Clinical and Economic Implications ofNon-Adherence to HAART in HIV InfectionAlissa Scalera,1,2,3 Ahmed M. Bayoumi,3,4,5 Paul Oh,6 Nancy Risebrough,6 Neil Shear2 and Alice Lin-in Tseng7,8

1 Neurobehavioral Research, Mental Health Service, St Michael’s Hospital, Toronto, Ontario, Canada2 Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada3 Inner City Health Research Unit, St. Michael’s Hospital, Toronto, Ontario, Canada4 Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada5 Ontario HIV Treatment Network, Toronto, Ontario, Canada6 HOPE Research Centre, Sunnybrook and Women’s College Health Science Center, Toronto, Ontario, Canada7 Immunodeficiency Clinic, Toronto General Hospital, Toronto, Ontario, Canada8 Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Abstract Highly active antiretroviral therapy (HAART) has dramatically altered the natural history of HIV disease.Studies demonstrate that ≥95% adherence is necessary to garner the full benefits of HAART. However, appro-priate adherence to treatment is difficult and challenging. This paper provides an overview of potential clinicaland economic outcomes associated with poor adherence to HAART. Since there are no studies exploring thecosts associated with poor adherence to HAART, we discuss potential direct and indirect costs accrued withmore frequent treatment failures, selection of resistant strains, increased hospitalizations and a faster progressionto AIDS associated with poor adherence to HAART. Additionally, we review studies of interventions andstrategies to improve adherence to HAART. Although, single-focus interventions have enhanced the chancesof achieving viral suppression by 10 to 23%, the literature has demonstrated that for long-term treat-ments, programs employing diverse interventions that continue over time are more effective. Under constrainedhealthcare budgets, government, healthcare managers and policy makers require accurate and timely informationconcerning the cost effectiveness of adherence intervention programs. We discuss considerations in determiningthe cost effectiveness of an adherence intervention program.

LEADING ARTICLE Dis Manage Health Outcomes 2002; 10 (2): 85-911173-8790/02/0002-0085/$25.00/0

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Current treatment guidelines recommend highly active anti-retroviral therapy (HAART) for HIV infection.[1] HAART regimens,composed of a combination of at least three antiretroviral agents,have significantly altered the progression of HIV disease.[2-4]

However, HAART regimens are complex and often have difficultscheduling, high pill burden, low therapeutic indices, numerousadverse effects, high acquisition costs and significant drug andfood interactions.[5] Although the introduction of newer drugs andimproved formulations of older drugs has overcome some of theseobstacles, non-adherence to HAART regimens remains a prob-lem.[1] In this article, we review the scope of non-adherence toHAART, discuss potential costs associated with non-adherence,examine strategies to improve adherence and discuss considera-tions in determining the cost effectiveness.

1. Non-Adherence to Highly Active AntiviralTherapy (HAART)

The term adherence is synonymous with compliance but gen-erally preferred by researchers and clinicians since it is interpre-ted to be non-judgmental and affirmative of the patient’sactive participation in choosing and maintaining a medicationregimen.[6,7] Adherence is defined as the taking of medicationin the manner prescribed. Imperfect adherence to prescribedmedications is a dynamic behavior that can take many differentforms.[8] For example, while some individuals may not have theirprescriptions filled or may have them filled but never take themedication, others take their medication infrequently, irregularly,intermittently or incorrectly. Taking non-prescribed ‘drug holi-

days’ or excess doses, not following dietary requirements or in-structions concerning concomitant medications and not complet-ing the therapeutic course are also common forms of non-adherence.

1.1 Frequency of Non-Adherence to HAART

In general, adherence rates observed in clinical practice varywidely and are generally lower than the observations in clinicaltrials.[8] Although, several observational studies[2,9-14] have inves-tigated the prevalence of non-adherence to HAART in HIV infec-tion, study designs and endpoints vary widely, making study com-parisons difficult to generalize. Specifically, studies use variousdefinitions and measurements of adherence. The following threestudies illustrate this point.[2] Adherence was monitored in a sub-set of patients for a period of 90 days using Medication EventManagement System (MEMS) in which a microchip in the cap ofa medication container recorded the date and time the cap wasremoved.[2] Using the definition of adherence as the proportionof prescribed doses taken yielded adherence rates of 82 to 88%.[2]

However, when adherence was defined as the proportion of pre-scribed doses taken correctly and at the prescribed frequency,the adherence rates dropped to 55 to 76%.[2] In a cross-sectionalstudy, the non-adherence rate to protease inhibitor-containing re-gimens was reported according to one or more criteria determinedby the investigators of the study.[10] Among the 140 participants,31% were classified non-adherent on the basis of one or more ofthe following: 14% had a drug plasma concentration below quan-tification limits; 18% claimed to have finished at least one courseof antiretrovirals before the visit; and 12% had forgotten to takeat least one antiretroviral dose the day before.[10] In another study,adherence to protease inhibitor-based combination therapy wasassessed by self-report and MEMS during a 3-month period.[9]

The mean dose percentage (defined as the percentage of prescribeddoses taken by the patient in the previous month) by self-reportversus MEMS was 97.5 vs 90.3% during month 1 of adherencemonitoring, 96.5 vs 90.1% during month 2, and 98.4 vs 92.8%during month 3.[9]

1.2 Factors Impacting Non-Adherence to HAART

An important question is whether people at high probabilityof poor adherence with HAART can be accurately identified. Al-though, the literature strongly and consistently demonstrates thatno single sociodemographic criteria can predict whether individ-uals are likely to be adherent to HAART, studies suggest thatseveral factors contribute to poor adherence.[8] In general, amongpatients who reported skipping doses the most commonly citedfactor is forgetfulness.[11,12,14-19] Other common reasons given bypatients for missing doses are summarized in table I.

1.3 Consequences of Non-Adherence to HAART

Adherence is an especially crucial issue in HIV therapeuticssince subtherapeutic antiretroviral concentrations may lead to in-creases in plasma HIV RNA levels, selection of resistant virusand subsequent increases in morbidity and mortality. In patientswith brief periods (defined as a period of three or more days) oftaking very little or none of the protease inhibitor saquinavir,plasma HIV RNA levels increased by 1 to 2 log10 copies/ml inclose proximity to the drug holiday.[20] However, shortly afterthese patients began taking their medication regularly again (about1 month), plasma viral load levels decreased promptly.[20]

Similarly, in a survey of HIV-infected patients at San FranciscoGeneral Hospital’s AIDS Clinic who were taking proteaseinhibitor-containing HAART regimens, adherence was associ-ated with achieving undetectable viremia (odds ratio = 4.7;95% confidence interval 1.1-20.6) after controlling for CD4+ cellcount prior to beginning treatment, type of protease inhibitor,and whether new or changed reverse transcriptase inhibitors werestarted with the regimen.[21] In the Italy, Netherlands, Canada, andAustralia Study (INCAS; a randomized double-blind, controlledtrial comparing combinations of zidovudine, nevirapine anddidanosine in antiretroviral-naïve patients), medication non-ad-herence was found to be an independent predictor of virologicfailure, defined as failing to achieve or maintain plasma HIVRNA levels less than 20 copies/ml.[22] After controlling for viralload nadir and treatment arm, non-adherence doubled the risk ofvirologic failure.[22]

Table I. Common reasons for non-adherence to antiretrovirals in HAARTregimens[12,15-19]

Reasons Prevalence (% of patients)

Forgot 34-66

Away from home 46-57

Busy with other things 7-53

Change in daily routine 45-51

Fell asleep 40

Problems taking medications at specifictimes

40

Felt sick or ill 13-28

Wanted to avoid adverse effects 9-27

Felt depressed/overwhelmed 18-27

Had too many pills to take 14-19

Treatment skepticism 14-18

Disease stigma 14-17

Lack of interest 4-19

Too drunk or high 5

HAART = highly active antiretroviral therapy.

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© Adis International Limited. All rights reserved. Dis Manage Health Outcomes 2002; 10 (2)

Two studies have demonstrated a positive correlation be-tween level of adherence and viral suppression.[23,24] In one study,self-reported adherence to antiretroviral therapy over 6 monthswas investigated in 112 patients.[23] A significant trend of im-proved HIV RNA level reduction across ordered categories ofincreasing adherence (<80, 80 to 95, 95 to 99, 100%) was ob-served (p = 0.009 for test for trend).[23] In a second study, adher-ence to the protease inhibitor component of a HAART regimenwas investigated using MEMS caps for a median period of 6months in 84 patients. The degree of adherence was significantlyassociated with the risk for virologic failure (>400 copies/ml; p< 0.001).[24] In both studies, among patients reporting less than80% adherence no antiviral effect or immune restoration was ob-served in a significant proportion of patients studied.[23,24] Thus,a very high level of adherence (>95%) to HAART is necessaryfor maximal virologic suppression and immune restoration.

The rapid turnover of HIV coupled with the high error rateof the HIV reverse transcriptase results in the generation of ge-netically distinct variants that evolve from the initial virus inoc-ulum.[25,26] Suboptimal drug levels due to inadequate adherenceor low bioavailability incompletely suppress HIV virus replica-tion, creating an evolutionary selective pressure that leads to re-placement of wild type virus by resistant virus.[25] Resistance toantiretroviral drugs is determined by mutations in the genes thatencode the protease and reverse transcriptase enzyme.[26] HIVvariants resistant to antiretroviral drugs have been detectedfor every agent introduced into clinical practice. For some anti-retrovirals, such as lamivudine, and non-nucleoside reverse trans-criptase inhibitors, such as nevirapine, a single mutation can re-sult in rapid development of resistance mutation.[25] For otherdrugs such as zidovudine and indinavir, high-level resistance re-quires the accumulation of 3 or more resistance mutations in asingle viral genome and emerges more slowly.[25] Combinationregimens capable of completely inhibiting HIV replicationcan delay or prevent the emergence of drug-resistant variants.[27]

Careful selection of antiretroviral agents in combination regimensminimizes the chances for emergence of drug resistance andis key to maximizing the clinical benefits of antiretroviral ther-apy.[27] Thus, strict adherence to all agents in the regimen is im-portant. Furthermore, it has been demonstrated that some mu-tations cause broad cross-resistance among antiretrovirals ofa given class. Cross-resistance is very common among non-nucleoside reverse transcriptase inhibitors and nucleoside reversetranscriptase inhibitors but is only seen among some proteaseinhibitors.[28] Accordingly, non-adherence may affect both the re-sponse to the current antiretroviral regimen and the efficacy offuture regimens. Viral resistance may limit treatment options foran individual since there may be only two or three possible se-

quential regimens for each patient.[7] Furthermore, as the num-ber of individuals in the population harboring drug resistanceincreases, the population-based risk for transmission of resistantHIV may rise. Transmission of drug-resistant variants has alreadybeen reported in several parts of the world.[29] In one study,16.8% of newly HIV-infected patients were harboring drug-resistant variants.[30]

Adherence to HAART has also been associated with improvedlong-term clinical outcomes. In a prospective cohort study, patientswith 95% or greater adherence had shorter hospitalizations thanthose with less than 95% adherence (2.6 vs 12.9 days per 1000days of follow-up; p = 0.001).[24] Furthermore, no opportunisticinfections or deaths occurred in patients with 95% or greater ad-herence.[24] In a recent study of a population-based cohort, ratesof progression to AIDS were 38, 8 and 0% among those with≤50%, 51 to 90% and >90% adherence, respectively.[31] Thus,these data support the concept that virologic and clinical out-comes are related to medication adherence.

Preliminary results have demonstrated that antiretroviral ad-herence and quality of life are significantly associated.[32] In 200patients followed-up for 12 months, both 7-day self-reportedadherence (100, 80 to 99, <80%) and quality of life as assessedby the Medical Outcomes Study 12-Item Short Form Health Sur-vey (SF-12) were measured at baseline, 1, 4, 8 and 12 months.[32]

Patients reporting 100% adherence had significantly higher SF-12 scores than patients reporting 80 to 99% and <80% adher-ence.[32] At 8 months all six SF-12 dimensions were positivelyassociated with adherence (p < 0.02); at 12 months, after adjust-ment for adherence, only general health rating and physical rat-ings of quality of life remained associated with adherence (p <0.01).[32] Thus, self-reported antiretroviral adherence and qualityof life are significantly associated, but their causal relationship isnot clear and further research is needed to elucidate the natureand direction of the relationship among these measures and itsbearing on therapeutic effectiveness.[32]

2. Cost

To date, no published study has reported the cost of non-adherence to HAART. Conceptually, the economic cost of non-adherence is the total value of all resources used or lost by indi-viduals, healthcare providers, or other segments of society as aresult of the behavior. Since the concept of adherence is elusive,the true cost may never be accurately determined. However, esti-mates can be obtained by identifying the different types of costsassociated with consequences of non-adherence to HAART.

Implications of Non-Adherence to HAART in HIV 87

© Adis International Limited. All rights reserved. Dis Manage Health Outcomes 2002; 10 (2)

2.1 Direct Cost

Direct costs are those fixed and variable costs associated di-rectly with a medical condition or healthcare intervention. Thedirect cost associated with consequences of non-adherence in-cludes the cost of additional laboratory tests, inpatient proceduresand services, outpatient consultations and medication. For exam-ple, the measurement of adherence may present an additional costsince there is conflicting evidence on which measure generatesthe best estimate of adherence (table II).[33-35] Since it is recom-mended that at least two different methods are used to measureadherence,[35] costs can range from zero to several hundred USdollars depending on the methods chosen, frequency of measure-ments and number of antiretrovirals in the regimen assessed. Sincenon-adherent patients are at risk of developing drug resis-tance, they are candidates for new expensive tests such as geno-type ($US500/test), phenotype ($US700 to $US900/test) or vir-tual phenotype ($US500/test) resistance testing (year of costing2000). In a recent study, Stansell[36] evaluated retrospective dataon 743 patients for the period 1996 through 1998 to determinethe incremental costs associated with therapeutic failure (definedas two successive viral loads >1000 copies/ml, at least 2 weeksapart). Therapeutic failure can result from lack of adherence,poor absorption, development of resistance and viral reservoirs.[37]

However, reasons for therapeutic failure in the study cohort werenot indicated in the abstract. Since the lack of adherence has beendemonstrated to be associated with therapeutic failure,[23,24] thisstudy is used to illustrate the additional direct costs that may be

associated with a consequence of non-adherence. The resourcecosts in the study included hospitalizations; pharmacy; labora-tory; skilled nursing facility care; home health; professional andinfusion care costs. The difference in hospital costs [$US123 perpatient per month (PPPM); 1998 US values] between patientswho never failed treatment and those who failed treatment oncewas significant (p < 0.05) as was the difference in the total costof care ($US228 PPPM; p = 0.05).[36] Furthermore, the differ-ence in hospital costs ($US87 PPPM) between patients who failedtreatment once and those who failed treatment more than oncewas also significant (p < 0.05) as were the differences in drugcosts ($US329 PPPM; p < 0.05) and the total cost of care ($US430PPPM; p = 0.014).[36] Thus, total cost of care is minimized by themaintenance of an undetectable viral load, and hospitalizationand medication account for the majority of direct cost increasesfor patients who failed initial HAART.[36]

2.2 Indirect Costs

The indirect costs associated with consequences of non-adherence would include loss of productivity, informal care andsupport services, disability benefits, the cost of impaired qualityof life and premature death costs. However, the inclusion of in-direct costs in economic evaluation depends on the viewpoint ofthe analysis. Since non-adherent patients experience greater mor-bidity and progress more quickly to death, these costs would in-crease with decreasing adherence to HAART. However, indirectcosts already represent an economic burden several times that of

Table II. Methods of measurement of adherence[9,33-35,38]

Method Advantages Disadvantages Cost

Questionnaire Simple Too subjective None

Inexpensive Overestimates adherence

Interview Simple Overestimates adherence Interviewer time

Pill Count Simple Affected by ‘pill dumping’ None

Inexpensive

Pharmacy refill Simple Cannot assess if medication ingested None

Inexpensive

Overestimates adherence

Plasma drug concentrations(protease inhibitors only)

Assesses if medication ingested Affected by pharmacokinetics $US50-$US100 per test

Patients may ‘load up’ on medications justbefore assessment

Expensive

Electronic monitors Identifies overall dosage frequency andadministration patterns from day to day

Cannot assess if medication ingested $US75-$US105a per drug

Expensive

Most reliable estimate of adherence

a An approximate cost of electronic monitors manufactured by Aprex, a division of AARDEX Corp., Union City, CA, USA.

88 Scalera et al.

© Adis International Limited. All rights reserved. Dis Manage Health Outcomes 2002; 10 (2)

direct treatment and care costs in HIV. For example, in a recentstudy, a societal perspective of patient-based annual indirect costsof HIV in England for 1997 to 1998 were estimated.[39] Excludingdisability payments and assuming 100% economic-productivityloss, patient-based annual indirect costs were $US6515 per

patient-year for asymptomatic individuals, $US12 302 forsymptomatic patients without AIDS, and $US25 269 for patientswith AIDS.[39] Thus, costs are lower if patients can be maintainedat the earlier stages of HIV infection for longer periods. For exam-ple, $US5787 and $US12 967 per patient-year could be saved foreach asymptomatic individual who remained asymptomatic for alonger period and for each individual in whom progressionto AIDS from symptomatic non-AIDS was forestalled, respec-tively.[39]

3. Interventions

Although several interventions to improve adherence toHAART are currently under study, few results are available. Onlytwo studies have been published in peer-reviewed literature. Inone study, a group receiving counseling intervention by a psy-chologist demonstrated significantly better viral load suppressionthan the group that did not receive counseling intervention.[40]

Counseling included information about therapy, an adapted med-ication schedule, and adherence problem-solving training. At week48, 94% of the intervention group was greater than 95% adher-ent compared with 69% of the control group (p = 0.008).[40] Fur-thermore, 88.9% of the intervention group, compared with 65.8%of controls, had viral loads less than 400 copies/ml at 48 weeks(p = 0.026). [40] The other study was published in Spanish buttranslated into English in a recent systematic review prepared bythe Cochrane Collaboration.[41,42] In the study, the efficacy of apharmacist-based intervention was investigated.[41] The interven-tion consisted of a meeting between the patient and pharmacistprior to treatment initiation. At the meeting, the pharmacist pro-vided information about the regimen, how to manage adverseeffects, and issues such as social support and substance abuse.Participants maintained contact with the study pharmacist by tele-phone or visit. At 6 months, a significantly higher proportion inthe intervention group was adherent compared with the controlgroup (76.7 vs 52.7%; p < 0.0005).[41,42] Adherence was definedas at least 90% adherence with the prescribed doses and more than90% adherence to the medication schedule in relation to mealswhile at the same time allowing no more than a once-daily mis-take in taking medication.[42] However, there was no significantassociation between the intervention and achieving an undetect-able viremia at 6 months.[41,42]

All other reports of HIV-specific trials examining potentialadherence-improving interventions have appeared at national andinternational meetings. Among those reported, one study investi-gated the efficacy of a reminder device to improve adherence in49 patients.[43] The reminder device consisted of a small portablealarm system that was customizable to each participant’s dosageadministration schedule. At 12 weeks, an 11% improvement inmean pill adherence was observed.[43] In another study, directlyobserved therapy (DOT), an intervention successful in tubercu-losis treatment, was proposed for improving adherence with sim-plified HAART regimens. Simplified HAART regimens arecomposed of antiretrovirals with longer half-lives, fewer pills andless frequent daily administration. For example, a simplified reg-imen may consist of twice-daily administration of five tabletsof nelfinavir and one tablet of the combined zidovudine and lami-vudine formulation. The pilot study of DOT among 32 poorlyadherent patients has provided favorable results.[44] In this study,outreach workers were employed to administer the morning doseof twice-daily regimens. At 6 months, missed doses in the pre-vious 4 days fell from 47 to 15% and plasma viral load fell anaverage 1.32 log.[44] Overall, these strategies have enhanced ad-herence to HAART by 11 to 32%.[44] Furthermore, the proportionachieving viral suppression in the intervention groups increasedby 10% (<50 copies/ml) to 23% (<400 copies/ml) comparedwith the usual care groups.[44] Although, the improvement is clin-ically significant, these interventions were investigated overa short timeframe and in small samples. The literature in otherchronic diseases has demonstrated that most successful interven-tions for long-term treatments are not only diverse but continueover time for their effect to be durable.[45] An intervention pro-gram employing several modalities addressing cognitive, behav-ioral, and affective components is more effective than single-focus interventions.[45]

4. Cost Effectiveness of Intervention

Studies are needed to determine and recommend to healthcaredecision makers the circumstances in which it is cost effective toimplement HAART adherence intervention programs. No currentestimates of the cost or potential savings of an intervention pro-gram to improve treatment adherence to HAART have beenpublished. For example, if programs costing between $US10 and$US3000 per patient per year (PPPY) [year of costing 2001]can increase the proportion achieving viral suppression (<50 cop-ies/ml) by 2 to 20%, then the cost per additional patient with viralsuppression decreases as the cost of the program decreases andthe proportion achieving viral suppression increases (figure 1).However, determining the ‘cost-effectiveness’ or ‘efficiency’ of

Implications of Non-Adherence to HAART in HIV 89

© Adis International Limited. All rights reserved. Dis Manage Health Outcomes 2002; 10 (2)

a program is not this simple. Efficiency or cost effectiveness canbe defined as achieving the maximal health benefit for a fixedamount of resources.[46] Thus, a cost effectiveness analysis of anadherence intervention program involves estimating the incre-mental cost-effectiveness ratio, that is the additional costs thatone program imposes over standard care or another program com-pared with the additional effects it delivers.[47]

There are several considerations in undertaking a cost-effectiveness analysis of an adherence intervention program. Forexample, when will the program(s) be offered in the time courseof the regimen sequence (i.e. at the start of any HAART regimen,once non-adherence is determined or after a therapeutic failure)?To whom will the program(s) be offered (i.e. universal or targetedpopulation)? Where will the program be offered (i.e. outpatienthospital clinic or community center)? What will be the durationof the program(s) [i.e. 6 months or lifetime]? Furthermore, thecosts are not limited to the costs of the program(s) but include allcosts related to the program(s) and primarily depend on the per-spective of the analysis.[47] For example, direct costs of a pro-gram may include the cost of medications, laboratory tests,outpatient or inpatient consultations and HIV-related hospitaliza-tions whereas indirect costs may include loss of productivity,transportation and other non-medical costs. Since the economicevaluation assumes effectiveness, some indication of prior vali-dation of effectiveness or efficacy of the program(s) to be evalu-ated should be available.[47] The measure of effectiveness maydepend on the available information, clinical significance, reli-ability or validity of measurement and perspective or time hori-zon of the analysis. For example, effectiveness measures foradherence programs may include: achieving 95% or greater ad-herence, attaining an undetectable viral load or improved qualityof life. Thus, cost-effectiveness analyses can guide clinical prac-

tice not only in the selection of the intervention to be usedbut also in targeting populations for whom health benefits areparticularly large.

5. Conclusion

Strict adherence to HAART is necessary to attain the clinicalbenefits observed in clinical trials of HAART regimens. Adher-ence to HAART is influenced by pharmacological, behav-ioral, environmental and demographic factors. Consequently, aHAART adherence intervention program should contain a varietyof options and application of strategies must be individualized.For example, DOT may be feasible in prisons, at needle-exchangesites and in drug treatment programs such as methadone main-tenance programs while psychotherapy may be appropriate forthose with mental illnesses. However, before providing recom-mendations to government, healthcare managers and policy mak-ers, studies examining the clinical and economic consequences ofprograms with multifaceted interventions to improve adherenceto HAART are necessary.

Acknowledgements

The authors have stated that there was no conflict of interest related to thecontents of this paper and there was no funding to assist with the preparationof this study.

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0

20 000

40 000

60 000

80 000

100 000

120 000

140 000

160 000

0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 0.18 0.20

Effectiveness of programs

Cos

t per

add

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al p

atie

nt a

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($U

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Fig. 1. Cost effectiveness of highly active antiretroviral therapy (HAART) adherence intervention programs. Units are cost per additional patient acheiving viralsuppression per year.

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About the Author: Alissa Scalera is currently completing her PhD in theDepartment of Pharmacology at the University of Toronto, Ontario, Canada.Her areas of research include adherence and health-realted quality of lifeissues pertaining to antiretroviral therapy in HIV infection.Correspondence and offprints: Alissa Scalera, Neurobehavioral Research,Mental Health Service, St Michael’s Hospital, 30 Bond St, Shuter Wing, 2ndFloor Room 2050, Toronto, Ontario, Canada, M5B 1W81.E-mail: alissa.scalera@utoronto.ca

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