This study will test the safety, side effects and anti-HIV activity of different doses of
capravirine in children and adolescents with HIV infection. Capravirine belongs to a class
of drugs called non-nucleoside reverse transcriptase inhibitors (NNRTIs), which prevent the
virus from replicating (making more copies of itself). Other NNRTIs are nevirapine,
delavirdine and efavirenz.
HIV-infected children between the ages of 4 months and 21 years may be eligible for this
study if they: 1) have received less than 6 weeks of treatment with antiretroviral drugs;
2) have not benefited from antiretroviral therapy after 12 weeks of treatment; 3) cannot
continue antiretroviral treatment because of harmful side effects.
For the first week of the study, participants will have a 1-week "washout period" in which
they will receive no anti-HIV therapy. During this time, they will have physical, eye and
neuropsychologic examinations, blood and urine tests, echocardiogram, electrocardiogram
(EKG), chest X-ray, head CT scan and skin tests. These physical exams and tests will be
repeated throughout the study to determine changes in health.
After the washout period, patients will take capravirine once a day in the morning for 6
days. After each dose, a small amount of blood will be drawn at 8 different times over 12
hours to measure the activity of the drug and HIV blood levels. A heparin lock will be
placed in the vein to avoid multiple needlesticks. After the 6 days of capravirine there
will be another washout period, this time for 21 days. During this time, doctors will
determine the optimum combination therapy for the individual patient.
After the second washout, patients will begin combination therapy with capravirine plus at
least two other anti-HIV medicines. (These may include a reverse transcriptase inhibitor
such as zidovudine, didanosine, lamuvidine, zalcitabine, or stavudine, and maybe one or more
protease inhibitors such as ritonavir, nelfinavir, saquinavir, indinavir or amprenavir.) For
the first week, patients will have a daily blood test to determine HIV blood levels.
Afterwards, treatment will continue on an outpatient basis with clinic visits every 4 to 8
weeks for physical exams, lab tests and other procedures as required. The study will last
approximately 48 weeks. Patients who benefit from capravirine therapy may be able to
continue to receive the drug from the drug company sponsor or as part of another study, or
the protocol for this study may be amended to lengthen the treatment period.
This is a pediatric phase I dose escalation study to determine a biologically active dose
and to obtain information concerning the safety, tolerability, and pharmacokinetics of
1549)(5-[(3,5-dichlorophenyl)thio]-4-(1-methylethyl)-1-(4-pyridinylmethyl)-1H-imidazol-2-methanol carbamate), a potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitor, that induces a novel pattern of resistance mutations. In addition to obtaining needed biological activity, pediatric safety, tolerability, and pharmacokinetic data, the study will utilize capravirine's potent antiretroviral activity and novel resistance mutation pattern, together with serial measurements of plasma HIV viral load, flow cytometry, and genotypic and phenotypic viral resistance analysis to conduct pilot studies in pediatric HIV pathogenesis, the response to antiretroviral therapy, and to develop strategies to optimize the management of pediatric antiretroviral therapy. We will also use initial viral decay dynamics and other patient characteristics to model predictions for the long-term response to antiretroviral therapy. We will enroll children who have become refractory to or have experienced toxicity on prior therapy. The study will include resistance testing on the failing regimen, a one week period off antiretrovirals (washout period), an initial 6 days of capravirine monotherapy followed by capravirine in combination with the optimal antiretroviral therapy as determined by their baseline viral resistance mutation pattern and history. The patients will be followed for at least 48 weeks to assess long-term tolerability and toxicity, and to assess the clinical, virological, and immunological response to capravirine.
Age: Two age groups will be enrolled and studied separately.
Group 1: 4 months to less than 2 years.
Group 2: 2 years to less than 21 years.
Gender and Ethnicity: There will be no restriction as to genderor ethnicity. A resonable
effort will be made to include chldren of both genders and all ethnic backgrounds.
HIV-infected children between the ages of 4 months and 21 years.
An indication for treatment with antiretrovirals.
One of the following: Children failing current treatment after at least 12 weeks of
therapy as defined by the most recent Guidelines for the Use of Antiretroviral Agents in n
Pediatric HIV Infection or accepted practice OR Intolerant to or are showing evidence of
toxicity from other antiretroviral treatments.
HIV RNA greater than or equal to 5,000 copies per/mL within the past 3 months (may be from
Women of childbearing age must agree to avoid becoming pregnant while on study and for 4
Total WBC greater than 1,500/mm(3),
Absolute neutrophil count greater than 750/mm(3),
Hemoglobin greater than 8.0 gm/dL, and
Platelet count greater than 75,000/mm(3) at study entry.
Liver transaminases must be less than or equal to 3.0 times the upper limit of normal;
Serum amylase less than 1.5 times the upper limit of normal and if abnormal, fractionated
pancreatic amylase less than 45 U/L;
Lipase less than 1.5 times the upper limit of normal;
Creatinine phosphokinase (CPK) less than 2.5 times the upper limit of normal.
Patients must have an age-adjusted normal serum creatinine OR a creatinine clearance
greater than or equal to 70 mL/min/1.73:
Therapeutic regimens including:
Immunomodulating agents (within 30 days of entry), other than GCSF, erythropoeitin,
corticosteroids, IVIG, or anti-D;
Treatment with chemotherapeutic agents (including hydroxyurea) or radiation therapy within
the past 6 weeks;
Current chronic use of medications known to inhibit or induce cytochrome P450, including
but not limited to: isoniazid, rifampin, rifabutin, astemizole, terfenadine, cisapride,
triazolam, midazolam, nifedipine, diltiazem, verapamil, cimetidine, dexamethasone,
carbamazepine, phenytoin, phenobarbital, propoxyphene, quinidine, amiodarone, or ergot
alkaloids, azole antifungals (ketoconazole, fluconazole, itraconazole), or macrolide
antibiotics (erythromycin, clarithromycin);
Current use of highly plasma protein bound drugs including but not limited to, warfarin
Current use, or use within the last 28 days, of any investigational agent.
Clinically significant, unrelated systemic illness (serious infections or significant
cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgement of the
Principal Investigator or Chairperson would compromise the patient's ability to tolerate
this therapy or is likely to interfere with the study procedures or results will be
Weighting less than 10 kg.
Pregnant or breast feeding females will be excluded.