Jiajia Wang

Bone mineral density in children and adolescents with perinatal HIV infection

Objective:To estimate prevalence of low bone mineral density (BMD) in perinatally HIV-infected (HIV+) and HIV-exposed but uninfected (HEU) children, and to determine predictors of BMD in HIV+. Design:Cross-sectional analysis within a 15-site United States and Puerto Rico cohort study. Methods:Total body and lumbar spine BMD were measured using dual energy-X-ray absorptiometry. BMD Z-scores accounted for bone age and sex. Multiple linear regression was used to evaluate differences in Z-scores by HIV status and for predictors of BMD in HIV+. Results:350 HIV+ and 160 HEU were enrolled. Mean age was 12.6 and 10.7 years for HIV+ and HEU, respectively. Most (87%) HIV+ were receiving HAART. More HIV+ than HEU had total body and lumbar spine Z-scores less than −2.0 (total body: 7 vs. 1%, P = 0.008; lumbar spine: 4 vs. 1%, P = 0.08). Average differences in Z-scores between HIV+ and HEU were attenuated after height and/or weight adjustment. Among HIV+, total body Z-scores were lower in those with higher CD4% and in those who ever used boosted protease inhibitors or lamivudine. Lumbar spine Z-scores were lower with higher peak viral load and CD4%, more years on HAART, and ever use of indinavir. Conclusion:Rates of low BMD in HIV+ children were greater than expected based on normal population distributions. These differences were partially explained by delays in growth. As most HIV+ children in this study had not entered their pubertal growth spurt, prepubertal factors associated with BMD, magnified or carried forward, may result in sub-optimal peak BMD in adulthood.

Raltegravir pharmacokinetics during pregnancy.

Objective:We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum. Methods:International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 &mgr;g/mL, the estimated 10th percentile in nonpregnant historical controls. Results:Median raltegravir area under the curve was 6.6 &mgr;g·h/mL for second trimester (n = 16), 5.4 &mgr;g·h/mL for third trimester (n = 41), and 11.6 &mgr;g·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010–0.917 &mgr;g/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were <400 copies per milliliter in 92% of women at delivery. Adverse events included elevated liver transaminases in 1 woman and vomiting in 1. All infants with known status are HIV uninfected. Conclusions:Median raltegravir area under the curve was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.

Pubertal onset in children with perinatal HIV infection in the era of combination antiretroviral treatment.

Objective:To evaluate associations of perinatal HIV infection, HIV disease severity, and combination antiretroviral treatment with age at pubertal onset. Design:Analysis of data from two US longitudinal cohort studies (IMPAACT 219C and PHACS AMP), conducted during 2000–2012, including perinatally HIV-infected (PHIV) and HIV-exposed but uninfected (HEU) youth. Tanner stage assessments of pubertal status (breast and pubic hair in girls; genitalia and pubic hair in boys) were conducted annually. Methods:We compared the timing of pubertal onset (Tanner stage ≥2) between PHIV and HEU youth using interval-censored models. For PHIV youth, we evaluated associations of HIV disease severity and combination antiretroviral treatment with age at pubertal onset, adjusting for race/ethnicity and birth cohort. Results:The mean age at pubertal onset was significantly later for the 2086 PHIV youth compared to the 453 HEU children (10.3 vs. 9.6, 10.5 vs. 10.0, 11.3 vs. 10.4, and 11.5 vs. 10.7 years according to female breast, female pubic hair, male genitalia, and male pubic hair staging, respectively, all P < 0.001). PHIV youth with HIV-1 RNA viral load above 10 000 copies/ml (vs. ⩽10 000 copies/ml) or CD4% below 15% (vs. ≥15%) had significantly later pubertal onset (by 4–13 months). Each additional year of combination antiretroviral treatment was associated with a 0.6–1.2-month earlier mean age at pubertal onset, but this trend did not persist after adjustment for birth cohort. Conclusion:Pubertal onset occurs significantly later in PHIV than in HEU youth, especially among those with more severe HIV disease. However, in the current era, combination antiretroviral treatment may result in more normal timing of pubertal onset.

Aggregate Risk of Cardiovascular Disease Among Adolescents Perinatally Infected With the Human Immunodeficiency Virus

Background— Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. Methods and Results— Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. Conclusions— A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.

Pharmacokinetics of an Increased Atazanavir Dose with and without Tenofovir During the Third Trimester of Pregnancy

Background:Reduced atazanavir exposure has been demonstrated during pregnancy with standard atazanavir/ritonavir dosing. We studied an increased dose during the third trimester of pregnancy. Methods:International Maternal Pediatric Adolescent AIDS Clinical Trials Group 1026s is a prospective, nonblinded, pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including 2 cohorts (with or without tenofovir) receiving atazanavir/ritonavir 300/100 mg once daily during the second trimester, 400/100 mg during the third trimester, and 300/100 mg postpartum (PP). Intensive steady-state 24-hour pharmacokinetic profiles were performed. Atazanavir concentrations were measured by high-performance liquid chromatography. Pharmacokinetic targets were the 10th percentile atazanavir area under the concentration versus time curve (AUC) (29.4 &mgr;g·hr−1·mL−1·) in nonpregnant adults on standard dose and 0.15 &mgr;g/mL, minimum trough concentration. Results:Atazanavir pharmacokinetic data were available for 37 women without tenofovir, 35 with tenofovir; median (range) pharmacokinetic parameters are presented for second trimester, third trimester, and PP and number who met target/total. Atazanavir Without Tenofovir:AUC 30.5 (9.19–93.8), 45.7 (11–88.3), and 48.8 (9.9–112.2) &mgr;g·hr−1·mL−1, and 8/14, 29/37, and 27/34 met target. C24 h was 0.49 (0.09–4.09), 0.71 (0.14–2.09), and 0.90 (0.05–2.73) &mgr;g/mL; 13/14, 36/37, and 29/34 met target. Atazanavir With Tenofovir:AUC 26.2 (6.8–60.9) (P < 0.05 compared with PP), 37.7 (0.72–88.2) (P < 0.05 compared with PP), and 58.6 (6–149) &mgr;g·hr−1·mL−1, and 7/17, 23/32, and 27/29 met target. C24 h was 0.44 (0.12–1.06) (P < 0.05 compared with PP), 0.57 (0.02–2.06) (P < 0.05 compared with PP), and 1.26 (0.09–5.43) &mgr;g/mL; 7/17, 23/32, and 27/29 met target. Atazanavir/ritonavir was well tolerated with no unanticipated adverse events. Conclusions:Atazanavir/ritonavir increased to 400/100 mg provides adequate atazanavir exposure during the third trimester and should be considered during the second trimester.

Pharmacokinetics of tenofovir during pregnancy and postpartum

Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum.

Pharmacokinetics of once versus twice daily darunavir in pregnant HIV-infected women

Objective:To describe darunavir (DRV) pharmacokinetics with once-and twice-daily dosing during pregnancy and postpartum in HIV-infected women. Design:Women were enrolled in International Maternal Pediatric Adolescent AIDS Clinical Trials Network Protocol P1026s, a prospective nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included separate cohorts receiving DRV/ritonavir dosed at either 800 mg/100 mg once daily or 600 mg/100 mg twice daily. Methods:Intensive steady-state 12- or 24-hour pharmacokinetic profiles were performed during the second trimester, third trimester, and postpartum. DRV was measured using high-performance liquid chromatography (detection limit: 0.09 &mgr;g/mL). Results:Pharmacokinetic data were available for 64 women (30 once daily and 34 twice daily dosing). Median DRV area under the concentration–time curve (AUC) and maximum concentration were significantly reduced during pregnancy with both dosing regimens compared with postpartum, whereas the last measurable concentration (Clast) was also reduced during pregnancy with once daily DRV. DRV AUC with once daily dosing was reduced by 38% during the second trimester and by 39% during the third trimester. With twice daily dosing, DRV AUC was reduced by 26% in both trimesters. The median (range) ratio of cord blood/maternal delivery DRV concentration in 32 paired samples was 0.18 (range: 0–0.82). Conclusions:DRV exposure is reduced by pregnancy. To achieve DRV plasma concentrations during pregnancy equivalent to those seen in nonpregnant adults, an increased twice daily dose may be necessary. This may be especially important for treatment-experienced women who may have developed antiretroviral resistance mutations.

Reduced indinavir exposure during pregnancy

AIM To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period. METHODS IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9 μg ml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1 μg ml(-1), the suggested minimum target. RESULTS Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative. CONCLUSION Indinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and ∼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.

Insulin Resistance in HIV-Infected Youth is associated with decreased mitochondrial respiration

Objective: To identify relationships between insulin resistance (IR) and mitochondrial respiration in perinatally HIV-infected youth. Design: Case–control study. Methods: Mitochondrial respiration was assessed in perinatally HIV-infected youth in Tanner stages 2–5, 25 youth with IR (IR+) and 50 without IR (IR−) who were enrolled in the Pediatric HIV/AIDS Cohort Study. IR was defined as a homeostatic model of assessment for IR value at least 4.0. A novel, high-throughput oximetry method was used to evaluate cellular respiration in peripheral blood mononuclear cells. Unadjusted and adjusted differences in mitochondrial respiration markers between IR+ and IR− were evaluated, as were correlations between mitochondrial respiration markers and biochemical measurements. Results: IR+ and IR− youth were similar on age, sex, and race/ethnicity. Mean age was 16.5 and 15.6 years in IR+ and IR−, respectively. The IR+ group had significantly higher mean BMI and metabolic analytes (fasting glucose, insulin, cholesterol, triglycerides, and venous lactate and pyruvate) compared with the IR−. Mitochondrial respiration markers were, on average, lower in the IR+ compared with IR−, including basal respiration (417.5 vs. 597.5 pmol, P = 0.074), ATP production (11 513 vs. 15 202 pmol, P = 0.078), proton leak (584.6 vs. 790.0 pmol, P = 0.033), maximal respiration (1815 vs. 2399 pmol, P = 0.025), and spare respiration capacity (1162 vs. 2017 pmol, P = 0.032). Nonmitochondrial respiration did not differ by IR status. The results did not change when adjusted for age. Conclusion: HIV-infected youth with IR have lower mitochondrial respiration markers when compared to youth without IR. Disordered mitochondrial respiration may be a potential mechanism for IR in this population.

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.