Retroviral therapy and clinical trials for

HIV-infected children
K e i t h Krasinski, MD
From New York University Medical Center

Antiretroviral therapy in children has built on advances in

the treatment of HIV-infected adults, in conjunction with
an appreciation of the developmental impact of AIDS in
children and the different clinical manifestations and
altered pharmacokinetics of drugs in the pediatric population. The first effective drug for the treatment of AIDS is
the dideoxynucleoside AZT. This drug's principal mode of
action is to block HIV replication by inhibition of the DNA
polymerase reverse transcriptase. 1 In a double-blind placebo-controlled study of adults with AIDS and advanced
AIDS-related complex, patients treated with AZT had improved survival and decreased incidence of opportunistic
infections2; this study led to approval by the Food and Drug
Administration of the drug for use in the treatment of adults
with AIDS. In this study, clinical status, T lymphocyte
counts, and surrogate markers of viral activity also improved. However, therapeutic effects were offset against
significant bone marrow toxicity, resulting in dose-limiting
neutropenia and anemia that required transfusion)
Treatment with AZT was introduced to pediatric patients with HIV infection on the basis of successful interventions in adults. Initial dose ranging, safety, and shortterm toxicity studies in children indicated a safety profile
similar to that in adults. In a dose escalation study in children between the ages of 5 months and 13 years, neutropenia (defined as <750 cells/ram 3) occurred in 25%, and anemia requiring transfusion in 20%; this study included
sequential intravenous and oral therapy. 4 Infectious complications of HIV-1 infection continued to occur despite
therapy, and included 22 catheter-related infections in 13
patients, otitis media, sinusitis, impetigo, and localized cellulitis. However, only two of these infections were temporally related to neutropenia. Of note is that the frequency
of viral isolation from individual patients did not change
over the period of the study. In a limited number of patients
for whom data were available, viral cultures from cerebrospinal fluid tended to become negative. This study also

9/0/30163

found that the treated patients experienced weight gain,

stabilization of CD4 + T lymphocyte counts, moderation of
hypergammaglobulinemia, reductions in organomegaly and
lymphadenopathy, and an overall sense of improved wellbeing during treatment with specific antiretroviral therapy.
Similar objective and subjective improvements also were
noted in a high-dose constant infusion study of AZT. 5 In
particular, improvements in gait, coordination, social interactions, expressive and receptive language, and IQ were associated with AZT treatment. Formal neurodevelopmental
assessments were performed on a subset of the children receiving oral intermittent therapy; these tests indicated improved neurodevelopmental function. However, serial psychometric testing of this group indicated no improvement in
IQ. 6 In addition, AZT appears to have other central nervous
system effects, such as irritation, hyperactivity, and agitation.
AZT
ddC

Zidovudine
Dideoxycitidine

Antiretroviral therapy must be regarded as palliative, not

curative. Data from phase II studies reveal that approximately 12% of children died while receiving therapy, and
12% of children were removed from the study because of
toxicity or noncompliance with the study protocol. 7, 8 Some
survivors experienced reductions in serum and cerebrospinal fluid HIV-1 p24 antigen concentrations, whereas others
did not. The use of p24 as a "surrogate marker" of viral activity has not been substantiated in children. 9 Another limitation of AZT therapy is the development of resistance
mediated by viral or cellular enzymes, l~
Although no controlled trials of AZT have been conducted in children and the beneficial effects have not conclusively been demonstrated to be caused by antiviral activity, the severity and ultimately fatal prognosis of the
primary disease, the occurrence of mild toxicities, the success of therapy in adults, and the lack of suitable alternative therapies strongly support treatment recommendations
for immunocompromised and symptomatic HIV-1-infected

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The Journal of Pediatrics

July 1991

children. In May 1990, A Z T was licensed for use in HIV1-infected children with symptomatic disease or severely
compromised immune systems.
GUIDELINES
CHILDREN

F O R AZT T H E R A P Y I N

Children who are HIV positive and have manifestations

of the disease may begin AZT treatment regardless of their
immunologic status. It should be noted that very ill children
may have no measurable immune dysfunction, and some
children may have opportunistic infections with CD4 counts
as high as 1500/ram 3.
Therapy with AZT in asymptomatic children with normal or near normal immune function and for prophylaxis of
perinatally acquired infection are the subjects of ongoing
studies. No recommendations can be made at this time.
The drug is available in a 10 mg/ml raspberry-flavored
syrup, and is administered at 180 m g / m 2 of body surface
area per dose every 6 hours. Anemia and neutropenia may
require dosage reductions to 120 rag/m:. Additional dosage
reductions to 80 to 90 m g / m 2 or dose interruption for a period of time to allow the normalization of hematologic values may be required. Dose comparison studies are under
way to determine whether any potentially beneficial effects
on the central nervous system accrue to patients at these
reduced doses of drug.
Before treatment or at the time of therapy institution,
baseline laboratory values (CBC count, blood chemistry
panel) should be obtained. Elevations in liver function tests
in HIV-1 infected children occur frequently and are not
contraindications to therapy. These blood tests should be
obtained biweekly for the first month. If no significant toxicity is observed, testing may be done monthly, and subsequently bimonthly. It is prudent to examine each child at
least once a month for clinical evidence of anemia. Severe
anemia may require dose reduction and transfusion. When
transfusion is not suitable management for anemia, human
recombinant erythropoietin therapy may be attempted.
AZT therapy also is commonly associated with an increase
in red blood cell mean corpuscular volume; this value
can be used as a measure of compliance with the drug
regimen.
When children are examined, immunologic, virologic,
and clinical factors may possibly be used as markers for
drug effect) 0 These markers should not be construed as being evidence of beneficial drug effect.
Immunoglobulin levels. Most children with HIV infection
have elevated serum levels of immunoglobulin. Phase I and
Phase II trials of AZT revealed that most children in the
study experienced a modulation in immunoglobulin levels, t 1
Therefore serum immunoglobulins may serve as a useful
indicator of drug effect.
CD4 lymphocyte counts. Children have approximately

four times as many lymphocytes as adults, and normative

data for CD4 counts in children younger than 1 year of age
are now being defined. However, ratios of CD4 to total
lymphocytes are similar in children and adults and may be
a useful measurement to follow. CD4 lymphocyte counts
should be monitored every 3 months while a patient is receiving antiretroviral therapy.
p24 antigen. The presence of this viral protein has been
correlated to disease state. Declines in p24 levels have been
noted in phase I and phase II AZT trials. However, the major limitation is that not all children with HIV infection
have measurable p24 antigenemia.
Clinieal observations. Clinical factors such as growth and
development should be followed, because changes may be
detected soon after the initiation of drug therapy.
At the present time, no alternative therapy is routinely
available to children. The pharmacokinetics of A Z T have
been described in conjunction with the above-mentioned
studies)a. 13 Lower doses of A Z T may be required in symptomatic children during the first few months of life when
drug pharmacokinetics change rapidly in association with
developmental changes in volume of distribution and liver
and renal function. Preliminary data indicate that oral doses
of 2 mg/kg given every 6 hours for infants younger than 1
month of age, and 3 mg/kg given every 6 hours for infants
between 1 and 3 months of age, may be appropriate. 13 An
infant younger than 3 months of age should have clear indications of HIV-related disease and evidence of HIV
infection before A Z T therapy is initiated. It must be
emphasized that no dosage recommendations can be made
with confidence for children younger than 3 months of age.
Clinical treatment trials for infants and children with
HIV-1 infection that are currently being conducted in the
United States are summarized (Table). In addition, several
trials are investigating other forms of anti-HIV-1 therapy
and other antiviral, antifungal, or antiparasitic therapies.
These trials may be appropriate for adolescents and young
adults who are in the care of pediatricians. Further information on these trials can be obtained from the Table.

OTHER S T R A T E G I E S FOR
ANTIRETROVIRAL THERAPY
Other nucleosides are under clinical investigation for
their safety and efficacy as therapeutic agents in children.
ddC is being developed as salvage therapy for patients intolerant or refractory to AZT. Preliminary data indicate
that neutropenia and pancreatitis with associated abnormalities in calcium and phosphate metabolism are the
dose-limiting toxicities. On the other hand, clinical and
laboratory measures have improved in some children during therapy) 4 Dideoxycytidine is associated with reductions
in HIV p24 antigenemia in adults and appears to spare the
bone marrow. 15'16 Treatment with ddC can result in

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Retroviral therapy and clinical trials for HIV-infected children

Table. T r e a t m e n t trials for infants a n d children with HIV-1 infection

Protocol Title/
description

Protocol
number

Phase I I / I l l double-blind
placebo-controlled trial of
intravenous immunoglobulin for
symptomatic and/or
immunologically abnormal
children with HIV infection
Phase III randomized
placebo-controlled trial to
evaluate the efficacy, safety,
and tolerance of oral AZT
versus placebo in pregnant
HIV-infected women and their
infants
Phase 1 trial to evaluate AZT in
HIV-1 infected pregnant
women and their infants
Phase I study of the safety and
pharmacokinetics of
recombinant CD4 (rCD4) in
infants,and children infected
with or at risk for H1V
infection
Randomized trial to evaluate the
impact of maintaining
steady-state concentrations of
AZT versus an intermittent
schedule of AZT delivery versus
intermittent ddI in children
with HIV infection
Phase I study of the safety,
tolerance, and pharmacokinetics
of aerosolized pentamidine and
parenteral pentamidine in
children with symptomatic HIV
infection and suspected

ACTG 045

Closed

L. Mofenson, M.D.
301-496-7339

ACTG 076

In development

E. Connor, M.D.
201-268-8484

ACTG 082

Open

Y. Bryson, M.D.
213-825-5235

ACTG 101

Genentech IND

P, Weintrub, M.D.
415-476-8016

ACTG 103

National Cancer
Institute only

P. Pizzo, M.D.
301-496-4256

ACTG 115

Not yet open

Y. Bryson, M.D.
213-825-5235

Comments

Contact/
telephone number

Pneumocystis earinii
pneumonia
ACTG 139
Not yet open under
Pharmacokinetics and safety of
Genentech IND
recombinant human
CD4-immunoglobulin G
(rCD4-IgG) in HIV infected
infants and children
ACTG 128
Near accrual
Randomized trial to evaluate the
safety and tolerance of high
versus low doses of AZT
administered to children with
HIV
ACTG 146
In development
Phase i study of recombinant
CD4-immunoglobulin
(rCD4-1gG) in HIV-infected
pregnant women and their
newborn infants
Additional Information
The AIDS Clinical Trials Unit for Protocol Inquiry
Directory of AIDS/HIV Clinical Trials open in New York and New Jersey
The American Foundation for AIDS Research
The National AIDS Hotline
The New York State AIDS Hotline
The New York City AIDS Hotline

R. Yogev, M.D.
312-880-4187
W. Shearer, M.D.
713-790-1345
P. Weintraub, MD
415-476-8016

W. Shearer, M.D.
713-790-1345
R. Yogev, M.D.
312-880-4187

(301) 230-3150
(800)-TRIALS-A
(212) 333-3118
1-800-342-AIDS
1-800-872-2777
(212) 587-4000

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The Journal of Pediatrics

July 1991

peripheral neuropathy that increases with increasing doses

of drug and long durations of treatment. Preliminary data
in children, in a study in which ddC is alternated with AZT,
indicate that HIV p24 antigen levels decrease and patient's
affect and activity increase during therapy. 17 Neutropenia
and anemia were not observed; however, 60% of patients
developed oral ulcerations while on therapy.
One additional strategy under investigation is the use of
the recombinant CD4 molecule to block receptor sites for
virus entry into cells. At the present time, only preliminary
safety and pharmacokinetic information are available.
Optimal antiretroviral therapies for children are not yet
available. Suitable agents should minimize toxicity, maximize antiviral effects, and be easily administered to and well
accepted by children. Any treatment strategy must also take
into account the ongoing development of the child and the
frequency with which central nervous system effects are
observed in HIV-infected children. The alternating ddC/
A Z T regimen attempts to minimize toxicities of each drug
while maximizing antiviral activity. Other potential strategies will combine activities such as blocking viral entry
with the CD4 molecule, exploiting other vulnerable targets
of the HIV- 1 life cycle, or applying immunomodulators to
children. These and other experimental therapies are available at various centers throughout the country. More information on antiretroviral therapeutic trials for children can
be obtained from local pediatric immunologists or infectious disease consultants, the multiple AIDS Hot Lines, the
A m F A R directory of treatment trials, or from the National
Institute of Allergy and Infectious Diseases.
CLINICAL TRIALS
CHILDREN

FOR HIV-INFECTED

Evolution of therapeutic clinical trials. The randomized

clinical therapeutic trial was developed and perfected in the
early 1950s. 18 Since then, this methodologic tool has been
proved to assess objectively and effectively the clinical efficacy and toxicity of new drugs in both adults and children.
To be effective, trials need the full cooperation of a relatively
large number of persons. As such, they require complementary scientific and social aims. These trials involve a three
tier process.
Phase I:
Phase I involves relatively few patients with
a disease, and tests the pharmacokinetics
and safety of a new therapeutic intervention.
Phase II:
The purpose of phase II is to determine the
safety and efficacy of the new therapy, based
on data determined from phase I of the
study. These studies, involving larger numbers of patients, are still relatively small.
Phase III: The purpose of phase III is to determine the
clinical efficacy of the new therapy. As such,

it requires the involvement of large numbers

of patients and often is carried out nationwide at various institutions.
Traditionally, the process described is long and arduous;
it has been designed as such to provide a thorough evaluation that minimizes patient exposure to ineffective or
potentially harmful experimental treatments. In the AIDS
era, the timetable of trials has had to be reexamined because
of increased public demands for treatments.
Clinical trials for HIV-infected children are conducted at
hospitals supported by the National Institutes of Health.
The Table lists the current trials being conducted in the
United States.
PROBLEMS WITH CLINICAL
HIV-INFECTED
CHILDREN

TRIALS

IN

There is an urgent need for well-designed clinical trials

in HIV-infected children and adolescents. Because the presentation and course of HIV infection in these patients are
different from those in adults, data regarding therapeutic
interventions are crucial. Guidelines developed by trials in
adult patients may not be applicable to the pediatric population. In addition, a number of special social and scientific issues have arisen with attempts to conduct clinical trials in HIV-infected children.
Sociologic factors, The vast majority of children infected
with HIV are members of minority populations. In addition,
most acquire their infection from infected mothers who engage or have engaged in high-risk behavior (i.e., intravenous
drug users or sexual consorts of intravenous drug abusers).
The society that these children live in is therefore chaotic,
with little or no organization. Often natural parents may
have died of AIDS or are unable to care for their children.
Children lack political power, and few advocacy groups are
working in their behalf. Therefore these children may not
be identified, come to medical care, or have access to clinical trials.
Compliance and clinical follow-up. Families of pediatric
patients with HIV infection have enormous social problems
that make contact with the medical establishment erratic.
Issues of compliance become important, especially in large
clinical trials in which multiple follow-up visits are needed
for complete data evaluation. Therefore it is most advantageous to patients if primary care is offered at the same time
andplace as the research trial. This has implications for increasing the cost of operation of clinical trials, because
funding needs to cover the staff and additional monies
needed for primary care.
Children who are wards of the state. The existence of a
large population of HIV-infected children who are wards of
the state further complicates the enrollment of children in
clinical trials. It is estimated that approximately 30% to

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Retroviral therapy and clinical trials for HIV-infected children

50% of HIV-infected children require foster care. Presently

0nly those children whose natural parents give consent may
be enrolled in clinical trials. Children who are in foster care
often may have deceased or unreachable parents. These
children then are denied access to potentially beneficial experimental therapies.
Currently three states (Maryland, Massachusetts, and
North Carolina) have permitted HIV-infected children in
foster care to participate in clinical trials without the consent of natural parents; five other states have procedures
pending implementation.19 These procedures include court
approval, transference of medical guardianship to foster
parents, or approval of protocols by the state department of
health and individual review of each case.
Enrollment of infants and adolescents. It is currently estimated that 30% of newborn infants exposed perinatally to
HIV infection will actually acquire the infection. Therefore
ethical issues are raised concerning the potentially harmful
long-term effects of experimental drugs used to treat large
numbers of uninfected infants. Conversely, early therapy
may prevent the establishment of HIV infection contracted
perinatally. Accurate methods of diagnosing HIV infection
in this age period are urgently needed.
Adolescents are often omitted from pediatric and adult
clinical trials. Even though guidelines have been developed
for adults and children, issues of consent for testing, partner notification, and confidentialityare yet to be clarified for
adolescent minors.
Compassionate use of drugs. A variety of drugs, either for
opportunistic infections or effectiveness against HIV, will
not be available for general use in children in the near future. Adequate numbers Of HIV-infected children may not
be available for a satisfactory assessment of these drugs.
There are some critically ill children who may benefit from
one of these therapies. Criteria for the Compassionate use of
certain drugs (and means of paying for them if drug companies are not willing to bear the cost) need to be defined.
Sites of care. Large numbers of children with HIV infection do not necessarily receive their medical care at large
university centers, where clinical trials traditionally have
been run. In addition, families may not be mobile enough
to travel repeatedly to regional referral centers. Therefore
close linkages between identified hospitals with significant
HIV populations and those with available clinical trials
need to be promoted.
INFORMATION
TRIALS

REGARDING CLINICAL

A special toil-free phone number (1-800-TRIALS-A)

has been established by the Public Health Service to provide
up-to-date information regarding every privately sponsored
experimental AIDS and AIDS-related treatment undergo-

S67

ing clinical testing. This information includes the name of

the drug, the purpose of the study, the status of the study
in regard to patient accrual, study locations, eligibility requirements, and names and telephone numbers of contact
persons (Table).
For a number of reasons, few clinical therapeutic trials
are available for children with HIV infection in the United
States. Better means of identifying and referring patients to
centers with trials need to be defined. Other issues, such as
access to care for minors who are wards of the state and for
adolescents, need to be clarified in order to open these trials
to the maximum number of persons.

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