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Effect of adherence to newly initiated antiretroviral therapy on plasma viral load
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].
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, PŠ 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 Š0.02).
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.
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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