Double Standards in Global Health

The human rights arguments that underpinned the fight against HIV over the last three decades were poised, but ultimately failed, to provide a similar foundation for success against multidrug-resistant TB (MDR-TB) and other diseases of the poor. With more than 1.5 million deaths since 2000 attributed to strains of MDR-TB, and with half a million new, and mostly untreated, MDR-TB cases in the world each year, the stakes could not be higher. The World Health Organization (WHO), whose mandate is to champion the attainment by all peoples of the highest possible level of health, recommended unsound medical treatment for MDR-TB patients in resource-poor settings from 1993-2002. Citing cost considerations, WHO did not recommend the available standard of care that had been successfully used to contain and defeat MDR-TB in rich countries. By acting as a strategic gatekeeper in its technical advisory role to donor agencies and countries, it also facilitated the global implementation of a double standard for TB care in lowand middle-income countries (LMICs), upending important legal and scientific priorities. This raises serious questions about whether the organization violated international human rights standards and those established in its own constitution. While calling for additional analysis and discussion on this topic, the authors propose that policymakers should reject double standards of this kind and instead embrace the challenge of implementing the highest standard of care on a global level. Thomas Nicholson, MIDP, is Associate in Research at Duke Center for International Development, Sanford School of Public Policy, Duke University, Durham, NC, USA. Catherine Adcock Admay, JD, is Lecturer of Public Policy at Duke Center for International Development and at Sanford School of Public Policy, Duke University, Durham, NC, USA, and affiliate faculty for Duke Global Health Institute, Duke University, Durham, NC, USA. Aaron Shakow, PhD, is Research Associate, Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, US, and Lecturer in History, Brandeis University, Waltham, MA, USA. Salmaan Keshavjee, MD, PhD, ScM, is Associate Professor of Global Health and Social Medicine, Associate Professor of Medicine, Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA, and Director, Harvard Medical School Center for Global Health Delivery, Dubai, United Arab Emirates. Please address correspondence to Thomas Nicholson. Email [email protected] Competing interests: None declared. Copyright © 2016 Nicholson, Admay, Shakow, and Keshavjee. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. Health and Human Rights Journal HHr HHR_final_logo_alone.indd 1 10/19/15 10:53 AM T. Nicholson, C. Admay, A. Shakow, and S. Keshavjee / TB and the Right to Health, 85-102 86 J U N E 2 0 1 6 V O L U M E 1 8 N U M B E R 1 Health and Human Rights Journal Introduction Between the late 1990s and the present, human rights activists successfully institutionalized the principle that the highest standard of clinical care for HIV is a public good. Although much remains to be accomplished in the treatment and prevention of HIV, this moral and pragmatic orientation enabled more than 15 million individuals out of an estimated 36.9 million people living with HIV to access antiretroviral therapy in 2015. AIDS-related deaths dropped by 42% between 2004 and 2014; new HIV infections in adults fell by 35% after 2000 and by 58% in children.1 Gains against HIV have not been replicated against TB, despite the fact that it remains the biggest killer of people living with HIV and is now the top infectious killer of adults in the world.2 This airborne bacterial disease has been treatable and preventable since the 1950s, yet kills 1.5 million annually—4,000 people each day.2 Although an estimated 9 million people are thought to become sick with TB each year, only 6 million are diagnosed and given some form of treatment. Of the 1 million children sickened by TB each year, a very small fraction receives care.3 Rates of TB have dropped a mere 1.65% per year despite a two-decade international effort led by the World Health Organization (WHO) to control the disease.4 Despite the reduction in deaths from TB since 1990, a worrisome aspect of the disease remains largely unaddressed in practice: drug resistance.5 Between 2000 and 2009, an estimated 5 million people were infected with multidrug-resistant TB (MDR-TB): strains of Mycobacterium tuberculosis resistant to isoniazid and rifampin, the backbone of first-line anti-TB therapy. Of these, an estimated 1.5 million died.6 According to WHO, 190,000 people died of MDR-TB and an estimated 480,000 cases occurred in 2014 alone; of these, only 123,000 were detected and reported; even fewer received appropriate treatment; and only half of those treated were cured.7 Almost 10% of these individuals were infected with extensively drug-resistant TB (XDRTB), difficult-to-cure strains of TB resistant not only to isoniazid and rifampin but also the drugs that form the backbone of the second-line anti-TB regimen (fluoroquinolones and parenteral agents).8 Without treatment, most people sick with any form of TB will infect people in their families and communities, and will eventually die from the disease. Despite the dangers of this airborne killer, for most of the 1990s, international donors, non-profit organizations, and national governments were advised by WHO not to treat patients infected with MDR-TB, but rather to focus on preventing the emergence of drug resistance.9 There were rationalizations for this policy: weak health systems in poor countries; lack of capacity to implement complex health interventions; even scientifically disproven ideas that drug-resistant strains would not be as transmissible. However, the driving force was a concern over cost.10 These MDR-TB policies from WHO were emblematic of a long-standing conflict between principles of cost-effectiveness and sound epidemic control strategies for TB in lowand middle-income countries (LMICs).11 The juxtaposition of arguments for equal treatment of those sick with epidemic HIV against the simultaneous failure of those arguments for global solidarity in relation to epidemic MDR-TB highlights significant gaps in human rights-based decision-making in global health. As rates of MDRTB shot up in the 1990s, policymakers were able to shroud substandard care in a discourse of cost that overrode the best available clinical judgment for a decade. The scientific standards of care which would otherwise have been appropriate to treat MDR-TB were thus systematically excluded in resource-poor settings. In this article, we discuss how a series of MDRTB diagnostic and treatment policies—driven primarily by economistic considerations and propagated by WHO from 1993 to 2002 may have led to hundreds of thousands of avoidable deaths, and set the stage for increased transmission of drugresistant strains. In endorsing double standards, excusing—and even mandating—failing to care for the sick living in low-resource settings, this approach simultaneously violated bedrock principles of scientific medicine and of human rights law. Our purpose is to advocate for accountability, oriented towards prospective policy transformation rather T. Nicholson, C. Admay, A. Shakow, and S. Keshavjee / TB and the Right to Health, 85-102 J U N E 2 0 1 6 V O L U M E 1 8 N U M B E R 1 Health and Human Rights Journal 87 than retrospective legal liability.12 Where contemporary decisions in favor of double standards are driven by similar cost considerations, we hope our analysis will give policymakers due cause to reject this approach.13 Multidrug-resistant TB and short-course chemotherapy Rifampin, an oral medication, is one of the most potent anti-TB drugs found in the 70 years since antibiotics first came into use.14 Before rifampin was introduced in the 1960s, the full course of treatment for TB took a year or more, often involving daily injections and hospitalization.15 Rifampin made it possible to cure TB in six to nine months. In wealthy countries, it became the cornerstone of short-course chemotherapy (SCC). Elsewhere, rifampin’s cost was considered prohibitive until years after the US patent expired in 1987. Before then, many public health experts advocated more toxic, less effective drugs for use in poor countries.16 It was eventually shown that a multidrug SCC regimen based on isoniazid and rifampin, supplemented with pyrazinamide and ethambutol, cured almost all patients who adhered to treatment—unless they were infected with a rifampin-resistant strain of TB.17 This regimen was soon regarded as the gold standard of empirical first-line care.18 Other studies had already demonstrated that home-based treatment was safe and highly effective when appropriately supervised.19 The reduced cost of drugs and clinicians for outpatient SCC made it attractive in settings with limited resources and infrastructure. Yet the well-known ability of disease-causing microorganisms to develop resistance during chemotherapy remained a challenge.20 It was soon established that monotherapy allows some M. tuberculosis organisms to evolve into drug-resistant forms, and anti-TB medications had to be taken in combination.21 Still, some people undergoing therapy were either not cured or suffered a relapse post-cure, often indicating that the infecting strain of TB was resistant to one or more of the medicines from the beginning—primary drug resistance—or that it developed resistance during treatment. Care providers turned to second-line anti-TB drugs, many of which cause a variety of treatable adverse events. Drug-resistant strains—which, like all forms of TB, are transmitted in families, communities, health facilities, and places of work, when appropriate treatment is not provided—require up to two years of treatment.22 In the late 1980s, outbreaks of MDR-TB were reported all over the US, most notably in New York City. Deploying clinical knowledge from national reference centers, the US dealt with the epidemic decisively. The treatment strategy, pioneered in the 1950s and 60s, included active case-finding, diagnosis using mycobacterial cell culture and drug sensitivity testing, second-line drugs, infection control, and delivery of care under direct observation and with patient supports. Health officials reined in the epidemic. Such comprehensive public health strategies, along with the use of second-line drugs, became the standard of care.23 As noted in one report from New York City in the early 1990s, clinicians found it “easy to prevent transmission by ensuring that patients with recently acquired disease are treated promptly, appropriately, and completely—ideally, with directly observed therapy (DOT).”24 The US outbreaks of MDR-TB foreshadowed a global problem. DR-TB was observed around the world, making it clear that SCC alone would not suffice.25 An “amplifier effect” of improperly applied SCC—where resistance to most drugs in a treatment cocktail allowed for the evolution of resistance to the other drugs in the cocktail—had been proposed in the mid-1980s.26 In 1995, the NGO Partners In Health (PIH) encountered an outbreak of MDR-TB in a slum area of Lima, Peru, and published evidence that that seemed to suggest such “amplification.”27 The Peruvian National Tuberculosis Program maintained a close working relationship with the WHO Global Tuberculosis Program, receiving extensive technical support from Geneva, and providing operational feedback for WHO recommendations.28 In 1995, Peru revised its guideline regimens under WHO supervision to include a standardized eight-month retreatment regimen T. Nicholson, C. Admay, A. Shakow, and S. Keshavjee / TB and the Right to Health, 85-102 88 J U N E 2 0 1 6 V O L U M E 1 8 N U M B E R 1 Health and Human Rights Journal which added the antibiotic streptomycin to the default regimen of four first-line drugs (isoniazid, rifampin, pyrazinamide, and ethambutol); the following year, WHO named Peru a “model DOTS program.”29 Yet retrospective analysis of laboratory samples makes clear that by adding a single drug to failing regimens, the retreatment protocol was promoting further resistance.30 In 1997, WHO published global guidelines for the treatment of DR-TB, advising countries to divide patients into ranked priority categories.31 The first category regarded new cases presumed to be infected with drug-susceptible TB strains. The next category included retreatment cases for whom six months of SCC had already proven unsuccessful; as in Peru, they were to receive the four drugs of SCC plus streptomycin. The third category included patients with extra-pulmonary TB or those whose sputum otherwise tested negative for TB. The last category included “chronic” patients who had failed the retreatment regimen.32 As these guidelines were being drawn up, the WHO Global Tuberculosis Program recommended a course of action to the Peruvian Ministry of Health following these categories, including a standardized retreatment regimen for so-called crónicos, the cost of which was less than one-fifth that of the regimen for MDR-TB patients being suggested to European countries.33 Instead of turning to the successful approach from New York City and elsewhere, Peru was advised to implement an untested standardized therapy.34 Although this involved 18 months of treatment with second-line drugs (at sub-therapeutic doses), it still included ethambutol and pyrazinamide. Because it did not involve drug sensitivity testing, a hallmark of the strategy used in New York, patients received second-line drugs to which they were already resistant. Unsurprisingly, the outcomes of this approach were poor: only 48% achieved cure and a significant number died.35 Many acquired further drug resistance.36 Echoing arguments of HIV activists, PIH rejected this double standard of care that triaged patients by their location in the global economy. Using outside resources, the organization demonstrated that the approach used to stem the New York epidemic—modified for community-based care in Lima’s slums—could achieve higher cure rates (83% probable cure for patients who received at least four months of treatment, and 66.3% validated cure for all enrolled MDR patients) and prevent death.37 DOTS and the political economy of MDR-TB On what was WHO advice to Peru based? A 1993 address by then-Director-General Hiroshi Nakajima gives some insight. Speaking to the World Health Assembly, Nakajima spoke of increasingly strong “working relationships with the World Bank (WB) and regional development banks,” adding that the agency “has been closely associated with the WB in preparing its 1993 report Investing in Health.”38 Three years later, armed with the published outcomes of TB treatment with the WB-funded medicines, Nakajima proclaimed “a new approach to improve compliance with treatment of TB (DOTS), first tested in Africa and China,” which he asserted were “successfully applied later in New York to overcome episodes of drug resistance.”39 The DOTS brand name (as it was called in subsequent WHO publications) was a portmanteau of DOT and SCC.40 Despite claims in the press, DOTS was mostly touted for its low cost rather than scientific rigor.41 While health officials in New York used DOT to monitor adverse events and increase treatment compliance, they did not rely on SCC to stop the spread of MDR-TB. The international response to the MDR-TB epidemic, however, focused on cost. Nakajima argued that treatment for a single patient in developed countries was “up to US$250,000,” which assumed two years of continuous hospitalization and was explicitly contradicted by government sources.42 A year after this claim, a cost analysis based on US data produced a figure of US$6,000-$8,000, assuming precisely the ambulatory treatment model adopted by PIH in Peru two years later.43 Meanwhile, the inflated figure of US$250,000 was used to imply that if DOTS and SCC were supplemented by the longer regimens that could cure MDR-TB patients, the cost-effectiveness of TB treatment, touted by both WHO and T. Nicholson, C. Admay, A. Shakow, and S. Keshavjee / TB and the Right to Health, 85-102 J U N E 2 0 1 6 V O L U M E 1 8 N U M B E R 1 Health and Human Rights Journal 89 the WB, would be undermined.44 WHO’s alliance with donors, including the WB, made it difficult for countries to reject WHO advice without putting national TB programs in financial jeopardy. For example, in approving loan funding for TB control, the WB relied on WHO as a gatekeeper in two key areas: (1) standardized global treatment protocols that were compared for conformity to country-level documents and practices; (2) the Model List of Essential Drugs (EDL) which, after its inception in 1977, formed the basis for standard formularies of international procurement agencies accepted by WB country-level staff in project planning.45 Not only did most health ministries rely on WHO’s EDL to compile their own formularies, they were often limited by law to these essential drugs in procurement for WB-funded projects.46 Even when WHO literature acknowledged that second-line drugs were the only way to treat MDR-TB, the contradiction with DOTS and the EDL on which it was based was resolved by an even more explicitly discriminatory and economistic rationale. For example, guidelines issued in 1997 by the Southeast Asian WHO Regional Office stated only second-line drugs could be effective against MDR-TB. However, the authors continued: “In many high-TB-prevalence countries, second-line drugs are prohibitively expensive and unavailable,” and thus: “Multi-drug resistant TB is... often untreatable.”47 It was not that patients with MDR-TB in poor countries were not being treated, or that a choice should be made not to treat them, but rather that, due to costs, they could not be treated at all. Even toward the end of the 1993-2002 period, this approach was pervasive. It informed the 2002-2003 editions of the EDL which include comparative cost-effectiveness, rather than simply effectiveness, as a criterion for inclusion of a drug, despite the fact that the stated purpose of the list is to make effective drugs more affordable.48 This circular approach prohibits, on the basis of cost, the inclusion of certain drugs whose pricing could be reduced through negotiation with manufacturers or other market mechanisms (for example, through an advance-purchase option or bulk purchases). It also shifts the focus away from clinical needs to an economistic rationalization of double standards based on one’s place in the global economy. This discrimination was and is compounded on a national level by the economic and political marginalization experienced by TB patients in general. WHO Director-General Nakajima stated that because of the high expense (again: “up to US$ 250,000 per case”), the conditions of treatment for MDR-TB “can be met only in the industrialized countries and in sophisticated hospital settings,” concluding that “for those who develop the disease in the developing world MDR is a virtual death sentence.”49 This pessimism was self-fulfilling. First, it was contradicted by price reductions in rifampin that had made the DOTS strategy itself possible. Second, it legitimated a crude application of cost-effectiveness criteria that neglected long-term epidemiological and fiscal impact. The pessimism also proved unrealistic. After a multi-national group of stakeholders convened to form a Green Light Committee for MDR-TB treatment—exchanging stringent programmatic oversight for lower drug prices from manufacturers concerned about the misuse of second-line anti-TB drugs—many programs successfully treated MDRTB in resource-limited settings.50 Countries like Russia and Turkey, with some capacity to support TB treatment without donor financing, refused initially during this period to adopt DOTS protocols.51 The Russian national program head went so far as to call it “soup-kitchen medicine,” but ultimately did accept DOTS protocols during the post-Soviet period.52 For many countries, the MDR-TB epidemic worsened from 1995 to 2005.53 For example, six years after Belarus adopted DOTS-based WHO treatment protocols almost identical to the ones rejected in the 1990s by PIH and others (including the United States Centers for Disease Control and Prevention), nearly half of diagnosed TB patients had either MDRor XDR-TB.54 WHO’s persistence in choosing to recommend sub-standard treatment regimens due to cost for treatment of DR-TB in these countries clearly had deadly stakes. In the circumstances, were human rights standards violated? T. Nicholson, C. Admay, A. Shakow, and S. Keshavjee / TB and the Right to Health, 85-102 90 J U N E 2 0 1 6 V O L U M E 1 8 N U M B E R 1 Health and Human Rights Journal Violation of WHO’s Constitution and ICESCR standards We proceed along two broad lines of policy-directed legal argument: one concerned with cost considerations and sound medical care; the other with the predictable elusiveness of equality—touchstone of a human rights regime—for vulnerable people. As to the first line: perhaps the most decisive factual consideration is the biomedical one. The standard of care, to which so many patients were subjected, did not actually meet the biomedical threshold for care. Re-treating TB patients with first-line drugs after they failed to respond, without any attempt to determine their sensitivity to those drugs, is not, properly speaking, providing patients with care. It is even less so when low-income countries are guided to ignore patients infected with MDR–TB. WHO has a distinctive constitutional burden and policy imperative to uphold the international human rights regime that drives towards the highest standard of health for everyone without allowing socioeconomic realities to invert medically sound care. Although a high-stakes debate exists among commentators about the legal acceptability of different standards of medical care for proven therapies—where some maintain that standards may vary according to state resource level—few would embrace WHO’s brand of cost-effective non-care as justified. As to the second line: we need to understand that WHO’s treatment protocol harmed the most vulnerable of TB patients with legally protected interests. The reason to recognize this harm—and its unacceptability within the human rights regime—is to help foster transformative accountability, moving away from double standards.55 Our policy-oriented legal analysis follows. At the threshold, we account for the relevance to the actors of the sources of law. Next, we identify relevant legal standards from WHO’s Constitution and the International Covenant on ESCR (ICESCR). Finally, we discuss those standards in light of our two broad lines of policy concern, taking into account anticipatable legal counter-argument.