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Journal of Clinical Microbiology, November 2000, p. 4015-4020, Vol. 38, No. 11
National Serology Reference Laboratory,
Australia, at St Vincent's Institute of Medical Research, Fitzroy,
Victoria 3065, Australia
Received 2 May 2000/Returned for modification 29 June 2000/Accepted 30 August 2000
This study determined the proficiencies of laboratories measuring
human immunodeficiency virus type 1 (HIV-1) viral loads and the
accuracies of two assays used for HIV-1 viral load measurement in
Australia and investigated the variability of the new versions of these
assays. Quality assessment program panels containing (i) dilutions of
HIV-1 subtype B, (ii) replicates of identical samples of HIV-1 subtype
B, and (iii) samples of subtype E and B were tested by laboratories.
Total variability (within and between laboratories) was tested with
quality control samples. The coefficients of variation (CVs) for the
Roche AMPLICOR HIV-1 MONITOR version (v) 1.0 and Chiron Quantiplex bDNA
2.0 assays ranged from 53 to 87% and 22 to 31%, respectively. The
widespread occurrence of invalid runs with the AMPLICOR HIV-1 MONITOR
1.0 assay was identified. The CVs of the new versions of the assays
were 82 to 86% for the AMPLICOR HIV-1 MONITOR v 1.5 assay and 16 to
23% for the Quantiplex bDNA 3.0 assay. For virus dilution samples, all
but 5 of 19 laboratories obtained results within 2 standard deviations
of the mean. The Quantiplex bDNA 2.0 assay reported values lower than
those reported by the AMPLICOR HIV-1 MONITOR version 1.0 assay for
samples containing HIV-1 subtype B, whereas the reverse was true for
subtype E. Identification and resolution of the problem of invalid runs
markedly improved the quality of HIV-1 viral load testing. The
variability observed between laboratories and between assays, even the
most recent versions, dictates that monitoring of viral load in an
individual should always be by the same laboratory and by the same
assay. Results for an individual which differ by less than 0.5 log10 HIV-1 RNA copy number/ml should not be considered
clinically significant.
The quantification of human
immunodeficiency virus (HIV) to establish the viral load or amount of
measurable virus in the blood has become essential to the clinical
management of HIV infection. It has been demonstrated that the viral
load is the most reliable predictor of the course of infection if it is
estimated once a steady state in viremia is achieved following
seroconversion (8). Viral load increases with the
development of resistance to antiretroviral therapy or with a
detrimental alteration in clinical status (5). It has been
advocated that the aim of current antiviral therapy for HIV infection
should be to maintain the viral load below the level of detection of
the available assays (3, 7).
The majority of commercial assays for the quantification of viral load
use techniques involving amplification either of target nucleic acid
(AMPLICOR HIV-1 MONITOR [Roche Molecular Systems, Pleasanton,
Calif.]) or a hybridization signal (Quantiplex HIV RNA [Chiron
Corporation, Emeryville, Calif., now Bayer Diagnostics], abbreviated
in the text as Quantiplex bDNA). The majority of the data in this
report were generated with version (v) 1.0 of the AMPLICOR HIV-1
MONITOR assay and the Quantiplex bDNA 2.0 assay. The report presents
limited data from tests with the latest versions of these assays (v 1.5 and 3.0, respectively) over the period encompassed by the present
study. The NucliSens HIV-1 QT assay (Organon Teknika, Boxtel, The
Netherlands), which uses amplification of nucleic acid sequences, is
not widely used for therapeutic monitoring in Australia.
It is a condition of registration of all HIV assays for use in
Australia that laboratories that use the assay participate in the
quality assurance (QA) programs run by the National Serology Reference
Laboratory (NRL), Melbourne, Australia. This report presents the
findings of the HIV type 1 (HIV-1) viral load QA program in Australia
for the AMPLICOR HIV-1 MONITOR and Quantiplex bDNA assays. We
investigated the proficiencies of laboratories measuring viral load
across a range of dilutions (range of viral RNA copy number per
milliliter), the reproducibility of determinations for replicate
samples, and whether the performances of the assays were consistent
between HIV-1 subtypes. The report also addresses the implication of
reporting of data from invalid runs.
Nineteen laboratories (testing sites) in Australia and one in
New Zealand participate in the NRL's QA program for HIV viral load
testing. The program was instituted in August 1996 and consists of two
elements: a quality control (QC) program and a quality assessment
program (QAP). All laboratories return QAP and QC program data to the NRL.
QC program.
A QC program provides a mechanism to monitor the
run-to-run performance of an assay. For the HIV viral load QC program,
NRL prepared and distributed the QC samples. The between-run,
between-laboratory, and between-lot-number performances of the assays
were monitored for laboratories returning data for QC samples to NRL.
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Quality of Human Immunodeficiency Virus Viral
Load Testing in Australia
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
70°C prior to
dispatch to the laboratories on dry ice. Laboratories were required to
include the QC samples in at least every fourth assay run and with a
change of lot number or a change of operator. QC sample data were
returned to NRL on a monthly basis and included not only the viral
loads measured in the QC samples but also the numbers of invalid runs,
the reasons for invalid runs, as well as the numbers of invalid patient results.
Run validity. Run validity was determined according to the manufacturer criteria. Two positive controls and one negative control are provided by the manufacturer for the AMPLICOR HIV-1 MONITOR assay, with a designated range into which the results for those controls must fall for an assay run to be valid. The Quantiplex bDNA assays include a standard curve with four standards, each of which is tested in duplicate in every run. The software accompanying the detection luminometer determines whether the linearities and variabilities of the values obtained for the standards and controls are acceptable for a valid run.
QAP. HIV viral load QAP panels were distributed twice yearly to the 20 participating laboratories and consisted of up to eight samples, coded to disguise their identities. Laboratories were provided with a results sheet on which to record run information and results. Data were returned to the NRL for collation and analysis. To maintain confidentiality, each laboratory was assigned a unique code number under which results were reported (note that some laboratories may appear with more than one laboratory code in this study).
The first QAP panel, panel VLQA 97-1, contained five coded samples, four of which were members of a fivefold dilution series of HIV-1 Ba-L in Basematrix (subtype B), including one dilution presented in duplicate. The fifth sample contained diluent only. The second QAP panel, panel VLQA 98-1, investigated whether sites achieved similar values within a run. Two samples (QC105 or QC105C and QC106) were coded and were included four times each in the panel. Panels containing QC105 or QC105C were distributed to laboratories that use the AMPLICOR HIV-1 MONITOR v 1.0 or Quantiplex bDNA 2.0 assay, respectively, for the reasons given above. In addition, laboratories were also requested to run the QC samples in the same run as the QAP samples, when practical. The third panel, panel VLQA 98-2, contained five coded plasma samples from subjects infected with HIV-1 subtype B (one sample) or subtype E (four samples) and a control sample of anti-HIV-negative, pooled normal human plasma. These samples were estimated not to contain very high viral loads (<20,000 RNA copies/ml), but their loads were expected to fall comfortably within the linear range of the assays at the various testing sites. Again, when practical, laboratories were also requested to run QC samples QC105 or QC105C and QC106 (subtype B-spiked normal human plasma) in the same run as the QAP samples.Data presentation and statistical analysis. For the QC data, results for each QC sample are presented as the mean ± 1 standard deviation (SD) HIV-1 RNA copy number per milliliter. The coefficient of variation (CV) is given as a percentage and has been calculated as the SD divided by the mean. For the QAP panel data, the mean ± 2 SD was calculated from the raw data for the number of HIV-1 RNA copy number per milliliter. When the data are presented as residuals, values for copy number per milliliter were first transformed to log10 values and residuals were derived as the difference between the reported log10 copy number per milliliter and the mean log10 copy number per milliliter for each sample.
Statistical analysis. The results obtained for QC samples were compared between the two assay types by the t test. The incidence of invalid runs between different assay lot numbers was analyzed by the chi-square test. Between-sample data for the QAP panels were analyzed by two-way analysis of variance (ANOVA) to test variance between samples in the panel and between testing sites. When significance was observed across the ANOVA table, a t test was applied to locate significance within the data set.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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QC program.
The results from two separate sets of QC samples
(set QC101 and QC102 and set QC105, QC105C, and QC106) tested by
previous assay versions and one set tested by the new versions of the
AMPLICOR HIV-1 MONITOR and Quantiplex bDNA assays are presented in
Table 1. Only results obtained from valid
runs are included (specific data for invalid run rates in each assay
appear below). The number of observations for the AMPLICOR HIV-1
MONITOR v 1.0 assay is substantially greater than the number of
observations for the Quantiplex bDNA 2.0 assay due to the more
widespread use of the former: 17 laboratories used the AMPLICOR HIV-1
MONITOR assay and between 2 and 6 laboratories used the Quantiplex bDNA
assay (some laboratories used both assays for a period within the
study). Despite the smaller numbers of observations, the variability of the data from the Quantiplex bDNA 2.0 assay was consistently lower than
the variability of the data from the AMPLICOR HIV-1 MONITOR v 1.0 assay
across both QC sample sets. The data obtained by the AMPLICOR HIV-1
MONITOR v 1.0 assay had a reduced variability with the more recent QC
sample set (Table 1) compared to the data obtained a maximum of 2 years
previously with the earlier QC101 and QC102 sample set (Table 1).
Values for HIV-1 copy number per milliliter were consistently lower by
the Quantiplex bDNA 2.0 assay than by the AMPLICOR HIV-1 MONITOR v 1.0 assay with these QC samples containing subtype B (P < 0.001).
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Invalid assay runs. (i) AMPLICOR HIV-1 MONITOR v 1.0 assay.
Early monitoring of HIV viral load tests revealed that approximately
half the laboratories did not achieve consistently valid runs. Invalid
runs were more likely to occur for particular lot numbers of AMPLICOR
HIV-1 MONITOR v 1.0. Figure 1 shows the
invalid run rate, according to the manufacturer's criteria, for six
different lots supplied in 1998. The variability in the number of
invalid runs between lots was not predictable from one lot to the next.
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(ii) Quantiplex bDNA 2.0 assay. During the reporting period for the first QC sample set for viral load (QC101 and QC102), the Quantiplex bDNA 2.0 assay had fewer invalid runs, with 5 of 77 runs being invalid. Results for a small percentage (<10%) of individual samples were rejected according to the manufacturer's criteria, because the CV between the mandatory two replicates per sample was >40% for negative samples (<500 HIV-1 RNA copies per ml) and >30% for positive samples. When repeated, these samples usually yielded valid results.
In the reporting period with QC105C and QC106, a low rate of invalid runs continued: 2 of 91 runs were invalid. There was a period of approximately 4 months in which one laboratory that used the Quantiplex bDNA 2.0 assay experienced an increase in the number of invalid runs (from August to November 1997) which was not seen in other laboratories using the assay. However, despite intensive investigation by the laboratory and the manufacturer, no clear cause of the invalid runs was established. Insufficient data have been generated to permit analysis of the invalid run rate with the new versions of each assay.QAP. (i) Panel VLQA 97-1: accuracy across a range of viral
concentrations.
The results of testing of panel VLQA 97-1 by
laboratories using the AMPLICOR HIV-1 MONITOR v 1.0 and Quantiplex bDNA
2.0 assays are shown in Fig. 2. Results
were received from 19 laboratories: 13 used the AMPLICOR HIV-1 MONITOR
v 1.0 assay only, 2 used the Quantiplex bDNA 2.0 assay only, and 4 used
both assays. The data for the fivefold dilution series are presented as
residuals (difference of the reported value of log10 HIV-1
RNA copy number per milliliter for each sample from the mean
log10 HIV-1 RNA copy number per milliliter) and are given
by testing site for each sample in the panel (dilution). The results
for the 1:25 dilution were averaged, as this dilution was presented in
duplicate in the panel. The panel also contained a negative sample with
diluent only, which is not included on the graph, giving a total of
three results for each testing site.
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), a 1/5 dilution of a sample (
), and a 1/25 dilution of a
sample in duplicate, shown as the average (
). Data are presented as
residuals (difference of the reported value from the mean). The mean is
indicated by the horizontal line, and 2 SDs above and below the mean
are shown by the shaded region. (A) AMPLICOR HIV-1 MONITOR assay; (B)
Quantiplex bDNA assay.
(ii) Panel VLQA 98-1: within-run reproducibility.
QAP panel
VLQA 98-1 was decoded, and the values reported by each testing site for
samples QC105, QC105C, and QC106 are shown in Fig.
3. When testing sites had included the
matching samples for quality control, they were reported in the data
set, giving five datum points for some testing sites. For sample QC106
tested by the AMPLICOR HIV-1 MONITOR v 1.0 assay, 14 of 81 results
(17%) were greater than 7.5 × 105 copies/ml, the
upper detection limit of the assay. To calculate the mean ± SD
(Fig. 3B), these results have been included in the data set as 7.5 × 105 copies/ml, as it was not considered valid to
extrapolate values beyond the upper limit of detection cited by the
manufacturer. In practice, this is the value which would be reported
clinically for a sample with a viral load which exceeded the upper
limit of detection.
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(iii) Panel VLQA 98-2: detection of HIV-1 subtypes.
The
results obtained from testing sites for panel VLQA 98-2 are presented
in Table 2. Results were received from 19 laboratories. Only one laboratory used both the AMPLICOR HIV-1 MONITOR
v 1.0 and the Quantiplex bDNA 2.0 assays. Two laboratories used the Quantiplex bDNA 2.0 assay only, but in one of those laboratories, the
run containing the QAP samples was invalid. Therefore, those results
were excluded from the analysis. The remaining 16 laboratories used the
AMPLICOR HIV-1 MONITOR v 1.0 assay only. All testing sites except site
128 included samples QC105 or QC105C and QC106 in the run. Site 39 included only QC106. Data for the HIV-1-negative sample were <400
copies/ml for the AMPLICOR HIV-1 MONITOR v 1.0 assay and <500
copies/ml for the Quantiplex bDNA 2.0 assay (data not shown). For the
same sample, the averaged results obtained for the samples with HIV-1
subtype by the AMPLICOR HIV-1 MONITOR v 1.0 assay were consistently
lower than those obtained from either laboratory by the Quantiplex bDNA
2.0 assay. In contrast, for the samples with HIV-1 subtype B, the
AMPLICOR HIV-1 MONITOR v 1.0 assay viral load results were higher than
the Quantiplex bDNA 2.0 assay results. This was true for both the
subtype B-containing sample in the panel and QC106. Although the viral
loads in QC105 and QC105C fell within the same range, they are
different samples, one being used in each assay. Thus, it is not valid
to compare the values for the latter samples.
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The use of viral load assessments is relatively new in Australia compared to the United States, where clinical trials (American Clinical Trials Group) necessitated the establishment of a QA program at an earlier date (13). Both the AMPLICOR HIV-1 MONITOR and Quantiplex bDNA assays were first registered in Australia in 1996 and, together with the Organon Teknika NucliSens HIV-1 QT, are the only assays currently licensed for diagnostic viral load testing. In contrast, a larger variety of assays is used in the United States, including in-house assays set up within individual laboratories. There is abundant evidence to show that without quality assurance, the performance parameters of such assays are poor (3).
The institution of monitoring of HIV viral load tests in Australia found that approximately half the laboratories performing the AMPLICOR HIV-1 MONITOR v 1.0 assay had intermittent or continuing difficulty achieving assay runs which were valid according to the manufacturer's criteria. Consistently, the reason for invalidity was a failure to achieve a value for the high-positive kit control which was within the specified range. With cooperation between the manufacturer and personnel in several laboratories, very close attention to equipment calibration, and strict adherence to the assay protocol, the proportion of invalid runs by the AMPLICOR HIV-1 MONITOR v 1.0 assay was reduced from 16 to 3% over a period of 6 months across all laboratories. However, although laboratories demonstrated this improved performance, increased invalid run rates continue to occur periodically and can be correlated with the supply of different assay lots. A combination of factors, including minor manufacturing and laboratory variations, probably contribute to an invalid run. Prior to the availability of the NRL's program, results from invalid runs were regularly reported to clinicians in the belief that a single invalid control result did not necessarily invalidate the entire run. This practice was justified on the basis of the nature of the test and its cost rather than on the criterion of accuracy. The NRL's QA program has shown that, when analyzed overall, the numerical results for QC samples do not change significantly in invalid runs (data not shown). However, in multiple instances the high-positive control, provided by the manufacturer, returned values greater than the upper limit of detection and the value for the higher-load NRL QC sample was greater than 2 SDs from the mean. Thus, while values reported from invalid runs may not affect the collective interpretation of a large amount of data, this argument cannot be used to defend reporting of values from invalid runs, as the error in an individual run may be substantial.
Familiarity with the assays and attention to detail have also served to reduce the between-run variability both within and between laboratories, reflected by the reduction in CVs seen between the data generated by the AMPLICOR HIV-1 MONITOR v 1.0 assay for the first set of QC samples (samples QC101 and QC102) and the more recent set of samples (samples QC105 and QC106). In the new version of the AMPLICOR HIV-1 MONITOR assay, v 1.5, results collected to date suggest that there is no difference in the CV from the previous version of the same assay except when Ultrasensitive sample preparation is used. The high CV observed when the modified sample preparation is used may reflect the inexperience of the operators with the new technique but may also highlight a difficulty obtaining precise results for samples with low viral loads by the AMPLICOR HIV-1 MONITOR assay in conjunction with Ultrasensitive sample preparation. As the new version does not differ in practical terms from the previous version, it is not anticipated that the CV will decrease with use of the assay but reflects inherent assay variability. It should be noted that the variability observed with the Quantiplex bDNA 2.0 assay, and now with the Quantiplex bDNA 3.0 assay, has remained consistently less than 35% throughout the program.
Each QAP is designed to ask a question specifically of the quality of HIV viral load testing. In the present study, the questions were, "Can laboratories consistently distinguish a 5-fold difference in viral load?," "What is the within-run reproducibility of the same sample?," and "Are assays equally effective for detection of different HIV-1 subtypes?" Only 5 of 19 laboratories, using either assay, produced one result for one of the dilution samples (a different one in each case) which fell outside the range of acceptable variability. The reproducibility of the results obtained with replicate samples demonstrated greater variability, particularly in laboratories using the AMPLICOR HIV-1 MONITOR assay, which may be expected for the PCR technique. Of 17 laboratories, 3 had widely divergent results for replicate samples with high and low viral loads. Only one of these laboratories had problems with reproducibility for samples with both high and low viral loads. The overall results indicate that while variability is important, there are no systematic testing problems with any laboratory in the detection of virus dilutions.
It has previously been recognized that quantification of viral load by the different assays varies. A lower copy number by the Quantiplex bDNA 2.0 assay has consistently been reported (1, 11, 12) and is also supported by the present study. Of greater significance, however, is the fact that the genetic variability of HIV-1 can influence viral load quantification by the various assays. The AMPLICOR HIV-1 MONITOR v 1.0 assay demonstrated poorer sensitivity for some HIV-1 non-B subtypes, with the Quantiplex bDNA 2.0 assay more efficiently detecting subtypes A and E (1, 4, 9, 11). In the present study the values obtained by the AMPLICOR HIV-1 MONITOR v 1.0 assay for subtype E were lower than those obtained for subtype B. The predominance of HIV-1 subtype B in Australia reduced the impact of this finding. However, with the prevalence of subtype E in Southeast Asia (2), the incidence of this subtype in Australia might reasonably be expected to change. The updated version of the AMPLICOR HIV-1 MONITOR assay has been designed to address the deficiency in detection of HIV-1 non-B subtypes seen in v 1.0 by the use of modified primers for nucleic acid amplification. When alternative primers have been used, improved detection of subtype A has been observed (9). Furthermore, in a recent direct comparison, the updated versions of the AMPLICOR HIV-1 MONITOR and Quantiplex bDNA assays demonstrated very close correlations in the number of copies per milliliter, unlike the earlier versions of the same assays (6). Insufficient data have been obtained through the NRL QA program to establish whether improved sensitivity to HIV-1 non-B subtypes has been achieved or whether a better correlation of results is demonstrated by the newer versions of the assays.
In conclusion, the results obtained from the NRL QA program support the recommendation that testing for HIV-1 viral load in an individual patient should always be conducted by the same test and by the same laboratory. The continued variability observed with new versions of the most commonly used assays suggests that this recommendation should remain in place. As long as the same test is consistently used for within-patient measures, the relative values obtained will indicate the efficacy of antiretroviral treatment. The new versions of the viral load assays will probably redress some of the problems associated with the sensitivities of the assays for various HIV-1 subtypes. However highly divergent subtypes may remain undetectable (10). In addition, despite the increased levels of sensitivity claimed by each manufacturer, problems of variability in the assays continue with low viral loads, particularly in the Roche assay.
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ACKNOWLEDGMENTS |
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NRL's HIV viral load QA program was partially funded by a grant from the Diagnostics and Technology Branch of the Department of Health and Aged Care (DHAC) of the Australian Government. NRL is funded by an operational grant from the Population Health Division of DHAC.
We are grateful to A. Dunne and Professor S. Crowe of the Macfarlane Burnet Centre for Medical Research for the generous supply of HIV-1 subtype B supernatants used in the preparation of the QC samples and to S. Walker for assistance with data collection. In addition, we acknowledge the cooperation of the participating laboratories.
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FOOTNOTES |
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* Corresponding author. Mailing address: National Serology Reference Laboratory, Australia, at St Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Vic 3065, Australia. Phone: 61 3 9418 1111. Fax: 61 3 9418 1155. E-mail: sue{at}nrl.gov.au.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Journal of Clinical Microbiology, November 2000, p. 4015-4020, Vol. 38, No. 11
0095-1137/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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