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

Drug Therapy in Pregnancy Balancing act Benefit of MaternalTreatment Risk of AdverseFetalEffects Unfortunately, Often Little Scientific Data to Make Recommendations

2010 WHO Antiretroviral Drugs Use for Treating Pregnant Women and Prevention MTCT The PMTCT recommendations refer to two key approaches: 1.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.

ARV Prophylaxis Options for Women Who Don’t Need Therapy for Own Health Option A: Maternal AZTOption B: Maternal Triple ARV Prophylaxis MOTHER Antepartum AZT (from14 wks gestation) sdNVP at onset labor * AZT/3TC during labor/delivery* AZT/3TC for 7 d postpartum * * If mother receives >4 wks antepartum AZT, consider omitting sdNVP and AZT/3TC Triple ARV (from 14 wks gestation until 1 week after all exposure to breast milk ceased)  AZT/3TC/LPV/r  AZT/3TC/ABC  AZT/3TC/EFV  TDF/3TC or FTC/EFV INFANT Breastfeeding Infant Daily NVP until 1 week after all exposure to breast milk ceased Non-Breastfeeding Infant sdNVP + twice daily AZT for 6 weeks or daily NVP for 4 to 6 weeks Breastfeeding Infant Twice daily AZT or daily NVP for 4 to 6 weeks Non-Breastfeeding Infant Twice daily AZT or daily NVP for 4 to 6 weeks

Modification of Drug Pharmacokinetics by Pregnancy Adequacy of Drug Dosing in Pregnancy?

Physiologic Changes During Pregnancy Can 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

Pregnancy & Antiretroviral Pharmacokinetics NRTIs NNRTIs PIs 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  NUCLEOTIDES Saquinavir AUC  Tenofovir AUC  FUSION INHIBITORS Tipranavir No data Enfuvirtide No data INTEGRASE INHIBITORS Raltegravir No data CCR5 CO-RECEPTOR ANTAGONISTS Maraviroc No data

ARV Resistance in Women Stopping Triple Drug ARV Prophylaxis for PMTCT After Delivery Paredes 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 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).

Antiretroviral Safety and Pregnancy

Timing (Gestational Age) of Drug Exposure Affects Fetal Risk 1st3rd2nd Embryogenesis potential for major organ defects (eg, cardiac, CNS) Fetal development potential for developmental defects (eg, brain development, fetal growth, bone development) Ex: Neural tube closure by day 28 Oral structures form by day 36 Ex: Alcohol exposure after 24 wks Smoking after 20 wks

 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. Antiretroviral Drugs Bring Great Benefits But We Also Must be Cognizant of Potential Risks

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 Will continue to apply to thousands of infants born every year

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

Antiretroviral Pregnancy Registry 1/89- 1/10 Prospective Cases ( Atazanavir sulfate-containing (9/393) ABC-containing (19/670) AZT-containing (100/3,289) 3TC-containing (99/3,481) d4T-containing (19/795) Efavirenz containing (14/546) FTC containing (12/456) Indinavir-containing (6/276) Nelfinavir-containing (37/1,080) Nevirapine-containing (19/882) Ritonavir-containing (24/1,122) Lopinavir-containing (10/590) Tenofovir-containing (19/879) ddI-containing (17/380) 2.3% ( %) 2.8% (1.7 – 4.4%) 3.0% ( %) 2.8% ( %) 2.4% (1.4 – 3.7%) 2.6% ( %) 2.6% (1.4 – 4.6%) 2.2% ( %) 3.4% (2.4 – 4.7%) 2.2% (1.3 – 3.3%) 2.1% (1.4 – 3.2%) 1.7% (0.8 – 3.1%) 2.2% (1.3 – 3.4%) 4.5% (2.6 – 7.1%) CDC general birth defect surveillance2.7% ( %) 1 st trimester any ARV exposure2.8% ( %) % Birth Defect

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

Example of Neural Tube Teratogen: Valproic Acid  Crosses placenta; cord/maternal blood ratio  Valproic acid is teratogenic in most animal species – mice, rats, and primates (IUGR, craniofacial defects, skeletal abnormalities), but humans seem most susceptible.  1 st 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.

Abnormalities in Neutrophils, Lymphocytes, Platelets with ARV Exposure in Uninfected Infants Le Chenadec J et al. AIDS 2003;17: Hemoglobin Platelets Lymphocytes Neutrophils ARV-exposedNo ARV exposure Small but persistent abnormalities Transient initial abnormality resolves by 3 mos

Possible Mitochondrial Dysfunction and Perinatal Exposure to Nucleoside Analogues Blanche. Lancet 1999;354:1084-9; Barrett. AIDS 2003;17: ; 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, %).  18 month mortality 0.07% (2 of 2,644).  Also reported elevated risk of first febrile seizure in uninfected ARV-exposed children.

Mma Bana: Stillbirths, Prematurity, Low Birth Weight, and Congenital Abnormalities Shapiro R et al. NEJM 2010;362: AZT/3TC/ ABC AZT/3TC/ LPV/r Stillbirths (% of deliveries) 8 (3%) 5 (2%) Live births (including twins) Prematurity (< 37 weeks*) 42 (15%)61 (23%) Low Birth Weight (< 2.5 kg) 37 (13%)45 (17%) Congenital Abnormality5 (2%) * Gestational age determined by last menstrual period and/or ultrasound (p=0.04)

Impact of HAART vs AZT on Fetal/Infant Growth Powis K et al.17 th 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

Incidence of Cancer in Uninfected Children with In Utero Antiretroviral Exposure Benhammou V et al. AIDS 2008;22:  10 cases of cancer detected among 9,127 ARV-exposed uninfected children (median age 5.4 years), no significantly different from the cases expected for general population.  5 cases CNS cancer observed compared to 1.6 in regional rates (p=0.05) or 2.4 in regional rates (p=0.12). Type cancerObserved cases Expected: regional rates (p value) Expected: regional rates (p value) All cancer108.9 (p=0.80)9.6 (p=0.98) Leukemia32.8 (p=0.94)2.9 (p=0.89) CNS tumor51.6 (p=0.05)2.1 (p=0.12) Retinoblastoma 20.4 (p=0.10)0.5 (p=0.18)  The relative risk of cancer was higher (HR 13.6, 95% CI 3-74) for children exposed to ddI/3TC than to AZT.

What do We Know About Antiretroviral Drugs in Breast Milk?

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.

DrugAnimal Breast MilkComments ABC AZT ddI FTC 3TC d4T TFV YES (rats) Not stated YES (rats) YES (rat) YES (primate)BM/Mat serum: 3% peak-20% AUC EFV ETV NVP YES (rats) Not stated YES (rats) APV ATV DRV IDV LPV NFV SQV TPV RAL MVC YES (rats) Not stated YES (rats) “Extensive secretion in rat milk”

DrugAnimal MilkHuman Breast MilkBreast Milk/Maternal Blood Drug Ratio ABC AZT ddI FTC 3TC d4T TFV YES (rats) Not stated YES (rats) YES (rat) YES (primate) Unk YES Unk YES Unk YES BM/Mat plasma ratio ~50% BM 2-3x higher than Mat serum Very low levels, unclear if bioavailable EFV ETV NVP YES (rats) Not stated YES (rats) YES Unk YES BM/Mat plasma ratio 54% BM/Mat plasma ratio 67-90% APV ATV DRV IDV LPV NFV SQV TPV RAL MVC YES (rats) Not stated YES (rats) Unk YES Unk YES Unk BM/Mat plasma ratio: % BM/Mat plasma ratio: 6-24% “Extensive secretion in rat milk”

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

Drug Resistance in Infants Infected Despite Maternal HAART CharacteristicsSWEN, N=7PEPI-Malawi, N=4KiBS, N=16 Author/Meeting-Year/ Abs # Lidstrom/CROI 2010/ Abs 920 Lidstrom/HIV Resistance Workshop 2009/Abs 135 Zeh/CROI 2008/ Abs 84LB CountryUgandaMalawiKenya Maternal PMTCT regimen sdNVPsdNVP (early presenters)HAART Infant PMTCT regimen sdNVP (N=2) or sdNVP + extended NVP (N=5) sdNVP +1 wk ZDV + extended NVP (2) or NVP/AZT (2) x 14 wks sdNVP Timing Infant +PCRBirth (3), 2 wks (3), 6 wks (1) Birthby 24 wks Time Maternal HAART started 12 wks (6) or 24 wks (1) 4-6 wks postpartum28 wks gestation Maternal HAART Regimen d4T/3TC (3) or AZT/3TC (4) + NVP d4T/3TC/NVPZDV/3TC/NVP (6) ZDV/3TC/NFV (10) Major HIV subtypeACC NNRTI resistance7/7 (100%)4/4 (100%)6/6 [NVP exp] (100%) NRTI resistance6/7 (86%)3/4(75%)14/16 (87%) (no PI) Multi-class resistance (NNRTI + NRTI) 6/7 (86%) TAMS 3/7 (43%) 3 /4 (75%)4/6 [NVP+NRTI exp] (67%)

Conclusions  Pregnant women need to receive appropriate treatment for their own health.  Pregnant women who require therapy should initiate it even during the 1 st 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.

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.

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