Jennifer S. Read

Late Postnatal Transmission of HIV-1 in Breast-Fed Children: An Individual Patient Data Meta-Analysis

BACKGROUND We analyzed individual patient data to determine the contribution of late postnatal transmission to the overall risk of mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) and the timing and determinants of late postnatal transmission. METHODS Eligible trials were conducted where breast-feeding was common; included >/=2 HIV-1 tests by 3 months, and, if follow-up continued, >/=2 tests at 3-12 months; and regularly assessed infant-feeding modality. Data on children born before January 2000 were analyzed. RESULTS Of 4085 children from 9 trials (breast-fed singletons for whom HIV-1 testing was performed), 993 (24%) were definitively infected (placebo arms, 25.9%; treatment arms, 23.4%; P=.08). Of 539 children with known timing of infection, 225 (42%) had late postnatal transmission. Late postnatal transmission occurred throughout breast-feeding. The estimated hazard function for time to late postnatal transmission was roughly constant. The cumulative probability of late postnatal transmission at 18 months was 9.3%. The overall risk of late postnatal transmission was 8.9 transmissions/100 child-years of breast-feeding and was significantly higher with lower maternal CD4(+) cell counts and male sex. CONCLUSIONS Late postnatal transmission contributes substantially to overall mother-to-child transmission of HIV-1. The risk of late postnatal transmission is generally constant throughout breast-feeding, and late postnatal transmission is associated with a lower maternal CD4(+) cell count and male sex. Biological and cultural mechanisms underlying the association between sex and late postnatal transmission should be further investigated. Interventions to decrease transmission of HIV-1 through breast-feeding are urgently needed.

The Relationship between Serum Human Immunodeficiency Virus Type 1 (HIV-1) RNA Level, CD4 Lymphocyte Percent, and Long-Term Mortality Risk in HIV-1—Infected Children

Association of human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 cell percent, and mortality was examined in stored sera from 254 infected children in an intravenous immunoglobulin infection prophylaxis trial. Ninety-two children (36.2%) died (41 during the study, 51 during long-term follow-up). The geometric mean baseline HIV-1 RNA level was 104,626 copies/mL, and the mean CD4 cell percent was 25%. Relative risk of death (RR) was 2.1 if the baseline RNA level was >100,000 copies/mL (95% confidence interval [CI], 1.4-3.0) and was 3.0 if the baseline CD4 cell percent was <15% (95% CI, 2.2-4.0). If RNA levels increased after baseline, the RR was 1.8 (95% CI, 1.3-2.6), and if the CD4 cell percent dropped to <15%, the RR was 2.8 (95% CI, 1.6-4.9). In a multivariate model, both baseline RNA level and CD4 cell percent were independently associated with mortality risk. In a time-dependent model, the RR per log 10 increase in HIV-1 RNA copy numbers was 2.8 (95% CI, 2.1-3.6) and per 5 percentage point decrement in CD4 cell percent was 1.3 (95% Cl, 1.2-1.5). Both variables should be considered for in decision-making regarding therapy and evaluation of antiretroviral response.

Pregnancy and infection.

Pregnant women have an increased severity of infections with some organisms, including influenza virus, hepatitis E virus, herpes simplex virus, and malaria parasites. This review includes an update on immunologic alterations during pregnancy.

Reduced lopinavir exposure during pregnancy.

Background:Optimal antiretroviral exposure during pregnancy is critical for prevention of mother-to-child HIV transmission and for maternal health. Pregnancy can alter antiretroviral pharmacokinetics. Our objective was to describe lopinavir/ritonavir (LPV/r) pharmacokinetics during pregnancy. Methods:We performed intensive steady-state 12-h pharmacokinetic profiles of lopinavir and ritonavir (three capsules: LPV 400 mg/r 100 mg) at 30–36 weeks gestation and 6–12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. We measured LPV and ritonavir by reverse-phase high-performance liquid chromatography. Target LPV area under concentration versus time curve (AUC) was ≥ 52 μg h/ml, the estimated 10th percentile LPV AUC in non-pregnant historical controls (mean AUC = 83 μg h/ml). Results:Seventeen women completed antepartum evaluations; average gestational age was 35 weeks. Geometric mean antepartum LPV AUC was 44.4 μg h/ml [90% confidence interval (CI), 38.7–50.9] and 12-h post-dose concentration (C12h) was 1.6 μg/ml (90% CI, 1.1–2.5). Twelve women completed postpartum evaluations; geometric mean LPV AUC was 65.2 μg h/ml (90% CI, 49.7–85.4) and C12h was 4.6 μg/ml (90% CI, 3.7–5.7). The geometric mean ratio of antepartum/postpartum LPV AUC was 0.72 (90% CI, 0.54–0.96). Fourteen of 17 (82%) pregnant and three of 12 (25%) postpartum women did not meet our target LPV AUC. The ratio of cord blood/maternal LPV concentration in ten paired detectable samples was 0.2 ± 0.13. Conclusions:LPV/r exposure during late pregnancy was lower compared to postpartum and compared to non-pregnant historical controls. Small amounts of lopinavir cross the placenta. The pharmacokinetics, safety, and effectiveness of increased LPV/r dosing during the third trimester of pregnancy should be investigated.

Breast-feeding and Transmission of HIV-1.

Breast-feeding substantially increases the risk of HIV-1 transmission from mother to child, and although peripartum antiretroviral therapy prophylaxis significantly decreases the risk of mother-to-child transmission around the time of delivery, this approach does not affect breast-feeding transmission. Increased maternal RNA viral load in plasma and breast milk is strongly associated with increased risk of transmission through breast-feeding, as is breast health, and it has been suggested that exclusive breast-feeding could be associated with lower rates of breast-feeding transmission than mixed feeding of both breast- and other milk or feeds. Transmission through breast-feeding can take place at any point during lactation, and the cumulative probability of acquisition of infection increases with duration of breast-feeding. HIV-1 has been detected in breast milk in cell-free and cellular compartments; infant gut mucosal surfaces are the most likely site at which transmission occurs. Innate and acquired immune factors may act most effectively in combination to prevent primary HIV-1 infection by breast milk.

Safety and immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine in HIV-infected children 7 to 12 years old.

Background:Quadrivalent human papillomavirus vaccine (QHPV) is >95% effective in preventing infection with vaccine-type human papillomavirus. The safety and immunogenicity of QHPV are unknown in HIV-infected children. Methods:HIV-infected children (N = 126)-age >7 to <12 years, with a CD4% ≥15-and on stable antiretroviral therapy if CD4% was <25-were blindly assigned to receive a dose of QHPV or placebo (3:1 ratio) at 0, 8, and 24 weeks. Adverse events were evaluated after each dose. Serum antibody against QHPV antigens was measured by a competitive Luminex immunoassay 1 month after the third QHPV dose. Results:The safety profile of QHPV was similar in the 2 study arms and to that previously reported for QHPV recipients. QHPV did not alter the CD4% or plasma HIV RNA. Seroconversion to all 4 antigens occurred in >96% of QHPV recipients and in no placebo recipients. Geometric mean titer was >27 to 262 times greater than the seropositivity cutoff value, depending on the antigen, but was 30%-50% lower against types 6 and 18 than those of age-similar historical controls. Conclusions:QHPV was safe and immunogenic in this cohort of HIV-infected children. Efficacy trials are warranted.

The risk of childhood cancer after neonatal exposure to vitamin K.

Background Two recent studies have found that infants who received intramuscular vitamin K were at twice the expected risk for cancer during childhood. Since nearly all newborns in the United States receive this drug, the public health implications of this association, if confirmed, would be substantial. Methods We examined the relation between vitamin K and cancer in a nested case-control study that used data from the Collaborative Perinatal Project, a multicenter, prospective study of pregnancy, delivery, and childhood. Among 54,795 children born from 1959 through 1966, 48 cases of cancer were diagnosed after the first day of life and before the eighth birthday. Each case child was matched with five randomly selected controls whose last study visit occurred at or after the age when the case childs cancer was diagnosed. Exposure to vitamin K was determined from study forms and medical records. Results Vitamin K had been administered to 68 percent of the 44 case children and 71 percent of the 226 control...

Maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth

Objective:To determine the relationship between maternal antiretroviral regimens during pregnancy and adverse infant outcomes [low birth weight (LBW) and preterm birth]. The a priori hypothesis was that protease inhibitor (PI)-containing regimens are associated with an increased risk of LBW and preterm birth. Design:Prospective cohort study of HIV-1-infected women and their infants (NISDI Perinatal Study). Methods:Data were analysed from 681 women receiving at least one antiretroviral drug [in order of increasing complexity: one or two nucleoside reverse transcriptase inhibitors (1–2 NRTI), two NRTI plus one non-nucleoside reverse transcriptase inhibitor (NNRTI) (HAART/NNRTI), or two NRTI plus one PI (HAART/PI)] for at least 28 days during pregnancy, and who delivered live born, singleton infants with known birth weight and gestational age by 1 March 2005. Multivariable logistic regression modeling was used to assess the relationship of maternal ART with LBW and with preterm birth, adjusting for covariates. Results:The incidence of LBW and preterm birth, respectively, was 9.6% and 7.4% (1–2 NRTI), 7.4% and 5.8% (HAART/NNRTI), and 16.7% and 10.6% (HAART/PI). There was no statistically significant increased risk of LBW [adjusted odds ratio (AOR), 1.5; 95% confidence interval (95% CI), 0.7–3.2] or preterm birth (AOR, 1.1; 95% CI, 0.5–2.8) among women who received HAART/PI compared with women receiving 1–2 NRTI. Conclusions:Among a population of HIV-1-infected women in Latin America and the Caribbean, maternal receipt of PI-containing ART regimens during pregnancy was not associated with a statistically significant increase in risk of LBW or preterm birth.

Diagnosis of HIV-1 Infection in Children Younger Than 18 Months in the United States

The objectives of this technical report are to describe methods of diagnosis of HIV-1 infection in children younger than 18 months in the United States and to review important issues that must be considered by clinicians who care for infants and young children born to HIV-1–infected women. Appropriate HIV-1 diagnostic testing for infants and children younger than 18 months differs from that for older children, adolescents, and adults because of passively transferred maternal HIV-1 antibodies, which may be detectable in the childs bloodstream until 18 months of age. Therefore, routine serologic testing of these infants and young children is generally only informative before the age of 18 months if the test result is negative. Virologic assays, including HIV-1 DNA or RNA assays, represent the gold standard for diagnostic testing of infants and children younger than 18 months. With such testing, the diagnosis of HIV-1 infection (as well as the presumptive exclusion of HIV-1 infection) can be established within the first several weeks of life among nonbreastfed infants. Important factors that must be considered when selecting HIV-1 diagnostic assays for pediatric patients and when choosing the timing of such assays include the age of the child, potential timing of infection of the child, whether the infection status of the childs mother is known or unknown, the antiretroviral exposure history of the mother and of the child, and characteristics of the virus. If the mothers HIV-1 serostatus is unknown, rapid HIV-1 antibody testing of the newborn infant to identify HIV-1 exposure is essential so that antiretroviral prophylaxis can be initiated within the first 12 hours of life if test results are positive. For HIV-1–exposed infants (identified by positive maternal test results or positive antibody results for the infant shortly after birth), it has been recommended that diagnostic testing with HIV-1 DNA or RNA assays be performed within the first 14 days of life, at 1 to 2 months of age, and at 3 to 6 months of age. If any of these test results are positive, repeat testing is recommended to confirm the diagnosis of HIV-1 infection. A diagnosis of HIV-1 infection can be made on the basis of 2 positive HIV-1 DNA or RNA assay results. In nonbreastfeeding children younger than 18 months with no positive HIV-1 virologic test results, presumptive exclusion of HIV-1 infection can be based on 2 negative virologic test results (1 obtained at ≥2 weeks and 1 obtained at ≥4 weeks of age); 1 negative virologic test result obtained at ≥8 weeks of age; or 1 negative HIV-1 antibody test result obtained at ≥6 months of age. Alternatively, presumptive exclusion of HIV-1 infection can be based on 1 positive HIV-1 virologic test with at least 2 subsequent negative virologic test results (at least 1 of which is performed at ≥8 weeks of age) or negative HIV-1 antibody test results (at least 1 of which is performed at ≥6 months of age). Definitive exclusion of HIV-1 infection is based on 2 negative virologic test results, 1 obtained at ≥1 month of age and 1 obtained at ≥4 months of age, or 2 negative HIV-1 antibody test results from separate specimens obtained at ≥6 months of age. For both presumptive and definitive exclusion of infection, the child should have no other laboratory (eg, no positive virologic test results) or clinical (eg, no AIDS-defining conditions) evidence of HIV-1 infection. Many clinicians confirm the absence of HIV-1 infection with a negative HIV-1 antibody assay result at 12 to 18 months of age. For breastfeeding infants, a similar testing algorithm can be followed, with timing of testing starting from the date of complete cessation of breastfeeding instead of the date of birth.

Adherence to Antiretrovirals Among US Women During and After Pregnancy

Background:Antiretrovirals (ARVs) are recommended for maternal health and to reduce HIV-1 mother-to-child transmission, but suboptimal adherence can counteract its benefits. Objectives:To describe antepartum and postpartum adherence to ARV regimens and factors associated with adherence. Methods:We assessed adherence rates among subjects enrolled in Pediatric AIDS Clinical Trials Group Protocol 1025 from August 2002 to July 2005 on tablet formulations with at least one self-report adherence assessment. Perfectly adherent subjects reported no missed doses 4 days before their study visit. Generalized estimating equations were used to compare antepartum with postpartum adherence rates and to identify factors associated with perfect adherence. Results:Of 519 eligible subjects, 334/445 (75%) reported perfect adherence during pregnancy. This rate significantly decreased 6, 24, and 48 weeks postpartum [185/284 (65%), 76/118 (64%), and 42/64 (66%), respectively (P < 0.01)]. Pregnant subjects with perfect adherence had lower viral loads. The odds of perfect adherence were significantly higher for women who initiated ARVs during pregnancy (P < 0.01), did not have AIDS (P = 0.02), never missed prenatal vitamins (P < 0.01), never used marijuana (P = 0.05), or felt happy all or most of the time (P < 0.01). Conclusions:Perfect adherence to ARVs was better antepartum, but overall rates were low. Interventions to improve adherence during pregnancy are needed.