1 / 53

Prevention of Mother-to-Child HIV Transmission in the U.S. and Globally

Prevention of Mother-to-Child HIV Transmission in the U.S. and Globally. 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.

jagger
Download Presentation

Prevention of Mother-to-Child HIV Transmission in the U.S. and Globally

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Prevention of Mother-to-Child HIV Transmission in the U.S. and Globally 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 • Perinatal transmission in the U.S.: • PACTG 076 - mechanism efficacy • Risk factors for transmission in antiretroviral era • Transmission in the post-076 era • Challenges • Perinatal transmission global basis • Short-course antiretroviral prophylaxis trials results and relevance to U.S. • Challenges

  3. Perinatal Transmission in the U.S.

  4. Perinatal HIV Transmission: U.S. • In U.S., ~6,000-7,000 HIV-infected women give birth annually. • Prior to 1994, ~25% of infants born to HIV+ mothers became infected. • Thus, 1,500-1,750 infants newly infected with HIV were born each year before 1994. • More than 16,000 HIV-infected children born in the U.S. since the beginning of the epidemic.

  5. PACTG 076 AZT Regimen Targeted Multiple Potential Time Points of Transmission

  6. How Did the PACTG 076 AZT Regimen Lower Perinatal HIV Transmission? • Effect on viral load: In PACTG 076, change in HIV RNA accounted for only 17% of observed AZT efficacy (Sperling et al. NEJM 1996;335:1621-9). • Two other important mechanisms through which AZT reduces transmission: • Pre-exposure prophylaxis of infant (through transplacental AZT passage). • Post-exposure prophylaxis of infant (through continued AZT administration to the infant after birth).

  7. How Does AZT Lower Perinatal Transmission? Effect of AZT on Viral Load in PACTG 076Sperling RS et al. NEJM 1996;335:1621-9

  8. AZT Lowers Transmission Even in HIV-Infected Women with Very Low Viral LoadIoannidis JPA et al. J Infect Dis 2001;183 • Meta-analysis of 7 prospective cohorts/trials. • 44 cases transmission among 1,202 HIV+ women with delivery HIV RNA <1,000. • Transmission differed by receipt of AZT: • Mothers receiving AZT: 8/834, 1.0% • Mothers not receiving AZT: 36/368, 9.8% • Multivariate analysis (adjusting for maternal CD4 count, mode delivery and infant birth weight), AZT independently reduced transmission. • Data show importance of infant pre- and post-exposure prophylaxis in addition to lowering maternal viral load as mechanism prevention.

  9. Importance of the Infant Pre- and Post-Exposure Prophylaxis Component of PACTG 076 RegimenWade N et al. N Engl J Med 1999;339:1409 AP+IP+PP IP+PP PP<24 hr PP>48 hr No AZT Even When No Maternal AZT Received, Infant AZT Started Within 24 Hours Reduces Transmission

  10. Why Might Pre/Post-Exposure Prophylaxis Be Important?Amount of Cell-Free and Cell-Associated HIV in Cervicovaginal Canal is Associated with Transmission • Chuachoowong R et al. J Infect Dis 2000;181:99-106 • Quantified CVL HIV RNA at 38 weeks gestation in 310 women in Thai short-course AZT trial. • Presence CVL RNA associated with 3.4-fold increase in transmission; effect independent of plasma RNA, and greatest when plasma RNA low. • AP AZT was associated with median 0.8 log decrease in HIV RNA in CVL. • Tuomala RE et al. J Infect Dis 2003;187:375-84 • Assessed cell-associated HIV DNA in CVL in 78 women receiving antiretroviral therapy (65% AZT alone, 33% combination therapy). • Detection/titer of CVL DNA associated with transmission; 2.3-fold increase for each 1 log increase DNA.

  11. 1 2 3 Lumen M cell Epithelium Mono- nuclear cells Peyer’s Patch Lamina Propria Infant Exposure to HIV in Vaginal Secretions: Potential Mechanisms of HIV-1 Transmission Through Intestinal Mucosa of Infant

  12. PETRA Study of AZT/3TC Prophylaxis: Pre-Exposure Prophylaxis Alone is Ineffective Petra Study Team. Lancet 2002;359:1178-86 % Efficacy at 6 Wk 63% 42% 0% 1 wk mom & baby 36 wks PRENATAL INTRA POST INTRA POST INTRA PLACEBO

  13. Risk Factors for Transmission In Women/Infants in Post- PACTG 076 Era: Viral Load Type of Antiretroviral Therapy Mode of Delivery

  14. Delivery Plasma HIV RNA Level is Associated with Perinatal Transmission Women & Infants Transmission Study, 1990-1999Cooper E et al. JAIDS 2002;29:484-94

  15. More Potent Antiretroviral Regimens Are Associated with Lower Perinatal Transmission Women & Infants Transmission Study, 1990-1999Cooper E et al. JAIDS 2002;29:484-94

  16. Elective Cesarean Delivery Reduces Transmission When PACTG 076 AZT Regimen is GivenThe International Perinatal HIV Grp. N Engl J Med 1999;340:977-87 Meta-analysis 8,533 women from 15 cohorts Addition of an intrapartum intervention further reduces perinatal transmission in face of AZT prophylaxis

  17. Activities in U.S. Following the Results of PACTG 076 • Feb 1994: PACTG 076 results announced • Aug 1994: U.S. Public Health Service guidelines for use AZT to prevent transmission published. • July 1995: U.S. Public Health Service guidelines for prenatal HIV counseling and testing. • Periodic updates to guidelines when new information becomes available: • Latest update prophylaxis guidelines: Nov 2002 • Latest update testing guidelines: Nov 2001

  18. Current USPHS Guidelines for Prevention of Mother-to-Child Transmission • Maternal plasma HIV RNA >1,000: • HAART • Elective C/S if >1,000 near delivery • Maternal plasma HIV RNA <1,000: • HAART or use of PACTG 076 AZT alone • No treatment prior to labor: • Intrapartum-postpartum AZT; AZT/3TC; nevirapine; or AZT/nevirapine • No treatment prior to or during labor: • Infant prophylaxis for 6 weeks with combination regimen or AZT alone

  19. Maternal Antiretroviral Use During Pregnancy at PACTG Sites,1998-2000 Data from PACTG 367, N = 1,527

  20. Increasing Rates of Cesarean Delivery Among HIV-Infected Women in U.S., 1994-2000Pediatric Spectrum of Disease, CDC N=6,467

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

  22. 81% decline PACTG 076 500 USPHS AZT Recommendations 400 300 No. of Cases 200 100 0 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 Half Year of Diagnosis Incidence of Perinatally-Acquired AIDS United States, 1985-2000* 500 400 300 200 100 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 * Reported through December 2000

  23. Progress on Reducing Mother-to-Child HIV Transmission in the U.S. • Mother to child transmission has been reduced to <2% in the U.S. • Number of infected infants born each year in U.S. has decreased from 2,000 before 1994 to under 300-400 currently. • Reduction transmission secondary to: • Enhanced prenatal HIV counseling and testing. • Recognition of the importance of viral load in transmission, and increase in use of HAART by pregnant women. • Increase in elective cesarean delivery.

  24. Challenges Remain • Remaining significant barriers to elimination of perinatal HIV in U.S.: • Continued HIV transmission to women, especially adolescents, who have high rates of unintended pregnancy. • Lack of prenatal care, particularly in women who are illicit drug users (15% of HIV-infected women lack prenatal care). • Failure to identify HIV infection during pregnancy. • Antiretroviral drug resistance.

  25. Antiretroviral Resistance in Adults with New HIV Infection, U.S./Canada • Frequency of antiretroviral resistance mutations among newly infected persons increasing: • Grant et al. JAMA 2002;288:181-8 (San Francisco) • From 1996-97 to 2000-01(N=225) • NRTI: 25% to 21% • NNRTI: 0% to 13% • PI: 3% to 8% • Resistance correlated with viral response • Little et al. NEJM 2002;347:385-94 (10 cities) • From 1995-98 to 1998-2000 (N=377) • Any: 8% to 23% • Multidrug: 4% to 10% • more pregnant women are now treatment-experienced.

  26. More HIV-Infected Pregnant Women are Antiretroviral-Experienced and Have ARV Resistance: Resistance in Women in PACTG 316*Cunningham C et al. J Infect Dis 2002:186:181-8 *23% on AZT alone; Combo no PI 36%; Combo PI 41%

  27. Impact of Antiretroviral Resistance on Prevention of Perinatal Transmission • Mofenson L et al. AIDS Conf 2002 • PACTG 185 (86% AZT, 14% combo NRTI), case-control study of 24 transmitters, 72 controls • At delivery: • AZT resistance: 25% transmitters vs 11% controls (p=0.14) • Any NRTI resistance: 46% transmitters, 25% controls (p=0.15) • Welles S et al. AIDS 2000;14:253-71 • WITS, case-control study of 142 pregnant women • Prevalence AZT resistance, 24% • Multivariate analysis, genotypic AZT resistance associated with 5.1-fold increased risk transmission • At present, most cases of antiretroviral failure with transmission despite antiretroviral prophylaxis are not due to drug resistance, but this may change as resistance becomes more frequent.

  28. Perinatal Transmission Global Picture

  29. Perinatal HIV Transmission: Global12 • 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 25-40%. • About 2,000 children become infected daily; in 2002, an estimated 800,000 infants were newly infected with HIV. • An estimated 3.2 million children were living with HIV in 2002.

  30. Importance of Breastfeeding Postnatal Transmission:Timing of Mother-to-Child HIV Transmission with Breastfeeding and No Antiretroviral Prophylaxis Early Postpartum (0-6 months) Late Postpartum (6-24 months) Early Antenatal (<36 wks) Labor and Delivery Late Antenatal (36 wks to labor) 0% 20% 40% 60% 80% 100% Proportion of infections

  31. International Perinatal HIV Trials • Following PACTG 076: • 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 simple regimens.

  32. Completed Trials: Focused on Prevention AP/IP 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?

  33. Short-Course AZT Studies • Short-course AZT prophylaxis is effective. • Longer (28 weeks) antepartum treatment is more effective than shorter (36 weeks) antepartum therapy, showing that a significant proportion of in utero infection occurs between 28 and 36 weeks. • Efficacy of prophylaxis is diminished by breastfeeding, but still persists at 24 months with short-course AZT.

  34. Short-Course AZT Prophylaxis: Efficacy in Formula-Fed vs Breast-Fed Infants % Efficacy at 6 Mos 50% 37% % Efficacy at 24 Mos 50% 26% Placebo-controlled trials Thailand Formula Feeding PRENATAL 36 wks INTRA Shaffer et al. Lancet 1999;353:773-80 Ivory Coast BreastFeeding PRENATAL 36 wk INTRA Wiktor et al. Lancet 1999;353:781-5

  35. Short-Course AZT Prophylaxis, Formula-Fed Infants: Duration of AP/PP Therapy Lallemant M et al. N Engl J Med 2000;343:982-91 AP IP PP Infant 28 wk 36 wk 6 wk 3 d Most Effective (Tx 4% [vs SS]) Long- Long Long- Short Intermediate (Tx 5%) Intermediate (Tx 9%) Short- Long Short- Short Least Effective (Tx 11%)

  36. Long Better than Short Maternal Antepartum Therapy for Preventing In Utero Transmission Lallemant M et al. N Engl J Med 2000;343:982-91 5.1% P<0.001 1.6% AP: 28 wks AP: 36 wks

  37. Short-Course Combination Regimens • After short-course AZT found effective, researchers then asked if short-course combination regimens would be more effective than AZT alone. • AZT/3TC prophylaxis appears more effective than AZT alone. • 3-part AP/IP/PP drug prophylaxis is more effective than IP/PP alone. • IP-only not effective, showing importance of post-exposure prophylaxis component. • Efficacy diminished by breastfeeding and did not persist at 18 mos for the IP/PP AZT/3TC regimen.

  38. AZT/3TC Better than AZT Alone:Open-Label AZT/3TC Perinatal Prophylaxis Studies in Formula-Fed Populations AP IP PP (baby) Tx 14 wks 32 wks 6 wks France ANRS 075 Mandelbrot JAMA 2001 1.6% 076 Backbone vs AZT only 1994-1996 hx control, 6.8% 34 wks 4 wks Thailand Chaisilwattana CID 2002 2.8% Short AZT Backbone vs AZT only 1994-1996 hx control, 11.7% AZT AZT plus 3TC

  39. AZT/3TC Prophylaxis in Breast-Fed Infants Petra Study Team. Lancet 2002;359:1178-86 % Efficacy 6 Wk18 Mo 63% 32% 42% 18% 0% 0% 1 wk mom & baby 36 wks PRENATAL INTRA POST INTRA POST INTRA PLACEBO

  40. Alternative Prophylaxis Regimens • Research asked whether alternative drugs (like nevirapine) might provide efficacy similar to short combination regimens. • When only IP/PP prophylaxis is given, single-dose NVP is superior to IP/PP AZT alone, and similar to IP/PP AZT/3TC. • Efficacy diminished by breastfeeding, but while 2-part AZT/3TC was not effective at 18 months, NVP retained efficacy. • Addition of single-dose NVP to short-course AZT appears to improve efficacy. • However, adding NVP to standard regimens used in U.S. does not offer additional benefit.

  41. Alternative Antiretrovirals: Single-Dose Nevirapine vs Ultra-Short AZT - HIVNET 012 Guay L et al. Lancet 1999;354:795-802 Breastfed Infants % Transmission 14-16 Wks18 Mos 13.1% 15.7% 25.1% 25.8% Efficacy 47% 41% INTRA POST Nevirapine 2 mg/kg x1 200 mg x1 versus Ultra-Short AZT INTRA POST 300 mg q 3 hr 4 mg/kg bid x1 wk

  42. Comparison of IP/PP Regimens: Single-Dose Nevirapine vs PETRA AZT/3TC - SAINT Moodley D et al. JID 2003;187:725-35 % Transmission BirthBtn Birth-8 Wks 7.0% 5.7% (2.0-5.3) Overall, 8 wks: 12.3% 5.9% 3.6% (3.7-7.8) Overall, 8 wks: 9.3% (Overall: p=0.11) Nevirapine (variant of HIVNET 012) INTRA POST Mom 200 mg x1 Baby 2 mg/kg x1 200 mg x1 versus AZT/3TC (PETRA) INTRA POST Q 3 hr Mom & baby x1 wk

  43. Does the Addition of Single Dose NVP to Short-Course AZT Improve Efficacy? Lallemant M et al. 2002 AIDS Conf, Barcelona Abs LBOr22 AZT 28 wk oral 1 wk DSMB stopped AZT alone (arm 3) @ interim analysis due to significantly higher transmission Plus: Arm 1 - NVP NVP Arm 2 - NVP PL Arm 3 - PL PL Formula fed F Dabis F et al. 2002 AIDS Conf, Barcelona Abs ThOrD1428 AZT Transmission 7% compared to 13% historical control AZT alone (95% breastfed) 36 wk oral 1 wk NVP NVP 50% breastfed

  44. Single-Dose NVP Does Not Improve Efficacy of Longer or More Complex ARV RegimensDorenbaum A et al. JAMA 2002;288:189-98 PregnancyLaborNewborn Transmission Rates Women receiving ARV during pregnancy Continue ARV AZT Perinatal Prophylaxis 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

  45. Infant Prophylaxis • Many women may not present until in labor and only infant prophylaxis may be possible. • Epidemiologic data suggest infant AZT for 6 weeks after birth reduces transmission. • Infant prophylaxis must begin within 24-48 hours after birth to be effective when the mother has not received AP/IP drug. • Preliminary data suggest: • Single dose NVP given to the infant at birth may have efficacy similar to AZT. • Single dose NVP plus AZT may have better efficacy than NVP alone if mother hasn’t received single dose IP NVP.

  46. Preliminary Data: Infant Post-Exposure Prophylaxis Trials (South Africa, Malawi; ongoing) Gray G. 2002 AIDS Conf, Barcelona Abs LBOr13 * 7% 11% NB NVP AZT 6 wk * Problem: 25% loss to follow-up between birth-6 wks Taha T. 2002 AIDS Conf, Barcelona Abs ThOrD1427; ThPpD2146 * 22% 14% NB NVP Stratify: Late vs Early Presenter NB NVP AZT 1 wk 14% 18% IP NVP NB NVP IP NVP NB NVP AZT 1 wk

  47. Is Combination Better than Standard 6 Wk AZT Post-Exposure Prophylaxis in Formula-Fed Infants? Post-Exposure Infant Prophylaxis (PEPI) NICHD/HPTN 040 Trial (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

  48. Current/Planned International Perinatal TrialsInfant or Maternal Antiretroviral Prophylaxis to Reduce Postnatal Breast Milk HIV Transmission

  49. Design of Ongoing/Planned Infant 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 Malawi (CDC/NICHD) S. Africa/Brazil Thai (Harvard) DITRAME+1 Malawi (ongoing) Zambia (Harvard)/SA/ HIVNET 024/Uganda PP: Optimal duration? Will it work alone? What drug? Is combo better? Exclusive BF, type weaning? AP: Optimal duration? Is it needed?

More Related