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editorial note:
This ia an interesting article about adherence and how much adherence is
required to achieve longterm fully suppressed HIV. Although the abstract just
below suggests 93% adherence is required for full viral suppression the
authors discuss below many potential questions about how much adherence is
necessary. Upon further reading of their article they suggest that perhaps
80% may be adequate. This study was small and there are a number of other
confounding factors. The use of MEMS caps, as they did in this study, has
potential flaws. They were only able to evaluate 1 drug (the PI) in the
regimen, although data suggests from other diseases this is reflective of
overall adherence. The authors suggest adherence is hard to evaluate and
simplfy in terms of how much adherence is necessary. For example, perhaps
strict adherence in the first few months or year is required and a lesser
degree of adherence after that may suffice. These ideas, however, are
speculative and point to the notion that studying adherence is more difficult
that it may seem, and that the question of how much adherence is required is
perhaps more complex than we think. Perhaps how much adherence required
depends on individual factors: adherence in first 1-6 months, viral load at
baseline, prior drug resistance, virulence of virus a person may have, CD4
count at baseline, and perhaps a number of factors we don't yet ubderstand.
More research is needed in this area we do not understand well, but do not
take this study as conclusive about how much adherence is needed, and do not
think that this study concludes that less adherence is acceptable. I think
this study nicely points out the difficulty in evaluating how much adherence
is required, and merely suggests that more research is needed to better
understand this question. In the meantime I think close adherence to taking
regimens is recommended.
Robert Grossa,b,c; Warren B. Bilkerb,c; Harvey M. Friedmana; Brian L. Stromb,c
From the Division of Infectious Diseases, Department of Medicine, the
bCenter for Clinical Epidemiology and Biostatistics and the cCenter for
Education and Research on Therapeutics, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania, USA.
AIDS 2001;15:2109-2117
Objective: To determine whether differences in adherence to newly initiated
antiretroviral therapy exist between subjects who do and do not achieve
undetectable plasma viral loads.
Design: Observational cohort study monitoring adherence and virological and
immunological parameters over the initial 4 months of therapy with
nelfinavir. Adherence was measured using the microelectronic monitoring
system (MEMS; APREX Corporation, Menlo Park, California, USA).
Setting: General Clinical Research Center at a tertiary care center.
Participants: Forty-one protease inhibitor-naive subjects with viral loads
10 000 copies/ml newly starting a regimen including nelfinavir, referred from
HIV clinics in Philadelphia.
Main outcome measures: The primary outcome was undetectable viral load (< 50
copies/ml) after 4 months. Secondary measures included changes in viral load
and CD4 cell counts. We hypothesized that adherence would be greater in
subjects who achieved undetectable viral loads.
Results: Adherence was greater in undetectable subjects, who took a median of
93% of prescribed doses [interquartile range (IQR) 8496%], whereas
detectable subjects took a median of 70% (IQR 4693%). Adherence correlated
with viral load decrease (Spearman's = 0.38, P < 0.01) and CD4 cell count
increase (Spearman's = 0.25, P = 0.06). Despite differences between the
groups over 4 months of therapy, there were no adherence differences over the
first month [undetectables, 95% (IQR 8898%) versus detectables, 94% (IQR
8798%), P > 0.50], so checking viral load at 1 month after starting therapy
can give false assuration that patient is being adherent. This data shows
nonadherence can kick in after 1 month. Adherence was 90% in responders &
nonresponders at 1 month. The authors recommend monthly visits after 1 month
for non-judgemental inquiries about non-adherence. Inadequate viral
suppression at 1 month of therapy may be more likely to be caused by
resistance than poor adherence. Therefore, resistance testing should be
strongly considered even after only 1 month of therapy if the subject denies
poor adherence.
Conclusions: Adherence is important in determining whether or not individuals
achieve suppression with a newly initiated antiretroviral regimen. Adherence
begins to wane after the first month of therapy. Therefore, closer assessment
of adherence
particularly after this first month is important.
Study design
We conducted a prospective observational cohort study of adherence to HAART
at the University of Pennsylvania Medical Center between February 1998 and
November 1999. All medical management was left to the discretion of the care
providers and data were not shared with the study subjects or their
physicians until the subject had completed the study.
Measurement of adherence
Adherence was tracked continuously using microelectronic monitors on the
nelfinavir bottle (MEMS 1 ; APREX Corporation, Menlo Park, California, USA).
The data recorded consisted of the date and time of each pill bottle opening
as well as the serial number of the pill cap, to ensure that each subject
continued to use his/her own cap.
As the various highly active agents have different pharmacokinetics and
pharmacodynamics, it may be inappropriate to compare adherence in subjects on
different highly active agents. Furthermore, adherence behavior in
experimental studies is likely to be different
from the clinic setting. Therefore, we chose to study subjects newly starting
a single protease inhibitor in a clinic setting to determine whether
adherence was different between those who did and did not achieve viral
suppression to below the limit of detection ('undetectable'). Nelfinavir was
chosen because, at the time this study began, it was the most commonly
prescribed highly active agent in protease inhibitor naive subjects at the
Philadelphia HIV clinic sites from which we recruit study subjects.
Study population
Entry criteria included being naive to protease inhibitors, having an initial
plasma viral load of . 10 000 copies/ml, and being newly started on a HAART
regimen including nel®navir, dosed either 750 mg three times daily or 1250 mg
twice daily, in combination with two nucleoside analogue reverse
transcriptase inhibitors (NRTI). At least one of the NRTIs had to be new to
the patient, per standard treatment guidelines [22]. We excluded subjects
with previous protease
inhibitor treatment to decrease the possibility of subjects entering with
protease inhibitor-resistant virus.
A sample size of 40 subjects was targeted to yield 80% power to detect a 30%
difference in the percentage of prescribed doses taken between the detectable
and undetectable groups. This calculation was performed using the Power
software program [30] and based on a variance estimate from a prior study of
adherence to antiretroviral therapy using microelectronic monitors [20].
Results
Between February 1998 and July 1999, 58 subjects were recruited into the
study. Of this initial cohort, 16 (27%) subjects dropped out before reaching
study completion. One additional subject was mistakenly terminated from the
study after the 3 month visit and
was not included in the analyses. The most common reason for dropping out was
defaulting from therapy (10 of 16 subjects, 63%), defined as
self-discontinuation of antiretroviral therapy against providers' advice. Of
the 10 subjects defaulting, five did so after the initial visit, two
defaulted after month 1, two after month 2, and one after month 3. The other
reasons included two subjects losing the MEMS cap, two subjects deciding not
to participate after enrolling, one subject changing protease inhibitor
during the study, and one subject dying. Dropouts were similar to those who
completed the study with respect to sex, race, site of recruitment,
being treatment naive, initial viral loads and initial CD4 cell counts.
Twenty-five subjects (61%) achieved undetectable viral loads. The treatment
characteristics included 19 (44%) being treatment experienced, of whom 12
(63%) started two NRTIs to which they were naive at the time of enrollment,
10 (24%) were started on didanosine plus hydroxyurea and another NRTI. No one
received abacavir. There were no signi®cant differences in these treatment
characteristics between the detectable and undetectable groups (all P values
. 0.50).
Pill-taking gaps were also different between the detectable and undetectable
groups. The undetectable group had a median of zero 3-day gaps (range 0±6)
whereas the detectable group had a median of one 3-day gap (range 0±8, P ,
0.02). Similarly, only one in 25 (4%) individuals in the undetectable group
had a 7-day gap, whereas seven of 16 (44%) individuals in the detectable
group had such a 'drug holiday' ( P , 0.002). Of these seven individuals,
four had multiple week-long 'drug holidays'.
Although a classic dose-response relationship is not present, and the number
of subjects in each subcategory were small, there is a significant trend in
the proportion of individuals who achieve undetectable viral load as the
adherence category increases (test for linear trend,
PÐ 0.01). There was also a statistically significant trend for greater viral
suppression with increases in adherence by category of percentage of
prescribed doses (test for
linear trend, P Ð0.02).
As adherence problems did not arise until after the first month of therapy,
we recommend monthly visits immediately after initiating antiretroviral
therapy to allow physicians time for non-judgmental inquiry about adherence.
It is important that these inquiries be undertaken at the time when adherence
is likely to wane (i.e. after the ®rst month). As these data suggest
that the end of the first month is a period of high risk for waning
adherence, investigators designing adherence interventions should strongly
consider focusing their strategies on this time window as it may be the time
at which the greatest impact occurs. In addition,
because the median adherence was above 90% in both groups after the first
month, inadequate viral suppression at 1 month of therapy may be more likely
to be caused by resistance than poor adherence. Therefore, resistance testing
should be strongly considered even after only 1 month of therapy if the
subject denies poor adherence.
DISCUSSION & FINAL OPINION
The findings of this study confirm the importance of adherence on HIV outcome
as described recently in a different cohort [12]. However, our results do not
agree with the conclusion by Paterson et al. that . 95% adherence is required
for substantially better virological outcomes. In contrast, we found a
greater proportion of individuals with undetectable viral loads in the range
of 80-95% adherence. In fact, there is a suggestion of a threshold effect at
80% rather than 95% adherence although it must be recognized that relatively
few subjects in our study took less than 80% of their doses. The reason for
this discrepancy may be due to any of several differences in study design and
study population. Our study included patients who were newly starting their
first protease inhibitor rather than including subjects at various stages of
treatment. We included subjects on only a single protease inhibitor,
nelfinavir, rather than a variety of protease inhibitors. Our definition of
'undetectable' was , 50 copies/ml rather than, 400 copies/ml. Finally, our
follow-up lasted 4 months rather than a median of 6 months. Further
work in this area is needed to clarify the discrepancies between the studies.
An important point to note is that more adherence may not always be better
than less adherence. In fact, this may differ depending on how much an
individual is adhering initially, and how much adherence is necessary for
resistant virus to emerge. Although the
extremely poor adherers will not achieve suppression, they may not develop
resistant virus if their drug exposure is minimal. However, if these
individuals increase their adherence by only a modest amount in response to
an intervention, they may achieve a greater degree of viral suppression
early, but may also be more likely to develop resistant virus. Thus, we need
to
determine if a threshold amount of adherence is necessary to achieve both a
signi®cant immunological benefit as well as forestall the emergence of
resistance. If this threshold is found, it should be the target amount of
adherence for intervention studies.
This study has several limitations. The small sample size prevented us from
drawing conclusions about a possible threshold effect of less than 80%
adherence resulting in a substantial drop-off in the proportion of subjects
with undetectable viral load. This same limitation have prevented us from
determining whether one of the adherence variables is a better discriminator
of
achieving undetectable viral load than the others.
Selection bias may have been present for two reasons. First, this study
involved volunteers who agreed to using MEMS caps, have extra clinic visits
and more frequent blood sampling in order to participate. If these volunteers
were more motivated to adhere than non-participants, then this study
underestimates the rate of poor adherence. The monetary compensation may
have mitigated this volunteer effect. Participants who were motivated by the
compensation, rather than the desire to contribute to scientific advancement,
were probably no more likely to adhere than the target population. Second,
study dropouts mean that our conclusions are based on a subset of the
participants. It is probable that subjects who dropped out had worse
adherence than those who remained within the study. This selection would bias
our results toward the null as the data on the less adherent patients would
have magnified the differences in pill taking between the detectables and
undetectables. Despite the potential selection bias, we found large
differences between the groups suggesting that the impact of adherence is
likely to be even greater than we estimate from these data. The study is also
potentially affected by the inherent limitations of using MEMS in measuring
adherence.
First, these devices only measure a surrogate of pill taking (i.e. pill
bottle opening). One cannot be certain that the correct number of pills were
taken at each dose or that individuals did not either take out more doses for
later use without opening the bottle or conversely, opened the bottle without
taking the dose. However, if study subjects were 'gaming' the system, the
results would be biased toward a lack of effect of adherence. Given the
dramatic differences we observed, it is unlikely that this potential
limitation was present, but if it were, the findings would be even stronger.
Second, we only monitored a single drug in the regimen due to
the impracticality of having multiple MEMS on an individual's bottles.
Therefore, we are only able to make conclusions about adherence to nelfinavir
and not the other drugs in the regimen. Of note, however, is a study which
demonstrated in the renal transplant setting that adherence to one drug in a
regimen is strongly correlated to adherence to other drugs in the regimen
[32]. This phenomenon may mitigate the limitation of only monitoring a single
drug.
Studies of adherence behavior are always potentially limited by the
possibility that the behavior being studied is modified by the very fact that
it is being observed. In this case, we believe that subjects who participated
in the study were more likely than non-participants to adhere as the study
was voluntary. This effect would tend to dampen any differences we might
find. Thus, the real differences between the subjects may have been even more
pronounced than we found.
This study was also limited by its narrow focus on the relation between early
adherence and virological suppression in individuals newly starting on HAART.
Given that long-term adherence is currently the desired approach, these
results may not be generalizable to the setting of maintenance therapy. For
example, after an individual has achieved an undetectable viral load, the
amount of adherence required to maintain that level of suppression may differ
from the amount required to achieve it. This will be an important area to
explore in the future. Finally, although several groups are currently under-
taking research into identi®able and potentially modifiable behavioral
factors associated with adherence to HAART [10,11,33,34], more work needs to
be done to further elucidate the degree of adherence that should be
considered 'optimal' to serve as the outcome in studies of behavioral risk
factors.
The type of data
presented here can be used to set cut points for the amount of pill taking
that should be considered 'good adherence' in both prospective observational
and experimental studies. Furthermore, as these microelectronic monitors are
able to measure the adherence
differences between subjects who do and do not achieve the desired
virological outcomes, they are likely to be able to measure whether
interventions increase adherence.
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