This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned.

Risk summary:
-Emtricitabine/rilpivirine/tenofovir alafenamide: Insufficient data available on use of tenofovir alafenamide in pregnant women to inform a drug-related risk.
-Emtricitabine/rilpivirine/tenofovir disoproxil fumarate (DF): Malformative risk with use of this product in pregnant women is unlikely.

Comments:
-A pregnancy exposure registry is available.
-Lower exposures of rilpivirine were observed during pregnancy (compared to postpartum period); viral load should be monitored closely.
-According to some authorities: Effective contraception is recommended during therapy.
-According to some authorities: Pregnancy testing should be performed in patients of childbearing potential before starting emtricitabine/rilpivirine/tenofovir DF.

Animal studies have failed to reveal evidence of embryofetal toxicity, reproductive toxicity, or teratogenicity. Data in pregnant women (between 300 to 1000 outcomes [rilpivirine] and more than 1000 outcomes [emtricitabine and tenofovir disoproxil]) showed no malformations, fetotoxicity, or neonatal toxicity associated with emtricitabine, rilpivirine, and tenofovir disoproxil. There are no controlled data in human pregnancy with this combination drug.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with emtricitabine and tenofovir DF, moderate to high (cord blood/maternal delivery plasma drug ratio at least 0.3) with rilpivirine, and low (cord blood/maternal delivery plasma drug ratio less than 0.3) with tenofovir alafenamide.

In a clinical trial, rilpivirine (in combination with background regimen) was evaluated in 19 HIV-1-infected pregnant patients (who were using a rilpivirine-based regimen at time of enrollment) during the second and third trimesters and postpartum; 12 patients completed the trial through postpartum period (6 to 12 weeks after delivery) and 6 pregnancy outcomes were missing. Total rilpivirine exposure was about 30% to 40% lower during pregnancy compared with postpartum (6 to 12 weeks); protein binding was similar (greater than 99%) during the second and third trimester and postpartum. One patient discontinued the trial after fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Of the 12 patients who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was sustained in 10 patients (83.3%) through the third trimester visit and in 9 patients (75%) through the 6- to 12-week postpartum visit; virologic outcomes during the third trimester visit were missing for 2 patients who were withdrawn (1 was nonadherent to study drug; 1 withdrew consent). Of the 10 infants with HIV test results available (born to 10 HIV-1-infected pregnant patients), all had negative HIV-1 test results at time of delivery and up to 16 weeks postpartum; all 10 infants received antiretroviral prophylaxis with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum (no new safety findings compared with its known safety profile in HIV-1-infected adults).

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Healthcare providers are encouraged to prospectively register patients. For additional information: apregistry.com

The APR has received prospective reports of over 5025 exposures to emtricitabine-containing regimens (over 3600 exposed in the first trimester; over 1425 exposed in the second/third trimester) resulting in live births; there was no difference between emtricitabine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For emtricitabine, enough first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of cardiovascular and genitourinary defects (the more common classes); no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to emtricitabine was 2.6% and 2.4%, respectively.

The APR has received prospective reports of over 650 exposures to rilpivirine-containing regimens (over 475 exposed in the first trimester; over 175 exposed in the second/third trimester) resulting in live births; there was no difference between rilpivirine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. Enough first-trimester exposures have been monitored to detect at least a 2-fold increased risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to rilpivirine was 1.4% and 1.5%, respectively.

The APR has received prospective reports of over 425 exposures to tenofovir alafenamide-containing regimens (over 325 exposed in the first trimester; over 100 exposed in the second/third trimester) resulting in live births; available data showed 17 birth defects in the first trimester compared with 1 birth defect in the second/third trimester. For tenofovir alafenamide, enough first-trimester exposures have been monitored to detect at least a 2-fold increase in risk of overall birth defects; no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to tenofovir alafenamide was 4.9% and 1.9%, respectively.

The APR has received prospective reports of over 6075 exposures to tenofovir disoproxil fumarate (DF)-containing regimens (over 4250 exposed in the first trimester; over 1825 exposed in the second/third trimester) resulting in live births; there was no difference between tenofovir DF and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For tenofovir DF, enough first trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of cardiovascular and genitourinary defects (the more common classes); no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to tenofovir DF was 2.4% and 2.4%, respectively.

AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

See references

EMTRICITABINE:
Emtricitabine has been relatively well studied during breastfeeding; on occasion, it has been used to treat HIV-infected mothers who were breastfeeding. During long-term maternal use of this drug (200 mg/day), breastfed infants usually have undetectable blood levels.

Samples of breast milk obtained from 5 HIV-1-infected women show that emtricitabine is secreted in human milk. Average peak and trough drug levels in breast milk were 679 and 177 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 2% of the proposed emtricitabine dose for infants and achieve serum levels that may lead to emergence of viral resistance to emtricitabine. Breastfeeding infants whose mothers are treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in such infants are unknown.

During ongoing therapy, emtricitabine was measured after a 300-mg dose to 6 nursing mothers with HIV infection. Peak breast milk level was 872 mcg/L (range: 696 to 1063 mcg/L) at about 3 hours; 1 breastfed infant had detectable emtricitabine serum level of 17.5 mcg/L.

Emtricitabine (200 mg once a day) was part of a combination regimen for HIV in 16 Nigerian women exclusively breastfeeding their infants (on demand). Expressed milk samples were collected before dosing and at 0.5, 1, 2, 4, 8, and 12 hours after dosing; peak breast milk level from dried breast milk spots was 843 mcg/L (interquartile range [IQR]: 702 to 1132 mcg/L) at 4 hours (IQR: 2 to 8 hours) after dosing. Infant blood samples were collected at 2 and 8 hours after maternal dosing; analysis of the dried blood spots showed only 3 samples with quantifiable (greater than 16.6 mcg/L) emtricitabine blood levels of 17.5, 18.8, and 19.4 mcg/L.

TENOFOVIR:
Bioavailability of tenofovir is very poor; it is available in 2 formulations, tenofovir DF (more bioavailable) and tenofovir alafenamide. Tenofovir DF releases tenofovir in the bloodstream while tenofovir alafenamide releases tenofovir after entering cells; both are metabolized intracellularly to tenofovir diphosphate (active metabolite). Although not known, the bioavailabilities of tenofovir and tenofovir diphosphate from breast milk are believed to be very low.

Most published experience is with tenofovir DF in HIV therapy and prophylaxis; exposure of the breastfed infant to tenofovir is trivial in HIV-infected mothers. Some data suggest tenofovir alafenamide produces lower milk levels of tenofovir than tenofovir DF. Among HIV-infected mothers who have breastfed during tenofovir DF therapy, no infant side effects have occurred up to 2 years of age.

Samples of breast milk obtained from 5 HIV-1-infected mothers show that tenofovir is secreted in human milk. Average peak and trough drug levels in breast milk were 14.1 and 6.8 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 0.03% of the proposed tenofovir dose for infants and attain trivial infant serum levels. The impact of this exposure in infants breastfed by mothers treated with tenofovir DF is unknown.

In a multicenter study, a single 600 or 900 mg dose of tenofovir DF was administered to mothers during labor; samples of breast milk were collected at various times postpartum. In 75% of samples obtained from 25 mothers during the first 2 days postpartum, tenofovir was detected (greater than 2.5 mcg/L); levels ranged from 6.3 to 17.8 mcg/L. Only 1 of 21 milk samples had detectable tenofovir level (15.7 mcg/L) at 4 to 6 days postpartum.

Tenofovir DF (dose not provided; presumed 300 mg/day), efavirenz, and lamivudine were administered daily (between 6 and 8 p.m.) for prevention of mother-to-child HIV transmission. At 1 month postpartum, milk samples collected in the morning from 33 women had a median tenofovir level of 5 mcg/L (IQR: 0 to 6.1 mcg/L); at 12 months postpartum, milk samples collected in the morning from 47 women had a median tenofovir level of 2.5 mcg/L (IQR: 0 to 5.5 mcg/L). Blood samples were obtained from 25 of their breastfed infants; the median morning infant plasma level of tenofovir at 6 months of age was 24 mcg/L (IQR: 0 to 51.6 mcg/L) and was 0 mcg/L at 12 months of age.

Tenofovir DF 300 mg/day was administered to 6 HIV-infected breastfeeding mothers; tenofovir was measured after dosing during ongoing therapy. Peak breast milk tenofovir level of 5.9 mcg/L (range: 5.5 to 8 mcg/L) was reached at about 3 hours (range: 1 to 7 hours) after dosing; none of the breastfed infants had detectable tenofovir serum levels.

Nigerian and Ugandan women (n=48) used tenofovir DF 300 mg once a day (either in the morning or evening) as part of combination HIV therapy. Expressed milk samples were collected before dosing and several times during the 12 hours after the morning dose (n=30) or at 12, 16, and 20 hours after the prior evening dose (n=18). Using dried breast milk spots, peak breast milk level averaged 5.98 mcg/L (IQR: 0 to 8.05 mcg/L) at about 4 hours (IQR: 1 to 6 hours) after dosing. Their exclusively breastfed infants were fed on demand and had blood samples collected at 2 and 8 hours after maternal dosing; no infants had measurable (greater than 4.2 mcg/L) tenofovir blood level in dried blood spots.

From 28 weeks of pregnancy to delivery, 52 pregnant women with hepatitis B received tenofovir alafenamide (n=26) or tenofovir DF (n=26) to prevent mother-to-child transmission; dosages were not provided. Milk samples collected 6 hours after delivery contained no detectable (less than 0.5 mcg/L) tenofovir In women using tenofovir alafenamide and 12.83 mcg/L (IQR: 7.46 to 29.46 mcg/L) of tenofovir in women using tenofovir DF.

Serum tenofovir levels were measured in 5 infants exclusively breastfed by 4 mothers using tenofovir 245 mg (presumably tenofovir DF 300 mg) daily; infant age averaged 1.8 months. In 4 infants, serum tenofovir was undetectable (less than 0.005 mg/L); in 1 infant, serum tenofovir was 0.0055 mg/L. At 4 months of age, no adverse outcomes (on standard developmental parameters) were observed in 2 of the infants exclusively breastfed for 3 months.

In a study of women and their infants using antiretroviral therapy for HIV infection, mothers who used a tenofovir DF-containing regimen were compared to those who did not. The risk of infant death decreased by 57% in infants breastfed and exposed to tenofovir compared to infants who were not breasted; no alterations in growth and development were observed in breastfed infants during 2 years of follow-up.

A study of 136 breastfed infants of mothers who used tenofovir DF, efavirenz, and lamivudine during pregnancy and postpartum measured bone markers at 1, 6, and 12 months of age; markers included bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen. Although tenofovir is known to affect bone density and bone mineral density in adults, no effects were seen on infants' bone markers in the study.

A prospective cohort study compared growth and development of infants of non-HIV-infected mothers and infants of HIV-infected mothers using tenofovir DF and efavirenz for prevention of mother-to-child HIV transmission; infants were followed up to 12 months of age. No differences in the groups were found in any growth parameters.

RILPIVIRINE:
No published data available regarding use during breastfeeding; an alternate agent may be preferred.

Breastfeeding is not recommended during use of this drug.

Emtricitabine/rilpivirine/tenofovir alafenamide:
-Excreted into human milk: Yes (emtricitabine); Unknown (rilpivirine, tenofovir alafenamide)
-Excreted into animal milk: Yes (rilpivirine); Unknown (tenofovir alafenamide)

Emtricitabine/rilpivirine/tenofovir disoproxil fumarate (DF):
-Excreted into human milk: Yes (emtricitabine, tenofovir); Unknown (rilpivirine)
-Excreted into animal milk: Yes (rilpivirine)

Comments:
-The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects similar to those in adults
-The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.
-Local guidelines should be consulted if replacement feeding is not an option.

See references