![Alejandro Dorenbaum](https://profiles.stanford.edu/proxy/api/cap/profiles/6765/resources/profilephoto/350x350.1509499398244.jpg)
Alejandro Dorenbaum
Clinical Professor, Pediatrics - Immunology and Allergy
Clinical Focus
- Pediatric Allergy/Immun
- Pediatric Allergy and Immunology
Administrative Appointments
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Clinical Assistant Professor, Stanford University School of Medicine (2000 - 2004)
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Clinical Associate Professor, Stanford University School of Medicine (2004 - Present)
Honors & Awards
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Schering Travel Grant Award, 47th Annual Meeting of the AAAAI (1991)
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Schering Travel Grant Award, 48th Annual Meeting of the AAAAI (1992)
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Excellence in Teaching Award, Department of Pediatrics, UCSF (1995)
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Excellence in Teaching Award, Department of Pediatrics, UCSF (1997)
Professional Education
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Residency: University of Texas Health Science Center (1990) TX
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Internship: University of Texas Health Science Center (1988) TX
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Fellowship: Baylor College of Medicine (1992) TX
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Board Certification: American Board of Allergy and Immunology, Allergy and Immunology (1997)
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Board Certification, American Board of Pediatrics, Pediatrics (1990)
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Medical Education: Universidad Autonoma Metropolitana (1986) Mexico
Community and International Work
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New Anti-HIV Medications: A Look at Nevirapine
Partnering Organization(s)
KEST, 1450 AM, radio station
Populations Served
San Francisco Bay Area
Location
International
Ongoing Project
No
Opportunities for Student Involvement
No
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National Youth Leadership Forum on Medicine
Topic
Why and How I Became a Pediatric Immunologist
Partnering Organization(s)
National Youth Leadership Forum
Populations Served
Students
Location
Bay Area
Ongoing Project
No
Opportunities for Student Involvement
No
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Bring Your Daughter to Work Program, UCSF
Topic
What Every Teen Needs to Know about HIV
Partnering Organization(s)
UCSF
Populations Served
Teens
Location
California
Ongoing Project
No
Opportunities for Student Involvement
No
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Pediatric HIV Infection, from Diagnosis to Chronic Care, San Francisco
Partnering Organization(s)
Mission Health Center, San Francisco
Populations Served
Underserved
Location
International
Ongoing Project
No
Opportunities for Student Involvement
No
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Introduction to the Human Immune System, San Francisco
Partnering Organization(s)
Saint Ignatius High School
Populations Served
Students
Location
Bay Area
Ongoing Project
No
Opportunities for Student Involvement
No
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HIV Weekly Update
Topic
The Women's and Children's Specialty Clinic at UCSF
Partnering Organization(s)
KALW, National Public Radio affiliate
Location
Bay Area
Ongoing Project
No
Opportunities for Student Involvement
No
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Is Pediatric HIV Increasing in Our Community?, Temple Beth El, San Francisco
Partnering Organization(s)
Bay TV, television broadcast
Populations Served
General
Location
California
Ongoing Project
No
Opportunities for Student Involvement
No
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Can Infants Clear the HIV Infection from Their Blood?, San Francisco
Partnering Organization(s)
Bay TV, television broadcast
Populations Served
General
Location
California
Ongoing Project
No
Opportunities for Student Involvement
No
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Pediatric Disease Prevention, radio broadcast, San Francisco
Partnering Organization(s)
KIQI Radio, Spanish Broadcasting, Inc.
Populations Served
Spanish-speaking
Location
Bay Area
Ongoing Project
No
Opportunities for Student Involvement
No
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Immunodeficiency in Children, radio broadcast, San Francisco
Partnering Organization(s)
KIQI Radio, Spanish Broadcasting, Inc.
Populations Served
Spanish-speaking
Location
International
Ongoing Project
No
Opportunities for Student Involvement
No
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Hemophilia Camp
Topic
Immunodeficiency in hemophilia patients
Partnering Organization(s)
UCSF & Hemophilia Foundation of Northern California
Populations Served
Hemophilia patients and their families
Location
California
Ongoing Project
No
Opportunities for Student Involvement
No
2023-24 Courses
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Independent Studies (5)
- Directed Reading in Pediatrics
PEDS 299 (Win, Spr) - Early Clinical Experience
PEDS 280 (Win, Spr) - Graduate Research
PEDS 399 (Win, Spr) - Medical Scholars Research
PEDS 370 (Win, Spr) - Undergraduate Directed Reading/Research
PEDS 199 (Win, Spr)
- Directed Reading in Pediatrics
All Publications
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Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study.
Hepatology communications
2023; 7 (6)
Abstract
BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC.METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed.RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84mol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3mol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline.CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540.
View details for DOI 10.1097/HC9.0000000000000153
View details for PubMedID 37184523
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Maralixibat for the treatment of PFIC: Long-term, IBAT inhibition in an open-label, Phase 2 study.
Hepatology communications
2022
Abstract
Children with progressive familial intrahepatic cholestasis, including bile salt export pump (BSEP) and familial intrahepatic cholestasis-associated protein 1 (FIC1) deficiencies, suffer debilitating cholestatic pruritus that adversely affects growth and quality of life (QoL). Reliance on surgical interventions, including liver transplantation, highlights the unmet therapeutic need. INDIGO was an open-label, Phase 2, international, long-term study to assess the efficacy and safety of maralixibat in children with FIC1 or BSEP deficiencies. Thirty-three patients, ranging from 12months to 18years of age, were enrolled. Eight had FIC1 deficiency and 25 had BSEP deficiency. Of the latter, 6 had biallelic, protein truncating mutations (t)-BSEP, and 19 had ≥1 nontruncating mutation (nt)-BSEP. Patients received maralixibat 266mug/kg orally, once daily, from baseline to Week 72, with twice-daily dosing permitted from Week 72. Long-term efficacy was determined at Week 240. Serum bile acid (sBA) response (reduction in sBAs of >75% from baseline or concentrations <102.0mumol/L) was achieved in 7 patients with nt-BSEP, 6 during once-daily dosing, and 1 after switching to twice-daily dosing. sBA responders also demonstrated marked reductions in sBAs and pruritus, and increases in height, weight, and QoL. All sBA responders remained liver transplant-free after >5years. No patients with FIC1 deficiency or t-BSEP deficiency met the sBA responder criteria during the study. Maralixibat was generally well-tolerated throughout the study. Conclusion: Response to maralixibat was dependent on progressive familial intrahepatic cholestasis subtype, and 6 of 19 patients with nt-BSEP experienced rapid and sustained reductions in sBA levels. The 7 responders survived with native liver and experienced clinically significant reductions in pruritus and meaningful improvements in growth and QoL. Maralixibat may represent a well-tolerated alternative to surgical intervention.
View details for DOI 10.1002/hep4.1980
View details for PubMedID 35507739
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Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study.
Lancet (London, England)
2021; 398 (10311): 1581-1592
Abstract
BACKGROUND: Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome.METHODS: ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 mug/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 mug/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment.FINDINGS: Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 mumol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 mumol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 mumol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity.INTERPRETATION: In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome.FUNDING: Mirum Pharmaceuticals.
View details for DOI 10.1016/S0140-6736(21)01256-3
View details for PubMedID 34755627
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Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study
LANCET
2021; 398 (10311): 1581-1592
View details for Web of Science ID 000713316000023
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DURABILITY OF TREATMENT EFFECT WITH LONG-TERM MARALIXIBAT IN CHILDREN WITH ALAGILLE SYNDROME: 4-YEAR SAFETY AND EFFICACY RESULTS FROM THE ICONIC STUDY
WILEY. 2019: 1479A
View details for Web of Science ID 000500824000046
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SAFETY AND EFFICACY OF MARALIXIBAT IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS: AN OPEN-LABEL PROOF-OF-CONCEPT STUDY
WILEY. 2019: 764A–765A
View details for Web of Science ID 000488653502410
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Phase 2 open-label study with a placebo-controlled drug withdrawal period of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with Alagille Syndrome: 48-week interim efficacy analysis
ELSEVIER SCIENCE BV. 2019: E119–E120
View details for Web of Science ID 000463481700212
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A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis
HEPATOLOGY COMMUNICATIONS
2019; 3 (3): 365–81
Abstract
Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium-dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (-26.5; 95% confidence interval [CI], -31.8, -21.2) and placebo (-23.4; 95% CI, -30.3, -16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.
View details for PubMedID 30859149
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Development of a Novel Tool to Assess the Impact of Itching in Pediatric Cholestasis
PATIENT-PATIENT CENTERED OUTCOMES RESEARCH
2018; 11 (1): 69–82
Abstract
The aim was to develop a clinical outcome assessment (COA) for itching in children with cholestatic pruritus.This prospective study aimed to enroll patients aged 4-30 years with Alagille syndrome (ALGS) or progressive familial intrahepatic cholestasis type 1 and caregivers of patients aged 5 months to 14 years. Eligible patients experienced itching during ≥3 of the 7 days before enrollment and had not undergone liver transplant or surgical interruption of the enterohepatic circulation. Open-ended qualitative interviews confirmed that itching was a primary concern for patients and caregivers. Diaries were modified and then evaluated by participants during cognitive debriefing. Interview results were reviewed by clinical, COA and statistical experts. Diary questions were revised following an interim analysis before finalizing the Itch Reported Outcome (ItchRO).Thirty-six interviews were analyzed, representing 25 families of patients with ALGS. Itching was reported spontaneously (without prompting by the interviewer) by ten of 12 patients with ALGS and 19 of 20 caregivers. Consequences of itching included skin damage (78%), mood changes (59%), and difficulties staying asleep (59%) or falling asleep (53%). Two versions of the ItchRO were developed: ItchRO(Patient) for self-completion by patients and ItchRO(Observer) for caregivers. The ItchRO diaries comprise a single scorable item to assess itch and are to be completed twice daily (morning and evening).Itching was the most bothersome ALGS symptom reported by study participants. We have developed the ItchRO(Patient) and ItchRO(Observer) to assess itching in children with ALGS and other cholestatic liver diseases. These diaries are being validated for use in clinical trials.
View details for PubMedID 28710680
View details for PubMedCentralID PMC5766715
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CLARITY: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF LOPIXIBAT CHLORIDE (FORMERLY LUM001), A NOVEL APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITOR, IN THE TREATMENT OF PRIMARY BILIARY CIRRHOSIS ASSOCIATED WITH ITCHING
ELSEVIER SCIENCE BV. 2016: S197
View details for DOI 10.1016/S0168-8278(16)00146-X
View details for Web of Science ID 000398711700140
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A Recombinant Antibody to Siglec-8 Shows Selective ADCC Activity Against Mast Cells from Systemic Mastocytosis Patients
AMER SOC HEMATOLOGY. 2015
View details for Web of Science ID 000368021801034
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Impact of asthma exacerbations and asthma triggers on asthma-related quality of life in patients with severe or difficult-to-treat asthma.
The journal of allergy and clinical immunology. In practice
2014; 2 (5): 544-52 e1 2
Abstract
Few data are available that evaluate the relationship among asthma exacerbations, asthma triggers, and asthma-related quality of life (QoL).To evaluate the impact of asthma exacerbations and asthma triggers on QoL.Patients with severe or difficult-to-treat asthma, ages ≥13 years (n = 2679) from the TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) 3-year observational study were included. Exacerbations were defined hierarchically in descending order of severity (hospitalization, emergency department [ED] visit, steroid burst, no exacerbation) by using data from months 6 and 12. The total number (frequency) of exacerbations was assessed. Asthma-related QoL was measured at month 12 by using the Mini-Asthma QoL Questionnaire (Mini-AQLQ); self-reported asthma triggers were collected at baseline and annually. We used 1-way ANOVA to test for differences in Mini-AQLQ domain scores across asthma exacerbation severity, the total number of asthma exacerbations, and the number of asthma triggers.A significant decrease (P < .001) in Mini-AQLQ domain scores was seen with increasing severity of asthma exacerbation (no exacerbation, steroid burst, ED visit, and hospitalization); symptom (5.5, 4.8, 4.3, and 4.2), activity (5.8, 5.2, 4.6, and 4.4), emotional (5.6, 5.0, 4.4, and 4.2), exposure (5.0, 4.5, 4.0, and 3.9); and overall (5.5, 4.9, 4.3, and 4.1). Increasing exacerbation frequency and the number of baseline asthma triggers also were associated with significant decreases in Mini-AQLQ domain scores. An increasing number of asthma triggers were associated with an increase in severity and frequency of exacerbations.Avoidance of asthma triggers may reduce exacerbation rates and improve asthma-related QoL in patients with severe or difficult-to-treat asthma. Interventional studies are warranted to further explore these outcomes.
View details for DOI 10.1016/j.jaip.2014.02.011
View details for PubMedID 25213047
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Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial
LANCET
2014; 384 (9937): 37-44
Abstract
Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria.In this open-label, phase 1, multicentre trial, single subcutaneous injections of rAvPAL-PEG were given in escalating doses (0·001, 0·003, 0·010, 0·030, and 0·100 mg/kg) to adults with phenylketonuria. Participants aged 18 years or older with blood phenylalanine concentrations of 600 μmol/L or higher were recruited from among patients attending metabolic disease clinics in the USA. The primary endpoints were safety and tolerability of rAvPAL-PEG. Secondary endpoints were the pharmacokinetic characteristics of the drug and its effect on concentrations of phenylalanine. Participants and investigators were not masked to assigned dose group. This study is registered with ClinicalTrials.gov, number NCT00925054.25 participants were recruited from seven centres between May 6, 2008, and April 15, 2009, with five participants assigned to each escalating dose group. All participants were included in the safety population. The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0·100 mg/kg) developed a generalised skin rash. By the end of the study, all participants had developed antibodies against polyethylene glycol, and some against phenylalanine ammonia lyase as well. Drug concentrations peaked about 89-106 h after administration of the highest dose. Treatment seemed to be effective at reducing blood phenylalanine in all five participants who received the highest dose (mean reduction of 54·2% from baseline), with a nadir about 6 days after injection and an inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine returned to near-baseline concentrations about 21 days after the injection.Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·100 mg/kg was fairly safe and well tolerated in adult patients with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. In view of the development of antibodies against polyethylene glycol (and in some cases against phenylalanine ammonia lyase), future studies are needed to assess the effect of repeat dosing.BioMarin Pharmaceutical.
View details for DOI 10.1016/S0140-6736(13)61841-3
View details for PubMedID 24743000
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Phenotypes determined by cluster analysis in severe or difficult-to-treat asthma
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
2014; 133 (6): 1549-1556
Abstract
Asthma phenotyping can facilitate understanding of disease pathogenesis and potential targeted therapies.To further characterize the distinguishing features of phenotypic groups in difficult-to-treat asthma.Children ages 6-11 years (n = 518) and adolescents and adults ages ≥12 years (n = 3612) with severe or difficult-to-treat asthma from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study were evaluated in this post hoc cluster analysis. Analyzed variables included sex, race, atopy, age of asthma onset, smoking (adolescents and adults), passive smoke exposure (children), obesity, and aspirin sensitivity. Cluster analysis used the hierarchical clustering algorithm with the Ward minimum variance method. The results were compared among clusters by χ(2) analysis; variables with significant (P < .05) differences among clusters were considered as distinguishing feature candidates. Associations among clusters and asthma-related health outcomes were assessed in multivariable analyses by adjusting for socioeconomic status, environmental exposures, and intensity of therapy.Five clusters were identified in each age stratum. Sex, atopic status, and nonwhite race were distinguishing variables in both strata; passive smoke exposure was distinguishing in children and aspirin sensitivity in adolescents and adults. Clusters were not related to outcomes in children, but 2 adult and adolescent clusters distinguished by nonwhite race and aspirin sensitivity manifested poorer quality of life (P < .0001), and the aspirin-sensitive cluster experienced more frequent asthma exacerbations (P < .0001).Distinct phenotypes appear to exist in patients with severe or difficult-to-treat asthma, which is related to outcomes in adolescents and adults but not in children. The study of the therapeutic implications of these phenotypes is warranted.
View details for DOI 10.1016/j.jaci.2013.10.006
View details for Web of Science ID 000336672500005
View details for PubMedID 24315502
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Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort.
Current respiratory care reports
2012; 1 (4): 259-269
Abstract
Patients with severe or difficult-to-treat asthma account for substantial asthma morbidity, mortality, and healthcare burden despite comprising only a small proportion of the total asthma population. TENOR, a multicenter, observational, prospective cohort study was initiated in 2001. It enrolled 4,756 adults, adolescents and children with severe or difficult-to-treat asthma who were followed semi-annually and annually for three years, enabling insight to be gained into this understudied population. A broad range of demographic, clinical, and patient self-reported assessments were completed during the follow-up period. Here, we present key findings from the TENOR registry in relation to asthma control and exacerbations, including the identification of specific subgroups found to be at particularly high-risk. Identification of the factors and subgroups associated with poor asthma control and increased risk of exacerbations can help physicians design individual asthma management, and improve asthma-related health outcomes for these patients.
View details for DOI 10.1007/s13665-012-0025-x
View details for PubMedID 23136642
View details for PubMedCentralID PMC3485530
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Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response?
JIMD reports
2012; 5: 59-70
Abstract
Prospectively enrolled phenylketonuria patients (n=485) participated in an international Phase II clinical trial to identify the prevalence of a therapeutic response to daily doses of sapropterin dihydrochloride (sapropterin, KUVAN(®)). Responsive patients were then enrolled in two subsequent Phase III clinical trials to examine safety, ability to reduce blood Phenylalanine levels, dosage (5-20 mg/kg/day) and response, and bioavailability of sapropterin. We combined phenotypic findings in the Phase II and III clinical trials to classify study-related responsiveness associated with specific alleles and genotypes identified in the patients. We found that 17% of patients showed a response to sapropterin. The patients harbored 245 different genotypes derived from 122 different alleles, among which ten alleles were newly discovered. Only 16.3% of the genotypes clearly conferred a sapropterin-responsive phenotype. Among the different PAH alleles, only 5% conferred a responsive phenotype. The responsive alleles were largely but not solely missense mutations known to or likely to cause misfolding of the PAH subunit. However, the metabolic response was not robustly predictable from the PAH genotypes, based on the study design adopted for these clinical trials, and accordingly it seems prudent to test each person for this phenotype with a standardized protocol.
View details for DOI 10.1007/8904_2011_96
View details for PubMedID 23430918
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Safety of extended treatment with sapropterin dihydrochloride in patients with phenylketonuria: Results of a phase 3b study
MOLECULAR GENETICS AND METABOLISM
2011; 103 (4): 315-322
Abstract
Phenylketonuria (PKU) results from impaired breakdown of phenylalanine (Phe) due to deficient phenylalanine hydroxylase (PAH) activity. Sapropterin dihydrochloride (sapropterin, Kuvan®) is the only US- and EU-approved pharmaceutical version of naturally occurring 6R-BH(4), the cofactor required for PAH activity. Sapropterin enhances residual PAH activity in sapropterin-responsive PKU patients and, in conjunction with dietary management, helps reduce blood Phe concentrations for optimal control. Approval was based on the positive safety and efficacy results of four international clinical studies, the longest of which was 22 weeks in duration.To evaluate the safety of long-term treatment with sapropterin in PKU subjects who participated in previous Phase 3 sapropterin trials.PKU-008 was designed as a Phase 3b, multicenter, multinational, open-label, 3-year extension trial to evaluate the long-term safety of sapropterin in patients with PKU who were classified as sapropterin responders and participated in prior Phase 3 sapropterin studies: 111 subjects aged 4-50 years completed prior studies and were subsequently enrolled in study PKU-008. Routine safety monitoring was performed at 3-month intervals and included adverse event reporting, blood Phe monitoring, clinical laboratory evaluations, physical examinations and vital sign measurements.Average exposure during PKU-008 was 658.7±221.3 days (range, 56-953; median, 595). The average total duration of participation in multiple studies (PKU-001, PKU-003, PKU-004, and PKU-008; or PKU-006 and PKU-008) was 799.0±237.5 days (range, 135-1151). The mean sapropterin dose was 16.2±4.7 mg/kg/day. Most adverse events were considered unrelated to treatment, were mild or moderate in severity, and were consistent with prior studies of sapropterin. No age-specific differences were observed in adverse event reporting. Three subjects discontinued treatment due to adverse events that were considered possibly or probably related to study treatment (one each of difficulty concentrating, decreased platelet count, and intermittent diarrhea). No deaths were reported. Of seven reported serious adverse events, one was considered possibly related to study treatment (gastroesophageal reflux). There were no laboratory or physical examination abnormalities requiring medical interventions. For most subjects, blood Phe concentrations were consistently within target range, confirming the durability of response in subjects undergoing extended treatment with sapropterin.Sapropterin treatment was found to be safe and well tolerated at doses of 5 to 20mg/kg/day for an average exposure of 659 days. This study supports the safety and tolerability of sapropterin as long-term treatment for patients with PKU.
View details for DOI 10.1016/j.ymgme.2011.03.020
View details for Web of Science ID 000294096400002
View details for PubMedID 21646032
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Relative Bioavailability of Sapropterin From Intact and Dissolved Sapropterin Dihydrochloride Tablets and the Effects of Food: A Randomized, Open-Label, Crossover Study in Healthy Adults
CLINICAL THERAPEUTICS
2010; 32 (2): 338-346
Abstract
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder characterized by hyperphenylalaninemia in association with neurocognitive and neuromotor impairment. Sapropterin dihydrochloride (hereafter referred to as sapropterin) administered orally as dissolved tablets is approved by the US Food and Drug Administration for hyperphenylalaninemia in patients with tetrahydrobiopterin responsive PKU.This study compared the relative oral bioavailability of sapropterin when administered as intact and dissolved tablets. It also assessed the effect of food on the oral bioavailability of sapropterin administered as intact tablets.This was a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study in healthy male and female subjects. Subjects were randomized to receive single oral 10-mg/kg doses of sapropterin administered as dissolved tablets after a fast; as intact tablets after a fast; and as intact tablets with a high-calorie, high-fat meal. The 3 dosing periods were separated by a washout period of at least 7 days. In each dosing period, blood samples were obtained within 40 minutes before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, and 24 hours after dosing. A follow-up assessment was performed 5 to 7 days after the last dosing period. The relative bioavailability of sapropterin from the 3 dosing regimens was assessed based on C(max), AUC(0-t), and AUC(0-infinity), estimated from calculated plasma tetrahydrobiopterin concentrations using a noncompartmental model. Safety assessments included physical examinations, clinical laboratory tests, and ECGs at the beginning and end of the study. Vital signs were monitored periodically during each treatment period.The study enrolled 32 healthy subjects (16 men, 16 women) with a mean (SD) age of 29.2 (9.0) years, height of 172.7 (10.0) cm, weight of 73.0 (13.9) kg, and body mass index ranging from 18 to 30 kg/m(2). Twenty-three were white, 5 African American, 2 Asian/Pacific Islander, 1 Hispanic, and 1 Native American. The estimated geometric mean ratio of AUC(0-t) for intact compared with dissolved tablets under fasting conditions was 141.24% (90% CI, 122.05-163.43), and the geometric mean ratio of AUC(0-t) for intact tablets under fed compared with fasting conditions was 143.46% (90% CI, 124.22-165.69). Nine subjects (28.1%) reported a total of 20 treatment-emergent adverse events (AEs). The most frequently reported AEs were gastrointestinal disorders (6 subjects [18.8%]) and central nervous system disorders (4 [12.5%]). Eight AEs considered possibly or probably related to sapropterin were reported by 4 subjects (12.5%); these were of mild severity and gastrointestinal in nature. No severe or serious AEs or discontinuations due to AEs occurred during the study.Administration of sapropterin as intact tablets and with a high-calorie, high-fat meal was associated with increased drug exposure. Oral administration of sapropterin 10 mg/kg as intact tablets with or without food was generally well tolerated.
View details for DOI 10.1016/j.clinthera.2010.02.012
View details for Web of Science ID 000275495200012
View details for PubMedID 20206791
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Efficacy of Sapropterin Dihydrochloride in Increasing Phenylalanine Tolerance in Children with Phenylketonuria: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study
JOURNAL OF PEDIATRICS
2009; 154 (5): 700-707
Abstract
To evaluate the ability of sapropterin dihydrochloride (pharmaceutical preparation of tetrahydrobiopterin) to increase phenylalanine (Phe) tolerance while maintaining adequate blood Phe control in 4- to 12-year-old children with phenylketonuria (PKU).This international, double-blind, randomized, placebo-controlled study screened for sapropterin response among 90 enrolled subjects in Part 1. In Part 2, 46 responsive subjects with PKU were randomized (3:1) to sapropterin, 20 mg/kg/d, or placebo for 10 weeks while continuing on a Phe-restricted diet. After 3 weeks, a dietary Phe supplement was added every 2 weeks if Phe control was adequate.The mean (+/-SD) Phe supplement tolerated by the sapropterin group had increased significantly from the pretreatment amount (0 mg/kg/d) to 20.9 (+/-15.4) mg/kg/d (P < .001) at the last visit at which subjects had adequate blood Phe control (<360 micromol/L), up to week 10. Over the 10-week period, the placebo group tolerated only an additional 2.9 (+/-4.0) mg/kg/d Phe supplement; the mean difference from the sapropterin group (+/-SE) was 17.7 +/- 4.5 mg/kg/d (P < .001). No severe or serious related adverse events were observed.Sapropterin is effective in increasing Phe tolerance while maintaining blood Phe control and has an acceptable safety profile in this population of children with PKU.
View details for DOI 10.1016/j.jpeds.2008.11.040
View details for Web of Science ID 000265501200016
View details for PubMedID 19261295
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Safety and Efficacy of 22 Weeks of Treatment With Sapropterin Dihydrochloride in Patients With Phenylketonuria
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2008; 146A (22): 2851-2859
Abstract
Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation, which can lead to neurocognitive and neuromotor impairment. Sapropterin dihydrochloride, an FDA-approved synthetic formulation of tetrahydrobiopterin (6R-BH4, herein referred to as sapropterin) is effective in reducing plasma Phe concentrations in patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4)-responsive PKU, offering potential for improved metabolic control. Eighty patients, > or =8 years old, who had participated in a 6-week, randomized, placebo-controlled study of sapropterin, were enrolled in this 22-week, multicenter, open-label extension study comprising a 6-week forced dose-titration phase (5, 20, and 10 mg/kg/day of study drug consecutively for 2 weeks each), a 4-week dose-analysis phase (10 mg/kg/day), and a 12-week fixed-dose phase (patients received doses of 5, 10, or 20 mg/kg/day based on their plasma Phe concentrations during the dose titration). Dose-dependent reductions in plasma Phe concentrations were observed in the forced dose-titration phase. Mean (SD) plasma Phe concentration decreased from 844.0 (398.0) micromol/L (week 0) to 645.2 (393.4) micromol/L (week 10); the mean was maintained at this level during the study's final 12 weeks (652.2 [382.5] micromol/L at week 22). Sixty-eight (85%) patients had at least one adverse event (AE). All AEs, except one, were mild or moderate in severity. Neither the severe AE nor any of the three serious AEs was considered related to sapropterin. No AE led to treatment discontinuation. Sapropterin is effective in reducing plasma Phe concentrations in a dose-dependent manner and is well tolerated at doses of 5-20 mg/kg/day over 22 weeks in BH4-responsive patients with PKU.
View details for DOI 10.1002/ajmg.a.32562
View details for Web of Science ID 000260846800002
View details for PubMedID 18932221
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Pharmacokinetics of Sapropterin in Patients with Phenylketonuria
CLINICAL PHARMACOKINETICS
2008; 47 (12): 817-825
Abstract
Untreated phenylketonuria is characterized by neurocognitive and neuromotor impairment, which result from elevated blood phenylalanine concentrations. To date, the recommended management of phenylketonuria has been the use of a protein-restricted diet and the inclusion of phenylalanine-free protein supplements; however, this approach is often associated with poor compliance and a suboptimal clinical outcome. Sapropterin dihydrochloride, herein referred to as sapropterin, a synthetic formulation of 6R-tetrahydrobiopterin (6R-BH4), has been shown to be effective in reducing blood phenylalanine concentrations in patients with phenylketonuria. The objective of the current study was to characterize the pharmacokinetics and pharmacokinetic variability of sapropterin and to identify the characteristics that influence this variability.This was a 12-week, fixed-dose phase of an open-label extension study. The study was conducted at 26 centres in North America and Europe.Patients with phenylketonuria were eligible to participate if they were > or =8 years of age and had received > or =80% of the scheduled doses in a previous 6-week, randomized, placebo-controlled study or had been withdrawn from that study after exceeding a plasma phenylalanine concentration of > or =1500 micromol/L to > or =1800 micromol/L, depending on the subject's age and baseline plasma phenylalanine concentration. A total of 78 patients participated. Patients received oral once-daily doses of sapropterin (Kuvan) 5, 10 or 20 mg/kg/day. Blood samples for the pharmacokinetic analysis were obtained during weeks 6, 10 and 12. A D-optimal sparse sampling strategy was used, and data were analysed by population-based, nonlinear, mixed-effects modelling methods.In a prospectively planned analysis, the apparent clearance, apparent volume of distribution, absorption rate constant and associated interindividual variabilities of each parameter were estimated by modelling observed BH4 plasma concentration-time data.The best structural model to describe the pharmacokinetics of sapropterin was a two-compartment model with first-order input, first-order elimination and a baseline endogenous BH4 concentration term. Total bodyweight was the only significant covariate identified, the inclusion of which on both the apparent clearance (mean = 2100 L/h/70 kg) and central volume of distribution (mean = 8350 L/70 kg) substantially improved the model's ability to describe the data. The mean (SD) terminal half-life of sapropterin was 6.69 (2.29) hours and there was little evidence of accumulation, even at the highest dose.These findings, taken together with the observed therapeutic effect, support bodyweight-based, once-daily dosing of sapropterin 5-20 mg/kg/day.
View details for Web of Science ID 000262692400005
View details for PubMedID 19026037
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Pharmacokinetics of oral zidovudine administered during labour: a preliminary study
HIV MEDICINE
2007; 8 (7): 451-456
Abstract
The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would provide a similar systemic exposure to the established intravenous regimen used to prevent mother-to-child transmission in HIV-infected pregnant women.ZDV pharmacokinetic parameters following oral administration during labour were determined in 10 HIV-infected pregnant women in active labour. All subjects were converted to intravenous ZDV prior to delivery.In cohort 1 (n=6), subjects received 300 mg oral ZDV every 3 h for three doses. Oral therapy was well tolerated but plasma ZDV concentrations were substantially lower than previously reported with continuous intravenous therapy. Based on the pharmacokinetic results from cohort 1, women in cohort 2 (n=4) received an initial 600 mg dose followed by two 400 mg doses every 3 h. ZDV area under the curve and concentrations in cohort 2 increased approximately in proportion to the increase in dose but varied 6-7-fold. In both cohorts, ZDV pharmacokinetic parameters suggested erratic absorption.While ZDV exposure improved with the increased dosing regimen, our sample size was small and larger studies are needed to establish whether oral ZDV administration during labour can consistently provide equivalent exposure to intravenous administration.
View details for Web of Science ID 000248997100006
View details for PubMedID 17760737
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The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label, screening study
JOURNAL OF INHERITED METABOLIC DISEASE
2007; 30 (5): 700-707
Abstract
This study aimed to evaluate the response to and safety of an 8-day course of sapropterin dihydrochloride (6R-tetrahydrobiopterin or 6R-BH4) 10 mg/kg per day in patients with phenylketonuria (PKU), who have elevated blood phenylalanine (Phe) levels, and to identify a suitable cohort of patients who would respond to sapropterin dihydrochloride treatment with a reduction in blood Phe level. Eligible patients were aged > or = 8 years, had blood Phe levels > or = 450 micromol/L and were not adhering to a Phe-restricted diet. Suitable patients were identified by a > or = 30% reduction in blood Phe level from baseline to day 8 following sapropterin dihydrochloride treatment. The proportion of patients who met these criteria was calculated for the overall population and by baseline Phe level (< 600, 600 to < 900, 900 to < 1200 and > or = 1200 micromol/L). In total, 485/490 patients completed the study and 20% (96/485) were identified as patients who would respond to sapropterin dihydrochloride. A reduction in Phe level was observed in all subgroups, although response was greater in patients with lower baseline Phe levels. Wide variability in response was seen across all baseline Phe subgroups. The majority of adverse events were mild and all resolved without complications. Sapropterin dihydrochloride was well tolerated and reduced blood Phe levels across all PKU phenotypes tested. Variability in reduction of Phe indicates that the response to sapropterin dihydrochloride cannot be predicted by baseline Phe level.
View details for DOI 10.1007/s10545-007-0605-z
View details for Web of Science ID 000250065300012
View details for PubMedID 17846916
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Phenylalanine blood levels and clinical outcomes in phenylketonuria: A systematic literature review and meta-analysis
MOLECULAR GENETICS AND METABOLISM
2007; 92 (1-2): 63-70
Abstract
Blood phenylalanine (Phe) levels provide a practical and reliable method for the diagnosis and monitoring of metabolic status in patients with phenylketonuria (PKU). To assess the reliability of blood Phe levels as a predictive biomarker of clinical outcomes in the development of treatments for PKU, a systematic literature review and meta-analysis of published trials of PKU, which included Phe level and neurological and dietary compliance outcome measures, was conducted. Within-study correlations between Phe level and intelligence quotient (IQ) were extracted from 40 studies. Significant, proportional correlations were found during critical periods (from 0 to 12 years of age) for early-treated patients with PKU (r=-0.35; 95% confidence interval [CI]: -0.44 to -0.27), where each 100 micromol/l increase in Phe predicted a 1.3- to 3.1-point reduction in IQ. Similar significant correlations were observed between IQ and mean lifetime Phe level for early-treated patients (r=0.34; 95% CI: -0.42 to -0.25), where each 100 micromol/l increase in Phe predicted a 1.9- to 4.1-point reduction in IQ. Moderate correlations were found between concurrent Phe level and IQ for early-treated patients. In conclusion, these results confirm a significant correlation between blood Phe level and IQ in patients with PKU, and support the use of Phe as a predictive biomarker for IQ in clinical trials.
View details for DOI 10.1016/j.ymgme.2007.05.006
View details for Web of Science ID 000249992300009
View details for PubMedID 17591452
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Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study
LANCET
2007; 370 (9586): 504-510
Abstract
Early and strict dietary management of phenylketonuria is the only option to prevent mental retardation. We aimed to test the efficacy of sapropterin, a synthetic form of tetrahydrobiopterin (BH4), for reduction of blood phenylalanine concentration.We enrolled 89 patients with phenylketonuria in a Phase III, multicentre, randomised, double-blind, placebo-controlled trial. We randomly assigned 42 patients to receive oral doses of sapropterin (10 mg/kg) and 47 patients to receive placebo, once daily for 6 weeks. The primary endpoint was mean change from baseline in concentration of phenylalanine in blood after 6 weeks. Analysis was on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT00104247.88 of 89 enrolled patients received at least one dose of study drug, and 87 attended the week 6 visit. Mean age was 20 (SD 9.7) years. At baseline, mean concentration of phenylalanine in blood was 843 (300) micromol/L in patients assigned to receive sapropterin, and 888 (323) micromol/L in controls. After 6 weeks of treatment, patients given sapropterin had a decrease in mean blood phenylalanine of 236 (257) micromol/L, compared with a 3 (240) micromol/L increase in the placebo group (p<0.0001). After 6 weeks, 18/41 (44%) patients (95% CI 28-60) in the sapropterin group and 4/47 (9%) controls (95% CI 2-20) had a reduction in blood phenylalanine concentration of 30% or greater from baseline. Blood phenylalanine concentrations fell by about 200 micromol/L after 1 week in the sapropterin group and this reduction persisted for the remaining 5 weeks of the study (p<0.0001). 11/47 (23%) patients in the sapropterin group and 8/41 (20%) in the placebo group experienced adverse events that might have been drug-related (p=0.80). Upper respiratory tract infections were the most common disorder.In some patients with phenylketonuria who are responsive to BH4, sapropterin treatment to reduce blood phenylalanine could be used as an adjunct to a restrictive low-phenylalanine diet, and might even replace the diet in some instances.
View details for Web of Science ID 000248717800029
View details for PubMedID 17693179
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Efficacy and safety of heparinase I versus protamine in patients undergoing coronary artery bypass grafting withl and without cardiopulmonary bypass
ANESTHESIOLOGY
2005; 103 (2): 229-240
Abstract
Hemodynamic protamine reactions with heparin reversal during cardiac surgery are common and associated with adverse outcomes. As an alternative to protamine, the authors examined heparinase I reversal of heparin after aortocoronary bypass graft surgery.In a randomized, double-blind, double-dummy trial, 167 on- and off-pump aortocoronary bypass graft surgery patients received either heparinase I (maximum 35 microg/kg) or protamine (maximum 650 mg) for heparin reversal, monitored by activated clotting time values and clinical assessment. Hemodynamic parameters were recorded electronically; safety evaluation was to 30 days postoperatively. Noninferiority was predefined as 400 ml or less median 12-h chest tube drainage from intensive care unit arrival for heparinase I patients, after risk adjustment. Hemodynamic instability was defined as systemic hypotension (> or = 30 mmHg decrease) and/or pulmonary hypertension (> or = 40 mmHg with an increase > or = 10 mmHg) within 30 min of heparin reversal initiation.Patient enrollment was terminated on advisement of the Data Safety Monitoring Board. Although heparinase I was noninferior for 12-h chest tube drainage, protamine had a superior safety profile. Overall, heparinase I subjects had longer hospital stays (P = 0.04), were more likely to experience a serious adverse event (P = 0.01), and were less likely to avoid transfusion (P = 0.006). A composite morbidity score was not different (P = 0.24), and similar rates of hemodynamic instability were observed between groups. Findings were consistent in analyses stratified by on- and off-pump surgery.Heparinase I reverses heparin anticoagulation after aortocoronary bypass graft surgery but is not equivalent to protamine because of its inferior safety profile.
View details for Web of Science ID 000230983800004
View details for PubMedID 16052104
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The impact of race/ethnicity on mother-to-child HIV transmission in the united states in pediatric AIDS clinical trials group protocol 316
JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
2004; 36 (3): 800-807
Abstract
The present analysis was designed to determine whether race/ethnicity was independently associated with mother-to-child HIV-1 transmission risk in subjects enrolled in a trial of 2-dose intra-partum nevirapine in combination with standard antiretroviral therapy and to determine what factors, including race/ethnicity, predicted maternal viral suppression at the time of delivery. Women enrolled in Pediatric AIDS Clinical Trials Group (PACTG) 316 from sites in the United States and Puerto Rico were included. Distribution of selected maternal disease and treatment characteristics was assessed by race/ethnicity category. Logistic regression models were fit to evaluate possible association of factors with HIV transmission and with viral load at delivery. Variables associated with the outcome at P < 0.05 level were retained in the final models. Of 1052 women randomized at PACTG sites, 891 were included in the present analysis: 572 (64%) were black; 206 (23%) were Hispanic; and 113 (13%) were white. All women who had infected infants were black or Hispanic (11/572 and 3/206, respectively), whereas none of the women identified as white had an infected infant (0/113). This difference was not statistically significant (P = 0.54). White women had higher entry CD4 cell counts and lower HIV-1 RNA at delivery than women of other races/ethnicities. Black and Hispanic women were more likely than white women to start therapy during their current pregnancy but did not initiate prenatal care later. In bivariate models that included antiretroviral type and variables that had values of P < or = 0.25 in univariate analysis, time of antiretroviral initiation, time of prenatal care initiation, and race/ethnicity each retained significance in predicting viral suppression at delivery. Race/ethnicity remained predictive of viral suppression at delivery in a multivariate model incorporating all of these variables (P = 0.01). Higher HIV-1 RNA and lower CD4 cell counts in women identified as black or Hispanic have significant implications for the health of these women and their newborns. Race/ethnicity is significant in predicting viral suppression at the time of delivery.
View details for Web of Science ID 000222481700005
View details for PubMedID 15213563
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Maternal toxicity and pregnancy complications in human immunodeficiency virus-infected women receiving antiretroviral therapy: PACTG 316
10th Conference on Retroviruses and Opportunistic Infections
MOSBY-ELSEVIER. 2004: 506–16
Abstract
The purpose of this study was to evaluate rates of maternal toxicity, pregnancy complications, and peripartum morbidity by type and duration of antiretroviral therapy (ART) during pregnancy.The Pediatric AIDS Clinical Trials Group (PACTG) Protocol 316 (PACTG 316) study evaluated the addition of intrapartum/neonatal nevirapine to background ART to reduce perinatal transmission of human immunodeficiency virus-1 (HIV-1). For this secondary analysis, women were categorized into one of six groups on the basis of ART during pregnancy (monotherapy [monoRx], combination without protease inhibitor [PI], combination with PI), and start time (early: before or during first trimester; late: second or third trimester).One thousand four hundred seven women were included: 288 monoRx late, 34 monoRx early, 327 combo, no PI late, 175 combo, no PI early, 320 combo, PI late, and 263 combo, PI early. Symptoms and laboratory abnormalities of moderate grade or more occurred in less than 5% of women. Only gestational diabetes (highest in combo PI early) varied significantly by therapy group.In HIV-infected women receiving prenatal care and ART, adverse events were uncommon.
View details for DOI 10.1016/j.ajog.2003.07.018
View details for Web of Science ID 000189250500035
View details for PubMedID 14981398
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Predose infant nevirapine concentration with the two-dose intrapartum neonatal nevirapine regimen: Association with timing of maternal intrapartum nevirapine dose
9th Conference on Retroviruses and Opportunistic Infections
LIPPINCOTT WILLIAMS & WILKINS. 2003: 153–56
Abstract
To evaluate cord blood and predose nevirapine concentrations in infants exposed to the two-dose intrapartum neonatal nevirapine regimen.The authors obtained plasma samples for nevirapine assay from cord blood and just prior to the 48-hours to 72-hours after birth neonatal nevirapine dose from a subset of infants participating in PACTG 316, a randomized, placebo-controlled trial of the two-dose intrapartum neonatal nevirapine regimen added to standard antiretroviral therapy.Nevirapine concentrations were measured in 109 cord blood samples and 149 predose samples. Cord blood nevirapine concentrations were below the target concentration of 100 ng/mL (10-times the in vitro IC(50) of nevirapine against wild-type HIV) in eight (7%) of 109 infants (95% confidence interval [CI], 3%-14%); the concentrations in six of these infants were below the assay limit of quantitation. Predose infant nevirapine concentrations were below 100 ng/mL in 23 (15%) of 149 infants (95% CI, 10%-22%); the concentrations in 13 of these infants were below the assay limit of quantitation. Lower predose nevirapine concentrations were associated with lower cord blood concentrations and a shorter interval between maternal dosing and delivery. All but one of the infants with predose nevirapine concentrations below the assay limit of quantitation were born less than 2 hours after maternal dosing.Infants born less than 2 hours after maternal nevirapine dosing during labor should receive a dose of nevirapine immediately after birth in addition to the standard infant dose at 48 to 72 hours.
View details for Web of Science ID 000183815400006
View details for PubMedID 12794547
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When the time comes to talk about HIV: Factors associated with diagnostic disclosure and emotional distress in HIV-infected children
JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
2002; 31 (3): 309-317
Abstract
To determine factors related to the timing and probability of nondisclosure of HIV status to perinatally HIV-infected children, and to explore factors associated with emotional distress in HIV-infected children.This is a cross-sectional study of 51 HIV-infected children based on medical records, parent interviews, and child assessments.1) Probability of earlier age of disclosure is associated with higher child IQ (p =.04) and more family expressiveness (p =.01); 2) controlling for child age, disclosure status at time of study is associated with major life events, but not with medical status; and 3) factors associated with increased parent-rated anxiety in HIV-infected children in univariate analyses are: HIV disclosure (p =.04), other major life events (p =.001), higher medication dose frequency ( p=.01), and child age (p =.01). Increased depression is associated only with more medication doses (p =.02).These data indicate that higher child IQ and greater family expressiveness increase the probability of earlier diagnostic disclosure to HIV-infected children. Factors associated with emotional distress highlight important areas of clinical attention. These data suggest that diagnostic disclosure may not necessarily minimize emotional distress, indicating the need for further evaluation of the appropriate timing and type of disclosure for pediatric HIV.
View details for Web of Science ID 000179082800006
View details for PubMedID 12439206
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Concentrations of protease inhibitors in cord blood after in utero exposure
PEDIATRIC INFECTIOUS DISEASE JOURNAL
2002; 21 (9): 835-838
Abstract
To determine the concentrations of protease inhibitors in cord blood after prenatal protease inhibitor use by pregnant women.Retrospective analysis of samples collected in a clinical trial.Protease inhibitor concentrations were measured in cord blood samples collected from women enrolling in the PACTG 316 study who were receiving prenatal protease inhibitor antiretroviral therapy.In cord blood samples from 68 women treated with protease inhibitors during pregnancy, the concentration of these drugs was below the assay lower limit of detection in most samples, including all samples from women receiving indinavir (n = 21) and saquinavir (n = 8), 5 of 6 samples (83%) from women receiving ritonavir and 24 of 38 samples (63%) from women receiving nelfinavir.Low protease inhibitor concentrations in the fetus decrease the likelihood of teratogenic and toxic effects of these drugs but could fail to provide protection from transplacental or intrapartum transmission of HIV-1.
View details for DOI 10.1097/01.inf.0000027591.04920.c7
View details for Web of Science ID 000178091400007
View details for PubMedID 12352805
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Envelope-based HIV vaccines
SCIENCE
2002; 297 (5585): 1277-1277
View details for Web of Science ID 000177573900020
View details for PubMedID 12194177
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Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: A substudy of Pediatric AIDS Clinical Trials Group protocol 316
8th Conference on Retroviruses and Opportunistic Infections
UNIV CHICAGO PRESS. 2002: 181–88
Abstract
Pediatric AIDS Clinical Trials Group protocol 316 was an international, multicenter, placebo-controlled trial comparing single-dose oral nevirapine (200 mg to mother and 2 mg/kg to infant) with placebo in human immunodeficiency virus (HIV)-infected pregnant women receiving standard antiretroviral therapy. This substudy evaluated the emergence of nevirapine-resistance mutations at 6 weeks postpartum in a subgroup of participants. Maternal risk factors for the emergence of nevirapine-resistance mutations were evaluated. Mutations associated with nevirapine resistance were detectable at delivery, prior to receipt of study drug, in 5 (2.3%) of 217 women. Fourteen (15%; 95% confidence interval, 8%-23%) of 95 women who received intrapartum nevirapine developed a nevirapine-resistance mutation 6 weeks postpartum. The most common mutation was K103N, which was present in 10 women. The risk for development of a new nevirapine-resistance mutation did not correlate with CD4 cell count or HIV-1 RNA load at delivery or with type of antepartum antiretroviral therapy. The risk of nevirapine resistance should be considered when determining the risks or benefits of intrapartum nevirapine in women receiving antepartum antiretroviral therapy.
View details for Web of Science ID 000176668500005
View details for PubMedID 12134253
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Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission - A randomized trial
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2002; 288 (2): 189-198
Abstract
A 2-dose intrapartum/newborn nevirapine regimen reduced perinatal human immunodeficiency virus (HIV) transmission in Ugandan women not receiving antenatal antiretroviral therapy (ART). However, it is unknown whether the addition of the 2-dose nevirapine regimen to standard ART would further reduce perinatal HIV transmission.To determine whether a 2-dose nevirapine regimen can decrease perinatal transmission of HIV in nonbreastfeeding women receiving standard ART.International, blinded, placebo-controlled, phase 3 trial enrolling women between May 1997 and June 2000 at clinical sites providing care for HIV infection throughout the United States, Europe, Brazil, and the Bahamas.A total of 1270 women received nevirapine (n = 642) or placebo (n = 628). Infants were followed up for 6 months to determine HIV-infection status, which was available for 1248 deliveries.A 200-mg dose of oral nevirapine to women after onset of labor and a 2-mg/kg dose of oral nevirapine to newborns between 48 and 72 hours after birth.Detection of HIV infection in infants and grade 3 and 4 toxic effects in women and newborns.After review by the data and safety monitoring board, the trial was stopped early because the overall transmission rates were significantly lower than assumed for the study design. Antenatal ART included zidovudine alone in 23%; combinations without protease inhibitors in 36%; and combinations with protease inhibitors in 41%. Thirty-four percent of women had elective cesarean delivery. No significant safety concerns were identified for women or infants. Detection of HIV infection occurred in 9 (1.4%; 95% confidence interval [CI], 0.6%-2.7%) of 631 nevirapine group deliveries and 10 (1.6%; 95% CI, 0.8%-2.9%) of 617 placebo group deliveries. The 95% CI for the difference in transmission rate (-0.2) between the 2 study arms ranged from -1.5% in favor of nevirapine to 1.2% in favor of placebo (P =.82, Fisher exact test). The transmission rate was higher in women with lower baseline CD4 cell counts and higher delivery HIV RNA levels, but there was no significant difference between treatment arms in any subgroup.Risk of perinatal HIV transmission was low and no benefit from additional intrapartum/newborn nevirapine was demonstrated when women received prenatal care and antenatal ART, and elective cesarean section was made available.
View details for Web of Science ID 000176711100019
View details for PubMedID 12095383
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When parents reject interventions to reduce postnatal human immunodeficiency virus transmission
ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE
2001; 155 (8): 927-933
Abstract
In a recent Oregon case, the state successfully sued for custody of an infant to prevent his human immunodeficiency virus (HIV)-infected mother from breastfeeding him and to require antiretroviral prophylaxis. As more HIV-infected women give birth, pediatricians may increasingly face dilemmas when parents reject medical recommendations to forego breastfeeding and to administer antiretroviral prophylaxis to the infant. Such disagreements create ethical dilemmas because pediatricians have an obligation to both protect the infant and respect parental decision making. Pediatricians need to balance these obligations in deciding whether to ask the courts to intervene on the infant's behalf. To that end, we analyze the legal and ethical issues that arise when an HIV-infected mother refuses interventions to reduce neonatal transmission of HIV to her infant, provide an approach for addressing these disagreements, and present illustrative scenarios in which pediatricians should, may, and should not seek a court order to intervene.
View details for PubMedID 11483121
- HIV medical advances explored at retrovirus conference AIDS Policy Law 2001; 16 (10): 4
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Nevirapine - Pharmacokinetic considerations in children and pregnant women
CLINICAL PHARMACOKINETICS
2000; 39 (4): 281-293
Abstract
Nevirapine is a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is effective when used as part of combination therapy to treat HIV-1-infected individuals and as monotherapy for prevention of mother-to-child HIV-1 transmission. Nevirapine pharmacokinetics are characterised by rapid absorption and distribution, followed by prolonged elimination. Nevirapine is generally well tolerated. The most common toxicity is rash, which is usually mild and self-limiting. The primary route of nevirapine elimination is through metabolism by the cytochrome P450 enzyme system. Nevirapine elimination accelerates during long term administration because of autoinduction of the enzymes involved in its elimination pathway. The recommended regimen for adults is nevirapine 200mg once daily for 2 weeks, followed by 200mg twice daily. Nevirapine elimination is prolonged in pregnant women during labour and in newborns. A regimen of a single 200mg oral dose administered to the mother during labour and a single 2 mg/kg dose administered to the newborn at 48 to 72 hours after birth maintains serum nevirapine concentrations above 100 microg/L (10 times the in vitro 50% inhibitory concentration against wild-type HIV-1) throughout the first week of life. This limited regimen has been shown to be extremely well tolerated and to reduce mother-to-child transmission by nearly 50% in mothers and infants receiving no other antiretrovirals. There are few data describing the safety and pharmacokinetics of nevirapine during long term use in pregnancy. In children, nevirapine elimination accelerates during the first years of life, reaching a maximum at around 2 years of age, followed by a gradual decline during the rest of childhood. Children should receive 4 mg/kg once daily for the first 2 weeks of therapy, followed by 7 mg/kg doses twice daily if below the age of 8 years or 4 mg/kg twice daily if older than 8 years. Alternatively, children may receive 150 mg/m2 across all ages, once daily for the first 2 weeks of therapy followed by the same dose twice daily.
View details for Web of Science ID 000090117300004
View details for PubMedID 11069214
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Cytokine profile of a long-term pediatric HIV survivor with hyper-IgE syndrome and a normal CD4(+) T-cell count
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
1999; 104 (5): 1045-1051
Abstract
An elevated IgE level and increased production of T(H2) cytokines are factors associated with poor prognosis in HIV infection. We report a pediatric long-term survivor of vertically acquired HIV infection with a normal CD4 count and a low viral burden despite the lack of antiretroviral therapy and a phenotype resembling hyper-IgE syndrome.We sought to characterize the patient's T(H1) versus T(H2) cytokine profile and anti-HIV-specific immune responses.Supernatants collected from cultures of peripheral blood T cells stimulated with phorbol myristate acetate plus ionomycin were assayed for T(H1) and T(H2) cytokines by means of ELISA. Specific IgE antibodies were determined by immunoblot. HIV-specific cytotoxic T-lymphocyte responses were measured from cell lysis by fresh T cells of autologous B-lymphoblastoid cells expressing recombinant HIV proteins.Patient CD4(+) T cells secreted significantly more T(H2) cytokines, IL-4 (P <.003) and IL-5 (P <.03), than HIV-infected and seronegative control cells. No difference was noted in T(H1) cytokine production. IgE specific for HIV gp160, p24, p17, and p66 proteins and Aspergillus fumigatus was detected in patient sera. Despite predominance of T(H2) cytokines, HIV-specific cytotoxic T-lymphocyte activity was vigorous.The patient demonstrated predominantly T(H2) cytokine production in vitro. Unlike other patients with HIV who have hyper-IgE and increased T(H2) cytokine production, our patient has maintained HIV-specific immune responses, a low viral load, and a normal CD4 count without antiretroviral therapy. These findings support a diagnosis of primary hyper-IgE syndrome. Presence of anti-HIV-specific IgE may represent a protective mechanism against HIV replication in our patient.
View details for Web of Science ID 000083778400029
View details for PubMedID 10550751
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Sleep disturbances in children with human immunodeficiency virus infection
PEDIATRICS
1999; 104 (5)
Abstract
To describe the sleep patterns and level of fatigue in children and adolescents (6-18 years of age) with HIV infection, compared with ethnic-, gender-, and age-matched healthy children in the home setting.Descriptive, comparative.Conducted in each child's home environment.Eighteen HIV-infected and 15 noninfected children completed the study. The Centers for Disease Control and Prevention HIV classifications for the 18 HIV-infected children were: A (n = 7), B (n = 6), and C (n = 5).A symptom diary was developed using a previously validated fatigue assessment scale, modified for use with children. Content validity of the diary was established with a panel of 5 experts in child development and pediatric HIV disease. Children were asked to complete the diary each morning and evening for 3 days. Each child wore a wrist actigraph during the same period.The HIV-infected children had significantly more wake time after sleep onset, compared with noninfected children (13.55% vs 7. 47%). The HIV-infected children had more awakenings (25.33 vs 16.71) and were awake for longer periods (3.01 vs 1.01 minutes), compared with noninfected children. By parent report, 7 HIV-infected children napped and 2 noninfected children napped, indicating greater daytime fatigue in the HIV-infected children. HIV-infected children also reported a greater level of evening tiredness (2.47 vs 1.8).The findings from this study suggest that sleep disturbances occur in HIV-infected children, similar to findings previously described in HIV-infected adults. Additional research is necessary to characterize the nature and patterns of sleep disturbance and fatigue related to pediatric HIV-infection, to assess the impact these may have on daily activities, and to develop strategies to improve sleep for these children.
View details for Web of Science ID 000083448000042
View details for PubMedID 10545588
- Current applications for the use of nevirapine in HIV 1-infected pregnant women, infants and children Journal of HIV Therapy 1999; 4 (3)
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Classification, diagnostic criteria, and treatment recommendations for orofacial manifestations in HIV-infected pediatric patients. Collaborative Workgroup on Oral Manifestations of Pediatric HIV Infection.
journal of clinical pediatric dentistry
1999; 23 (2): 85-96
Abstract
The criteria for diagnosis of HIV-related oral lesions in adults are well established, but corresponding criteria in the pediatric population are not as well defined. The Collaborative Workgroup on the Oral Manifestations of Pediatric HIV infection reached a consensus, based upon available data, as to the presumptive and definitive criteria to diagnose the oral manifestations of HIV infection in children. Presumptive criteria refer to the clinical features of the lesions, including signs and symptoms, whereas definitive criteria require specific laboratory tests. In general, it is recommended that definitive criteria be established whenever possible. Orofacial manifestations have been divided into three groups: 1) those commonly associated with pediatric HIV infection; 2) those less commonly associated with pediatric HIV infection; and 3) those strongly associated with HIV infection but rare in children. Orofacial lesions commonly associated with pediatric HIV infection include candidiasis, herpes simplex infection, linear gingival erythema, parotid enlargement, and recurrent aphthous stomatitis. In contrast, orofacial lesions strongly associated with HIV infection but rare in children include Kaposi's sarcoma, non-Hodgkin's lymphoma, and oral hairy leukoplakia. Treatment recommendations, specific for this age group, have been included for some of the more common HIV-related orofacial manifestations.
View details for PubMedID 10204447
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Phase I safety and pharmacokinetics study of micronized atovaquone in human immunodeficiency virus-infected infants and children
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
1998; 42 (6): 1315-1318
Abstract
A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 micrograms/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 micrograms/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.
View details for Web of Science ID 000073952400002
View details for PubMedID 9624466
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Transplantation of CD34(+), CD3 haplocompatible peripheral blood stem cells (PBSC) for children with severe combined immunodeficiency disease (SCID).
AMER SOC HEMATOLOGY. 1997: 455–55
View details for Web of Science ID A1997YG42400455
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Transmission of HIV-1 in infants born to seropositive mothers: PCR-amplified proviral DNA detected by flow cytometric analysis of immunoreactive beads
JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY
1997; 15 (1): 35-42
Abstract
The diagnosis of HIV infection in newborns is established by amplification of proviral DNA using the polymerase chain reaction (PCR). We developed a nonisotopic method for heminested PCR using a biotinylated primer among sets of three oligonucleotides, each selected from the HIV long terminal repeat (LTR) and gag sequences. An internal probe incorporating digoxigenin-dUTP was also synthesized by PCR. The PCR products, hybridized with LTR region or gag region probes, were captured with streptavidin-coated magnetic beads and detected by fluorescein isothiocyanate-labeled antidigoxigenin in flow cytometric analysis. This immunoreactive bead assay (PCR-IRB) detected about three copies of HIV proviral DNA. A panel of 50 coded DNA specimens of infants previously assayed by conventional PCR and with known clinical results revealed that the PCR-IRB findings using LTR, but not gag, were in agreement. A double-blind prospective study of blood samples from 14 mother-infant pairs using the PCR-IRB amplification of LTR gave results similar to the commercial Amplicor HIV-1 PCR test and were consistent with the clinical outcomes. PCR-IRB results were positive for 11 mothers and three infants, one at birth, one at 2 weeks after birth, and one at 8 weeks after birth. PCR-IRB is a simple, reliable, specific, and automatable assay useful in the early diagnosis of perinatal HIV infection in clinical practice and regional screening programs.
View details for Web of Science ID A1997XH94600006
View details for PubMedID 9215652
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RECURRENT STAPHYLOCOCCUS-AUREUS RENAL ABSCESS IN A CHILD POSITIVE FOR THE HUMAN-IMMUNODEFICIENCY-VIRUS
UROLOGY
1995; 46 (2): 246-248
Abstract
A 10-year-old girl with the human immunodeficiency virus was found to have a Staphylococcus aureus renal abscess with perinephric extension. The abscess was drained first percutaneously and then surgically, and the patient received a 6-week course of intravenous antibiotics. Three months later, the abscess recurred, necessitating a nephrectomy. The extended morbidity and difficulty of eradicating S aureus suggest that, in immunocompromised patients, early aggressive surgical management is indicated.
View details for Web of Science ID A1995RM64100021
View details for PubMedID 7624995
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RECOVERY OF MALASSEZIA-PACHYDERMATIS FROM 8 INFANTS IN A NEONATAL INTENSIVE-CARE NURSERY - CLINICAL AND LABORATORY FEATURES
PEDIATRIC INFECTIOUS DISEASE JOURNAL
1988; 7 (6): 398-401
Abstract
A 15-month retrospective survey of 507 admissions to a neonatal intensive care unit revealed 8 patients from whom Malassezia pachydermatis was isolated from one or more clinical specimens. The fungus was cultured from blood (four patients), central venous catheter tips (three patients), urine (four patients), cerebrospinal fluid (one patient), eye discharge (one patient), ear discharge (one patient) and tracheal aspirate (one patient). Seven of the eight infants displayed an episode of one or more of the following symptoms: apnea, bradycardia, temperature instability and hepatosplenomegaly. These episodes were temporally related to recovery of M. pachydermatis from clinical specimens. The seven symptomatic infants had received multiple antibiotics as well as long term hyperalimentation, including lipids, by infusion through deep vein catheters; the single asymptomatic infant did not. These data suggest an association between M. pachydermatis and the febrile systemic syndrome of neonates recently described for extracutaneous infections due to Malassezia furfur.
View details for Web of Science ID A1988N815200006
View details for PubMedID 3134645
- Case Report Infectious Disease Newsletter 1987; 6 (5): 38