The case for actualism

First, actualism links claims about the value of scientific knowledge to actors and institutions that are in a position to promote those values.26 That is, the value of scientific research, in this case, is instrumental and contingent on the kind of world into which science and technology emerges. Actualists can be optimistic about science's potential, while being realistic about the value science has qua implementable cure.

Further, actualism bears—as per Jackson's and Pargetter's initial case—on ranking our options for action when setting research priorities. In our example, Do-Good only has two choices: pursue research or not pursue research. What is more likely, however, is that Do-Good has a larger set of options available: it could fund different kinds of research; design scalability or implementation research into a project's specific aims or promote other projects to pursue institutional reform, aid work or activism.

Actualism, finally, frames the value of scientific discovery in terms of its place in a social and political process of improving community health and makes room for ranking research aimed at a sterilising or functional cure intervention against other interventions that may achieve similar effects. For example, a sterilising HIV cure might encounter difficulties in implementation not experienced by programs to increase barrier contraception use, or other strategies to break transmission of HIV. Moreover, allocating resources to surmount one set of challenges may come at the expense of other potential implementation strategies. Evaluating the value of scientific research as an actualist involves assessing its implementation as a necessary component of the instrumental value of research.

Objections

A possibilist might reply with three objections:

1. Actualism is fatalistic. Scientific research that finds no application now might be just a generation, a political administration or a wealthy benefactor away from making a better world.

2. Actualism is overly demanding in terms of the epistemic burden required to ascertain whether or not research will actually lead to a working cure for HIV. Whether or not actualism holds, it is impossible to put into practice.

3. One could be an actualist for the purpose of honing interventions and their implementation but a possibilist for the purposes of prioritising research.

The actualist's reply

These three objections, we believe, can be successfully resisted. To the first, an actualist will indeed rank their options in a way that accounts for changes in politics, but we do not take this to be fatalistic. In the case of a HIV cure, a candidate cure is arguably more desirable if its deployment is not contingent on particular kinds of funding or aid programmes that may vanish with a change in government. Actualism can account for current institutional arrangements being subject to change, while still requiring that proposed research be sensitive to present and expected future institutional arrangements.

The second concern is about actualism's demandingness characteristic, but it could also be about the incentives that actualism places on researchers. Consider, for example, the AZT (zidovudine) 076 breakthrough that led to the WHO conference to find an affordable and accessible AZT regimen for HIV-positive pregnant women in low-income countries.29 Given how difficult and costly drug/device development is, it might seem like an extra hurdle to attempt to secure implementation commitments before the development has shown promise. Accepting actualism does not entail that scientists themselves make such determinations. Individual scientists are rarely the best qualified to make complex, institutional evaluations of their own work.16 ,30 Governments, academic institutions and funding bodies, however, may have the epistemic and logistical capacities to make these assessments and are moreover in a position to inform the direction of research through funding mechanisms. A commitment to actualism requires only that scientific research be evaluated in terms of its capacity to actually bring about a valuable outcome and not who the evaluator ought to be.

Moreover, judging what lines of inquiry are most likely to succeed is challenging even if one is a possibilist. Uncertainty about, say, the technical possibility of a cure is the same, independent of the stance one takes about actualism. Actualists do not differ from possibilists on questions that turn on the likelihood of a line of inquiry paying dividends in the form of promoting health (or some other good). There is evidence that ‘blue skies’ research, for example—research that is not pursued with an explicit pragmatic goal in mind, but rather out of curiosity about some feature of the natural world—can lead to considerable benefits31; an actualist can acknowledge the value of blue skies research while maintaining the argument that when discussing priorities of goal-driven clinical research, we ought to account for our motivations to carry out our actions. If actualist considerations are burdensome, it is only a matter of degree, not of kind. And, as we claim, there is no in-principle reason why deliberation about feasibility ought to be something pursued by lone researchers.

The third objection is curious: on the one hand, it appears to reveal some kind of ‘moral split personality’, whereby the relationship between an agent's reasons for action and their motivation to carry out that action changes by turns at different stages of a particular activity. On the other hand, it mirrors a stereotype of scientist's indifference to the practical outcomes of their work, exemplified by Robert Oppenheimer: ‘When you see something that is technically sweet, you go ahead and do it and argue about what to do about it only after you've had your technical success’. Our response is simply that in the case we provide, if Do-Good decides to become an actualist after deciding to fund the research, they will consistently end up with the worst outcome, as judged by both the actualist and the possibilist. That is, Do-Good qua possibilist funder of science will fund the cure research, but qua actualist will then choose a more plausible line of implementation even if the research exists, because the problems of implementation are external to the mere existence of the cure research. In practice—given multiple research options—we might not always see the worst outcomes were we to try and be possibilists and actualists, but we are less likely to see the best, or good outcomes, at least when judged from the perspective of the social value of research.

In light of our responses to objections two and three, however, one could envisage a division of labour where scientists are possibilists, but funders are actualists. Here, the tension is less apparent, because each role-holder maintains a single identity. Given that the scope of our inquiry relates to whether we should fund and pursue research, we maintain that funders should be actualists. As a preliminary response to the question of scientists, it seems likely that if our account of actualism holds, then scientists ought to be actualists as well. Note, however, that actualism is concerned with what an agent ought to do, given their own motivations—there is a separate question, which we discuss in following sections, about what an agent ought to do in response to the motivations of others. Insofar, however, as scientists are in general neither capable nor responsible for, say, eradicating a disease single-handedly, then the obligations that follow from their actualism qua a cure for HIV/AIDS are more limited.

Scientific/technical challenges in developing an effective HIV cure

HIV eradication from the human host is challenging because the virus has the ability to hide in cells that lie dormant while evading host immune mechanisms. The biggest challenge in curing HIV is finding a drug that forces the virus out of all latent reservoirs that have been established in the HIV-infected person.32 Latency reversing interventions seek to overcome this barrier using drugs that can awaken the virus from dormant cells to make them accessible to drugs that can kill the awakened virus.

An additional challenge in HIV cure research is the absence of sensitive technologies that can prove that the virus has been completely purged and an individual no longer has HIV.33 Interventions that aim to completely eradicate the virus will require a tool that can prove the absence of HIV in a previously infected person.

Based on feasibility and likelihood of eliminating the virus, with no consideration for implementation, the candidate interventions can be ranked and prioritised from the possibilist perspective as follows:

1. Cell-based therapy: In theory, it would be a one-time treatment to ‘cure’ an otherwise chronic disease.

2. Latency reversing agents: This combination approach promises a long-term ART-free remission.

3. Early intensive ART treatment for neonates: This intervention could bring about long-term ART-free remission in infants.

4. Immune-based interventions: Therapeutic vaccines or antibodies may not eliminate the virus but they could lead to long-term ART-free remission.

Implementation challenges for future HIV cure interventions

Several examples exist of health technologies that worked effectively in developed countries, but which failed to perform in low-resource settings. Strategies like prophylactic ART and replacement feeding have worked well in programmes to prevent mother-to-child HIV transmission (PMTCT) in developed countries. However, in some low-income countries with limited access to healthcare and clean water, implementation has failed due to these strategies being untested or unsuitable.34

In the remainder of this paper, we examine the challenges in implementing the HIV cure research that are surmountable with effort and the challenges that in actuality are unlikely to be surmountable. We list these challenges in order of resolvability and, finally, we ‘re-prioritise’ cure interventions accordingly.

Healthcare worker shortages

Many low-income countries have inadequate trained healthcare workers and this could be a major barrier for implementing HIV cure interventions. Rather than train new healthcare workers in resource-limited settings to perform medically complex cell-based therapy procedures, it would be more cost-effective and sustainable to use workers who are already involved in treating other diseases.34 Also, auxiliary health workers could be properly integrated into health systems to fill in the gaps created by healthcare worker shortages and strengthen health systems in low-income countries. Preliminary analysis by the Elizabeth Glaser Pediatric AIDS Foundation of the implementation of WHO policy guidelines for PMTCT in some African countries shows that it is feasible to train additional healthcare workers to scale up HIV therapy.35

Public reluctance to accept new health technologies and adherence challenges

We foresee patients who are doing well on ART or who have their HIV under control being hesitant to try out potentially risky yet relatively valuable HIV cure interventions like cell-based therapy or latency reversing treatment. Put another way, patients may not value a sterilising or functional cure if the management of HIV through ART is seen as sufficient or preferable to novel interventions. Results from a qualitative study on barriers to ART initiation in Swaziland showed that community outreach and engagement helped in increasing ART acceptance.35 It is realistic that initial public reluctance towards a cure can be overcome with some effort. To resolve adherence challenges, researchers should prioritise developing one-time interventions requiring single hospital visits or short course regimens that eliminate the need for follow-up visits.

Financing cost and delivery of interventions

Worldwide, drug prices usually determine their accessibility. At present, the cost of cell-based therapy is very high—autologous cell transplant is estimated at US$75 000–$150 000 and allogeneic cell transplant is estimated at US$150 000–$300,000.36 ,37 These estimated costs remain lower than the current cost of lifelong ART in developed countries, which is estimated at US$420 000–$755 000 per individual in the USA.38

While the price of cure interventions will likely become lower with time, some elements of cost are insurmountable. In low-income countries, sophisticated and technology-intensive HIV cure interventions like cell-based therapy will be challenging to deliver in rural regions without reliable power supply. The apheresis procedure, which is used for collecting cells (T cells or stem cells) in cell-based therapy, is medically and technically demanding and is not currently available worldwide. As of 2014, only one country (out of 16) in West Africa had the capacity to perform apheresis procedures.39 Overcoming these technical challenges would require strengthening health systems in low-income countries and making resources available to transport people from rural regions to urban centres that are equipped to deliver these complex interventions. Constrained public budgets make it difficult for governments in low-income countries to purchase innovative health technologies for use in healthcare centres.40 As such, political commitment and donor efforts would need radical expansion to support access to a complex or sophisticated candidate cure. We are not confident that such an expansion is likely to occur; bottlenecks to point-of-care delivery will remain. As actualists, these bottlenecks support the argument for prioritising less complex cure interventions.

High-risk intervention

Cell-based therapy that involves stem cell transplantation is highly risky and requires continuous medical attention and immunosuppressant use. Some latency reversing agents currently being considered for HIV cure are mutagenic and may potentially cause cancer in the long term.6 Unless transformed to become low-risk with fewer inpatient procedures, it will be challenging to convince patients who are doing very well on ART to undergo these potentially risky interventions.