Evaluation and Management of the Infant Exposed to HIV in the United States.

Pediatricians play a crucial role in optimizing the prevention of perinatal transmission of HIV infection. Pediatricians provide antiretroviral prophylaxis to infants born to women with HIV type 1 (HIV) infection during pregnancy and to those whose mother's status was first identified during labor or delivery. Infants whose mothers have an undetermined HIV status should be tested for HIV infection within the boundaries of state laws and receive presumptive HIV therapy if the results are positive. Pediatricians promote avoidance of postnatal HIV transmission by advising mothers with HIV not to breastfeed. Pediatricians test the infant exposed to HIV for determination of HIV infection and monitor possible short- and long-term toxicity from antiretroviral exposure. Finally, pediatricians support families living with HIV by providing counseling to parents or caregivers as an important component of care.

Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy.

BACKGROUND: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r). METHODS: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants > or =14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 microg/mL and area under the curve (AUC) <170 microg hr/mL. RESULTS: Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC = 36.6 (range, 27.9-62.6) microg hr/mL; predose concentration = 2.2 (range, 0.99-4.9) microg/mL; maximum concentration = 4.76 (range, 2.84-7.28) microg/mL and apparent clearance (L/h/m) = 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure. CONCLUSIONS: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.

The PHACS SMARTT Study: Assessment of the Safety of In Utero Exposure to Antiretroviral Drugs.

The Surveillance Monitoring for ART Toxicities (SMARTT) cohort of the Pediatric HIV/AIDS Cohort Study includes over 3,500 HIV-exposed but uninfected infants and children at 22 sites in the US, including Puerto Rico. The goal of the study is to determine the safety of in utero exposure to antiretrovirals (ARVs) and to estimate the incidence of adverse events. Domains being assessed include metabolic, growth and development, cardiac, neurological, neurodevelopmental (ND), behavior, language, and hearing. SMARTT employs an innovative trigger-based design as an efficient means to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. After adjusting for birth cohort and other factors, there was no significant increase in the likelihood of meeting overall case status (case in any domain) with exposure to combination ARVs (cARVs), any ARV class, or any specific ARV. However, several individual ARVs were significantly associated with case status in individual domains, including zidovudine for a metabolic case, first trimester stavudine for a language case, and didanosine plus stavudine for a ND case. We found an increased rate of preterm birth with first trimester exposure to protease inhibitor-based cARV. Although there was no overall increase in congenital anomalies with first trimester cARV, a significant increase was seen with exposure to atazanavir, ritonavir, and didanosine plus stavudine. Tenofovir exposure was associated with significantly lower mean whole-body bone mineral content in the newborn period and a lower length and head circumference at 1 year of age. With ND testing at 1 year of age, specific ARVs (atazanavir, ritonavir-boosted lopinavir, nelfinavir, and tenofovir) were associated with lower performance, although all groups were within the normal range. No ARVs or classes were associated with lower performance between 5 and 13 years of age. Atazanavir and saquinavir exposure were associated with late language emergence at 1 year, but not at 2 years of age. The results of the SMARTT study are generally reassuring, with little evidence for serious adverse events resulting from in utero ARV exposure. However, several findings of concern warrant further evaluation, and new ARVs used in pregnancy need to be evaluated.

Ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age.

BACKGROUND: Few data are available regarding clinical outcomes or dosing requirements for the protease inhibitor ritonavir in human immunodeficiency virus (HIV)-infected children younger than under 24 months of age. METHODS: This prospective, multicenter phase I/II open label treatment trial used ritonavir, zidovudine and lamivudine to treat protease inhibitor-naive, HIV-infected infants between the ages of 4 weeks and 24 months. Two sequential dosing cohorts were treated with 350 or 450 mg/m(2) ritonavir every 12 hours; this report includes results of pharmacokinetics, safety, tolerability and efficacy through 104 weeks of follow-up of all subjects. RESULTS: Fifty HIV-infected children were treated. By week 16, 36 had achieved HIV-1 RNA <400 copies/mL (72% intent-to-treat, 84% as-treated analysis); by week 104, 18 maintained durable viral suppression (36% intent-to-treat, 46% as-treated). Poor medication adherence by caregiver report contributed to virologic failure. Few subjects experienced treatment-limiting toxicity: emesis or ritonavir refusal in 6 (12%); and severe but reversible anemia or elevated serum hepatic transaminases in 1 (4%) each. Apparent oral clearance was higher and the median predose concentrations were substantially lower than those found in adults. Median z scores for weight and height for age/gender were below normal at baseline but improved by week 104. CONCLUSIONS: A combination regimen of ritonavir, zidovudine and lamivudine was generally safe and produced sustained viral suppression in more than one-third of infants who initiated therapy before 2 years of age. Improved palatability of liquid preparations of protease inhibitors, supporting infrastructure and behavioral approaches to improve medication adherence with antiretrovirals will likely be necessary to further improve efficacy.

Early archiving and predominance of nonnucleoside reverse transcriptase inhibitor-resistant HIV-1 among recently infected infants born in the United States.

BACKGROUND: The extent to which drug-resistant human immunodeficiency virus type 1 (HIV-1) acquired through mother-to-child transmission (MTCT) or failed chemoprophylaxis populates viral reservoirs and limits responses to antiretroviral treatment in infants is unknown. METHODS: We evaluated the presence, type, and persistence of drug-resistant HIV-1 in pretreatment plasma and resting CD4(+) T cells from US infants enrolled in a multicenter, open-label, phase 1/2 treatment trial of lopinavir/ritonavir (Pediatric AIDS Clinical Trials Group Protocol 1030) in young infants. RESULTS: Twenty-two consecutively enrolled infants initiating highly active antiretroviral therapy at a median age of 9.7 weeks and treated for up to 96 weeks were studied. Drug-resistant HIV-1 was present in 5 (23.8%) of 21 infants analyzed; 4 (80.0%) had nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1, only 1 of whom had a history of receiving nevirapine chemoprophylaxis. All 4 infants had NNRTI-resistant variants other than the K103N mutation. The fifth infant had the M184V mutation. Drug-resistant virus was archived in the resting CD4(+) T cell latent reservoir in all 5 infants. CONCLUSIONS: The high rate, types, and early archiving of drug-resistant HIV-1 suggests that resistance testing be considered for infants, especially when an NNRTI-based regimen is planned. Furthermore, drug-resistance outcomes in infants should be an important secondary end point in MTCT trials.