This study will test the safety and effectiveness of hydroxyurea, an anti-cancer drug, given
together with the anti-HIV drugs didanosine, stavudine and efavirenz for treating children
infected with human immunodeficiency virus (HIV). Some studies have found that hydroxyurea
may help certain anti-HIV drugs to work better and that the virus does not become resistant
to it, as it does other drugs. This study will also examine how hydroxyurea affects the
body's immune system and virus levels.
Patients 3 through 21 years old with HIV infection may be eligible for this 52-week study.
They will be screened for eligibility with a thorough physical examination, including chest
X-ray, electrocardiogram and echocardiogram, head CT scan, eye examination and blood tests.
All patients in the study will take didanosine twice a day, stavudine twice a day and
efavirenz once a day. All patients will also take hydroxyurea twice a day, but some will
take a low dose of the drug, while others will take a high dose. Within each of these two
groups (high and low dose) some patients will start taking hydroxyurea the same day they
begin the anti-HIV drugs; others will not start hydroxyurea until after they have taken the
anti-HIV drugs for 5 weeks. Patients will have a physical examination every 3 weeks until
week 12, then every 4 weeks until week 24, and then every 8 weeks until the end of the
study. Blood tests to measure virus levels will be done every other day for the first 7
days and periodically after that. For the first 8 weeks after starting hydroxyurea, blood
tests will be done weekly. An eye examination, chest X-ray, electrocardiogram, and CT scans
of the head will be done about every 6 months.
This is a pilot study to determine the safety, toxicity, virologic and immunologic effects
of combination therapy with hydroxyurea, a cytostatic chemotherapeutic agent, two nucleoside
reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor in
children with HIV infection. We will enroll HIV-infected children who have detectable viral
loads (greater than 10,000 copies/ml). Patients will be stratified upon enrollment by CD4
cell count (less than or greater than 200 CD4 cells/mm(3)). Two dose levels of hydroxyurea
will be utilized (7.5 mg/kg/dose twice daily and 12.5 mg/kg/dose twice daily). It is
anticipated that 15 patients will be enrolled at the Low Dose Level and 10 patients at the
High Dose Level of hydroxyurea within each CD4 cohort, for a total of 50 patients on study.
Within each dose level patients will receive the antiretroviral agents didanosine, stavudine
and efavirenz beginning on study Day one and will be randomized to receive hydroxyurea
either on Day 1 or week 6. The cohorts will be escalated and analyzed separately. The
study duration will be 52 weeks. This study will attempt to define an effective and
tolerable dose of hydroxyurea.
Patients must have a diagnosis of HIV-1 infection as defined by the Centers for Disease
All patients must have availability of a parent or legal guardian able and willing to give
informed consent and comply with the requirements of the study.
Post menarchal adolescent females must have a negative urine pregnancy test within 14 days
prior to initiation of study therapy and consent to urine pregnancy testing at every visit
for the remainder of the study. If sexually active, must also be willing to use a
barrier method of contraception or willing to remain sexually abstinent during the course
of the study.
Sexually active males must agree to practice barrier contraception for the duration of the
Patients must have a plasma HIV-RNA viral load of greater than or equal to 10,000
copies/ml (4.0 log10) on 2 occasions at least 1 week apart at study entry.
Patients must be between the ages of 3 years to 21 years old and able to swallow capsules.
Patients must have an age-adjusted normal serum creatinine or a creatinine clearance
greater than or equal to 60 ml/min/1.73 m(2).
Patients must have an absolute granulocyte count greater than 1,500/mm(3), hemoglobin
greater than 8 gm/dL, and platelet count greater than 75,000/mm(3).
Patients must have an SGOT/SGPT/GGT less than 2.5 times normal unless considered to be
attributable to underlying HIV disease.
Patients must have a serum amylase less than 1.5 times the upper limit of normal. If
abnormal, a fractionated pancreatic amylase less than 45 U/L.
Immunomodulating agents such as corticosteroids for LIP, IVIG, erythropoietin, and anti-D
will be allowed.
Must not be critically ill or clinically unstable.
Must not have a history or a prior malignancy requiring active treatment within the last 2
Must not have a prior history of hydroxyurea use.
Must not have the presence of an active infection requiring acute intervention at the time
Patients receiving treatment for an infection that requires prolonged treatment must have
been stable on therapy for at least 7 days prior to study entry.
Prophylaxis for PCP as well as maintenance anti-mycobacterial therapy, antifungal, and
anti-viral therapy at the time of study will be allowed.
Must not currently use G-CSF or GM-CSF to maintain an adequate neutrophil count.
No evidence of active peripheral neuropathy.
No history of peripheral neuropathy of Grade III or greater severity associated with the
use of antiretroviral agents.
No patients with a previous history of pancreatitis attributed to ddI.
No previous history of pancreatitis requiring total parental nutrition within 2 years of
Patients will be excluded if unable to tolerate antiretroviral therapy with stavudine,
didanosine or efavirenz due to allergic symptoms felt to be related to these
antiretroviral therapeutic agents.
Patients must not have a history of erythema multiforme or Stevens Johnson Syndrome
attributable to stauvudine, didanosine or nonnucleoside RTI.
No patients with multiple circumscribed active retinal lesions characterized by
alterations in retinal pigmentary epithelium consistent with didanosine toxicity.
No antiretroviral therapy within two weeks of study entry.