aStanford University, Division of Infections Disease, Stanford, California, USA
bInstitute of Tropical Medicine, Antwerp, Belgium (currently on leave to CDC-Global AIDS Program, Côte d'Ivoire)
cFrench Agency for AIDS Research ANRS & INSERM U 379, Marseille, France.
Correspondence and requests for reprints to Pr Jean Paul Moatti, INSERM U379 'Epidémiologie & Sciences Sociales Appliquées à l'Innovation Médicale', 232 Bld Sainte Marguerite- 13273 Marseille, France. Tel: +33 (0)49 122 3502; fax: +33 (0)49 122 3504; e-mail: firstname.lastname@example.org
David Katzenstein is a recipient of a Doris Duke Distinguished Clinical Scientist Award which provided support.
Effective antiretroviral treatment of AIDS in resource-limited settings, particularly sub-Saharan Africa, has become a bellwether issue for patients, physicians and policy-makers. The immense tragedy and enormous challenge of global AIDS raises fundamental questions in ethics and human rights accompanied by key logistic and technical issues in medicine, immunology, virology, public health, macroeconomics and social development. The successes of science and public health interventions in wealthy nations must be translated into a sustainable response for the 90% of people with HIV and AIDS in resource-limited settings.
In the first two decades of the HIV epidemic, the parallel efforts of activists, scientists and clinicians resulted in a largely successful paradigm that included prevention of HIV infection and treatment of AIDS. In resource-rich countries these two key modalities reduced the growth of the epidemic and mortality, morbidity and health care costs, the latter most dramatically in the late 1990s with widespread (although not universal) access to highly active antiretroviral therapy (HAART). By contrast, for the vast majority of HIV-infected people that live in sub-Saharan Africa, surveillance, education and information and (potential) vaccines strategies were thought to be the only possible modalities to combat the epidemic. Although the efficacy of antiretroviral therapy was evident from results presented at the 11th World Aids Conference in 1996 in Vancouver, access to antiretroviral treatment (ART) was not considered feasible in developing countries by most experts in the field [1–3].
Despite the powerful reluctance to introduce ART in the South, various non-governmental organizations (NGOs) and some governments of developing countries moved quickly to address access to effective treatments for HIV infection. Responding to their demands, the UNAIDS secretariat launched the so-called Drug Access Initiative (DAI) in November 1997. The DAI was designed to explore the feasibility of a ‘structured introduction of price-reduced ARV therapy’ and of a ‘rational and affordable use’ of ART ‘in a range of developing countries’. Participants in an initial phase of the DAI were Chile, Côte d'Ivoire, Uganda and Vietnam. In these countries, the explicit goal of the DAI was to set up the necessary infrastructure and systems to increase access to HIV-related drugs ‘on a small but sustainable scale’ . In sub-Saharan Africa, the projects respectively started in June 1998 in Côte d'Ivoire, with a population of almost 13 million and over 800 000 people infected with HIV, and in August 1998 in Uganda, with 21 million people of whom 1 million were estimated to be living with HIV/AIDS. In parallel, building upon a successful national prevention campaign, and with an HIV prevalence of less than 2% among adults, the Senegalese government introduced its own pilot Initiative for Access to Antiretroviral Drugs (ISAARV) in 1998.
In the context of global scepticism, very real economic and political barriers surrounded even small-scale programs for access to ART in developing countries. Thus, UNAIDS and the Ministries of Health of Côte d'Ivoire, Senegal and Uganda developed programs to carefully evaluate these first experiences of organized ARV delivery in Africa. Independent teams of researchers conducted evaluations of these HIV Drug Access Initiatives between 1998 and 2002, benefiting from the technical assistance of the French Agency for AIDS Research (ANRS) in Senegal, of the Centers of Disease Control and Prevention (CDC) in Uganda, and of both agencies in Côte d'Ivoire.
During this 5-year period, the attention of the world and the public health community has become progressively more focused on drug access and equity in HIV treatment [5–7]. The International AIDS Society (IAS) meetings ‘Bridging the Gap’ in Geneva in 1998, and ‘Breaking the Silence’ in Durban in 2000, emphasized the growing inequity in access to care and treatment. These events led to the United Nations General Assembly Special Session on AIDS in 2001, culminating in the establishment of a multi-lateral Global Fund to Fight AIDS, Tuberculosis and Malaria at the beginning of 2002. While it is currently estimated that 4 million people are in immediate medical need of ART in sub-Saharan Africa alone, the goal of scaling up access to ART is increasingly shared by governments and international donor organizations. A recent analysis of the national HIV/AIDS plans of 90 developing countries conducted by WHO indicates that about 60% of these countries have now either incorporated ART into their national strategies to fight the epidemic or have defined specific ART coverage targets . In July 2002 at the 14th International AIDS Conference in Barcelona, WHO and other UN organizations committed themselves to the goal of expanding access to ART to 3 million people in the developing world by 2005 . For this special edition of AIDS, the investigators who led the evaluation of the DAIs in Côte d'Ivoire, Senegal and Uganda provide reports on a wide range of topical issues that inform the feasibility and practicalities of scaling up antiretroviral therapies in resource-limited settings, especially in Africa.
Papers in this issue from project RETRO-CI in Côte d'Ivoire (Djomand et al., Koblavi-Dème et al.) and from ISAARV in Senegal (Desclaux et al.), as well as previous evidence from the DAI in Uganda  and Senegal , clearly establish that ART can be successful in Africa. Virologic and immunologic outcomes, adverse events, and estimated survival are similar among patients in African DAIs and ART-treated patients in Europe and the USA. Small pilot studies suggest that sustained viral suppression can also be achieved in HIV-2 infected patients which is still largely confined to Africa and Africans (van der Ende et al.; Adjé-Touré, Cheingsong et al.). Overall, biological and clinical results strongly suggest that physicians involved in the DAIs have expertise and knowledge about HAART, an observation reinforced by the detailed survey carried out in a sample of Ivoirian physicians by Souville et al. These pilot programs also suggest that once financial barriers to access to drugs have been overcome, adherence to HAART can be as high among HIV-infected patients in Africa as that generally observed in industrialized countries (Lanièce et al.).
The risk of dissemination of resistant viral strains due to suboptimal anti-HIV drug combinations, inadequate prescription and patients' non-adherence with ARV may mitigate the long-term benefit of expanded ART . Data presented here show rates of phenotypic resistance and corresponding genotypic mutations among ART- treated patients in the Ivoirian (Adjé-Touré, Célestin et al.), Senegalese (Vergne et al.) and Ugandan (Weidle et al.) initiatives that are similar, or in fact lower, than similar studies in the North. Thus, implementation of ART with clinical, biological and logistical monitoring can limit the emergence of drug resistance in Africa. Observations of drug-resistant HIV at levels below those in the US and Europe provide evidence to counter arguments for withholding diffusion of ART in developing countries. The additional concern that access to effective treatment may jeopardize prevention efforts, especially by inducing a ‘disinhibition effect’ on risk taking  is addressed by the evaluation of the DAI in Côte d'Ivoire where access to ARV treatment was not associated with an increase in HIV-related risky sexual behaviours (Moatti et al.). However, the follow-up period of these studies is rather short and the possibility that drug resistance and risky behaviours will go up quickly, once ARVs are used on a larger scale, cannot be excluded. There remains a clear need for continuous surveillance of resistance at an international level , and for operational research about how to assure life-long adherence to taking ARV drugs and to maintaining preventive behaviours in a developing country setting.
The efficiency of government systems, including national health service systems, has gradually declined over the past decades in many African countries. It is obvious that scaling up access to ART will often take place in a context of limited health care resources with little absorption capacity . The evaluation of the DAIs has, however, demonstrated the feasibility of initiating delivery and monitoring of ART in the context of existing health care infrastructures. An additional common lesson emerges from the evaluations: namely that strong public control and support are essential for a successful diffusion of ART. In the African context of scarce resources and the huge unmet demands for HIV care, efficient programs clearly require the delivery of ARV drugs through organized channels. The observations by Vergne et al. and Adjé-Touré, Célestin et al. provide evidence that drug resistance rates were higher in Senegal and Côte d'Ivoire before the introduction of organized DAIs. The DAIs were based on the commitment of governments to promote access to ART in the public health sector and to regulate their delivery in the whole health care system (including the private not-for-profit and private sectors). In other countries, such as Burkina-Faso, whose experience is reported here by Nguyen et al., NGOs played a pioneering role for the introduction of ART to the point that the dynamism of the community response resulted in synergies with the public health care system. Strong public health regulation, clinical education and organization in concert with NGO , academic and private partnerships are needed to reduce the risk of ‘antiretroviral anarchy’ [16,17]. Economic and equity barriers which restrict availability of ARV drugs to the most privileged will only fuel diversion to ‘black market’ sales, irrational prescribing and increase the risk of drug resistance.
Of course, the African DAIs whose evaluation is reported have been limited in size, concerning a few hundreds or thousands of patients in each of the three countries. Of necessity, these pilot ARV delivery programs were initiated in medical centres restricted to the capitals and the most populated urban areas. The process of scaling up access to ART through delivery by centres at regional level is already ongoing in Senegal and Uganda and, although planned, has been delayed in Côte d'Ivoire due to the recent political situation. Additional challenges will face the extension and ‘scaling up’ of access to ART in more diverse geographic settings. However, evaluation of these urban pilot projects has identified limitations that must be overcome to promote wider access to ART in both urban and rural settings.
Economic sustainability remains a major problem for ART programs in Africa. The three DAIs benefited from significant price reductions for ARVs and other HIV- related drugs. These price decreases were facilitated by the partnership between five UN organizations (UNAIDS, UNFPA, UNICEF, WHO and World Bank) and six pharmaceutical companies introduced in May 2000 following the DAI pilot projects . However, the world-wide campaign to improve access to essential drugs in poor countries [19,20] and the introduction of generic competition have been the driving forces that have decreased the price of HIV drugs. Between 1996 and 2000, prices of ARVs were lower in Côte d'Ivoire where the Public Health Pharmacy introduced a tender mechanism open to all international suppliers, including generic producers, than in Uganda where procurement was restricted to a private not-for-profit company (Medical Access Uganda Ltd.) which represented the interests of international patent-holding companies. In 2001, the Joint Clinical Research Centre in Kampala imported generic drugs, and there was a 20–45% decrease in the cost of the most frequently prescribed combinations in Uganda . In Côte d'Ivoire, Senegal and Uganda the annual cost of HAART is still higher than the average GDP per capita (US$ 660, 490 and 310, respectively). Scaling up access to ART will drive further reductions in costs of delivery, further reduce drug prices and identify cheaper techniques for clinical and biological monitoring of therapy in resource-limited settings . The paper by Diomandé et al. proposes to identify persons eligible for ART with CD4 cell measures alone, which significantly improves the cost-effectiveness of strategies for initiating treatment. However, the paper by Souville et al. suggests that consensus may be difficult to achieve through guidelines that are specific to resource-limited settings. Evolution of flexible and effective guidelines for ARV use and their acceptance will require continuous evaluation and educational efforts by national and international public health authorities.
No matter the resources, ART will remain out of reach for the great majority of the HIV-infected population in Africa. In Uganda, the government considered that it did not have the financial capability to provide any subsidy for covering the costs of ARVs, regardless of private health insurance. In Côte d'Ivoire and Senegal, governments adopted the provision of ARVs at a 50–95% subsidized price for persons who meet predefined socio-economic conditions. The Ivoirian DAI has indeed facilitated access to ART for several hundred patients with limited ability to pay, but the majority of HIV-infected patients seeking care faced persisting socio-economic barriers for access to ARVs and basic prophylaxis of opportunistic infections (Msellati et al.). A similar ‘mixed’ result in terms of equity has also been shown in Senegal . Obviously, constraints on government expenditures will prevent the public and private sector from establishing equitable access to ART in most developing countries. The experience of the DAIs nonetheless suggests that a national consensus can be reached in each country about the priorities for subsidizing costs of treatment. Local experiences show that it is possible to directly involve communities of people living with HIV/AIDS, a process that is under way in Uganda between the government and the community-based organization TASO, and in South Africa in private notfor-profit projects supported by Médecins Sans Frontières and Treatment Action Campaign.
Basic informational barriers continue to restrict access to ART. Evaluation of the DAIs show that more appropriate public information and accessible voluntary testing and counselling (VCT) are needed to define HIV/AIDS as ‘a public health and infectious disease emergency’ . Policies and practices around HIV prevention and testing with a focus on treatment include broader training and information about ART for health care professionals, beyond the limited number working in a few specialized centres. Lack of adequate information currently remains a major barrier to equitable access to health care. Scaling up access to ART in Africa will require dissemination of information about these treatments and their availability to the population at large.
Accomplishments in bridging the North/South gap in access to ART have, so far, remained modest. It is estimated that ART was initiated for an additional 70 000 patients during 2002, leading to only 300 000 HIV-infected individuals in developing countries currently receiving ARVs of any kind, nearly one-half of them in Brazil alone . The first funding commitments by the Global Fund made in 2002 will allow a two-fold increase world-wide in the total number of individuals receiving ART in developing countries, and a six-fold increase in Africa. A recent pledge of 15 billion US$ in bilateral assistance for prevention, care and treatment was made by the US government . These ART programs are not limited to experimental projects. There are recent models which suggest that they can also provide significant public health impact by reducing transmission . Although limited, the experience reported here of the evaluation of the first African DAIs may serve as a foundation for future evaluation efforts that will have to be scaled up in parallel to the increase in size of ARV delivery programs in Africa.
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