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Antiretroviral Drugs in Pregnancy and Breastfeeding: Importance of Surveillance and

Antiretroviral Drugs in Pregnancy and Breastfeeding: Importance of Surveillance and Implications for Developing Countries. Lynne M. Mofenson, M.D. Pediatric, Adolescent and Maternal AIDS Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Antiretroviral Drugs in Pregnancy and Breastfeeding: Importance of Surveillance and

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  1. Antiretroviral Drugs in Pregnancy and Breastfeeding: Importance of Surveillance and Implications for Developing Countries Lynne M. Mofenson, M.D. Pediatric, Adolescent and Maternal AIDS Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Department of Health and Human Services

  2. Drug Therapy in Pregnancy Balancing act Risk of Adverse Fetal Effects Benefit of Maternal Treatment Unfortunately, Often Little Scientific Data to Make Recommendations

  3. 2010 WHO Antiretroviral Drugs Use for Treating Pregnant Women and Prevention MTCT • The PMTCT recommendations refer to two key approaches: • Lifelong ART for HIV-positive women in need of treatment (WHO Stage 3 or 4 or CD4 <350 cells/uL). • 2. Prophylaxis, or the short-term provision of ARVs, to prevent HIV transmission from mother to child in women who don’t need treatment for own health.

  4. ARV Prophylaxis Options for Women Who Don’t Need Therapy for Own Health

  5. Modification ofDrug Pharmacokineticsby Pregnancy Adequacy of Drug Dosing in Pregnancy?

  6. Physiologic Changes During PregnancyCan Affect Therapeutic Drug Administration • Cardiovascular changes • Cardiac output increase, volume expansion, change regional blood flow – dilutional effects • Gastrointestinal changes • Delayed gastric emptying and acidity, increased transit time – drug absorption changes • Renal changes • Increased GFR 20-60% - clearance changes • Hepatic enzyme activity changes • CYP34A, CYP2D6 increased, others decreased – clearance changes Result: Dosing changes may be needed

  7. Pregnancy & Antiretroviral Pharmacokinetics NRTIs NNRTIsPIs Abacavir No ∆ Efavirenz No data Atazanavir AUC  Didanosine No ∆ Etravirine No data Darunavir No data Emtricitabine No ∆ Nevirapine No ∆ Fosamprenavir AUC  Lamivudine No ∆Indinavir AUC  Stavudine No ∆Lopinavir/rit AUC  Zidovudine No ∆Nelfinavir AUC  Ritonavir AUC  NUCLEOTIDESSaquinavir AUC  Tenofovir AUC FUSION INHIBITORSTipranavir No data Enfuvirtide No data INTEGRASE INHIBITORS Raltegravir No data CCR5 CO-RECEPTOR ANTAGONISTS Maraviroc No data

  8. ARV Resistance in Women Stopping Triple DrugARV Prophylaxis for PMTCT After DeliveryParedes R et al. AIDS 2010;24:45-53 • 2, 6 month postpartum resistance study in 94 women receiving triple ARV prophylaxis with AZT/3TC + NFV (91%) or NVP (8%) (and stopping postpartum) between 1998-2005 in WITS. • Postpartum M184V/I rates was 28.7% (51.6% by ASPCR). • Other NRTI resistance mutations ~1% (1% each M41L; D67N; K70R; L210F; K219Q). • PI resistance mutations ~1% (1% each D30N and L90M).

  9. Antiretroviral Safety and Pregnancy

  10. Timing (Gestational Age) of Drug Exposure Affects Fetal Risk Embryogenesis potential for major organ defects (eg, cardiac, CNS) Ex: Neural tube closure by day 28 Oral structures form by day 36 1st 2nd 3rd Fetal development potential for developmental defects (eg, brain development, fetal growth, bone development) Ex: Alcohol exposure after 24 wks Smoking after 20 wks

  11. Antiretroviral Drugs Bring Great Benefits But We Also Must be Cognizant of Potential Risks • With use of more complex and effective antiretroviral regimens we will see a dramatic reduction in new perinatal infections. • However, thousands of infants who are now uninfected have in utero exposure to multiple drugs with limited data on long-term safety. • Longest and most complex regimens most effective but also pose greatest potential risk. • Critical need and ethical obligation to evaluate long- term effects of such exposure.

  12. Need for Surveillance for Potential Toxicities of In Utero ARV Exposure • Potential consequences of concern: • Congenital anomalies (EFV) • Prematurity/low birth weight (PI) • Abnormal fetal bone mineralization and growth (TDF) • Hematologic abnormalities (NRTI) • Mitochondrial dysfunction (NRTI) • Increased malignancy risk? (NRTI) • Cardiovascular abnormalities? (NRTI) • Neurodevelopmental problems? Will continue to apply to thousands of infants born every year

  13. Wouldn’t We Already Know if ARV Use During Pregnancy Caused Significant Problems? • Diethylstilbesterol (DES) • Effects in female offspring not recognized for decades • 40-fold increased risk of rare cervical/vaginal cancer in young women (30s-40s) • 25-33% with cervical malformations Advertisement for DES from a 1957 medical journal Source: CDC http://www.cdc.gov/des/hcp/resources/materials/clinician_handouts.pdf

  14. Antiretroviral Pregnancy Registry 1/89- 1/10Prospective Cases (http://www.APRegistry.com) % Birth Defect CDC general birth defect surveillance 2.7% (2.7-2.8%)

  15. Ability to Detect an Increase Birth Defect Risk is Related to Incidence of Defect and Number Observed 1st Trimester Exposures • If overall rate defect 3%, with 200 live births with 1st trimester exposure can rule out 2-fold increase • To detect increase in relatively rare birth defects, need many more exposed pts • To detect increase of relatively common birth defects, need fewer exposed pts • If overall rate neural tube defect 0.1%, need >2,000 1st trimester exposures to rule out 3-fold increase Neural tube defect Incidence 0.1% RR 3.0 RR 2.0 Overall defects Incidence 3% Watts DH. Curr HIV/AIDS Rep 2007;4:135-140

  16. Example of Neural Tube Teratogen: Valproic Acid • Crosses placenta; cord/maternal blood ratio 1.4-2.4. • Valproic acid is teratogenic in most animal species – mice, rats, and primates (IUGR, craniofacial defects, skeletal abnormalities), but humans seem most susceptible. • 1st trimester exposure in pregnancy is associated with ~10-fold increase in the rate of neural tube defects, primary myelomeningocele, and rarely anencephaly, cardiac, craniofacial – facial clefts, skeletal and limb defects. • Exposure in pregnancy is associated with 1-2% incidence of all types neural tube defects. • Women who need to receive valproate in pregnancy should receive high dose (4-5 mg/day) periconceptional folic acid.

  17. Abnormalities in Neutrophils, Lymphocytes, Platelets with ARV Exposure in Uninfected Infants Le Chenadec J et al. AIDS 2003;17:2053-61 No ARV exposure ARV-exposed Small but persistent abnormalities Neutrophils Lymphocytes Platelets Hemoglobin Transient initial abnormality resolves by 3 mos

  18. Possible Mitochondrial Dysfunction and Perinatal Exposure to Nucleoside Analogues Blanche. Lancet 1999;354:1084-9; Barrett. AIDS 2003;17:1769-85; French Perinatal Cohort Study Grp. Lancet 2002;359:583-4 • French Perinatal Cohort has reported 12 cases mitochondrial dysfunction in cohort of 2,644 uninfected ARV-exposed children (2 deaths). • Primarily neurologic symptoms • May have hyperlactatemia • Abnormalities respiratory chain function • 18 month incidence 0.26% (95% CI, 0.10-0.54%). • 18 month mortality 0.07% (2 of 2,644). • Also reported elevated risk of first febrile seizure in uninfected ARV-exposed children.

  19. Mma Bana: Stillbirths, Prematurity, Low Birth Weight, and Congenital Abnormalities Shapiro R et al. NEJM 2010;362:2282-94 (p=0.04) * Gestational age determined by last menstrual period and/or ultrasound

  20. Impact of HAART vs AZT on Fetal/Infant Growth Powis K et al.17th CROI, San Francisco, CA, Feb 2010 Abs 928 In utero HAART exposure compared to AZT resulted in birth weight reduction, but this difference was no longer present by age 3 months In utero HAART exposure compared to AZT resulted in lower length for age z scores through age 6 months

  21. Incidence of Cancer in Uninfected Children with In Utero Antiretroviral ExposureBenhammou V et al. AIDS 2008;22:2165-77 • 10 cases of cancer detected among 9,127 ARV-exposed uninfected children (median age 5.4 years), no significantly different from the 8.9-9.6 cases expected for general population. • 5 cases CNS cancer observed compared to 1.6 in 1990-1999 regional rates (p=0.05) or 2.4 in 2000- 2004 regional rates (p=0.12). • The relative risk of cancer was higher (HR 13.6, 95% CI 3-74) for children exposed to ddI/3TC than to AZT.

  22. What do We Know AboutAntiretroviral Drugs in Breast Milk?

  23. Antiretroviral Drugs and Breastfeeding • Differential secretion of drugs into breast milk: • If penetrate but in subtherapeutic levels? • If one penetrates but others do not? • May end up with resistant virus in milk (eg, NVP resistance higher in milk than plasma). • Infant exposure: Breastfeeding infants with moms on HAART have detectable 3TC and NVP levels but below therapeutic levels. • Infant exposure gives potential protection but also exposes to potential toxicity and drug resistance if becomes infected.

  24. Higher Rates of Grade 3 or 4 Anemia in Breastfeeding Infants of Mothers on HAART Dryden-Peterson S et al.17th CROI, San Francisco, CA, Feb 2010 Abs 927

  25. Drug Resistance in Infants Infected Despite Maternal HAART

  26. Conclusions • Pregnant women need to receive appropriate treatment for their own health. • Pregnant women who require therapy should initiate it even during the 1st trimester as the benefits to the mother outweigh potential risks. • When giving antiretroviral drugs solely for prophylaxis, it is important to consider the risks and benefits to both infant and mother when choosing between equally effective regimens. • As use of triple drug combination regimens in pregnancy increases in developing countries, it will be important to develop surveillance for potential adverse effects to better inform choices.

  27. Conclusions • Critical surveillance needs include: • Evaluation of effect of different drug regimens on pregnancy outcomes such as prematurity and low birth weight as well as birth defects. • Longer-term infant outcomes – growth, hematologic/cardiac/renal/bone systems, neurodevelopment, cancer • Drug resistance in mothers with prophylaxis regimens that are stopped. • Drug resistance in infants infected despite prophylaxis.

  28. Thank You For Your Attention

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