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Dr Steve Welch
Birmingham Heartlands Hospital
Friday 20 January 2012, Royal College of Obstetricians and Gynaecologist , London
HIV in PregnancyJoint RCOG/BHIVA Multidisciplinary Conference
Long term effects of in utero and neonatal antiretroviral drug exposure on exposed but uninfected infants
Steve Welch, HIV in PregnancyJoint RCOG / BHIVA Multidisciplinary ConferenceLondon 20th January 2012
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Potential adverse effects ofART on infant
• Pregnancy outcome• Adverse effect on maternal health• Teratogenicity• Short term toxicity• Long-term effects
Potential adverse effects ofART on infant
• Pregnancy outcome• Adverse effect on maternal health• Teratogenicity• Short term toxicity• Long-term effects
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AP registry
• Comparator: US CDC birth defects surveillance system 1989-2003
• Rate of birth defects/ 100 live births 2.72(2.68-2.76)
• Prospective outcome data on over 14,000 pregnancies
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First Trimester Exposure• Regimen Defects/Live Births Prevalence (95% CI)• Lamivudine 122/3966 3.1% (2.6%, 3.7%) • Zidovudine 120/3699 3.2% (2.7%, 3.9%) • Ritonavir 35/1567 2.2% (1.6%, 3.1%) • Tenofovir 27/1219 2.2% (1.5%, 3.2%) • Nelfinavir 46/1196 3.8% (2.8%, 5.1%) • Nevirapine 26/1002 2.6% (1.7%, 3.8%) • Lopinavir 18/816 2.2% (1.3%, 3.5%) • Stavudine 19/799 2.4% (1.4%, 3.7%) • Abacavir 25/781 3.2% (2.1%, 4.7%) • Emtricitabine 18/764 2.4% (1.4%, 3.7%) • Efavirenz 17/644 2.6% (1.5%, 4.2%) • Atazanavir 12/576 2.1% (1.1%, 3.6%) • Didanosine 19/409 4.6% (2.8%, 7.2%) • Indinavir 6/285 2.1% (0.8%, 4.5%)
First Trimester Exposure• Regimen Defects/Live Births Prevalence (95% CI)• Lamivudine 122/3966 3.1% (2.6%, 3.7%) • Zidovudine 120/3699 3.2% (2.7%, 3.9%) • Ritonavir 35/1567 2.2% (1.6%, 3.1%) • Tenofovir 27/1219 2.2% (1.5%, 3.2%) • Nelfinavir 46/1196 3.8% (2.8%, 5.1%) • Nevirapine 26/1002 2.6% (1.7%, 3.8%) • Lopinavir 18/816 2.2% (1.3%, 3.5%) • Stavudine 19/799 2.4% (1.4%, 3.7%) • Abacavir 25/781 3.2% (2.1%, 4.7%) • Emtricitabine 18/764 2.4% (1.4%, 3.7%) • Efavirenz 17/644 2.6% (1.5%, 4.2%) • Atazanavir 12/576 2.1% (1.1%, 3.6%) • Didanosine 19/409 4.6% (2.8%, 7.2%) • Indinavir 6/285 2.1% (0.8%, 4.5%)
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Numbers of pregnancies enrolled per drug
First Trimester Second Trimester Third Trimester Overall • Pregnancies Enrolled 6477 5726 1993 14198 • 3TC 4368 4816 1617 10840 • ABC 852 752 306 1920 • ADV 60 0 0 60 • APV 31 5 8 45 • ATV 627 241 71 940 • d4T 898 110 87 1105 • ddC 61 8 5 75 • ddI 467 296 167 940 • DLV 13 1 2 16 • DRV 104 55 24 185 • EFV 763 45 34 849 • ETR 29 14 7 51 • ETV 45 2 0 47 • FOS 97 20 11 129 • FTC 846 321 140 1308 • IDV 331 116 47 501 • LdT 15 5 4 24 • LPV 901 1344 524 2774 • MVC 4 3 0 7 • NFV 1250 1978 727 3967 • NVP 1107 955 544 2620 • RAL 78 34 19 131 • RTV 1714 1653 643 4018 • SQV 196 134 84 415 • T20 24 6 8 38 • TDF 1418 455 257 2133 • TPV 4 0 1 5 • ZDV 4063 5606 2582 12279
Efavirenz
• 3/20 cynomolgus macaque infantswith birth defects:
– Anencephaly with unilateral anophthalmia– Microphthalmia– Cleft palate
• Retrospective case reports of neural tube defects in humans
• FDA classified as category D• Avoidance recommended in BHIVA 2008
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First Trimester Exposure• Regimen Defects/Live Births Prevalence (95% CI)• Lamivudine 122/3966 3.1% (2.6%, 3.7%) • Zidovudine 120/3699 3.2% (2.7%, 3.9%) • Ritonavir 35/1567 2.2% (1.6%, 3.1%) • Tenofovir 27/1219 2.2% (1.5%, 3.2%) • Nelfinavir 46/1196 3.8% (2.8%, 5.1%) • Nevirapine 26/1002 2.6% (1.7%, 3.8%) • Lopinavir 18/816 2.2% (1.3%, 3.5%) • Stavudine 19/799 2.4% (1.4%, 3.7%) • Abacavir 25/781 3.2% (2.1%, 4.7%) • Emtricitabine 18/764 2.4% (1.4%, 3.7%) • Efavirenz 17/644 2.6% (1.5%, 4.2%)• Atazanavir 12/576 2.1% (1.1%, 3.6%) • Didanosine 19/409 4.6% (2.8%, 7.2%) • Indinavir 6/285 2.1% (0.8%, 4.5%)
Ford AIDS 2010
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BHIVA 2012
• No restriction on use of efavirenz in pregnancy or potential pregnancy
Which boosted PI in pregnancy?
• Drug with better established safety data recommended
• “PI’s do not cross placenta”• Darunavir exempted from PIP <3 years by
EMA based on animal data
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Numbers of pregnancies enrolled per drug
First Trimester Second Trimester Third Trimester Overall • Pregnancies Enrolled 6477 5726 1993 14198 • 3TC 4368 4816 1617 10840 • ABC 852 752 306 1920 • ADV 60 0 0 60 • APV 31 5 8 45 • ATV 627 241 71 940 • d4T 898 110 87 1105 • ddC 61 8 5 75 • ddI 467 296 167 940 • DLV 13 1 2 16 • DRV 104 55 24 185 • EFV 763 45 34 849 • ETR 29 14 7 51 • ETV 45 2 0 47 • FOS 97 20 11 129 • FTC 846 321 140 1308 • IDV 331 116 47 501 • LdT 15 5 4 24 • LPV 901 1344 524 2774 • MVC 4 3 0 7 • NFV 1250 1978 727 3967 • NVP 1107 955 544 2620 • RAL 78 34 19 131 • RTV 1714 1653 643 4018 • SQV 196 134 84 415 • T20 24 6 8 38 • TDF 1418 455 257 2133 • TPV 4 0 1 5 • ZDV 4063 5606 2582 12279
ADVISORY COMMITTEE CONSENSUS
• In reviewing all reported defects from the prospective registry, informed by clinical studies and retrospective reports of antiretroviral exposure, the Registry finds no apparent increases in frequency of specific defects with first trimester exposures and no pattern to suggest a common cause. The Registry notes modest but statistically significant elevations of overall defect rates with didanosine and nelfinavir compared with its population based comparator, the MACDP. While the Registry population exposed and monitored to date is not sufficient to detect an increase in the risk of relatively rare defects, these findings should provide some assurance when counseling patients. However, potential limitations of registries such as this should be recognized. The Registry is ongoing. Health care providers are encouraged to report eligible patients to the Registry at www.APRegistry.com.
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Potential adverse effects ofART on infant
• Pregnancy outcome• Adverse effect on maternal health• Teratogenicity• Short term toxicity• Long-term effects
Short-term toxicities of neonatal PEP
• Zidovudine anaemia, lactic acidosis• Kaletra gi disturbances• Didanosine food restrictions
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Potential adverse effects ofART on infant
• Pregnancy outcome• Adverse effect on maternal health• Teratogenicity• Short term toxicity• Long-term effects
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Long term effects
• Bone marrow• Malignancy• Mitochondrial function• Cardiac function• Neurodevelopment
Bone marrow
• Decreased levels of neutrophils, lymphoctes, platelets up to age 8 years in uninfected ARTexposed children
• Significance?
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• Early absence of neurocognitive difference after AZT exposure
• Animal models of persistent mitchondrial toxicity• Infants with hyperlactataemia• 21/5000 uninfected infants in French cohort with
mitochondrial neurological disorders• US 223 deaths/20000 exposed infants –none
with evidence of mitochondrial dysfunction
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Summary – antenatal maternal ART
• Balance of risk is hugely in favour of ART• Balance of risk in favour of not changing
successful regimen• Balance of risk in favour of using most
effective regimen in pregnancy• No current reason to avoid specific drugs• Maintain vigilance
Summary – neonatal PEP
• Effectiveness of PEP less well established than antenatal ART
• Balance of risk in favour of AZT in low risk of transmission
• Balance of risk in favour of 3 drug ART in higher risk, evidence less clear
• Avoid kaletra in preterms (ddi, nelfinavir, stavudine)
• Maintain vigilance
