ACCESS TO ANTIRETROVIRAL THERAPY IN RESOURCE-POOR SETTINGS Author: Joep MA Lange, MD PhD

Until quite recently, bringing antiretroviral therapy to severely resource-constrained countries was not considered to be a priority. It was widely felt that in these settings a preventive HIV vaccine is the only way to win the war. Antiretroviral therapy was perceived to be too expensive, complex, to pose impossible monitoring demands, and to drain valuable resources from more important prevention efforts, to mention just a few of the often-voiced concerns. However, both from a humanitarian as well as an economic and developmental perspective, we cannot afford not to bring highly active antiretroviral therapy (HAART) to these settings

WHY ANTIRETROVIRAL THERAPY?
Of the 40 million people that are infected with HIV globally, approximately 95% live in severely resource-constrained settings. From a humanitarian perspective alone, not bringing antiretroviral therapy to those in need implies accepting a number of casualties that is difficult to imagine and impossible to accept. But there is another important argument to take up the challenge: HIV/AIDS mainly affects adults in their productive prime, leaving the very young and old to cope alone. This severely hampers economic growth and development of countries concerned. There is little doubt that poverty facilitates the spread of HIV/AIDS, but conversely HIV/AIDS perpetuates poverty. Generalizing HIV/AIDS into a problem of poverty will paralyze an effective and specific response to it, and conflicts with the “art of the soluble” principle [1] that we should adhere to. By nature of the population it affects, the economic and developmental impact of HIV/AIDS is likely to be much greater than that of other major infectious “killer diseases”, like malaria. Moreover, efforts to control tuberculosis, the other disease belonging to the “big three” of that category, are greatly thwarted by the “dual epidemic” of HIV and tuberculosis. Even from a purely selfish motive, improving the standard of living in developing countries is of direct interest to the developed countries. In an era of globalization, current gross inequalities in wealth and health between nations and regions will continue to threaten the stability and safety of the world as a whole.

The introduction of highly active antiretroviral therapy [HAART] in the developed countries can be called one of the great success stories of modern medicine. Current concerns regarding long-term toxicity, adherence and development of viral resistance cannot negate the remarkable reductions in HIV-associated morbidity and mortality brought about by the introduction of HAART. Moreover, ongoing research on toxicity will guide choices for less toxic regimens, adherence is facilitated by simplification of regimens, and new drugs that are active against viruses resistant to currently available agents are being developed. There can be no question that the only acceptable antiretroviral therapy in any setting consists of triple drug regimens that suppress viral replication to minimal levels. Not only does triple drug therapy lead to considerably greater clinical and immunological benefit than previously used mono- and dual drug therapies, through prevention of development of viral resistance it is also crucial for durability of effect. In fact, in the developed world HAART has proven to be a highly cost-effective intervention.

To summarize, there is a humanitarian and economic need to block the devastating effects of HIV in infected persons throughout the world and in principle we have the technical tools to do so.

CHALLENGES
Table 1 lists what we feel to be the most important obstacles to the wide-scale introduction of appropriate antiretroviral therapy in developing countries and we briefly discuss these here.

Lack of political commitment It is a sad truth that of all the ills that kill the poor, none is as lethal as bad government [2]. Unfortunately, in quite a few developing countries the public sector is either incompetent, or corrupt, and often both. The South African example does not help. South Africa, by virtue of the fact that it has both a sizable economy and a high HIV prevalence, should be leading the way. Instead its leadership is entrenched in a fruitless denial of the viral origin of the AIDS epidemic. Disputes about the use of generic formulations and compulsory licensing of antiretrovirals should not blind people to the fact that the South African government is still actively obstructing provision of antiretroviral care, including simple measures to reduce mother-to-child transmission of HIV, to its subjects. How can one expect from much poorer countries that they act in the face of the complacency of their big and rich neighbor? Especially in view of the fact that in dirt-poor societies, almost by definition, the value of human life is very low and that there often is a striking lack of the civil society we take for granted elsewhere. All the more commendable are the efforts of countries like Uganda, Senegal, and Ivory Coast, where the leadership, prompted by the UN Accelerating Access Initiative, is taking up the challenge to try to provide comprehensive HIV care to those who need it, albeit as yet on a small scale. We should also not lose sight of the fact that in many developing countries the HIV problem is “overwhelming”. Imagine treating 20% of the adult population of the US or Europe with antiretrovirals. This would be a serious onslaught on our health systems and resources. In addition, in many developing countries, HIV is “just” one of many problems, including other major diseases, social conflicts and wars.

Cost
Since mid 2000, undoubtedly accelerated by the fact that the International AIDS Conference for the first time in history was held in a developing country, antiretroviral drug prices have come down substantially for developing countries. Not only did major research-based companies reduce their prices; more and more generic copies of popular antiretroviral agents are becoming available at even lower prices. Nevertheless, the sheer size of the patient population is still prohibitive of widespread introduction of antiretroviral therapy in developing countries. At $2/day for a triple drug HAART regimen, treating a million people means over $700 million in annual drug costs. Treating the 20 million people who are estimated to be eligible for HAART amounts to $15 billion in annual drug costs. This leaves out costs for voluntary testing and counseling, infrastructure, personnel, monitoring, etc.

Lack of infrastructure and expertise
In most developing countries there is an enormous lack of facilities and manpower to deliver comprehensive HIV care and of laboratory facilities to support and monitor the therapy. There is a similar lack of medical personnel with sufficient knowledge of antiretroviral therapy. Possibilities for drug distribution to remote corners are limited and storage facilities are often lacking. The need for refrigeration that some antiretrovirals pose cannot always be met.

Lack of a common agenda and leadership in implementation Here it is fitting to use a quote from a recent book by Science journalist Jon Cohen, about the bungled efforts to develop an HIV vaccine: “…the field had no real leadership, no real funding, no real sense of urgency, …it was a fragmented venture with many competing interests that excelled at spelling out what needed to be done but had a tremendously difficult time building on those insights” [3]. Instead of devoting our best efforts to a joint operation to make access to antiretroviral care work on a grand scale, we are pursuing our little pet projects here and there, carving out little pieces of the developing world for ourselves, often to answer relatively irrelevant and redundant questions. This modern day scramble for Africa, apart from the ordinary human pettiness and lack of vision, is perpetuated by the current grant system. A good example is the actual competition, on various levels, between efforts directed at prevention of mother-to-child transmission of HIV and bringing HAART to developing countries. We have been subject to a situation where we wanted to provide HAART to HIV-infected pregnant women and their infected family members in rural India, but were told that we could only enroll women who presented late in pregnancy, because those who presented earlier had been committed to a study on prevention of mother-to-child transmission by another group. These women and their family members will therefore be deprived of effective antiretroviral therapy, which in addition would be a highly effective means to prevent transmission to their children, much more effective than the intervention planned.

THE WAY FORWARD Given the fact that in the face of the unfathomable disaster we have but one choice, which is to go ahead with bringing HAART to resource-poor settings, we should not be distracted by the fact that the problem is “overwhelming” or that HIV is “just” one of many problems. Neither should a demand for equality be an impediment to starting somewhere. The public sector may not be motivated or unable to cope with providing antiretroviral therapy and HIV care for the population at large, but more and more countries are considering introducing antiretroviral therapy programs for their army personnel and their dependants. Reprehensible as it may seem to restrict public sector support to particular segments of the population, we should view such programs as a beginning of larger schemes. Similarly, governments, through the UN Accelerating Access Initiative, are increasingly willing to support programs for civilians who are able and willing to pay for the drugs and monitoring of therapy. In addition we should not forget that there is a private sector that might be interested in providing antiretroviral care to its personnel and dependants, driven by an economic perspective as well as considerations of responsible entrepeneurship. With the reduction in drug prices it is not too difficult to demonstrate economic gains of providing HAART to employees in high prevalence areas. Moreover, the private sector has an important role in promoting civil society through setting an example from which it will benefit in both the short- and long-term. It is both our hope and conviction that such private sector and limited public sector schemes will create a demand within larger segments of the population, and will provide infrastructure and expertise that can be built upon. A way to tackle cost as an obstacle to antiretroviral therapy in resource-poor settings could be the establishment of a global drug bulk-purchasing mechanism where competing tenders and volume will lead to a further reduction in prices. At the same time, antiretroviral drug prices in the developed world should not suffer from the pressure for further cost reductions for resource-constrained settings and serious attempts should be made to avoid parallel import of drugs from resource-constrained to high-income countries, to preserve the interest of research-based companies in HIV drug development. Cost reductions can also be made by the development of cheap and simple monitoring tools. At the moment, the cost of “standard” monitoring of antiretroviral therapy, with regular determinations of plasma HIV-1 RNA load and peripheral blood CD4+ lymphocyte counts, exceeds that of antiretroviral drugs in developing countries in a considerable manner. Along the same line, addressing the enormous lack of care and laboratory facilities and of manpower to deliver comprehensive HIV care dictates that we adapt to the local situation and do not let preconceived ideas about what constitutes “appropriate” HAART monitoring be an impediment to bring HAART to those in need. Promising pilot studies have demonstrated the feasibility of providing HAART through directly observed therapy (DOT-HAART) without any laboratory monitoring at all [4]. It is conceivable that success rates of providing DOT-HAART without laboratory monitoring will be superior to those of providing HAART with state-of-the-art laboratory monitoring, but without observed therapy. The absence of laboratory monitoring availability may never be a reason to deprive populations in need of antiretroviral therapy from HAART: it is clearly better to let two out of one hundred people die of HAART toxicity because of minimal monitoring, than one hundred out of one hundred of HIV infection because HAART is not available. Efforts should be made to learn from treatment programs for other diseases, such as tuberculosis, that in many developing countries have reasonable success rates. Apart from logistical and infrastructural advantages, an argument to link HIV treatment to tuberculosis treatment programs is constituted by the fact that in the settings we are discussing more than 50% of people with active tuberculosis are HIV-infected. One can also envisage drawbacks to linking HIV treatment to tuberculosis treatment, but at least this approach should be piloted in a number of sites. The Rockefeller Foundation’s MTCT-Plus program points the way at how to build on programs for the prevention of mother-to-child transmission of HIV, for the provision of chronic antiretroviral therapy. When building infrastructure for the provision of HIV care, this should be done with an eye to the future availability of HIV vaccines. If effective vaccines eventually will become available we should be ready to conduct the necessary studies and implement vaccination programs in the most efficient manner. Moreover, it is necessary to combine HIV treatment programs with other prevention efforts, and to study the opportunities and threats that treatment provides for prevention. Among the challenges for the scaling-up of antiretroviral access programs are ensuring continuous drug availability, widespread drug distribution and safe and appropriate storage facilities for the medicines. I certainly don’t have the answers, but if we can get beer and Coca Cola to every remote corner of Africa, we must be able to profit from that experience. Obviously, it is wise to avoid drugs that require refrigeration in the most rural settings. The greatest impediment to the large-scale introduction of HAART is the lack of dedicated and knowledgeable personnel to do the job. This can only be solved by massive training and exchange programs. The trainees will then have to become the trainers. Here is a role for various professional organizations such as the International AIDS Society (IAS), the Academic Alliance for AIDS Care & Prevention in Africa, to mention just a few. It should be realized that something approaching full-time dedication of local care providers to antiretroviral access programs will be required, and that this can only be the case if involvement in antiretroviral access programs constitutes a viable career path for them. To bridge the expertise gap, it is essential to initiate programs with relatively simple drug regimens, to restrict the number of options and to keep the monitoring as simple as possible. The recently formulated WHO guidelines for scaling up antiretroviral therapy in resource-limited settings provide an invaluable resource for countries embarking upon antiretroviral access programs. It is my conviction that the wide-scale introduction of adequate antiretroviral therapy in developing countries within reasonable timelines, like the development and application of an effective HIV vaccine, requires a Manhattan project-type approach. This requires far more money than is currently allotted to the Global Fund to Fight AIDS, Tuberculosis and Malaria, and calls for central leadership and coordination. I would plea for the establishment of a separate body, set up under the auspices of WHO, but with enough flexibility and independence, dedicated solely to roll out antiretroviral access programs in a creative and responsible manner. Milestones for regions and countries should be identified up front and “top-down” should meet “bottom-up” approaches. Lastly, it should be evident that monitoring the impact of therapy on both an individual and population level should be an integral part of access programs [5]. This includes documenting therapy success and success/failure rates, studying determinants of therapy success and failure, surveillance of antiretroviral drug resistance, and studying the effects of therapy on HIV transmission. A significant proportion of money allotted to access programs should be set aside for such operational research.

CONCLUSION If we don’t get our act together, the WHO aim of providing HAART to at least 3 million people in need in developing countries by 2005, let alone providing HAART to all who need it, will be just one more elusive goal that the international community has set itself. The Accelerating Access Initiative and the WHO treatment guidelines have been essential steps, but they need to be followed by coordinated action on multiple levels, instead of fragmented and isolated efforts. The Global Fund does not address this need. Another quote from Jon Cohen predicts what will happen if we continue in the current mode: “Unfortunately, so little progress was made resolving any of these issues that nearly identical hearing could have occurred more than a decade later” [3].

References: 1. Peter Medawar, The Art of the Soluble, incorporated in Pluto’s Republic, Oxford University Press, 1984. 2. The Economist, August 14, 1999. 3. Jon Cohen, Shots in the Dark: The Wayward Search for an AIDS Vaccine, W.W. Norton & Company, 2001. 4. Farmer P, Leandra F, Mukherjee JS, et al. Community-based approaches to HIV treatment in resource-poor settings. Lancet 2001;358:404-9. 5. Report of the Commission on Macroeconomics and Health. Macroeconomics and Health: Investing in Health for Economic Development, WHO, Geneva, 20 December 2001.

Table 1
Challenges to bringing antiretroviral therapy to severely resource-constrained settings - Lack of political commitment - Cost - Lack of infrastructure - Lack of expertise - Lack of a common agenda and leadership in implementation