Our search resulted in 29 peer-reviewed articles and 19 grey literature sources that were included in data extraction and literature mapping. Figure 1 presents a modified version of the PRISMA-style flow diagram to reflect our inclusions/exclusion processb. Three dominant themes emerged in our analysis with respect to the ethical questions pertaining to TasP implementation and scale-up: (a) balancing individual- and population-level interests; (b) power relations within clinical practice and competing resource demands within health care systems; (c) effec tiveness considerations and socio-structural contexts of HIV-related experiences within broader implementation contexts.
Balancing individual- and population-level interests
The ethical implications of initiating individuals on ART regardless of their CD4 count emerged as the most salient and contentious question related to the ethical implementation of TasP [9]. This debate centers on whether or not it 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. Individualistic frameworks, communitarian and utilitarian frameworks are used to advance arguments in this debate.
Individualistic (e.g., social libertarian) frameworks tend to prioritize individual autonomy against a set of communitarian frameworks that emphasize the interests of the broader population [19]. Applications of individualistic frameworks suggest that scaling up TasP programs will result in overly coercive testing and treatment regimes that disregard voluntary consent and participation. Within these arguments, it is suggested that TasP represents an intervention on individuals that burdens individuals in order to promote public health [9], thereby violating principles of beneficence, non-maleficence and autonomy – hallmarks of applied medical ethics [20]. For example, the early initiation of ART is largely positioned as a negative option for the individual due to the potential for various side effects, including altered lipids, reduced bone density and kidney damage [21] as well as the potential for increased antiretroviral resistance [21]. Thus, these arguments suggest that an individual’s choice not to commence treatment confers an individual benefit that outweighs concerns for public beneficence [21]. Additional arguments that suggest individual autonomy trumps overall beneficence rest on the notion that the long-terms effects of ART adherence are not yet fully known. For example, some have suggested that TasP burdens individuals with chronic disease management at an early stage of their disease progression, thereby altering their capacity for economic productivity as well as their overall quality of life [22].
Questions about the ethics of early initiation of ART have also been closely embedded in matters of agency. If the individual freely chooses to initiate TasP (e.g., they have a sufficient level of autonomy, the process remains voluntary, and they are equipped with sufficient information to make an informed choice), then TasP meets the ethical criteria set out within applied medical ethics – regardless of the potential for individual or population-level harms/benefits [8, 21]. However, the positioning of agentic choice as devoid of contextual and structural factors has also been problematized. These arguments reveal the dependence of truly free choice on a variety of conditions, including whether or not a person will have the capacity to adhere, whether or not there will be a consistent and ‘never-ending’ supply of ART available [23], and if an individual will have the opportunity to start ART at a later date if they choose to decline early initiation [19]. Finally, the potential for the stigmatization of individuals or groups who choose not to seek early treatment was also described as an important ethical consideration regarding the successful scaling up of TasP [24, 25].
Communitarian and utilitarian framings, on the other hand, offer a view that more strongly features the potential for TasP to prevent future cases as a primary consideration, counter-positioning previous HIV prevention approaches as ‘status quo’ and insufficiently equipped to decrease the spread of HIV [26]. These ‘greater good’ perspectives are often buttressed in the literature by arguments that turn on the extent to which the individual who uptakes ART could benefit (or at least not suffer) as the short-term effects of the early initiation of ART have not been demonstrated to be physically detrimental [27]. The view that populations and individuals may concomitantly benefit from beginning ART with CD4 counts above the previously defined thresholds for treatment has also been extended to the psychological realm (e.g., feeling relief in knowing one is less infectious and therefore less likely to transmit HIV to partners) [21] as well as other potential physiological benefits [27]. While detailed discussions regarding some of the mainstays of population and public health ethics (e.g., relational frameworks that emphasize notions of ‘the greater good’) did not feature as strongly in the literature captured in the current review, some authors did apply key principles, such as solidarity, stewardship and compassion, and argue that these principles ought to be considered in terms of their relevance to population and public health ethics – particularly with regard to concerns pertaining to the most vulnerable population sub-groups [28]. Some arguments appear to minimize the potential risks for individuals in the face of potentially large population-level gains. For example, it has been suggested that the addition of two to three years of treatment (e.g., before the immune system becomes compromised) could be considered as insignificant in the face of what could be decades of future treatment [27].
Power relations within clinical practice and competing resource demands within health care systems
The second dominant theme that emerged in the analysis related to power relations within patient-physician interactions and health care systems more broadly [9]. For example, some authors have suggested that without unequivocal evidence pertaining to the early uptake of ART, doctors will still be faced with the challenge of providing advice to their patients on courses of action in a context of uncertainty [29]. Particularly in situations where the evidence is either contradictory or unavailable (e.g., issues pertaining to the individual-level benefits of early uptake of ART), the ethical and effective negotiation of power relations inherent in patient-physician interactions will require a relatively high degree of sophistication from both parties [25, 30]. Thus, the importance of training of health care practitioners to competently relay evidence about the potential risks of early uptake of ART was also identified as an important component to ensure individuals can make informed decisions. However, inherent difficulties within the doctor-patient relationship regarding comprehension and translation of risk information were acknowledged (particularly in light of limited or conflicting evidence in this area) [31].
Questions also have been raised in the literature around the prioritization and distribution of limited resources. Indeed, in the context of scarce resources, issues related to TasP have led some to question the extent to which efforts should be focused on treatment versus prevention [32]. For example, some authors have suggested that, given a limited set of resources in HIV treatment and prevention programs, it is inequitable to divert resources from treatment to prevention [33] – particularly in relation to taking ARV treatment resources away from resource-poor settings in order to advance prevention efforts within high-resource or low-prevalence settings [34, 35]. Still others argued that the very nature of TasP should be seen as paradigm-shifting and that the goals of treatment and prevention are converging rather than conflicting [32]. Moreover, the unknown issues pertaining to the long-term preventative effects of TasP have been said to be so significant that predicting the associated costs and benefits is not yet possible [22]. Ultimately, the treatment versus prevention debates tend to flow from utilitarian frameworks which argue for the prevention of the greatest number of deaths versus deontological frameworks which argue for ethical rules (e.g., the rule/duty of rescue) and prioritarian principles (e.g., arguing that those who are currently sick are worse off than those who will become sick but are currently healthy) [28, 33].
Issues related to the scarcity of HIV prevention and health promotion resources have also led to a set of arguments around targeting efforts at specific population sub-groups considered most at-risk for transmitting HIV for cost-specific reasons [36], though many acknowledge the ethical complexities associated with deciding how efforts ought to be prioritized during implementation [37, 38]. For example, the literature generally acknowledges that population sub-groups that already face the highest levels of stigmatization (e.g., people who inject drugs) are likely the most at risk for HIV acquisition and transmission [39]. This presents a challenge regarding the population-level effectiveness of TasP, as stigma also deters people from accessing regular testing, thereby delaying the onset of diagnosis and treatment, and undermining the potential for reduced transmission [40]. As a result, some have called for more research on the efficacy of TasP in marginalized sub-groups in order to inform ways to ethically reach people at the earliest stages of infection (i.e., during the first 6 months) when their viral loads may be highest [36, 40].
Others have suggested that explicit criteria be used in order to determine who should be prioritized to receive treatment. In general, children and monogamous sex partners (those least likely to transmit the virus) are characterized as low priority groups for TasP, whereas those who are the most likely to spread HIV should be high priority (e.g., men who have sex with men in high-risk settings; people who inject drugs; migrant workers with multiple concurrent partners) [39]. These arguments are premised on the assumption that treatment is a finite resource and offering treatment to somebody who is not sick (e.g., individuals with a CD4 count well above 350 and not showing symptoms of HIV infection) may deprive a sick person (e.g., an individual with a CD4 count well below 200 and experiencing HIV-related symptoms) of treatment. As a result, the principle of providing treatment to those individuals who will benefit the most comes into conflict with principles related to health maximization in which the HIV negative partner in a sero-discordant relationship will benefit [34].
TasP is most widely referred to as one strategy within a set of HIV prevention programs, often referred to as a continuum, cascade or combination prevention strategy [1, 33, 36, 40, 41]. In addition to TasP, other HIV intervention strategies within health care systems include voluntary medical male circumcision, campaigns to increase HIV testing 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 implementation of TasP relies heavily on the capacity of health systems to accommodate its introduction. Key questions identified here concern issues pertaining to testing, effective linkage to care for those who test positive, retention in care, initiation of ART and assistance with adherence issues to attain viral suppression [41]. Given that the successful implementation of TasP requires a large increase in the uptake of HIV testing, prevention, treatment and support services, questions have been raised regarding the capacity of some health systems (which are ultimately embedded within larger socio-political systems) to introduce TasP in ways that ensure human rights are protected, HIV-related stigma and discrimination are reduced (or at least not exacerbated), and to facilitate a sustained and ethical engagement of the individuals accessing TasP-related programs over very long periods of time (e.g., indefinitely) [8, 24].
Effectiveness considerations and socio-structural contexts of HIV-related experiences
The third emergent theme centered on questions related to the external validity of randomized controlled trials supporting the role of TasP, leading to concerns about whether existing trial data is sufficient to justify the widespread implementation of TasP [20, 37, 43]. While some argue that the findings of clinical trials support offering ART to individuals in sero-discordant relationships [6], other evidence has suggested that a large proportion of new HIV infections do not occur within stable sero-discordant heterosexual relationships [38]. Thus, questions have emerged as to whether or not the evidence base warrants the implementation and scale up of TasP within epidemics that are not defined by vaginal-penile transmission [36]. Others have suggested that while the efficacy of TasP in clinical trials settings is acceptable, effectiveness considerations may render the approach’s ‘real-world’ effectiveness vulnerable to criticisms (e.g., effect sizes will diminish to non-clinically significant levels in the face of broader implementation realities) [24, 36]. Consequently, some have argued that the ethical evaluation of evidence to policy requires more than data from clinical trials and that a justification to proceeding to widespread scale up must also be informed by information pertaining to the social and economic realities of the implementation contexts [37], including community-based effectiveness trials that may better account for the heterogeneity of experiences for people living with HIV [23].
It also has been postulated that effectiveness studies could reveal TasP as having unintentional inequity-enhancing consequences. For example, effectiveness trials might demonstrate the potential for a skewing of beneficial impacts among various population sub-groups (e.g., differential uptake across social strata; variegations in the number and strength of barriers to access along the social gradient) [22, 44]. Unintended effects on individual-level behavior were also discussed in the literature, particularly risk compensation behavior (e.g., “condom migration” effects) [24, 42, 45, 46]. The potential for risk compensation has led some to ask how this effect could potentially undermine or blunt the preventative aspects of TasP, reinforcing arguments that point to the necessity of maintaining and perhaps enhancing current standards of HIV prevention (e.g., risk-reduction counseling in clinical settings) in TasP implementation and scale-up [46].
The issue of adherence in ‘real world’ settings was widely discussed in the literature, with many suggesting that the levels of adherence attained in clinical trials cannot be attained within most settings globally – particularly within resource-poor settings that present a set of geographical and sociocultural challenges [24, 44, 47, 48]. For example, some have argued that evidence pertaining to adherence must be contextualized to local settings [37, 41, 49], with particular attention focused on the social vulnerabilities that individuals may experience in their everyday lives (e.g., unstable housing) [8, 24, 31, 33, 44, 47, 48] . As such, specific implementation challenges were identified regarding engaging around TasP with individuals who already face social, cultural and economic barriers to accessing care [49]. For example, one article described possible scenarios in which some vulnerable individuals (e.g., people who inject drugs) may become “ghettoized” in that they can only live in places that support adherence to treatment [50]. And, it has been suggested that if the scale up and implementation of TasP is only partially successful, it could potentially concentrate future infections within highly vulnerable populations, thereby raising serious ethical concerns related to health equity and social justice [19]. Questions also have been raised regarding the ethical implications of incentivizing HIV testing (e.g., monetary compensation), particularly within seek and treat models targeted to vulnerable population sub-groups [51]. Finally, some have suggested that TasP approaches that induce treatment initiation ‘early’ may unintentionally incur system-wide opportunities for patient non-compliance with drug regimens, which therefore heightens the risk of additional drug resistance and limits future drug treatment options [21].
Given these concerns, the social determinants of health were often cited as a key priority within the literature. For example, organizations such as UNAIDS and the World Health Organization recommend comprehensive approaches to HIV treatment and prevention that also acknowledge and respond to the underlying and upstream causes of HIV infection, including gender inequality and access to health care, employment and housing [49, 52]. In some instances the social determinants of health were positioned against the remedicalization of the HIV epidemic through the use of biomedical interventions such as TasP; these arguments suggest that, without paying sufficient attention to the underlying causes of vulnerability and HIV infection, TasP will have only limited success [51]. Conversely, TasP is positioned as having already been grounded in the social and structural dimensions of HIV-related experiences. For example, in some implementation settings, legal and policy barriers (e.g., the criminalization of HIV; absence of evidence-based HIV prevention and addiction treatment opportunities or programs) are positioned as key ‘forces’ that will contribute to the differential uptake/success of TasP, thereby exacerbating health inequity – particularly among already vulnerable population sub-groups (e.g., people who inject drugs) [11].
Some of the most impassioned arguments in the literature related to the socio-structural contexts of HIV-related experiences, with some authors characterizing TasP’s commitments to addressing the distal causes of HIV as rhetoric [8]. For these authors, TasP’s capacity to be effective requires ongoing commitments to human rights, including the provision of access to non-discriminatory services, policies and laws [8]. In particular, laws that criminalize HIV transmission have been identified as a significant socio-structural barrier to the ethical and effective scaling up of TasP, as well as other HIV-related interventions in which TasP is implicated (e.g., routine HIV testing) [8, 42].
