Recommendations For Antiretroviral Chemoprophylaxis To Reduce Perinatal HIV Transmission

The following recommendations for the use of antiretroviral chemoprophylaxis to reduce the risk for perinatal transmission are based on various scenarios that may be commonly encountered in clinical practice (Table 3), with relevant considerations highlighted in the subsequent discussion sections. These scenarios present only recommendations, and flexibility should be exercised according to the patient's individual circumstances. In the 1994 Recommendations (2), six clinical scenarios were delineated based on maternal CD4+ count, gestational age, and prior antiretroviral use. Because current data indicate that the PACTG 076 ZDV regimen also is effective for women with advanced disease, low CD4+ count, and prior ZDV therapy, clinical scenarios by CD4+ count and prior ZDV use are not resented. Additionally, because current data indicate most transmission occurs near the time of or during delivery, ZDV chemoprophylaxis is recommended regardless of gestational age; thus, clinical scenarios by gestational age also are not presented.

The antenatal dosing regimen in PACTG 076 (100 mg administered orally five times daily) (Table 1) was selected on the basis of standard ZDV dosage for adults at the time of the study. However, recent data have indicated that administration of ZDV three times daily will maintain intracellular ZDV triphosphate at levels comparable with those observed with more frequent dosing (91-93). Comparable clinical response also has been observed in some clinical trials among persons receiving ZDV twice daily (94-96). Thus, the current standard ZDV dosing regimen for adults is 200 mg three times daily, or 300 mg twice daily. Because the mechanism by which ZDV reduces perinatal transmission is not known, these dosing regimens may not have equivalent efficacy to that observed in PACTG 076. However, a regimen of two- or three-times daily is expected to enhance maternal adherence.

The recommended ZDV dosage for infants was derived from pharmacokinetic studies performed among full-term infants (97). ZDV is primarily cleared through hepatic glucuronidation to an inactive metabolite. The glucuronidation metabolic enzyme system is immature in neonates, leading to prolonged ZDV half-life and clearance compared with older infants (ZDV half-life: 3.1 hours versus 1.9 hours; clearance: 10.9 versus 19.0 mL/minute/kg body weight, respectively). Because premature infants have even greater immaturity in hepatic metabolic function than full-term infants, further prolongation in clearance may be expected. In a study of 15 premature infants who were 26-33 weeks' gestation and who received different ZDV dosing regimens, mean ZDV half-life was 7.2 hours and mean clearance was 2.5 mL/minute/kg body weight during the first 10 days of life (98). At a mean age of 18 days, a decrease in half-life (4.4 hours) and increase in clearance (4.3 mL/minute/kg body weight) were found. Appropriate ZDV dosing for premature infants has not been defined but is being evaluated in a phase I clinical trial in premature infants <34 weeks' gestation. The dosing regimen being studied is 1.5 mg/kg body weight orally or intravenously every 12 hours for the first 2 weeks of life; for infants aged 2-6 weeks, the dose is increased to 2 mg/kg body weight every 8 hours.

Because subtherapeutic dosing of antiretroviral drugs may be associated with enhanced likelihood for the development of drug resistance, women who must temporarily discontinue therapy because of pregnancy-related hyperemesis should not reinstitute therapy until sufficient time has elapsed to ensure that the drugs will be tolerated. To reduce the potential for emergence of resistance, if therapy requires temporary discontinuation for any reason during pregnancy, all drugs should be stopped and reintroduced simultaneously.

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