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Conference Report: Developing an HIV/AIDS Therapeutic Agenda for Resource-Limited Countries

Coverage of the Infectious Diseases Society of America Conference to Develop an HIV/AIDS Therapeutic Research Agenda for Resource-Limited Countries

By Ian M. Sanne, M.D.
Medscape HIV/AIDS 7(6), 2001
October 24, 2001, San Francisco, California

Introduction

As access to antiretroviral therapy in resource-poor countries starts to improve, many questions regarding practical implementation need to be addressed. International research funding agencies are starting to fund therapeutic research in developing countries, to enable local and international researchers to conduct regionally appropriate projects.

Therapeutic research in resource-limited countries requires a unique paradigm, with emphasis placed on sustainable interventions and ethical conduct. In an attempt to begin a dialogue to establish the outline of a research agenda that could be funded, the Infectious Diseases Society of America (IDSA) hosted a conference in San Francisco, California, cosponsored by the US National Institutes of Health, the United Nations Joint Programme on HIV/AIDS (UNAIDS), the Rockefeller Foundation, and DuPont Pharmaceuticals Company. Leading HIV researchers from American universities and resource-poor countries attended the meeting. The specific aim of the attendees was to prioritize research—and perhaps even to design initial studies—to set the stage for the development of the research agenda. Through this process the IDSA hopes to facilitate the initiation of research in resource-poor settings.

The design of therapeutic research in resource-poor regions will need to take into account the operational components. The research agenda must be implemented at the clinical level appropriate for the country in which it will be conducted. The ethical issues should address and engage the local community.

What Should the Research Agenda Be?

The following questions are the main priorities of the research agenda for the implementation of treatment in resource-poor countries:

  1. When should treatment be started?
  2. With what should treatment be started?
  3. Which population should be prioritized for treatment (because not all citizens of poor countries can be treated immediately)?
  4. How should patients be monitored—how frequently, and with which laboratory tools?
  5. How should healthcare personnel be trained, given the available resources of the setting?

Resource-limited countries are not all the same. Treatment interventions will need to be adapted to meet the resources of each of the countries to ensure feasible and sustainable solutions for each country.

Background: Healthcare Resources in Africa

Research funded by international agencies has focused to date on prevention of HIV disease, in an attempt to reduce the lifetime risk for a 15-year-old to die of HIV/AIDS, estimated to be 55% in Zambia. However, HIV/AIDS activists and physicians are increasingly calling for the implementation of treatment programs to address the huge burden of HIV disease in those already infected.

Current prevention and vaccine research therefore needs to be expanded to include therapeutic interventions. Many believe that vaccine trials will only be feasible in settings where treatment is available. Antiretroviral therapy is also likely to be an important stimulus for voluntary counseling and testing, and may prevent HIV transmission by lowering viral load in genital secretions—a hypothesis that will be tested in the HPTN 052 study proposed by Myron Cohen. A number of investigators have already demonstrated that HIV transmission is related to serum and seminal viral load.1-4

Funding issues are pivotal to the question of treating HIV in the developing world. Shortages of funds mean that treatment guidelines are established through clinical practice and not necessarily through clinical research. A number of speakers were invited to illuminate the available resources of African countries.

KwaZulu-Natal, South Africa

Dr. Zweli Mkize, Provincial Minister of Health in KwaZulu-Natal Province, South Africa, noted that KwaZulu-Natal has the highest HIV prevalence of all the provinces of South Africa, at 36%. Reasons for the high prevalence include high mobility of the citizens—predominantly employed in the mining, transport, and shipping industries—many of whom frequently travel to neighboring countries. The main obstacles to implementation of antiretroviral therapy programs include financial constraints, lack of healthcare infrastructure, constraints on human capacity, insufficient political will, and competing health priorities such as the provision of clean water, education, and electricity.

The mean annual per capita income in South Africa is $3020, with 10% of the population receiving 46% of the income, and 60% receiving 18% of the income. Infrastructure for healthcare delivery and even access to water in KwaZulu-Natal is limited to centralized areas. A total of 48% of South Africans access piped water; 18% use public or communal taps; 6.7% use borehole water; 24.3% access water directly from dams or rivers; and 2.9% from tankers. This limited water supply resulted in the recent cholera outbreak in the province.

The clinical infrastructure in most rural areas in Africa is also limited. KwaZulu-Natal has 96 hospitals and 487 clinics, serving a population of 8.7 million. The mean distance to a clinic is 4.2 km, and walking is often the only means of transport. Nevertheless, South Africa is better off than other countries in Africa, with political stability, relative absence of corruption, and relative wealth.

Dr. Mkize stressed that community mobilization at the grass-roots level is considered a political priority in the fight against AIDS. Finally, she observed that for research to be successfully conducted, nongovernmental organizations (NGOs), government, and researchers must work together to coordinate the use of funding opportunities and achieve a feasible and sustainable research agenda.

Uganda

Elly Katabira, Associate Dean of Research at Makerere Hospital in Uganda, described how the growing demand for antiretroviral therapy is constrained by a lack of adequately trained healthcare workers, laboratory facilities, pharmacy procurement, and distribution services. In most countries in Africa, pharmaceutical industry distribution networks are often poorly regulated, ill-coordinated, and subject to high levels of theft. Medications including generic drugs are often unavailable because of regulatory restraints in the registration process. In some countries the regulatory committees are underresourced and inadequately educated to be able to review the drug brochures for registration.

Nevertheless, through pressure from the patients, affordable access to antiretroviral therapy is being widely facilitated in Uganda. In most cases the drugs are procured from private pharmacies or through NGO programs. Patients who can afford to do so often travel internationally to obtain treatments, resulting in inconsistent supplies. Medication is priced in US dollars, whereas income is in local currencies—resulting in treatment becoming progressively more unaffordable.

Malawi

Brian Hertz of Médecins Sans Frontières (MSF; Doctors Without Borders) recounted how his organization is engaged in HIV treatment research across the continent. Achievements include the provision of health support and advice in countries such as Malawi and Mozambique, and challenges leading to reductions in the price of medications including antiretroviral agents and other essential medications.

MSF is active in an 80-bed hospital in the Chiradzulu district of Malawi, where 70% of admissions are HIV-related. Laboratory and radiology facilities are limited, and staffing levels are between 0.5 and 1 nurse practitioner per ward; no Malawian doctors are present. The HIV clinic provides 300 consultations per month, with an outpatient voluntary testing program, counseling for those who have tested HIV-positive, a home-based hospice, an active program to prevent mother-to-child HIV transmission, and the provision of primary and secondary prophylaxis regimens for opportunistic infections. The provision of antiretroviral therapy has also begun in the hospital, using zidovudine/lamivudine/nevirapine as the first-line regimen. Monitoring of treatment adherence is augmented with home visits by monitors. No results of the program were presented as it is still in its initial phase, but Dr. Hertz's impression is that patients provided with antiretroviral therapy are highly motivated and compliant.

Equity in Pricing

Recent events in the United States have highlighted the disparity in patent and trade policies. The urgent need for adequate stocks of ciprofloxacin to treat possible future cases of anthrax has led to a price negotiation with the principal manufacturer, resulting in a 75% price reduction, and the Senate has called for provisions to be made to fast-track the generic manufacture of the drug. As Gregg Gonsalves of Gay Men's Health Crisis in New York pointed out, a relatively small number of cases of anthrax has yielded this rapid response in the United States, in contrast with the slow progress towards securing affordable treatments for the 40 million people living with HIV worldwide. MSF and other parties also argue that differential pricing of drugs has been introduced in other situations such as polio vaccine, hepatitis B vaccine, and hormonal contraceptives.

Pricing of drugs and laboratory monitoring will need to be reduced to enable (1) sustainable therapeutic initiatives; (2) government participation in treatment programs; (3) efficient investment in infrastructure; and (4) the development of autonomy in resource-poor countries. There will not be a single uniform solution to the drug pricing problem; it will require a mixture of strategies, including local production, global procurement and distribution mechanisms, voluntary or compulsory licensing, and generic competition. Industrialized nations can assist in these initiatives by developing enforceable legislation to prevent the reimportation of medicines into primary markets.

Low-Cost Laboratory Monitoring

Initiating antiretroviral therapy will require some degree of laboratory monitoring. In most African countries the cost of laboratory monitoring in line with federal guidelines would be completely unaffordable—totalling as much as the annual drug cost. Thus, the current focus on drug prices is already expanding to explore mechanisms to lower laboratory testing.5

Dr. Wendy Stevens, director of contract laboratory services at the National Health Laboratory Services, Johannesburg, South Africa, noted that while at present much advocacy is trying to achieve reductions in the price of current assays, more innovative thinking is required to ensure feasible, sustainable, low-cost monitoring options. Suzanne Crowe from the Barnet Institute in Melbourne, Australia, presented a review of current work performed in her laboratory and internationally to address low-cost monitoring techniques. She highlighted the fact that laboratory testing to measure immune paresis, combined with clinical staging according to the modified WHO classification,6 provides relatively accurate prognostic value in terms of predicting disease progression.

Clinical management in industrialized countries relies more on measuring the CD4+ cell count than viral load. The gold standard of flow cytometry is difficult to implement in resource-poor countries because of the costs of equipment, consumables, maintenance of equipment, and staff training. Nonflow methods with potential benefit include enzyme-linked immunosorbent assay (ELISA) techniques (Capcellia), magnetic beads, dynabeads, and counter cytospheres. There have been conflicting reports on the potential utility of the total lymphocyte count (TLC). While the sensitivity of a low TLC as a predictor of a low CD4+ cell count is good (TLC < 2000 cells/mL predicts a CD4+ cell count < 200 cells/mm3),7 its specificity is poor.

A further question is how viral load testing should be implemented in resource-poor settings, since these assays have inherent difficulties related to standardization, reproducibility, training requirements, and cost. Currently available viral load techniques also perform with varying degrees of success, depending on the viral subtypes in question. Alternatives to the PCR and bDNA assay techniques available in industrialized countries need to be considered. Dr. Stephens evaluated the RT Viral Load (Cavidi; Uppsala, Sweden) assay, an ultrasensitive reverse transcriptase PCR technique, measured by an ELISA assay, which may be more cost-effective and reproducible in low-cost settings.8

Different countries in Africa and other resource-poor regions have different levels of financial resources, laboratory infrastructure, and flexibility in treatment decision making; thus, the monitoring schedule and test methods will also differ from region to region.

Centralization or decentralization of laboratory tools is an important consideration. In some cases, it is possible to bring the test to the patient (for example, rapid HIV testing). When the CD4+ cell count and viral load cannot be brought to the patient, centralization of laboratory services provides important cost savings through volumes of samples. Transportation of samples from the peripheral clinics to the central laboratories then becomes the limiting factor. Research on this issue needs to consider the transport media, the stability of samples, the transport route, and the batching of frozen specimens.

A Research Agenda for Low-Cost Monitoring

The following were proposed as the main areas in which research related to laboratory monitoring in resource-poor settings is needed:

  1. Impact and benefit of qualitative PCR testing in the diagnosis of infants with HIV
  2. Alternative monitoring techniques that can provide the same information as CD4+ cell counts and viral load testing
  3. Studies of voluntary counseling and testing techniques, including cost-benefit ratios and implementation of rapid testing
  4. Assessment of low-cost monitoring techniques widely available, eg, total lymphocyte count to replace CD4+ cell count testing
  5. Combining low-cost monitoring techniques with clinical assessment (eg, weight loss, wasting, neurologic signs, onset of opportunistic infections) may provide an alternative to costly laboratory monitoring techniques
  6. Adaptation of monitoring schedules to reduce monitoring time-points, or trigger more expensive laboratory testing based on inexpensive screening tests
  7. Development of internal and external quality-assurance and quality-control programs for laboratory testing in resource-poor countries to reduce cost and ensure the program is regionally appropriate
  8. Studies to establish normal ranges of laboratory value for resource-poor patient populations, and to define the natural history of disease progression. The results of these laboratory projects will influence treatment guidelines.

When to Start Treatment?

This author addressed the question of when to start HIV treatment in resource-poor countries. The many challenges facing resource-poor countries will require a unique approach to this issue.9 Some of these challenges include the high volumes of patients (often up to 10% of the population), high rates of heterosexual HIV transmission, an ongoing pediatric HIV epidemic, poor data on the natural history of HIV/AIDS in resource-poor settings, the impact of low literacy levels on methods to enhance adherence, and the high occurrence of opportunistic pathogens and sexually transmitted diseases. In most resource-poor countries, HIV treatment will be limited to the provision of therapy to patients presenting with AIDS-defining illnesses. Only in settings where resources are not extremely limited can the treatment of asymptomatic patients be contemplated.

Unlike industrialized nations, resource-poor countries have underresourced voluntary counseling and testing programs, and thus the majority of patients are diagnosed with HIV at the onset of symptomatic disease. However, mothers who present for testing during pregnancy often still have high CD4+ cell counts (for example, in the PETRA study10 the mean CD4+ cell count at presentation was > 350 cells/mm3).

In the poorest countries, the main emphasis of resource allocation will be to treat patients presenting with symptomatic, AIDS-defining opportunistic infections (OIs). Only in countries where the therapeutic bar can be raised (eg, South Africa, Brazil, and Thailand) will treatment of asymptomatic patients be feasible. Thus, in these latter settings it may be appropriate to design studies to compare the initiation of therapy in symptomatic vs asymptomatic infection.

Tuberculosis has a disproportionate influence as it is the most common opportunistic infection (OI)—affecting up to 50% of patients—and the leading cause of death among HIV-infected patients in Africa.11-13 If available, it would be reasonable to initiate antiretroviral therapy in patients who present with tuberculosis, although the potential drawbacks include the inflammatory immune reconstitution syndrome observed in a proportion of patients with tuberculosis who start highly active antiretroviral therapy (HAART), the drug-drug interactions between HAART and antituberculosis agents, and the additive liver toxicity of these drugs.

For antiretroviral therapy to be successful, the social circumstances of patients must be considered, including their family structure, income, and transport to clinic. Since these factors may influence adherence to therapy and the patient's ability to tolerate side effects, they have a bearing on the issue of when to initiate therapy. The panel agreed that while the social circumstances of patients are important considerations, it will be difficult to design a study to further evaluate their impact; nevertheless, it should be possible to collect important observational data on these factors.

The implementation of antiretroviral therapy will require laboratory facilities; thus, the availability of those facilities—which often reflects the overall level of healthcare resources in that setting—influences the decision of when to start therapy. One proposed approach, accounting for both disease stage and the availability of laboratory monitoring, is summarized in Table 1.

Special Issues Regarding Pregnant and Breastfeeding Women

Strategies to reduce rates of mother-to-child HIV transmission in resource-poor countries currently focus on the use of single-dose nevirapine. However, the implications of this strategy include selection of nevirapine resistance in up to 19% of patients.14 An important question to evaluate is whether this resistance—or indeed that selected by short-course zidovudine, zidovudine/lamivudine, or other regimens—is likely to be clinically significant if treatment with HAART is subsequently initiated.

Recent data have suggested that mortality rates may be higher among HIV-infected women who breastfeed their infants, compared with those who formula-feed.15 This raises the questions: Should HAART be provided during breastfeeding, and would this also influence rates of HIV transmission? The US Centers for Disease Control is funding a study in Malawi to explore these issues.

Selecting Treatment Regimens in Resource-Poor Settings

There are a number of reasons why the safety and efficacy of HIV-related therapies may be different in resource-poor settings compared with the industrialized world:

These unique limitations faced by resource-poor countries may result in the adoption of treatment guidelines that differ from those in industrialized countries. While it would be preferable to initiate therapy with a HAART regimen—and many advocates have argued that this is also a moral imperative—the consensus of the meeting was that this should not be considered a prerequisite. If the treatment bar is raised too high, doctors in resource-poor settings where it is not currently possible to offer HAART may become complacent about the lack of treatment. Moreover, a dogmatic insistence that triple therapy is the only acceptable treatment of HIV is likely to lead to the neglect of attention to other, equally important aspects of treatment implementation in developing countries.

Antiretroviral regimens are currently limited to those drug combinations available through access-priced initiatives and generic manufacture. When triple-therapy regimens are not accessible, lesser regimens may be the only alternative. Treatment with dual-NRTI combinations and hydroxyurea-containing regimens has been successfully implemented in Brazil and Thailand, leading to reductions in viral load that are associated with reduced rates of HIV disease progression.16

When deciding how best to sequence the available medications, local physicians must balance issues of compliance, drug toxicity, and drug resistance. Specific research addressing aspects of sequencing nucleoside reverse transcriptase inhibitors (NRTIs), preservation of nonnucleoside reverse transcriptase inhibitors (NNRTIs) for use in preventing mother-to-child transmission, and resistance monitoring should be considered.

Specific environmental aspects also could affect the choice of antiretroviral therapy. The prevalence of infectious diseases such as tuberculosis, malaria, and gastrointestinal parasites in resource-limited settings must be considered: Drug absorption, drug interactions and the incidence of infectious illnesses presenting with fevers will all determine the applicability of specific antiretroviral regimens administered at a primary healthcare level.

Often multiple members of a single household may require therapy. As a result of the heterosexual transmission of HIV, women of child-bearing potential are the most affected group, and a key priority for therapy. Regimens that can be taken safely during pregnancy will thus be prioritized in low-resource settings. Issues of compliance and affordability will also affect the treatment priority assigned to each family member.

The pharmacoeconomic impact of decisions regarding antiretroviral therapy also must be taken into account. Within a household, the deaths of untreated family members affect the well-being and economic viability of the remaining members, most significantly among orphans. Within the society, the impact of the additional cost of treatment on disposable income, and the cost of health burdens on the society as a whole, are reflected in declines in the retail industry, the education status of the society, and overall productive industry and gross domestic product (GDP).

A Research Agenda: Which Treatment Regimen?

More research is needed on a variety of factors that influence the issue of what treatment can be provided in resource-poor settings:

  1. Financial aspects—patients' disposable income and/or national healthcare expenditure—will determine the available drug combinations.
  2. Aspects of work environment need to be considered; for example, a mining population will not be able to receive medication that causes diarrhea and dizziness.
  3. Should HAART be unaffordable, should dual NRTI or dual protease inhibitor (PI) therapy be considered as alternatives? Combinations of a single NRTI and a single PI carry a high risk of development of resistance, but—as we have learned from studies of salvage therapy in industrialized countries—continued therapy despite the presence of resistance is often beneficial, as reflected by a stable CD4+ cell count.
  4. Very resource-limited countries such as Malawi and Mozambique are likely to initiate treatment only in patients with advanced AIDS. In this setting, which triple therapy combination will be considered the regimen of choice?
  5. There are only limited data on the pharmacokinetics of antiretrovirals when used by poor populations. Factors influencing the pharmacokinetics include nutritional status, ethnic origin, hepatic metabolism, and use of herbal medications. In most cases, there are no data on the absorption and metabolism of generic drugs. Dose adjustments according to weight may be of particular importance in women and Asian populations.
  6. Much research is being devoted to how to sequence 3-drug combinations using triple-NRTI-, NNRTI-, and PI-based regimens. In a resource-poor setting the sequence of the NRTIs may be more important than previously acknowledged. Preservation of this class of drugs is a priority, as treatment combinations that exclude the NRTIs are not likely to be affordable. The potency of the various regimens, and the barrier they present to resistance, need to be taken into consideration.
  7. The high incidence of tuberculosis, and the high prevalence of HIV among women of childbearing potential, are 2 important considerations when choosing treatment combinations for large-scale implementation.
  8. Will the provision of HAART affect the uptake of voluntary counseling and testing, and influence rates of HIV transmission?
  9. When choosing a treatment combination, is there a difference between rates of adherence to once-daily and twice-daily regimens? How are rates of adherence to once- and twice-daily regimens affected by the use of directly observed therapy or adherence counseling?
  10. The availability of coformulated zidovudine/lamivudine/abacavir (Trizivir) is considered an important advance in drug adherence. However, the use of abacavir is associated with a potentially life-threatening hypersensitivity reactions in a small minority of recipients, and thus requires careful management. In a resource-poor setting in which the management of antiretroviral therapy is likely to be the responsibility of primary healthcare personnel and not doctors, the role of abacavir in first-line therapy is therefore uncertain. Should abacavir be retained for patients who have failed prior NRTI-based therapy?
  11. The inclusion of nevirapine in treatment regimens is attractive because of the access pricing and/or generic manufacture of the medication, as well as its safety when used in pregnancy. However, hepatotoxicity is a concern, and rates have been noted to be higher in women.17 Although the incidence of hepatotoxicity in black populations is similar to that in whites, the incidence of hepatotoxicity in Asian populations has not been established. The role of nevirapine in patients with low CD4+ cell counts and high viral loads has not been established.
  12. In view of the recent marked price reduction to less than $0.50 per treatment day, what is the role of zalcitabine in resource-poor countries?
  13. Since most countries do not have enough physicians to provide individualized, expert patient care, can we construct standard treatment algorithms similar to those used in tuberculosis treatment (ie, regimen 1 regimen 2 regimen 3)?
  14. Is structured treatment interruption a viable option for resource-poor settings?

Ethical Considerations of Research in Resource-Poor Settings

Jack Killen from the Department of Clinical Bioethics at the US National Institutes of Health presented a discussion on the ethics of clinical research in resource-poor settings. The debate currently underway in the research community, as evidenced by the modification of the Declaration of Helsinki, is providing a moral dilemma for clinical researchers. Ethics are of principal importance, but dogmatism is counterproductive. HIV/AIDS research in the developing world is now providing the route-map for the development of ethics guidelines for broader application. At the same time as clinical research is undertaken in resource-poor settings, there are opportunities for exploratory research into ethical issues—for example, aspects of informed consent.

Emmanuel and colleagues18 recently published 7 criteria for considering the ethics of research in resource-poor countries:

  1. The social value of the research. Research must be conducted in partnership with the society in which the study is conducted. Such partnerships also allow social aspects of the conduct of research to be addressed.
  2. The scientific validity of the clinical research
  3. The equitable and fair selection of participants in the clinical trial
  4. A favorable risk-benefit ratio of the intervention
  5. Independent review of the clinical research, locally by an ethics committee and/or scientific review body
  6. Implementation of individual informed consent procedure, not necessarily written but involving a socially appropriate process. The consent must be uncoerced, freely and willingly provided.
  7. Respect for enrolled subjects and recruited communities

When undertaking research in resource-poor settings, the standard of care with which new interventions are compared does not need to be that of industrialized countries. However, the standard of care should be reasonable given the resources of the research setting, and should be regularly reviewed in the light of progress.

Conclusions

There remain many issues regarding the implementation of antiretroviral therapy in the developing world that must be addressed through clinical research performed in appropriate resource-poor countries. Available resources vary from country to country, requiring the development of specific treatment guidelines that are appropriate for the situation. There is thus an urgent need for a funding commitment for a research agenda specific to resource-poor countries.

References

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Ian Sanne, M.D., is Director of the Clinical HIV Research Unit at the University of the Witwatersrand, Johannesburg, South Africa.

© 2001 Medscape, Inc.