This study will evaluate a new treatment strategy called therapeutic drug monitoring (TDM)
in HIV-infected children and adolescents. TDM involves analyzing the virus, giving drugs the
virus is most sensitive to, monitoring drug blood levels to make sure there is enough drug
to work against the virus, and changing the drug dose if it is too low.
HIV-infected children between 0 and 21 years of age who may benefit from treatment with a
protease inhibitor and who are not benefiting from their current antiretroviral drug
treatment regimen may be enrolled in this 48-week study. Patients who are not currently
receiving antiretroviral treatment, including patients who have never received
antiretroviral treatment, may be enrolled in the study.
Participants will have blood drawn to learn what anti-HIV drugs the patient's virus is
resistant to-that is, what drugs are no longer effective against the virus. This is
determined by analyzing the virus's genotype (detailed genetic structure) and phenotype
(response to exposure to anti-viral drugs). Based on these test results and the patient's
prior medication history, a drug regimen tailored to the individual patient will be
prescribed. It may include one or two nucleoside reverse transcriptase inhibitors, such as
zidovudine, didanosine, lamuvidine, zalcitabine, stavudine), a non- nucleoside reverse
transcriptase inhibitor such as nevirapine or efavirenz, and a protease inhibitor such as
amprenavir, nelfinavir, saquinavir, ritonavir, or Kaletra (a combination of lopinavir and
After the patients begin treatment, the amount of the protease inhibitor in the blood will
be measured. If not enough of the drug is found in the blood, the dose of the drug will be
increased and the amount of the drug in the blood will be checked again. In this study, the
dose may be increased up to three times.
Patients will be seen in clinic for 6 days when treatment begins to measure blood levels of
the medicines and evaluate the response of the virus. Treatment will then continue on an
outpatient basis. Drug levels will be measured periodically throughout the study. The viral
load will also be measured and additional tests to determine whether the resistance pattern
of the patients' virus has changed. In addition, patients will undergo the following tests
and procedures at various times throughout the study, more frequently for the first few
months and then less often:
- Blood tests to measure cell counts and viral load
- Routine laboratory tests to measure kidney, liver, bone marrow, and other organ
- Eye and neuropsychologic examinations
- Echocardiogram (heart ultrasound)
- Electrocardiogram (EKG - heart rhythm test)
- Chest X-ray
- Computed tomography (CT) scan of the head
- Skin tests
To make sure the medicines work, they must be taken as directed. In addition, since higher
than usual doses of some of the anti-HIV drugs may be given, it will be important to know
whether the patients are taking all of the medicine that has been prescribed. This study
will therefore also measure patients' adherence to their medication regimen in two ways: 1)
some medicines will be packaged in a bottle with an electronic medicine bottle cap that will
record when the bottle is opened, and 2) patients and their parents will be interviewed by
phone or in person at various times during the study about adherence and may be asked to
fill out forms that record the number of doses taken. This will allow the doctor and patient
to work together to make sure the medicines are being taken properly. Patients and parents
will also be interviewed periodically about their understanding of HIV disease, about social
supports that are available, and about the child's emotional adjustment.
This is a single arm study to determine whether a novel dose adjustment strategy that
individualizes protease inhibitor dosing to maintain drug concentrations above
virologic-based threshold values (TDM) in pediatric patients with HIV is able to result in a
potentially clinically useful proportion of patients who achieve a targeted inhibitory
quotient (IQ). The study will consist of up to 34 children between 0 and 21 years of age
(minimum weight 10 kg). Patients will have viral resistance testing performed at baseline
and that information, combined with treatment history analysis and drug tolerability issues
will be used to design a combination antiretroviral regimen. After the new regimen is
started, pharmacokinetic monitoring will guide dose adjustments of protease inhibitors. An
algorithm will be followed to make dose adjustments based upon viral phenotype and drug
levels. The primary outcome measure will be the fraction of patients who attain adequate
protease inhibitor levels above target values. Secondary measures will include virologic
and immunologic benefits and evaluation of toxicity and tolerability.
HIV-infected children between the ages of 0 and 21 years
An indication for treatment with a PI containing antiretroviral regimen as defined by the
2001 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (one of
Clinical symptoms associated with HIV Infection (i.e., clinical categories A, B, or C)
Evidence of immune suppression indicated by CD4 T-lymphocyte count or percentage (i.e.,
immune category 2 or 3)
Age less than 12 months - regardless of clinical, immunologic, or virologic status
High or increasing HIV RNA copy number
Rapidly declining CD4 T-lymphocyte number or percentage to values approaching those
indicative of moderate immune suppression (i.e., immune category 2)
Children failing current treatment as defined by the 2001 Guidelines for the Use of
Antiretroviral Agents in Pediatric HIV Infection (http://www.hivatis.org/) (one of the
Less than a 10-fold decrease from baseline viral load in patients on a HAART regimen
(combination regimen that includes a PI and/or NNRTI) after 8-12 weeks of therapy.
Less than a 5-fold decrease in viral load from baseline in patients on non-HAART regimen
(e.g., dual NRTI combinations)
Viral load not suppressed to undetectable levels after 4-6 months of antiretroviral
Repeated detection of HIV RNA in patients who initially responded to antiretroviral
therapy with undetectable levels.
An increase in viral load of greater than 3-fold.
Change in immunologic classification
For children in immunologic category 3, a decline of five percentiles or more in CD4 cell
A greater than 30 percentage decline in absolute CD4 cell count.
Progressive neurodevelopmental deterioration
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
Sexually active patients must be willing to use a medically acceptable form of birth
control, which includes abstinence, while they are on this study.
Hematologic Function: 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
Hepatic Function: Liver transaminases must be less than or equal to 3.0 times the upper
limit of normal; Lipase less than 1.5 times the upper limit normal; Creatine phosphokinase
(CPK) less than 2.5 times the upper limit of normal.
Renal Function: Patients must have an age-adjusted normal serum creatinine OR a creatinine
clearance greater than or equal to 70mL/min/1.73.
History of non-adherence that in the opinion of the PI or study chairperson makes it
unlikely that the patient will adhere to protocol.
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
Weight less than 10 kg.
Pregnant or breast feeding females.