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Efficacy and Toxicity of Antiretroviral Therapy Using 4 or More Agents
Application of a Strategy for Antiretroviral Management in Human Immunodeficiency Virus–Infected Children
Ann J. Melvin, MD, MPH;
Paul F. Lewis, MD;
Kathleen M. Mohan, RN, MS;
W. Scott Naugler, MD;
Lisa M. Frenkel, MD
Arch Pediatr Adolesc Med. 2002;156:568-573.
ABSTRACT
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Objective To characterize the long-term tolerance and virologic efficacy of combination
antiretroviral therapy consisting of 4 or more agents in a clinical setting.
Methods An observational review of 36 children infected with human immunodeficiency
virus 1 (HIV-1) treated with 4 or 5 antiretroviral agents in 2 university
hospital clinics between April 1, 1996, and October 31, 2000. Highly active
antiretroviral therapy regimens were chosen with regard to the child's past
antiretroviral exposure or results of genotypic resistance data. Plasma HIV-1
RNA levels were monitored weekly to monthly after initiation of highly active
antiretroviral therapy, and adherence efforts were actively supported and
monitored.
Main Outcome Measure Number of children with undetectable plasma HIV-1 RNA levels at longest
follow-up.
Results Four- or 5-drug highly active antiretroviral therapy reduced plasma
HIV-1 RNA levels to less than 50 copies/mL in 32 (89%) of 36 children. After
a median of 28.7 months of observation, 28 children (78%) remained at this
level of suppression. Adverse reactions were limited to mild neutropenia and
mild transient or persistent elevations in alanine aminotransferase levels
in 11% of children.
Conclusions Treatment with 4 or 5 antiretroviral agents was well tolerated in HIV-1–infected
children and resulted in a high degree of viral suppression, even in children
with previous antiretroviral drug experience.
INTRODUCTION
MOST STUDIES1-3
of combination antiretroviral therapy in human immunodeficiency virus 1 (HIV-1)–infected
children published to date suggest that long-term control of viral replication
is difficult to achieve in children, as only 27% to 48% experience suppression
of plasma HIV-1 RNA levels to below the limits of detection when treated with
"standard" highly active antiretroviral therapy (HAART) regimens that include
2 nucleoside reverse transcriptase inhibitors (NRTIs) and a protease inhibitor
(PI). Recently, results of 2 clinical trials4-5
using up to 4 antiretroviral agents demonstrated improved virologic outcome
(60%-63% viral suppression at 6-12 months), suggesting that sustained viral
suppression may be better achieved with multidrug regimens.
Concern has been raised, however, about potential increased toxic effects
and difficulty in adherence to regimens that include more than 3 antiretroviral
agents.6 Our clinical experience treating HIV-1–infected
children with 4 or more antiretroviral agents suggests that these regimens
are well tolerated and result in sustained viral suppression in most treated
children.
PATIENTS AND METHODS
PATIENTS
All children with HIV-1 followed at the pediatric HIV clinics at Children's
Hospital and Regional Medical Center (CHRMC), Seattle, Wash, and Oregon Health
Sciences University (OHSU), Portland, treated with 4 or more antiretroviral
agents between April 1, 1996, and October 31, 2000, were included in this
review. This included children switching from 3-drug regimens owing to concerns
about incomplete viral suppression and all children newly initiating HAART
after mid-1997, except for 2 children who were randomized to a 3-drug arm
of the Pediatric AIDS Clinical Trials Group (PACTG) 377.5
The multidrug HAART regimen for each child was chosen for ease of administration
and for potency, with avoidance of agents to which the virus was unlikely
to be susceptible based on previous use, known patterns of drug cross-resistance,
and/or "resistance" mutations found on genotypic testing.7-8
Six children received treatment as part of the PACTG protocol: 3 participated
in the PACTG 382,4 2 in the PACTG 377,5 and 1 in the PACTG 397.9
This retrospective review was approved by the institutional review boards
of CHRMC and OHSU.
PLASMA HIV-1 RNA LEVEL
The level of HIV-1 RNA in plasma was determined for most children every
3 months before initiating combination antiretroviral therapy; at the start
of therapy; weeks 1, 2, and 4 after initiating therapy; then monthly until
undetectable for at least 2 consecutive months; and then every 2 to 3 months
thereafter. Plasma RNA concentration was measured using a branched chain DNA
assay (Chiron Corp, Emory, Calif) sensitive to 500 copies/mL before June 1997,
and by reverse transcription polymerase chain reaction (Amplicor 1.0; Roche
Molecular Systems, Somerville, NJ) sensitive to 400 copies/mL after that date.
Beginning December 1997, plasma samples with RNA levels less than 400 copies/mL
were quantified using the ultrasensitive reverse transcription polymerase
chain reaction (Amplicor 1.0) sensitive to 50 copies/mL.
LYMPHOCYTE SUBSET ANALYSIS
CD4 and CD8 lymphocyte counts were determined from blood samples collected
in potassium-EDTA by standard 2-color fluorescent-activated cell sorter analysis
using the Coulter EPICS XL Flow Cytometry System (Coulter Electronics, Miami,
Fla).
ADHERENCE TO THE HAART REGIMEN
Before initiating a combination regimen, the goal of complete viral
suppression was discussed with families, including the need for close to 100%
adherence to prevent the emergence of HIV-1 that is resistant to therapy.
The families were actively involved in choosing the regimens with consideration
for the lifestyle of the family and the medication-taking skills of the child.
The families were provided with written instructions regarding the medications,
including dosages, frequency, and dates of dosage changes. In most cases,
the first dose of HAART was administered in the clinic. In addition, if the
child had had difficulty tolerating liquid medications in the past, therapy
was delayed until either the child was taught to swallow pills or a gastrostomy
tube was placed. Personnel from the HIV team contacted the family by telephone
frequently after the regimen was started. Most families were seen at 1- or
2-week intervals several times after initiation of therapy and then at least
monthly until the child's RNA level was less than 50 copies/mL. Adherence
to the regimen was discussed with the family by the authors (A.J.M., P.F.L.,
K.M.M., or L.M.F.) at each of these visits. The child's caretaker was asked
about difficulties with medications during the past month and specifically
about missed doses in the past week. Attempts were made to address any difficulties
identified. Families were also provided with a data table showing the child's
sequential RNA levels and CD4 cell counts, growth variables, and results of
all tests performed to monitor drug toxic effects. Medications for the CHRMC
cohort were filled on a monthly basis at the hospital pharmacy, and lapses
in refills were recorded. At OHSU, medications were filled at outside pharmacies,
with the clinic physician (P.F.L.) called for refills.
MONITORING TOXIC EFFECTS
Blood specimens for a complete blood cell count, serum alanine aminotransferase
measurement, and glucose and cholesterol (nonfasting) measurements were obtained
to monitor for hematologic, hepatic, and metabolic toxic effects, respectively,
every 4 to 16 weeks. Toxic effects were graded according to the Division of
AIDS Toxicity Table for Grading of Pediatric Adverse Experiences. Clinical
and laboratory adverse events are graded on a scale of increasing toxicity
(grades 1-4).
HIV-1 DRUG SUSCEPTIBILITY ASSESSMENT
When an increase in HIV-1 plasma RNA concentration was detected at greater
than 50 copies/mL, the pol genotype of the rebounding
virus was determined by direct consensus or end point sequencing of plasma
viral RNA.7 Two milliliters of plasma was used
when the viral copy number was less than 2000 copies/mL. The viral particles
were extracted using silica.10 The entire protease
gene and amino acids 1 through 375 of the reverse transcriptase gene were
amplified through nested polymerase chain reactions after reverse transcription
polymerase chain reaction using random hexamers. The amplified DNA was directly
sequenced using the Biosystems Genetic Analyzer 310 (Perkin Elmer, Foster
City, Calif) and was compared with wild-type HIV-1 (Consensus B from the Los
Alamos database8).
RESULTS
CLINICAL CHARACTERISTICS OF CHILDREN STUDIED
All 36 children treated with 4- or 5-drug HAART were included in this
analysis (27 from CHRMC and 9 from OHSU). Their median age at the start of
therapy was 6 years (range, 0.2-16.0 years). Eight children were naïve
to antiretroviral therapy before starting 4- or 5-drug HAART; the remaining
children had previous experience with a variety of NRTIs (n = 14), NRTIs and
PIs (n = 9), or NRTIs, nonnucleoside reverse transcriptase inhibitors (NNRTIs),
and PIs (n = 4). Past treatment records were not available for 1 child. Twelve
children had been treated initially with a 3-drug HAART regimen and were changed
to a 4- or 5-drug regimen owing to either viral rebound (9 children) or concerns
regarding the potency of their initial regimen (3 children). Six children
(17%) were treated with a 5-drug regimen. The median time being treated with
a 4- or 5-drug regimen was 28.7 months (range, 3.5-43.0 months). Twenty-eight
(78%) of the 36 children were receiving 4- or 5-drug HAART for at least 18
months (median, 31 months).
Initial multidrug HAART regimens are detailed in Table 1. Children were treated with full recommended dosages of
all agents. Nelfinavir was administered at 55 mg/kg every 12 hours and ritonavir
at 400 mg/m2 every 12 hours, except for the child younger than
2 years, who was given 450 mg/m2. Saquinavir was initially administered
at 350 mg/m2 every 12 hours when given in conjunction with ritonavir
until February 2000,10 when it was increased
to 50 mg/kg every 12 hours.
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Table 1. Initial Multidrug Combination Antiretroviral Treatment Regimens
Used in This Study*
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VIROLOGIC RESPONSES AFTER INITIATION OF HAART
The median RNA level before HAART was 4.9 log10(range, 3.3-6.5
log10) (Table 2). After
initiation of HAART, all children experienced a decrease in plasma HIV-1 RNA
concentration, with the plasma RNA nadir being below 50 copies/mL (1.7 log10) in 32 children (89%). The median RNA level at the last follow-up
during 4- or 5-drug HAART was 1.7 log10(range, 1.7-5.8 log10), with 28 children (78%) having RNA levels suppressed to below 50
copies/mL. Virologic rebound, defined as an increase in RNA levels to greater
than 50 copies/mL on at least 2 time points 4 weeks apart or 1 value greater
than 1000 copies/mL, occurred in 13 children during 4- or 5-drug therapy.
Failure to achieve RNA suppression or viral rebound was associated with documented
nonadherence, either chronic or episodic, in 10 of the 13 children.
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Table 2. CD4 Cell Count and Percentage and HIV-1 RNA Levels at Initiation
of HAART and at Longest Follow-up in HIV-1–Infected Children Treated
With 4 or 5 Antiretroviral Agents*
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In 5 of the 13 children, viral suppression was again achieved after
adjusting their regimens. New resistance mutations did not develop at the
time of the viral rebound (RNA increases to 3.1 and 3.4 log10)
in 2 children, and viral levels decreased to below 50 copies/mL with only
minor modifications in their regimens (changing from nelfinavir to ritonavir
in one child and increasing the dosage of saquinavir in the other). New resistance
mutations were present in 3 of the 5 children at the time of viral rebound,
which occurred in 2 of the 5 children after decreased adherence associated
with emesis caused by an intercurrent illness. Suppression of plasma RNA levels
to less than 50 copies/mL was again achieved in each of these 3 children after
changing 2 to 4 drugs in their regimens. The HAART was suspended in the remaining
8 children at the time of rebound while issues relating to nonadherence were
addressed.
CD4 RESPONSES AFTER INITIATING HAART
Median CD4 cell count and percentage at baseline were 406 cells/µL
(range, 7-3249 cells/µL) and 18.5% (range, 1%-41%), respectively (Table 2). After a median of 28.7 months
of 4- or 5-drug HAART, the median CD4 cell count was 986 cells/µL (range,
349-2895 cells/µL) and the percentage was 34% (range, 9%-50%), representing
a median increase of 339 cells/µL (range, –358 to 1845 cells/µL)
and 12% (range, –7% to 37%), respectively. CD4 cell counts improved
to or remained at age-appropriate levels for all children maintaining HIV
plasma RNA levels less than 50 copies/mL during HAART.
ADHERENCE OF CHILDREN TO HAART REGIMENS
Adherence, as assessed through parental report, was greater than 95%
(missing only 1 or 2 doses a month) in 24 (67%) of 36 children. These families
also were timely in obtaining medication refills. For the remaining families,
either parental report or pharmacy refill data suggested chronic nonadherence
(8 families), or the clinicians felt unable to judge the level of adherence
(4 families). All of the children whose families reported chronic nonadherence
experienced virologic rebound. As detailed in the "Virologic Responses After
Initiation of HAART" subsection, viral rebound occurred in 2 children during
adherence difficulties associated with an intercurrent illness. Both of these
children again achieved viral suppression after instituting a new regimen.
A variety of factors were associated with chronic poor adherence in the remaining
families, including family disorganization, parental ambivalence regarding
the value of HAART, and the child's dislike of taking medicines (liquid or
pills). The number of antiretroviral agents in the regimen was specifically
noted as a barrier to adherence for 5 families.
Gastrostomy tubes were placed for the purpose of medication administration
in 7 children, and they were successful aids to adherence for 5 children,
as assessed by the families and the clinicians. In these cases, the main obstacle
to adherence was convincing the children to take unpalatable medicines. In
the other 2 children, poor adherence was in large part due to ambivalence
on the part of the caretaker, and sustained virologic suppression was not
achieved in these children despite use of the gastrostomy tube.
TOLERANCE OF HAART REGIMENS
Both the 4- and 5-drug regimens were well tolerated. Several children
initiating therapy that included an NNRTI developed a mild to moderate rash.
However, in all children the rash resolved without modification of therapy,
and no child discontinued therapy because of rash. Biochemical and hematologic
toxic effects were minimal, with no toxicities greater than grade 1 present
at the latest point during 4- or 5-drug HAART (Table 3). Serum alanine aminotransferase level was elevated at the
longest follow-up in 3 children (8%), although none above grade 1 toxicity
(range, 33-147 U/L). Serum alanine aminotransferase level was moderately elevated
(range, 165-331 U/L) for 16 weeks in an additional child treated with ritonavir;
the elevation resolved spontaneously without any change in the medication
regimen. Grade 1 neutropenia (absolute neutrophil count, 750-1200 cells/µL3) was present in 4 children (11%) at longest follow-up. These children
developed persistent neutropenia during therapy that fluctuated between grades
1 and 2 (absolute neutrophil count, 400-1200 cells/µL3) without
any clinical symptoms. No child developed significant anemia or thrombocytopenia
during therapy. Grade 1 elevation in cholesterol level (measured on nonfasting
blood specimens) (range, 171-499 mg/dL [4.42-12.90 mmol/L]) developed in 27
(79%) of 34 children.
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Table 3. Laboratory Evaluation at Longest Follow-up During HAART in
36 HIV-1–Infected Children Treated With 4 or 5 Antiretroviral Agents*
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COMMENT
We began using 4- and 5-drug HAART regimens after 4 of the first 10
children treated at CHRMC and OHSU with 3-drug HAART either did not achieve
viral suppression or rebounded within the first 6 months of treatment.11 In addition to increasing the number of antiretroviral
agents included in a regimen, we modified our approach to initiating HAART
in several other ways. Regimens were selected to include antiretroviral agents
not previously used or unlikely to have high levels of cross-resistance based
on genotypic analysis, and the agents were prescribed at the highest recommended
dosages. Frequent monitoring of plasma HIV-1 RNA levels was instituted, and
antiretroviral drug regimens were intensified soon after any detectable viral
rebound to minimize the selection of mutations associated with high-level
resistance to PIs. Adherence was facilitated by prescribing regimens that
were given twice daily, maintaining frequent contact with the families, monitoring
pharmacy refills, and evaluating and discussing adherence at every clinic
visit.
Using this approach, 28 children (78%) treated with 4- or 5-drug regimens
at CHRMC and OHSU achieved and maintained plasma HIV-1 RNA levels of less
than 50 copies/mL during a median of more than 28 months of HAART. This occurred
despite most children being highly antiretroviral drug experienced (28 children
[78%] with previous exposure to multiple NRTIs and 9 [25%] with previous PI
exposure), although data12 suggest that the
effectiveness of therapy is adversely affected by previous treatment with
antiretroviral agents.
It is not clear which component of this strategy is the most important.
In most previous studies,1-3
the rate of suppression of viral replication with HAART in children has been
low (<50% in most studies), and only short-lived suppression of viral replication
has been documented in children. However, recently the PACTG 377 demonstrated
an improved virologic outcome in children treated with 4 agents. Sixty percent
of children treated with the combination stavudine, lamivudine, nevirapine,
and nelfinavir had plasma RNA levels less than 400 copies/mL at 6 months.5 Similarly, improved outcome was seen in PACTG 382,4 an investigation of efavirenz and nelfinavir with
1 or 2 NRTIs. In this study, which in addition used therapeutic drug monitoring,
63% of children had RNA levels less than 50 copies/mL through 48 weeks.
In adults, the number of new drugs included in a regimen13-14
and the number of agents to which the virus seems susceptible by genotypic
testing15-16 have been associated
with the duration of viral suppression. More potent HAART regimens may be
needed for children because of their higher viral burden,17-18
relatively immature immune system,19 or unfavorable
antiretroviral pharmacokinetics.20-21
Alternatively, a 4- or 5-drug regimen may provide greater efficacy owing to
the low probability of selection of virus resistant to all agents22-23 or because it may allow for a greater
degree of nonadherence.
Intensive virologic monitoring after initiation of a new antiretroviral
regimen allows for rapid determination of response to therapy, documentation
of complete suppression to below 50 copies/mL, and timely determination of
viral rebound, thus allowing initiation of a salvage regimen before development
of high-level PI resistance. Failure to achieve complete viral suppression
has been associated with increased risk of virologic failure and development
of viral resistance mutations.24 The plasma
RNA level and the presence of high-level PI resistance mutations have been
associated with the failure of salvage therapy.25-26
Documenting the decline of plasma RNA levels may also provide encouragement
to children and their families because they can see the effects of their efforts
to adhere to the medications.
Lack of adherence to the medication regimen has been cited as the primary
reason for failure of HAART.3, 27-28
The level of adherence necessary to optimize virologic outcome has been shown
to be 95% or greater in adults undergoing HAART.29
Adherence to the prescribed therapy is complicated for children because of
many factors: the caretaker's schedule must be meshed with that of the child,
young children lack understanding and motivation to take the medications and
may resist for behavioral reasons, and young children may have difficulty
in ingesting large quantities of unpalatable liquids or large numbers of capsules
or tablets. Watson and Farley3 found that only
58% of children in their clinic were adherent to their medications at a level
of 75% or greater. We attempted to support and monitor adherence through frequent
contact with the families, monitoring pharmacy refills, placement of gastrostomy
tubes (particularly in younger children), and careful assessment of parental
ability and commitment before initiation of HAART. Despite all of these efforts,
nonadherence seemed to be the primary cause of viral rebound in 10 (77%) of
the 13 children who experienced virologic rebound while taking 4 or 5 antiretroviral
agents. Although most treated children were believed to be adherent to the
level of greater than 95%, the accuracy of the assessment of level of adherence
is limited by the use of self-report measures, which, in general, overestimate
adherence.30
Many health care workers and HIV-1–infected individuals are concerned
that the increased potency potentially provided by a multidrug regimen might
be offset by increased toxic effects and difficulty in adherence, and thus
could diminish the ultimate efficacy of multidrug regimens. Although the children
in our cohort experienced few adverse effects from the medications, as discussed
previously, the absolute level of adherence could not be determined with confidence.
It is possible that increased toxic effects from the 4- and 5-drug regimens
would have been demonstrated if all patients achieved 100% adherence. Nevertheless,
our clinic experience reported herein, and the higher continuation of the
4- vs 3-drug regimens in the PACTG 377,5 indicate
that multidrug HAART regimens are well tolerated in children.
We believe that in addition to the use of multidrug HAART at the highest
recommended dosages, the intensive monitoring of plasma HIV-1 RNA levels and
active support of adherence was critical to the success of therapy in these
children. We hypothesize that intensive monitoring allows timely intensification
of regimens before the development of high-level resistance to PIs and assists
families in affirming the benefit of their high-level adherence to therapy.
The success of HAART in our clinic population suggests that HAART therapy
can result in long-term virologic suppression in most children and that strategies
critical to achieving a high level of treatment success should be investigated.
| What This Study Adds
Antiretroviral treatment of HIV-1–infected children is difficult,
and most published studies using HAART have demonstrated suppression of HIV-1
RNA to undetectable levels in only 40% to 60% of treated children. In addition,
previous studies have been short term, reporting on 24 to 48 weeks of therapy.
We developed a treatment strategy using multidrug antiretroviral regimens,
frequent monitoring of HIV-1 RNA levels, and aggressive adherence support.
Although this is an observational review of our clinical experience, the results
suggest that use of 4- or 5-drug regimens to treat HIV-1 in children is well
tolerated and results in long-term viral suppression in most children.
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AUTHOR INFORMATION
Accepted for publication February 7, 2002.
This study was supported in part by grants AI32910 and R01 HD36184 from
the National Institutes of Health, Bethesda, Md.
Corresponding author and reprints: Ann J. Melvin, MD, MPH, Children's
Hospital and Regional Medical Center, 4800 Sandpoint Way NE, CH-32, Seattle,
WA 98105 (e-mail: amelvi{at}chmc.org).
From the Departments of Pediatrics (Drs Melvin and Frenkel and Ms Mohan)
and Laboratory Medicine (Ms Mohan and Drs Naugler and Frenkel), University
of Washington, Seattle; and the Department of Pediatrics, Oregon Health Sciences
University, Portland (Dr Lewis).
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