2003: Clinical Research in Service of the Public Health - Health Services, Outcomes and Operational Research Abroad, Setting an Agenda for Action - Report

On 16-18 May 2003 an international group of 32 AIDS researchers, research sponsors, donor agency representatives and treatment advocates met at Stony Point, New York, for a workshop on Effectiveness Research on Antiretroviral Therapy (ART) in the Developing World: Setting an Agenda for Action. The workshop, funded by the John M. Lloyd AIDS Project at Stony Point Center and organized by Gay Men's Health Crisis (GMHC), provided an opportunity for AIDS researchers in developed and developing countries to exchange ideas and lay out a road-map for operational and effectiveness research on HIV/AIDS treatment in developing countries. The workshop organizers hoped that participants would leave with a fuller understanding of the key issues facing operational and effectiveness research on HIV/AIDS treatment in developing countries, and with new opportunities for working together to implement key research projects and protocols.

Participants in the meeting included leading clinical researchers, representatives from national AIDS programs and people with HIV/AIDS from Africa, Latin America, the former Soviet Union, Europe and North America as well as representatives of multilateral agencies such as the World Health Organization.

The Questions
Currently, antiretroviral medications for AIDS are given marketing approval by the US Food and Drug Administration on the basis of 48-week data on viral load. While this expedited approval of new AIDS drugs is particularly important for people with AIDS who have limited remaining treatment options, it has created an incentive for industry and clinical researchers not to pursue long-term studies on the clinical effects of antiretroviral therapy (ART). Yet, every day thousands of people living with HIV agonize about whether or not to begin ART. The questions frequently asked by consumers include:

• How high can my viral load rise or my CD4 count fall before it's too late?
• How safe are the medications?
• If I start now, will the drug complications and toxicities outweigh the benefits?
• Should I wait for newer and better medications?
• How long can I afford to wait?
• Which is the best drug regimen to start with?

In addition, along with almost everyone already on antiretrovirals, they worry about drug complications and resistance.

• What are the long-term complications and toxicities?
• What are my chances of getting them?
• If the drug regimen doesn't work or stops working, what should I do next?
• How long before I develop resistance to the drugs?
• How high can I let my viral load climb before I need to change drugs?
• What should I do when multi-drug resistance develops?

Are the answers to these questions different for women and men? For different ethnicities? For different age groups? How about those with additional diseases, such as hepatitis, diabetes, cardiovascular disease or addiction disorders? These are issues that will affect the lives and health of hundreds of thousands of people, involve billions of dollars in annual medication and other health care costs, and influence the standards of HIV care for decades. Yet there is precious little scientific data to help them make these decisions.

These essential questions about the "real world" medical management of ART become even more acute as these drugs begin to be used in developing countries. With far fewer resources in these settings, provision of antiretroviral therapy will be less individualized and more standardized for scale-up. Answers to the questions posed above are essential to optimize the use of ART in the developing world, as wrong turns in these large-scale interventions will affect the lives of millions. There are also questions particular to these settings that have yet to be answered as well:

• Can ART be managed without laboratory monitoring in the developing world?
• What is the relationship between virologic and clinical failure?
• Are there clinical indicators of treatment failure?
• What is the relationship between malaria and other parasitic diseases, HIV and ART?

The new World Health Organization treatment ART guidelines for the developing world, Scaling Up Antiretroviral Therapy in Resource Limited Settings: Guidelines for a Public Health Approach , raise many new questions that need to be answered about the "real-world" use of ART in the context of developing nations' health care capacity and infrastructure.

Getting Answers
Several major questions were addressed at the workshop:

1. When to start ART?
2. What regimen to start with?
3. Which treatment strategies could reduce time on therapy, reduce toxicities, reduce drug costs?
4. When to change treatment?
5. How to monitor & evaluate ART programs?

After a day and a half of presentations and discussions, the group came to the following conclusions and defined additional questions for further research:

1. When to Start/What to Start With

• Can starting people on treatment earlier allow more time off therapy?
• Can the current WHO guidelines prevent major opportunistic infections? What about preventing TB, which often occurs at higher CD4 counts?
• A registry/database of studies on ART in the developing world needs to be established.
• WHO needs to help develop:
  • Standardized diagnostic manual for defining stage 2, 3, and 4 disease;
  • Standardized diagnostic algorithms for diagnosing, starting, switching;
  • Standardized therapeutic manual for treatment of AIDS indicator diseases.
  • In addition to studies of when to start there is a need to study how to start and what to start with.
  • Is there enough spread between these different regimens that we should do trials? Or should we just implement and make decisions based on cost?
  • Most participants felt the when to start question would remain of vital importance until answered.

• The best way to minimize drug cost would be to answer when to start.
• The most efficient way of minimizing exposure to ART would be either to delay exposure or to take ART briefly for a short period and delay chronic treatment. Would treating earlier for just one year delay the time of starting chronic therapy?
• Studies are needed of strategies for staying on drug - using DOTS/modified DOTS, peer counseling, what kinds of treatment education modules are effective?
• Packaging drugs in fixed-dose combinations (FDCs) or blister packs could enhance adherence.

• In many settings, the decision on when to change regimens will have to be made by nurse practitioners without laboratory information in real time. Studies are needed looking at simple indicators for switching such as weight/body mass index (BMI), hematocrit, TLC, etc.
• Leaving when to change decisions to clinical discretion is problematic since most practitioners have limited clinical experience with ART - they're asking for extraordinarily concrete, detailed guidelines.
• With very sick patients it will be very hard to get a simple algorithm. Secondary support systems will be needed.

• Some recommended the use of electronic patient records.
• Early mortality will be high in most scale-up programs because those coming in for ART will be quite sick. This will impact the reported efficacy of the treatment programs.
• More data are needed on the impact of ART on mortality in a variety of real-world settings, and this should be gathered as part of the scale-up process.
• Mortality will be lower among women in MTCT programs since they will come in at all CD4 levels.
• WHO or another player should bring together people involved in these early programs to share collective experiences.
• Well-designed prospective regional cohort studies could help provide baseline data and the basis for generating hypotheses for RCTs and operational research.
• A minimal dataset to be used across programs is critically needed.
• Short- and long-term mortality data are needed.
• Prevention, care and treatment programs need to be the foundation for further RCTs and operational research.

David Stanton (United States Agency for International Development), Phill Wilson (The Black AIDS Institute), Robin Wood (Somerset Hospital and University of Cape Town, South Africa), Vitaly Zhumagaliev (Open Health Institute, Russia), Timothy Flanigan (Miriam Hospital and Brown University), Charles Gilks (World Health Organization and Imperial College, United Kingdom), and Gregg Gonsalves (Gay Men's Health Crisis). Marie Charles (International Center for Equal Healthcare Access), Dorothy Bray (Medical Research Council Clinical Trials Unit, United Kingdom), Marie Christine Ryckaert, David Barr (Open Society Institute), Roman Dudnik (AIDS Foundation East West, Russia), Abdel Babiker (Medical Research Council Clinical Trials Unit, United Kingdom), Mauro Schechter (Universidade Federal do Rio de Janeiro, Brazil), and David Saunders (United States Agency for International Development). Mary Lloyd Estrin (The John M. Lloyd Foundation), Melanie Havelin (The John M. Lloyd Foundation), Mark Harrington (Treatment Action Group), Arata Kochi (World Health Organization), Veronica Miller (Forum for Collaborative HIV Research) and Paolo Miotti (Office of AIDS Research, National Institutes of Health). James Neaton (University of Minnesota), Miriam Rabkin (Rockefeller Foundation and Columbia University), Michael Bennish (Africa Centre for Health and Population Studies, South Africa), Catherine Seyler (Agence Nationale de Recherches sur le SIDA, Ivory Coast), and Peter Cherutich (National AIDS/STD Control Program, Ministry of Health, Kenya).