Too little, too late? Burning to the ground

2003 Retrovirus Conference Report - International Treatment Policy Report prepared for Treatment Action Group By Rob Camp, Mark Harrington

Introduction
Approximately 3,900 academic clinicians and scientists, primarily from the developed world, attended the 10th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, USA, 10-14 February 2003.

The conference sound-bite seemed to be, "The pipeline of new antiretrovirals is fuller than it has been for a long time" (see "pipeline" report). Some 800 studies were presented, many of which concentrated on new therapies. Also discussed were the complications of antiretroviral therapies and the impact of other infections such as hepatitis on the course of HIV disease. Researchers outlined early-stage work in RNA interference strategies. (1)

In one press conference, the research director of Community Research Initiative of New England, took time out from the giddiness of it all to remind us of the time frame from research to patient (i.e., not overnight), as well as the pitfalls of side effects not anticipated.

Possibly because less toxic drugs have not been easy to come by, the emphasis this year was on easier to take versions. This may also be useful because it may allow for easier delivery of treatment in developing nations, a concern at this meeting, if not actually a priority: The spread of the HIV pandemic around the world was the subject of several studies and there were presentations on how therapies are being applied in developing nations. (2)

How much would it cost to turn on that fire extinguisher?
Ex-President Bill Clinton gave the conference keynote address. His most important comments were the recognition that results are based on systems (which I translated to mean good methodology) and that words are not enough (which I took to mean that political good will only goes so far, and action is needed).

Clinton praised the current president's pledge of $15 billion to fight AIDS in the developing world (yes, the just-signed bill was actually first talked about at the State of the Union speech some six months ago). Clinton said steps must be taken to ensure that countries getting the cash are prepared to spend it effectively. "It's a big step forward," Clinton said.

Clinton said that the global HIV epidemic threatens to undermine fledgling democracies around the world (i.e., AIDS as a security threat). Clinton said he hopes most of the US AIDS money would be distributed through the Global Fund to Fight AIDS, TB & Malaria (GFATM). However, the recently-passed Congressional AIDS bill contains some disturbing earmarks, such as the specification that one-third of the prevention funds must go to abstinence-only programs. This is based on an ideologically motivated misunderstanding of the partially successful Ugandan prevention program, which involved "abstinence, be faithful, USE CONDOMS"—or ABCs—Uganda, to its credit, recently ordered 80 million condoms, which demonstrates that its approach is based on the whole ABC, not just "A" alone.

Of the $15 billion authorized under the President's Emergency Plan for AIDS Relief (EPAR), one billion will be given to the Global Fund in $200 million annual allotments over five years. Overall, 50% of the funds will go to treatment, 30% for prevention, and 20% for care, including orphan care. The budget creates a Special Coordinator for International HIV/AIDS Assistance at the State Department "to ensure accountability for results." (7)

Clinton admitted he made a mistake during his presidency in opposing needle exchange programs. "We have to put science over politics," he said, for which he got thundering applause, though his admission had the familiar and convenient ring of many of his post-Presidential apologies. (3, 4)

HIV brush fires in the US
Reports of new HIV infections have risen in the United States for the first time in a decade, health officials said. "AIDS complacency" means people are not getting tested for the virus, according to Ron Valdiserri, a deputy director of the National Center for HIV, Sexually Transmitted Diseases and Tuberculosis Prevention at the CDC, although the ones who are, are testing positive more than ever before, so it is not simply a question of getting tested.

In the 25 states that reported new HIV diagnoses, there was a striking 8% increase in the number of cases between 1999 and 2001. "We see a 14% increase in HIV diagnoses in men who have sex with men and a 10% increase in heterosexual transmissions," Valdiserri said. About half the new cases of HIV are in women. "We are very concerned that it could represent a reversal in the trends that we believe have been relatively stable ... at about 40,000 new cases every year," Valdiserri added. "We have seen a slight increase in reported AIDS cases, it is just a 1% increase, but it's the first time since 1993."

"We are dealing with a perception that HIV/AIDS is not a problem in America—it is just a problem overseas," he added. "Some people call it AIDS complacency. I think it is an issue among all people, not just people of high risk." An estimated 950,000 people in the United States are infected with HIV. Among gay African-American men, 91% of those found to be infected were unaware that they carried the virus. "The patient can … be referred to community-based organizations [for support])," Valdiserri said. (5, 6) However, flat funding for Ryan White CARE Act programs means that the demand for AIDS services will continue to outstrip the supply.

In a separate statement, Gay Men's Health Crisis (GMHC) noted the administration flat-lined funding for the Minority AIDS Initiative, and specifically noted that among all parts of the Ryan White CARE Act - the primary funding source for many AIDS programs - only ADAP was getting an increase. GMHC Executive Director Ana Oliveira said in a statement, "This administration's abject failure to respond to the critical prevention and treatment needs in the United States and around the world is appalling." "The CARE Act programs will continue to be underfunded," said David E. Munar, associate director of AIDS Foundation of Chicago.

Burning down the house, Firefighting 101
With the aforementioned promise of US $15 billion to fight AIDS in fourteen nations in Africa and the Caribbean, AIDS relief has a new found urgency. Some are selling the plan as a national security issue, arguing that large populous countries could potentially be destabilized by AIDS without action, while others feel that the epidemic has reached a magnitude that can no longer be ignored on a human rights scale. Executive director of the Minnesota AIDS Project Lorraine Teel noted, "We're seeing very similar rampant, rapid growth of HIV in every one of the former Soviet states, in India and China. And so the need to curtail the spread of HIV worldwide is immediate." (8, 9)

In the Session International Models and Perspectives in Addressing the Pandemic, Srdan Matic from WHO spoke on the needs of designing new models and public health strategies. Tuberculosis is interconnected with HIV in such a way that the two (HIV and TB) must always be talked about together. Matic blamed the low price of heroin as a cause for the explosion of HIV in the Russian states. Other causes left out by Matic include social and economic breakdown and hopelessness, punitive drug laws, separation of drug programs from TB programs from HIV programs, and other factors. He also stated that for gay people, the stigma of being homosexual means that not only are there few or no gay groups and gay rights groups—so no community education or outreach—but even after diagnosis, many gays prefer to be categorized under a different heading, including drug user, rather than as homosexual. Also, their marginalization may lead to an under-testing: Queers, IVDUs and sex workers—HIV is still a disease of the social outcasts. He mentioned that TB is explosive and said that although there is a growing advocacy movement, it is not growing fast enough or big enough. Thirty-six of every one thousand Russian prisoners (3.6%) are HIV-infected, while 10% of the Russian population has been in jail! According to Matic, there will not be significant advance in the social arena until there are 100,000 people marching in Red Square. He says that without an effective involvement of HIV+ people on the front lines, nothing will be achieved, and we will be pouring drops of water on a situation burning out of control. (10)

Richard Chaisson from Johns Hopkins talked about tuberculosis (TB) and HIV. Chaisson suggested that DOTS—the WHO-sanctioned Directly Observed Therapy, Short-Course TB control model—as a program cannot control TB where HIV is prevalent, although an expansion of DOTS as well as access to HIV medicines is necessary in all high-prevalence areas. TB control in high burden HIV regions depends on an active case finding, contact evaluation, and isoniazid as prophylaxis. In South Africa, Smit did a study of miners in the 60s. Adding isoniazid to beer reduced TB to insignificant levels! Although it was stopped because beer is contraindicated, it brings up an interesting idea of using imagination when thinking about administration / delivery of product. Chaisson also mentioned what has been reported on recently at other meetings, that HAART can reduce TB incidence by 60-80%. (11)

Paul Farmer from Harvard Medical School and Zanmi Lasante Clinic in Haiti once again had listeners soul searching. He probably needs to offer advice to us rapt admirers on how to lobby also. He said very eloquently, "we have been party to the weakening of solid public health throughout the world". We have known how to prevent, treat, and control TB and HIV for years, but the refusal of global public health agencies and national governments to fight for the global application of prevention and treatment suggests complacency and inaction. To date there have been almost no donor-funded programs seeking to integrate HIV prevention efforts with the full range of therapeutic options required to treat advanced HIV disease effectively in poor settings.

In 1998-99, Partners In Health built upon an established tuberculosis control program to introduce "DOT-HAART"—directly observed therapy with highly active antiretroviral therapy. A "biosocial analysis" relying on a mix of cohort analysis, sero-surveillance, chart reviews, ethnographic study, focus groups, and open-ended interviews with people and staff was used to assess the impact of DOT-HAART to some 360 people in Haiti, trying to assess both the costs of DOT-HAART and its impact on costs of hospitalization.

Effective use of ARVs is feasible in even the most resource-poor settings. HIV mortality declined sharply even though only 12% of all HIV+ people received ARVs; tuberculosis incidence declined by > 50% between 1999 and 2002. There was a sharp increase in demand for voluntary counseling and testing during the years following introduction of ARVs. A declining proportion of hospital admissions are related to HIV. Less easy to quantify are trends revealed through ethnographic research: diminished AIDS-related stigma, improved quality of life, improved staff morale, and more widespread interest in prevention efforts.

The Haiti project suggests that, in the context of a mature epidemic, the introduction of ARVs may strengthen prevention efforts while reducing AIDS mortality, tuberculosis incidence, and HIV-associated hospitalizations. False debates regarding "prevention vs. treatment" have delayed effective integration of HIV prevention and care. These delays have taken their greatest toll where HIV is already the leading cause of young adult deaths. (12)

Can Generics get it under control?
Generic antiretroviral (ARV) medications are becoming available in many developing countries at costs cheaper than discounted proprietary agents. There are currently no publicly available data describing the integrity (drug content vs. label claim) of these preparations. The NIH analyzed the content of several generic and proprietary ARV formulations containing nevirapine (NVP) as part of a pilot, quality assurance investigation.

Tablets containing NVP (alone or in combination with other ARVs) were obtained from six international sources. NVP content of the six products was determined by high pressure liquid chromatography (HPLC). In total, six chromatographic analyses were performed for each individual tablet. Products tested included Triomune from Cipla (Kenya, Zambia), Viramune from Boehringer-Ingelheim (Lithuania and South Africa), Nevimune from Cipla (Zambia), and Nevirex from Aurobindo (Zambia).

The average NVP content among the tested preparations was 197.9 mg (coefficient of variation [CV] = 3.4%). Average accuracy of NVP content in tested preparations versus labeled amounts (200 mg) was 99.0%.

This data may represent the first publicly available account of drug content among generic ARV preparations. The results are consistent with stringent manufacturing standards (+ 3% of labeled drug amount) and so, encouraging, given the relative widespread use of NVP-containing products in the developing world. Quality assurance analyses such as this one must be conducted on a large-scale basis and include all generically available ARVs. When this information is available, health care providers and governmental agencies can determine which ARV formulations are most likely to provide the greatest clinical benefit. (13)

A developing example, the fire in Zambia
In most industrialized nations, the success of highly active antiretroviral therapy (HAART) has provided a partial reprieve from the AIDS epidemic. Yet in developing nations—home to 90% of those living with HIV in the world—antiretroviral treatment is beyond the reach of most people living with the disease.

According to recent estimates from UNAIDS, 25 million people have died of AIDS to date, and 42 million people are currently living with the disease. Of these, approximately one million are in North America, compared to 28.4 million in sub-Saharan Africa, six million in South and Southeast Asia, and two million in the Caribbean and South America. Providing a snapshot of one of the hardest hit countries as an example, Miriam Rabkin discussed the experience in Zambia, a country in Southern Africa, where HIV prevalence among people of reproductive age is > 30%. Among men between the ages of 15 and 60 in Zambia, mortality has increased 68% since the beginning of the AIDS epidemic. There has also been a 50% increase in mortality among children under five years of age. And life expectancy at birth has dropped to 36 years, a statistic linked to the fact that 650,000 people have died of AIDS in this country of 11 million.

In recent years some headway has been made. First, there has been an increase in international financial support. Annual global resources for HIV/AIDS have grown from approximately $300 million in 1999 to $3 billion in 2002, although the recent promises from the US may be so much "dust in the wind". Second, there has been a decrease in the cost of treatment. Pharmaceutical companies producing brand-name and generic versions of various antiretroviral drugs have radically reduced the costs of HAART in resource-poor settings, which can now be purchased for as little as $350 a year (still higher than either the average per-capita income in many resource-poor countries or the annual government per-capita health expenditure). Others are working to decrease the cost of monitoring tests, and to develop cost-effective and simpler treatment algorithms. These changes have permitted nongovernmental organizations, such as Doctors without Borders (MSF) to initiate small pilot treatment programs in a number of resource-poor settings, and have encouraged the development of MTCT-Plus, a $50-million treatment initiative aimed at providing care to 10,000 HIV+ individuals in Africa and Asia over the next three years. (14)

Thus far, antiretroviral coverage in resource-poor countries remains ridiculously low. Rabkin explained that some 50,000 HIV+ people in sub-Saharan Africa are currently receiving antiretroviral treatment—less than two percent of the 4.1 million people thought to require HAART today. Some other estimates are even less than that. IAS suggests some 30,000 people maximum in sub-Saharan Africa. In Asia, the coverage rate may be 4%; in North Africa and the Middle East, the rate is 29%; in Latin America and the Caribbean, a slightly more optimistic coverage rate of 53% has been projected; in Eastern Europe and Central Asia, the rate is 9%. Bringing all the numbers together, it is estimated that of the 5.5 million people worldwide who are believed to be in immediate need of antiretroviral medications, a maximum of 300,000 (5%) are currently receiving therapy. (15)

While the availability of HAART is critical, fundamental questions about HIV care in resource-poor settings remain. Longitudinal care, patient education, and psychosocial support may demand different approaches in different places and will require strengthening of weak and often overburdened health-care systems. Strategies for optimal antiretroviral sequencing, patient monitoring, and adherence support in resource-limited environments also remain undefined. Can HAART be given safely if laboratory testing is unavailable? Can HIV care be provided by non-physicians? According to Rabkin, "Some of these questions may take a long time to answer and some may not be answerable. This does not mean that we should put treatment programs on hold, but that we should identify the most important questions and coordinate our efforts to find solutions."

Rabkin notes, "one way to start is to ask ourselves: what are the questions whose answers may expand access to care?" These questions have been explored by a working group supported by the Health Equity Division of the Rockefeller Foundation and were published—along with potential research suggestions to help answer these questions—in the November 9, 2002 issue of The Lancet (Rabkin, 2002). What follows is a review of the more basic questions, along with the efforts that are now under way to address them.

When to call the fire trucks?
According to Scaling Up Antiretroviral Therapy in Resource-Poor Settings—treatment guidelines published in June 2002 by the World Health Organization (WHO)—clinical HIV staging alone, or in combination with CD4 cell testing, or cheaper, more widely available laboratory parameters may suffice to make decisions about when to start antiretroviral therapy. For the complete document, including recommended first- and second-line therapy combinations, please go to http://www.who.int/hiv/pub/prev_care/pub18/en/ or http://www.who.int/hiv/pub/prev_care/ScalingUp_E.pdf. (16)

Using water and what else?
"In wealthy countries, the selection of antiretrovirals is based on academic questions and individual circumstances," Rabkin says. "In many resource-poor settings, we need to use simple standardized regimens that will work for large numbers of people. We're not going to be seeing many doctors prescribing these drugs, simply because there are not enough doctors available. It's going to be nurses and community health workers who are providing HIV care. In turn, treatment decisions will be based on standardized algorithms, as they are in TB control programs. We may not be able to find a 'one-size-fits-all' regimen, but a 'one-size-fits-most' combination would be almost as helpful."

TB therapy, country-specific and cultural issues all must be taken into account. Choosing standardized "one-size-fits-most" regimens is a complicated task. One concern raised involves the use of efavirenz (Sustiva). "The MTCT-Plus program is designed for pregnant women and their families. In this context, it's going to be difficult to use efavirenz, given its teratogenicity, at least that seen in animal studies. There's concern regarding widespread use of this drug in women of childbearing age, particularly where birth control is not widely available and where some women may not have complete control over their own fertility. We don't plan to exclude its use in non-pregnant women, but we will have to be very careful."

Other obstacles include interactions between antiretroviral agents and tuberculosis medications. "The prevalence of tuberculosis among HIV+ persons in sub-Saharan Africa is very, very high," Rabkin says. "So it's going to be difficult to use nevirapine (Viramune) or the protease inhibitors in the setting of simultaneous TB treatment."

Other issues raised include the ineffectiveness of some anti-HIV medications, most notably the non-nucleoside reverse transcriptase inhibitors, in individuals whose HIV-2 is the primary concern, not HIV-1. Another factor to consider is that medications like ritonavir and liquid d4T need to be refrigerated, which is not an option in many settings. Anemia is prevalent in many areas and could be problematic when AZT is used. Hydration issues with indinavir can also be a deal-breaker, explained Rabkin, "in places where the average temperature is 100ºF and people simply don't have access to eight glasses of clean water a day." Abacavir may also prove to be troublesome. Many of the symptoms of abacavir-associated hypersensitivity are similar to those of malaria and other common endemic illnesses, and excluding the syndrome without laboratory testing may be nearly impossible.

The cost of antiretroviral medications will be a significant factor in decisions regarding standardized regimens, and has already resulted in some countries endorsing one drug over another. Organizations working in developing countries are eager to procure and distribute generic versions of antiretrovirals that are significantly cheaper than discounted brand-name antiretrovirals. In fact, the WHO has included some generic antiretrovirals in its March 2002 prequalification list of agents suitable for use in resource-poor settings, although significant questions remain regarding quality control, quality insurance, and international trade law infringement. "With WHO support, many countries are planning to use these generic drugs."

Questions regarding the most appropriate antiretrovirals to use, at least when it comes to putting together an initial regimen, have also surfaced in programs designed to prevent mother-to-child-transmission of HIV (pMTCT programs). "These programs are … in many ways, beacons of hope in terms of decreasing vertical transmission of HIV. But they also mean that there is a growing number of women and infants who have received single-dose nevirapine, which may lead to high-level nevirapine resistance." Should NNRTIs be reserved exclusively for pMTCT programs? Should women and infants who receive single-dose nevirapine to prevent transmission subsequently receive nevirapine-containing triple-drug regimens?

Is it out?
Another major issue to consider is how to monitor patients for efficacy, toxicity, and emerging drug resistance. In the US and other countries where both HAART and laboratory monitoring are widely available, CD4 cell counts, viral load, and chemistries are typically checked every three to four months after antiretroviral therapy is initiated. Needless to say, the high costs of such tests place them beyond the reach of most people living in resource-poor areas. In fact, the cost of routine laboratory monitoring is now on a par with the cost of antiretroviral therapy itself. "Can ARVs be used without lab monitoring of asymptomatic patients? What about less frequent monitoring, or monitoring using less expensive tests? Are these strategies safe? Are they effective?" Systematic evaluation of this "cost-conscious" approach to care is an essential prerequisite to widespread antiretroviral use.

Keeping the hoses aimed at the fire
As issues of poor adherence become better understood—both in industrialized and developing countries—it is likely that tools to promote adherence will continue to evolve. These tools can be divided into four broad categories: patient education, behavior modification, streamlined regimens, and interpersonal support (including directly observed therapy). Adherence programs in resource-poor areas will likely need to rely on a combination of these tools—once the specific issues associated with adherence in these settings are identified. Another issue we need to consider is the effect of traditional healers and parallel health-care systems on adherence to antiretroviral treatment. "Can these care providers be enlisted to help us support adherence?" she wondered.

Fighting fire with fire
Clearly, there are many questions regarding how best to provide widespread HIV care in resource-poor settings. "What I've tried to outline are the vitally important questions that remain unanswered—questions that are going to make or break the success of expanded access to antiretroviral therapy and HIV care," Rabkin said. A real concern, Rabkin explains, is the fact that it's not clear who will go about answering these questions. "The countries themselves do not have the resources to fund the necessary large-scale clinical studies to answer these questions. Some of the organizations that do have the resources don't necessarily have the mandates to do research in sub-Saharan Africa and elsewhere. This is an area of advocacy that we all need to think about." (15)

1. Barollier P, AIDS researchers say they have gained edge over virus, Agence France-Presse, 12.2.03, ENGLISH: http://ww2.aegis.org/news/afp/2003/AF030226.html, FRENCH: http://ww2.aegis.org/news/afp/2003/AF030226_FR.html

2. Smith S, Scientists See New Hope in Treating AIDS, Boston Globe, 12.02.03

3. Barollier P, Agence France Presse, 10.02.03

4. Presented at the 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 10-14, 2003. From the William J. Clinton Presidential Foundation, New York. NEJM, Vol 348:1800-1802, 1.5.03, N 18

5. M Lasalandra, Boston Herald, 11.02.03

6. Fox M, AIDS, HIV Up in U.S. for First Time in Decade, Reuters NewMedia, 11.02.03, Health and Science Correspondent, http://ww2.aegis.org/news/re/2003/RE030213.html

7. Garrett L, US AIDS Cases Climb Slightly, Newsday, 12.02.03, Staff Correspondent, http://ww2.aegis.org/news/newsday/2003/ND030202.html

8. Osborne D, Bush AIDS Budget Draws Praise, but More Fire, Gay City News, New York City, 07.02.03,

9. Ford T, Hotakainen R. AIDS Crisis Finds New Urgency on Capitol Hill, Minneapolis Star Tribune, 10.02.03.

10. Matic S, Abstract 45 The Evolving Epidemic of HIV/AIDS in Eastern Europe, 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003. Boston, MA, USA.

11. Chaisson RE, Abstract 46, Beyond DOTS: Approaches to Tubeculosis Control in Areas where HIV prevalence is High, 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003. Boston, MA, USA.

12. Farmer P, Abstract 48, Use of Antiretroviral Therapy in Developing Countries: A Biosocial Analysis, 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003. Boston, MA, USA.

13. Penzak S, Tavel J, et al. Quality-Control Analysis of Generic Nevirapine Formulations in the Developing World: An Initial Report, Abstract 549a, 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003. Boston, MA, USA.

14. Horn T, Fullem A, Miller V, Identifying HIV Treatment and Research Priorities in Resource-Poor Settings, Miriam Rabkin, Columbia University.

15. Rabkin M, El-Sadr W, Katzenstein DA, et al. Antiretroviral treatment in resource-poor settings: clinical research priorities. Lancet 360:1503-5, 2002.

16. World Health Organization. Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Guidelines for a Public Health Approach. Accessed at: http://www.who.int/docstore/hiv/scaling/ 19.02.03.