1. Perinatal Transmission and HIV: Two Realities “National and International Perspectives” Tanya Zangaglia, MD Medical Director, Project Streetbeat Curriculum Coordinator, NY/VI AETC Columbia Univ. School of Public Health

2. 2 What has been the most significant accomplishment of the HIV/AIDS era? Perinatal Transmission and HIV: Two Realities

3. 3 The number of women living with HIV/AIDS is growing Perinatal Transmission and HIV: Two Realities

4. 4 Over four-fifths of all HIV- infected women in the U.S. are of childbearing age Perinatal Transmission and HIV: Two Realities

5. 5 HIV positive women are: Living longer Feeling more hopeful Choosing life Perinatal Transmission and HIV: Two Realities

6. 6 HIV positive women are choosing to become pregnant Perinatal Transmission and HIV: Two Realities

7. 7 Perinatal Transmission continues to exist in the United States Perinatal Transmission and HIV: Two Realities

8. 8 Perinatal Transmission has declined by at least 80% between 1992 and 1999 JAMA 1999; 282:531 Perinatal Transmission and HIV: Two Realities

9. 9 It is now possible to achieve Perinatal Transmission rates as low as 1-2%… this contrasted to 25-30% a decade ago The Hopkins HIV Report Jean R. Anderson, MD July 2001; p2 Perinatal Transmission and HIV: Two Realities

10. 10 Many women who are pregnant are not offered counseling and testing and remain undiagnosed – many of these women are not perceived to be “at risk” Perinatal Transmission and HIV: Two Realities

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12. 12 Conducted in 7 states Found that 20% of women with HIV- infection were not diagnosed before delivery Reported that 36% of HIV-infected women using illicit drugs during pregnancy had no prenatal care HIV SURVEILLANCE REPORT Wortley, et. al. MMWR 2001; 50:RR6-17

13. 13 Universal HIV testing with patient notification as a routine part of Prenatal care is currently supported by the: –Institute of Medicine –American College of Obstetricians and Gynecologists MANDATORY HIV TESTING OF PREGNANT WOMEN

14. 14 Maternal plasma viral load is viewed as perhaps the most important correlate of perinatal transmission in both antiretroviral treated and naïve women Garcia, et. al. NEJM 1999; 341:394 Mofensen et. al. NEJM 1999; 341:385 MATERNAL VIRAL LOAD

15. 15 MATERNAL VIRAL LOAD A meta-analysis of 7 European and U.S. prospective studies examined mother-to- child transmission when maternal viral load was < 1000 c/ml The study found that the risk of HIV transmission was lowered from 9.8% in untreated women to 1% in women treated with antiretroviral therapy (generally AZT alone) Ionnides, et. al. J. Infect Diseases 2001; 183:539

16. 16 In the past decade the clinical thinking has shifted from being reluctant to treat HIV positive pregnant women to now recommending antiretrovirals for all pregnant women with HIV regardless of CD4 count or viral load MATERNAL VIRAL LOAD

17. 17 PACTG 076 STUDY PROTOCOL AZT administered from week 14 of gestation AZT continued throughout pregnancy AZT given as an IV infusion to the mother during labor AZT given to the newborn for 6 weeks

18. 18 Anger, skepticism, thoughts of genocide, reluctance Adverse fetal effects Unethical to withhold AZT from some women who might receive direct benefit themselves, but instead were randomized to receive a placebo PACTG 076 EARLY CONCERNS

19. 19 Study stopped prematurely Review by the data and safety Monitoring board found a highly significant difference in transmission rates between women who received AZT and those randomized to placebo PACTG 076 EARLY RESULTS

20. 20 VT was reduced by 66% VT decreased from 22.6% (in placebo recipients) to 7.6% (in those receiving AZT) PACTG 076 IMPACT ON VERTICAL TRANSMISSION (VT)

21. 21 Immediate action taken Study protocol became the standard of care for pregnant women with HIV infection PACTG 076 PUBLIC HEALTH RESPONSE

22. 22 Original study cohort consisted of women with CD 4 > 200 cells/mm 3 and no prior AZT exposure Subsequent observational studies confirmed the effectiveness of 076 in women with more advanced disease who were not antiretroviral naive PACTG 076

23. 23 Many women do not present for care until much later in pregnancy (ex: 3 rd trimester rather than 2 nd trimester) IV catheters are not available to women in labor in a large part of the world where HIV predominates The cost of the 076 regimen is prohibitive for all but a few of the worlds’ nations PACTG 076 ONGOING DEBATE

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25. 25 In this study AZT was started as late as 36 weeks of pregnancy AZT was given orally in labor There was no neonatal component Lancet Shaffer, et. al. 1999; 353:773 THAI SHORT-COURSE AZT STUDY

26. 26 Still achieved significant reductions in mother-to-child transmission 50% decline noted compared to placebo in a non-breast feeding population Lancet Shaffer, et. al. 1999; 353:773 THAI SHORT-COURSE AZT STUDY

27. 27 Study also found that both plasma and genital tract viral load were suppressed by AZT treatment Both were independently correlated with transmission J. Infectious Diseases Chuachoowong, et. al 2000; 181:99 THAI SHORT-COURSE AZT STUDY

28. 28 Showed that the length of maternal treatment is a significant variable in reducing HIV transmission Therapy started at 28 weeks gestation is far superior to therapy started at 35 weeks NEJM Lallemont, et. al. 2000; 343:1036 OTHER SHORT-COURSE AZT STUDIES

29. 29 Studies highlighted the fact that approximately 1/3 of transmission occurs earlier in pregnancy Also studies demonstrated that the effectiveness of therapy is blunted by breastfeeding NEJM Lallemont, et. al. 2000; 343:1036 THAI SHORT-COURSE AZT STUDY

30. 30 A single oral dose of Nevirapine was given to a pregnant women at the onset of labor A single oral dose of Nevirapine was given to her newborn within 48-72 hours of birth Lancet Guay, et. al. 1999; 354:795 HIV NET 012 TRIAL

31. 31 Results show an approximate 50% reduction in transmission compared with oral AZT given intrapartum and to the infant for one week Lancet Guay, et. al. 1999; 354:795 HIV NET 012 TRIAL

32. 32 Less expensive Offers the most realistic option for the developing world Allows women to be treated who first present for medical care in labor It can be given as directly observed therapy (DOT) Lancet Guay, et. al. 1999; 354:795 HIV NET 012 TRIAL THE REGIMENTS

33. 33 No clinical trials evaluating HAART for the purpose of reducing perinatal transmission have been completed Yet and still, HAART is the standard of care in the majority of HIV positive pregnant women in the U.S. This is especially true in women who require HAART for their own infection HAART

34. 34 HAART is effective in reducing Viral Load to undetectable levels This in turn further lowers the likelihood of transmission between mother and fetus HAART

35. 35 International Phase III trial Compares: Standard antiretroviral therapy (2-3 drug regimen) Plus 2-dose Nevirapine VS Standard antiretroviral therapy Plus placebo 8th CROI [Abstract LB7] Dorenbaum, et. al. Chicago 2/01 PACTG 316

36. 36 Very low rates of transmission in both study arms 1.5% NVP 1.4% Placebo Study concludes: –Effective treatment of mom allows for effective prophylaxis of the fetus 8th CROI [Abstract LB7] Dorenbaum, et. al. Chicago 2/01 PACTG 316

37. 37 Is Cesarean Section an appropriate choice/option for “preventing” Perinatal HIV Transmission? CESAREAN SECTION

38. 38 Randomized clinical trial comparing: –Scheduled C-Section vs. Vaginal Delivery –Transmission Rates: 1.8% in women randomized to planned C-Section 10.6% in women with planned vaginal delivery Lancet The European Mode of Delivery Collaboration 1999; 353:1035 CESAREAN SECTION

39. 39 Observational data from 15 prospective cohort studies examined in a meta- analysis A total of 7,800 mother-infant pairs in the study NEJM The International Perinatal HIV Group 1999; 340:9770 CESAREAN SECTION

40. 40 The study found that women undergoing C-Section before the onset of labor or ruptured membranes had significantly lower Perinatal HIV Transmission NEJM The International Perinatal HIV Group 1999; 340:9770 CESAREAN SECTION

41. 41 These rates were compared to those women having Vaginal Delivery or C- Section after membrane rupture, regardless of AZT use NEJM The International Perinatal HIV Group 1999; 340:9770 CESAREAN SECTION

42. 42 Current data is insufficient to evaluate potential benefits of planned C-Sections in women treated with antiretroviral therapy with viral loads less than 1000 c/ml The Hopkins HIV Report Jean R. Anderson, MD July 2001 CESAREAN SECTION

43. 43 Resistance is increasing in frequency, even among antiretroviral-naïve individuals…the implication for perinatal transmission is unknown The role of C-Sections in women with low viral loads or with short duration of ruptured membranes is not yet established Should serum concentrations of antiretrovirals in pregnant women be monitored for purposes of safety and for efficacy? OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPED WORLD

44. 44 Are drugs toxicities more common in HIV positive pregnant women? What, if any, long term effects will we see in exposed but uninfected infants? What are the issues involved in the use of rapid tests to make a diagnosis of HIV in labor? OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPED WORLD

45. 45 Issues in the developing world are much more basic, yet more overwhelming OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPED WORLD

46. 46 The majority of AIDS ORPHANS reside in the developing world and is estimated at 13.2 million globally OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD

47. 47 Issues of access to antiretroviral therapy continue to arise: –Resources are needed to offer HIV counseling and testing –Affordable and available drugs are needed –A healthcare infrastructure is needed to allow for proper distribution and education OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD

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49. 49 Breastfeeding (BF) –The mode of transmission in up to 50% of newly infected children world-wide –Affordable alternatives are not widely available –The general benefits in infant nutrition and infant morbidity and mortality are established OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD

50. 50 Breastfeeding (BF) –BF vs. formula feeding (FF) in Kenya FF prevented 44% of infant infections FF was associated with HIV-free survival But FF is expensive Clean water and the ability to sterilize appropriately is not ubiquitous Nduati, et. al. JAMA 2000; 283:1167 OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD

51. 51 Breastfeeding (BF) –In areas of the world where BF is common and HIV remains highly stigmatized a real social pressure exists for women to BF –By not BFing women signal that something is wrong and alienation from their families and their communities ensues –So the debate no longer centers exclusively on whether or not to BF in these countries, but perhaps how long to BF and how best to BF OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD

52. 52 It has been shown that the longer the duration of BF the higher the risk of HIV transmission It has also been shown that mixed-feeding versus exclusive breastfeeding also leads to a higher risk of HIV transmission The conclusion from studies conducted to date suggest that exclusive breastfeeding with early weaning may be an appropriate alternative Leroy et. al. Lancet 1998; 353:597 Coutsoudis et. al. Lancet 1999; 354:471 OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD

53. 53 “In the past, I never allowed myself to think about having a baby or even look at a baby. I was just waiting to die. But now, everything has changed, and I suddenly have the opportunity to have a child.” Dr. Prager – A New Yorker living in Istanbul …She was infected with HIV 15 years ago after being pricked by a needle during her medical residency… The New York Times, Health & Fitness Tuesday, August 7 th,2001 pF7 Perinatal Transmission and HIV: Two Realities

54. 54 AIDS 1998; 12:5241, Lorenzi, et al. Obstet Gynecol 1999; 94:641, McGowan, et al. Internat J. STD AIDS 2000; 11:200, Clarke, et al. NEJM 1999; 341:205 Beckerman, et al. The Women & Infants Transmission Study Investigators XIII International Conference 2000 Abstract LBOr4 Society for Maternal Fetal Medicine Annual Meeting 2000, Abstract 289, Helfgott, et al. REFERENCES

55. 55 U.S. Public Health Task Force Guidelines for the Management of HIV in pregnancy: http://www.hivatis.org http://hopkins-aids.edu WEB RESOURCES

56. 56