens Breast-fed Formula-fed AZT AZT/ AZT AZT NVP AZT/ NVP AZT AZT/ AZT 3TC 3TC 3TC

  12. Conclusions from Completed Trials • While 3-part AP/IP/PP prophylaxis is most effective, both AP/IP and IP/PP ARV regimens can significantly reduce transmission (PHPT-1, PETRA,Thai, 012). • Longer (28 weeks) AP treatment is more effective than shorter (36 weeks) AP therapy, showing that a significant proportion of in utero infection occurs between 28 and 36 weeks (PHPT-1). • AZT/3TC prophylaxis is more effective than AZT alone in short-course regimens (ANRS 075, Thai MOH, DITRAME) . • However, IP/PP AZT/3TC has similar efficacy to single-dose NVP (SAINT).

  13. Conclusions from Completed Trials • Results from trials indicate utility of both viral load reduction at delivery and of neonatal pre- and post-exposure prophylaxis. • Some washout AZT effect and NVP effect by late breast feeding transmission through age 18-24 months but still effective (Ivory Coast, 012).

  14. Second Phase Perinatal Trials Enhancing Efficacy of Short-Course Regimens: Single-Dose NVP plus Short-Course AZT

  15. More Recent Completed Trials Have Focused on Enhancement of Short-Course Regimens • Addition of single-dose NVP to short-course AZT regimens appears to improve efficacy in formula- and breast-fed populations (PHPT-2, DITRAME-Plus). • However, addition of NVP to standard ARV regimens used in U.S. did not offer additional benefit (PACTG 316). • Single dose NVP plus AZT has better efficacy than NVP alone if mother hasn’t received single dose IP NVP (NVAZ). • However, if mother has received single dose IP NVP, combination doesn’t appear to offer benefit (NVAZ).

  16. Formula-Fed Populations Enhancing Efficacy of Short-Course Regimens: Combining Single-Dose NVP + Short-Course AZT

  17. Does the Addition of Single Dose NVP to Short-Course AZT Improve Efficacy in Formula-Fed Infants?Lallemant M et al. 11th Retrovirus Conf, Feb 2004 Abs 40LB 28 wk oral 1 wk AZT Backbone Plus: Arm 1 - NVP NVP Is infant NVP dose needed? {+} Does SD NVP provide added efficacy? Arm 2 - NVP PL Arm 3 - D/C’d 04/02 PL PL Interim analysis April 2002 after ~50% enrollment: PL/PL arm discontinued; continued enrollment into NVP arms

  18. Comparing Combination Single-Dose NVP + AZT Arms to Short-Course AZT AloneLallemant M et al. 11th Retrovirus Conf, Feb 2004 Abs 40LB 28 wk oral 1 wk AZT Backbone Plus: Arm 1 - Does SD NVP provide added efficacy to short-course AZT? NVP NVP {+} Arm 2 - NVP PL N=686 Arm 3 - PL PL N=349

  19. Short-Course AZT plus Single-Dose NVP is 73% More Effective Than Short-Course AZT AloneLallemant et al. 11th Retrovirus Conf, Feb 2004 (abs 40LB) # infected/total 22/349 11/686 Comparing AZT/Placebo-Placebo To AZT/NVP-Placebo + AZT/NVP-NVP

  20. Addition of Single-Dose Maternal/Infant NVP toAZT is Most Effective at Higher Maternal RNA LevelsLallemant et al. 11th Retrovirus Conf, Feb 2004 (abs 40LB) HIV RNA Comparing Difference in Transmission Rates AZT/Placebo-Placebo and AZT/NVP-NVP

  21. Addition of Single-Dose Maternal/Infant NVP toAZT is Most Effective at Lower Maternal CD4Lallemant et al. 11th Retrovirus Conf, Feb 2004 (abs 40LB) CD4 count Comparing Difference in Transmission Rates AZT/Placebo-Placebo and AZT/NVP-NVP

  22. Comparing Combination Single-Dose Maternal/Infant Single-Dose NVP + AZT to Infant-Only NVP + AZTLallemant M et al. 11th Retrovirus Conf, Feb 2004 Abs 40LB 28 wk oral 1 wk AZT Backbone Plus: Arm 1 - NVP NVP Is infant NVP dose needed? N=693 Arm 2 - NVP PL N=672

  23. Single-Dose NVP Given to the Mother Alone is“Equivalent*” to Single-Dose Maternal/Infant NVPLallemant et al. 11th Retrovirus Conf, Feb 2004 (abs 40LB) # infected/total 19/672 14/693 Comparing AZT/NVP-Placebo to AZT/NVP-NVP *Equivalent defined + 2.5%

  24. Addition of Infant to Maternal Single-Dose NVP Better at Higher Maternal RNA Levels (>4000)Lallemant et al. 11th Retrovirus Conf, Feb 2004 (abs 40LB) HIV RNA Comparing Difference in Transmission Rates AZT/NVP-Placebo and AZT/NVP-NVP

  25. Addition of Infant to Maternal Single-Dose NVP Most Important for Women with Low CD4 (<200) Lallemant et al. 11th Retrovirus Conf, Feb 2004 (abs 40LB) CD4 count Comparing Difference in Transmission Rates AZT/NVP-Placebo and AZT/NVP-NVP

  26. Short-Course AZT + Single-Dose Maternal/Infant NVPThailand Studies (Formula-Fed Infants):Longer Maternal Therapy = Lower Transmission Lallemant M et al. 11th Retrovirus Conf, Feb 2004 Abs 40LB AZT Backbone* *If mom <4 wk AZT, infant gets 4 wks AZT 28 wk oral 1 wk NVP NVP Transmission 2.0% (95% CI 1.2-3.4%) [N=693] Chalermchokcharoenkit et al. 11th Retrovirus Conf, Feb 2004 (abs 96) AZT Backbone 34-36 wk oral 4 wk NVP NVP Transmission 4.6% (95% CI 2.5-8.5%) [N=220]

  27. Single-Dose NVP Does Not Improve Efficacy of 076 AZT or Combo ARV (Women with Low RNA, High CD4)Dorenbaum A et al. JAMA 2002;288:189-98 PregnancyLaborNewborn Transmission Rates Women receiving ARV during pregnancy IV AZT (+- other ARV) AZT Prophylaxis x 6 wks 1.4% (95% CI, 1-3%) 1.6% (95% CI, 1-3%) 200 mg dose of NVP vs NVP Placebo 2 mg/kg dose of NVP @ 48-72 hr vs NVP Placebo Randomize, stratified by: 1) AP ARV (no, mono, combo) 2) Entry CD4 77% Combination ARV Median RNA <400

  28. Why Differences Between Thai Studies and PACTG 316 in SD NVP Efficacy? • Thai studies: • Evaluated efficacy of SD NVP combined with short-course AZT alone. • Single-dose NVP most effective with: • Higher HIV RNA levels (low if RNA <4,000). • Lower maternal CD4 (low if CD4 >400). • PACTG 316: • Evaluated efficacy of SD NVP combined with 076 AZT or combination ARV (77% received antenatal combination ARV). • Median HIV RNA: 400 (IQR, 200-2,309). • Median CD4 count: 434 (IQR, 296-594).

  29. Breast-Fed Populations Enhancing Efficacy of Short-Course Regimens: Combining Single-Dose NVP + Short-Course AZT

  30. Addition Single-Dose NVP to Short-Course AZT or AZT/3TC Improves Efficacy in Breast-Fed InfantsF Dabis F et al. 2nd IAS Conf, Paris, France, 2003 Abs 219 Ditrame Historical: Tx 4-6 wk,13.1% 95% BF AZT 36 wk oral 1 wk Ditrame-Plus 1.0 ANRS 1201 1.0: Tx 4-6 wk,6.2% 50% BF AZT 36 wk oral 1 wk NVP NVPx1 Ditrame-Plus 1.1 AZT + 3TC ANRS 1201 1.1: Tx 4-6 wk,5.0% (1.7-11.4%) >50% BF 32 wk oral 3 d NVP NVPx1

  31. One Week of AZT Added to Single-Dose Infant NVP Improves Efficacy When No Maternal IP NVP DoseTaha T et al. Lancet 2003;362:1171-7 -- NVAZ StudyTaha T. 2002 AIDS Conf, Barcelona Abs ThPpD2146 MotherInfant p=0.03 Stratified: Late Presenter vs Early Presenter (got maternal NVP) 20.9% 15.3% NB NVP NB NVP AZT 1 wk 15.4% 15.3% IP NVP NB NVP IP NVP NB NVP AZT 1 wk When maternal intrapartum NVP dose is received, addition of AZT doesn’t offer benefit

  32. Current Third Phase Perinatal Trials: Infant Prophylaxis Breastfeeding NVP Resistance

  33. New Focus of Perinatal Trials • Infant prophylaxis in formula-fed infants: enhancing efficacy of standard 6 week AZT? • Exclusive breastfeeding/timing weaning. • Prophylaxis of breastfeeding: • Immunoprophylaxis. • ARV prophylaxis of infants. • ARV prophylaxis of mothers. • NVP resistance after single dose • Response to NVP prophylaxis in 2nd pregnancy after prior single-dose NVP. • Response to NNRTI therapy after receipt of single-dose NVP. • Ways to decrease develop resistance.

  34. Infant Prophylaxis: Formula-Fed Populations Enhancing Efficacy of Standard 6 Wk AZT Infant Prophylaxis

  35. Is Combination Better than Standard 6 Wk AZT Post-Exposure Prophylaxis in Formula-Fed Infants? Post-Exposure Infant Prophylaxis (PEPI) NICHD/HPTN 040 Trial – PACTG 1043 (Brazil, U.S.) Infant IV AZT* AZT x 6 wks NVP birth, 72, 168 hr IV AZT* AZT x 6 wks 3TC/NFV x 2 wks IV AZT* AZT x 6 wks *If mom diagnosed in time for IP prophylaxis

  36. Breastfeeding Transmission and Prevention

  37. Effect of Breastfeeding on PMTCT Prophylaxis 37% No ARV, BF 22.5% AZT AP-IP 20% 18.1% AZT/3TC IP-PP 16.5% 15.7% NVP IP-PP 14.9% AZT/3TC AP-IP-PP 11.8% 8.9% 8.6% 076 AZT-no BF 5.7% 1.6% 316 comb-no BF Infant Age

  38. Modifying Infant Feeding Practices • Exclusive breastfeeding vs mixed feeding Rationale: S. African study suggests exclusive BF associated with less transmission than mixed feeding • Timing and duration of breastfeeding cessation Rationale: Earlier BF cessation and reducing period of mixed feeding with a shorter weaning duration might reduce the risk of transmission • Exclusive Breastfeeding study - Kwazulu Natal, South Africa (ongoing) • ZEBS - Lusaka, Zambia (ongoing) • ZVITAMBO - Harare, Zimbabwe (recruitment completed) • DITRAME Plus - Abidjan, Côte d’Ivoire (ongoing) • MASHI - Botswana (ongoing)

  39. Immunoprophylaxis of BF Transmission Passive immunoprophylaxis • HIV1GLOB/NVP study - Kampala, Uganda • Mother: NVP at onset labour • Child: NVP at birth Study arms: 1) Child – 6 wks infant NVP vs 2) HIV1GLOB: Mother – 37-38 weeks pregnancy + Child – <24 hours birth vs 3) No added treatment • Monoclonal antibodies – Phase I pharmacokinetic and safety study - Durban, S. Africa (RO1, Coovadia) Active immunoprophylaxis • HIVNET 027 – canarypox HIV vaccine in neonates

  40. Design of Ongoing/Planned Infant BF Prophylaxis Trials AP IP PP -- Infant 34 wks 36 wks 1 wk 6 wks 28 wks 6 mo 14 wks Botswana SIMBA/MITRA HPTN 046 Ethiopia/India/Uganda Malawi (CDC/NICHD) S. Africa/Brazil DITRAME+1 Malawi (ongoing) Zambia (Harvard)/SA/ HPTN 057 PP: Optimal duration? Will it work alone? What drug? Is combo better? Exclusive BF, type weaning? AP: Optimal duration? Is it needed?

  41. Infant Prophylaxis Trials: A Variety of Regimens/Durations Under Study

  42. SIMBA (“Stopping Infection from Mother-to-child from Breastfeeding in Africa”) Infant ProphylaxisVyankandondera J et al. IAS Meeting, Paris, France 2003 All women get AZT+ddI “PETRA Arm A”-like 3-part regimen Counseling exclusive breastfeeding for 3-6 months Breastfeeding infants randomized to NVP vs 3TC Arm 1: AZT +ddI start 36 wks AZT +ddI Mother: AZT + ddI x 1 wk Infant: 3TC x 6 months Birth-14 days, 2 mg/kg bid; then 4 mg/kg bid Arm 2: AZT +ddI start 36 wks AZT +ddI Mother: AZT + ddI x 1 wk Infant: NVP x 6 months Birth-14 days, 2 mg/kg once/d; then 2 mg/kg bid

  43. SIMBA vs HIVNET 012 Maternal Characteristics Critical covariates associated with risk HIV tx differ: maternal therapy, delivery RNA, type & duration of BF

  44. HIV Transmission in SIMBA Kaplan-Meier EstimatesVyankandondera J et al. IAS Meeting, Paris, France 2003(Revised as per 12/9/03 clarifications) Median duration BF (period at risk of BF tx) 3.3-3.5 mos

  45. Important Issues in Interpreting Results and Policy Implications • No control arm. • Background maternal AP/IP/PP ARV not standard in many countries. • BF tx associated with RNA plasma/milk; in SIMBA, mom’s AP ARV resulted in delivery RNA 2.7 log & mom got 1 wk PP ARV - could BF tx be decreased even without infant ARV? • Exclusive BF rate high; effect on BF tx? • BF duration (and risk tx) short, median 3.5 mos: comparison should be with tx rate in infants at risk for BF tx for same time period. • 2.4% rate postnatal tx comparable to postnatal tx between birth and 4 months in HIVNET 012 women with RNA <4.4 (median 3.8 log) = 2.8%.

  46. What is Effect of Infant Prophylaxis with Standard PMCTC: Does Infant Prophylaxis Improve SD NVP in BF infants? Is Duration of Infant Prophylaxis Important? IPPP HPTN 046 NVP x1 Infant NVP x1 Infant: NVP x 6 months NVP x1 Infant NVP x1 Infant: Placebo x 6 months Ethiopia (Nigat) Uganda (HIV1Glob/NVP) India NVP x1 Infant NVP x1 Infant: NVP x 6 wks NVP x1 Infant NVP x1 Infant: Placebo x 6 wks

  47. Does Short-Term Combination Infant Prophylaxis Increase Efficacy of NVAZ Infant Single-Dose Nevirapine + 1 Wk AZT in Breastfeeding Infants? (Malawi) IPPP NVP x1* Infant NVP x1 Infant AZT x1 wk NVP x1* Infant NVP x1 Infant AZT x1 wk Infant: AZT x 16 wks NVP x1* Infant NVP x1 Infant AZT x1 wk Infant: NVP + AZT x 16 wks *If mom diagnosed in time for IP prophylaxis

  48. Maternal Antiretroviral Prophylaxis and Reduction of Postnatal Transmission? • Maternal combination ARV would: • Improve maternal health and survival and possibly limit development of resistance from drugs where a single mutation causes resistance (3TC, nevirapine are special concerns). • Lower maternal antenatal viral load and decrease antepartum and intrapartum transmission. • Has potential for prevention of breast milk transmission.

  49. Randomized Maternal HAART Prophylaxis Trial Design AP IP PP 34-36 wks 6 mos 1 wk Malawi (CDC/ UNC) ZDV/3TC NVP x1 ZDV/3TC NVP x1 ZDV/3TC NVP x1 ZDV/3TC NVP x1 ZDV/3TC/NVP Mother ZDV/3TC NVP x1 ZDV/3TC NVP x1 NVP Infant Multisite Africa (WHO) Kesho Bora ZDV ZDV NVP x1 ZDV NVP x1 ZDV/3TC/NVP ZDV/3TC/NVP ZDV/3TC/NVP Mother ZDV x 1 wk + NVP x1 Infant In randomized studies, CD4 <200 all get HAART, CD4 >200 are randomized and stop ARV at 6 months

  50. Single-Dose NVP for MTCT and Resistance: Pharmacokinetics of NVP

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