Research Interests: Microbiology, Aging, Medical Microbiology, Pharmacokinetics, Medicine, and 15 moreBirth Weight, Population, Humans, Female, Male, Hiv Infection, Human immunodeficiency virus, Gestational Age, Antiviral Agents, Dosing, Premature infant, Pharmacology and pharmaceutical sciences, HIV infections, Infant Premature, and Zidovudine
The purpose of this study was to assess the population pharmacokinetics (PK) and pharmacodynamics (PD) of zidovudine (ZDV) in infants and children. This evaluation includes 394 subjects who participated in Pediatric AIDS Clinical Trials... more
The purpose of this study was to assess the population pharmacokinetics (PK) and pharmacodynamics (PD) of zidovudine (ZDV) in infants and children. This evaluation includes 394 subjects who participated in Pediatric AIDS Clinical Trials Group (PACTG) Study 152 and received either ZDV alone or in combination with didanosine. The most significant PK covariate was age, with infants < 2 years of age having reduced size‐adjusted clearance. ZDV exposure was weakly related to maximal reduction in immune complex‐dissociated (ICD) p24 antigen but not to reduction at 6 months. Mild chronic anemia occurred in 7.6% of subjects with ZDV average concentration < 1.3 μM (350 ng/mL) versus in 23.4% subjects with higher ZDV concentrations (p < 0.001). There was a direct linear relationship between hemoglobin and ZDV levels. It was concluded that ZDV oral clearance is reduced in infants compared to older children. This lower clearance leads to higher ZDV exposure in infants and contributes to increased hematologic toxicity.
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Research Interests: Ophthalmology, Medicine, Visual acuity, Prospective studies, Humans, and 15 moreFemale, Male, Cytomegalovirus, Microbial genetic and drug resistance, Retinitis, Clinical Sciences, Optometry and Ophthalmology, Adult, Public health systems and services research, Survival Rate, Microbial Sensitivity Tests, Cytomegalovirus Infections, Cytomegalovirus retinitis, Ganciclovir, and Foscarnet
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Objective:Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics (PK) with TB therapy, formulation, age, and CYP2B6... more
Objective:Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics (PK) with TB therapy, formulation, age, and CYP2B6 genotype.Design:PK data from three IMPAACT/PACTG studies (P382, P1021, P1070) for children initiating therapy less than 40 months of age were evaluated.Methods:PK data were combined in a population PK model. Exposure from the 2-week PK visit was compared to changes in viral RNA between the Week 0 and Week 4 visits.Results:The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first PK visit was 17.0 months (range: 2.0 to 39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared to opened capsules. TB therapy (isoniazid [INH] and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target AUC range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on CL in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (AUCs) than for higher quartiles (p=0.013).Conclusion:EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.
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ImportanceThe COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the... more
ImportanceThe COVID-19 pandemic has caused millions of infections and deaths and resulted in unprecedented international public health social and economic crises. As SARS-CoV-2 spread across the globe and its impact became evident, the development of safe and effective vaccines became a priority. Outlining the processes used to establish and support the conduct of the phase 3 randomized clinical trials that led to the rapid emergency use authorization and approval of several COVID-19 vaccines is of major significance for current and future pandemic response efforts.ObservationsTo support the rapid development of vaccines for the US population and the rest of the world, the National Institute of Allergy and Infectious Diseases established the COVID-19 Prevention Network (CoVPN) to assist in the coordination and implementation of phase 3 efficacy trials for COVID-19 vaccine candidates and monoclonal antibodies. By bringing together multiple networks, CoVPN was able to draw on existing...
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Pregnancy outcomes of perinatally HIV-infected women (PHIV) are poorly defined. We compared preterm delivery and birth weight (BW) outcomes [low BW (LBW, <2500 g), small-for-gestational-age (SGA), and BW z-scores (BWZ)] in HIV-exposed... more
Pregnancy outcomes of perinatally HIV-infected women (PHIV) are poorly defined. We compared preterm delivery and birth weight (BW) outcomes [low BW (LBW, <2500 g), small-for-gestational-age (SGA), and BW z-scores (BWZ)] in HIV-exposed uninfected infants of PHIV vs. non-perinatally HIV-infected (NPHIV) pregnant women in the PHACS SMARTT or IMPAACT P1025 studies. Mixed effects models were fit to assess the association of maternal PHIV status with infant BWZ; log binomial models were used to estimate adjusted relative risks (aRR) for dichotomous outcomes. Age-stratified analyses were also performed. From 1998-2013, 2,270 HIV-infected pregnant women delivered 2,692 newborns (270 born to PHIV and 2,422 to NPHIV women). PHIV women were younger, (mean age 21 vs. 25 years, p<0.01), more likely to have a pregnancy CD4 count <200 cells/mm3 (19% vs. 11%, p=0.01), delivery HIV RNA level ≥400 copies/mL (28% vs. 17%, p<0.01), and receipt of ≥3-class antiretroviral therapy during pregn...
Research Interests: Obstetrics, Medicine, Birth Weight, Biological Sciences, Prospective studies, and 14 morePregnancy, Population, Humans, United States, Female, Male, Young Adult, Adult, Gestational Age, Clinical Infectious Diseases, Premature Birth, Confidence Interval, Medical and Health Sciences, and HIV infections
Combination antiretroviral therapy (cART) has resulted in a dramatic decrease in human immunodeficiency virus (HIV)-related opportunistic infections and deaths in US youth, but both continue to occur. We estimated the incidence of... more
Combination antiretroviral therapy (cART) has resulted in a dramatic decrease in human immunodeficiency virus (HIV)-related opportunistic infections and deaths in US youth, but both continue to occur. We estimated the incidence of complications and deaths in IMPAACT P1074, a long-term US-based prospective multicenter cohort study conducted from April 2008 to June 2014. Incidence rates of selected diagnoses and trends over time were compared with those from a previous observational cohort study, P219C (2004-2007). Causes of death and relevant demographic and clinical features were reviewed. Among 1201 HIV-infected youth in P1074 (87% perinatally infected; mean [standard deviation] age at last chart review, 20.9 [5.4] years), psychiatric and neurodevelopmental disorders, asthma, pneumonia, and genital tract infections were among the most common comorbid conditions. Compared with findings in P219C, conditions with significantly increased incidence included substance or alcohol abuse...
Research Interests: Pediatrics, Incidence Geometry, Adolescent, Mortality, Medicine, and 15 moreBiological Sciences, Prospective studies, Humans, Metabolic diseases, Female, Pneumonia, Male, Incidence, Adult, Age Factors, Risk Factors, AIDS Dementia Complex, Clinical Infectious Diseases, Medical and Health Sciences, and HIV infections
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Research Interests: Genetics, Immunology, Pathogenesis, Biology, Medicine, and 15 moreHIV, Humans, Child, Female, Disease, Pediatric, Chemokine, Human immunodeficiency virus, Immune system, Disease Progression, Innate Immune System, Infectivity, Paediatrics and reproductive medicine, HIV infections, and Genetic predisposition to disease
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Research Interests: Infectious Diseases, Adolescent, Medicine, HIV, Biological Sciences, and 15 moreHumans, Child, Female, Male, Infectious, Adult, Highly Active Antiretroviral Therapy, European Continental Ancestry Group, Lamivudine, Regimen, Efavirenz, Acquired immunodeficiency syndrome, High risk, Medical and Health Sciences, and HIV infections
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Research Interests: Adolescent, Medicine, Antiretroviral Therapy, Pregnancy, Population, and 15 moreHumans, Child, United States, Female, Male, Cohort Study, Cohort, Clinical Sciences, Protease Inhibitors, Time Factors, Highly Active Antiretroviral Therapy, Cohort Studies, Viral Load, Prospective Cohort Study, and HIV infections
Research Interests: Virology, Medicine, HIV clinical trials, Humans, Disease, and 13 moreCytomegalovirus, Polymerase Chain Reaction, Hiv Infection, Clinical Sciences, Middle Aged, Adult, Highly Active Antiretroviral Therapy, Cytomegalovirus Infections, Proportional Hazards Models, Antiviral Agents, Acquired immunodeficiency syndrome, Ganciclovir, and HIV infections
To assess the characteristics and outcomes of antiretroviral treatment (ART) interruption (TI) in perinatally HIV-infected children.
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Research Interests: Cardiovascular disease, Lipids, Humans, Diabetes mellitus, American Indian, and 15 moreBlood Pressure, Female, Alcohol Drinking, Male, Aged, Longitudinal Studies, Binge drinking, Alcohol Abuse, Cardiovascular Diseases, High Density Lipoprotein, Annals, Albuminuria, Alcohol Use, cardiovascular disease risk factor, and Medical and Health Sciences
Research Interests: Adolescent, Medicine, HIV, Antiretroviral Therapy, Humans, and 15 moreHIV drug resistance, Female, Drug Resistance, Male, Adult, Public health systems and services research, Highly Active Antiretroviral Therapy, Genotyping, Combination drug therapy, Observational Study, Regimen, Molecular Sequence Data, antiretroviral treatment, reverse transcriptase inhibitors, and HIV infections
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Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells,... more
Effective antiretroviral therapy has led to significant human immunodeficiency virus type 1 (HIV-1) suppression and improvement in immune function. However, the persistence of integrated proviral DNA in latently infected reservoir cells, which drive viral rebound post-interruption of antiretroviral therapy, remains the major roadblock to a cure. Therefore, the targeted elimination or permanent silencing of this latently infected reservoir is a major focus of HIV-1 research. The most studied approach in the development of a cure is the activation of HIV-1 expression to expose latently infected cells for immune clearance while inducing HIV-1 cytotoxicity—the “kick and kill” approach. However, the complex and highly heterogeneous nature of the latent reservoir, combined with the failure of clinical trials to reduce the reservoir size casts doubt on the feasibility of this approach. This concern that total elimination of HIV-1 from the body may not be possible has led to increased empha...
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HIV-1 is a major global health challenge. The development of an effective vaccine and/or a therapeutic cure is a top priority. The creation of vaccines that focus an antibody response toward a particular epitope of a protein has shown... more
HIV-1 is a major global health challenge. The development of an effective vaccine and/or a therapeutic cure is a top priority. The creation of vaccines that focus an antibody response toward a particular epitope of a protein has shown promise, but the genetic diversity of HIV-1 hinders this progress. Here we developed an approach using nanoengineered CD4 + T cell membrane-coated nanoparticles (TNP). Not only do TNP effectively neutralize all strains of HIV-1, but they also selectively bind to infected cells and decrease the release of HIV-1 particles through an autophagy-dependent mechanism with no drug-induced off-target or cytotoxic effects on bystander cells.
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Although antiretroviral therapy is highly effective in suppressing human immunodeficiency virus type-1 (HIV) replication, treatment has failed to eliminate viral reservoirs and discontinuation of treatment results in viral reactivation.... more
Although antiretroviral therapy is highly effective in suppressing human immunodeficiency virus type-1 (HIV) replication, treatment has failed to eliminate viral reservoirs and discontinuation of treatment results in viral reactivation. Here, we demonstrate that peptides Tat-vFLIP-α2 and Tat-Beclin 1/BECN1 which have been shown to induce a Na/K-ATPase- and a macroautophagy/autophagy-dependent form of cell death, autosis, can preferentially kill HIV-infected macrophages while preventing virological rebound. To improve bioavailability and drug delivery, Tat-vFLIP-α2 was encapsulated into biodegradable PLGA (poly lactic-co-glycolic acid)-lipid-PEG (polyethylene glycol) nanoparticles for long-lasting intracellular delivery. After a single dose of NP-vFLIP-α2, HIV-infected macrophages were preferentially killed in a dose-dependent manner compared to uninfected or untreated HIV-infected cells with complete inhibition of HIV infection at 10 μM of peptide. HIV-infected macrophages treated w...
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In this study, we investigated the effect of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/ MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523 and... more
In this study, we investigated the effect of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/ MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523 and the BET inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1 and SF2523 all decreased HIV replication in macrophages in a dose dependent manner via degradation of intracellular HIV through autophagy. Macrophages treated with dactolisib, JQ1 or SF2523 displayed an increase in LC3B lipidation combined with SQSTM1 degradation without inducing increased cell death. LC3B-II levels were further increased in the presence of pepstatin A suggesting that these inhibitors induce autophagic flux. RNA interference forand, and pharmacological inhibitors of autophagosome-lysosome fusion, and of l...
Research Interests: Chemistry, Macrophages, Autophagy, Infectious Diseases, Biological Chemistry, and 15 moreMedicine, HIV, Biological Sciences, Humans, Macrophage, Infection, CHEMICAL SCIENCES, Human immunodeficiency virus, Cells, Hiv Aids, Imidazoles, Cell Cycle Proteins, Cultured, Medical and Health Sciences, and HIV infections
ABSTRACT To determine the incidence, pathophysiology, clinical outcome, and survival in patients with clinically resistant retinitis. Cytomegalovirus (CMV) retinitis was prospectively studied in 100 patients with acquired immune... more
ABSTRACT To determine the incidence, pathophysiology, clinical outcome, and survival in patients with clinically resistant retinitis. Cytomegalovirus (CMV) retinitis was prospectively studied in 100 patients with acquired immune deficiency syndrome (AIDS). In 11 of these patients, clinically resistant retinitis developed, defined as new activity or progression, despite at least 8 consecutive weeks of induction doses of either foscarnet or ganciclovir. Fundus photography, pharmacokinetics, CMV cultures and sensitivities, and survival analyses were studied. The therapeutic interventions attempted after clinically resistant retinitis was identified included continuing a high dose (induction level) of the same antiviral drug, changing the antiviral drug, and combining antiviral therapy with foscarnet and ganciclovir. Clinically resistant retinitis occurred in 11 (11%) of 100 patients with CMV retinitis and appeared to be a manifestation of acquired CMV antiviral drug resistance. Drug metabolism and pharmacokinetics in these patients were normal. The use of combination therapy with foscarnet and ganciclovir was effective in halting the progression of retinitis in three (75%) of four patients (6 of 7 eyes able to be evaluated) receiving combination therapy. Clinically resistant retinitis is a manifestation of infection by CMV that has acquired drug resistance. In these patients, combination antiviral drug treatment should be considered. It is likely that clinically resistant retinitis will become more frequent as patients with CMV retinitis and AIDS survive longer.
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Background Persons living with human immunodeficiency virus (HIV) (PLWH) with high cytomegalovirus (CMV)–specific interferon (IFN) γ response have increased numbers of endothelium homing receptor (CX3CR1)+–expressing cells that are... more
Background Persons living with human immunodeficiency virus (HIV) (PLWH) with high cytomegalovirus (CMV)–specific interferon (IFN) γ response have increased numbers of endothelium homing receptor (CX3CR1)+–expressing cells that are associated with cardiovascular disease. The current study was performed to investigate the effect of cellular levels of CMV DNA on these markers. Methods Eighty paired peripheral blood mononuclear cell samples were collected ≥12 months apart from 40 CMV-seropositive PLWH with suppressed HIV RNA, who started antiretroviral therapy at median of 3-months of infection. The samples were assessed for CMV-specific IFN-γ response by means of enzyme-linked immunospot assay, and participants were classified as low responders (LRs) or high responders (HRs) based on IFN-γ production (≤100 or >100 spot-forming units [SFUs]/105 cells). Results Of the 40 participants, 26 (65%) were HRs and 14 (35%) LRs at baseline, which did not change over time or by CMV levels (med...
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HIV/CMV co-infected persons despite prolonged viral suppression often experience persistent immune activation, have an increased frequency of myeloid derived suppressor cells (MDSC) and are at increased risk for cardiovascular disease. We... more
HIV/CMV co-infected persons despite prolonged viral suppression often experience persistent immune activation, have an increased frequency of myeloid derived suppressor cells (MDSC) and are at increased risk for cardiovascular disease. We examined how HIV MDSC control CD4(+) T cell IFNγ response to a CMVpp65 peptide pool (CMVpp65). We show that HIV/CMV co-infected persons with virologic suppression and recovered CD4(+) T cells compared to HIV(-)/CMV(+) controls exhibit an increase in CD4(+)CX3CR1(+)IFNγ(+) cells in response to CMVpp65; MDSC depletion further augmented CD4(+)CX3CR1(+)IFNγ(+) cells and IFNγ production. IL-2 and IFNγ in response to CMVpp65 were enhanced with depletion of MDSC expanded in presence of HIV (HIV MDSC), but decreased with culture of HIV MDSC with autologous PBMCs. CMVpp65 specific CD4(+)CX3CR1(+)IFNγ(+) cells were also decreased in presence of HIV MDSC. HIV MDSC overexpressed B7-H4 and silencing B7-H4 increased the production of IL-2 and IFNγ from autologou...
Research Interests: Immunology and Medicine
Background: We previously reported that specific CYP2B6 genetic variants were associated with nevirapine (NVP) and efavirenz (EFV) pharmacokinetics in HIV-infected children. We found that children with these CYP2B6 genetic variants, which... more
Background: We previously reported that specific CYP2B6 genetic variants were associated with nevirapine (NVP) and efavirenz (EFV) pharmacokinetics in HIV-infected children. We found that children with these CYP2B6 genetic variants, which were associated with higher plasma NVP levels, had better immunologic recovery, but this was not observed with EFV-based regimens. Because EFV is known to induce mitochondrion-dependent apoptosis in peripheral blood mononuclear cells (PBMCs), we hypothesized that NVP induced less apoptosis than EFV, leading to different immunologic recovery. Methods: PBMCs from healthy donors were collected and incubated in serum-free medium for 2 days with or without EFV or NVP. The cells were treated with the mean plasma peak steady-state concentrations achieved with NVP and EFV during antiretroviral therapy (Cmax, 3.65 and 3.59 log10 ng/mL, respectively). Induction of apoptosis was evaluated using flow cytometry and intracellular concentrations (ICs) of NVP and ...
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Background: HIV infection is associated with decreased antibody responses to inactivated influenza vaccines. We investigated the antibody functionality (avidity and neutralization) and the immune determinants of antibody response to a... more
Background: HIV infection is associated with decreased antibody responses to inactivated influenza vaccines. We investigated the antibody functionality (avidity and neutralization) and the immune determinants of antibody response to a pH1N1 inactivated vaccine. Methods: 90 HIV-infected subjects 4-25 -years old received two doses of pH1N1 vaccine at weeks 0 and 3 and had plasma and cells frozen at week 0 and after both doses (weeks 3 and 5). Hemagglutinin inhibition (HAI), avidity, B-cell phenotype (flow cytometry) (N=58), pH1N1-B cell-memory (IgG ELISPOT) (N=46) were measured at all timepoints; neutralization, and pH1N1-Th1 and Th2 cytokine responses (Luminex of stimulated culture supernatants, N=72) were measured at weeks 0 and 3. Results: pH1N1-IgG ELISPOT values increased after vaccinations (p<0.048), which correlated with HAI (rho>0.34, p<0.03). B-cell phenotypes did not change after vaccination. pH1N1-IL2 and IL4 production increased after vaccination (p<0.005), but...
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been used widely for treating human immunodeficiency virus type 1 (HIV-1) infected patients as a component of highly active antiretroviral therapy (HAART) and for the... more
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been used widely for treating human immunodeficiency virus type 1 (HIV-1) infected patients as a component of highly active antiretroviral therapy (HAART) and for the prevention of mother-to-child transmission (MTCT). Cytochrome P450 (CYP) 2B6 is an important hepatic isoenzyme responsible for the metabolism of NNRTIs including efavirenz and nevirapine. Recent pharmacogenetic studies have shown that CYP2B6 genetic variants alter hepatic CYP2B6 protein expression and function, and the pharmacokinetics of several CYP2B6 substrates. In particular, the CYP2B6-G516T polymorphism in exon 4 affects the pharmacokinetics of efavirenz. Other studies have shown associations of the CYP2B6-G516T genotype with nevirapine pharmacokinetics and central nervous system adverse effects related to efavirenz use. In total, CYP2B6 genetic variants are important determinants of efavirenz and nevirapine pharmacokinetics . Further studies are neede...
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This study characterizes temporal trends in HIV disease progression among perinatally infected children at a clinic in Baja California, Mexico. A total of 73 children were followed, 52% were categorized under US Centers for Disease... more
This study characterizes temporal trends in HIV disease progression among perinatally infected children at a clinic in Baja California, Mexico. A total of 73 children were followed, 52% were categorized under US Centers for Disease Control and Prevention (CDC) classification group C with a mean age of 2.3 years (SD ± 3.16) at HIV diagnosis. For the years 1998 to 2001, 2002 to 2003, 2004 to 2005, and 2006 to 2007, highly active antiretroviral therapy (HAART) use increased to 60%, 75%, 83%, and 94% ( P < .001) as did mean CD4 percentage of 23.4%, 23.2%, 26.9%, and 29.0%, respectively ( P = .009), while HIV plasma RNA log10 decreased significantly (4.49, 4.23, 4.00, and 3.79, respectively; P = .019). Overall mortality was 31% (23 of 73), with pneumonia being the most common cause of death (43% of all deaths) followed by tuberculosis (22%). Mortality rates declined from 30.4% to 25%, 8.9%, and 9.3% ( p = 0.035) for the years 1998 to 2001, 2002 to 2003, 2004 to 2005, and 2006 to 2007,...
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Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. We used... more
Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.
Research Interests: Pediatrics, Pharmacokinetics, Drug interactions, Clinical Pharmacology, Adolescent, and 15 moreMedicine, Parameter estimation, Population, Humans, Child, Female, Male, Infant, Hiv Infection, Human immunodeficiency virus, Area Under Curve, Child preschool, Dapsone, Pneumocystis carinii pneumonia, and Pharmacology and pharmaceutical sciences
This study evaluated an obstetrical program using rapid HIV testing for the prevention of mother-to-child HIV transmission (MTCT) in Baja California, Mexico. Between 2003 and 2005, 45 women in labor and 17 prenatal care women were HIV... more
This study evaluated an obstetrical program using rapid HIV testing for the prevention of mother-to-child HIV transmission (MTCT) in Baja California, Mexico. Between 2003 and 2005, 45 women in labor and 17 prenatal care women were HIV infected. Among labor patients, 14 (31%) delivered by cesarean section compared with 17 (100%) prenatal care patients (P < .001). Intravenous maternal zidovudine (ZDV) and infant oral ZDV were more frequently administered in prenatal care compared to labor patients: 94% versus 33% (P < .001) and 100% versus 79% (P < .001), respectively. All prenatal care women received combination therapy. All 10 HIV-infected infants were in the labor group, resulting in a MTCT rate of 23% (95% confidence interval [CI] 9.5-34.8) compared to 0% (95% CI 0-1.8; P < .001) among the prenatal care group. Five (50%) of the HIV-infected infants had an AIDS diagnosis and 2 (20%) died within 18 months of birth. Women diagnosed during labor had a high HIV MTCT and poo...
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Dapsone is an alternative drug for Pneumocystis carinii pneumonia (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy of dapsone in... more
Dapsone is an alternative drug for Pneumocystis carinii pneumonia (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy of dapsone in children. Design. Randomized, multicenter trial comparing daily (1 or 2 mg/kg) with weekly (4 mg/kg) dapsone regimens in 94 HIV-infected children intolerant to T/S. Hematologic and hepatic toxicity was monitored, as well as the occurrence of skin rash, PCP or death. Initial pharmacokinetic data indicated that adequate serum dapsone concentrations were not achieved with the daily 1-mg/kg regimen; the daily dose was then increased to 2 mg/kg. Both short and long term hematologic toxicities were marginally greater in children receiving the daily 2 mg/kg compared with the weekly regimen. Allergic skin rashes were similar in children receiving the daily and weekly regimens (17% in both) and were not associated with prior history of rash with T/S. PCP occurred most frequently with the daily 1-mg/kg regimen (22.0 cases/100 patient years), least frequently with the daily 2-mg/kg regimen (0 case/100 patient years) and at intermediate frequency with the weekly regimen (9.5 cases/100 patient years). More deaths were observed in patients receiving the daily than the weekly regimen (8 vs. 2, respectively), although the deaths were not directly attributable to dapsone treatment. Although a weekly dapsone regimen of 4 mg/kg produced less hematologic toxicity than a daily regimen of 2 mg/kg, this advantage was offset by a trend toward higher breakthrough rates of PCP.