Is Ritonavir safe while breastfeeding?

Summary of use during breastfeeding

Ritonavir is excreted into milk in measurable concentrations and low levels can be found in the blood of some breastfed infants. No adverse reactions in breastfed infants have been reported. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.[1,2]

Effects on the breastfed infant

Fourteen exclusively breastfeeding women with HIV were receiving ritonavir 100 mg and atazanavir 300 mg daily, as part of a multi-drug regimen. Thirteen of fourteen infants received nevirapine-based prophylaxis. No infant experienced a Grade 3 or higher event or serious adverse event. Three infants (21%) experienced Grade 2 adverse events: one with viral rhinitis (16.6 weeks), one with a chest abscess (7.4 weeks), and one with pruritus and papular rash (4.9 weeks). None of the reported events were considered to be related to atazanavir-ritonavir exposure via breastmilk.[9]

Effects on milk supply

Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen.[11-13] Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients,[14,15] although this has been disputed.[16] The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

Levels in milk

Maternal Levels. One study measured ritonavir in breastmilk samples from nursing mothers who had been randomized to receive the drug as part of a clinical trial to evaluate maternal-to-child transmission of HIV infection. The dosages, dosage regimens and times of breastmilk sample collection times were not reported. Ritonavir was not detected in any of 60 breastmilk samples.[3]

Nine mothers who were receiving lopinavir 400 mg plus ritonavir 100 mg twice daily as part of a combination antiretroviral regimen provided a total of 23 milk samples at birth, 1 month, 3 months and/or 6 months postpartum. Milk samples were collected at a median of 4.5 hours (range 3.5 to 6 hours) after the previous dose. The median breastmilk ritonavir concentration was 79 mcg/L (range 31 to 193 mcg/L).[4]

Thirty women were studied at 6, 12 or 24 weeks postpartum (10 at each time). Each mother was taking zidovudine 300 mg, lamivudine 150 mg, lopinavir 400 mg, and ritonavir 100 mg twice daily by mouth starting at delivery. On the study day, at a median of 14.9 hours after the previous evening’s dose, maternal plasma and breastmilk samples were obtained prior to the morning dose and 2, 4 and 6 hours after the dose. One hundred twelve of the 121 breastmilk samples contained detectable quantities (10 mcg/L or greater) of ritonavir, with a median breastmilk concentration of 79 mcg/L over the 6 hours.[5]

Nine HIV-positive women about to undergo cesarean section received 3 doses of lopinavir 200 mg, ritonavir 150 mg, zidovudine 300 mg, lamivudine 50 mg at 3 hour intervals before the procedure. Breastmilk samples were collected at a mean of 25 hours postpartum. In the 8 women where it was quantified, the average milk concentration of ritonavir was 240 mcg/L (range 98 to 402 mcg/L).[6]

Eight women who were taking nirmatrelvir-ritonavir and had donated milk samples to a breastmilk repository had their milk analyzed for nirmatrelvir. All were taking a ritonavir dose of 100 mg twice daily and reported taking milk samples at 0, 1, 2, 4, 6, 8, 10, and 12 hours after a dose. The peak ritonavir concentration in milk occurred at 4 hours after the dose was 55.6 mcg/L and the average concentration was 33.5 mcg/L. This translated into a daily infant dose of 0.005 mg/kg or a relative infant dose of 0.19%.[7]

Eight healthy lactating women who were at least 12 weeks postpartum were administered 3 oral doses of 300 mg of nirmatrelvir and 100 mg of ritonavir every 12 hours. The geometric mean peak milk concentration was 72 mcg/L, and the median half-life in milk was 3.17 hours. The mean daily amount ritonavir recovered in breastmilk was 0.027 mg, representing 0.014% of the corresponding administered daily maternal dose (unadjusted for weight). The estimated daily infant dosage (assuming average milk consumption of 150 mL/kg/day), was 0.006 mg/kg or 1 0.19% of the maternal dose for ritonavir.[8]

Fourteen breastfeeding women with HIV were receiving ritonavir 100 mg and atazanavir 300 mg daily, as part of a multi-drug regimen. Milk samples were collected at three postpartum visits: 5 to 9 days postpartum, 2 to 12 weeks postpartum, and 16 to 24 weeks postpartum. The median breastmilk ritonavir concentration was 13.6 mcg/L (IQR 2.12, 24.3 mcg-L) for ritonavir, with a median time of 17.2 hours (IRQ 14.5, 18.9 hours) between dose and sample collection. The median ritonavir RID was 0.12% (maximum 1.10%).[9]

Infant Levels. Breastfed infants of 9 mothers who were receiving lopinavir 400 mg plus ritonavir 100 mg twice daily as part of a combination antiretroviral regimen had a total of 6 blood samples analyzed at 1 month, 3 months and/or 6 months postpartum. Samples were collected at a median of 4.5 hours (range 3.5 to 6 hours) after the previous maternal dose and a median of 30 minutes (range 20 to 60 minutes) after the previous nursing. The infants’ median ritonavir plasma concentration was 7 mcg/L (range 0 to 138 mcg/L), which was a median of 12% (range 11 to 40%) of the maternal serum concentration.[4]

Ritonavir was measured in 117 breastfed (90% exclusive) infants whose mothers were taking lopinavir plus ritonavir for HIV infection during pregnancy and postpartum. At 8 and 12 weeks postpartum, none of the infants had detectable ritonavir in their plasma; 91% of infants had detectable ritonavir in their hair samples at 12 weeks postpartum at a mean concentration of 0.15 ng/mg of hair (range 0.03 to 0.42 ng/mg). The authors interpreted the results to mean that infants receive negligible exposure to ritonavir during breastfeeding.[10]

Thirty nursing mothers were studied at 6, 12 or 24 weeks postpartum (10 at each time). Each mother was taking ritonavir 100 mg twice daily by mouth starting at delivery. Infant plasma samples were obtained before their mother’s first dose and at 2, 4 and 6 hours after the mother’s dose. Infants were allowed to breastfeed ad libitum during the study period. Ritonavir was undetectable (<10 mcg/L) in all of the 115 infant plasma samples.[5]