It was Stephen who conceived, initiated and produced the green sheet weekly summary of the Wednesday night Treatment+Data meetings of ACT UP in 1989, the Treatment + Data Digest.

TAGline grew out of the T+D Digest immediately after the founding of TAG in 1992.

Without Stephen's caring and ingenuity, it is unlikely that either of these would have come into being, or that TAGline would exist today. ¤

Ten years ago, when the AIDS death toll in the United States crossed 100,000, few paid heed to a grim prediction by the World Health Organization (WHO) that "by the year 2000, 40 million persons may be infected with HIV." In the rich world, AIDS was seen as a serious but smallish disease, restricted to gay men, drug users, hemophiliacs, and the innocent offspring of all three. In the developing world, just a few courageous voices were warning about the silent spread of a deadly new plague.

Today, WHO's grim prediction has come true. Africa is in crisis. In some countries, a quarter or more of the adult population is infected. Millions have died, and millions more will follow, leaving their societies trapped in poverty, burdened with a generation of orphans, and facing demographic catastrophe. The grim statistics are not confined to Africa. Asia and the Caribbean face explosive HIV epidemics, while the nations of the former Soviet empire peer over the precipice of drug addiction, untreated sexual diseases, and unchecked HIV spread. HIV is out of control, and finally the world has begun to take notice.

In January 2000, the United Nations Security Council held a special session in which for the first time it identified a disease—AIDS—as a global security threat. Some American cynics have mocked this move as domestic political theater, but no serious observer denies that HIV is undermining nations and economies. HIV kills young people in their most productive years. In a growing number of countries, workers, teachers, nurses, civil servants, and others will perish in astonishing numbers. The backbone of civil society is threatened in many nations, and the threat remains uncontrolled.

The security threat is real, but only half the story. HIV began as an obscure simian virus in equatorial Africa in the first half of the twentieth century and, within fifty years, had spread throughout the world. The forces that brought HIV to America in the 1970s—world travel, globalization, and urbanization—are accelerating. One need only look at the number of variant strains of HIV-1 spreading worldwide, at the outbreak of West Nile Virus in the Northeast, or at the number of HIV-2 cases now emerging in New York and other gateway American cities, to see how the forces of globalization are adding new ingredients to the world's microbial soup. When HIV remains unchecked in large regions of the globe, as it does now, no country is safe, including America. Fighting AIDS abroad is in America's own interest.

In response, the U.S. government now proposes new initiatives to fight the global spread of AIDS. TAG welcomes them. But the U.S. has conducted global AIDS programs for more than a decade, and related international health programs for even longer. Any new AIDS funding builds on this foundation. Yet no analysis exists of the present U.S. role in the global AIDS pandemic. Without review and evaluation, any new programs run the risk of being scattershot and ineffective. In other words, recent good intentions may, without good planning and evaluation, lead nowhere. If the U.S. cannot summarize its current programs accurately, how can they grow effectively?

This report is a first, imperfect documentation of what the U.S. government spent in 1998 on international HIV programs. We hope this analysis can serve as a foundation, a basis for decision-making, a hopeful call to action. Inside, we describe what the U.S. government has done, so others may better answer what can and should be done. We hope others in the developed, democratic world take this report as a model to press for more and better responses from their governments. We hope people in poorer countries will use this report to navigate the U.S. government and become full partners with the American effort. (The complete international report can be obtained by calling the TAG office, 253-7922, or by retrieving it from our website.)

Information from U.S. agencies ranged from clear to chaotic to non-existent. The lack of clear information hampers not only this analysis but any attempt to understand and evaluate the successes and limitations of the U.S. program. If the program cannot be defined, how can anyone know if it succeeded? The findings in our report should be viewed as a first step, an exploration of the U.S. government's emerging response to the global AIDS pandemic, and a call to action for the future.

Summary Findings
Three U.S. government agencies formed the core of the American response to the global AIDS pandemic in 1998. The U.S. Agency for International Development (USAID) spent $123.7 million on international AIDS programs in 1998, including a $23 million contribution to the United Nations AIDS program, the single largest component of that international agency's budget. The National Institutes of Health spent $52 million on international AIDS research projects in 1998. The Centers for Disease Control spent $9 million.

Overall, the U.S. government supported 463 HIV/AIDS projects in 79 developing nations: 28 African countries (36% of the budget), 20 Asian nations (15% of the budget), 19 Latin American and Caribbean countries (12% of the budget) and 12 Eurasian countries (1% of the budget). The U.S. also supported 53 projects that were global, multi-region, or undefined in scope, reaching many countries across regions. These global programs accounted for approximately 34% of the U.S. funds.

In our report, we describe the U.S. international HIV/AIDS 1998 program activities in nine categories. The largest (31% of the total budget) was the development of health systems infrastructure by the U.S. Agency for International Development in 36 countries. USAID supported HIV prevention programs (20% of the budget) in 37 countries. Support for the United Nations AIDS Program took up 12% of the total budget. NIH-funded academic research projects (11% of the budget) in 37 countries. All three agencies funded epidemiology and surveillance projects (8% of the budget) that operated globally and in 12 countries. The National Institutes of Health (NIH) supported a vaccine discovery program (7% of the budget) in 10 countries. NIH trained researchers (5% of the budget) from 43 countries. USAID developed community and governmental leadership (3% of the budget) in 29 countries. NIH supported reference labs and other research resources in the U.S. (3% of the total budget) that served global needs.

Other U.S. agencies played a role in the global AIDS response, but that role is small and, in some cases, unclear. The most important example is the Department of Defense (DOD), which maintains an international HIV research program. (DOD officials refused to cooperate with the preparation of this report.) Other agencies with an international presence are the departments of State, Labor, and Commerce. The limited information we could obtain about these programs is summarized in our report but is not otherwise included in the analysis.

The U.S. international HIV program is not direct aid to foreign governments or agencies; rather, the it included the direct overseas programs of 12 divisions of the U.S. government, support for the United Nations, and contracts and grants to 48 universities or nongovernmental organizations (NGOs), all but three of which are located in the U.S.

Most contracts and grants in the U.S. international program were concentrated at 17 academic or non-governmental organizations (16 American and one British). These organizations all received more than $1 million from the U.S. government for international HIV programs, and collectively received 43% ($79.8 million) of the total program. The single largest contractor was Family Health International, a Virginia-based NGO, which alone received $25 million. Johns Hopkins University received $4.4 million, more than any other academic institution.

The U.S. international AIDS program is a small part of larger initiatives in global health and research. In 1998, the NIH international AIDS research program was 2% of the $1.8 billion AIDS research program. CDC's international AIDS program was less than 1% of its overall AIDS program. Even at USAID, AIDS was just a fraction of that agency's development agenda. AIDS programs accounted for less than 9% of USAID's entire budget, and less than 22% of its health programs. In countries where USAID operates missions, AIDS funding typically never exceeded 5% of the total mission budget. In those few cases where the relative portion of AIDS funding was higher at a USAID mission, the absolute funding for AIDS and other activities was generally low. As a portion of the U.S. domestic $8.7 billion AIDS budget, the entire U.S. international program barely reached 2%.

While the U.S. is the largest contributor of AIDS-related development assistance in absolute terms, other rich countries spend far more when population and gross national product are taken into account. The Netherlands, Norway, Sweden, Denmark, Australia, Canada, the U.K. and even Belgium contributed more on this adjusted basis. These comparisons, however, do not include funding for AIDS research—an area in which the U.S. clearly outspends all other countries. These two factors should be considered when comparisons are made.

This year, the U.S. proposed its new Leadership and Investment in Fighting an Epidemic (LIFE) initiative. Funded with $100 million in new or redirected resources (opinions vary), LIFE will reprogram $54 million for international AIDS activities to USAID, $26 million to CDC, and $10 million each to the Departments of Defense and Labor in fiscal year 2001. While supportive of this new initiative, we would support inclusion of new resources for NIH as well, which has a substantial ($53 million) investment in international research, as well as significant expertise and infrastructure. The LIFE initiative represents a minimum acceptable increase in U.S. support for international HIV/AIDS activities and we hope resources continue to increase substantially. ¤

Too Many Questions, Not Enough Answers: The urgent need for long-term effectiveness research
Every day thousands of people living with HIV agonize over questions about whether or not to begin antiretroviral therapy: "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?" And, 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 diseases, such as hepatitis, diabetes, cardiovascular disease or drug addiction?"

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 us make these decisions.

We, the undersigned, call on the National Institutes of Health to address this situation immediately. NIH must immediately commit significant financial and organizational resources to research these questions and develop, as expeditiously as possible, a detailed plan for that research. We are years behind where we should be and the lives and health of an increasing number of people are at risk.

As a first step in this process, NIH should immediately consult with a variety of advisors—including members of the HIV/AIDS community, researchers, clinicians, statisticians, and members of the pharmaceutical industry—to begin development of a long-term clinical research plan. We insist upon full and immediate community participation in all stages of planning this research, utilizing the experience, knowledge and commitment of HIV/AIDS community activists reporting back to the larger affected community.

Priority Areas
We call on NIH to demonstrate leadership and expedite the design and funding of long-term effectiveness research to answer these priority questions:

• When and how should antiretroviral therapy be started?
• When should antiretroviral therapy be changed and to what?
• What are the long-term complications and toxicities of antiretroviral therapy?
• What are the consequences of moderately unsuppressed viral load and treatment interruption?

It is important that the answers are relevant to as many people living with HIV as possible including women, the elderly, adolescents, African Americans, Hispanics, other ethnic groups as well as those living with hepatitis, diabetes, or other life-threatening conditions.

Research Design
NIH must confront its institutional biases and restrictions and provide creative, collaborative and flexible leadership in conducting trials that will certainly be larger and longer than those it has traditionally conducted for HIV/AIDS.

• NIH should consult a wide range of experts, including those who have done long-term research in other fields of medicine.
• The NIAID funding cycle is currently five years. NIH needs to ensure that there is adequate funding for the longer time periods required to complete these kinds of studies.
• NIH must demonstrate leadership to begin collaboration among national and international HIV research networks and to secure the cooperation and participation of the pharmaceutical industry. The well-being of those living with HIV must supersede personal and institutional agendas and in-fighting.
• NIH should give priority to trial designs that permit analysis according to the subpopulations we have highlighted—whether by stratification, nested substudies or other appropriate trial designs.
• The landscape of antiretroviral therapy is constantly changing. Trial designs must be flexible to accommodate new developments and ensure the relevance of answers at the conclusion. The length and size of these studies, as well as the great importance of the answers for determining proper standards of care for HIV treatment, require extraordinary efforts for recruitment and retention.
• NIH needs to conduct educational campaigns, targeted at patients and providers, to aid in the recruitment and retention of people from all affected communities.
• Trials should be conducted in the settings in which patients receive their regular medical care.
• The complexity of these trials may require assessments of their feasibility, including pilot studies.

Not every question may require a randomized clinical trial. Some, such as the elucidation of long-term complications and toxicities of antiretroviral therapy, may be better answered with observational databases. Yet, NIH is ultimately responsible for guaranteeing that these questions will be answered in an efficient, ethical and scientifically rigorous manner. Too much time has already been lost. The risk of continued delay is too great. We, the undersigned, call on NIH to act now. ¤

This report is a collaborative effort. Jeffrey Schouten was a great partner who worked with me over these two years, and he wrote selected hepatitis C chapters and the section on hepatitis and HIV coinfection. Version 2.0 of this report, already in production, will include an analysis of the research and treatment of hepatitis viruses A and B. Expert hepatitis researchers—including Marion Peters, Thierry Poynard, Teresa Wright, Jay Hoofnagle, Leonard Seeff, and Douglas Dieterich—went out of their way in varying capacities to help me, an AIDS treatment advocate they had never met.

My appreciation of and desire to study hepatitis C virus research is something new. It started off as mere curiosity during my research of AIDS-related opportunistic infections (OIs) when I thought about adding a short chapter on hepatitis C to TAG's OI Report because it was well-known that many individuals with HIV are also coinfected with hepatitis C. Two years later, it seems laughable that one could write a short chapter on hepatitis C. It has become apparent to me that there is a need for a thorough study, review, and critical analysis of hepatitis C research and treatment.

Over the years, AIDS treatment advocates have critically analyzed the numerous facets of HIV clinical and basic research with great aplomb. They have produced a wealth of patient-readable HIV treatment information so that people with HIV/AIDS can become experts in understanding their disease. In my two years of researching hepatitis C, I found that there were only a few hepatitis C treatment advocates, yet none had created one text that contained a complete overview of the disease, analyzed the research, and offered important and sound hepatitis C treatment information as well as policy recommendations to move the field of hepatitis C research forward. Since I have been well-trained and mentored in researching and writing such documents on HIV-related complications, I felt I would initiate TAG's Hepatitis Project and write a report on hepatitis C, as well as on hepatitis and HIV coinfection. People with hepatitis C deserve the same tools as those with HIV so that they can become experts about their disease.

I quickly realized that people with hepatitis C were not the only ones who needed to become experts. Many primary care physicians lack a complete breath of knowledge of the epidemiology and clinical management of hepatitis C. This was blatantly obvious in the 1999 Hepatology article, "Current Practice Patterns of Primary Care Physicians in the Management of Patients with Hepatitis C," by Shehab and colleagues from Anna Lok's group at the University of Michigan. In a survey of over 400 primary care physicians from the Detroit area, 20% and 8%, respectively, considered blood transfusion in 1994 and casual household contact as significant risk factors for hepatitis C infection. Forty-three percent overestimated the likelihood of a sustained response to a course of interferon therapy, while 29% had no idea what the sustained response rate was. Thirty-eight percent would not refer an individual with a positive hepatitis C antibody test to a gastroenterologist—even though they had no experience in treating hepatitis C themselves.

Another study by Villano and colleagues from Johns Hopkins found that a majority of the intravenous-drug-using individuals in their natural history cohort tested hepatitis C antibody-positive their first time on study—yet were under the care of clinic or primary care physicians. This striking lack of awareness by health care providers about hepatitis C epidemiology, risk factors, and clinical management is unacceptable. Let us hope that this report gets into the hands of the physicians and people with HCV who need it.

I also wrote the report in an attempt to quell the mass hysteria about hepatitis C created by major weekly news magazines as well as by the obnoxious "Get tested, get treated" hepatitis C advertising campaign of a greedy pharmaceutical company. The push to immediately treat everyone who tests positive for hepatitis C made my blood boil, because that is often the same message given to those who initially test positive for HIV. (For HIV, clinical endpoint studies have shown a survival advantage to starting potent, combination antiretroviral therapy only once a person's CD4 count has dropped below 200 cell/mm3. Yet with both viruses, we still have not fully answered the question, "When should one initiate antiviral therapy?"

This hepatitis C report attempts to answer that question and documents what we know and what we don't know about the epidemiology, natural history, diagnosis, and treatment of hepatitis C infection.

After an exhaustive analysis of peer-reviewed articles, over 40 researchers, clinicians, primary care physicians, government heath administrators, industry representatives, and patients with viral hepatitis were interviewed.

Research and treatment policy recommendations have been issued and will need to be implemented in order to carefully find answers to the many basic and clinical science questions in hepatitis C research.

More collaborative and concentrated efforts on the part of industry, physicians, government, and the hepatitis community alike are needed if we are to effectively challenge, overcome, and cure hepatitis C infection. ¤

1. The CDC should further investigate the role of HCV sexual transmission in men who have sex with men.
2. The CDC should update its 1998 HCV recommendations to suggest HCV testing for all persons with HIV/AIDS.
3. More research should be conducted to completely understand the immunologic responses associated with control of HCV infection.
4. The NIAAA should commence studies on the effects of alcohol in patients with HCV. The findings should be widely distributed to patients and community physicians in a timely manner.
5. Large natural history studies should be initiated to determine the current natural history of HIV/HCV coinfected individuals.
6. The NIH ICDs (i.e., NIAID, NIDDK, NHLBI) should issue multiple RFAs for cross-training of fellows in hepatology and infectious disease/HIV research.
7. The NIH's Office of AIDS Research should make available some of its discretionary funding for basic and clinical research on HIV/HCV coinfection.
8. The NIH should explore the desirability and feasibility of a Hepatitis Clinical Trials Network. The network would carry out Phase I to IV clinical studies with nested basic science research.
9. Future HCV treatment trials should stratify for HIV serostatus and enroll both HIV- positive and HIV-negative people in order to gather these critical data.
10. HCV treatment should be mandated in all state and federal prison systems.
11. Transplant centers in the U.S. should consider HIV-positive people for liver transplantation.
12. HCV patients must have access to their HCV RNA levels at timely intervals (e.g., week 24) while on HCV treatment studies.
13. Schering Plough must unbundle Rebetron so that ribavirin can be purchased separately.
14. Research should be conducted to determine the lowest effective dose of ribavirin to minimize unnecessary toxicity.
15. All 50 U.S. states should add ribavirin to their Medicaid and ADAP formularies.
16. Industry should conduct drug interaction studies of anti-HIV drugs in HIV/HCV coinfected people while drugs are in development so that potential hepatotoxicity and drug interactions are defined prior to approval.
17. The FDA should grant Hoffmann-La Roche's pegylated interferon NDA a "priority review" because of the unmet medical need for therapies for HCV patients with cirrhosis.
18. HCV treating physicians should fully explain the risk and benefits of interferon/ribavirin combination therapy with their patients as well as estimates of treatment response according to host and viral characteristics.
19. Industry must actively recruit African Americans in all phases of HCV clinical trials. These studies should have the statistical power to assess racial differences in viral clearance and response rates.
20. Hepatitis treatment advocates should be included in all facets of NIH decision making about hepatitis clinical and basic science research, including protocol development, scientific agenda committees and grant reviews.

CDC= Centers for Disease Control and Prevention; NIAAA= National Institute on Alcohol Abuse and Alcoholism; NIAID= National Institutes of Allergy and Infectious Disease; NIDDK=National Institute of Diabetes, Digestive and Kidney Diseases; NHLBI=National Heart, Lung, Blood Institute; RFA= Request for Applications; ADAP= AIDS Drug Assistance Program; NDA= New Drug Application