Antiretroviral Drugsin 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 DevelopmentNational Institutes of Health

Department of Health and Human Services

Drug Therapy in Pregnancy

Balancing act

Benefit ofMaternal Treatment

Risk ofAdverse Fetal Effects

Unfortunately, Often Little Scientific Data to Make Recommendations

2010 WHO Antiretroviral Drugs Use for TreatingPregnant 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 AZT Option B: Maternal Triple ARV ProphylaxisMOTHER 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 INFANTBreastfeeding 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 ofDrug Pharmacokinetics

by Pregnancy

Adequacy of Drug Dosing in Pregnancy?

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

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 DrugARV 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 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).

Antiretroviral Safety and Pregnancy

Timing (Gestational Age) of Drug Exposure Affects Fetal Risk

1st 3rd2nd

Embryogenesispotential for

major organ defects(eg, cardiac, CNS)

Fetal developmentpotential 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

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

Antiretroviral Pregnancy Registry 1/89- 1/10 Prospective Cases (http://www.APRegistry.com)

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% (1.0 - 4.3%)2.8% (1.7 – 4.4%)3.0% (2.5 - 3.7%)2.8% (2.3 - 3.5%) 2.4% (1.4 – 3.7%)2.6% (1.4 - 4.3%)2.6% (1.4 – 4.6%)2.2% (0.8 - 4.7%)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 surveillance 2.7% (2.7-2.8%)1st trimester any ARV exposure 2.8% (2.3 - 3.3%)

% Birth Defect

Ability to Detect an Increase Birth Defect Risk is Related to Incidence of Defect and Number Observed 1st Trimester Exposures

To detect increase of relatively common birth defects, need fewer exposed pts

Watts DH. Curr HIV/AIDS Rep 2007;4:135-140

Neural tube defectIncidence 0.1%

Overall defectsIncidence 3%

• To detect increase in relatively rare birth defects, need many more exposed pts– If overall rate defect 3%, with 200 live births with 1st trimester exposure can rule out 2-fold increase

– If overall rate neural tube defect 0.1%, need >2,000 1st trimester exposures to rule out 3-fold increase

RR 3.0RR 2.0

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.

Abnormalities in Neutrophils, Lymphocytes, Platelets with ARV Exposure in Uninfected Infants

Le Chenadec J et al. AIDS 2003;17:2053-61

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;17:1769-85;

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.

Mma Bana: Stillbirths, Prematurity, Low Birth Weight, and Congenital Abnormalities

Shapiro R et al. NEJM 2010;362:2282-94

AZT/3TC/ABC

AZT/3TC/LPV/r

Stillbirths (% of deliveries) 8 (3%) 5 (2%)

Live births (including twins) 283 270

Prematurity (< 37 weeks*)

42 (15%) 61 (23%)

Low Birth Weight (< 2.5 kg)

37 (13%) 45 (17%)

Congenital Abnormality 5 (2%) 5 (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.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 toAZT 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;22:2165-77 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).

Type cancer Observedcases

Expected: 1990-1999 regional rates (p value)

Expected: 2000-2004 regional rates (p value)

All cancer 10 8.9 (p=0.80) 9.6 (p=0.98)

Leukemia 3 2.8 (p=0.94) 2.9 (p=0.89)

CNS tumor 5 1.6 (p=0.05) 2.1 (p=0.12)Retinoblastoma 2 0.4 (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 AboutAntiretroviral 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.

Drug Animal Breast Milk CommentsABCAZTddIFTC3TCd4TTFV

YES (rats)YES (rats)YES (rats)Not statedYES (rats)YES (rat)YES (primate) BM/Mat serum: 3% peak-20% AUC

EFVETVNVP

YES (rats)Not stated YES (rats)

APVATVDRVIDVLPVNFVSQVTPVRALMVC

YES (rats)YES (rats)YES (rats)YES (rats)YES (rats)YES (rats)Not statedNot statedYES (rats)YES (rats) “Extensive secretion in rat milk”

Drug Animal Milk Human Breast Milk Breast Milk/Maternal Blood Drug RatioABCAZTddIFTC3TCd4TTFV

YES (rats)YES (rats)YES (rats)Not statedYES (rats)YES (rat)YES (primate)

UnkYESUnkUnkYESUnkYES

BM/Mat plasma ratio ~50%

BM 2-3x higher than Mat serum

Very low levels, unclear if bioavailableEFVETVNVP

YES (rats)Not stated YES (rats)

YESUnkYES

BM/Mat plasma ratio 54%

BM/Mat plasma ratio 67-90%APVATVDRVIDVLPVNFVSQVTPVRALMVC

YES (rats)YES (rats)YES (rats)YES (rats)YES (rats)YES (rats)Not statedNot statedYES (rats)YES (rats)

UnkUnkUnkYESUnkYESUnk

UnkUnkUnk

BM/Mat plasma ratio: 90-540%

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.17th CROI, San Francisco, CA, Feb 2010 Abs 927

Drug Resistance in Infants Infected Despite Maternal HAARTCharacteristics SWEN, N=7 PEPI-Malawi, N=4 KiBS, N=16Author/Meeting-Year/

Abs #Lidstrom/CROI 2010/

Abs 920Lidstrom/HIV Resistance Workshop 2009/Abs 135

Zeh/CROI 2008/ Abs 84LB

Country Uganda Malawi Kenya

Maternal PMTCT regimen

sdNVP sdNVP (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 +PCR Birth (3), 2 wks (3), 6 wks (1) Birth by 24 wks

Time Maternal HAART started

12 wks (6) or 24 wks (1) 4-6 wks postpartum 28 wks gestation

Maternal HAART Regimen

d4T/3TC (3) or AZT/3TC (4) + NVP

d4T/3TC/NVP ZDV/3TC/NVP (6)ZDV/3TC/NFV (10)

Major HIV subtype A C C

NNRTI resistance 7/7 (100%) 4/4 (100%) 6/6 [NVP exp] (100%)

NRTI resistance 6/7 (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 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.

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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