paper inggris new
TRANSCRIPT
-
7/28/2019 Paper Inggris NEW
1/21
The Relationship between Serum Human Immunodeficiency
Virus Type 1 (HIV-1) and Long-Term Mortality Risk in HIV-1-
Infected Children In 20 -30 old men in Jakarta 2000
By:
YOLANDA NABABAN
030.08.260
FACULTY OF MEDICINE
TRISAKTI UNIVERSITY
JAKARTA
2009
i
-
7/28/2019 Paper Inggris NEW
2/21
PREFACE
This paper titled The Relationship between Serum Human Immunodeficiency Virus
Type 1 (HIV-1) RNA Level, CD4 Lymphocyte Percent, and Long-Term Mortality Risk in
HIV-1-Infected Children in 20 -30 old men in Jakarta 2000 was created for the purpose of
completing the assignment for the Medical English II in Trisakti University, Faculty of
Medicine. In this paper is discussed all the information about the relationship between HIV-1
RNA level and CD4 lymphocyte percent, as well as their prognostic values, that may be
affected by the pathogenesis of HIV infection. By reading the content of this paper, the reader
will become more aware of the fatality of this disease and will take the steps to prevent these
disease from happening.
Many thanks and appreciation to those who have helped in the process of making thispaper. Furthermore, my apologizes if there are errors contained in this paper for it is created
during a learning process.
Jakarta, 12 04-2009
Yolanda Nababan
ii
-
7/28/2019 Paper Inggris NEW
3/21
TABLES OF CONTENTS
Preface.......................................................................................................................................ii
I. Introduction...................................................................................................................1
I.1 Background..............................................................................................................1
I.2 Methods....................................................................................................................2
I.3 Result........................................................................................................................4
I.4 Discussions.............................................................................................................13
I.5 References...............................................................................................................18
INTRODUCTION
iii
-
7/28/2019 Paper Inggris NEW
4/21
I.1 Background
Primary human immunodeficiency virus type 1 (HIV-1) infection among adults is
characterized by an initial burst of viremia, with HIV-1 RNA levels as high as 1O6-107
copies/mL, followed by a 100- to 1000-fold decline over the subsequent 2-3 months until
reaching a steady-state plateau that may persist for years [1 -3]. A number of studies among
infected adults have demonstrated that plasma RNA levels after seroconversion are
independently predictive of risk for HIV-1 disease progression; higher HIV-1 RNA levels
correlate with more rapid disease progression and elevated mortality risk, while treatment-
induced declines in RNA levels have been associated with clinical benefit [4-6]. These
studies have led to the development of treatment recommendations for infected adults based
on measurement of plasma HIV-1 RNA; RNA levels exceeding a threshold of ~ 10,000
copies/mL are viewed as indicative of the need to consider initiating therapy [7, 8].
Fewer data exist regarding HIV-1 RNA levels among infected children, particularly
regarding the relationship of RNA with long-term clinical outcome. Several studies of
perinatally infected children have shown persistent high RNA levels (s= 106 copies/mL)
throughout the first 2 years of life, with only 2- to 10-fold declines from initial peak valuesduring the first 12 months of life; these high levels may be observed despite normal CD4
lymphocyte counts and lack of symptoms [9-13]. RNA levels then appear to fall slowly until
24-36 months of age, independent of antiretroviral treatment and immunologic or clinical
status [10-12]. These findings may reflect the influence of an immature but developing
immune system that requires several years before achieving the capacity to control viral
replication to an extent similar to that observed in infected adults.
In perinatally infected children, RNA levels that are extremely elevated after 1-2
months of age (>300,000 copies/ mL) have been associated with more rapid progression to
AIDS early in life. However, because of significant overlap in RNA levels between rapid and
non-rapid progressors, no single threshold level predictive of disease progression has yet
been identified in children [11, 12].
The National Institute of Child Health and Human Development (NICHD)
Intravenous Immunoglobulin (IVIG) Clinical Trial was initiated to evaluate the effect of
IVIG versus albumin placebo for prophylaxis of bacterial infections in HIV-1-infected
iv
-
7/28/2019 Paper Inggris NEW
5/21
children. Although mortality was similar between study groups, reduction in the incidence of
infections and hospitalizations, as well as slowing of decline in CD4 lymphocytes, was
observed with IVIG treatment [14-17]. During the course of this trial, blood was collected
from patients at baseline and every 3 months during the study and sera were stored in a
central repository. Additionally, follow-up data on the vital status of enrolled children 5 years
after completion of the trial were obtained. Thus, these stored sera provide a unique oppor-
tunity to retrospectively evaluate HTV-1 KNA levels in a large HIV-1-infected pediatric
cohort with well-defined long-term clinical outcomes.
The objectives of the current analysis were to describe the distribution of baseline
HIV-1 RNA levels at study entry and changes over time in this cohort of children with mild
to moderate HIV-1 disease, to evaluate the association of long-term mortality risk with
baseline RNA level and subsequent RNA levels over time, and to evaluate the independent
contributions of HIV-1 RNA level and CD4 lymphocyte percent to long-term mortality risk.
I.2 Methods
The NICHD IVIG Clinical Trial was a randomized, double-blind placebocontrolled
phase III outpatient clinical trial of the use of IVIG for prophylaxis of bacterial infections.
The trial was conducted between March 1988 and January 1991 in 28 clinical centers in the
mainland United States and Puerto Rico. Three hundred seventy-six HIV-1 -infected,
nonhemophiliac children between the ages of 1 month and 12 years were enrolled, the
majority of whom acquired infection perinatally and had only mild to moderate symptoms of
HIV-1 disease. IVIG (Gamimune N; Miles, Berkeley, CA) was administered every 28 days to
187 patients (400 mg/kg of body weight), while 189 patients received a visually
indistinguishable placebo consisting of 0.1% albumin without preservatives in 10% maltose,
administered in an identical fashion. Children were seen monthly for examination and
infusion. During these visits, information regarding intercurrent infections and medications
was collected. Prophylaxis against Pneumocystis carinii pneumonia with a 3 consecutive day-
per-week regimen of tri-methoprim-sulfamethoxazole and use of zidovudine antiretroviral
therapy at any time after study entry were permitted, according to the prevailing medical
standard of care as determined by the patient's physician with consent of the parent or
v
-
7/28/2019 Paper Inggris NEW
6/21
guardian. Further study methods and results are given elsewhere [14-17]. Additionally, in
September 1996, each clinic site was contacted and asked to provide current vital status
information for their study patients.
Blood was collected from patients at entry to the trial and every 3 months thereafter
during the course of the trial. Serum was separated, stored at 20 to 70C, and
periodically shipped to a central repository on dry ice, where specimens were stored at
70C. All frozen specimens from children who had available baseline samples were retrieved
and tested for HIV-1 RNA, using the nucleic acid sequence-based amplification (NASBA)
assay according to manufacturer's instructions (Organon Teknika, Durham, NC). Specimens
had been stored for 4-7 years before testing. All assays were performed by a single laboratory
that was participating in the AIDS Clinical Trials Group HIV-1 Virology Quality Assurance
program [18]. Testing was done over a 6-month period in late 1995 and early 1996.
The NASBA assay involves extraction of nucleic acid by binding to silicon dioxide
particles. The process can be used for testing many body fluids, including serum and plasma.
HIV-1 RNA is amplified by an isothermal amplification procedure and quantified by
coamplification with internal kit RNA calibrator standards of 10,000, 100,000, and 1,000,000
copies/mL. The quantity of amplified RNA was measured by means of an
electrochemiluminescence technique, and results were expressed as copies of HIV-1 RNA
per milliliter. The assay can detect up to a 4 log,0 variation in copy number; for the input
volume of 100 yuL of serum used in this study, the lower limit of detection was 4000
copies/mL. Evaluation of interassay precision at the central laboratory indicated an interassay
SD of 0.18 Iog10.
CD4 lymphocyte percent and absolute count were measured at study entry and every
3 months during the trial. Flow cytometry was performed locally at laboratories participating
in one of several national quality assurance programs. Procedures for performance of flow
cytometric evaluations during the study have been described [16]. Because CD4 lymphocyte
percent exhibits less measurement variability than the absolute count and varies less by age
[19], CD4 cell percent rather than absolute count was used in the analyses.
The evaluation included baseline HIV-1 RNA copy number, baseline CD4
lymphocyte percent, and two measures of change in HIV-1 RNA copy number: absolute
vi
-
7/28/2019 Paper Inggris NEW
7/21
change (final value - baseline value) and yearly rate of change (slope of least squares
regression line). The relationship between HIV-1 RNA level and age was assessed with a
mixed-effects repeated-measures model. Intrapatient changes from baseline were assessed
with the t test. The relationship of baseline HIV-1 RNA level and changes in RNA levels
with mortality was evaluated with the %2 test for linear trend and Kaplan-Meier analyses.
Proportional hazard analyses using time-fixed (baseline values) and time-dependent (all
available measurements) methods were used to evaluate the independent relationship of RNA
level and CD4 lymphocyte percent with mortality. Time-fixed models were adjusted for
baseline value of the primary independent variable, age at baseline, and IVIG or placebo
treatment group; time-dependent models were adjusted for all available measurements of the
primary independent variable, age at time of measurement, zidovudine use at time of
measurement, and IVIG or placebo treatment group.
I.3 Results
Study population. Of the 376 children in the trial, 254 (68%) had 1 sample available
for testing. Characteristics of the analysis cohort are shown in table 1.
Children in the analysis cohort were similar to the overall study cohort in terms of
sex, race or ethnicity, age at entry, entry CD4 lymphocyte count and percent, prior history of
AIDS-defining infections, use of zidovudine therapy and tri-methoprim-sulfamethoxazole P.
carinii pneumonia prophylaxis during the study, duration of follow-up, and percentage of
mortality. Forty-one children (16%) died during the course of the trial, and an additional 51
children (20%) died during the extended follow-up period.
Table 1. Characteristics of children included in the HIV-1 RNA analysis cohort
(children with available baseline serum specimens) compared with characteristics of the
overall National Institute of Child Health and Human Development Intravenous
Immunoglobulin Clinical Trial study population.
Characteristic Analy
sis cohort
Overall
study cohort
vii
-
7/28/2019 Paper Inggris NEW
8/21
No. of patients
% male
% minority race or ethnicity
% with perinatal infection
Age at entry (%)
1 year
1-2 years
2-6 years
>6 years
Mean years (SD)
Mean CD4 lymphocyte values at
entry
Absolute count (/mm3) %
History of AIDS-defining infection at
entry (%)
Opportunistic infection
Recurrent serious bacterial infection
Opportunistic or recurrent serious
bacterial infection % who used zidovudine
during study % who used trimethoprim-
sulfamethoxazole for PCP
prophylaxis (cumulative)
Mean years of vital status follow-up
(SD)
No. of deaths (%)
Total no. of serum samples
Mean no. of serum samples of
patients
254
55.5
92.1
90.2
12.2
20.1
53.1
14.6
3.41
(2.32)
1105
25.1
3.9
15.7
18.1
44.1
51.2
5.1
(2.8)
92
(36.2)
1124
4.4
376
54.8
91.8
91.5
13.6
19.7
52.9
13.8
3.36
(2.33)
1127
25.3
6.4
19.1
22.3
43.6
46.5
5.0 (2.9)
149 (39.6)
NOTE. PCP = Pneumocystis carinii pneumonia.
viii
-
7/28/2019 Paper Inggris NEW
9/21
Response to the vital status survey was received from 100% of trial sites. Of the 213
children in the HIV-1 RNA analysis cohort who were alive at the end of the clinical trial, 199
(93.4%) had updated vital status information available.
HIV-1 RNA. A wide range of HIV-1 RNA levels were observed at baseline, from
undetectable ( 500,000 copies/mL.
Despite prolonged serum storage, the NASBA assay demon-stated a >4-fold
difference in logio baseline HIV-1 RNA levels in this population. In addition, the
distributions of mean and median RNA levels were similar, regardless of year of study entry,
further suggesting that length of storage did not greatly affect serum HIV-1 RNA levels when
measured by the NASBA assay. Most of the children entered in 1988 and 1989 (136 and 87,
respectively); entry characteristics (mean age, CD4 cell percent, and history of AIDS-
defining infections) were similar for children entering in each year. The 31 children who
entered in 1990 had ages and CD4 cell percents similar to those of the children who entered
in the previous years but were somewhat less likely to have a history of AIDS-defining
infections at entry. Geometric mean baseline RNA levels were 117,175 copies/mL (logio
value, 105'07) for children who entered in 1988, 88,281 (10495) for those who entered in
1989, and 102,527 (105 01) for those who entered in 1990.
In a longitudinal evaluation of geometric mean HIV-1 RNA levels by age at time of
measurement, RNA levels were highest among infants 400,000 copies/mL for infants < 12 months of age (figure 2). Although there was a
slow decrease in HIV-1 RNA levels with increasing age, mean levels did not decline to
1,000,000 HTV-1 RNA copies/mL, respectively). In contrast, for children >2 years old,
mortality risk increased when HTV-1 RNA exceeded 100,000 copies/mL (24%, 25%, 56%,
and 67% for =slO,000, 10,001-100,000, 100,001-1,000,000^ and > 1,000,000 HIV-1 RNA
copies/mL, respectively).
In addition to the percentage of subjects who died during the study, the mortality rate
was also examined. Table 2 provides the mortality rate (per 100 person-years) for subjects
with different baseline HIV-1 RNA levels. The same gradient observed for mortality
xi
-
7/28/2019 Paper Inggris NEW
12/21
percentages was seen for mortality rates; mortality risk increased with increasing baseline
HIV-1 RNA levels. The mortality rate for subjects with baseline HIV-1 RNA > 100,000
copies/mL was 2.8 times greater than the rate for subjects with HIV-1 RNA levels below this
value (95% CI, 1.8-4.4; P < .001).
Figure 3 A depicts a Kaplan-Meier analysis of the probability of survival by baseline
HIV-1 RNA categories of^l 0,000, 10,001-100,000, 100,001-1,000,000, and > 1,000,000 cop-
ies/mL. The probability of survival during the study for children with baseline HIV-1 RNA
levels < 10,000 copies/mL was similar to that observed for children with baseline levels of
10,001-100,000 copies/mL (P = .82). However, there was a significant decrease in probability
of survival for those with baseline levels of 100,001-1,000,000 copies/mL compared with
those with baseline levels =s 100,000 copies/mL (P = .003) and for those with baseline levels
> 1,000,000 copies/ mL compared with those with baseline values =S 1,000,000 copies/mL
(P < .001).
The positive predictive value of different baseline HIV-1 RNA thresholds for
mortality risk was evaluated (table 3). This measure reflects the percentage of patients with
baseline HIV-1 RNA levels above a chosen cutpoint who subsequently died during the study
or extended follow-up period. As expected, the positive predictive value increased as the
HIV-1 RNA cutpoint increased. However, the positive predictive value, which is determined
by the prevalence of the outcome of interest and the sensitivity and specificity of the
screening test, was relatively low for the various cutpoints. Use of a baseline HIV-1 RNA
level > 100,000 copies/mL as the threshold for assessing mortality risk produced a test
sensitivity of 67.4% and a specificity of 59.9%. These values, combined with the overall
mortality percentage of 36.2%, yielded a positive predictive value of 48.8%.
The relative risk of death (RR) associated with having baseline HTV-1 RNA values
above versus below selected thresholds also is shown in table 3. At 10,000 copies/mL, the RR
was elevated but not statistically significant. Changing the threshold value-from 10,000 to
100,000 copies/mL increased the RR to 2.1 (95% CI, 1.4-3.0). There was only a slight
increase in the RR as the baseline HIV-1 RNA threshold was raised to 1,000,000 copies/mL.
HTV-1 RNA in HIV-1-Infected Children
Table 2. Association of baseline HIV-1 RNA and CD4 cell percent with mortality
during study and follow-up.
xii
-
7/28/2019 Paper Inggris NEW
13/21
Baselin
e
N
o. ofdeaths
N
o. ofpatients
Mortalit
y percent*
Person
-time
Mortalit
y rate
HIV-1
RNA level
(copies/mL)
10.00
0
10.000
1-100.000
100.00
1-1.000.000
>
1.000.000
Total
CD4cell percent
25%
15%-
24.9%
< 15%
Total
9
21
37
25
92
31
16
44
91
40
87
92
35
25
4
13
0
62
60
252
22.5
24.1
40.2
71.4
36.2
23.8
25.8
73.3
36.1
243.30
506.87
453.13
96.90
1300.2
1
761.10
341.12
192.18
1294.4
0
3.70
4.14
8.17
25.80
7.08
4.07
4.69
22.90
7.03
* P < .001, x2 test for trend, for both HIV-1 RNA level and CD4 cell percent.
f Person-years of follow-up.
J Per 100 person-years of follow-up.
Excludes 2 subjects who did not have an available baseline CD4 cell
measurement.
Subjects were grouped into quartiles on the basis of the value of their average rate of
change (i.e., the slope). The mortality percentage among subjects in the fourth quartile
(largest HTV-1 RNA increase) was greater than the mortality percentage in the first three
xiii
-
7/28/2019 Paper Inggris NEW
14/21
quartiles (59.6% vs. 26.9%, P < .001). Subjects also were grouped on the basis of whether
their average rate of change in HIV-1 RNA level increased over the study (i.e., slope >0.0) or
decreased or remained constant (i.e., slope =sO.O). The mortality percentage among those
who had increasing HIV-1 RNA levels was 1.8 times greater than that among the group with
decreasing or constant HIV-1 RNA levels (95% CI, 1.3-2.6; P = .001). Similar results were
seen when the difference (i.e., final value baseline value) was used as a measure of intra-
individual change.
To further examine the relationship between HIV-1 RNA values and mortality, while
controlling for potential confounding covariates, proportional hazards models were
constructed. Table 4 presents the mortality risk ratios per Iog10 difference in HIV-1 RNA
values. Time-fixed and time-dependent models were used that included only HIV-1 RNA
(unadjusted) as well as models that controlled for study treatment group, age, and zidovudine
use. The risk ratios per 1 Iog10 difference in HIV-1 RNA from these models varied from 2.2
to 3.3 and were statistically significant in each model.
CD4 lymphocyte percent. - The mean baseline CD4 cell count among the analysis
cohort was 1105/mm3 (SD, 892/ mm3). The mean and median baseline CD4 lymphocyte per-
cents were 25.1% and 25.0%, respectively.
The percentages of deaths and the mortality rate during the study according to the
baseline CD4 lymphocyte percent is shown in table 2. Both measures indicate a strong
relationship between decreasing CD4 cell percent and increasing mortality risk.
Survival curves for subjects with baseline CD4 lymphocyte percents of
-
7/28/2019 Paper Inggris NEW
15/21
shown in figure 4 (Pearson correlation coefficient, -0.12; P = .061). Thus, baseline CD4
lymphocyte percent does not provide an accurate indication of the specific baseline HIV-1
RNA level and vice versa.
The joint relationship of HTV-1 RNA and CD4 lymphocyte percent with mortality is
given in table 5. Subjects were divided into groups on the basis of the combination of their
baseline HTV-1 RNA results (> 100,000 or ss 100,000 copies/mL) and CD4 lymphocyte
percents (5=15% or
-
7/28/2019 Paper Inggris NEW
16/21
I.4 Discussion
A wide range of HIV-1 RNA levels were observed for children in this study, from
-
7/28/2019 Paper Inggris NEW
17/21
Although there was an inverse relationship between HIV-1 RNA level arid CD4
lymphocyte percent, the correlation was only modest, 'and a 3-4 Iog10 range in number of
HIV-1 RNA copies was observed for any selected CD4 lymphocyte percent.
Table 4. Time-fixed and time-dependent proportional hazards models: relationship of
HIV-1 RNA level, CD4 cell percent, and combined effect of HIV-1 RNA level and CD4
lymphocyte percent with mortality.
Primary
independent
variable s
Time-fixed Time-dependent
Unadjuste Adjust Unadj Adjusted
HlV-l
RNA level
2.16
(1.67-2.81)
2.74
(2.06-3.65)
1.42 1.29-
2.74
(2.16-3.47)
1.54 1.39-
3.32
(2.54-4.33)
NOTE. Data are mortality risk ratio per 1 logic increase in HIV-1 RNA level and per
5 percentage point decrease in CD4 lymphocyte percent (95% confidence interval). Time-
fixed, unadjusted model includes only baseline value of primary independent variable(s);time-fixed, adjusted model includes baseline value of primary independent variable), plus
treatment group (intravenous immunoglobulin or placebo) and age at baseline; time-
dependent, unadjusted model includes all available measurements of primary independent
variable(s); time-dependent, adjusted model includes all available measurements of primary
independent variable(s), plus treatment group, age at time of measurement, and zidovudine
use at time of measurement. P < .001 for all comparisons.
This poor correlation of CD4 lymphocyte count with viral RNA load has also been
observed in cohorts of infected adults [5, 21].
The prolonged follow-up (3=5 years) available in this study enables evaluation of the
association of HIV RNA levels and CD4 cell percents with long-term clinical outcome that is
unavailable in any published pediatric cohort data. Higher baseline HIV-1 RNA levels were
associated with increased long-term mortality risk. This is similar to what has been observed
among infected adults [1, 3, 5]. However, defining a discrete HIV-1 RNA cutpoint for
potential clinical decision-making is difficult, as evidenced by the poor predictive value of
xvii
-
7/28/2019 Paper Inggris NEW
18/21
HIV-1 RNA levels < 1,000,000 copies/mL for mortality risk. The HIV-1 RNA threshold of
10,000 copies/mL suggested as a cutoff for considering initiation of therapy for infected
adults [7] had a very poor predictive value for mortality among this cohort of infected
children, with a positive predictive value of only 39%. When a threshold of 100,000
copies/mL was used, a 2-fold RR was seen between subjects above this cutpoint compared
with that for subjects below this cutpoint. The positive predictive value, however, was still
only 49%. Additionally, because of age-related changes in HIV-1 RNA early hi life, the
prognostic value of specific RNA levels may differ by age.
In studies of infected adults, an increase in HIV-1 RNA levels over time has been
associated with elevated mortality risk, and therapy-related declines in RNA levels have been
associated with improved prognosis [5, 6, 22, 23]. In this pediatric cohort, there also was an
association between increases in HIV-1 RNA levels observed during the clinical trial and
elevated long-term mortality risk. It is important to note that this pediatric clinical trial was
conducted during a time when few antiretroviral therapies were available for children.
Table 5.
xviii
-
7/28/2019 Paper Inggris NEW
19/21
Association of baseline HIV-1 RNA level and CD4 lymphocyte percent with
mortality during study.
HIV-1 RNA
level(copies/mL)
CD4
cell percent
No.
of deaths
No. of
patients
Morta
lity (%)
100,000
> 100,000
100,000
> 100,000
15
15
-
7/28/2019 Paper Inggris NEW
20/21
lymphocyte measurement obtained at the same time. After a subject's immune system has had
time to be affected by the infection, however, immunologic measures are likely to become
more relevant. This study group was first examined an average of almost 3.5 years after
infection, and both HIV-1 RNA and CD4 lymphocyte levels were independent and
complementary markers of disease stage. In many instances, a clinician may not examine a
patient until several years after the initial infection. Therefore, both markers should be
considered together for decision-making regarding therapy and evaluation of response to
antiretroviral agents.
xx
-
7/28/2019 Paper Inggris NEW
21/21
References1. Katzenstein TL, Pedersen C, Nielsen C, Lundregren JD, Jakobsen PH,
Gersetof J. Longitudinal serum HIV RNA quantification : correlation to viral
phenotype at seroconversion and clinical outcome. AIDS 1996; 10 :167-73
2. Henrard DR, Philips JF, Muenz LR, et al. Natural history of HIV-1 cell-free
viremia JAMA 1995;274:554-8
3. Havlir DV, Rihman FF. Viral dynamics of HIV : implications for drug
developmeny and therapeutic strategies. Ann Intern Med 1996;124:984-94
xxi