Audra Deveikis

Early Prognostic Indicators in Primary Perinatal Human Immunodeficiency Virus Type 1 Infection: Importance of Viral RNA and the Timing of Transmission on Long-Term Outcome

The time of perinatal human immunodeficiency virus type 1 (HIV-1) transmission and the pattern of early plasma viremia as predictors of disease progression were evaluated in infected infants followed from birth. Cox proportional hazards modeling demonstrated that a 1-log higher HIV-1 RNA copy number at birth was associated with a 40% increase in the relative hazard (RH) of developing CDC class A or B symptoms (P = .004), a 60% increase in developing AIDS (P = .01), and an 80% increase in the of risk death (P = .023) over the follow-up period of up to 8 years. The peak HIV-1 RNA copy number for infants during primary viremia was also predictive of progression to AIDS (RH, 9.9; 95% confidence interval [95% CI], 1.8-54.1; P = .008) and death (RH, 6.9; 95% CI, 1.1-43.8; P = .04). The results indicate that high levels of HIV-1 RNA at birth and during primary viremia are associated with early onset of symptoms and rapid disease progression to AIDS and death in perinatally infected children.

Pneumococcal and influenza immunization and human immunodeficiency virus load in children

Objective. HIV‐infected children receiving influenza vaccine, pneumococcal vaccine and both vaccines concurrently were studied to examine the effect of immunization on plasma HIV viral load. Methods. Thirteen children received immunizations: pneumococcal vaccine, 5; pneumococcal and influenza vaccines, 7; and influenza vaccine, 1. Most patients (12 of 13) were receiving combination reverse transcriptase inhibitor antiretroviral therapy without protease inhibitors at the time of immunization. Baseline plasma HIV RNA was determined 1 month prior (11 of 13), 2 weeks prior (12 of 13) and on the day of immunization (12 of 13). Plasma HIV RNA was assayed at 2 weeks (11 of 13), 4 weeks (12 of 13) and 3 months (5 of 13) after immunization. T cell activation markers (HLA‐DR+, CD38+ and CD45RO+, CD28+) were examined for both CD4+ and CD8+ lymphocytes on the day of immunization and 2 weeks after immunization for 11 children. Results. Only one child developed a >0.5‐log increase in viral load at any time after immunization. There was no correlation between an increase in viral load and antibody response to pneumococcal vaccine. At least one activation marker increased (>10%) for two children receiving pneumococcal vaccine and two children receiving pneumococcal and influenza vaccines. One of these children experienced an increase in viral load. Conclusion. Immunization with pneumococcal and influenza vaccines, alone or in combination, is rarely associated with a significant increase in HIV plasma RNA in children receiving combination antiretroviral therapy.

Psychiatric symptoms and antiretroviral nonadherence in US youth with perinatal HIV: a longitudinal study.

Objectives:The relationship of specific psychiatric conditions to adherence has not been examined in longitudinal studies of youth with perinatal HIV infection (PHIV). We examined associations between psychiatric conditions and antiretroviral nonadherence over 2 years. Design:Longitudinal study in 294 PHIV youth, 6–17 years old, in the United States and Puerto Rico. Methods:We annually assessed three nonadherence outcomes: missed above 5% of doses in the past 3 days, missed a dose within the past month, and unsuppressed viral load (>400 copies/ml). We fit multivariable logistic models for nonadherence using Generalized Estimating Equations, and evaluated associations of psychiatric conditions (attention deficit hyperactivity disorder, disruptive behavior, depression, anxiety) at entry with incident nonadherence using multivariable logistic regression. Results:Nonadherence prevalence at study entry was 14% (3-day recall), 32% (past month nonadherence), and 38% (unsuppressed viral load), remaining similar over time. At entry, 38% met symptom cut-off criteria for at least one psychiatric condition. Greater odds of 3-day recall nonadherence were observed at week 96 for those with depression [adjusted odds ratio (aOR) 4.14, 95% confidence interval (CI) 1.11–15.42] or disruptive behavior (aOR 3.36, 95% CI 1.02–11.10], but not at entry. Those with vs. without attention deficit hyperactivity disorder had elevated odds of unsuppressed viral load at weeks 48 (aOR 2.46, 95% CI 1.27–4.78) and 96 (aOR 2.35, 95% CI 1.01–5.45), but not at entry. Among 232 youth adherent at entry, 16% reported incident 3-day recall nonadherence. Disruptive behavior conditions at entry were associated with incident 3-day recall nonadherence (aOR 3.01, 95% CI 1.24–7.31). Conclusion:In PHIV youth, comprehensive adherence interventions that address psychiatric conditions throughout the transition to adult care are needed.

Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women.

Background:Rilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown. Methods:International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography–mass spectrometry; lower limit of quantitation was 10 ng/mL. Results:Median (range) AUC0–24 were 1969 (867–4987, n = 15), 1669 (556–4312, n = 28), and 2387 (188–6736, n = 28) ng·h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37–225, n = 17), 56 (<10–181, n = 30), and 81 (<10–299, n = 28) ng/mL (P < 0.05 for either trimester vs postpartum). High variability in pharmacokinetic parameters was observed between subjects. Median (range) cord blood/maternal concentration ratio was 0.55 (0.3–0.8, n = 21). Delivery HIV-1 RNA was ⩽50 copies per milliliter in 70% and ⩽400 copies per milliliter in 90% of women. Cmin were significantly lower at 15 visits with detectable HIV-1 RNA compared with 61 visits with undetectable HIV-1 RNA, 29 (<10–93) vs 63 (15–200) ng/mL (P = 0.0001). Cmin was below the protein binding–adjusted EC90 concentration (12.2 ng/mL) at 4 visits in 3 of 31 women (10%). Conclusions:Rilpivirine exposure is lower during pregnancy compared with postpartum and highly variable. Ninety percent of women had minimum concentrations above the protein binding–adjusted EC90 for rilpivirine.

Maraviroc Pharmacokinetics in HIV-1–Infected Pregnant Women

OBJECTIVE To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum. METHODS HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated. RESULTS Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60-.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58-0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03-0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing. CONCLUSIONS Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUCtau and maximum concentration of about 30%. Ctrough was reduced by 15% but exceeded the minimum Ctrough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy. CLINICAL TRIALS REGISTRATION NCT00825929 and NCT000422890.