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Journal of Virology, January 1999, p. 362-367, Vol. 73, No. 1
Department of Pediatrics,
Received 24 June 1998/Accepted 8 October 1998
Plasma human immunodeficiency virus type 1 (HIV-1) turnover and
kinetics were studied in children aged 15 days to 2 years following the
initiation of a triple antiretroviral drug regimen consisting of
zidovudine, lamivudine, and nevirapine. HIV-1 turnover was at
least as rapid as that previously described in adults; turnover rates
were more rapid in infants and children aged 3 months to 2 years than
in infants less than 3 months of age. These data confirm the central
role of HIV-1 replication in the pathogenesis of vertical HIV-1
infection and reinforce the importance of early, potent
combination therapies for the long-term control of HIV-1 replication.
Improvements in assays to detect and
quantify human immunodeficiency virus type 1 (HIV-1) RNA in
peripheral blood and tissues have allowed the appreciation of the
central role of HIV-1 replication in HIV-1 pathogenesis
(5-7). By using molecular techniques, HIV-1 can be detected
in peripheral blood plasma and mononuclear cells shortly after
infection (16, 24, 25). Within weeks of infection, plasma
HIV-1 RNA copy numbers ranging from 105 to 107
per ml of plasma have been documented.
During primary infection in adults, peak plasma HIV-1 RNA
levels fall by 100- to 1,000-fold within 1 to 2 months after the onset
of symptoms (8, 24). This decline is observed even in the
absence of antiretroviral therapy; host immune responses (1, 2,
8) or exhaustion of permissive host cells (20) is
believed to contribute to this phenomenon. By 4 to 6 months after
primary infection, a steady-state plasma HIV-1 RNA level is reached
(13, 24); this steady-state plasma HIV-1 RNA level has been
found to be predictive of the rate of subsequent disease progression
and survival independent of other parameters such as CD4 lymphocyte
count. The analysis of changes in plasma HIV-1 RNA levels following the
initiation of potent antiretroviral therapies to perturb the virus-host
steady state has allowed an improved understanding of the dynamics of
HIV-1 replication in vivo (3, 4, 6, 7, 18, 19, 27). From
such studies, it has been calculated that an average of
1010 HIV-1 virions are produced daily in adults with
established disease. These studies have formed the basis for a model of
HIV-1 replication in which the majority of plasma virions (>93 to
99%) are produced by productively infected CD4 T lymphocytes, while
smaller contributions (<10%) to the plasma virion pool are made by
populations of long-lived cells (e.g., macrophages) and latently
infected lymphocytes (18).
Rapid increases in the plasma HIV-1 RNA copy numbers to 105
to 107 copies per ml of plasma have also been documented in
vertically infected infants during the first weeks of life (15,
17, 25). In contrast to the natural history of HIV-1 RNA levels
following primary infection in adults, plasma HIV-1 RNA levels remain
high (mean 105 copies per ml of plasma) over the first 2 years of life. After the first 1 to 2 years of life, a reduction in
plasma HIV-1 RNA (mean, Little information regarding the kinetics of HIV-1 replication in
vertically infected infants and children is available. We therefore undertook a study in which potent antiretroviral
therapies were used to probe the kinetics of HIV-1 replication in
infants and children. In this study, a triple antiretroviral drug
regimen consisting of zidovudine (ZDV), lamivudine (3TC), and
nevirapine (NVP) was administered to infants and children aged 15 days
to 2 years with limited or no prior antiretroviral therapy. Frequent blood sampling for plasma HIV-1 RNA copy number following the initiation of antiretroviral therapy allowed the estimation of HIV-1
kinetic parameters. The implications of these studies regarding the
pathogenesis and therapy of vertical HIV-1 infection are discussed.
Study design.
This open-label, phase I/II study was
conducted at 13 Pediatric AIDS Clinical Trials Group sites, including
Bellevue Hospital Study medications.
Infants 15 to 29 days old at the time of
enrollment received the following doses of study drugs: ZDV (Retrovir;
Glaxo Wellcome), 4 mg/kg three times daily through 29 days of age, then
160 mg per m2 of body surface area three times a day
beginning at 30 days of age; 3TC (Epivir; Glaxo Wellcome), 2 mg/kg
every 12 h through 29 days of age, then 4 mg/kg every 12 h
beginning at 30 days of age; NVP (Viramune; Boehringer-Ingelheim), 5 mg/kg once daily for 14 days, then 120 mg per m2 of body
surface area for 14 days, and then 200 mg per m2 every
12 h. Infants who were 30 days or older at the time of enrollment
received the following doses of study drugs: ZDV, 160 mg per m2 of body surface area three times a day; 3TC, 4 mg/kg
every 12 h; and NVP, 120 mg per m2 of body surface
area for 14 days and then 200 mg per m2 every 12 h.
All medications were administered as a syrup or a suspension, at
concentrations of 10 mg/ml.
Quantification of plasma HIV-1 RNA copy number by reverse
transcriptase PCR.
HIV-1 RNA was quantified in 200 µl of
EDTA-anticoagulated plasma (stored at Patient population.
Sixteen infants aged 15 days to 2 years
enrolled in this study, and therapy was initiated with the triple
antiretroviral drug regimen of ZDV, 3TC, and NVP. Subjects were
stratified into two age cohorts (seven infants of
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Dynamics of Human Immunodeficiency Virus Type 1 Replication in Vertically Infected Infants
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
0.2 to 0.3 log decline per year) has been
observed in vertically infected children that continues through 5 to 6 years of age (12, 14, 16). As observed in infected adults,
higher plasma HIV-1 RNA levels are independently associated with
increased risk of progression to AIDS or death in older children
(14, 16, 26, 30). Additionally, antiretroviral
therapy-induced reductions in plasma HIV-1 RNA have been associated
with clinical benefit in both children (16) and adults
(23).
MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
New York University, Boston Children's
HospitalBoston City Hospital, University of MassachusettsBaystate
Medical Center, Children's HospitalPhiladelphia, Duke University,
State University of New York Health Science Center at Syracuse,
University of Mississippi, University of CaliforniaLos Angeles,
University of CaliforniaSan Francisco, Medical University of South
Carolina, and Tulane University. The full details of this study will be
described separately (unpublished data).
70°C within 6 hours after
phlebotomy) by PCR after reverse transcription (Amplicor; Roche). The
lower detection limit of the assay is 400 copies of HIV-1 RNA per ml of
plasma. All assays were performed in a single laboratory that
participates in an ongoing quality certification program for HIV-1 RNA
quantitation sponsored by the National Institutes of Health. Sequential
samples through 12 weeks of therapy from individual patients were
assayed in batches to avoid variability between assays.
RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
3 months of
age and nine infants or children of >3 months). The stratification was
performed because it was hypothesized that viral kinetics of infants
who were experiencing primary infection (3 months of age) and of
those who were past the period of primary infection (>3 months) might differ.
3 months and 7 children aged >3 months to 2 years). In the
remaining four infants, initial reductions in plasma HIV-1 RNA copy
numbers were not maintained. Potential explanations for the observed
rebounds in plasma HIV-1 load in these four children include incomplete
adherence to the prescribed medication regimens and the selection of
drug-resistant variants. Since these factors could affect the
calculated viral clearance rates, these children were excluded from
analysis. The calculation of HIV-1 kinetic parameters for the 12 children (Table 1) who had sustained
reductions in plasma HIV-1 RNA copy numbers form the basis of this
report.
TABLE 1.
Summary of patient characteristics and viral
kinetic parameters
Antiretroviral activity of ZDV-3TC-NVP.
Baseline plasma HIV-1
RNA copy numbers were defined as the arithmetic mean of the plasma
HIV-1 RNA measured just prior to the initiation of study therapy and at
least one other measurement obtained within the prior 2 weeks. Baseline
plasma HIV-1 RNA copy numbers ranged from 104.70 to
106.82 (median, 105.8 per ml) (Table 1). These
plasma HIV-1 RNA copy numbers are of similar magnitude to those
reported by others for the age range studied (15, 16, 25).
Pretreatment plasma HIV-1 RNA levels were similar for the two age
cohorts (for 3 months, range of 104.81 to
106.82 and median of 105.9; for >3 months,
range of 104.70 to 106.47 and median of
105.70), even though four of the five infants of 3 months
of age had received ZDV therapy prior to study enrollment.
|
Kinetics of plasma HIV-1 decay following the initiation of
ZDV-3TC-NVP therapy.
The biphasic decay observed in this study is
similar to that described by Perelson and colleagues following the
initiation of potent combination antiretroviral therapies in adults
(18). We therefore used a model similar to that of Perelson
et al. to calculate plasma viral load decay rates during each phase of
viral load reduction. As in previous studies (18, 19), if
the treatment is assumed to completely block new viral replication, the
first phase decay rate (
) represents the death rate of productively infected cells and the second phase decay rate (µ) represents the
death rate of long-lived or latently infected cells. In our calculations, we considered the long-lived and latently infected cells
as one cellular compartment since they cannot be distinguished by using
plasma HIV-1 RNA measurements alone.
) and second
(µ) phase decay constants:
![V(t) = V<SUB>0</SUB> [Ae<SUP><UP>−</UP>&dgr;t</SUP> + Be<SUP>−&mgr;t</SUP> + (1 − A − B)e<SUP>−ct</SUP>]](/content/vol73/issue1/fulltext/362/img001.gif)
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(1) |
and µ when c is >5. We used a c of 3 per day to allow
comparison of our data with those from adult studies by Perelson and
colleagues (18).
Since a majority of the infants and children were studied close to the
time of the acquisition of infection, their viral load and CD4 T-cell
numbers were not likely to be in a steady state prior to the initiation
of therapy. We therefore used a model not restricted by the
steady-state condition in which the terms A and B
in equation 1 are treated as arbitrary constants. Further discussion
regarding the evaluation of the non-steady-state condition can be found
in the work of Wu and Ding (29).
Both phases of viral load reduction appeared to be more rapid in the
older group of infants (>3 months to 2 years) than in the younger
group of infants (3 months). Overall, first-phase viral decay rates
ranged from 0.26 to 2.02 (median, 1.03), which corresponds to
calculated half-lives ranging from 0.34 to 2.69 (median, 0.66) days.
First-phase viral decay rates were notably lower in the younger group
of infants (range, 0.26 to 1.03; median, 0.56) than in the older group
of infants (range, 0.97 to 2.02; median, 1.14). These values correspond
to calculated half-lives (i.e., the time necessary for reduction of the
plasma virus level by one-half) ranging from 0.67 to 2.69 days (median,
1.23 days) in the younger group and 0.34 to 0.71 days (median, 0.61 days) in the older group. The difference in first-phase viral decay rates between the younger and older children was examined by using the
Wilcoxon rank sum test and was found to be highly significant (P = 0.0051) (Table 1). No apparent correlations
were observed between the first-phase decay rate () and any of the
following: baseline plasma RNA levels, peripheral blood CD4 T-cell
counts (absolute numbers or percentages), the percentage of peripheral blood CD4 T cells coexpressing CD45RA (naive CD4 T cells) or CD45RO (memory CD4 T cells), peripheral blood CD8 T-cell counts (absolute numbers or percentages), or the percentage of peripheral blood CD8 T
cells coexpressing the activation antigen DR (data not shown).
The transition time between first- and second-phase decay ranged from 3 to 17 days, with a median of 5 days. Second-phase viral decay rates
ranged from 0.02 to 0.15 (median, 0.06), which correspond to calculated
half-lives ranging from 4.68 to 33.26 days (median, 9.3 days). Again,
the second-phase decay rates were notably lower in the younger group
(range, 0.02 to 0.04; median, 0.04) than in the older group (range,
0.06 to 0.15; median, 0.06). These values correspond to calculated
half-lives ranging from 15.38 to 33.26 days (median, 17.17 days) in the
younger group and 4.68 to 12.26 days (median, 11.27 days) in the older
group. The difference in second-phase viral decay rates between the
younger and older children was also examined by using the Wilcoxon rank sum test and was found to be highly significant (P = 0.0025). In addition, a highly significant positive linear
correlation was found between age at initiation of therapy and the
second-phase decay rate (P = 0.0052) (Fig.
2). No apparent correlations were observed between the second-phase decay constant (µ) and any of the
following: baseline plasma RNA levels, peripheral blood CD4 T-cell
counts (absolute numbers or percentages), the percentage of peripheral
blood CD4 T cells coexpressing CD45RA (naive CD4 T cells) or CD45RO
(memory CD4 T cells), peripheral blood CD8 T-cell counts (absolute
numbers or percentages), or the percentage of peripheral blood CD8 T
cells coexpressing the activation antigen DR (data not shown).
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DISCUSSION |
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In this study, potent antiretroviral therapies were used to probe the kinetics of HIV-1 replication in infants and children aged 15 days to 2 years with limited prior antiretroviral therapy. Frequent blood sampling to measure plasma HIV-1 RNA copy number following the initiation of potent antiretroviral therapy allowed the calculation of the first detailed evaluation of viral kinetics in young, HIV-1-infected infants and children.
The clearance of HIV-1 virions in plasma following the initiation of therapy was biphasic. The majority (>90%) of virus in plasma was cleared during an initial rapid, exponential decline. A slower, exponential second-phase decline was then observed. This pattern of virion clearance is similar to that previously described following the initiation of potent combination antiretroviral therapy in cohorts of adults experiencing primary infection (9) and in adults with established disease (18). The consistency in this pattern is striking given the diversity in age, viral load, disease stage, and CD4 counts of the patient populations studied, in addition to the various regimens used.
As suggested by Ho, Perelson, and coworkers (6, 18, 19), the observed biphasic pattern of viral clearance likely represents two distinct cellular sources for plasma virions: short-lived, productively infected cells (CD4 T cells; first phase) and long-lived cells with stably integrated HIV-1 provirus (tissue macrophages, dendritic cells, or latently infected CD4 T cells undergoing activation; second phase). Alternatively, the biphasic decay following the initiation of therapy could represent an exponential decay of viral production by a single cellular source with a decreasing exponent over time due to a reduction in either the number of virus-producing cells or the ability of the cells to produce virus (e.g., an increased number of cells moving from the activated state to a resting state).
Viral decay rates were used to calculate half-lives for viral turnover.
During the first phase of viral decay (representing >90% of plasma
virus), half of the plasma virus turned over approximately every
30 h on average in the younger group and approximately every 14 h on average in the older group. These estimates are likely a
composite of the clearance of free virions and short-lived, productively infected cells. Due to limitations in the blood volumes that we were able to obtain from these young children, we were unable
to obtain samples at a sufficient frequency to distinguish the separate
contributions of the free virions and the short-lived productively
infected cells. Data from adult studies suggest that primarily
reflects the clearance rate of short-lived productively infected cells;
the calculated first-phase half-lives measured in the young infants are
comparable to the half-lives of productively infected CD4 T cells
reported in similar studies of adults. Overall, these data suggest
rates of HIV-1 production and turnover that are at least as rapid as
those previously reported for adults. Interestingly, the half-lives in
the older infants and children are approximately half those reported in
adults, suggesting even more rapid production and turnover of HIV-1 in
plasma in these children.
Several hypotheses could be raised to explain the observed age-related differences in clearance rates. The slower clearance of HIV-1 from the younger infants might reflect a reduced activity of the regimen in those infants. Plasma NVP levels were measured at several time points during the study; plasma NVP levels in the younger infants were similar to or exceeded those measured in the older infants (data not shown). Differences in NVP absorption and metabolism are thus unlikely explanations for the observed age-related differences in clearance rates.
Alternatively, the slower clearance rates observed in the younger infants could reflect a lesser activity of the regimen due to the effects of prior therapy (e.g., preexisting resistance mutations). In this regard, it must be noted that while none of the older children had received antiretroviral therapy prior to study entry, the majority of the young infants had received ZDV therapy prior to their enrollment in the study. Sequencing of the reverse transcriptase gene from viral isolates obtained prior to the initiation of therapy is under way. This should allow the assessment of whether mutations associated with resistance to any of the reverse transcriptase inhibitors used in this study might have influenced the response to therapy.
A difference in the proportion of virus produced by different cellular sources and a differential susceptibility of these sources to the effects of antiretroviral therapies could also explain the observed age-related differences in viral kinetics. Likewise, age-related differences in the number of cells capable of supporting productive infection (particularly activated CD4 T cells) might explain the observed age-related differences. Finally, less vigorous or delayed development of HIV-1-specific immune responses (most notably antibody-dependent cellular cytotoxicity and cytotoxic T-lymphocyte responses [11, 21, 22]) have been described in young infants and could contribute to the less rapid clearance of HIV-1 following the initiation of antiretroviral therapy. The analysis of additional cohorts of infants who have begun therapy with quadruple-therapy regimens (ZDV-3TC-NVP-abacavir or stavudine-3TC-NVP-nelfinavir) is currently under way and should allow us to distinguish between these possibilities.
Based on their initial studies with adults, Perelson et al. (19) suggested that the use of potent combination therapies that arrest HIV-1 replication might allow the eradication of HIV-1 infection over time; a minimum of 2 to 3 years of continuous therapy was estimated to be necessary to clear HIV-1 from the two major cellular compartments (productively infected T cells and the long-lived cell population). In the present study, extrapolation of the first- and second-order viral decay rates in infants suggest a time to viral extinction of 10 to 74 days (median, 20 days) in the first compartment (productively infected T cells) and from 102 to 721 days (median, 303 days) in the second compartment (long-lived infected cells). As we (10) and others (5, 6, 28) have noted, however, none of the regimens studied to date are capable of eradicating an integrated HIV-1 genome from infected cells. These cells, then, represent a small but potentially significant barrier to the eradication of infection from an individual. Sufficient blood samples to estimate the size of this potentially long-lived pool of infected cells in infants and children were not obtained in this study but are currently being collected for cohorts of infants who have begun therapy with quadruple-therapy regimens (ZDV-3TC-NVP-abacavir or stavudine-3TC-NVP-nelfinavir).
In summary, HIV-1 turnover and kinetics in plasma were studied in children aged 15 days to 2 years. Calculated rates of HIV-1 turnover were at least as rapid as those previously described in adults; turnover rates were more rapid in older infants and children than in younger infants. These data confirm the central role of HIV-1 replication in the pathogenesis of vertical HIV-1 infection and reinforce the importance of early, potent combination therapies for the long-term control of HIV-1 replication.
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ACKNOWLEDGMENTS |
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We thank the children who participated in this study and their guardians. We also thank Meg Gwynne and Barbara Wells for support in protocol development and implementation; Linda Lambrecht, Randy Huelsman, John Latino, Kevin Byron, and Dena Giokas for technical support; Bobbie Graham for data management; A. Adam Ding, Jane Lindsey, and Peter Gaccione for assistance in analysis of the data; and Melinda Engel for preparation of the manuscript.
This study was supported by the Pediatric AIDS Clinical Trials Group of the National Institutes of Health, by NIH grants AI-32907/97PICL02/97PVCL09 and AI-43220, and by Boehringer-Ingelheim Pharmaceuticals. Katherine Luzuriaga is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Pediatrics, Program in Molecular Medicine, Room 318, Biotech 2, 373 Plantation St., Worcester, MA 01605. Phone: (508) 856-6282. Fax: (508) 856-5500. E-mail: katherine.luzuriaga{at}ummed.edu.
PACTG 356 Investigators who contributed to this study include
George Johnson (Medical University of South Carolina, Charleston), Hannah Gay (University of Mississippi Medical Center, Jackson), Stuart
Starr (Children's Hospital, Philadelphia, Philadelphia, Pa.),
Diane Wara (University of California, San Francisco, San Francisco),
Yvonne Bryson (University of California, Los Angeles, Los Angeles),
Colleen Cunningham (SUNY Syracuse, Syracuse, N.Y.), Ross McKinney,
Jr. (Duke University Medical Center, Durham, N.C.), and Barbara
Stechenberg (Baystate Medical Center, Springfield, Mass.).
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Journal of Virology, January 1999, p. 362-367, Vol. 73, No. 1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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