Antiretroviral Drugs in Pregnancy and Breastfeeding: Importance of Surveillance and Implications for...
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Transcript of Antiretroviral Drugs in Pregnancy and Breastfeeding: Importance of Surveillance and Implications for...
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 Prophylaxis
MOTHER 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 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 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
dataEmtricitabine 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 3.0
RR 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 Comments
ABCAZTddIFTC3TCd4TTFV
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 Ratio
ABCAZTddIFTC3TCd4TTFV
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 bioavailable
EFVETVNVP
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 HAART
Characteristics SWEN, N=7 PEPI-Malawi, N=4 KiBS, N=16
Author/Meeting-Year/ Abs #
Lidstrom/CROI 2010/ Abs 920
Lidstrom/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.
Thank You ForYour Attention