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A scoping study to identify opportunities to advance the ethical implementation and scale-up of HIV treatment… Knight, Rod; Small, Will; Pakula, Basia; Thomson, Kimberly; Shoveller, Jean Jul 3, 2014

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RESEARCH ARTICLE Open AccessA scoping study to identify opportunities toadvance the ethical implementation and scale-upof HIV treatment as prevention: priorities forTasP within the continuum of HIV care models. Based on the results of this scoping review, we identify several ethicalKnight et al. BMC Medical Ethics 2014, 15:54http://www.biomedcentral.com/1472-6939/15/54Vancouver, CanadaFull list of author information is available at the end of the articleand implementation dimensions that hold promise for informing the process of scaling up TasP and that could benefitfrom new research.* Correspondence: rod.knight@ubc.ca1Interdisciplinary Studies Graduate Program, University of British Columbia,Conclusion: Ongoing research and normative deliberationempirical researchRod Knight1*, Will Small2, Basia Pakula3, Kimberly Thomson3 and Jean Shoveller3AbstractBackground: Despite the evidence showing the promise of HIV treatment as prevention (TasP) in reducing HIVincidence, a variety of ethical questions surrounding the implementation and “scaling up” of TasP have beenarticulated by a variety of stakeholders including scientists, community activists and government officials. Given thehigh profile and potential promise of TasP in combatting the global HIV epidemic, an explicit and transparentresearch priority-setting process is critical to inform ongoing ethical discussions pertaining to TasP.Methods: We drew on the Arksey and O’Malley framework for conducting scoping review studies as well assystematic approaches to identifying empirical and theoretical gaps within ethical discussions pertaining topopulation-level intervention implementation and scale up. We searched the health science database PubMed toidentify relevant peer-reviewed articles on ethical and implementation issues pertaining to TasP. We included Englishlanguage articles that were published after 2009 (i.e., after the emergence of causal evidence within this field) by usingsearch terms related to TasP. Given the tendency for much of the criticism and support of TasP to occur outside thepeer-reviewed literature, we also included grey literature in order to provide a more exhaustive representation ofhow the ethical discussions pertaining to TasP have and are currently taking place. To identify the grey literature, wesystematically searched a set of search engines, databases, and related webpages for keywords pertaining to TasP.Results: Three dominant themes emerged in our analysis with respect to the ethical questions pertaining to TasPimplementation and scale-up: (a) balancing individual- and population-level interests; (b) power relations withinclinical practice and competing resource demands within health care systems; (c) effectiveness considerations andsocio-structural contexts of HIV treatment experiences within broader implementation contexts.is required in order to successfully and ethically scale-up© 2014 Knight et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.Knight et al. BMC Medical Ethics 2014, 15:54 Page 2 of 13http://www.biomedcentral.com/1472-6939/15/54BackgroundThe role of antiretroviral therapy (ART) in preventingthe onward spread of HIV is now widely accepted as acrucial component within comprehensive HIV preven-tion efforts [1] based on a variety of empirical findings,including those stemming from mathematical modeling[2], population-level surveillance studies [3,4] and clin-ical trials [5]. Thus, ‘treatment as prevention’ (TasP) hasbeen positioned as a ‘double-hat trick’ [6] based on ART’srole in preventing disease progression among HIV-positive individuals, as well as population-level benefits ofdecreasing community-level viral loads and the likelihoodof onward transmission to uninfected partners [3,7]. Des-pite the evidence showing the promise of TasP in reducingHIV incidence, scientists, community activists and gov-ernment officials have raised ethical questions regardingthe implementation and scaling-up of TasP. To date, how-ever, the scope of these discussions in the literature hasremained largely unexamined [8], with the exception of arecent systematic review of a particular set of ethical is-sues associated with clinical and health service challengesrelated to the HIV “test and treat” strategies [9].Given the high profile and potential promise of TasP incombatting the global HIV epidemic, an explicit and trans-parent research priority-setting process is critical to mean-ingfully inform ongoing ethical discussions pertaining toTasP. This strategy requires a comprehensive and system-atic synthesis of the key ethical issues and concerns relatedto the implementation and scaling up TasP as expressed byboth scientists and community stakeholders. For example,within the TasP approach, clinical treatment guidelineswithin many settings now recommend ART for all individ-uals living with HIV, regardless of their individual CD4count or based on an expanded set of parametersa. Thisraises questions about the kinds of efforts that will be re-quired within these large-scale programs to identify andengage HIV positive individuals into long-term care andtreatment. As a result, questions related to an individual’sautonomy and the potential for coercive seeking and test-ing strategies during implementation warrant examination[9]. Moreover, there has been increasing concern thatthese efforts are being advanced for the benefit of futurepopulations, rather than for the benefit of individuals whoare currently HIV seropositive [9]. Despite criticisms thatthere is insufficient existing scientific evidence to substan-tiate the trend towards ‘early’ initiation of ART based onindividual-level benefits and/or burdens, recent evidencefrom an ongoing clinical trial (HPTN 052) points to a setof individual-level benefits to early uptake of ART, such asdelayed time to onset of AIDS and decreased incidence ofprimary and secondary infections [10]. Nonetheless, thereare increasing calls for more evidence in order to betterunderstand these and other issues pertaining to the ethicalimplementation and scale up of TasP, as well as the broadersocial and structural forces that shape individual experi-ences of TasP [11].In this paper, we draw on concepts and approachesfrom the field of population and public health ethics tocritically interrogate TasP approaches in order to morefully consider and negotiate a balance of individual andcollective interests and health outcomes [12]. Our aim isto provide strategic direction in this field by systematic-ally identifying and highlighting key ethical questionspertaining to implementation and scale-up of TasP thatwill benefit from new empirical research and theoreticaladvances.MethodsSearch strategy and resultsWe drew on the Arksey and O’Malley framework forconducting scoping review studies [13,14] as well as sys-tematic approaches to identifying empirical and theoreticalgaps within ethical discussions pertaining to population-level intervention implementation and scale up [15]. Wesearched the health science database PubMed to identifyrelevant peer-reviewed articles on ethical and implementa-tion issues pertaining to TasP. We included English lan-guage articles that were published after 2009 (i.e., after theemergence of causal evidence within this field) by using thefollowing search terms: HIV, HIV infections, treatment asprevention, TasP, HIV prevention, and ethics. We includedreview articles, and used citation tracking to identify otherrelevant sources. We included only articles that included adiscussion of the ethical issues pertaining to the implemen-tation and/or scaling up of TasP. Articles that only dis-cussed issues pertaining to TasP research (e.g., ethical issuesthat arise in randomized controlled trials) were excluded,as well as articles that focused exclusively on other HIVprophylaxis regimes (e.g., PreP). Empirical studies that didnot engage with implementation/scale up or ethical issueswere excluded.Searches yielded 374 results in PubMed. We reviewedall abstracts for content, removed duplicates, and in-cluded those articles related to the ethical and imple-mentation issues related to TasP, resulting in a total of19 articles. We also hand searched the references of rele-vant articles and special journal issues within this field,and co-authors searched their own library archives,resulting in additional articles, for a total of 8 peer-reviewed articles. Finally, one article was added via cit-ation chasing and one from the library of a reviewer,resulting in a total of 29 articles.Given the tendency for the exclusion of grey literaturewithin systematic reviews [16], as well as the indicationthat much of the criticism of TasP occurs outside thepeer-reviewed literature (e.g., selection bias), we decidedthe inclusion of grey literature would provide a more ex-haustive representation of how the ethical discussionsKnight et al. BMC Medical Ethics 2014, 15:54 Page 3 of 13http://www.biomedcentral.com/1472-6939/15/54pertaining to TasP have and are currently taking place. Inorder to identify relevant grey literature, we used methodsoutlined by the The Centre for Reviews and Dissemination[17]. This included searching various search engines(e.g., google), databases (e.g., CATIE), and webpages(e.g., World Health Organization’s webpage), for the abovelisted keywords. This search yielded 26 results (12 onlinearticles, 6 reports, 5 position statements, and 3 powerpoint presentations). Including only those sources thatexplicitly discussed the ethical and implementation issuesof TasP resulted in a final list of 11 online articles, 3 re-ports, 3 position papers, and 2 power point presentations.Data extraction and analysisCo-authors BP and RK screened the search results foreligibility. Data containing ethical discussions of TasPadvanced within the peer-reviewed and grey literaturewere extracted and managed in Microsoft Excel. Tables 1and 2 list the peer-reviewed articles and the grey litera-ture (respectively) included in our scoping review. Dur-ing data extraction and analysis, we focused onidentifying excerpts from the included documents thatpertain to one or more of the following three questions:(1) What are the dominant moral concerns associatedwith the scaling up and implementation of TasP?; (2)What are the empirical and/or theoretical gaps that areeither implicitly or explicitly revealed within these discus-sions?; and (3) To what extent is evidence characterizedor used to morally justify or prohibit various public healthpractices pertaining to TasP, and where might additionalresearch and evidence yield benefits in moving these dis-cussions towards theoretical or dialogical consensus?Using these questions as a rubric, we were guided byboth deductive and inductive approaches as we employedtechniques from thematic analysis to identify patterns andthemes within the literature [18]. The co-authors adoptedan iterative process throughout the analysis, so that earlydata analysis informed our subsequent decisions aboutinterpreting the materials. Together, we developed inter-pretations about recurring, converging and contradictorythemes within the data. As the analysis progressed, wecompared and contrasted the emergent themes and identi-fied the various rhetorical techniques that were employed.Key concepts within each theme, along with examplesfrom the literature, are presented below.ResultsOur search resulted in 29 peer-reviewed articles and 19grey literature sources that were included in data extrac-tion and literature mapping. Figure 1 presents a modifiedversion of the PRISMA-style flow diagram to reflect ourinclusions/exclusion processb. Three dominant themesemerged in our analysis with respect to the ethical ques-tions pertaining to TasP implementation and scale-up: (a)balancing individual- and population-level interests; (b)power relations within clinical practice and competingresource demands within health care systems; (c) effec -tiveness considerations and socio-structural contexts ofHIV-related experiences within broader implementationcontexts.Balancing individual- and population-level interestsThe ethical implications of initiating individuals on ARTregardless of their CD4 count emerged as the most salientand contentious question related to the ethical implemen-tation of TasP [9]. This debate centers on whether or notit is ethically justifiable to initiate an intervention (ART)focused on an individual to derive public health benefits,rather than for the benefit of the individual. Individualisticframeworks, communitarian and utilitarian frameworksare used to advance arguments in this debate.Individualistic (e.g., social libertarian) frameworks tendto prioritize individual autonomy against a set of com-munitarian frameworks that emphasize the interests ofthe broader population [19]. Applications of individualis-tic frameworks suggest that scaling up TasP programswill result in overly coercive testing and treatment re-gimes that disregard voluntary consent and participation.Within these arguments, it is suggested that TasP repre-sents an intervention on individuals that burdens indi-viduals in order to promote public health [9], therebyviolating principles of beneficence, non-maleficence andautonomy – hallmarks of applied medical ethics [20].For example, the early initiation of ART is largely posi-tioned as a negative option for the individual due to thepotential for various side effects, including altered lipids,reduced bone density and kidney damage [21] as well asthe potential for increased antiretroviral resistance [21].Thus, these arguments suggest that an individual’schoice not to commence treatment confers an individualbenefit that outweighs concerns for public beneficence[21]. Additional arguments that suggest individual au-tonomy trumps overall beneficence rest on the notionthat the long-terms effects of ART adherence are not yetfully known. For example, some have suggested thatTasP burdens individuals with chronic disease manage-ment at an early stage of their disease progression,thereby altering their capacity for economic productivityas well as their overall quality of life [22].Questions about the ethics of early initiation of ARThave also been closely embedded in matters of agency. Ifthe individual freely chooses to initiate TasP (e.g., theyhave a sufficient level of autonomy, the process remainsvoluntary, and they are equipped with sufficient infor-mation to make an informed choice), then TasP meetsthe ethical criteria set out within applied medical ethics –regardless of the potential for individual or population-level harms/benefits [8,21]. However, the positioning ofTable 1 Peer-reviewed publications included in the scoping studyPrimary authors Ethical issuesemphasizedSetting Method*Bärnighausen T, Salomon JA, Sangrujee N: HIV Treatment as Prevention: Issues in EconomicEvaluation. PLoS Med 2012, 9:e1001263.A, B, C Worldwide CommentaryBärnighausen T, Tanser F, Dabis F, Newell M-L: Interventions to improve the performance ofHIV health systems for treatment-as-prevention in sub-Saharan Africa. CurrentOpinion in HIV and AIDS 2012, 7: 140–150.C Sub-SaharanAfricaRapid ReviewBarr D, Amon JJ, Clayton M: Articulating a rights-based approach to HIV treatment andprevention interventions. Current HIV research 2011, 9: 396–404.A, B Worldwide CommentaryChan R: Biomedical Strategies for Human Immunodeficiency Virus (HIV) Prevention? ANew Paradigm. Ann Acad Med Singapore 2012, 41: 595–601.A, B, C Worldwide ReviewChang LW, Serwadda D, Quinn TC, Wawer MJ: Combination implementation for HIV prevention:moving from clinical trial evidence to population-level effects. Lancet Infect Dis 2013, 13:65–76.C Sub-SaharanAfricaReviewChen Y: Treatment-Related Optimistic Beliefs and Risk of HIV Transmission: A Review ofRecent Findings (2009–2012) in an Era of Treatment as Prevention. Curr HIV/AIDS Rep 2012,10: 79–88.C Worldwide ReviewCohen T, Corbett EL: Test and treat in HIV: success could depend on rapid detection.The Lancet 2011, 378: 204–206.A, B, C Sub-SaharanAfricaCommentaryDawson L: The Devil in the Details: Thorough Assessment of Evidence and Ethics IsNeeded in Evaluating New HIV Prevention Methods. Am J Bioethics 2012, 12: 33–34.A, C Worldwide CommentaryDennin RH, Lafrenz M, Sinn A, Li L: Dilemma of concepts and strategies for the preventionof spread of HIV in relation to human behavior, law and human rights. J Zhejiang U 2011,12: 591–610.A Worldwide CommentaryForsyth AD, Valdiserri RO: Reaping the prevention benefits of highly active antiretroviraltreatment. Current Opinion in HIV and AIDS 2012, 7: 111–116.A, B, C Worldwide CommentaryGarnett GP, Baggaley RF: Treating our way out of the HIV pandemic: could we, would we,should we? The Lancet 2009, 373: 9–11.A, C Worldwide CommentaryGupta RK, Wainberg MA, Brun-Vezinet F, Gatell JM, Albert J, Sonnerborg A, Nachega JB: OralAntiretroviral Drugs as Public Health Tools for HIV Prevention: Global Implications forAdherence, Drug Resistance, and the Success of HIV Treatment Programs. J Infect Dis 2013,207: S101–S106.C International CommentaryHaire BG: Because we can: clashes of perspective over researcher obligation in the failed PrEP trials.Dev world bioethics 2011, 11: 63–74.A, B, C Worldwide CommentaryHaire BG, Kaldor J, Jordens CFC: How good is “good enough”? The case for varying standards ofevidence according to need for new interventions in HIV prevention. Am J Bioethics 2012, 12: 21–30.A, B, C Worldwide CommentaryKrellenstein J, Strub, S: The ethical implications of “treatment as prevention” in the United States.2012, 16:1–4.A, C UnitedStatesCommentaryKulkarni SP, Shah KR, Sarma KV, Mahajan AP: Clinical Uncertainties, Health Service Challenges,and Ethical Complexities of HIV “Test-and-Treat”: A Systematic Review. Am J Public Health 2013,103: e14–e23.A, B, C Worldwide SystematicReviewMacklin R, Cowan E: Given financial constraints, it would be unethical to divert antiretroviral drugsfrom treatment to prevention. Health Aff 2012, 31:1537–1544.A, B UnitedStatesCommentaryMcNairy ML, Cohen M, El-Sadr WM: Antiretroviral Therapy for Prevention Is a Combination Strategy.Curr HIV/AIDS Rep 2013, 10: 152–8.B, C Worldwide CommentaryMcNairy ML, Howard AA, El-Sadr WM: Antiretroviral Therapy for Prevention of HIV and Tuberculosis:A Promising Intervention but Not a Panacea. JAIDS 2013, 63: S200–7.B, C Worldwide CommentaryMayer KH: Antiretrovirals for HIV prevention: translating promise into praxis. The Lancet 2011,378:206–208.B, C Sub-SaharanAfricaCommentaryMontaner JS: Treatment as prevention: a double hat-trick. The Lancet 2011, 378:208–209. C Canada CommentaryNguyen V-K, Bajos N, Dubois-Arber F, O’Malley J, Pirkle CM: Remedicalizing an epidemic: from HIVtreatment as prevention to HIV treatment is prevention. AIDS 2011, 25:291–293.A, C Worldwide CommentaryOstmann F, Saenz C: Separate Goals, Converging Priorities: On the Ethics of Treatment asPrevention. Developing World Bioethics 2013, 13:57–62.A, B Worldwide CommentarySingh JA: Antiretroviral resource allocation for HIV prevention. AIDS 2013, 27:863–865. B, C Worldwide CommentarySmall W, Kerr T: HIV Treatment as Prevention and the Role of Applied Social Science Research.Journal of AIDS & Clinical Research 2013, 02:102e.B, C Worldwide CommentaryKnight et al. BMC Medical Ethics 2014, 15:54 Page 4 of 13http://www.biomedcentral.com/1472-6939/15/54Table 1 Peer-reviewed publications included in the scoping study (Continued)Cates W: HPTN 052 and the future of HIV treatment and prevention. The Lancet 2011, 378: 224–5. A, B, C Worldwide CorrespondenceLancet Infectious Diseases: Editorial: Treatment as prevention for HIV. The Lancet InfectDis 2011, 11:651.B, C Worldwide CommentaryVonn M: British Columbia’s ‘seek and treat’ strategy: a cautionary tale on privacy rightsand informed consent for HIV testing. HIV/AIDS Policy & Law Review 2012, 16:1–4.A, C Canada CommentaryWilliams B, Wood R, Dukay V, Delva W, Ginsburg D, Hargrove J, Stander M, Sheneberger R,Montaner J, Welte A: Treatment as prevention: preparing the way. JIAS 2011, 14:S6.A, B, C Worldwide Commentary*Only articles that included methods were considered reviews. Articles without methods were considered commentaries.A = Balancing individual- and population-level interests.B = Power relations within clinical practice and competing resource demands within health care systems.C = Effectiveness considerations and socio-structural contexts of HIV-related experience.Table 2 Grey literature reviewed in the scoping study, including the source and titleYear Title DocumenttypeSourceorganizationEthical issuesemphasizedSetting2013 Mapping pathways: Developing evidence-based, people-centred strategiesfor the use of antiretrovirals as preventionReport Rand Website C Worldwide2012 Treatment as Prevention: recognising the creative potential of antiretroviralmedicationsOnlinearticleHIV, Science, andthe SocialA, B Worldwide2013 Reactions to the test-and-treat models OnlinearticleNAM AIDS MAP A, C Worldwide2012 Emerging Issues in Today’s HIV Response: Debate 6 Treatment as Prevention Report AIDSTAR-One B, C Worldwide2013 The Human Rights Issue OnlinearticleNAM AIDS MAP A, B Worldwide2010 Treatment as Prevention: Protecting Individual Autonomy Onlinearticleaidsperspective.net A, B Worldwide2009 Ethics of ART for HIV Prevention as a Public Health Intervention Presentation WHO A, B, C Worldwide2009 Consultation on Antiretroviral Treatment for Prevention of HIV Transmission:Meeting ReportReport WHO B, C Worldwide2013 Changing my mind on treatment as prevention OnlinearticlePositive Lite A, C Worldwide2010 Prominent Parisian Activist Weighs in on Treatment as Prevention OnlinearticlePOZ Blogs A Worldwide2010 Views from the front lines: Treatment as Prevention OnlinearticleCATIE B, C Canada2013 Treatment as prevention: Bob Leahy in conversation with James Wilton OnlinearticleCATIE A, C Canada2012 Treatment benefits for all? OnlinearticleCATIE A, B Canada2009 Antriretroviral treatment for prevention PositionstatementUN AIDS A Worldwide2012 Controlling the HIV Pandemic with Antiretrovirals: Treatment as Preventionand Pre-Exposure Prophylaxis - Consensus StatementPositionstatementIAPAC A, B, C Worldwide2013 The use of antiretroviral therapy to reduce HIV transmission PositionstatementBHIVA, EAGA C Worldwide2010 Biomedical Prevention Is Always About Social Justice, Too OnlinearticleHIV ResearchCatalyst ForumA Worldwide2010 USPHS guidelines: We need reliable evidence to justify an earlier start ofanti-retroviral therapyOnlinearticleaidsperspective.net C Worldwide2011 Are people living with HIV less likely to pass HIV to others if they are ontreatment? Exploring the use of treatment as preventionPresentation CATIE A WorldwideA = Balancing individual- and population-level interests.B = Power relations within clinical practice and competing resource demands within health care systems.C = Effectiveness considerations and socio-structural contexts of HIV-related experience.Knight et al. BMC Medical Ethics 2014, 15:54 Page 5 of 13http://www.biomedcentral.com/1472-6939/15/54Knight et al. BMC Medical Ethics 2014, 15:54 Page 6 of 13http://www.biomedcentral.com/1472-6939/15/54agentic choice as devoid of contextual and structural fac-tors has also been problematized. These arguments revealthe dependence of truly free choice on a variety of condi-tions, including whether or not a person will have the cap-acity to adhere, whether or not there will be a consistentand ‘never-ending’ supply of ART available [23], and if anindividual will have the opportunity to start ART at a laterdate if they choose to decline early initiation [19]. Fi-nally, the potential for the stigmatization of individualsor groups who choose not to seek early treatment wasalso described as an important ethical consideration re-garding the successful scaling up of TasP [24,25].Communitarian and utilitarian framings, on the otherhand, offer a view that more strongly features the potentialfor TasP to prevent future cases as a primary consider-ation, counter-positioning previous HIV prevention ap-proaches as ‘status quo’ and insufficiently equipped todecrease the spread of HIV [26]. These ‘greater good’perspectives are often buttressed in the literature byFigure 1 Flow-chart of articles included and excluded.arguments that turn on the extent to which the individ-ual who uptakes ART could benefit (or at least not suf-fer) as the short-term effects of the early initiation ofART have not been demonstrated to be physically detri-mental [27]. The view that populations and individualsmay concomitantly benefit from beginning ART withCD4 counts above the previously defined thresholds fortreatment has also been extended to the psychologicalrealm (e.g., feeling relief in knowing one is less infectiousand therefore less likely to transmit HIV to partners) [21]as well as other potential physiological benefits [27]. Whiledetailed discussions regarding some of the mainstays ofpopulation and public health ethics (e.g., relational frame-works that emphasize notions of ‘the greater good’) didnot feature as strongly in the literature captured in thecurrent review, some authors did apply key principles,such as solidarity, stewardship and compassion, and arguethat these principles ought to be considered in terms oftheir relevance to population and public health ethics –Knight et al. BMC Medical Ethics 2014, 15:54 Page 7 of 13http://www.biomedcentral.com/1472-6939/15/54particularly with regard to concerns pertaining to themost vulnerable population sub-groups [28]. Some argu-ments appear to minimize the potential risks for individ-uals in the face of potentially large population-level gains.For example, it has been suggested that the addition oftwo to three years of treatment (e.g., before the immunesystem becomes compromised) could be considered as in-significant in the face of what could be decades of futuretreatment [27].Power relations within clinical practice and competingresource demands within health care systemsThe second dominant theme that emerged in the ana-lysis related to power relations within patient-physicianinteractions and health care systems more broadly [9].For example, some authors have suggested that withoutunequivocal evidence pertaining to the early uptake ofART, doctors will still be faced with the challenge ofproviding advice to their patients on courses of action ina context of uncertainty [29]. Particularly in situationswhere the evidence is either contradictory or unavailable(e.g., issues pertaining to the individual-level benefits ofearly uptake of ART), the ethical and effective negoti-ation of power relations inherent in patient-physician in-teractions will require a relatively high degree ofsophistication from both parties [25,30]. Thus, the import-ance of training of health care practitioners to compe-tently relay evidence about the potential risks of earlyuptake of ART was also identified as an important compo-nent to ensure individuals can make informed decisions.However, inherent difficulties within the doctor-patient re-lationship regarding comprehension and translation ofrisk information were acknowledged (particularly in lightof limited or conflicting evidence in this area) [31].Questions also have been raised in the literaturearound the prioritization and distribution of limited re-sources. Indeed, in the context of scarce resources, is-sues related to TasP have led some to question theextent to which efforts should be focused on treatmentversus prevention [32]. For example, some authors havesuggested that, given a limited set of resources in HIVtreatment and prevention programs, it is inequitable todivert resources from treatment to prevention [33] –particularly in relation to taking ARV treatment re-sources away from resource-poor settings in order toadvance prevention efforts within high-resource or low-prevalence settings [34,35]. Still others argued that thevery nature of TasP should be seen as paradigm-shiftingand that the goals of treatment and prevention areconverging rather than conflicting [32]. Moreover, theunknown issues pertaining to the long-term preventativeeffects of TasP have been said to be so significantthat predicting the associated costs and benefits isnot yet possible [22]. Ultimately, the treatment versusprevention debates tend to flow from utilitarian frame-works which argue for the prevention of the greatestnumber of deaths versus deontological frameworks whichargue for ethical rules (e.g., the rule/duty of rescue) andprioritarian principles (e.g., arguing that those who arecurrently sick are worse off than those who will becomesick but are currently healthy) [28,33].Issues related to the scarcity of HIV prevention andhealth promotion resources have also led to a set of ar-guments around targeting efforts at specific populationsub-groups considered most at-risk for transmitting HIVfor cost-specific reasons [36], though many acknowledgethe ethical complexities associated with deciding how ef-forts ought to be prioritized during implementation[37,38]. For example, the literature generally acknowl-edges that population sub-groups that already face thehighest levels of stigmatization (e.g., people who injectdrugs) are likely the most at risk for HIV acquisition andtransmission [39]. This presents a challenge regardingthe population-level effectiveness of TasP, as stigma alsodeters people from accessing regular testing, therebydelaying the onset of diagnosis and treatment, andundermining the potential for reduced transmission [40].As a result, some have called for more research on theefficacy of TasP in marginalized sub-groups in order toinform ways to ethically reach people at the earlieststages of infection (i.e., during the first 6 months) whentheir viral loads may be highest [36,40].Others have suggested that explicit criteria be used inorder to determine who should be prioritized to receivetreatment. In general, children and monogamous sexpartners (those least likely to transmit the virus) arecharacterized as low priority groups for TasP, whereasthose who are the most likely to spread HIV should behigh priority (e.g., men who have sex with men in high-risk settings; people who inject drugs; migrant workerswith multiple concurrent partners) [39]. These argu-ments are premised on the assumption that treatment isa finite resource and offering treatment to somebodywho is not sick (e.g., individuals with a CD4 count wellabove 350 and not showing symptoms of HIV infection)may deprive a sick person (e.g., an individual with aCD4 count well below 200 and experiencing HIV-relatedsymptoms) of treatment. As a result, the principle ofproviding treatment to those individuals who will benefitthe most comes into conflict with principles related tohealth maximization in which the HIV negative partnerin a sero-discordant relationship will benefit [34].TasP is most widely referred to as one strategy withina set of HIV prevention programs, often referred to as acontinuum, cascade or combination prevention strategy[1,33,36,40,41]. In addition to TasP, other HIV interventionstrategies within health care systems include voluntarymedical male circumcision, campaigns to increase HIVKnight et al. BMC Medical Ethics 2014, 15:54 Page 8 of 13http://www.biomedcentral.com/1472-6939/15/54testing rates, condom availability and (in some settings)pre- and post-exposure prophylaxis (i.e., PEP and PreP)[38,40-42]. As a result, the successful and ethical imple-mentation of TasP relies heavily on the capacity of healthsystems to accommodate its introduction. Key questionsidentified here concern issues pertaining to testing, effectivelinkage to care for those who test positive, retention in care,initiation of ART and assistance with adherence issues toattain viral suppression [41]. Given that the successful im-plementation of TasP requires a large increase in the uptakeof HIV testing, prevention, treatment and support services,questions have been raised regarding the capacity of somehealth systems (which are ultimately embedded within lar-ger socio-political systems) to introduce TasP in ways thatensure human rights are protected, HIV-related stigma anddiscrimination are reduced (or at least not exacerbated),and to facilitate a sustained and ethical engagement of theindividuals accessing TasP-related programs over very longperiods of time (e.g., indefinitely) [8,24].Effectiveness considerations and socio-structural contextsof HIV-related experiencesThe third emergent theme centered on questions relatedto the external validity of randomized controlled trialssupporting the role of TasP, leading to concerns aboutwhether existing trial data is sufficient to justify thewidespread implementation of TasP [20,37,43]. Whilesome argue that the findings of clinical trials support of-fering ART to individuals in sero-discordant relation-ships [6], other evidence has suggested that a largeproportion of new HIV infections do not occur withinstable sero-discordant heterosexual relationships [38].Thus, questions have emerged as to whether or not theevidence base warrants the implementation and scale upof TasP within epidemics that are not defined by vaginal-penile transmission [36]. Others have suggested that whilethe efficacy of TasP in clinical trials settings is acceptable,effectiveness considerations may render the approach’s‘real-world’ effectiveness vulnerable to criticisms (e.g., ef-fect sizes will diminish to non-clinically significant levelsin the face of broader implementation realities) [24,36].Consequently, some have argued that the ethical evalu-ation of evidence to policy requires more than data fromclinical trials and that a justification to proceeding towidespread scale up must also be informed by informationpertaining to the social and economic realities of the im-plementation contexts [37], including community-basedeffectiveness trials that may better account for the hetero-geneity of experiences for people living with HIV [23].It also has been postulated that effectiveness studies couldreveal TasP as having unintentional inequity-enhancingconsequences. For example, effectiveness trials mightdemonstrate the potential for a skewing of beneficialimpacts among various population sub-groups (e.g.,differential uptake across social strata; variegations in thenumber and strength of barriers to access along the socialgradient) [22,44]. Unintended effects on individual-levelbehavior were also discussed in the literature, particularlyrisk compensation behavior (e.g., “condom migration” ef-fects) [24,42,45,46]. The potential for risk compensationhas led some to ask how this effect could potentiallyundermine or blunt the preventative aspects of TasP, re-inforcing arguments that point to the necessity of main-taining and perhaps enhancing current standards of HIVprevention (e.g., risk-reduction counseling in clinical set-tings) in TasP implementation and scale-up [46].The issue of adherence in ‘real world’ settings waswidely discussed in the literature, with many suggestingthat the levels of adherence attained in clinical trials can-not be attained within most settings globally – particularlywithin resource-poor settings that present a set of geo-graphical and sociocultural challenges [24,44,47,48]. Forexample, some have argued that evidence pertaining toadherence must be contextualized to local settings[37,41,49], with particular attention focused on the socialvulnerabilities that individuals may experience in theireveryday lives (e.g., unstable housing) [8,24,31,33,44,47,48] .As such, specific implementation challenges were identifiedregarding engaging around TasP with individuals whoalready face social, cultural and economic barriers to acces-sing care [49]. For example, one article described possiblescenarios in which some vulnerable individuals (e.g., peoplewho inject drugs) may become “ghettoized” in that theycan only live in places that support adherence to treatment[50]. And, it has been suggested that if the scale up andimplementation of TasP is only partially successful, itcould potentially concentrate future infections withinhighly vulnerable populations, thereby raising seriousethical concerns related to health equity and social just-ice [19]. Questions also have been raised regarding theethical implications of incentivizing HIV testing (e.g.,monetary compensation), particularly within seek andtreat models targeted to vulnerable population sub-groups[51]. Finally, some have suggested that TasP approachesthat induce treatment initiation ‘early’ may unintentionallyincur system-wide opportunities for patient non-compliancewith drug regimens, which therefore heightens the riskof additional drug resistance and limits future drugtreatment options [21].Given these concerns, the social determinants of healthwere often cited as a key priority within the literature. Forexample, organizations such as UNAIDS and the WorldHealth Organization recommend comprehensive ap-proaches to HIV treatment and prevention that also ac-knowledge and respond to the underlying and upstreamcauses of HIV infection, including gender inequality andaccess to health care, employment and housing [49,52]. Insome instances the social determinants of health wereKnight et al. BMC Medical Ethics 2014, 15:54 Page 9 of 13http://www.biomedcentral.com/1472-6939/15/54positioned against the remedicalization of the HIV epi-demic through the use of biomedical interventions suchas TasP; these arguments suggest that, without payingsufficient attention to the underlying causes of vulner-ability and HIV infection, TasP will have only limitedsuccess [51]. Conversely, TasP is positioned as havingalready been grounded in the social and structural di-mensions of HIV-related experiences. For example, insome implementation settings, legal and policy barriers(e.g., the criminalization of HIV; absence of evidence-based HIV prevention and addiction treatment oppor-tunities or programs) are positioned as key ‘forces’ thatwill contribute to the differential uptake/success of TasP,thereby exacerbating health inequity – particularlyamong already vulnerable population sub-groups (e.g.,people who inject drugs) [11].Some of the most impassioned arguments in the litera-ture related to the socio-structural contexts of HIV-related experiences, with some authors characterizingTasP’s commitments to addressing the distal causes ofHIV as rhetoric [8]. For these authors, TasP’s capacityto be effective requires ongoing commitments tohuman rights, including the provision of access tonon-discriminatory services, policies and laws [8]. Inparticular, laws that criminalize HIV transmission havebeen identified as a significant socio-structural barrierto the ethical and effective scaling up of TasP, as wellas other HIV-related interventions in which TasP is im-plicated (e.g., routine HIV testing) [8,42].DiscussionIn the current scoping review, a variety of normativeethical theories were either implicitly or explicitly usedto ground the arguments advanced in the literature re-garding the implementation of TasP. Specifically, we ex-plored three key themes that have important ethical andimplementation implications: (1) Effectiveness consider-ations and socio-structural contexts of HIV-related ex-periences; (2) Power relations within clinical practiceand competing resource demands within health care sys-tems; and (3) Balancing individual- and population-levelinterests. While conflicting interests associated with vari-ous ethical frameworks may not be fully resolvable (e.g.,utilitarian versus deontological approaches), ongoing dis-cussion and deliberation in this area will help provide pro-gress towards a reflective equilibrium in which a degree ofethical coherence and acceptability is acquired. Below weoutline where priorities for empirical research will advancethese ethical discussions. Based on the results of this scop-ing review, we identify several areas that hold promise forinforming the ethical implementation and scale up of TasPand that could benefit from new research (see Table 3 foran abbreviated list of key recommendations from thesefindings).Effectiveness studies that integrate ethical dimensions ofTasP implementationMany questions about the ethical implementation ofTasP are based on a set of uncertainties surrounding itsscale up beyond efficacy trials. These questions tend tofocus on the potential for unintended effects of TasP onindividuals (e.g., long-term effects on those initiatingearly ART) as well as on population subgroups (e.g.,further stigmatization of people who inject drugs) [11].Ongoing experimental research such as the START(Strategic Timing of Antiretroviral Treatment; clinicaltrial NCT00867048) will provide important informationrelated to the individual-level physiological effects of earlyART initiation (e.g., long-term side effects) though thesefindings will not be available until at least 2015. Findingsfrom clinical trials represent an important first step in de-veloping new and much-needed evidence. Embeddingvarious research approaches within clinical trials (e.g.,using a variety of social science research methods, includ-ing qualitative and ethno-epidemiological approaches) willbridge some of the knowledge gaps identified in our re-view by studying the social, economic and political con-texts that influence the capacity for successfully andethically implementing and scaling up TasP.There also is an urgent need to support new empiricalresearch that characterizes how interactions betweenTasP and its various implementation contexts affect thehealth and social well being of individuals as well aspopulations. Limited data exist on issues pertaining torisk compensation behavior and the capacity for non-adherence or early initiation to lead to drug resistance(despite many of the ethical arguments being premisedon this concern) [51]. While we acknowledge the chal-lenges related to studying risk compensation (e.g., ex-perimental designs in this area are themselves unethicalto undertake) [53,54], research efforts focusing on therelationship between treatment, adherence and HIV riskbehavior is urgently required in order to advance morefully informed discussion in this area. Nonetheless,emerging evidence in this area is showing a strong con-nection between social and structural influences onadherence among vulnerable populations, including thelegal context of HIV (e.g., HIV non-disclosure legis-lation) [55]. Indeed, within the current scoping review,social vulnerability and economic disadvantage emergedas a dominant ethical concern. As such, issues pertain-ing to vulnerability require careful and context-specificempirical and normative analyses that can extend tomany of the upstream issues often considered outside ofthe realm of intervention research methodology (e.g., ran-domized controlled trials; pharmaceutical research). Adopt-ing techniques from the realm of science and technologystudies (STS) may help reveal how implementation andethical considerations are inextricably linked and embeddedplescaesehickinnssopuKnight et al. BMC Medical Ethics 2014, 15:54 Page 10 of 13http://www.biomedcentral.com/1472-6939/15/54in one another. For example, the field of STS emphasizesthe connections between knowledge about human biologyand technologies (e.g., TasP) alongside the ‘social’ (e.g., so-cial contexts) and the ‘ethical’ (e.g., normative theory).In addition, effectiveness studies offer opportunities toembrace heterogeneous experiences associated with TasPimplementation as well as the social and structural fac-tors that shape HIV-related experiences – particularlyamong vulnerable and socially disadvantaged populationsub-groups. While clinical trials have provided informa-tion related to heterosexual sero-discordant couples, add-itional information related to men who have sex with menand other vulnerable population sub-groups (e.g., peoplewho inject drugs) is urgently required in order to advancethese discussions. Highly-controlled clinical trial settingswith primarily homogenous samples do not have sufficientcapacity to detect the diversity of pathways and mecha-nisms through which TasP might be implemented acrosscontexts; thus, relying exclusively on information regard-ing implementation and ethical considerations gleanedfrom controlled trials may point us in unrealistically uni-form future directions. Furthermore, homogenous sam-ples effectively limit (by default) forms of variability thatare important considerations in ethical implementation,including behavioural characteristics, cultural and ethnictraditions and gender norms. Building capacity in effect-Table 3 Priorities for future research1 Effectiveness studies that integrate ethical dimensions of TasP iminfluence the capacity for successfully and ethically implementing and2 Examinations of power relations in clinical interactions: Empirical rinformed decisions about TasP that are free of coercion.3 TasP as a case study of ‘targeting’: Ongoing empirical and philosopaffects population sub-groups.4 Empirical estimations to inform resource distribution decision-ma‘treatment versus prevention’ debate and focus energies on developingof scaling up TasP.5 Public engagement and interdisciplinary science: Use techniques apolicy analysis) and moral frameworks from the field of population andiveness studies also could enhance the likelihood ofundertaking international comparative studies to furtherdetermine the extent to which context-based heterogen-eity (e.g., different forms of health systems) shape or re-spond to the ethical and implementation dimensions ofTasP.Examinations of agency, including agentic practices thatmay challenge dominant social normsMany authors argued that if an individual is fully in-formed and has the capacity to consent (e.g., is theoret-ically ‘autonomous’ within clinical interactions) to theearly initiation of TasP, public health practices associatedwith TasP are ethically justifiable. However, many ques-tions arose as to whether all individuals exposed to TasPwill have the capacity to be fully autonomous given thepower relations manifest in many clinical interactions –particularly among vulnerable or disadvantaged popula-tion sub-groups. In addition, while the literature reviewedhere does not surface concerns that clinicians might makea set of idiosyncratic ‘choices’ (e.g., those influenced byprejudices) about who should or should not be offeredTasP, these concerns have been identified in anotherbody of literature [56] – that pertaining to the allocationof ART. The roles that prejudice or discrimination playin relation to the scaling up of TasP as yet remain un-clear and merit further study. Empirical research in thisarea is needed in order to fully distil the conditions thatprovide patients with fully informed decisions that are freeas possible from coercion. For example, drawing onmethods and theories from the field of empirical bioethics,empirical data can be generated to explore the extent towhich clinical interactions pertaining to TasP are volun-tary [57]. Based on new evidence, there may be opportun-ities to either improve the ethical theory or change theclinical practices in order to attain the demands of speci-fied ethical principles, particularly when agentic practicesof individuals or groups run counter to dominant socialnorms [58].TasP as a case study of ‘targeting’mentation: Examining the social, economic and political contexts thatling up TasP.arch examining the conditions that enable patients to make fullyal work should aim to characterize the extent to which TasP differentiallyg in the context of natural experiments: Move beyond the ongoingew empirical estimations regarding the costs (including opportunity costs)ciated with implementation and social science (e.g., fieldwork; interviews;blic health ethics (e.g., social justice frameworks).Within the realm of public health, there is concern thatfeatures of various targeted public health interventions(whereby a particular subgroup of population is targetedfor an intervention or enhanced intervention focus) mayexacerbate health inequity [59,60], raising moral con-cerns regarding their use [61,62]. Targeted interventionshave been critiqued for burdening specific populationsubgroups with an intervention, while aiming to benefitthose not explicitly targeted through a dispersion of ben-efits. TasP represents an important area in which moreresearch, evidence and philosophical deliberation mayprovide some resolution pertaining to the ethical impli-cations of targeted public health practices. In order toprovide moral guidance in this area, ongoing empiricaland philosophical work should aim to characterize theKnight et al. BMC Medical Ethics 2014, 15:54 Page 11 of 13http://www.biomedcentral.com/1472-6939/15/54extent to which a burden negatively impacts individualsand population sub-groups targeted for TasP.Empirical estimations to inform resource distributiondecision in the context of evolving natural experimentsPerhaps one of the most salient and complex moral di-lemmas that arises relates to issues around resource distri-bution within the context of scarcity and various globalausterity measures. Based on our analysis of the literatureincluded in the current scoping review, we suggest itwould be productive to move beyond the ongoing ‘treat-ment versus prevention’ debate and focus energies on de-veloping new empirical estimations regarding the costs(including opportunity costs) of scaling up TasP. To makeinformed decisions globally and locally about ethical scal-ing up of TasP, it will be important to understand the de-gree to which investments in TasP efforts may implyopportunity costs (or have a multiplier effect) within abroader comprehensive spectrum of care and more up-stream prevention.Public engagement and interdisciplinary scienceWithin these efforts, interdisciplinary and collaborativeapproaches are required to engage in normative assess-ments of various sets of evidence. Indeed, based on thesefinding, techniques associated with implementation andsocial science (e.g., fieldwork; interviews; policy analysis)and moral frameworks from the field of population andpublic health ethics (e.g., social justice frameworks) willplay an important role in leveraging the successful andethical implementation of TasP. Finally, in order to miti-gate some of the conflicting arguments in this area, wesuggest the source origins of both the methodologicaland philosophical frameworks should be addressed tothe fullest extent possible, along with clear, transparentrationale with respect to how the empirical and norma-tive interacted to arrive at a moral conclusion. Indeed,the evaluation of data in this area should continue to en-gage in critical approaches, given the inherent difficulty oftransforming complex research findings (e.g., population-level studies) into moral conclusions [63].Strengths and limitationsThis scoping study was limited in its capacity to reveal allethical issues that will arise within this area (e.g., therecould be other publications that were not identified usingour search criteria; additional ethical debates pertaining toTasP take place ‘outside’ of the peer-reviewed and greyliterature). In addition, articles in languages other thanEnglish were not included. Moreover, this study did notappraise the quality of ethical arguments (e.g., based on alogic framework) nor the quality of the evidence base onwhich various arguments rest. However, by drawing onboth peer-reviewed and grey literature, our review doesprovide illustrations of some dominant ethical issues thatdemand new empirical work that could inform the ethicalimplementation and scaling up of TasP.ConclusionsNew research and normative deliberation is required inorder to successfully and ethically treat and prevent HIVthrough the inclusion of TasP within HIV continuum ofcare models. From an ethical and implementation per-spective, the process of scaling up TasP should not beconceptualized or practiced as linear, but rather as aconstant feedback loop in which new evidence con-stantly informs morally robust practices within and dur-ing its implementation.EndnotesaBefore the use of ART for TasP, the CD4 count (a meas-ure of white blood cells in units of cells/mm3) at which in-dividuals were recommended to begin ART was generallyaccepted to be at approximately 350 cells/mm3 or less[64]. Since the initiation of TasP, however, some jurisdic-tions such as British Columbia, Canada, no longer con-sider CD4 level thresholds [5,65] with respect to ARTinitiation. Currently, the World Health Organization rec-ommends a CD4 < 500 cells/mm3 [66] and some settings(e.g., Australia) do not provide funding for treatment orrecommend ART if CD4 count is above specifically de-fined thresholds (e.g., >500 cells/mm3). In other settings(e.g., low-resource settings), ART may be altogether un-available for prevention purposes [67-69].bWhile there are similarities between the methods as-sociated with systematic reviews and the methods andtechniques of scoping reviews with respect to ‘mapping’the extent, range and nature of various substantive areas(e.g., TasP), there are also important differences (see:Arksey & O’Malley, 2005; Levac & O’Brien, 2010). As aresult, we have modified the PRISMA flow chart to re-flect our inclusion/exclusion processes.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsRK and WS developed the study design and protocol. BP carried out theliterature search. BP and RK screened the literature collected for inclusion/exclusion criteria. KT provided analytic contributions to the (re) analysis ofdata and revisions to the manuscript upon important feedback fromreviewers. All authors contributed to the thematic analysis and drafting ofthe findings. All authors reviewed and approved the final manuscript.AcknowledgmentsRK, BP, and KT are supported by training awards from the Canadian Institutes ofHealth Research (CIHR). JS and WS are supported by career awards from CIHR.Author details1Interdisciplinary Studies Graduate Program, University of British Columbia,2Vancouver, Canada. Faculty of Health Sciences, Simon Fraser University,Burnaby, Canada. 3School of Population and Public Health, University ofBritish Columbia, Vancouver, Canada.Knight et al. BMC Medical Ethics 2014, 15:54 Page 12 of 13http://www.biomedcentral.com/1472-6939/15/54Received: 25 October 2013 Accepted: 13 June 2014Published: 3 July 2014References1. Chang LW, Serwadda D, Quinn TC, Wawer MJ: Combinationimplementation for HIV prevention: moving from clinical trial evidenceto population-level effects. Lancet Infect Dis 2013, 13:65–76.2. 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Glob Health Sci Pract 2013, 1:29–34.doi:10.1186/1472-6939-15-54Cite this article as: Knight et al.: A scoping study to identifyopportunities to advance the ethical implementation and scale-up ofHIV treatment as prevention: priorities for empirical research. BMC MedicalEthics 2014 15:54.Submit your manuscript at www.biomedcentral.com/submit


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