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Rate and predictors of self-chosen drug discontinuations in highly active antiretroviral therapy-treated hiv-positive individuals
AIDS PATIENT CARE and STDsVolume 23, Number 1, 2009ª Mary Ann Liebert, Inc. DOI: 10.1089=apc.2007.0248
Rate and Predictors of Self-Chosen Drug Discontinuations
in Highly Active Antiretroviral Therapy-Treated
Rita Murri, M.D.,1 Giovanni Guaraldi, M.D.,2 Piergiorgio Lupoli, Ph.D.,3 Raffaella Crisafulli, Ph.D.,3
Simone Marcotullio, Ph.D.,4 Filippo von Schloesser,4 and Albert W. Wu, Ph.D.5
Despite the clinical benefits of highly active antiretroviral therapy (HAART), sustained treatment remains a greatchallenge for HIV-infected people. The rate, consequences, and correlates of self-elected treatment interruptions(TI) are not known. The objectives of the study were to assess the rate of patient-elected TI in a cohort of HIV-infected people taking HAART, to evaluate whether patient-elected TI is correlated with suboptimal non-adherence, and to identify the predictors of self-chosen HAART interruptions. Using a Web-based cross-sectionalsurvey beginning in January 2006 primary outcomes were: (1) reports of having asked their physician to interruptthe current regimen (AskDisc) and (2) reports of at least one interruption of a minimum of 1 day of any of the drugsincluded in the regimen (INTERR). Three hundred fifty-nine people were enrolled; 296 were taking HAART. Twenty-three percent self-reported suboptimal adherence, 45% reported AskDisc, and 25% INTERR. Forty per-cent of people reporting INTERR self-reported suboptimal adherence. As expected, AskDisc and INTERR werecorrelated with suboptimal adherence. The AskDisc group had higher CD4 cell counts and HIV RNA, moresymptoms, and took more convenient regimens. The INTERR group had higher HIV RNA, were more likely tosmoke, seek more information on HIV=AIDS, and less likely to take non-nucleoside reverse transcriptase inhib-itors (NNRTIs). The rate of self-chosen TI was high and often related to suboptimal adherence. These findings mayhelp clinicians to better monitor patients, and identify patients for targeted counseling.
suggests disadvantages to this strategy.3 Particularly, an in-creased risk of cardiovascular diseases was observed dur-
Despiteimportantimprovementsintheconvenienceof ing the TI period.4 Similar results were confirmed in another
antiretroviral regimens, long-term therapy is a major
large study even showing that the heightened risks linked
challenge for people living with HIV=AIDS (PLWHA). Highly
to TI were not reversible after continuous treatment was re-
active antiretroviral therapy (HAART) is now better tolerated;
few daily pills and once-a-day regimens are common.1,2
Anecdotal evidence suggests that patients may undertake
However, in the absence of alternative immunologic and
TI, sometimes referred to as drug holidays, and not discuss
vaccines strategies, HAART remains a life-long therapy and
this decision with their physician. Few studies have exam-
treatment fatigue is a key barrier to an optimal adherence to
ined the issue of self-elected TI.5,6 The rate and predictors of
patient-elected TI, particularly of when not agreed upon with
Several studies have addressed the issue of treatment in-
terruptions (TI) as a possible strategy to offset treatment fa-
The objectives of the present study were to assess the rate of
tigue and enhance quality of life, limit adverse events, reduce
self-chosen TI in a cohort of HIV-infected people taking
costs, and contain the emergence of multidrug-resistant virus.
HAART and identify the warning signs (i.e., predictors) of
Results have been contradictory, but a recent large study
1Catholic University of Rome, Rome, Italy.
2University of Modena and Reggio Emilia, Modena, Italy.
4Fondazione Nadir Onlus, Rome, Italy.
5Department of Health Policy and Management, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland.
dence intervals (CI) were estimated. All analyses were donewith SPSS version 13.0 (SPSS, Chicago, IL).
This cross-sectional survey was conducted in conjunction
with LONGIS (LONGitudinal Information Study), a pro-
spective cohort study designed and supported by Nadir On-lus Foundation, a not-for-profit patient-based foundation,
Between January and December 2006, 359 patients were
enrolling adults HIV-infected people via the Web. The aim of
the cohort is to explore, using a patient-centered approach,
One hundred thirty-three subjects (44.9%) reported that
preferences regarding antiretroviral therapy, belief in the ef-
they had asked their physician to discontinue therapy in the 4
ficacy of HAART, adherence to drugs, the role of the patient in
choosing or switching the HAART regimens, cotherapies, and
Of the 296 patients taking HAART, 68 (23%) self-reported
different aspects of the patient–physician relationship.
suboptimal adherence in response to the question: ‘‘How do
In the present study patients were recruited through a
you think you are taking therapy?’’ and 13 patients (5.7%)
questionnaire posted on the Italian website of Nadir Onlus
reported that they missed at least one dose per week, even if
Foundation (www.nadironlus.org) between January and De-cember 2006. No specific selection procedures were adopted. Visitors to the Nadir website were invited to participate in the
Table 1. Characteristics of the Three Hundred
survey; they could be directly linked to the questionnaire. No
particular emphasis was placed on adherence to antiretrovirals
or to satisfaction with therapy but only to patient preferences.
The following definitions of self-reported adherence were
used: (1) patient rating report of accuracy of taking antiretro-
viral therapy; (2) report of missing doses in a fixed period (how
many doses the patient missed in the previous week and how
many in the previous month), (3) reported timing of therapy
(how often the patient took pills 2 hours before or after the
prescribed time), and (4) reporting at least one interruption of
a minimum of 1 day of any of the drugs included in the regi-
men without having informed the physician either before or
after (‘‘Have you ever discontinued your current regimen for at
least 1 day without informing your physician, before or after
the fact?’’). Suboptimal adherence was defined as answering
‘‘very bad,’’ ‘‘bad,’ or ‘‘not well enough’’ to the question: ‘‘How
do you think you are taking therapy?’’ or those reporting
having missed at least one dose in the previous week.
We also included a question on the willingness to dis-
continue drugs (‘‘Have you ever asked your physician to
discontinue your current regimen for a period?’’ with possible
options not or yes). This latter was considered the main out-
The survey also included questions on health status (‘‘How
do you define your physical health?’’ and ‘‘How do you define
your mental health?’’ with possible options ‘‘very bad,’ ‘ bad,’
‘‘not well enough,’’ ‘‘good,’ or ‘‘excellent’ ) and on self-reported
symptoms (25 among the most experienced symptoms in HIV-
infected people taking HAART with possible options from
‘‘not at all’ to ‘‘very much’’). A symptom score was calculated
summing scores for any single symptom. Data on age, gender,
mode of HIV transmission, educational attainment, smoking,
drinking alcohol, coinfection with viral hepatitis, as well as
on therapy characteristics (type of drugs, number of doses,
number of previous antiretroviral schemes), most recent HIV-
RNA level, and most recent CD4 cell count were collected.
Bivariate analysis was performed to assess the correlation
between the adherence dimensions and outcome and to
identify other potential predictors (both subjective and ob-
jective) associated with asking to discontinue drugs. Back-
Smokers were defined those reporting to smoke any number
ward stepwise logistic regression analysis was used to assess
bDaily alcohol drinkers were defined those answering ‘‘yes, daily’’
the independent effects of the significant ( p < 0.1) explanatory
at the question: ‘‘How often do you drink alcohol?’
variables on the outcome. Odds ratios (OR) and 95% confi-
HAART, highly active antiretroviral therapy; SD, standard deviation;
Table 2. Correlation of Different Adherence Definitions and of Drug Discontinuations with HIV RNA
Adherence dimensions—Univariate OR (95%CI)
they reported optimal adherence. Seventy-three patients
people reported a repeated drug holiday (defined as stopping
(24.7%) reported that they had discontinued therapy for at
the regimen entirely for more than 48 hours),6 while in a Swiss
least 1 day without informing their physicians, either before
cohort in which a drug holiday was defined as missing all the
or after the fact, and 40% self-reported suboptimal adherence.
drugs for at least 24 hours, it was reported only in 5.8%.7
Only 49 patients of 133 (36.8%) who had asked their physician
The results of this study also suggest that these behaviors
to discontinue therapy in the 4 weeks before the survey also
are potential markers of suboptimal adherence. People who
reported having discontinued their current regimen. One
ask to discontinue therapy have a fourfold higher risk to miss
hundred seven patients (36.1%) reported that they usually
at least one dose in the previous week. We believe that in-
took their medications 2 hours before or after the prescribed
vestigating multiple aspects of adherence behavior, including
time. Sixty-three percent of people had HIV RNA less than 50
timing of therapy and willingness of discontinuation of drugs,
copies per milliliter and 11% between 50 and 500 copies per
may allow better identification of people who need a stronger
milliliter. Only 2.5% and 8.3% of enrolled people did not re-
or a more targeted support for maintaining an optimal ad-
port data on CD4 cell count or on HIV RNA, respectively. The
herence and to prevent future nonadherent behavior. For
risk of having an HIV RNA greater than 500 copies per mil-
example, due to the long half-life of NNRTIs (namely efavir-
liliter was higher for those reporting suboptimal adherence as
enz and nevirapine), discontinuing this class of drugs at the
well as for people asking to discontinue therapy or having
same time of NRTI may lead to a period of NNRTI mono-
discontinued therapy for at least 1 day (Table 2).
therapy with dangerous consequences on the selection of
Of note, nonadherence with the prescribed dosing time was
drug-resistant viruses. It is also possible that increasing and
more frequent for people who asked to discontinue drugs (OR
supporting an optimal adherence could prevent unplanned
4.62 [95% CI 2.77–7.68] compared to people who did not ask
and casual TI.8,9 Appropriate counseling on the consequences
to discontinue drugs) and for people who had discontinued
of drug discontinuation, especially when not physician-
drugs for at least 1 day (OR 3.56 [95% CI 2.06–6.16] compared
driven and lasting for several days, could be crucial to moti-
to people not having discontinued drugs). Asking to dis-
vate patients to adhere to therapy or even, if necessary, to
continue drugs was significantly correlated with reports of
educate the patient ‘‘to be nonadherent in a rational way.’’10
having missed at least one dose in the previous week (OR 3.99
We also found that people taking NNRTIs were signifi-
[95% CI 1.96–8.11] compared to people not asking to dis-
cantly less likely to have discontinued drugs. Possible expla-
nations of this result are (1) a selection bias (more adherent
In Table 3, bivariate and multivariable analyses of factors
people were prescribed NNRTI more frequently); (2) people
associated with asking to discontinue therapy or to having
taking NNRTI were more informed on the importance to
discontinued drugs are shown. People who asked to dis-
avoid an uncontrolled discontinuation of the drug due to the
continue drugs had higher CD4 cell counts, higher HIV RNA,
long half-life; (3) NNRTI-containing regimens are better tol-
and more symptoms, took more convenient regimens, and
erated11,12 leading to less treatment fatigue; (4) people taking
self-reported suboptimal adherence. People who reported
NNRTI may have previously expressed concerns with prior,
having discontinued drugs had higher HIV RNA, were more
more complicated regimens resulting in a higher satisfaction
likely to smoke, have suboptimal adherence, seek more in-
with therapy with the current regimen.
formation on HIV=AIDS, and were less likely to take non-
It has been demonstrated that drug-related symptoms are
nucleoside reverse transcriptase inhibitors (NNRTIs).
related both to a higher rate of discontinuations13,14 but also toa higher risk of suboptimal adherence.15,16 Treatment fatiguemay be an important reason for willingness to discontinue
HAART in people reporting higher symptom scores. At the
In the present study, nearly half of those surveyed reported
same time, people with better clinical status (higher CD4 cell
having asked their physician to interrupt HAART, and nearly
count) or on more convenient regimens (with few daily doses
one quarter had interrupted HAART for at least 1 day without
and pills) were paradoxically more likely to discontinue
informing their physician. Reports of one of these behaviors
drugs. This may be because patients who are perceived likely
was significantly associated with suboptimal adherence and
to have adherence problems may be prescribed simpler regi-
mens. It is also likely that people with more complex regimens
There have been few reports on patient treatment inter-
are those with less available therapeutic options and these
ruptions from traditional cohort studies of HIV-infected
individuals are more aware of the importance of maintaining
people taking HAART. In a French study, 27% of HIV-infected
the current regimen. Moreover, people on more convenient
regimens could underestimate the real complexity of the
5. Calmy A, Nguyen A, Montecucco F, et al. HIV activates
regimen they are taking and consequently believe that they
markers of cardiovascular risk in a randomized treatment
are taking a less aggressive regimen or that they need less
interruption trial: STACCATO [Abstract 10]. 15th Confer-
treatment. It would be important to investigate in further
ence on Retroviruses and Opportunistic Infections. Boston,
studies whether a simpler or simplified HAART regimen may
be associated with being healthier and hence make patients
6. Parienti JJ, Massari V, Descamps D, et al. Predictors of viro-
more prone to missing doses or discontinuing them.
logic failure and resistance in HIV-infected patients treated
There are several limitations to this study. First, the cross-
with nevirapine- or efavirenz-based antiretroviral therapy.
sectional design did not allow us to establish the direction of
Clin Infect Dis 2004;38:1311–1316.
relationships among the variables in the study. Second, all
7. Glass TR, De Geest S, Weber R, et al. Correlates of self-
reported nonadherence to antiretroviral therapy in HIV-
variables were self-reported by patients, including clinical
infected patients: The Swiss HIV Cohort Study. J Acquir
measures such as viroimmunologic parameters. This may
Immune Defic Syndr 2006;41:385–392.
increase the variability beyond that in which these data are
8. Sidat M, Fairley C, Grierson J. Experiences and percep-
measured objectively. However, it should be noted that the
tions of patients with 100% to highly active antiretroviral
rate of missing data was very low and the population char-
therapy: A qualitative study. AIDS Patient Care STDs 2007;
acteristics are similar to that of other cohorts of HIV-infected
people. It can be also argued that self-report overestimates
9. Oyugi JH, Byakika-Tusiime J, Ragland K, et al. Treatment
some outcomes such as adherence to therapy.10 A self-
interruptions predict resistance in HIV-positive individuals
reported web survey was chosen to avoid the bias of the
purchasing fixed-dose combination antiretroviral therapy in
presence of the physician in answering to the question on self-
Kampala, Uganda. AIDS 2007;21:965–971.
chosen TI and potentially reduce this overestimation, even
10. O’Connor P. Improving medication adherence. Arch Intern
though internet access may induce a bias in the sample.17
Third, some of the measures used in the present survey were
11. Chou R, Fu R, Huffman LH, Korthuis PT. Initial highly-
not previously validated. Fourth, genotypic data were not
active antiretroviral therapy with a protease inhibitor versus
available in the case of virologic failure. Longitudinal studies
a non-nucleoside reverse transcriptase inhibitor: Discrepan-
are warranted to confirm the present findings.
cies between direct and indirect meta-analyses. Lancet 2006;
In conclusion, the proportion of people asking for or un-
dergoing self-elected TI appears to be high. TI can be con-
12. Riddler SA, Haubrich R, DiRienzo G, et al. A prospective,
sidered a measure of suboptimal adherence. The willingness
randomized, phase III trial of NRTI-, PI-, and NNRTI-
and desire of PLWHA on HIV therapy to undergo drug holi-
sparing regimens for initial treatment of HIV-1 infection:
days due to treatment fatigue should be discussed in the
ACTG 5142 [Abstract THLB0204]. Program and abstracts ofthe XVI International AIDS Conference. Toronto, Canada:
context of the patient–physician relationship. Risks and un-
certainties of monitored TI strategies may be different ac-
13. O’Brien ME, Clark RA, Besch CL, Myers L, Kissinger P.
cording to clinical status and to type of therapy and should be
Patterns and correlates of discontinuation of the initial
balanced with a higher risk of patient unilateral and danger-
HAART regimen in an urban outpatient cohort. J Acquir
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Immune Defic Syndr 2003;34:407–414.
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14. d’Arminio Monforte A, Cozzi Lepri AC, Rezza G, et al. In-
interpret viroimmunologic results, prevent the appearance of
sights into the reasons for discontinuation of the first highly
drug resistance or progression of HIV disease and, ultimately,
active antiretroviral therapy (HAART) regimen in a cohort
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of antiretroviral naı¨ve patients. I.CO.N.A. Study Group. AIDS 2000;14:499–507.
15. Ammassari A, Murri R, Pezzotti P, et al. Self-reported
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No competing financial interests exist.
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16. Heath KV, Singer J, O’Shaughnessy MV, Montaner JS, Hogg
RS. Intentional nonadherence due to adverse symptoms as-
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Studia Medyczne Akademi wiêtokrzyskiejMa³gorzata Nowak, Adam Kabza, Stanis³aw G³uszekZak³ad Chirurgi i Pielêgniarstwa KlinicznegoWydzia³ Nauk o Zdrowiu Akademi wiêtokrzyskiej w KielcachDyrektor: prof. dr hab. n. med. S. G³uszekNiepubliczny Zak³ad Opieki Zdrowotnej w. Aleksandra w KielcachINTESTINAL OBSTRUCTION DUE TO A COLONIC LIPOMAT³uszczaki s¹ rzadkimi ³agodnymi guzami
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