COMMENTARY
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Prior to the XIIIth World AIDS Conference in Durban, debate raged in the community over the practicalities, cost and ethics of delivering antiretroviral drugs to the developing world. Two years on, that discussion is history. Political and financial forces will now deliver these drugs to such nations. How then can we expect their arrival to alter the HIV landscape?
Antiretroviral therapy to treat and prevent HIV/AIDS in resource-poor settings tice7. Much emphasis has been placed Current estimates suggest that over 60 million have been infected with HIV so GEOFF P. GARNETT, LUCY BARTLEY, on lowering the price of the drugs for reNICHOLAS C. GRASSLY & far, with 3 million deaths occurring source poor countries, with some noROY M. ANDERSON from AIDS in 2001 (ref. 1). Although retable successes8. Drug purchase, source-poor regions of the world are the however, is but one part of a complex worst affected at present, HIV infection and AIDS are a global equation for successfully thwarting HIV. Effectively delivering problem. In both Europe and North America, the number of care, minimizing harmful side effects arising from treatment, HIV cases among heterosexuals continues to rise slowly but preventing the rapid evolution of drug-resistant strains of steadily, without adequate public knowledge or concern for HIV, recognizing the indirect benefit of treatment on the likethis trend2. lihood of transmission to sexual partners, and counseling treated patients to inform them that treatment does not eliminate infectiousness are all important contributing factors as The Global Fund There are signs that governments and international aid agen- well. In developing countries, perhaps the most important cies are beginning to fully appreciate the tremendous scale of task is to create an effective and durable infrastructure for this epidemic and the huge resources required to slow its inex- both treatment delivery and counseling. The treatment of tuberculosis and the concomitant evoluorable march through all regions and communities of the world. A glimmer of hope emerged in 2001 when the United tion and spread of drug resistance in developing countries Nations General Assembly Special Session (UNGASS) formally provides a good example of both the successes of communityrecognized that access to medication is integral to the human based drug therapy and the problems surrounding implemenright to health (article 15). The declaration committed the UN tation9,10. In areas where there are high levels of transmission, to put in place national and international strategies by 2003, but where directly observed treatment short-course (DOTS) to strengthen health care systems and to address factors affect- has been carefully implemented, levels of anti-tuberculosis ing the provision of antiretroviral (ARV) drugs (article 55)3. A drug resistance have remained low11–13. In regions with poorertarget of $7–10 billion per year to finance programs was set for managed programs, the prevalence of drug-resistant bacteria an international health fund entitled the ‘Global Fund to has risen steadily with treatment failure becoming a frequent Fight AIDS, Tuberculosis and Malaria’. occurrence14. After a decade of promotion, only a quarter of To date, only $2 billion has been raised despite many the world’s smear-positive tuberculosis cases have been promises made at the 2001 UNGASS meeting. This needs to in- treated within a DOTS program. crease to an estimated $9 billion per annum for HIV alone4. By direct analogy with experience of the tuberculosis treatHowever, the program is now in operation and the first round ment initiative, drug resistance in HIV quasispecies will domiof fund distribution has just been announced. Of the $174 nate where programs are poorly resourced and carelessly million approved for the coming year, 67% is assigned to HIV. implemented. Furthermore, two issues are of utmost imporThis includes $25 million for South Africa, $20 million for tance to the likely success of the recent UNGASS initiative: the Zambia, $10 million for Haiti and $11 million for Nigeria. proportion of the HIV-infected population that can be covSome funds are being given explicitly for the purchase of anti- ered by this treatment initiative, and its success in maintainretroviral therapies (ARVs); for example, Nigeria is to receive ing treatment throughout the patients’ lives. The risks of the emergence and spread of drug resistance in $6 million assigned for this purpose. The sums allocated are obviously insufficient to meet the HIV are much greater than with tuberculosis, owing to the global need, but they represent an important step forward. If high replication rate of the virus and its rapid evolution under spending is effective, it will strengthen the case for the dona- the intense selection imposed by drug therapy, particularly tion of further resources to reach $9 billion per annum5. In when patient adherence to prescribed regimens is less than one analysis, it was suggested that an equitable contribution ideal. For example, in the Ivory Coast and Gabon, where accould be based on the gross domestic product (GDP) and that cess to therapy is patchy, high levels of drug resistance in HIV the sum could be raised from 0.035% of the GDP of the 48 populations within treated patients have already been recountries with a high human development index. As of April ported15,16. 18, 2002, only the Netherlands (97%), Sweden (73%) and Italy Furthermore, treatment of HIV/AIDS with ARVs will only (57%) had committed more than 50% of what would be ex- ever be DOT, not DOTS, as there is no known short course of pected on this basis. Many countries have not yet committed therapy that suppresses viremia indefinitely (unless the focus any money6. is only on the prevention of mother-to-child transmission). The case for making ARVs widely available in developing Once treatment stops, viremia rapidly returns to pre-treatcountries has been based, in part, on arguments of social jus- ment levels. NATURE MEDICINE • VOLUME 8 • NUMBER 7 • JULY 2002
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Cumulative incidence per 100,000
Ratio of HIV infections prevented to those treated each decade
HIV i nc idence per 100,000 per yea r
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AIDS incidence per 100,000 per year
more complex set of selective pressures than do single drug therNo intervention 5000 Resistance acquired apies. They do not, however, during treatment 600 4000 negate the possibility of treatment Passive 3000 Primary (transmitted) failure due to the emergence of 400 resistance 2000 Active multi-drug-resistant viruses. Much 200 1000 recent research shows that the frequency of interruptions in ther0 0 0 25 50 apy is directly correlated with the Time (years) speed at which resistance emerges 1200 No intervention and, concomitantly, the likeli1 800 hood of treatment failure17. Good Passive Intervention adherence is of vital importance 400 Active in all communities where drug Resistant infection therapy is administered, not just 0 0 in resource-poor settings. The 1200 problem is most significant, howNo intervention Intervention targeted to highever, in regions where patients 800 Resistant 20 activity population only infection only have access to limited drug supplies, or a few types of drugs, 400 10 Intervention or where they cannot afford long 0 periods of therapy. 0 600 0–10 11–20 21–30 31–40 41–50 0 10 20 30 40 50 A carefully considered set of Time (years) Time (years) guidelines has been drafted by the World Health Organization Fig. 1 Mathematical model simulations of the potential epidemiological impact of the use of antiviral treat(WHO) to inform policy makers of ments in a generalized HIV epidemic where ARVs are introduced 30 years after the start of the epidemic. Here the most appropriate treatment we assume that effective use of antivirals reduces the transmission probability to zero for sensitive virus and regimens in resource-poor setthat resistance prevents effective treatment. In ‘passive’ treatment, individuals are recruited to the program late during the incubation period. In ‘active’ treatment, it is assumed that there is a rapid rate of uptake of tings18 (see page 649). The draft treatment in all those infected. Both programs reduce the incidence of AIDS, but a greater effect is achieved by details treatment regimens that the active program (top left). The incidence of HIV infections is reduced because of the lowering of average are highly effective, describes secviral load and its impact on infectiousness, while resistant infections evolve under both programs (‘Passive ond lines of treatment and sugtreatment’ middle left and ‘Active treatment’ bottom left). An increasing uptake of treatment increases the regests restrictions on laboratory duction in transmission but also increases the number of people in which resistance emerges. The cumulative assays in patient management. number of resistant infections acquired during treatment exceeds primary transmission of resistance but this Effective treatment requires exproblem increases (‘Passive treatment’ top right). An ‘indirect benefit’ is defined as the ratio of cases prevented pert medical supervision to decide to cases treated. The ratio is greater under the active program (middle right). Targeting treatment to high-risk groups has the greatest impact, per patient treated, on the magnitude of the indirect benefit of drug therapy on such issues as when to com(bottom right). Dotted line is the case where one treated patient prevents one other case of infection. mence treatment, and how to manage treatment failure and the high levels of toxicity associated with many drug regimens. Importantly, the wide-scale adopDrug resistance and patient adherence The key question surrounding drug resistance is not if it will tion of ARV therapy in developing countries will require a emerge, but when it will emerge. Given the high rates of viral marked increase in trained medical staff or a change in the population turnover in the patient and the rapid rate of evolu- scope of training of health-care workers. The guidelines emtion of the virus, all treatment programs will select for resistance. phasize the importance of treatment efficacy and practicality How well the resistant virus prospers in the patient by compari- in delivery, rather than costs. The effective management of son with the susceptible wild-type quasispecies depends on the HIV infection requires the use of ARVs that are both well tolerquality of patient adherence to prescribed regimens, most im- ated by the patient and as tolerant as possible of less than perportantly at the beginning of therapy when viral load is declin- fect adherence. The guidelines recognize the grave dangers of ing from high levels, but also throughout the duration of the cheaper option of using two nucleoside reverse-transcription inhibitors alone. The addition of another drug from a diflife-long therapy. The rate of evolution of the virus under selection by drug ther- ferent class (for example, protease inhibitors) is recommended apy is directly proportional to viral load. To slow the emergence to slow the emergence of drug resistance. Of the 28 recipient countries in the current round of Global of resistant phenotypes, viremia must be suppressed as much as possible and as quickly as possible. This requires patient adher- Fund grant awards, 21 specify the purchase of antivirals as a ence as well as the use of the most efficacious drugs—those that central aim in their programs. Most also aim to improve best inhibit viral replication, have the longest kinetic half-life in health-delivery systems. Over time it will be important to monthe patient (and thus are more permissive to poor adherence), itor whether appropriate drug regimens and better patient and require many mutations in the viral genome to significantly management flow from the increased investment. Other than treatment failure, what are the dangers of drugreduce the drug’s ability to suppress viral replication. Simultaneously administering multiple drug therapies also resistant HIV strains? There is a period of suppressed viremia slows the onset of resistance, as multiple drug classes impose a and reduced mortality after the start of therapy and before the 800
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COMMENTARY the resistant phenotype becomes dominant. During this time window, the resistant virus is likely to be transmitted if the patient is not aware that his or her infectiousness to susceptible sexual partners is lowered but not eliminated. There have been many reports of transmission of single- and multi-drug-resistant viral phenotypes within countries where therapy has been used widely19,20. There will be reduced transmission during periods of suppressed viremia, even in the absence of effective counseling, as there is a positive association between viral load and the likelihood of transmission21. Thus, even imperfect treatment has both direct benefits to the patient (reduced morbidity and mortality) and indirect benefits to the community (reduced transmission). The emergence of drugresistant viral phenotypes in resource-poor regions should not be viewed as grounds for limiting access to drugs. The problem has already emerged in the rich nations of the world. The task ahead is to inform of the dangers and to encourage the implementation of programs that serve to slow the emergence of resistance. Therapy as prevention ARV therapy must be viewed as a means for both reducing morbidity and mortality and for lowering rates of transmission within populations. The prevention potential of effective community-wide therapy has often been understated in recent discussions of HIV drug distribution in resource-poor countries. The programs recently approved by the Global Fund concentrate on HIV prevention rather than treatment. The international focus on prevention has often been criticized as a cost-saving approach that ignores the urgent need for care of the large number of infected patients in developing countries. However, the driving forces behind treatment and care—the patient suffering and the concomitant concern of the health professional involved—are often more powerful than those behind prevention. There is an equal need for both care and prevention, and it is important to recognize that the two act synergistically. Effective treatment can reduce the likelihood of transmission, and the infrastructure put in place for treatment and care also serves as a template for the delivery of preventative measures and counseling. The argument that care is an integral component of prevention programs has been adopted in the UNGASS declarations. However, the associated WHO guidelines recommend that treatment start only when clinical symptoms are manifest, or when the CD4+ cell count drops below 200. By this time, the patient will have been infectious for many years. The development of AIDS is far removed in time from the high viremia (and infectiousness) of primary infections and possibly far removed from the high-risk behaviors associated with the acquisition and transmission of HIV (Fig. 1). If antiviral treatment is to be viewed as a public health tool to reduce the spread of HIV, it will have to be implemented differently than has been proposed; patients without clinical symptoms of HIV infection will need to be identified and immediately administered ARV (Fig. 1). Although it is difficult to envisage the successful use of ARVs to control the spread of infection, it is reasonable to assume that reducing plasma viral load by treatment will counteract any increase in incidence associated with the longer survival (and potential infectiousness) of those treated22. Of more concern is the increase in high-risk behavior throughout a population that fears the consequences of HIV infection less, NATURE MEDICINE • VOLUME 8 • NUMBER 7 • JULY 2002
believing that it is treatable. Increases in reported high-risk behaviors and the incidence of other sexually transmitted infections have been recently observed in countries with wide use of antiretroviral therapies, such as in the USA, Europe and Australia23–26. The importance of voluntary testing and counseling to reduce high-risk behaviors27 is a central pillar in the argument that ARVs can be used as a tool to improve prevention. The difficult issue that needs to be addressed, however, is how voluntary counseling and testing (VCT) programs should be expanded in tandem with ARV use, with resources allocated appropriately for each activity. Much evidence from developing countries suggests that individuals, however poor, are willing to pay to preserve their own health or that of a family member28. But, in most regions badly affected by HIV, particularly in sub-Saharan Africa, the costs of long-term treatment for HIV are just too great to be sustainable for the vast majority of families. Even very short-term care and treatment is a significant expenditure. If drug treatment only provides a brief reprieve, then the high costs incurred have long-term consequences for the financial well being of surviving family members. In many societies, much of the HIV acquisition and transmission occurs among socially and economically marginalized sections of the population, sex workers being an obvious example. The cost effectiveness of any HIV prevention program is maximized by targeting these groups (Fig. 1). Failing to place the treatment of high risk groups as a first priority will, in general, result in the implementation of much less cost effective programs. It is rare in public health that the most efficient and cost effective strategy is also the most equitable. The challenges ahead are formidable. The first is to increase the rate of contributions to the Global Fund and to reduce the inter-agency rivalry for ownership and distribution of resources. The effort in fund raising needs to be more focused, with an emphasis on demonstrating that money can make a difference to block the steady march of the pandemic. The second is to ensure that both prevention and treatment receive equal attention, moving the need for an effective and durable health care infrastructure in resource-poor settings to the fore. This will help to ensure that prevention and treatment act synergistically, with the sum of the two components acting together being greater than the net effect of their separate contributions acting alone. The third is the issue of drug choice, drug delivery and the emergence of drug resistance. The spread of resistance is inevitable, as well illustrated by experiences in developed countries. The issue of good patient adherence to prescribed drug regimens is vital, in both developed and developing countries, and the task is to educate both patients and health professionals about its importance. Drug choice in resource-poor settings should be governed more by which drugs are most permissive of breaks in adherence, rather than issues of cost. There is now a window of opportunity raised by the creation of the Global Fund—we must ensure that the resources available for treatment are maximally used to both alleviate suffering and reverse the continuing rise in the global burden of infection. 1. UNAIDS & WHO. AIDS Epidemic Update: December 2001. (Joint United Nations Programme on HIV/AIDS (UNAIDS), Geneva, Switzerland, 2001). 2. Communicable Disease Surveillance Centre. AIDS and HIV infection in the United Kingdom. in CDR Weekly (www.phls.co.uk/publications/ CDR%20Weekly) (2002). 3. UNGASS. United Nations General Assembly Special Session S-26/2 Declaration of Commitment on HIV/AIDS (United Nations, 2001).
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Department of Infectious Disease Epidemiology Faculty of Medicine Imperial College of Science, Technology and Medicine London University, UK Email:
[email protected]
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