Andrew Wiznia

Albert Einstein College of Medicine, New York, New York, United States

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Publications (85)408.61 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: P1066 is an open-label study of raltegravir in HIV+ youth, ages 4 weeks-18 years. Here we summarize P1066 pharmacokinetic (PK) data and a population PK model for the pediatric chewable tablet and oral granules. Raltegravir PK parameters were calculated using non-compartmental analysis. A two-compartment model was developed using data from P1066 and an adult study of the pediatric formulations. Inter-individual variability was described by an exponential error model, and residual variability was captured by an additive/proportional error model. Twelve-hour concentrations (C12hr ) were calculated from the model-derived elimination rate constant and 8-hour observed concentration. Simulated steady-state concentrations were analyzed by non-compartmental analysis. Target area-under-the-curve (AUC0-12hr ) and C12hr were achieved in each cohort. For the pediatric formulations, geometric mean AUC0-12hr values were 18.0-22.6 µM*hr across cohorts, and C12hr values were 71-130 nM, with lower coefficients of variation vs the film-coated tablet. A two-compartment model with first-order absorption adequately described raltegravir plasma PK in pediatric and adult patients. Weight was a covariate on clearance and central volume, and incorporated using allometric scaling. Raltegravir chewable tablets and oral granules exhibited PK parameters consistent with those from prior adult studies and older children in P1066, as well as lower variability than the film-coated tablet. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    The Journal of Clinical Pharmacology 03/2015; DOI:10.1002/jcph.493 · 2.47 Impact Factor
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    ABSTRACT: Objectives: Some perinatally infected children do not regain normal CD4+ T cell counts despite suppression of HIV-1 plasma viremia by antiretroviral therapy (ART). The frequency, severity and significance of these discordant treatment responses remain unclear. Design: We examined the persistence of CD4+ lymphocytopenia despite virologic suppression in 933 children (>5 years of age) in the USA, Latin America and the Caribbean. Methods: CD4+ T-cell trajectories were examined and Kaplan-Meier methods used to estimate median time to CD4+ T cell count at least 500 cells/[mu]l. Results: After 1 year of virologic suppression, most (99%) children achieved a CD4+ T cell count of at least 200 cells/[mu]l, but CD4+ T cell counts remained below 500 cells/[mu]l after 1 and 2 years of virologic suppression in 14 and 8% of children, respectively. Median times to first CD4+ T cell count at least 500 cells/[mu]l were 1.29, 0.78 and 0.46 years for children with less than 200, 200-349 and 350-499 cells/[mu]l at the start of virologic suppression. New AIDS-defining events occurred in nine children, including four in the first 6 months of virologic suppression. Other infectious and HIV-related diagnoses occurred more frequently and across a wide range of CD4+ cell counts. Conclusion: ART improved CD4+ cell counts in most children, but the time to CD4+ cell count of at least 500 cells was highly dependent upon baseline immunological status. Some children did not reach a CD4+ T cell count of 500 cells/[mu]l despite 2 years of virologic suppression. AIDS-defining events occurred in 1% of the population, including children in whom virologic suppression and improved CD4+ T cell counts were achieved.
    AIDS 01/2015; DOI:10.1097/QAD.0000000000000598 · 6.56 Impact Factor
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    ABSTRACT: Background IMPAACT P1066 is a Phase I/II open-label multicenter trial to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple raltegravir (RAL) formulations in human immunodeficiency virus (HIV)-infected youth.
    01/2015; DOI:10.1093/jpids/piu146
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    ABSTRACT: Abstract We examined youth-caregiver adherence report concordance and association of different adherence self-report items with HIV RNA viral load (VL) in perinatally HIV-infected adolescents assessed in 2003-2008. Youth (n=194; 9-19 years) and their caregivers completed a multi-step 2-day recall, one item on last time medications were missed, and one item on responsibility for managing youths' medications. Across early (9-12 years), middle (13-15 years), and late (16+years) adolescence, both youth and caregivers reported having primary responsibility for youths' medication regimens and demonstrated poor to moderate youth-caregiver concordance on adherence items. Responses to the last-time-missed item had greater association with VL than did the 2-day recall, particularly for longer times (e.g., past month). By age group, significant associations with VL were found for caregiver reports in early adolescence, caregiver and youth reports in middle adolescence, and youth reports in late adolescence, suggesting that caregivers offer better reports of youth adherence during early adolescence, but by later adolescence, youth are better informants. Although design limitations preclude definitive conclusions about the reliability and validity of specific adherence items, this study suggests important issues related to age group, caregiver vs. youth informants of adherence, and recall periods for child adherence assessment that warrant further research.
    AIDS PATIENT CARE and STDs 11/2014; 29(1). DOI:10.1089/apc.2014.0058 · 3.58 Impact Factor
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    ABSTRACT: Background. IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate safety, pharmacokinetics (PK), tolerability and efficacy of multiple raltegravir (RAL) formulations in HIV-infected youth. Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to<12 years; and III: 2 to<6 years) was based on review of short term safety (4 weeks) and intensive pharmacokinetic (PK) evaluation. Safety data through Weeks 24 and 48, and Grade >3 or serious adverse events (AE) were assessed. The primary virologic endpoint was achieving HIV RNA<400 copies/mL or ≥1 log10 reduction between baseline and week 24. Results. The targeted PK parameters (AUC0-12 hr and C12 hr) were achieved for each cohort allowing dose selection for two formulations. Of 96 final dose subjects, there were 15 subjects with Grade 3+ clinical AEs (1 subject with drug related [DR] psychomotor hyperactivity and insomnia); 16 subjects with Grade 3+ laboratory AEs (1 with DR transaminase elevation); 15 subjects with serious clinical AEs (1 with DR rash); 2 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at Week 48 were observed in 78.9%, with a mean CD4 increase of 156 cells/uL (4.6%). Conclusions. 400 mg BID of RAL film-coated tablet (6 to <19 years, and ≥25 kg) and 6 mg/kg BID (maximum dose 300 mg) of RAL chewable tablet (2 to<12 years) were well-tolerated and showed favorable virologic and immunologic responses.
    Clinical Infectious Diseases 10/2013; DOI:10.1093/cid/cit696 · 9.42 Impact Factor
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    ABSTRACT: Background: P1093 is an ongoing Phase I/II multicenter open-label PK, safety, dose finding study of DTG plus optimized background regimen (OBR) in children and adolescents in age defined cohorts. The pediatric weight band dosing of ~1 mg/kg once a day achieved PK exposure in adolescents comparable to those observed at 50 mg once daily in adults. Methods: HIV infected treatment experienced children >12 to < 18 yrs on a failing antiretroviral (ARV) regimen with an HIV RNA of ≥1000 copies/mL (c/mL) were enrolled in Stage 1 (intensive PK) or Stage 2 (extended follow up). DTG was added to a stable, failing ARV regimen in Stage 1, with an OBR added after intensive PK (~Day5-10), or DTG was started with an OBR in Stage 2. Safety, tolerability, CD4 cell count and HIV-1 RNA were evaluated at Week 24. Virologic success was defined as achieving an HIV-1 RNA < 400 c/mL by Week 24 based on the FDA snapshot algorithm, with an additional secondary endpoint of HIV-1 RNA <50 c/mL. Results: Twenty three adolescents (Stage 1, n=10; Stage 2, n=13) were enrolled and completed the 24 week study visit. Demographics were as follows: 78% (18/23) female, 52% (12/23) African American, 35% (8/23) Caucasian, 26% (6/23) were of Hispanic ethnicity. Mean (SD) age 14 yrs (±1.8) and weight= 55.1 kg (±15.6). Median (IQR) baseline CD4+ cell count and % were 466 cells/µL (297, 771) and 22% (18.4, 29.2) respectively. Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 c/mL (3.9, 4.6). Virologic success with an HIV RNA < 400 c/mL was achieved in 82.6 % (19/23 ; 95% CI: 61.2 % to 95%) at Week 24. Additionally, 69.6% (16/23 ; 95% CI: 47.1% to 86.8%) had an HIV RNA load < 50 c/mL at Week 24. Median (IQR) gain in CD4 cell count and % at Week 24 was 63 cells/µL (-56, 180) and 4.9% (1, 8) respectively. DTG was well tolerated, with 2 subjects experiencing Grade 3 laboratory abnormalities; one developed unconjugated bilirubin elevation while on atazanavir as part of the OBR, and another subject developed asymptomatic lipase elevation, which was deemed treatment unrelated. There were no Grade 4 AEs, SAEs or discontinuations due to AEs. Conclusion: DTG plus OBR was safe and well tolerated in HIV infected adolescents. In addition, DTG treatment as part of an OBR provided high virologic efficacy through Week 24.
    IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
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    ABSTRACT: APOBEC3 proteins mediate potent anti-retroviral activity by hypermutating the retroviral genome during reverse transcription. To counteract APOBEC3 and gain a replicative advantage, lentiviruses such as HIV-1 and SIV have evolved the Vif protein, which targets APOBEC3 proteins for proteasomal degradation. However, the proteasome plays a critical role in the generation of T cell peptide epitopes. Whether Vif-mediated destruction of APOBEC3 proteins leads to the generation and presentation of APOBEC3-derived T cell epitopes on the surface of lentivirus-infected cells remains unknown. Here, using peptides derived from multiple Vif-sensitive APOBEC3 proteins, we identified APOBEC3-specific T cell responses in both HIV-1-infected patients and SIV-infected rhesus macaques. These results raise the possibility that these T cell responses may be part of the larger anti-retroviral immune response.
    Journal of Virology 03/2013; 87(11). DOI:10.1128/JVI.00579-12 · 4.65 Impact Factor
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    ABSTRACT: The introduction of combination antiretroviral therapy has resulted in improved survival and quality of life for individuals infected with the human immunodeficiency virus (HIV). There is, as expected, a growing population of perinatally HIV-infected women who are, have been, or will become pregnant. We describe a large cohort of perinatally infected women, compare it with a similar age-matched behaviorally HIV-infected group, and examine factors affecting maternal and infant health. We reviewed the records of 30 perinatally infected women who gave birth at two hospitals between January 2000 and December 2011. The comparison group comprised behaviorally infected women who delivered at these hospitals during the same period. The outcome measures were differences in CD4 counts and viral load between the cohorts, and comparisons of maternal morbidity, mortality, and mother-to-child HIV transmission. Median CD4 counts were significantly lower in the perinatal group before, during, and after pregnancy. The median viral load was significantly higher in the perinatal group. Interval prepregnancy to post partum viral load decline was also greater in the behavioral group. Viral load decreases in the perinatal population were not sustained in the post partum period, at which time viral load trended back to prepregnancy levels. There was one mother-to-child HIV transmission in a perinatally infected woman. Over an extended 4 years of follow-up, there were four deaths in the perinatal group and none in the behavioral group. After delivery, the differences between perinatally and behaviorally infected mothers accentuate, with immunologic deterioration in the former group. The perinatal population may require novel management strategies to ensure outcomes comparable with those observed in the behavioral group.
    Adolescent Health, Medicine and Therapeutics 01/2013; 4:51-8. DOI:10.2147/AHMT.S39885
  • Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 11/2012; 109(5):A34-A34. · 2.75 Impact Factor
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    ABSTRACT: As perinatally HIV-1-infected children grow into adolescents and young adults, they are increasingly burdened with the long-term consequences of chronic HIV-1 infection, with long-term morbidity due to inadequate immunity. In progressive HIV-1 infection in horizontally infected adults, inflammation, T cell activation, and perturbed T cell differentiation lead to an "immune exhaustion", with decline in T cell effector functions. T effector cells develop an increased expression of CD57 and loss of CD28, with an increase in co-inhibitory receptors such as PD-1 and Tim-3. Very little is known about HIV-1 induced T cell dysfunction in vertical infection. In two perinatally antiretroviral drug treated HIV-1-infected groups with median ages of 11.2 yr and 18.5 yr, matched for viral load, we found no difference in the proportion of senescent CD28(-)CD57(+)CD8(+) T cells between the groups. However, the frequency of Tim-3(+)CD8(+) and Tim-3(+)CD4(+) exhausted T cells, but not PD-1(+) T cells, was significantly increased in the adolescents with longer duration of infection compared to the children with shorter duration of HIV-1 infection. PD-1(+)CD8(+) T cells were directly associated with T cell immune activation in children. The frequency of Tim-3(+)CD8(+) T cells positively correlated with HIV-1 plasma viral load in the adolescents but not in the children. These data suggest that Tim-3 upregulation was driven by both HIV-1 viral replication and increased age, whereas PD-1 expression is associated with immune activation. These findings also suggest that the Tim-3 immune exhaustion phenotype rather than PD-1 or senescent cells plays an important role in age-related T cell dysfunction in perinatal HIV-1 infection. Targeting Tim-3 may serve as a novel therapeutic approach to improve immune control of virus replication and mitigate age related T cell exhaustion.
    PLoS ONE 09/2012; 7(9):e45733. DOI:10.1371/journal.pone.0045733 · 3.53 Impact Factor
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    ABSTRACT: This study prospectively examines the effects of maternal and child HIV infection on youth penetrative and unprotected penetrative sex, as well as the role of internal contextual, external contextual, social and self-regulatory factors in influencing the sexual behaviors of HIV-infected (PHIV+), HIV-affected (uninfected with an HIV+ caregiver), and HIV unaffected (uninfected with an HIV- caregiver) youth over time. Data (N=420) were drawn from two longitudinal studies focused on the effects of pediatric or maternal HIV on youth (51% female; 39% PHIV+) and their caregivers (92% female; 46% HIV+). PHIV+ youth were significantly less likely to engage in penetrative sex than HIV- youth at follow-up, after adjusting for contextual, social, and self-regulatory factors. Other individual- and contextual-level factors such as youth alcohol and marijuana use, residing with a biological parent, caregiver employment, caregiver marijuana use, and youth self-concept were also associated with penetrative sex. Youth who used alcohol were significantly more likely to engage in unprotected penetrative sex. Data suggest that, despite contextual, social, and self-regulatory risk factors, PHIV+ youth are less likely to engage in sexual behavior compared to HIV- youth from similar environments. Further research is required to understand delays in sexual activity in PHIV+ youth and also to understand potential factors that promote resiliency, particularly as they age into older adolescence and young adulthood.
    AIDS patient care and STDs 06/2012; 26(7):411-22. DOI:10.1089/apc.2012.0005 · 2.68 Impact Factor
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    ABSTRACT: As the pediatric HIV epidemic in resource-rich countries evolves into an adolescent epidemic, there is a substantive need for studies elucidating mental health needs of perinatally HIV-infected (PHIV +) youth as they transition through adolescence. This article examines the role of perinatal HIV infection in influencing mental health by comparing the changes in psychiatric disorders and substance use disorders (SUD) in PHIV + and perinatally HIV-exposed, but uninfected (PHIV -) youth over time. Participants were recruited from four medical centers in New York City. Individual interviews were administered at baseline and 18-month follow-up to 166 PHIV + and 114 PHIV- youth (49% male, age 9-16 years at baseline). Youth psychiatric disorder was assessed using the caregiver and youth versions of the Diagnostic Interview Schedule for Children (DISC-IV). Over two-thirds of participants met criteria for at least one psychiatric disorder at either baseline or follow-up, with few group differences. Among PHIV + youth, there was a significant decrease in the prevalence of any psychiatric disorder, as well as anxiety disorders specifically over time, whereas the prevalence of any psychiatric disorder among PHIV- youth remained the same and mood disorders increased. Rates of SUD were low in both groups, increasing slightly by follow-up. PHIV + youth reported more use of mental health services at follow-up. CD4 count and HIV RNA viral load were not associated with the presence or absence of disorder at either time point. In conclusion, among PHIV + and PHIV- youth, the rates of psychiatric disorder were high, even compared to other vulnerable populations, suggesting that factors other than perinatal HIV infection may be important determinants of mental health. PHIV + youth were more likely to improve over the observation period. The data underscore the critical need for mental health interventions for both PHIV + and PHIV- youth.
    AIDS Care 04/2012; 24(8):953-62. DOI:10.1080/09540121.2012.668174 · 1.60 Impact Factor
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    ABSTRACT: In the USA, most HIV-1 infected children are on antiretroviral drug regimens, with many individuals surviving through adolescence and into adulthood. The course of HIV-1 infection in these children is variable, and understudied. We determined whether qualitative differences in immune cell subsets could explain a slower disease course in long term survivors with no evidence of immune suppression (LTS-NS; CD4%≥25%) compared to those with severe immune suppression (LTS-SS; CD4%≤15%). Subjects in the LTS-NS group had significantly higher frequencies of naïve (CCR7+CD45RA+) and central memory (CCR7+CD45RA-) CD4+ T cells compared to LTS-SS subjects (p = 0.0005 and <0.0001, respectively). Subjects in the rapid progressing group had significantly higher levels of CD4+ T(EMRA) (CCR7-CD45RA+) cells compared to slow progressing subjects (p<0.0001). Rapid disease progression in vertical infection is associated with significantly higher levels of CD4+ T(EMRA) (CCR7-CD45RA+) cells.
    PLoS ONE 01/2012; 7(1):e29154. DOI:10.1371/journal.pone.0029154 · 3.53 Impact Factor
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    Journal of investigational allergology & clinical immunology: official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología 01/2012; 22(6):442-4. · 2.64 Impact Factor
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    ABSTRACT: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.
    HIV Medicine 12/2011; 13(5):264-75. DOI:10.1111/j.1468-1293.2011.00970.x · 3.45 Impact Factor
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    ABSTRACT: Our objective was to determine whether monitoring HIV-1 DNA concentration or new resistance mutations in peripheral blood mononuclear cells (PBMCs) during effective antiretroviral therapy (ART) predicts virologic failure. A retrospective analysis used blood specimens and clinical data from three nevirapine containing arms of a four-arm, open-label, randomized trial comparing ART regimens in HIV-1-infected children who had failed mono- or dual-nucleoside therapy. Sensitive assays compared cell-associated HIV-1 DNA concentrations and nevirapine (NVP) and lamivudine (3TC) resistance mutations in children with plasma HIV-1 RNA <400 copies(c)/ml who did or did not experience subsequent virologic failure. Forty-six children were analyzed through the last available follow-up specimen, collected at 48 (n=16) or 96 (n=30) weeks of ART. Thirty-five (76%) had sustained viral suppression and 11 (24%) had plasma viral rebound to ≥ 400 c/ml (virologic failure detected at a median of 36 weeks). HIV-1 DNA levels at baseline, 24, 48, and 96 weeks of ART were similar in children who did vs. did not experience virologic failure (p=0.82). HIV-1 DNA levels did not increase prior to viral rebound. NVP resistance mutations were detected in 91% of subjects in the failure group vs. 3% in the suppressed group (p <0.0001). Among nine evaluable children, NVP mutations were first detected prior to virologic failure in two (22%), at viral rebound in five (56%), and after failure in two (22%) children. HIV-1 DNA concentrations did not predict virologic failure in this cohort. New drug resistance mutations were detected in the PBMCs of a minority of virologically suppressed children who subsequently failed ART.
    AIDS research and human retroviruses 11/2011; 28(8):780-8. DOI:10.1089/AID.2011.0039 · 2.18 Impact Factor
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    ABSTRACT: Background: Children with perinatally acquired HIV- disease (PAD) are now of childbearing age and are increasingly facing the challenges of pregnancy. Women with PAD may not be comparable to women with horizontally acquired (HA) HIV with respect to disease status, viral resistance, treatment history and medication adherence. The two groups may also have different pregnancy complications and outcomes, and vertical transmission risk. We describe a group of pregnant women with PAD and compare them with an age matched pregnant HIV positive women with HA infection. Methods:In this retrospective study all 17 PAD subjects with 21 pregnancies were matched and compared to 22 women with HA HIV with 24 pregnancies. All women got comprehensive HIV and prenatal care and delivered in the same hospital. Data abstracted included demographics, mode of delivery, disease status, drug resistance, CD4 counts, viral load (VL), and antiretroviral regimens (ARV) before, during and after pregnancy. CD4 counts and VL were an average of all values one year antepartum, during the 3 trimesters, and one year postpartum. Newborn data included gestational age, and perinatal history. Results:There were 10 Hispanic (H), 5 African-American (AA), and 2 Caucasian (C) women in the PAD group; and 13 AA, 8 H and 1 C in the HA group. The mean age in the two groups was 21 and 22 y, respectively. There was one case of maternal-infant transmission in the PAD group. All women were treated with ZDV/3TC and a PI and or NNRTI except two who received only ZDV/3TC/ABC. In the PAD group there were 8 vaginal deliveries as opposed to 18 in the HA cohort. In the PAD group the median viral load was consistently higher before and during the pregnancy, but comparable at delivery. During the first trimester postpartum, there was rebound viremia in both groups. However, the HA group had a tendency to return to baseline VL, while the PAD group remained persistently viremic. CD4 counts were consistently and statistically lower in the PAD group. Conclusion: There was one case of vertical HIV transmission and we are troubled by the VL rises in the first two trimesters and in the postpartum periods in the PAD group. Sustained virologic suppression is rarely achieved in women with PAD, and this may have long term effects on maternal and infant health.
    Infectious Diseases Society of America 2011 Annual Meeting; 10/2011
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    ABSTRACT: Human endogenous retrovirus (HERV)-specific T cell responses in HIV-1-infected adults have been reported. Whether HERV-specific immunity exists in vertically HIV-1-infected children is unknown. We performed a cross-sectional analysis of HERV-specific T cell responses in 42 vertically HIV-1-infected children. HERV (-H, -K, and -L family)-specific T cell responses were identified in 26 of 42 subjects, with the greatest magnitude observed for the responses to HERV-L. These HERV-specific T cell responses were inversely correlated with the HIV-1 plasma viral load and positively correlated with CD4(+) T cell counts. These data indicate that HERV-specific T cells may participate in controlling HIV-1 replication and that certain highly conserved HERV-derived proteins may serve as promising therapeutic vaccine targets in HIV-1-infected children.
    Journal of Virology 08/2011; 85(21):11526-31. DOI:10.1128/JVI.05418-11 · 4.65 Impact Factor
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    ABSTRACT: HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naïve CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions.
    PLoS ONE 07/2011; 6(7):e21135. DOI:10.1371/journal.pone.0021135 · 3.53 Impact Factor
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    ABSTRACT: HIV-infected children are treated with tenofovir in combination with other, potentially interacting, antiretroviral agents. We report the pharmacokinetic parameters of tenofovir in combination with efavirenz, darunavir-ritonavir, or atazanavir-ritonavir in HIV-infected children. HIV-infected patients 8 to 18 years of age receiving a tenofovir (300 mg)-based regimen containing efavirenz (300 or 600 mg) once daily (group 1), darunavir (300 or 600 mg)-ritonavir (100 mg) twice daily (group 2), or atazanavir (150 to 400 mg)-ritonavir (100 mg) once daily (group 3) were enrolled. Plasma samples were collected over a 24-h time interval. The 90% confidence intervals (90% CI) of the geometric means for the area under the plasma concentration-time curve (AUC) and the minimum concentration of drug in serum (C(min)) of each antiretroviral were computed and checked for overlap with intervals bracketing published values obtained in adult or pediatric studies demonstrating safety and/or efficacy. Group 1 efavirenz plasma concentrations were observed to be higher in patients receiving fixed-dose combination tablets compared with subjects receiving the individual formulation. In group 2, tenofovir and darunavir exposure was observed to be lower than expected. In group 3, tenofovir and atazanavir administered concomitantly produced exposures similar to those published for adult patients. The 90% CI of AUC and C(min) for tenofovir overlapped the target range for all combinations. Informal comparisons of treatment groups did not indicate any advantage to any combination with respect to tenofovir exposure. Further study of exposures achieved with antiretrovirals administered in combination is warranted.
    Antimicrobial Agents and Chemotherapy 06/2011; 55(9):4290-4. DOI:10.1128/AAC.01334-10 · 4.57 Impact Factor

Publication Stats

2k Citations
408.61 Total Impact Points


  • 2002–2015
    • Albert Einstein College of Medicine
      • • Department of Pediatrics
      • • Infectious Diseases
      New York, New York, United States
    • The Rockefeller University
      New York City, New York, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2013
    • Stony Brook University
      Stony Brook, New York, United States
  • 1999–2013
    • University of California, San Francisco
      • • Division of Hospital Medicine
      • • Department of Pediatrics
      San Francisco, California, United States
    • The University of Manchester
      • School of Mathematics
      Manchester, ENG, United Kingdom
  • 2012
    • University of Hawaiʻi at Hilo
      Hilo, Hawaii, United States
  • 2011
    • University of Toronto
      • Department of Immunology
      Toronto, Ontario, Canada
    • New York Medical College
      New York City, New York, United States
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Maryland, United States
  • 2009
    • New York State Psychiatric Institute
      New York City, New York, United States
  • 2005
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 2003–2005
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2004
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 1993
    • Bronx-Lebanon Hospital
      Bronxville, New York, United States