antiretroviral drugs in the perinatal period. use of arv drugs by hiv-infected pregnant women and...

ANTIRETROVIRAL DRUGS INTHE 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

August 20122 www.aidsetc.org

Combination ART and Pregnancy OutcomeCombination 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)


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.


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


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.

6 www.aidsetc.orgAugust 2012

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)


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)


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)


Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (1)


Preferred Agents Concerns during Pregnancy

Lamivudine (3TC) 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.


Alternative Agents Concerns during Pregnancy

Abacavir (ABC) 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.




Tenofovir disoproxil fumarate (TDF)

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.



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.


Nonnucleoside Reverse Transcriptase Inhibitors (NRTIs) (1)


Nevirapine (NVP) 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.





Efavirenz (EFV) 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 EFV-based regimen who present for care in 1st trimester if there is virologic suppression on the regimen.



Insufficient Data to Recommend


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.


Protease Inhibitors (1)



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)

(When used as a low-dose booster)

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.

Class concerns for PIs: hyperglycemia, diabetes, question of increased risk of preterm delivery



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.



Insufficient Data to Recommend Use

Fosamprenavir (FPV)

Tipranavir (TPV)




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. Twice-daily dosing.

Nelfinavir (NFV) Lower rate of viral response compared with LPV/r or EFV regimes. Consider in special circumstances for prophylaxis. Twice-daily dosing.

Additional Recommendations by Class

Integrase Inhibitors



Raltegravir (RAL) Insufficient data to assess teratogenicity. Variable but high placental transfer to fetus. Consider if preferred and alternative agents cannot be used.

Entry Inhibitors

Insufficient Data to Recommend Use

Enfurvirtide (T20)

Maraviroc (MVC)


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