Greater moral imagination (the ability of individuals and communities to empathise with others) and innovative 21st century approaches are required to break the impasse we currently face in improving global health . . . The quest for improved global health will be elusive if we continue to neglect the upstream forces that cause, sustain, and aggravate the poverty and misery that characterise the lives of almost half the world's population. The writing is on the wall.1
The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic in Africa has raised important ethical issues for both researchers and clinicians. The most notorious controversy has been related to the zidovudine (AZT) trials in Africa in the late 1990s, in which the control groups were given a placebo rather than an effective drug to prevent vertical transmission. This raised concerns in the sponsoring country about exploitation of subjects, injustice and an ethical double standard between donor countries and resource-poor settings. However, the real double standard is between clinical practice standards in Western versus African countries, which must be addressed as part of the increasing global inequity of wealth both between countries and also within countries. There are important limitations to ethical declarations, principles and guidelines on their own without contextual ethical reasoning. The focus on research ethics with the HIV epidemic has led to a relative neglect of ethical issues in clinical practice. Although the scientific advances in HIV/AIDS have changed the ethical issues since the 1990s, there has also been progress in the bioethics of HIV/AIDS in terms of ethical review capability by local committees as well as in exposure to ethical issues by clinicians and researchers in Africa. However, serious concerns remain about the overregulation of research by bureaucratic agencies which could discourage African research on specifically African health issues. There is also a need for African academic institutions and researchers to progressively improve their research capacity with the assistance of research funders and donor agencies.
A major challenge of bioethics is bringing ethical considerations to bear meaningfully on clinical practice in Africa. One would have to say that it has been rather unsuccessful in meeting this challenge to date. Nowhere is the contrast between paediatric practice in Africa compared with developed countries more stark than in dealing with human immunodeficiency virus (HIV) infection, particularly in Southern Africa with the highest prevalence of infection and where the epidemic continues unabated, disproportionately affecting women and children. With the assistance of donors – notably the Global Fund and US President's Emergency Plan for AIDS Relief (PEPFAR) funding – there has been significant improvement in the availability of antiretroviral therapy (ARVs) and in prevention of mother-to-child transmission (PMTCT).
Nevertheless, major constraints in human resources for health in Africa – related partly to out-migration to developed countries such as Australia – and various logistical, financial and socio-cultural issues mean that this progress is now under threat.2 In Zambia, for example, the number of facilities providing PMTCT services increased from 67 to 678 between 2005 and 2007.3 The often impossible decisions needing to be made by health professionals managing children with HIV infection with scarce resources has led to a change in emphasis in medical ethics away from autonomy and beneficence to social justice. It is the sheer scale of the epidemic that has made justice such an important ethical issue in Africa because, in spite of the availability of lower cost ARVs in recent years, there is a logistical impossibility of treating all HIV patients with these drugs, even when indicated by current evidence.4
The ethical debates on HIV have focused mainly upon research, perhaps to the relative neglect of clinical practice issues in Africa. Since the author is based as a paediatrician in the Southern African region, where the consequences of acquired immunodeficiency syndrome (AIDS) are at its worst, this paper will also attempt to focus on the clinical realities of child health in this region from both a scientific and ethical perspective, trying to avoid any accusation of Western ethical pontificating by an armchair academic. In the words of Professor Solomon Benatar,5 who has made a major contribution to the bioethics of HIV, which I would like to acknowledge, the ‘relegation of the ethics debate to the pristine luxury of Western academics and armchair philosophers is a classic mistake, and makes many of the arguments irrelevant to much of the developing world’.6
One might fairly ask about the author's credentials to discuss ethical issues. In addition to a degree in philosophy, I have had many years of experience on human research ethics committees (HRECs). This may not constitute adequate training in ethical reasoning, and in any case this is not the forum for detailed philosophical arguments. Therefore, consider this paper as reflections upon the issues in the bioethics literature by a paediatric practitioner with long experience in developing countries. With the benefit of hindsight, I encountered my first cases of AIDS in Southern Zimbabwe in 1983 as fatal kwashiorkor in breastfed infants. Since then, I have witnessed the epidemic unfold in the Gambia, Malawi and now Botswana. It is difficult to exaggerate the devastating effect of this epidemic upon these African communities as well as the dramatic impact upon paediatric practice. However, the aim of this paper is to present some of the key ethical controversies that HIV/AIDS has raised in the medical literature as it relates to the effect of this epidemic on paediatric research and practice in Africa.
- 1Ethical guidelines do not resolve ethical issues without contextual ethical reasoning.
- 2HIV/AIDS research in Africa has been plagued with unfair accusations of an unethical double standard.
- 3The real ethical issue is the injustice of the inequity of clinical practice and health resources between African and western countries.
The key ethical issue of global health remains the enormous inequity in standards of clinical practice and health outcomes. Benatar has described global health ethics as a ‘means through which to promote . . . values that include meaningful respect for human life, human rights, equity, freedom, democracy, environmental sustainability, and solidarity’.7 He gives six reasons for the failure to improve global health (Table 1). Global inequity is clearly increasing at an unprecedented rate despite the Millennium Development Goals, with the gap between the income of the richest and poorest 20% globally having increased from a ninefold to a 30-fold to an 80-fold difference from 1900 to 1960 to 2000, respectively.7 In terms of HIV/AIDS, the focus of the ethical debate has been upon drug availability in the context of research. When the author worked in Malawi in the mid-1990s and a third of pregnant women were HIV-infected, zidovudine (AZT) was unavailable because the cost for a mother and child was more than 600 times the annual per capita allocation for health care.8 Researchers in Malawi at the time were criticised for not providing zidovudine to all research subjects, but this same concern was not extended to the many hospital patients with HIV infection who were not research subjects but had no access to zidovudine.
|1. Greater interest in doing research to acquire new knowledge than in using existing knowledge|
|2. Importance of market forces over health needs on medical practice|
|3. Only transient concern for unhealthy deprived populations, whose lives are less highly valued|
|4. A focus on new technologies and narrow (‘silo’) approaches to improving global health|
|5. Neglect of the social determinants of health|
|6. Inability to address the complex global system forces that underlie poverty and disease|
Even today, when ARVs are readily available to all Botswana citizens, outcomes of HIV-infected infants both in research publications as well as in clinical practice are still much worse than in developed countries.9–11 A recent review, for example, compared 40 developing and 28 developed country publications involving almost 20 000 subjects and found a significantly higher mortality after ARV treatment (highly active antiretroviral therapy (HAART)) in developing than developed countries (7.6 vs. 1.6, P < 0.001).9 This discrepancy in outcomes in published studies is of course much greater in non-research settings in Africa. But the inequity extends well beyond availability of drugs to include the standard of care such as the quality of nursing care, laboratory services, intensive care and even availability of transport. Outside of the research context, these issues have tended to be ignored in ethical discussions of HIV in developing versus developed countries. Perhaps this is related to unease about these inequities in health care on the part of Western doctors, part of the so-called ‘white man's burden’, which constrains frank discussion of these issues.
Global inequity in health standards is only part of the problem. A recent book on the issue of health inequalities documents the importance of income differences within societies.12 Although the authors focus on the USA and other developed countries, they provide convincing evidence of the importance of equity upon a wide variety of health and welfare outcomes. The more unequal societies (USA, UK and Australia) demonstrated consistently worse health and welfare outcomes than those with more equality of income distribution (Japan and Scandinavian countries). If improving global health is an ethical priority, this evidence suggests that economic growth alone is unlikely to achieve this without also reducing economic disparities within developing countries.
The bioethics literature on HIV/AIDS has mostly concentrated upon research ethics, so let us commence with the notorious zidovudine (AZT) controversy. Although the specific details of ARV drug availability have changed over time, it remains a relevant illustration of the kind of ethical issues that arose from the HIV epidemic in Africa. The story commenced in 1994 with the publication of the ACTG 076 study of zidovudine to reduce the risk of maternal–infant HIV transmission in HIV-infected pregnant women from 14 to 34 weeks gestation.13 This original zidovudine regimen included antepartum zidovudine orally five times daily, intrapartum zidovudine given intravenously until delivery and zidovudine for the newborn orally 6-hourly for 6 weeks. The proportions infected at 18 months were 8.3% (95% confidence interval (CI) 3.9–12.8) in the zidovudine group and 25.5% (CI 18.4–32.5) in the placebo group. The cost of zidovudine at the time was more than US$800 per mother and infant, which was obviously much more than African countries could afford,8 so the crucial question was whether a less expensive regimen was also effective in reducing transmission. The resulting studies to address this African issue – some of which were conducted under the auspices of the World Health Organization (WHO), the Joint United Nations Programme on HIV/AIDS, the Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) – were only embarked upon after serious consideration of the ethical and scientific issues posed by such research. The placebo-controlled trial designs were approved by ethics committees in both the sponsoring countries as well as the countries in which the trials were conducted where zidovudine was otherwise unavailable.
The controversy commenced in 1997 when the Public Citizen Health Research Group (PCHRG) in the USA criticised the trials, especially those funded by the USA, calling for them to either be terminated or effective prophylaxis to be provided for all participants, since the results of the ACTG 076 study made a control group unethical. Nevertheless, the US government reaffirmed support for the placebo-controlled studies after an assessment by the directors of the NIH and CDC of the design and ethical issues. However, this was not the end of the debate as it was rejuvenated in the New England Journal of Medicine by Lurie and Wolfe of the PCHRG, with an accompanying editorial by the journal's editor, Marcia Angell, supporting their position. Angell expressed scepticism that the local standard of care was different in Africa or that diseases and their treatments were very different, concluding that ‘people everywhere are likely to respond similarly to the same treatment’.14
This seemed a startling statement for those of us working in Africa at the time, as if external generalisability of the ACTG 076 results was unproblematic. If one permits a reductio ad absurdum argument, it implied that clinical research in neonatology in Africa would be unethical without first establishing a neonatal intensive care unit with Melbourne standards of care. Angell also invoked the notorious Tuskegee Study sponsored by the US Public Health Service from 1932 to 1972, in which poor African American men with untreated syphilis were followed to determine the natural history of the disease even after penicillin was known to be highly effective treatment.14 The analogy with the zidovudine studies hardly bears scrutiny as – unlike the syphilis study – these underwent serious ethical scrutiny before, during and after implementation. If one uses an analogy with clinical reasoning, this influence of the prior Tuskegee case would be considered an availability bias, exerting an exaggerated and inappropriate influence on reasoning about the zidovudine issue.15
Even ignoring cost considerations, there were feasibility issues around women to present early in pregnancy for HIV testing, to receive counselling about their HIV status, to comply with a lengthy oral regimen, to receive intravenous administration during labour, to refrain from breastfeeding, to administer 6 weeks of oral treatment to their newborn infants and to be monitored for adverse effects of the drug (especially anaemia). The issue of formula feeding in the African context raised major concerns about the dangers of poor hygiene leading to diarrhoea and the high cost contributing to malnutrition.
The difficult question was whether we should allow a ‘double standard’ of research ethics, one for the rich and one for the poor; and, if so, was it still possible for the developed world to pay for research that would be considered unethical at home? Lurie and Wolfe16 expressed concern about the potential exploitation of residents of impoverished, post-colonial countries and the hundreds of infants who have needlessly contracted HIV infection in the perinatal-transmission studies, seemingly ignoring the hundreds of thousands of infants infected outside of studies due to the cost of zidovudine. They also made frequent reference to the undesirability of a double standard of ethics, but the double standard of care between what was expected in research studies and what occurred in normal clinical practice within Africa was largely ignored or denied. The real double standard was not in the way the trials had been conducted but in the inequity of access to medicines between rich and poor countries.17
Declaration of Helsinki
The question then arises as to what basis can we use to make a rational judgement that a study is unethical? In this particular ethics debate, the Declaration of Helsinki was invoked as providing the fundamental guiding principles of research involving human subjects. The key relevant principles at the time were as follows:
- 1In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.
- 2In any medical study, every patient – including those of a control group, if any – should be assured of the best proven diagnostic and therapeutic method.18 (my emphasis)
As a result of the zidovudine controversy, the Declaration of Helsinki was revised in 2008, with the relevant section changed to:
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances:
• The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or
• Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.19
At face value, these revised guidelines seemed to concur with the view that these zidovudine studies were unethical, since the infants of the HIV-infected mothers in the control groups were at risk of contracting the infection and suffering serious harm without zidovudine as the best proven intervention. Indeed, a literal interpretation of the new guidelines could imply that even the intervention groups were not receiving the best proven intervention (namely the ACTG 076 regimen), which would have disallowed many important further studies that proved to be significant advances. Thus, deontological declarations without contextual ethical reasoning were really unable to resolve the issue satisfactorily.
Council for International Organizations of Medical Sciences (CIOMS) guidelines
In addition to the Helsinki Declaration, an alternative set of guidelines was developed by the CIOMS, which aimed specifically to address ethical issues in developing countries, including the placebo-controlled trials issue. In this document, guideline 3 stated that researchers working in developing countries had an ethical responsibility to provide treatment that conforms to the standard of care in the sponsoring country.20 Guideline 10 specifically dealt with the issue of research in populations and communities with limited resources, stating that before undertaking research in such communities, both sponsor and investigator must ensure that the research is responsive to the health needs and the priorities of the community, and any knowledge generated will be made reasonably available for the benefit of that community. Guideline 11 was directly relevant to the zidovudine issue, stating that:
research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive intervention should receive an established effective intervention. . . .Placebo may be used . . . when use of an established effective intervention as comparator would not yield scientifically reliable results and use of placebo would not add any risk of serious or irreversible harm to the subjects.20
The UK Nuffield Council on Bioethics interpreted ‘best proven’ as the standard of care available as part of the national public health system, which should be the minimum standard of care offered to the control group.21 Similarly, an important consensus workshop in 1999 concluded that there were circumstances in which a no-antiretroviral comparison may be ethically justified.22 A sort of compromise position was that internationally funded research would have to provide the best available treatment in the sponsoring country to the control group, whereas locally funded studies need only provide treatment consistent with the realities of health care in the country where the study was conducted. In either case, the justification of a placebo arm in a trial requires careful consideration of potential harms and benefits in specific contexts and cannot be simply deduced from any general declaration. That is one of the roles of HRECs, which had in fact approved the controversial zidovudine studies. Nevertheless, strong views continued to be expressed on both sides of the issue in correspondence to the major journals.
What happened in practice after this controversy? According to a systematic review of HIV, tuberculosis and malaria trials in Africa in 2004, HIV trials continued to use local standards.23 Out of 73 trials in the review, only 12 provided care meeting guidelines for both control and intervention groups. For HIV prevention trials, only one out of 34 complied with treatment guidelines. There was no correlation between source of funding and conformity to standard guidelines. So it seemed as if researchers and ethics committees continued to take local standards of care into account, rather than international guidelines, when performing HIV clinical trials in sub-Saharan Africa. This may have been because researchers chose to recognise that local levels of care should be applied if the results were to be relevant to the target population because the research questions were mainly addressing specifically African issues.
A deontological (as opposed to purely consequentialist) approach to resolving ethical conflicts is through the use of ethical principles, which should be familiar to readers (e.g. the Golden Rule). Bioethical principalism was articulated clearly by Beauchamp and Childress in their bioethics textbook.24 They proposed four principles that have since been reduced to three: (i) respect for persons (the recognition of the right of persons to exercise autonomy), (ii) beneficence, including non-maleficence (the minimisation of risk of harm to research subjects and maximisation of benefits), and (iii) justice (the principle that research should not unduly involve subjects from groups that are unlikely to benefit from the results of the research). While helpful, these principles do not always resolve ethical issues any more than the Helsinki Declaration ended the zidovudine controversy. There was no disagreement about the need for informed consent, which all the trials had obtained. The right to exercise autonomy, however, was seen as a specifically Western value of possessive individualism, which did not always apply fully in developing countries with more community-oriented values. But the real question was whether it was ethical to test interventions against a placebo control when an effective intervention was in use elsewhere in the world.8 Many saw this as exploitation of the poor in developing countries, whereas others saw it as vital research addressing locally relevant health issues.
There had also been a change in thinking from a focus on the burdens of participation in research (beneficence) to equitable access to clinical trials (justice). As noted already, the distribution of wealth among the nations of the world is inequitable, but this is also true for research. Commentators noted the injustice of 90% of all medical research being undertaken on diseases that cause 10% of the global burden of disease (10/90 gap). Although research ethical guidelines may not be able to fix this misdistribution, they should not impede researchers and funding agencies from assisting African countries in their efforts to develop affordable and feasible treatments. After all, developing countries deserve research that addresses their health needs. Given the limited resources and research capacity in Africa, it is recommended that all sponsored research in Africa should also increase research capacity through resource sharing, particularly of training resources (around ethics, research conduct and research capacity) in order to reduce the so-called ‘brain drain’ from the developing world. This is the opposite of the CIOMS recommendation that studies not be done in developing countries if they can be done in better-resourced nations, which would only worsen the existing 10/90 gap in research funding.
The irony of the zidovudine issue was that studies that were likely to benefit African communities and were not applicable to developed countries were declared unethical by moral dogmatists in developed countries. Without invoking ad hominem arguments, there was a distinct feeling that in the intense competition for research resources within developed countries, ethics was being exploited to limit the leakage of sponsored funding overseas. Certainly, it had the effect of greater scrutiny of such developing country studies, which has made them more difficult, frustrating and expensive to implement. Clearly, the historic practice of testing pharmaceutical products in developing countries without ensuring access for residents of the host country to the benefits of the research is no longer acceptable.25 Moreover, it is now generally accepted that there is an ethical obligation of developed country researchers and sponsors who are involved in research in developing countries to contribute to sustainable improvements in health and research capacity in order to help improve the standard of care for research participants and their communities.26 However, it is unclear how seriously this obligation is taken by commercially funded pharmaceutical research.
There were also methodological issues raised by the controversy. Opponents of the trials argued that ‘equivalency trials’ should have been used, comparing a lower cost zidovudine regimen with the ACTG 076 regimen instead of a placebo, as was done in a Harvard-sponsored Thai study.16 However, the aim of the zidovudine research was to provide definitive answers about the safety and value of the intervention in the setting in which the study was performed. It is difficult for African countries to make informed judgements about the appropriateness and financial feasibility of providing interventions without placebo-controlled trials that offer more definitive answers. Varmus and Satcher have argued that, unlike an equivalency trial, a placebo-controlled trial may be the only way to obtain an answer that is ultimately useful to people in similar circumstances.8
Even before the zidovudine controversy, researchers and clinicians had expressed concern about placebo-controlled trials of new drugs that failed to answer the question of whether the new drug was better than existing treatments (e.g. in asthma). However, it is worth noting in passing that, more recently, concerns about the external generalisability of randomised controlled trials (RCTs) to the real world have led to the emergence of a new research design, called ‘pragmatic trials’, which have demonstrated different results from RCTs.27,28
There was another more philosophical aspect to this zidovudine ethical controversy. The alleged double standard was seen as further support for the ethical relativism of postmodernism in social science and a denial of the possibility of universal ethical standards for research on humans. A full discussion of this issue is beyond the scope of this paper, but Benatar has pointed out that failure to distinguish moral relativism from the morally relevant considerations of context shows a lack of knowledge of the ethical decision-making process.29 He argues that it should be possible to justify by rational arguments the appropriate conduct of research in different contexts while avoiding both ethical imperialism and ethical relativism. In his own words:
those who dogmatically insist that what is ethical can be simply deduced from declarations, have failed to understand that just as constitutions may require complex legal interpretation, so declarations about ethics may require moral interpretation. Lack of insight into the way in which formal ethical principles have to be implemented with appropriate specification in different contexts, leads to ‘cookbook’ application of abstract principles and obstructs deeper understanding of what can be justified through ethical reasoning.30
The advent of evidence-based medicine has meant that we insist upon actual evidence to support our practice. What can we use to defend our ethical views? This has been a key philosophical issue since David Hume pointed out the naturalistic fallacy of deriving an ‘ought’ (value) from an ‘is’ (fact). Indeed, many postmodern thinkers have argued that ethical statements, including even to proscribe child abuse, express no more than individual likes and dislikes, thus denying the possibility of objective ethical truth. Three notable recent books have attempted to salvage ethical truth by appeals to human well-being supported by reasoned ethical arguments31 or by more of a scientific perspective.32,33 Readers with a philosophical bent are encouraged to pursue the issue further.
Finally, of course, the specific details of the PMTCT research question have changed dramatically since 1997. Firstly, ARVs are much more widely available in sub-Saharan Africa at a much lower cost. Secondly, there is clear evidence of the harm of bottle feeding with formulas because of increased diarrhoeal morbidity and mortality. Thirdly, research methods have moved on from the narrow concept of one study being definitive and rendering any further use of a placebo group unethical, in part due to the rise of systematic reviews that combine the results of multiple studies of similar methodology. The key PMTCT issue at present is how to enable exclusive breastfeeding in HIV-infected mothers by either starting them on HAART early in pregnancy regardless of immune status and/or preventing breastfeeding transmission of HIV using more long-term nevirapine treatment of the infant (rather than the single dose). The key concerns at present are compliance with exclusive breastfeeding34–36 and the emergence of drug resistance.37,38 This illustrates how the ethical issues have evolved with scientific advances and the reduced cost of ARVs, hence the need for contextual ethical reasoning.
The establishment and support for HRECs in Africa has been an important step forward in regulating research and ensuring a local perspective. Table 2 gives the requirements of ethical research review from an African perspective. However, a survey of 31 HRECs in sub-Saharan Africa identified serious areas of weakness in their operations, including scarcity of resources, inadequate training of members and poor staffing levels.39,40 The training issue in ethics is being addressed with the assistance of US and South African sponsors, including the Fogarty International Center. But the key constraints are the excessive workload, lack of biomedical and ethical expertise in smaller centres and unwillingness of experienced researchers and clinicians to participate in this time-consuming and often frustrating exercise.
|1. Analysis of the value of the research in terms of potential to improve health and/or knowledge|
|2. Scientific validity of design|
|3. Fair selection of participants|
|4. Favourable risk : benefit ratio with potential benefits outweighing potential risks|
|5. Independent ethical review of the research before implementation|
|6. Informed consent that encourages voluntary participation|
|7. Respect for the participants recruited|
|8. Community engagement with communities as partners in research|
In developed countries, concerns have been expressed about excessive regulation of research, particularly unreasonable bureaucracy, excessive documentation for ethics committees and resulting delays in the processes.41 Sadly, these problems are now being exported to Africa, including requirement that all clinical research accords with the International Committee of Harmonisation's guidelines to Good Clinical Practice, which were written primarily for commercially driven drug-registration studies and rely on specific operational rules and institutional resources. Such detailed rules and requirements may discourage clear ethical thinking and indirectly discourage responsible practice by allowing researchers, sponsors and institutions to bypass ethical issues of poverty and inequity.42 Recently, researchers in Thailand and Kenya have called for new sensible guidelines that can be adapted for all types of clinical research in different settings.43
There can be no doubt that the high-quality HIV research in Africa sponsored largely by US funding agencies has been beneficial, so it would be tragic if excessive regulation and bureaucracy greatly diminished such investment in the health sector. There is a serious threat from both a reduction in available resources for HIV/AIDS research as well as from anti-American and anti-research lobbies exploiting the ethics bandwagon. On the other hand, it is an agreed priority to progressively transfer this research capacity to the indigenous academic institutions and researchers in African countries.
Informed consent has become established as the cornerstone of research ethics. There are of course well-recognised difficulties in obtaining informed consent in cross-cultural settings, but these are also faced in multicultural settings in developed countries such as Australia. In addition to communication problems that can be dealt with by interpreters, there are also cultural issues that the investigative team needs to understand. In obtaining consent from impoverished subjects, it is generally accepted that excessive inducements to participate are unethical. Returning to the zidovudine controversy above, an obligation to provide life-long treatment to subjects infected during a trial could be considered an unethical inducement in regions where the health services might not be able to provide this at no charge.
The researcher–clinician may be faced with a conflict of obligations when he or she is both the investigator and the provider of patient care, as has been the case for the author. The interest in carrying out the research and eagerness to enrol research subjects may inadvertently take precedence over the need to protect the interests of research subjects. On the other hand, in the African setting, the choices may be stark for potential research subjects and their carers, between admission to a research area with a good standard of care but additional testing that may not always be of direct benefit, compared with admission to a general ward with limited nursing and medical care even if the same drug treatments are available. Poor, illiterate mothers can still see the trade offs and are quick to see the best option, yet may well resist what they perceive as inappropriate procedures for research purposes. It is difficult to see how increasing regulation would improve this situation, especially if one sacrifices the goodwill of researchers in the process.
Note that even in clinical practice in Africa, one is increasingly faced with mothers/carers refusing procedures such as lumbar puncture, nasogastric feeding or surgery, and administering harmful traditional remedies, inappropriately from a scientific perspective. But African notions of illness often use explanations in terms of ancestors, magic beliefs, authority figures and other strange concepts from a Western secular individualism perspective. It is often very difficult to appreciate what is in the mother and infant's best interests without a better understanding of their social context. It demands not only self-knowledge and a critical appreciations of one's own cultural traditions, but also the ability to imagine what it is like to be in their situation. Good communication is essential but is also very time consuming. Good medical practice may need to be grounded in good ethics, but it also takes time which is in short supply in busy clinics and ward rounds with inadequate staffing.
In the research context, the focus on protection of research subjects through informed consent in research protocols has led to excessive bureaucracy and legalism at the expense of improved monitoring and actual conduct of the research.44 Sponsors often require detailed consent forms that are intimidating for parents of subjects with low literacy levels. They reflect over-regulation of the clinical trials industry, as if mere compliance with regulations about what to include in consent forms ensured that the research met high ethical standards. A Tanzanian approach to informed consent may represent a model for researchers conducting HIV prevention trials among other vulnerable populations in resource-poor settings.45 This HIV study of microbicides showed that providing information to trial participants in a focussed, locally appropriate manner, using methods developed in consultation with the community, and within a continuous informed consent framework resulted in high levels of comprehension and message retention. Another innovative approach used in Haiti included the use of an educational video combined with an educational session with a counsellor during informed consent for an HIV prevention trial, which was associated with good message retention.46 The need to consider informed consent as a process rather than a discrete activity at study entry has increasingly been recognised in both developed and developing country settings.
Confidentiality and opt-out testing
The importance of maintaining medical confidentiality has been heightened by the HIV/AIDS epidemic due to the social stigma of the disease. At the same time, the need to control the spread of infection means that maintaining confidentiality must be balanced against the common good of preventing transmission.47 Confidentiality and individual pre-counselling before HIV testing were very sensitive issues early in the African epidemic, but artificial feeding makes it easier to identify infected mothers. In any case, with over a quarter of adults infected in many regions, the stigma of HIV has lessened, and of course homosexuality is not an epidemiological feature of African HIV. So the ethical issue in southern African settings is the 2007 WHO guidelines recommending expanding testing to all adults accessing health-care facilities in settings with high HIV prevalence unless they explicitly opt out.48 The intention is to catch the middle group of so-called ‘gap patients’ who would only be tested with an opt-out approach (i.e. would not bother being tested when asked for formal consent), as it would not affect consistent accepters and decliners.
Some ethicists have argued that opt-out testing is inconsistent with the ethical principle of patient autonomy. Taking a consequentalist perspective, April argues that the improved public health outcomes of opt-out screening with increased detection when ARVs are available clearly outweigh the loss of autonomy and possibility of discrimination.48 He also examines the issue from a deontological perspective of protecting individual rights, but where the right to autonomy can be infringed to protect others' welfare, which he calls the doctrine of libertarian paternalism. This view allows encouragement of people to make welfare-maximizing choices without being coercive. Since individual preferences are always affected by the way choices are framed by policymakers, it is impossible to avoid influencing a patient's choices. Therefore, April argues that it would be better to apply it in ways that lead to better health outcomes. He concludes that opt-out testing would be an effective public health response to Africa's epidemic that is ethically acceptable by the criteria of both popular moral theories.48 However, both of these arguments hinge upon consequentalist arguments, so it is doubtful that all libertarians would be convinced, especially those who are opposed to the enforced wearing of seatbelts. Nevertheless, one is tempted to apply the concept of opt-out testing for minimally invasive procedures such as lumbar punctures in clinical practice, which would also lead to improved outcomes if applied judiciously.
For paediatricians who have been active in breastfeeding promotion in developing countries, the HIV epidemic has been a major setback. The latest Cochrane review on interventions for preventing late post-natal mother-to-child transmission of HIV reported that breastfeeding with zidovudine prophylaxis and formula feeding had comparable HIV-free survival rates at 18 months and extended nevirapine prophylaxis demonstrated efficacy with exclusive breastfeeding.49 However, although there now seems a way to breastfeed safely with minimal risk of HIV transmission, it seems doubtful that we will be able to reverse the trend to artificial feeding in Southern Africa in the near future.
In Botswana, the provision of free formula milk to all HIV-infected mothers (excluding non-citizens) as part of the PMTCT programme has dramatically increased the morbidity and mortality from diarrhoeal disease and malnutrition because of unhygienic and improper artificial feeding.10,50,51 If breastfeeding is initiated, either exclusive breastfeeding during the first few months of life or chronic antiretroviral prophylaxis to the infant (nevirapine alone, or nevirapine with zidovudine) are efficacious in preventing transmission.49 In clinical practice in Botswana, one is overwhelmed with the adverse consequences of improper bottle feeding of infants exposed to HIV. At least in the short term, interventions to reduce transmission from breastfeeding in HIV-exposed infants are likely to be a more effective than trying to make formula feeding safe, even when the cost of formula is not an issue.
A related ethical issue for wealthier African countries with a high HIV prevalence is the provision of ARVs to non-citizens, particularly as part of a PMTCT programme. In Botswana, for example, Zimbabweans have to pay all their health-care costs, whether illegal or legal migrants. This results in many infant infections and deaths that are preventable. Expatriate paediatricians feel considerable moral unease about this situation, but fortunately, there are now some sources of external assistance for such patients.
The eloquent Canadian politician and former UN special envoy for HIV/AIDS in Africa, Stephen Lewis, believes that the international community has failed in its duty to implement male circumcision, which he argues should have been implemented a decade ago to be done at the same time as an immunisation visit.52 Although both the American and Australian/New Zealand official paediatric policies acknowledge the potential benefits, they do not recommend routine neonatal circumcision. What is the scientific evidence? Large recent African trials of circumcision in adult males decreased HIV acquisition by 50–60%, herpes simplex virus type 2 acquisition by 28–34% and human papillomavirus prevalence by 32–35% in men.53–55 With this evidence, the WHO in conjunction with the Joint United Nations Program on HIV/AIDS now recommends that male circumcision be provided as an important intervention to reduce heterosexually acquired HIV in men.
For paediatrics, the issue is circumcision at birth. There are ethical and human rights concerns about elective infant male circumcision because there are risks to the procedure, it causes bodily mutilation and the infant is unable to consent. The rates of neonatal circumcision complications vary, but the accepted rate is 0.2–0.6% of operations, mostly from bleeding and local infection. Complications of adolescent or adult circumcision are higher, so it is argued that the potential benefits justify the procedure soon after birth and that parents have the right to consent for their minor child, as they do for immunisations, which also have risks but confer long-term benefits.56 Of course, there are also other benefits to the earlier procedure such as prevention of urinary tract infections. With low rates of male circumcision and high rates of HIV in Southern Africa, neonatal circumcision could have a significant effect on prevalence, but it would take another 20 years for its effect, might have a low acceptance rate and requires substantial human resources to implement compared with condoms.57,58
Intensive care resources
Another difficult ethical and practical issue provoked by HIV/AIDS is the increasing demands on limited intensive care services in developing countries from the large numbers of infants presenting with Pneumocystis carinii pneumonia (PCP) requiring ventilation in intensive care units (ICUs). Such units are increasingly available in larger hospitals in Africa, although the outcomes from ventilating infants are often poor in adult-oriented units. Ideally, decisions on managing this disease should be made on the best available evidence of outcomes and the ethical principles guiding appropriate use of scarce resources. But even when outcomes are abysmal, it is difficult to refuse admission if an ICU bed is available. A South African report suggests that there are at least three ethical questions to be asked: are there clinical and moral reasons for admitting HIV positive children with PCP to the paediatric ICU, should more resources be committed to caring for HIV children who require an ICU and how can we morally choose candidates for the ICU?59 Due to the large number of cases in Southern Africa, there are difficult decisions on effective triage of admissions of HIV infected children with PCP based on individual case presentation, availability of resources and applicable ethical principles.
In Botswana, we would like to offer CPAP on the paediatric ward to as many infants as would benefit, but if there is an adult ICU bed available, it is difficult to decline it despite abysmal outcomes for infants. There are clearly higher health priorities than more or better ICU services, and if ventilation is not life saving then surely it should be ceased. In ethical terms, this means adopting a utilitarian approach to care depending on the context. But by refusing ICU care to these infants – in spite of the abysmal results – are we practising paternalism under the guise of evidence-based medicine and abrogating our responsibility of non-maleficence?59 Perhaps it is better to allow the infant to die of his disease while providing basic care than to prolong suffering and the infant to die of iatrogenic complications of ventilation. Although one would like to believe that any money saved would be put to better use, such a belief is probably naïve in this setting. It is easy to take the high moral ground, but the practical realities on the ground make clinical decision-making very difficult.
The ethical issues raised by the HIV epidemic in Africa have generated important and interesting debates. Just as there have been significant advances in the management of HIV-infected children, there has also been progress in our understanding of the ethical issues. The limitations of ethical declarations, principles and guidelines alone in solving ethical issues has been illustrated by the nevirapine controversy. Both ethical dogmatism and relativism seem less tenable than a position of contextual universalism in conjunction with ethical reasoning, which circumvents a double standard of ethics. The research ethics committees and processes in Africa have been greatly strengthened in recent years, but there are now concerns about excessive and inappropriate regulation.
On the debit side, we have also seen a democratic government denying that HIV was the cause of AIDS despite the scientific evidence. It is estimated that between 2000 and 2005, South Africa's decision cost more than 330 000 lives and 35 000 infected infants by not implementing a feasible ARV treatment and PMTCT programme.60 But we have also seen medical activism in that country help reverse this situation and also successfully pressure pharmaceutical companies to reduce the cost of ARVs. The HIV epidemic in Africa has also raised global awareness of the injustice of the inequity of global health-care standards. But there is a global inability to redress this inequity of wealth, which greatly contributes to the disparity in health outcomes of the poor due to the social determinants of health. As Benatar indicated in the opening quotation, the writing is on the wall, and we can no longer afford to ignore it.