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Limited Patient Adherence to Highly Active Antiretroviral Therapy for HIV-1 Infection in an Observational Cohort Study
Pythia T. Nieuwkerk, MA;
Mirjam A. G. Sprangers, PhD;
David M. Burger, PharmD, PhD;
Richard M. W. Hoetelmans, PharmD, PhD;
Patricia W. H. Hugen, PharmD, PhD;
Sven A. Danner, MD, PhD;
Marchina E. van der Ende, MD, PhD;
Margriet M. E. Schneider, MD, PhD;
Gerrit Schrey, MD, PhD;
Pieter L. Meenhorst, MD, PhD;
Herman G. Sprenger, MD, PhD;
Robert H. Kauffmann, MD, PhD;
Marielle Jambroes, MD;
Margaret A. Chesney, PhD;
Frank de Wolf, MD, PhD;
Joep M. A. Lange, MD, PhD;
for the ATHENA Project
Arch Intern Med. 2001;161:1962-1968.
ABSTRACT
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Background Adherence to highly active antiretroviral therapy (HAART) for human
immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain
viral suppression and prevent drug resistance. We investigated adherence to
HAART among patients in a clinical cohort study.
Methods Patients receiving HAART had their plasma concentrations of protease
inhibitors or nevirapine measured and completed a questionnaire on adherence.
We determined the percentage of patients who reported taking all antiretroviral
medication on time and according to dietary instructions in the past week.
Drug exposure was compared between patients reporting deviation from their
regimen and fully adherent patients. Among patients who received HAART for
at least 24 weeks, we assessed the association between adherence and virologic
outcome.
Results A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven
percent reported taking all antiretroviral medication on time and according
to dietary instructions. Patients who reported deviation from their regimen
showed lower drug exposure compared with fully adherent patients (median concentration
ratio, 0.81 vs 1.07; P = .001). Among those receiving
HAART for at least 24 weeks, patients reporting deviation from their regimen
were less likely to have plasma HIV-1 RNA levels below 500 copies/mL (adjusted
odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent
patients.
Conclusions Only half of the patients took all antiretroviral medication in accordance
with time and dietary instructions in the preceding week. Deviation from the
antiretroviral regimen was associated with decreased drug exposure and a decreased
likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence
should remain a prime concern in the management of HIV-1 infection.
INTRODUCTION
TREATMENT OF human immunodeficiency virus type 1 (HIV-1)–infected
patients with highly active antiretroviral therapy (HAART) has been shown
to be effective with respect to the suppression of plasma HIV-1 RNA below
detectable concentrations.1-2
However, the effectiveness of HAART to achieve and sustain viral suppression
may be hampered by insufficient patient adherence to the antiretroviral regimen.2-6
Moreover, suboptimal adherence, allowing ongoing viral replication, facilitates
the emergence of HIV-1 variants resistant to the drugs being used.2, 7 The emergence of drug resistance reduces
considerably the treatment options for the individual patient, since cross-resistance
exists to a large extent among antiretroviral agents within a therapeutic
class.7 Given the potential for transmission
of drug-resistant HIV-1, suboptimal adherence may have significant public
health implications.8-9
Adherence to HAART typically includes taking multiple drugs 2 to 4 times
a day according to a strict schedule. For several drugs, dietary instructions
are necessary.10 To date, a limited number
of studies have investigated the extent to which patients adhere to HAART
and have predominantly focused on the proportion of medications taken.2-6,11-12
We investigated the extent to which patients report adherence to their
antiretroviral regimen, including accurate timing of doses and keeping dietary
instructions in a nationwide cohort study in the Netherlands. We compared
exposure to protease inhibitors (PIs) and to a nonnucleoside reverse transcriptase
inhibitor (NNRTI) between patients who reported taking their antiretroviral
medication as prescribed and patients who reported deviation from their prescribed
regimen. Among patients taking HAART for at least 24 weeks, we additionally
investigated the association between adherence and virologic outcome.
PARTICIPANTS AND METHODS
THE ATHENA PROJECT
From May 1998, consecutive HIV-1–infected patients, 18 years or
older, from 22 hospital in the Netherlands were enrolled in an observational
cohort study called the ATHENA project. Eligible patients were either starting
or already receiving antiretroviral therapy with at least 1 of the drugs that
were licensed in the Netherlands from July 1996, ie, all PIs and NNRTIs, lamivudine,
and stavudine. Patients had to be able to complete Dutch or English self-report
questionnaires. Plasma concentrations of PIs and nevirapine were determined
at routine visits. The study was approved by the institutional review board
of all participating centers. All patients gave written informed consent.
ADHERENCE MEASUREMENT
Adherence was assessed by a self-report questionnaire each time plasma
concentrations of antiretroviral drugs were determined. Patients were informed
that their responses would remain confidential and would have no consequences
for their treatment. The completed questionnaire could be returned in a sealed
envelope. Patients were asked on which of the past 2 days they had taken all
antiretroviral medication, how many days in the past week they had been off
schedule by more than 1 hour, and how many days in the past week they had
taken their medication according to dietary instructions, if applicable. They
were asked about keeping the following dietary instructions: taking didanosine
half an hour before or 2 hours after a meal, taking indinavir sulfate 1 hour
before or 2 hours after a meal or taking indinavir with a low-fat meal, and
taking ritonavir and/or saquinavir mesylate with a meal or within 2 hours
after a meal. In addition, patients were asked to what extent their adherence
during the past week was comparable with the preceding period. Patients were
asked about reasons for nonadherence using a question with 5 response categories
and the option for providing additional reasons. Patients could provide more
than 1 answer.
PATIENTS
The present study describes patients who completed a questionnaire at
the first pharmacokinetic measurement between May 1998 and June 1999. We included
patients who were prescribed indinavir sulfate (800 mg 3 times a day), nelfinavir
mesylate (750 mg 3 times a day or 1250 mg 2 times a day), saquinavir mesylate
(1200 mg 3 times a day), ritonavir (600 mg 2 times a day), nevirapine (200
mg 2 times a day), or ritonavir (400 mg 2 times a day) combined with saquinavir
mesylate (400 mg 2 times a day) as part of their antiretroviral regimen.
ASSESSMENT OF DRUG EXPOSURE
Plasma concentrations of PIs and nevirapine were measured using high-performance
liquid chromatography.13-15
The timing of the previous dose was recorded on the laboratory form with the
timing of the sample drawn. Observed concentrations were divided by the expected
concentrations at the corresponding interval between drug ingestion and sampling.
The expected concentrations at different time points were obtained from a
reference group of HIV-1–infected patients using the same drug in the
same dosage for whom full pharmacokinetic curves were available. Concentration
ratios (CRs) served as measure of relative drug exposure, with 1 indicating
a concentration that is equal to the average time-adjusted concentration in
the reference population. Patients who were using any interacting drugs were
excluded from the analyses.
HIV-1 RNA QUANTIFICATION
Plasma concentrations of HIV-1 RNA were measured with the HIV-1 branched
DNA assay (version 1.0 or 3.0, Chiron Diagnostics, Emeryville, Calif) with
a lower detection limit of 500 (version 1.0) or 50 copies/mL (version 3.0),
the Nuclisens HIV-1 RNA assay (Organon Teknika, Turnhout, Belgium) with a
lower detection limit of 400 copies/mL, or the HIV-1 Amplicor Monitor assay
(Roche Molecular Systems, Branchburg, NJ) with a lower detection limit of
400 copies/mL, depending on the routine of the particular hospital. We assumed
comparability of results of these quantitative HIV-1 RNA measurements.16 We dichotomized virologic outcome into having plasma
HIV-1 RNA levels above or below 500 copies/mL.
ANALYSIS
We calculated the percentage of patients who reported taking all antiretroviral
medication in accordance with time and dietary instructions in the preceding
week. Those patients were considered fully adherent. If no food requirement
was applicable, patients were considered adherent with food requirements.
The questionnaire did not include the dietary advice that nelfinavir should
preferentially be taken with food. Patients treated with nelfinavir who reported
taking all antiretroviral medication according to schedule were handled in
the analysis as fully adherent.
Using the  2 test, the proportion of patients who reported
deviation from their regimen was compared across hospitals that enrolled at
least 10 patients.
We compared CRs between fully adherent patients and patients who reported
deviation from their regimen by the Mann-Whitney test. In patients prescribed
ritonavir combined with saquinavir, the lowest CR of both drugs was used.
We analyzed data from patients who completed a questionnaire within
1 week following pharmacokinetic sampling, because questions referred to the
past week. We additionally analyzed the data of patients who completed a questionnaire
on the same day the pharmacokinetic sample was taken.
Among patients who had received HAART for at least 24 weeks, we investigated
the association between adherence and virologic outcome. We calculated the
odds ratio (OR) and 95% confidence interval (CI) on having plasma HIV-1 RNA
levels above 500 copies/mL in patients who reported deviation from their regimen
compared with patients who reported being fully adherent by logistic regression
analyses. In a second logistic regression analysis, we adjusted for age, sex,
antiretroviral therapy before initiation of HAART, prior change of HAART because
of therapy failure, Centers for Disease Control and Prevention (CDC) stage
at initiation of HAART, HIV-1 transmission category (homosexual vs other),
and PI or NNRTI used as part of the current HAART regimen. Two-sided P values less than .05 were considered to indicate statistical
significance. Data analyses was performed using the SPSS software for Windows
version 8.0.2 (SPSS Inc, Chicago, Ill).
RESULTS
ADHERENCE
Between May 1998 and June 1999, CRs were calculated for 261 patients
in whom a first pharmacokinetic measurement was performed. Of those, 224 patients
(86%) completed a questionnaire within 1 week following pharmacokinetic sampling.
None of these patients were using any interacting drugs. Characteristics of
patients at the time of completion of the questionnaire are shown in Table 1.
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Table 1. Characteristics of the 224 Patients*
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Twenty-three patients (10.3%) reported that they did not take all antiretroviral
medication in the past 2 days. Seventy-three patients (32.6%) reported deviation
from the schedule in the past week. Forty patients (17.9%) reported deviation
from dietary instructions. Deviation from food requirements was reported by
3 (10%) of 31 patients prescribed didanosine, 20 (32%) of 62 patients prescribed
indinavir, 10 (18%) of 55 patients prescribed saquinavir, and 16 (24%) of
66 patients prescribed ritonavir.
Of 224 patients, 201 (89.7%) reported taking all antiretroviral medication,
134 (59.8%) reported taking all medication on time, and 119 (53.1%) reported
taking all medication on time according to food requirements and were thus
considered fully adherent. Figure 1
shows the percentages of patients within the 4 largest treatment groups who
reported taking all antiretroviral medication, on time, and according to food
requirements, respectively.
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Patient adherence to highly active antiretroviral therapy. IDV indicates
indinavir sulfate; NRTIs, nucleoside reverse transcriptase inhibitors; NFV,
nelfinavir mesylate; RTV/SQV, ritonavir and saquinavir mesylate; and NVP,
nevirapine. Asterisk indicates group "taking all medication on time according
to food requirements" not assessed.
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The overall percentage of fully adherent patients was 47% when patients
with a nelfinavir-containing regimen, in whom adherence to food requirements
was not known, were excluded. In total, 182 patients (81.2%) reported that
their level of adherence during the past week was comparable to that during
the preceding period. Twenty-three (10.3%) reported that it was better compared
with the preceding period, and 19 (8.5%) reported that it was worse.
Reasons for deviation from the regimen were as follows: forgetting (35%),
considering it impossible to combine taking medication with activities of
that particular moment (24%), feeling sick or ill (22%), having a change in
daily routine (19%), and not having the medications available at the requested
time (15%).
A total of 178 (79%) of 224 patients were enrolled at 9 sites that included
at least 10 patients. The proportion of patients who reported deviation from
their regimen ranged from 38% to 63% across these sites. Differences in adherence
across sites were not statistically significant (P
= .74, 2 test).
ADHERENCE AND DRUG EXPOSURE
Three patients (2 taking indinavir, 1 taking ritonavir and saquinavir)
had undetectable plasma concentrations of PIs. All 3 reported being not fully
adherent. For all treatment groups combined, patients who reported deviation
from their regimen showed significantly lower CRs, indicating lower drug exposure,
compared with patients who reported being fully adherent (Table 2). A CR of 1 indicates a concentration that is equal to the
average time-adjusted concentration in the reference population. The median
CR of patients who reported deviation from their regimen was below 1, whereas
it approximated 1 in fully adherent patients. Median CRs within treatment
groups are also shown in Table 2.
To date, the minimal effective CR has been established for indinavir only.
This minimal effective CR should be higher than 0.75, which corresponds with
an indinavir trough concentration of 0.10 mg/L.17
Similar minimal effective indinavir trough levels have been established by
others, using a different method.18-19
The median CR of patients in the indinavir group who reported deviation from
their regimen was below this minimal effective threshold.
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Table 2. Concentration Ratios of Protease Inhibitors and Nevirapine*
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When CRs were compared between fully adherent patients and patients
in whom nonadherence was based only on deviation from schedule and dietary
prescriptions, ie, those who reported taking all their medications but not
in accordance with time and/or dietary prescriptions (n = 82), the latter
group had statistically significantly lower CRs (Mann-Whitney test, P = .002), with a median of 0.78.
A total of 185 patients had completed a questionnaire on the same day
the pharmacokinetic sample was taken. A comparison of CRs between fully adherent
patients and patients who reported deviation from their regimen within this
group led to similar results. The median CR in fully adherent patients was
1.05, whereas it was 0.82 in patients who reported deviation from their regimen
(Mann-Whitney test, P = .001).
ADHERENCE AND VIROLOGIC OUTCOME
There were 156 patients who had received HAART for at least 24 weeks;
in 137 (88%) of these patients a plasma HIV-1 RNA measurement was performed
at completion of the questionnaire. Of those 137 patients, 107 (78.1%) had
plasma HIV-1 RNA levels below 500 copies/mL, 82 (59.9%) had received antiretroviral
therapy before initiation of HAART, and 36 (26.3%) had previously changed
their HAART regimen because of therapy failure.
Twenty (28%) of 72 patients who reported deviation from their regimen
had plasma HIV-1 RNA levels above 500 copies/mL compared with 10 (15%) of
65 patients who reported being fully adherent (OR, 2.1; 95% CI, 0.9-4.9) (Table 3). After adjustment for antiretroviral
therapy before initiation of HAART, prior change of HAART because of therapy
failure, and CDC stage at initiation of HAART, the OR was 4.0 (95% CI, 1.4-11.6).
Adjustment for age, sex, HIV-1 transmission category, and PI or NNRTI used
did not significantly improve the fit of the model, did not alter results,
and did not lead to statistically significant ORs. They are therefore not
reported.
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Table 3. Odds Ratios of Having Plasma HIV-1 RNA Concentrations Above
500 Copies/mL Among Patients Who Had Received at Least 24 Weeks of Highly
Active Antiretroviral Therapy*
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When we compared virologic outcome between fully adherent patients and
patients in whom nonadherence was only based on deviation from schedule and
dietary prescriptions, ie, those who reported taking all their medications
but not in accordance with time and/or dietary prescriptions, the latter group
tended to be more likely to have a viral load above 500 copies/mL (OR, 2.1;
95% CI, 0.9-5.2). When taking into account antiretroviral therapy before initiation
of HAART, prior change of HAART because of therapy failure, and CDC stage
at initiation of HAART, the OR was 5.5 (95% CI, 1.6-18.4).
We took a closer look at the association among adherence, virologic
outcome, and prior therapy failure. In the group of patients without prior
therapy failure, 10 (18%) of 55 patients who reported deviation from their
regimen had plasma HIV-1 RNA levels above 500 copies/mL compared with 1 (2%)
of 46 patients who reported being fully adherent (OR, 10.0; 95% CI, 1.2-81.3; P = .03). In the group of patients with prior therapy failure,
10 (59%) of 17 patients who reported deviation from their regimen had plasma
HIV-1 RNA levels above 500 copies/mL compared with 9 (47%) of 19 patients
who reported being fully adherent (OR, 1.6; 95% CI, 0.4-5.9; P = .49).
COMMENT
Only half of our patients reported taking all antiretroviral medication
in accordance with time and dietary instructions in the preceding week. Patients
reporting deviation from their antiretroviral regimen showed lower drug exposure
and were less likely to have suppressed plasma HIV-1 RNA loads.
The finding that a substantial number of patients did not succeed in
taking HAART as prescribed illustrates the difficulty of consistently taking
antiretroviral medication according to all requirements. To date, it is not
known what level of adherence to HAART is precisely needed to prevent viral
rebound and the emergence of drug-resistant virus variants, although "less
than excellent adherence" has been considered to be insufficient.20 There is evidence that rates of virologic failure
significantly increase when less than 95% of prescribed doses of PIs are actually
taken.5 The degree to which one can deviate
from a specific antiretroviral regimen without increasing the risk of treatment
failure will depend on characteristics of the particular drugs that are used,
such as the plasma elimination half-life and the degree to which drug exposure
is dependent on food intake.10 In the present
study, we found that the group of patients treated with an indinavir-containing
regimen, a PI sensitive to accurate adherence to both timing of drug intake
and specific dietary requirements, who reported deviation from this regimen
had a median CR that was below the minimal effective threshold. Since the
consequences of poor adherence will differ across various antiretroviral regimens,
we believe the present study underlines the importance of considering the
patients' ability to adhere when choosing among different treatment options.
Studies investigating the extent of adherence to HAART have predominantly
focused on the proportion of pills being taken. Median adherence rates from
84% to 92% have been reported,5 as well as
70% of patients taking more than 95% of prescribed medication,4
50% taking 100% of prescribed medication,3
and 58% taking more than 90%.21 In the present
study, we found that 90% reported taking all prescribed medication. When the
timing of doses and food requirements were taken into account, the percentage
of patients who reported having taken HAART medication as prescribed decreased
to 47%. Supposedly, this result may be representative for a number of other
cohorts as well: 78% of our patients who took HAART for at least 24 weeks
had suppressed plasma HIV-1 RNA loads, which is comparable to results reported
in other prospective cohort studies.22-23
Patients who reported taking all their medications but not in accordance with
time and dietary prescriptions also had lower CRs and were more likely to
have a viral load above 500 copies/mL compared with patients who reported
being fully adherent. This suggests that there is more to adherence than whether
or not someone takes one's dose. Patients also need to take it properly.
We found that the association between adherence and virologic outcome
was affected by prior therapy failure. Other studies22, 24
found the proportion of patients achieving undetectable plasma HIV-1 RNA concentrations
on the first HAART regimen to be higher than that of subsequent regimens.
In the present study, adherence was significantly related with virologic outcome
in patients without prior therapy failure but not in patients with prior therapy
failure. This could possibly be explained by decreased drug sensitivity in
the group with prior therapy failure. Clearly, this finding needs further
investigation and corroboration in other studies.
Our study had several limitations. We assessed patient adherence by
self-report. This is a method known to overestimate adherence but to reliably
assess nonadherence.25-26 Therefore,
it is likely that our results represent the highest estimate of the extent
to which patients are adhering to HAART.
Patients enrolled in the study needed to be literate in Dutch or English
because adherence was assessed by a self-report questionnaire; therefore,
our results might not be generalized to patients with insufficient language
skills to complete a self-report questionnaire.
We used a time frame of 7 days in our adherence questionnaire. This
might have caused some recall bias. However, other studies3-4,11
investigating adherence to HAART by self-report have suggested a reasonable
validity of using a time frame of 7 days or longer. We therefore believe that
the use of a 7-day time frame was justifiable.
We used CRs as a measure of relative drug exposure. Concentration ratios
may be affected by individual variability in pharmacokinetic profiles. Theoretically,
a patient with a profile characterized by a high peak and a low trough level
could obtain a more favorable CR compared with a patient with a profile characterized
by a low peak and a high trough level, depending on when the sample is drawn,
whereas a more favorable virologic response would be expected in the latter
patient. However, CRs have previously been used as a measure of exposure to
PIs among groups of HIV-1–infected patients and have been shown to be
related with adherence and virologic treatment failure,6
HIV-1 clearance rate,27 and toxic effects associated
with PIs.28-29 We therefore believe
that there is sufficient support for the use of CRs as measure of drug exposure
at a group level.
In the questionnaire, we had not included the dietary advice that nelfinavir
should preferentially be taken with food. This advice had been overlooked
in designing the questionnaire. Patients treated with nelfinavir who reported
taking all antiretroviral medication according to schedule were handled in
the analysis as being fully adherent. This might have decreased our ability
to differentiate between the level of adherence of patients who were treated
with a nelfinavir-containing regimen.
We found significantly lower drug exposure in patients who reported
deviation from their regimen compared with patients who reported being fully
adherent. However, we observed considerable variability in CRs within both
groups of patients. We found a median CR greater than 1 in the group of fully
adherent patients, although the median CR was not statistically significantly
greater than 1. A median CR greater than 1 in fully adherent patients could
be explained by the large interpatient variability in plasma drug concentrations
that is particularly common for PIs. This could result in observed concentrations
being slightly higher compared with the time-adjusted reference concentrations,
since reference values had been determined in relatively small reference groups
and, therefore, by chance could have been lower.
Within the group of patients who reported being fully adherent, we observed
CRs that were lower than 1. This might be indicative of a too favorable self-reported
level of adherence.
In conclusion, only half of the patients reported taking all antiretroviral
medication in accordance with time and dietary instructions in the preceding
week. Patient adherence should remain a prime concern in the management of
HIV-1 infection.
AUTHOR INFORMATION
Accepted for publication January 18, 2001.
This study was supported by grant 1325 from the AIDS Fund, Amsterdam,
the Netherlands, and by grant CURE/97-46486 from the Health Insurance Fund
Council, Amstelveen, the Netherlands.
Presented in part at the 13th International AIDS Conference, Durban,
South Africa, July 10, 2000 (Abstract MoPpD1055).
We thank the participants in this study.
| Members of the ATHENA Project
Clinical and Epidemiological Working Group:
W. Bronsveld, Medisch Centrum–Alkmaar; H. Weigel (site coordinating
physician), K. Brinkman, P. Frissen, Onze Lieve Vrouwe Gasthuis; J. ten Veen
(site coordinating physician), M. Hillebrand, S. Schieveld, Onze Lieve Vrouwe
Gasthuis–Lokatie Prinsengracht; J. Mulder (site coordinating physician),
E. van Gorp, P. Meenhorst, Slotervaart Ziekenhuis; A. van Eeden, Jan v. Goyen
Kliniek; F. Claessen (site coordinating physician), R. Perenboom, Academisch
Ziekenhuis Vrije Universiteit; S. Danner (site coordinating physician), J.
K. Eeftinck Schattenkerk, E. Gisolf, M. Godfried, J. van der Meer, J. Nellen,
D. Notermans, T. van der Poll, M. van Praag, J. Prins, P. Reiss, M. Reijers,
Th. Ruys, M. van der Valk, A. Verbon, F. Wit, Academisch Medisch Centrum–Amsterdam;
C. Richter (site coordinating physician), R. van Leusen, Ziekenhuis Rijnstate–Arnhem;
R. Vriesendorp, Westeinde Ziekenhuis–Den Haag; R. Kauffmann (site coordinating
physician), E. Kogger, Ziekenhuis Leyenburg–Den Haag; B. Bravenboer,
Catharina Ziekenhuis-Eindhoven; C. ten Napel (site coordinating physician),
K. Pogany, Medisch Spectrum Twente–Enschede; H. G. Sprenger (site coordinating
physician), G. Law, Academisch Ziekenhuis–Groningen; R. W. ten Kate,
Kennemer Gasthuis–Haarlem; M. Leemhuis, Medisch Centrum–Leeuwarden;
F. Kroon, Leids Universitair Medisch Centrum; G. Schrey (site coordinating
physician), S. van der Geest, A. van der Ven, Academisch Ziekenhuis–Maastricht;
P. Koopmans (site coordinating physician), M. Keuter, D. Telgt, Academisch
Ziekenhuis–Nijmegen; M. van der Ende (site coordinating physician),
I. Gyssens, S. de Marie, Erasmus Universiteit Medisch Centrum–Rotterdam;
J. Juttmann (site coordinating physician), C. van der Heul, St Elisabeth Ziekenhuis–Tilburg;
M. Schneider (site coordinating physician), J. Borleffs, I. Hoepelman, C.
Jaspers, Universitair Medisch Centrum–Utrecht; W. Blok, Ziekenhuis Walcheren–Vlissingen. Clinical Working Group: J. Tijssen (chair), G. Bonsel,
M. Dijkgraaf, S. Heisterkamp, Academisch Medisch Centrum–Amsterdam (Working
Group on Cost-effectiveness); J. Lange (chair), M. Jambroes, G. J. Weverling,
Academisch Medisch Centrum–Amsterdam. Toxicity Working
Group: M. Mulder, Dutch HIV Patient Association; J. Dieleman, I. Gyssens,
Erasmus Universiteit Medisch Centrum–Rotterdam; K. Brinkman, Onze Lieve
Vrouwe Gasthuis; P. Koopmans, H. ter Hoffstede, Academisch Ziekenhuis–Nijmegen;
P. Reiss (chair), M. Jambroes Academisch Medisch Centrum–Amsterdam. Medical Psychology Working Group: M. Sprangers (chair),
P. Nieuwkerk, Academisch Medisch Centrum–Amsterdam. Pharmacology Working Group: D. Burger (cochair), R. Aarnoutse, P. Hugen,
Academisch Ziekenhuis–Nijmegen; R. Hoetelmans (cochair), R. van Heeswijk,
A. Veldkamp, Slotervaart Ziekenhuis–Amsterdam. Virological
Working Group: P. Rietra, K. Roozendaal, Onze Lieve Vrouwe Gasthuis;
W. Pauw, A. van Zanten, Slotervaart Ziekenhuis; B. von Blomberg, P. Savelkoul,
Academisch Ziekenhuis Vrije Universiteit; F. de Wolf (cochair), J. Goudsmit,
L. van der Hoek, S. Jurriaans, Academisch Medisch Centrum–Amsterdam;
L. Nohlmans, Ziekenhuis Rijnstate–Arnhem; C. Jansen, Westeinde Ziekenhuis–Den
Haag; P. Franck, A. Lampe, Ziekenhuis Leyenburg–Den Haag; E. Boel, A.
Janz, Catharina Ziekenhuis-Eindhoven; R. Hendriks, Streeklaboratorium Twente–Enschede;
J. Schirm, Streeklaboratorium-Groningen; H. Storm, Medisch Centrum–Leeuwarden;
D. Veenendaal, LVF-Leeuwarden; A. Kroes (cochair), Leids Universitair Medisch
Centrum; C. Bruggeman, V. Goossens, Academisch Ziekenhuis–Maastricht;
J. Galama, Academisch Ziekenhuis–Nijmegen; A. Osterhaus (cochair), H.
Niesters, Erasmus Universiteit Medisch Centrum–Rotterdam; A. Buiting,
St Elisabeth Ziekenhuis–Tilburg; C. Boucher (cochair), N. Back, R. Schuurman,
Universitair Medisch Centrum–Utrecht. Steering Committee: J. Ruitenberg (chair), C. Boucher, D. Burger, S. Danner, R. Hoetelmans,
R. W. ten Kate, R. Kauffmann, F. Kroes, J. Lange, A. Osterhaus, J. Tijssen,
F. de Wolf. Coordinating Center: J. Lange, J. Tijssen,
F. de Wolf (project leaders); M. Jambroes, E. van der Ven, J. Wubbels (project
coordinator); S. Brouwer, M. Overveld, R. van Boxtel (clinical research associates). Data Collection Assistants: R. Runia, N. Wijdenes, Medisch
Centrum–Alkmaar; Rosa Regez, N. Troost, Onze Lieve Vrouwe Gasthuis;
M. Beerepoot, Onze Lieve Vrouwe Gasthuis–Lokatie Prinsengracht; E. Oudmaijer,
Slotervaart Ziekenhuis; J. Troon, Jan v. Goyen Kliniek; A. van Diggelen, Academisch
Ziekenhuis Vrije Universiteit; J. Ruijs, L. Veenenberg, Academisch Medisch
Centrum–Amsterdam; N. Langebeek, Ziekenhuis Rijnstate–Arnhem;
M. Groot, S. Wildebeest, Westeinde Ziekenhuis–Den Haag; A. de Haas,
Ziekenhuis Leyenburg–Den Haag; W. van Schaik, N. Slegers, Catharina
Ziekenhuis-Eindhoven; H. Heins, T. Lansink, Medisch Spectrum Twente–Enschede;
A. Bakker, S. Moolenburgh, Academisch Ziekenhuis–Groningen; E. Kloosterhuis,
M. Schoemaker, Kennemer Gasthuis–Haarlem; J. de Groot, A. Ketser, Medisch
Centrum–Leeuwarden; W. Dorama, Leids Universitair Medisch Centrum; Ch.
Leenders, Academisch Ziekenhuis–Maastricht; M. Meeuwissen, B. Zomer,
Academisch Ziekenhuis–Nijmegen; T. Royaards, Erasmus Universiteit Medisch
Centrum–Rotterdam; R. Santegoets, B. van der Ven, St Elisabeth Ziekenhuis–Tilburg;
F Bär, Universitair Medisch Centrum–Utrecht; S. Baas, C. Ruissen,
Ziekenhuis Walcheren–Vlissingen.
|
|
Corresponding author: Pythia T. Nieuwkerk, MA, Department of Medical
Psychology (J4-410), Academic Medical Center, PO Box 22700, 1100 DE Amsterdam,
the Netherlands (e-mail: p.t.nieuwkerk{at}amc.uva.nl).
From the Department of Medical Psychology (Ms Nieuwkerk and Dr Sprangers),
Division of Infectious Diseases, Tropical Medicine, and AIDS (Dr Danner),
Department of Human Retrovirology (Dr de Wolf), and the National AIDS Therapy
Evaluation Center (Drs Jambroes and Lange), Academic Medical Center, Amsterdam,
the Netherlands; Department of Clinical Pharmacy, University Medical Center
St Radboud, Nijmegen, the Netherlands (Drs Burger and Hugen); Departments
of Pharmacy and Pharmacology (Dr Hoetelmans) and Internal Medicine (Dr Meenhorst),
Slotervaart Hospital, Amsterdam, the Netherlands; Department of Internal Medicine,
Erasmus University Medical Center, Rotterdam, the Netherlands (Dr van der
Ende); Department of Internal Medicine, Utrecht Medical Center, Utrecht, the
Netherlands (Dr Schneider); Department of Internal Medicine, University Hospital
Maastricht, Maastricht, the Netherlands (Dr Schrey); Department of Internal
Medicine, University Hospital Groningen, Groningen, the Netherlands (Dr Sprenger);
Department of Internal Medicine, Hospital Leyenburg, the Hague, the Netherlands
(Dr Kauffmann); and Center for AIDS Prevention Studies, University of California,
San Francisco (Dr Chesney). Dr Lange has received consulting fees from Abbott
Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Chiron Corporation,
Gilead Sciences, GlaxoSmithKline, Roche, and Virco.
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