Nir Eyal

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the groups strategy.

The Diverse Ethics of Translational Research

Commentators on the ethics of translational research find it morally problematic. Types of translational research are said to involve questionable benefits, special risks, additional barriers to informed consent, and severe conflicts of interest. Translational research conducted on the global poor is thought to exploit them and increase international disparities. Some commentators support especially stringent ethical review. However, such concerns are grounded only in pre-approval translational research (now called T1). Whether or not T1 has these features, translational research beyond approval (T2: phase IV, health services, and implementation research) is unlikely to and, when conducted on the global poor, may support development. Therefore, insofar as T1 is morally problematic, and no independent objections to T2 exist, the ethics of translational research is diverse: while some translational research is problematic, some is not. Funding and oversight should reflect this diversity, and T2 should be encouraged, particularly when conducted among the global poor.

Using informed consent to save trust

Increasingly, bioethicists defend informed consent as a safeguard for trust in caretakers and medical institutions. This paper discusses an ‘ideal type’ of that move. What I call the trust-promotion argument for informed consent states: 1. Social trust, especially trust in caretakers and medical institutions, is necessary so that, for example, people seek medical advice, comply with it, and participate in medical research. 2. Therefore, it is usually wrong to jeopardise that trust. 3. Coercion, deception, manipulation and other violations of standard informed consent requirements seriously jeopardise that trust. 4. Thus, standard informed consent requirements are justified. This article describes the initial promise of this argument, then identifies challenges to it. As I show, the value of trust fails to account for some commonsense intuitions about informed consent. We should revise the argument, commonsense morality, or both.

‘Perhaps the most important primary good’: self-respect and Rawls’s principles of justice:

The article begins by reconstructing the just distribution of the social bases of self-respect, a principle of justice that is covert in Rawls’s writing. I argue that, for Rawls, justice mandates that each social basis for self-respect be equalized (and, as a second priority, maximized). Curiously, for Rawls, that principle ranks higher than Rawls’s two more famous principles of justice - equal liberty and the difference principle. I then recall Rawls’s well-known confusion between self-respect and another form of self-appraisal, namely, confidence in one’s determinate plans and capacities. Correcting that confusion forces Rawls to accept objectionable and illiberal politics. Surprisingly, a consistent Rawls must endorse absolute economic equality, deny liberty any priority whatsoever, or sponsor still other illiberal political views - evidence of a flaw in the ethical basis of Rawls’s politics.

Non-Physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians

Responding to critical shortages of physicians, most sub-Saharan countries have scaled up training of non-physician clinicians (NPCs), resulting in a gradual but decisive shift to NPCs as the cornerstone of healthcare delivery. This development should unfold in parallel with strategic rethinking about the role of physicians and with innovations in physician education and in-service training. In important ways, a growing number of NPCs only renders physicians more necessary - for example, as specialized healthcare providers and as leaders, managers, mentors, and public health administrators. Physicians in sub-Saharan Africa ought to be trained in all of these capacities. This evolution in the role of physicians may also help address known challenges to the successful integration of NPCs in the health system.

Challenges in clinical trial design for HIV-1 cure research

1464 www.thelancet.com Vol 382 November 2, 2013 The advent of highly eff ective, convenient, and well tolerated antiretroviral therapy (ART) for HIV-1 infection has substantially reduced AIDS-related morbidity and mortality. ART does not, however, eliminate HIV-1, which persists as a latent infection in resting memory CD4+ T cells. Treatment must therefore be continued throughout life. Therapeutic approaches that lead to durable drug-free remission or total eradication (cure) of HIV-1 would remove the burdens, costs, toxic eff ects, and stigma associated with long-term ART, as well as the social cost s and risks from development of drugresistant virus strains. Examples of apparent cure in a recipient of an allogeneic stem-cell transplant from a CCR5-negative donor and in an infected infant who received ART within 30 h of birth have stimulated renewed interest in research towards a cure, which was previously thought to be unattainable. The approaches being investigated include drugs to reactivate latent HIV-1 from resting T cells, immunebased therapies to boost HIV-1-specifi c immune responses, and transplantation of genetically modifi ed CD4+ T cells or autologous stem cells. Several of these approaches are in early-stage clinical trials. These trials raise both scientifi c and ethical challenges. Scientifi cally, the design of classic phase 1 studies seeking to establish the pharmacokinetics and preliminary safety of novel therapeutic agents in an HIV-1-infected population is straightforward. But the scientifi c design of phase 2 proof-of-concept studies is more complex. Should these studies aim to show a biological eff ect on the proximate target (eg, reactivation of HIV-1 transcription or boosting of HIV-1-specifi c immune responses)? Or should they show a signifi cant reduction in the viral reservoir, in which case what measure of the reservoir, assayed in which tissue compartment(s), should serve as the primary endpoint? Consensus seems to be emerging that the ultimate test of an intervention targeting the HIV-1 reservoir is an analytical treatment interruption. Specifi cally, the absence of virological rebound after cessation of ART, although not proof of absence of any residual virus, is generally regarded as an acceptable endpoint to show remission (or so-called functional cure) of HIV-1 infection. However, treatment Challenges in clinical trial design for HIV-1 cure research 2 Groopman JE, Mayer KH, Sarngadharan M, et al. Seroepidemiology of HTLV-III among homosexual men with the acquired immune defi ciency syndrome, generalized lymphadenopathy, and asymptomatic controls in Boston. Ann Intern Med 1985; 102: 334–37. 3 Simon V, Ho DD, Abdool Karim Q. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet 2006; 368: 489–504. 4 Sullivan A. When plagues end. New York Times Dec 1, 1996. http://www. nytimes.com/1996/12/01/magazine/l-when-plagues-end-490881.html (accessed Sept 25, 2013). 5 UNAIDS. Data and analysis. 2013. http://www.unaids.org/en/dataanalysis/ (accessed Sept 22, 2013). 6 Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363: 2587–99. 7 Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367: 399–410. 8 Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365: 493–505. 9 Ghoshal N. To stop the spread of HIV, address rights of marginalized groups. Human Rights Watch June 19, 2013. http://www.hrw.org/ news/2013/06/19/stop-spread-hiv-address-rights-marginalized-groups (accessed Sept 20, 2013). 10 Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009; 361: 2209–20. 11 Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009; 360: 692–98. 12 Henrich T, Hanhauser E, Sirignano M, et al. In depth investigation of peripheral and gut HIV-1 reservoirs, HIV-specifi c cellular immunity, and host microchimerism following allogeneic hematopoetic stem cell transplantation. 7th IAS Conference on HIV pathogenesis, treatment and Prevention; Kuala Lumpur, Malaysia; June 30–July 3, 2013. WELBA05 (abstr). 13 Persaud D. Towards a cure for HIV-infected children: hype and hope. Towards an HIV cure symposium. Satellite of the International AIDS Society 2013 meetings. Kuala Lumpur, Malaysia; June 29–30, 2013.

Nudging by Shaming, Shaming by Nudging

In both developing and developed countries, health ministries closely examine use of so-called nudges to promote population health and welfare. Cass Sunstein and Richard Thaler, who developed the concept, define a nudge as “any aspect of the choice architecture that alters people’s behavior in a predictable way without forbidding any options or significantly changing their economic incentives. To count as a nudge, the intervention must be easy and cheap to avoid. Nudges are not mandates” (1).

Medical students' characteristics as predictors of career practice location: retrospective cohort study tracking graduates of Nepal's first medical college.

Objective To determine, in one low income country (Nepal), which characteristics of medical students are associated with graduate doctors staying to practise in the country or in its rural areas. Design Observational cohort study. Setting Medical college registry, with internet, phone, and personal follow-up of graduates. Participants 710 graduate doctors from the first 22 classes (1983-2004) of Nepal’s first medical college, the Institute of Medicine. Main outcome measures Career practice location (foreign or in Nepal; in or outside of the capital city Kathmandu) compared with certain pre-graduation characteristics of medical student. Results 710 (97.7%) of the 727 graduates were located: 193 (27.2%) were working in Nepal in districts outside the capital city Kathmandu, 261 (36.8%) were working in Kathmandu, and 256 (36.1%) were working in foreign countries. Of 256 working abroad, 188 (73%) were in the United States. Students from later graduating classes were more likely to be working in foreign countries. Those with pre-medical education as paramedics were twice as likely to be working in Nepal and 3.5 times as likely to be in rural Nepal, compared with students with a college science background. Students who were academically in the lower third of their medical school class were twice as likely to be working in rural Nepal as those from the upper third. In a regression analysis adjusting for all variables, paramedical background (odds ratio 4.4, 95% confidence interval 1.7 to 11.6) was independently associated with a doctor remaining in Nepal. Rural birthplace (odds ratio 3.8, 1.3 to 11.5) and older age at matriculation (1.1, 1.0 to 1.2) were each independently associated with a doctor working in rural Nepal. Conclusions A cluster of medical students’ characteristics, including paramedical background, rural birthplace, and lower academic rank, was associated with a doctor remaining in Nepal and with working outside the capital city of Kathmandu. Policy makers in medical education who are committed to producing doctors for underserved areas of their country could use this evidence to revise their entrance criteria for medical school.

Precommitting to serve the underserved.

In many countries worldwide, especially in Sub-Saharan Africa, a shortage of physicians limits the provision of lifesaving interventions. One existing strategy to increase the number of physicians in areas of critical shortage is conditioning medical school scholarships on a precommitment to work in medically underserved areas later. Current practice is usually to demand only one year of service for each year of funded studies. We show the effectiveness of scholarships conditional on such precommitment for increasing physician supplies in underserved areas. Then we defend these scholarships against ethical worries that they constitute slavery contracts; rely on involuntary, biased, or unauthorized early consent by a young signatory; put excessive strains on signed commitments; give rise to domination; and raise suspicion of slavery contracts. Importantly, we find that scholarships involving far longer commitment than current practice allows would also withstand these worries. Policymakers should consider introducing conditional scholarships, including long-term versions, as a means to increasing the supply of physicians to medically underserved areas.

Ethical Questions in Medical Electronic Adherence Monitoring

Electronic adherence monitors (EAMs) record and report an array of health behaviors, ranging from taking daily medications to wearing medical devices. EAMs are utilized in research worldwide and are being investigated for clinical use. However, there is also growing popular concern about the extent to which electronic devices may be used to monitor individuals, including allegations in the media that EAMs represent a move towards “Big Brother” in medicine. Here, we highlight the unique benefits as well as the potential ethical challenges that electronic adherence monitoring generates. These challenges surround autonomy, privacy and confidentiality, trust, and ancillary care obligations. We describe key questions within each of these domains that warrant further investigation, and present potential solutions to many of the concerns raised.