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Pedro Chan, MD, PhD Chief, Infectious Diseases, Hospital Juan Fernandez; Assistant Professor on Infectious Diseases, Facultad de Ciencias Médicas de la Universidad de Buenos Aires, Buenos Aires Argentina | ||||||||||||||||||
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| In less than a decade, AIDS has evolved from a fulminant,
rapidly fatal illness into a chronic, although incurable disease. Recently
developed guidelines describe the standard of care in anti-retroviral (ARV)
therapy and define its goal: to achieve maximal viral suppression, for as long
as possible. The scientific principles and current therapeutic recommendations
are outlined in Dr. Bartlett's paper. The good news brought about by science and, specifically, by drug development are to be considered, however, on a background of unequal access to health care and uneven distribution of the epidemic, since by the year 2000 more than 90% of HIV-infected individuals will be living in underdeveloped countries. It is generally recognized that ARV therapy should be available globally for as many people as possible. Notwithstanding, in many of the areas most heavily affected by the AIDS epidemic, very useful tools, including viral load (VL) measurement and even CD4 counts, are unaffordable, and the new combination therapies are unavailable where the disease poses the greatest threat. Today's challenge is to provide adequate medical services to populations that have traditionally been poorly cared for by our health care systems. A rational approach to this should take into consideration widely varied issues, such as cost-effectiveness, cost-benefit, impact on national budgets, ethical issues, adherence, risk of resistance, community demands for access to medical services, etc. It is difficult to develop guidelines apt to be used throughout the world. It is also true, however, that scientists, NGOs, the pharmaceutical industry, and international organizations, such as PAHO, WHO and UNAIDS, must play a leading role in promoting a strong commitment with this problem on the part of all segments of our societies. The AIDS epidemic may provide a unique opportunity to start an extensive discussion on the way in which each country provides health care. AIDS may help to set into motion people living with HIV/AIDS, community groups and health care providers, with a view to developing a new paradigm for health care. The AIDS Epidemic in Latin America Latin America is a large region, with a surface area of more than 20 million square kilometers. About 460 million people, of different and mixed ethnic origins, are distributed in twenty two countries, of varied characteristics. More than 800,000 AIDS cases have been identified in the Americas as of September 1997. Of these, 25% (200,000 cases) occurred in Latin America. One and a half million people are supposed to be infected with HIV. While Latin America and the Caribbean represent 8.4% of the world population, 12% of the total HIV-infected population lives in the region. Annual incidence of AIDS cases per million people ranges from 2.3 in Paraguay to 113.5 in Honduras. All recognized forms of transmission are represented in various proportions in our countries. Information about opportunistic infections is not fully reliable because of suboptimal notification, insufficient diagnostic tools, very low rates of post-mortem studies, and different criteria for data registration. Some of these infections, like Pneumocistis carinii pneumonia (PCP), have approximately the same incidence as in developed countries. Others, instead, including histoplasmosis, tuberculosis (TB) and toxoplasmosis, are more frequent. PCP, toxoplasmosis, TB and cryptococcosis are the most prevalent opportunistic infections, with slightly variable incidences in different countries (Figure 1). Endemic diseases, including Chagas disease, leishmaniasis and certain fungal infections, are increasingly frequent among HIV-infected patients. These conditions are often misdiagnosed as toxoplasmic encephalitis, TB or other opportunistic infections. TB is an endemic disease in Latin America. Since the very beginning of the AIDS epidemic, pulmonary and extrapulmonary cases associated with HIV infection have been described in our region. This association poses a tremendous threat to public health and social development, and has significant relevance in the context of protease inhibitors (PI) use, because of the potential interaction between these drugs and rifampin. Figure 2 shows some data on TB incidence in AIDS patients in selected Latin American locations. Lack of isolation facilities for TB patients results in high risk for Opportunistic Infections in Latin America Data from selected countries  nosocomial transmission. At least one large outbreak of multidrug-resistant TB (MDRTB) has been reported in the region, and several isolated cases of resistance have been communicated in different countries. TB treatment should not be a problem; however, in a setting of insufficient health care facilities and extreme poverty, adequate supervision of therapeutic regimens is not easily accomplished. Thus, an increase in MDRTB cases is likely to occur in the future. Antiretroviral Treatments in Latin America Major constraints Latin America features a peculiar mixture of socio-economic, cultural and social conditions. Areas resembling Europe or the US coexist in close proximity with Africa-reminiscent surroundings. Each year, 700,000 children die due to diseases that might have been prevented with uncontaminated water, food and low-cost vaccines. Factors such as political instability, the heavy burden of a billionaire external debt, unequal social conditions and illegal migration, result in severe deficit in housing, sanitation, clean water supply, education, nutrition and immunization (Figure 3). In this context, AIDS has become a extremely negative added factor, making differences between and within nations even wider. Several, but not all, Latin American countries have developed treatment guidelines at a national level. These guidelines differ to some extent in each country. The Brazilian expert panel endorsed dual nucleoside therapy for naive asymptomatic individuals, deferring PI for patients with clinical or immunologic deterioration. In Argentina, the Ministry of Health convened a consensus panel that developed recommendations quite similar to those in the US, including triple combination therapy from the very beginning of HIV infection. These recommendations were endorsed by both the Argentine 
AIDS Society and the Argentine Infectious Diseases Society. Triple therapy is recommended for symptomatic patients, and for asymptomatic individuals with CD4 counts <500 or VL >10,000 copies/ml. Similar guidelines have been introduced in Uruguay. Other countries, including Mexico, Colombia and Venezuela, have issued documents containing similar recommendations, with minor differences. These guidelines are good standards of care, similar to those developed in the US. However, the point is: who is going to pay for the treatments? In Brazil, the government has passed Act 9313, which states that "the Unified Health System will provide to individuals with HIV or AIDS all the medications needed for their treatment, totally free of charge". The funding will come from Social Security budgets (federal, state and city governments). The estimated budget for 1988 is U$S 1 billion. The guidelines in Argentina are only partially applied in real life, due to financial constraints of the national budget. As a result, drug supply is not consistent, with temporary shortages of one agent or the other, that may lead to therapy discontinuation/re-initiation, with the deleterious effects known to all experts. This affects the majority of patients, since 75% of them receive the drugs through the Ministry of Health. Hence, almost all drugs used for HIV treatment and primary and secondary prophylaxis of opportunistic diseases are available to patients at no cost through public agencies in a few nations. But in most of them, drugs like PI, gancyclovir, foscarnet, amphotericin or fluconazol are distributed neither through health care systems nor by Social Security. The same holds true for laboratory facilities. Thousand of patients lack an opportunity to be timely tested and receive early ARV treatment and prophylaxis. A high proportion of HIV-infected individuals are diagnosed in advanced stages of the disease, when there is no longer room for primary prophylaxis. It follows from the above that improvement in prevention and care is mandatory, to avoid unnecessary suffering, disease and mortality in our region. Issues in ARV Therapy The situation is far from being ideal in most Latin American nations. Efforts should be done to identify at least the minimal requirements or desirable conditions necessary to make our recommendations operative in real life. "Standards" of therapy have proven to be moving targets; while treatment is becoming more aggressive, and given earlier, clinicians are moving at different paces. A dozen drugs are already in the market; more are in preclinical and clinical trials; and many are in the pipelines. Decisions to start ARV treatment in asymptomatic patients are based on VL and CD4 counts; therapeutic efficacy is also monitored by plasma VL measurements. But, in settings where resources are scant, can symptomatic patients with documented HIV infection receive at least dual therapy, if these very important laboratory tools are lacking? Though early treatment is beneficial, it may have unwanted consequences. In this respect, research should establish whether potent ARV therapy increases risk behaviours and dissemination of HIV, when not accompanied by strong preventive efforts. One of the major risks of ARV drugs is selection of resistant virus. Missing a couple of doses a week may lead to a 50% reduction in efficacy. As the Nevirapine INCAS trial showed, undetectable VL was attained by 90% of compliant patients, but by only 50% of those who were non-compliant. As drug-resistant forms may already exist in naive patients, non-adherence makes their appearance more likely. Adherence is a complex issue involving patients, physicians and health care systems. Improving adherence to treatment is not the patient's task, but ours, as health care providers. Compliance with medical regimens is generally poor; the medical literature suggest rates as low as 50% for various diseases. Data on triple therapy are scarce. However, there are ways to improve patient adherence. A key factor is patient-physician interaction. The decision to initiate ARV therapy should be openmindedly addressed and offered by the caregiver to all patients. Treatment options and benefits, potential adverse reactions, importance of, and capability for, compliance and the long term emotional commitment needed for successful ARV therapy should be discussed thoroughly with the patient before a joint decision is made. Once treatment is started, additional psychosocial support is needed to achieve high adherence; it should be provided by partners, relatives, and friends. Ready access to health care is also necessary. Currently available drugs do not favor compliance; hopefully, however, we will see some changes in the future. New drugs, easier to take, will be important to improve compliance. In this respect, we have a message to convey to the pharmaceutical industry: we need user-friendlier therapies, not only less expensive, but also easier to live with for a long time. ARV therapy is not limited to adult patients; our discussion should include pediatric treatment, perinatal prophylaxis, and even ourselves, health care workers, as potential candidates for preventive therapies. Perinatal prophylaxis is a good example of a short, relatively inexpensive, cost-effective intervention. But it also shows that, however important, ARV agents are not an all-solving tool. Counseling for pregnant and breastfeeding women is essential; however, our primary goal should be to increase antenatal care, counseling and testing. Access to ARVs must be seen from the more comprehensive outlook of a continuum of care for HIV/AIDS patients, with four mainstays: clinical management, nursing, counseling and social support (Figure 4). Our first obligation as members of the medical community is to provide care, and care should proceed along a continuum, going from hospitals to the community and backwards, with active participation of nurses, doctors, volunteers, patients and their relatives and friends. Prevention and care are simply two sides of the same coin. Without prevention, the number of infected individuals would increase, and patients would seek care when it is too late for early intervention and prophylaxis of opportunistic infections. An adequate drug delivery program is unthinkable without extended educational programs for physicians -infectious diseases trainees and general practitioners committed to HIV care- aimed to avoid unnecessary or inadequate therapeutic prescriptions. These programs should address key issues such as guidelines on drug use, what to avoid (e.g., monotherapy or non recommended combinations), early diagnosis and treatment of acute retroviral syndrome, management of HIV-infected pregnant women, and post-exposure prophylaxis. General population and medical education is mandatory to reinforce the idea of adherence as a critical aspect of treatment. The concept of a co-operative effort between patients and health-care providers is central to this issue. International organizations may play a significant role in the development of such educational programs.
Priorities Priorities are often mentioned in relation to HIV, AIDS, and ARV agents. Priority listings for different countries should be defined in terms of their respective cultural and socioeconomic realities. Figure 5 shows some suggested items. Mother-to-child transmission needs to be highlighted as a basic priority, and remains a unique scenario in which monotherapy may still be endorsable. Allocation of resources and limited budgets are a major constraint. The community must identify the problem, and choose the most affordable and efficient project among all the alternatives. More epidemiological data are needed as fresh input for economic analyses. Difficulties due to economic factors will never be surmounted by posing allegedly exclusive options, such as prevention versus treatment, or AIDS versus TB or malaria. Demands for an extensive discussion have long been made, not on how to allot already defective health resources, but on how to balance national overall budgets and where our money is going to be spent. Also, creative ways of using the money allocated to AIDS need to be explored. Availability of the necessary funds and less expensive drugs do not suffice to solve every problematic issue. Some involve political decisions; others, more technical approaches. Education and training, must be addressed, as well as management and implementation, monitoring and evaluation and public information. Governments and politicians should make clear statements and undertake effective actions regarding taxes, price regulations, profit margins, etc. International organizations, such as PAHO, WHO and UNAIDS, might help in bringing together government and regional agencies on the one hand, and pharmaceutical companies on the other, to obtain lower prices through bulk purchasing. Tax exemption for diagnostic kits and ARV drugs should be strongly recommended at national governmental level. Also, drug supply must be closely monitored. A database should be kept with every drug given to patients, warranting absolute confidentiality, in order to trace the origin of ARVs. The risk of having counterfeit or ineffective drugs distributed in settings where treatments seen as life-preserving are very expensive and not readily available, should be anticipated. Special programs should also be developed for selected populations: drug abusers, women, jail inmates,
homeless, people living in rural areas. This brings into focus a major issue in HIV management: ethics. Minimally, certain basic issues should be addressed, such as equity and justice in the access to treatment, and the appropriate approach to groups with chaotic life styles, including intravenous-drug users, or individuals whose social circumstances lead them to non adherence to treatment. Should they be ruled out as candidates for triple therapy, and thus condemned on the grounds of life styles or social circumstances that, obviously, are not merely the result of their own free choice? Should the so-called "community interest" be privileged, reducing the risk for viral resistance by restricting these individuals' access to treatment? A more ethical approach would be to provide a supportive and safe environment that makes adherence possible, and encourage these patients' capacity and willingness to lead a more ordered life. Emergence of resistance should be closely monitored. A network of laboratories might play a crucial role for this purpose, for example, by undertaking a collaborative study on resistant viral forms, or on HIV subtypes and their importance, if any, in treatment protocols. Final Remarks Experts would certainly agree on the goal of offering the best available treatment to everybody. They would also recognize that minimal requirements or desirable conditions have to be met in order to enhance therapeutic effect, whatever the treatment protocol is. To the items listed on figures 6 and 7, the following should be added:
(a) prevention campaigns to increase timely consultation and diagnosis of HIV infection; (b) universal access to HIV testing and counselling, at no cost for patients; (c) adequate management of opportunistic infections, including prophylaxis; (d) laboratory facilities and monitoring of adverse reactions; (e) appropriate training of health care providers in the adequate use of ARVs; (f) diffusion of information on three critical issues: perinatal transmission, health care workers exposure, and primary infection; (g) betterment of health and social services in a continuum of care, providing psychosocial support to patients receiving treatment; (h) joint decision-making by patient and physician on all aspects of ARV treatment; and (i) reliable, long term supply of ARV drugs at a central level. Developing nations, like HIV, comprise many "quasispecies". They may look alike, but are different. Perhaps a single proposal to be applied at the same time throughout Latin America is impracticable. But experts can help governments, NGOs, medical societies, and people living with HIV/AIDS to narrow the gap between our longed-for goals and today's hard reality. Developing recommendations, making information available to governments, care providers and patients is essential. By working together in prevention programs, we will be able to address such issues as counseling, promotion of adherence, psychosocial support, etc. If certain minimal social preconditions remain unmet, what is the use of speculating about complex treatment protocols? To swallow 10 to 20 pills every day you need clean water, and certainly, a lot of it. Finally, figure 8 shows some of the goals to be pursued in the future.
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