Tenofovir Disoproxil Fumarate Salvage Therapy in HIV-Infected Children and a Study of Its Effect on Bone Metabolism
Colección de datos
Enfermedades Transmisibles+10
+ Enfermedades Urogenitales
+ Infecciones Transmitidas por la Sangre
Estudio de Tratamiento
Resumen
Fecha de inicio: 1 de junio de 2004
Fecha en la que se inscribió al primer participante.Tenofovir disoproxil fumarate (TDF) was approved for the treatment of HIV-infected adults in October 2001. In November 2001, we began enrollment to our phase I/II study of tenofovir DF in HIV-infected children (02-C-0006). That study has completed enrollment. The virologic and immunologic responses seen on that study in a group of heavily treatment-experienced children with multidrug resistant HIV were surprisingly good. The drug was well tolerated, but significant decreases in bone mineral density were seen in a minority of patients. With the current study we will enroll and systematically investigate HIV-infected children for whom tenofovir DF is being used as part of salvage combination HIV therapy. The primary objective of the study is to characterize the change in bone mineral density (BMD), as measured by lumbar spine dual-energy x-ray absorptiometry (DEXA), during and following treatment with tenofovir DF-containing antiretroviral therapy in HIV-infected children. The study will enroll 3 cohorts of children: 1) HIV-infected children about to start a tenofovir DF-containing antiretroviral regimen, 2) HIV-infected children already on tenofovir DF with available baseline DEXA results, and 3) HIV-infected children already on tenofovir DF but without baseline DEXA results who will come here for investigations of bone metabolism. Studies of bone metabolism will include periodic measurements of serum and urine calcium and phosphorus, PTH and vitamin D levels, bone resorption markers (urinary collagen cross-linked N-telopeptide and free deoxypyridinoline), bone formation markers (serum osteocalcin and bone specific alkaline phosphatase), IGF-1 levels, bone age, and DEXA scans. Patients about to start tenofovir DF (cohort 1) will be offered the option of having a transiliac crest core bone biopsy with tetracycline labeling performed at baseline and at 6 months to assess static and dynamic parameters of bone quality and turnover (histomorphometry). Subjects with substantial presumed tenofovir DF-related bone toxicity who are deriving benefit from their tenofovir DF-containing antiretroviral drug regimen will be offered the option of pamidronate therapy. The effects of pamidronate treatment on bone toxicity associated with tenofovir DF in these patients will be assessed in an exploratory fashion. It is expected that up to 40 patients with baseline BMD measurements will be enrolled onto this protocol. An additional 10 patients who are undergoing tenofovir DF treatment but who did not receive baseline BMD measurements will also be permitted to enroll in order to contribute to the data used to characterize changes in toxicity.
Protocolo
Esta sección proporciona detalles del plan del estudio, incluyendo cómo está diseñado y qué se está evaluando.Se reclutarán 50 pacientes
Número total de participantes que el ensayo clínico espera reclutar.Estudio de Tratamiento
Elegibilidad
Los investigadores buscan pacientes que cumplan ciertos criterios, conocidos como criterios de elegibilidad: estado general de salud o tratamientos previos.Cualquier sexo
Sexo biológico de los participantes elegibles para inscribirse.Voluntarios sanos no permitidos
Indica si personas sanas, sin la condición que se estudia, pueden participar.Condiciones
Patología
Criterios
INCLUSION CRITERIA: Cohort 1 - patients about to start tenofovir DF * HIV-infected children between the ages of 4 years and less than 21 years. * Clinical decision has been made to start the patient on tenofovir DF-containing antiretroviral regimen * BSA greater than or equal to 0.85 m2 * Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. * Not pregnant or breast feeding * 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) * Less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) * AST and ALT less than or equal to 7.5 times the upper limit of normal * Age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to 70 mL/min/1.73. * Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Cohort 2 - patients already being treated with tenofovir DF who have baseline DEXA available * HIV-infected children between the ages of 4 years and less than 21 years. * Current tenofovir DF-containing antiretroviral regimen was started less than 6 months ago * Baseline DEXA for L-spine BMD is available and was performed less than six months prior to or within the first week of starting tenofovir DF * BSA greater than or equal to 0.85 m2 * Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. * Not pregnant or breast feeding * 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) * Less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) * AST and ALT less than or equal to 7.5 times the upper limit of normal * Age-adjusted normal serum creatinine OR a creatinine clearance greater than or equal to 70 mL/min/1.73. * Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Cohort 3 - patients already being treated with an antiretroviral regimen that includes tenofovir DF who DO NOT have baseline DEXA available * HIV-infected children between the ages of 4 years and less than 21 years. * Current antiretroviral regimen includes tenofovir DF * Baseline (within prior 6 months) DEXA for L-spine BMD is NOT available * BSA greater than or equal to 0.85 m2 * Sexually active patients must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study. * Not pregnant or breast feeding * 25-OH-Vitamin D level greater than 20 ng/ml (supplementation allowed) * less than or equal to grade 1 serum calcium or ionized calcium (supplementation allowed) * AST and ALT less than or equal to 7.5 times the upper limit of normal * Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73. * Informed consent: patient, parent or legal guardian must sign the study informed consent to document their understanding of the investigational nature and the risks of the study before any protocol-related studies are performed. INCLUSION CRITERIA: Eligibility criteria for pamidronate therapy (after enrollment on protocol) One of the following while on tenofovirDF-containing antiretroviral regimen: * Greater than 6% loss in L-spine BMD in the presence of a BMD Z score less than -2.5 at 6 months compared to baseline * Minimal trauma fracture * BMD Z-score less than -3 AND One of the following while on tenofovirDF-containing antiretroviral regimen: * Greater than or equal to 0.5 log decrease in VL from baseline * Greater than or equal to 25% increase in absolute CD4 count from baseline Improvement in HIV-related signs or symptoms OR BMD Z-score less than -3 (i.e., pamidronate therapy will also be considered for subjects whose BMD Z score is less than -3 at baseline) * Age-adjusted normal serum creatinine (see table below) OR a creatinine clearance greater than or equal to 70 mL/min/1.73. * Less than or equal to grade 1 serum phosphate, magnesium, and potassium (supplementation allowed) * Not pregnant or breast feeding * No history of hypersensitivity to bisphosphonates INCLUSION CRITERIA: Eligibility criteria for bone biopsy (after enrollment on protocol) * No history of bleeding abnormality * No history of hypersensitivity or intolerance to tetracycline or related drugs * Normal CBC and PT/PTT * BMD Z-score greater than -3 * Informed consent: patient, parent or legal guardian must sign a separate informed consent to document their understanding of the investigational nature and the risks of the bone biopsy.
Centros del Estudio
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