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Perinatal Transmission and HIV: Two Realities

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

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Perinatal Transmission and HIV: Two Realities

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

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

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

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

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

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

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

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

  9. Perinatal Transmission and HIV: Two Realities 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

  10. Perinatal Transmission and HIV: Two Realities 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”

  11. HIV SURVEILLANCE REPORT • 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 Wortley, et. al. MMWR 2001; 50:RR6-17

  12. MANDATORY HIV TESTING OF PREGNANT WOMEN 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

  13. MATERNAL VIRAL LOAD 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

  14. 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

  15. MATERNAL VIRAL LOAD 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

  16. PACTG 076STUDY 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

  17. PACTG 076EARLY CONCERNS • 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

  18. PACTG 076EARLY RESULTS • 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

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

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

  21. PACTG 076 • Original study cohort consisted of women with CD4 > 200 cells/mm3 and no prior AZT exposure • Subsequent observational studies confirmed the effectiveness of 076 in women with more advanced disease who were not antiretroviral naive

  22. PACTG 076ONGOING DEBATE • Many women do not present for care until much later in pregnancy (ex: 3rd trimester rather than 2nd 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

  23. THAI SHORT-COURSE AZT STUDY • 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

  24. THAI SHORT-COURSE AZT STUDY • 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

  25. THAI SHORT-COURSE AZT STUDY • 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

  26. OTHER SHORT-COURSE AZT STUDIES • 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

  27. THAI SHORT-COURSE AZT STUDY • 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

  28. HIV NET 012 TRIAL • 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

  29. HIV NET 012 TRIAL • 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

  30. HIV NET 012 TRIALTHE REGIMENTS • 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

  31. HAART • 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

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

  33. PACTG 316 • 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

  34. PACTG 316 • 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

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

  36. CESAREAN SECTION • 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

  37. CESAREAN SECTION • 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

  38. CESAREAN SECTION • 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

  39. CESAREAN SECTION • 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

  40. CESAREAN SECTION • 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

  41. OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPED WORLD • 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?

  42. OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPED WORLD • 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?

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

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

  45. OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD • 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

  46. OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD • 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

  47. OUTSTANDING ISSUES/ ONGOING DILEMNAS DEVELOPING WORLD • 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

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