Download Use in Special Circumstances Concerns during Pregnancy

ANTIRETROVIRAL DRUGS IN
THE PERINATAL PERIOD
Use of ARV Drugs by HIV-Infected Pregnant
Women and Their Infants
 Considerations for choice of ARV drugs for
pregnant women include:
 Possible changes in dosing requirements resulting
from physiologic changes associated with pregnancy
 Potential exacerbation of ARV drug toxicities
 Pharmacokinetics and toxicity of transplacentally
transferred drugs
 Potential short- and long-term effects of ARV drugs on
fetuses and newborns
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Combination ART and Pregnancy Outcome
 Possible small increased risk of preterm birth in
pregnant women receiving protease inhibitor
(PI)-based ART; however, given the clear
benefits, PIs should not be withheld for fear of
altering pregnancy outcome. (AII)
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Pharmacokinetic Changes
 Altered dosing during pregnancy may be
required for some PIs, such as lopinavir/ritonavir.
(AII)
 Concentrations of the following drugs are reduced
during the 2nd and/or 3rd trimesters
 Lopinavir/ritonavir (LPV/r)
 Atazanavir (ATV)
 Darunavir (DRV)
 Nelfinavir (NFV)
 The need for dosage adjustment depends on the
patient’s treatment experience and use of concomitant
medications.
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Teratogenicity
 Women of childbearing potential should undergo
pregnancy testing before initiating efavirenz
(EFV) and receive counseling about the potential
risk to the fetus and desirability of avoiding
pregnancy while on EFV. (AIII)
 Consider non-EFV regimens in patients who are:
(BIII)
 Planning to become pregnant
 Sexually active and not using effective contraception
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Report all cases of ARV use in pregnant women to
the Antiretroviral Pregnancy Registry:
http://www.APRegistry.com (AIII)
The registry collects observational, nonexperimental
data regarding ARV exposure during pregnancy to
assess potential teratogenicity.
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Nevirapine and Hepatic/Rash Toxicity
 Avoid initiating NVP in women with CD4 counts
>250 cells/µL unless the benefits outweigh the
risks. (AII)
 Risk of hepatotoxicity/hypersensitivity reaction
 Women who are tolerating NVP-containing
regimens and become pregnant can continue
regardless of CD4 count. (AII)
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NRTI Drugs and Mitochondrial Toxicity
 The combination of stavudine (d4T) and
didanosine (ddl) should not be prescribed during
pregnancy because of reports of lactic acidosis
and maternal/neonatal mortality with prolonged
use during pregnancy. (AII)
 Mitochondrial dysfunction should be considered
in uninfected children with perinatal exposure to
ARV drugs who present with severe clinical
findings, particularly neurologic. (AII)
 Long-term clinical follow-up is recommended for
any child with in utero exposure to ARV drugs.
(AIII)
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Protease Inhibitors and Hyperglycemia
 HIV-infected women taking ARV regimens during
pregnancy should undergo standard glucose
screening at 24-28 weeks’ gestation. (AIII)
 Owing to linkage with hyperglycemia:
 Consider earlier glucose screening in women
receiving PI-based regimens initiated before
pregnancy. (BIII)
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Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors (1)
Preferred Agents
Lamivudine (3TC)
Concerns during Pregnancy
Well-studied in pregnancy in combination with ZDV;
ZDV/3TC is a recommended dual-NRTI backbone in
pregnancy. PK not significantly altered. High placental
transfer. No evidence of teratogenicity.
Well tolerated. Short-term safety in mothers and
infants demonstrated.
If hepatitis B coinfected, possible hepatitis B flare if
drug is stopped postpartum.
Zidovudine (AZT,
ZDV)
PK not significantly altered. High placental transfer.
Well tolerated. Short-term safety in mothers and
infants demonstrated.
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Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors (2)
Alternative Agents
Abacavir (ABC)
Concerns during Pregnancy
PK not significantly altered. High placental transfer.
No evidence of teratogenicity.
Hypersensitivity reactions occur in 5-8% of
nonpregnant individuals; a much smaller percentage
are fatal and usually are associated with rechallenge.
Testing with HLA-B*5701 identifies patients at risk;
conduct before starting ABC and educate patients
about signs and symptoms.
Emtricitabine (FTC) Slightly lower PK levels in 3rd trimester, compared
with postpartum. No clear need to increase dosage.
High placental transfer. No evidence of teratogenicity.
If HBV coinfected, possible hepatitis flare if drug is
stopped postpartum.
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Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors (3)
Alternative Agents
Tenofovir disoproxil
fumarate (TDF)
Concerns during Pregnancy
Preferred NRTI in combination with 3TC or FTC in
women with chronic HBV infection. AUC lower in 3rd
trimester; trough levels adequate. High placental
transfer. No evidence of human teratogenicity; in
monkeys, decreased fetal growth and fetal bone
porosity.
Potential renal toxicity; renal function should be
monitored. Clinical studies in humans show bone
demineralization with chronic use; clinical significance
unknown. If HBV coinfected, possible hepatitis flare if
drug stopped postpartum.
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Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors (4)
Use in Special
Circumstances
Concerns during Pregnancy
Didanosine (ddI) PK not altered during pregnancy. Moderate placental
transfer.
Increased rate of birth defects compared with general
population noted after 1st trimester and later exposure; may
be related to maternal characteristics. No specific pattern of
defects noted and clinical relevance uncertain.
Lactic acidosis, sometimes fatal, has been reported in
pregnant women using ddI and d4T together.
Stavudine (d4T)
PKs not significantly altered. High placental transfer. No
evidence of human teratogenicity.
Potential toxicities: Should be used only in special
circumstances. Do not use with ddI or ZDV.
Lactic acidosis, sometimes fatal, has been reported in
pregnant women using ddI and d4T together.
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Nonnucleoside Reverse Transcriptase
Inhibitors (NRTIs) (1)
Preferred Agents
Nevirapine (NVP)
Concerns during Pregnancy
PK not significantly altered. High placental transfer. No
evidence of human teratogenicity.
Increased risk of potentially life-threatening hepatotoxicity
(often rash-associated) in women with high CD4 count at
the time of NVP initiation. If CD4 is >250 cells/µL, start NVP
only if benefit clearly outweighs risk. Increased
transaminase levels at baseline also may increase the risk.
Women who become pregnant while on NVP and are
tolerating it well can continue, regardless of CD4 count.
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Nonnucleoside Reverse Transcriptase
Inhibitors (NRTIs) (2)
Use in Special
Circumstances
Efavirenz (EFV)
Concerns during Pregnancy
AUC decreased in 3rd trimester, but nearly all subjects
exceeded target exposure. Moderate placental transfer.
FDA Pregnancy Class D: Neural tube defects observed in
3 of 20 monkeys; 5 human case reports + 1 case report of
anophthalmia. Relative risk unclear.
• Counsel nonpregnant women on risks and conduct
pregnancy test prior to initiation of EFV.
• Consider alternative regimen for women planning to
become pregnant and for those who are sexually active
and not using effective contraception, assuming
alternatives are acceptable to provider and will not
compromise health of the woman.
• Continue EFV in pregnant women receiving and EFVbased regimen who present for care in 1st trimester if
there is virologic suppression on the regimen.
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Nonnucleoside Reverse Transcriptase
Inhibitors (NRTIs) (3)
Insufficient Data to
Recommend
Concerns during Pregnancy
Etravirine (ETR)
Safety and PK data in pregnancy
insufficient; no significant changes in 4
women. Limited experience in human
pregnancy; no evidence of teratogenicity in
rats and rabbits.
Rilpivirine (RPV)
Safety and PK studies insufficient; no PK
studies in human pregnancy and placental
transfer unknown. No evidence of
teratogenicity in rats or rabbits.
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Protease Inhibitors (1)
Class concerns for PIs: hyperglycemia, diabetes,
question of increased risk of preterm delivery
Preferred Agents
Concerns during Pregnancy
Atazanavir + ritonavir
(ATV/r)
Decreased ATV plasma concentrations during
pregnancy. Use with ritonavir boosting. Serum levels
may be lower when used with TDF or H2-receptor
antagonists. Consider increased dosing during 2nd
and 3rd trimesters. Theoretical concern of increased
indirect bilirubin in neonates.
Lopinavir/ritonavir
(LPV/r)
Increase dosing in 2nd and 3rd trimesters. Oral
solution not optimal in pregnancy owing to alcohol
content. Use twice-daily dosing during pregnancy.
Ritonavir (RTV)
Recommended only as a PK booster for other PIs.
Should not be used alone owing to poor drug levels in
pregnant women and poor tolerance when given at a
full dosage. Oral solution not optimal in pregnancy
owing to alcohol content.
(When used as a lowdose booster)
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Protease Inhibitors (2)
Alternative Agents
Concerns during Pregnancy
Darunavir (DRV/r)
Limited safety and PK data during pregnancy but some
experts recommend twice-daily dosing. Insufficient data
to assess for teratogenicity in humans.
Saquinavir (SQV/r)
PR and/or QT interval prolongations have been
observed; baseline ECG recommended before starting.
Contraindicated if cardiac conduction system disease.
Twice-daily dosing. Insufficient data to assess for
teratogenicity in humans.
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Protease Inhibitors (3)
Use in Special
Circumstances
Concerns during Pregnancy
Indinavir +
ritonavir (IDV/r)
Potential for renal stones. Theoretical concern regarding
increased indirect bilirubin levels in neonates. Monitor HIV
RNA and IDV trough levels if used during pregnancy. Twicedaily dosing.
Nelfinavir (NFV)
Lower rate of viral response compared with LPV/r or EFV
regimes. Consider in special circumstances for prophylaxis.
Twice-daily dosing.
Insufficient Data to Recommend Use
Fosamprenavir (FPV)
Tipranavir (TPV)
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Additional Recommendations by Class
Integrase Inhibitors
Use in Special
Circumstances
Concerns during
Pregnancy
Raltegravir (RAL)
Insufficient data
to assess
teratogenicity.
Variable but high
placental transfer
to fetus. Consider
if preferred and
alternative agents
cannot be used.
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Entry Inhibitors
Insufficient Data to Recommend
Use
Enfurvirtide (T20)
Maraviroc (MVC)
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