Published in the Bulletin of Experimental Treatments for AIDS April 1999 issue, by the San Francisco AIDS Foundation.

April 1999 Table of Contents

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Current Challenges to HIV Research

By Greg Szekeres, Claire Rappoport, and Donald Abrams, MD

Over the past two decades, the HIV epidemic in the United States has changed dramatically. Shifts in the demographics of those infected have been marked by steadily increasing rates among women, people of  color heterosexuals, and youth.

Media reports just short of heralding "the end of AIDS," along with slick advertising campaigns for anti-HIV drugs, have contributed to changing perceptions about the disease among people with HIV as well as the general public.

In addition, there have been major advances in the realm of HIV treatment and care. Approved treatment options, limited to AZT alone a mere decade ago, have expanded to include over a dozen antiretrovirals, and more are in various stages of research and development. Due to the use of highly active antiretroviral therapy (HAART), the incidence of opportunistic infections (OIs) has plummeted; in most parts of the U.S. the death rate from AIDS has been dramatically reduced.

While not everyone with HIV has benefited from the new therapies, many people are now preparing to return to work or school, rather than to die.

Not surprisingly, the state of HIV research has also changed. What may be less obvious is that improvements in treatment, developed after years of research, have helped create an environment in which it is increasingly difficult to find volunteers and thus conduct important new trials. Without the ability to enroll adequate numbers of participants, researchers will be unable to obtain the answers needed to further improve methods of combating HIV disease.

This article will discuss some of the most important unanswered questions regarding the treatment of HIV disease as well as the barriers that prevent researchers from answering them. While the term "HIV research" may encompass a broad range of disciplines, including prevention research, behavioral studies, and epidemiology, this article focuses on clinical trials designed to test new drugs and treatment strategies.

Status Report

To a large extent, progress in the care and treatment of HIV disease has been the direct result of clinical trials. All of the currently available antiretrovirals approved by the Food and Drug Administration (FDA) were developed through clinical trials conducted by research institutions funded either by the federal government or by the pharmaceutical industry.

The benefits of currently available highly active combination therapies, credited with much of the improvement in HIV care, were demonstrated by trials such as the AIDS Clinical Trials Group (ACTG) study 320, Abbott Laboratories study 247, and DuPont Merck (DMP) study 006. Additional clinical trials have led to improvements in the prevention and treatment of the OIs and related complications that cause most HIV-related morbidity and mortality.

While these improvements have been most valuable, they are not sufficient to allow even a modicum of complacency. New therapies have brought with them new complications and questions requiring continued clinical research, and many important HIV treatment questions have not yet been answered.

Limitations of HAART

HAART may involve various problems. Some people cannot tolerate the currently available treatments. People who have acquired drug-resistant viruses or have experienced failure with most of the available drugs may not be able to construct effective regimens. It is also still not clear how long HAART regimens will remain effective before people become unable to use them due to side effects or viral resistance. Finally, adherence to complex HAART regimens can be exceedingly difficult. Since missed doses increase the likelihood of developing resistance, there has been a growing awareness that antiretroviral regimens must become simpler and easier to follow.

An ongoing study by San Francisco's Community Consortium, conducted at ten primary care sites in the Bay Area, exemplifies some of the issues complicating HAART. Of 233 participants, 124 (53%) whose viral loads fell to undetectable levels after taking antiretroviral therapy experienced a viral load rebound after a median of only 10.3 months. The degree of viral rebound above 500 copies/mL was generally low and there were very few clinical events. Nevertheless, the study results raise questions about the extended ability of HAART to suppress viral load.

Fifteen FDA-approved antiretrovirals from three main drug classes are now available to be combined in numerous ways. However, little conclusive information exists about how best to use them in clinical practice. The treatment guidelines that do exist are not based entirely on hard data and leave many basic questions unanswered. Guidelines still do not adequately address when to start treatment (especially for those with higher CD4 cell counts and lower viral loads), which specific drugs to start with and which provide the most prolonged benefit, when to switch to a different regimen, and which drugs to use when switching.

Along with a lack of information on ideal combinations and long-term efficacy of HAART, little guidance is available regarding new syndromes such as lipodystrophy, characterized by disturbances in fat metabolism and body habitus (physical characteristics), which may be related to protease inhibitor use, HAART in general, or HIV itself.

In addition to needing to learn how better to use available treatments, there continues to be a need for developing new, improved antiretroviral drugs. Ideal newer drugs would have different resistance profiles, different mechanisms of action, fewer side effects, and would be easier to take. Treatments that bolster the immune system's ability to fight HIV or that can rebuild immune systems damaged by the virus are also notably lacking. It is still not known whether eradication of HIV from the body is possible or, failing that, if HIV disease can become a condition easily managed with treatments accessible to everyone who needs them. 

In sum, much research remains to be done before victory can be declared.

Changes in the Research Climate

HIV clinical researchers today often struggle to design and implement feasible studies for various reasons. First, the epidemic and standards of care are rapidly evolving, while clinical trials designed to answer certain questions (for example, long-term effectiveness of a given treatment) may take months or years to complete. It therefore becomes difficult to formulate a trial of a treatment approach that will still be in use--and achieve results that will still be relevant--by the time the trial is over.

Second, many pharmaceutical companies are primarily interested in studies that will lead to FDA approval of their drugs or that might help to gain a larger market share. As a consequence, trials examining long-term consequences or comparing drugs "head-to-head" (to determine which works better in a given situation) are not often sponsored by most drug companies, since these trials might expose new side effects or reveal that a competitor's drug is more effective. Federally funded research institutions can attempt to conduct such studies, but without the support of drug companies, the trials become extremely expensive and difficult to implement. Third, and perhaps most disturbing, many clinical trials have simply been unable to enroll enough participants to answer the questions for which they were designed.

The rejection of the drug nitazoxanide (NTZ) by an FDA advisory committee in 1998 was a direct consequence of ACTG 336's inability to enroll an adequate number of subjects. NTZ appeared to hold promise as a safe and effective treatment for cryptosporidiosis, an AIDS-defining OI for which no standard effective treatment exists. Yet due to low enrollment the trial was cancelled, and sufficient data was therefore not obtained to determine whether or not to recommend FDA approval.

Other trials designed for HIV complications that have been extremely slow to enroll include ACTG 323, which compares episodic treatment of oral candidiasis (thrush) with prophylaxis, and ACTG 379, which examines stopping cytomegalovirus (CMV) maintenance therapy for people who have experienced a rebound in CD4 cells.

Trials concerning OIs have not been the only ones with enrollment problems. Cyclosporin, an agent used to prevent rejection of transplanted organs and tissues, is being studied for its potential ability to modulate immune activation in HIV disease. Despite its status as a novel treatment approach for HIV infection, studies of cyclosporin have been very slow to enroll participants.

If studies of new therapies have difficulty enrolling, one can imagine the challenge involved in recruiting participants for studies of drugs that are already available. The Community Programs for Clinical Research on AIDS (CPCRA) study 057, also known as the protease inhibitor progression or PIP study, is a trial aimed at enrolling patients whose initial HAART regimens are failing them. Participants in PIP would be randomized to receive one of a number of "second-line" regimens (containing various combinations of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors) in order to determine the best therapeutic approach following the failure of an initial regimen.

Studies like PIP are called "strategy trials" because they test treatment strategies rather than specific drugs. Despite the obvious importance of answering the clinical questions that strategy trials like PIP address, these trials are often extremely difficult to enroll. Open since October 1998, the PIP study seeks 800 participants from across the nation. By the end of February 1999, only 22 volunteers had enrolled.

The "Burnout" Theory

A constellation of factors has contributed to declining participation in HIV clinical trials. Perhaps not least among them is the effect new treatment strategies have had on people's interest in research and their willingness to participate in the process. Improvements in treatment may have fostered a degree of complacency, leading many people with HIV to feel more secure about their current and future health prospects. People now may assume that research has fulfilled its mission and that the urgency to enroll in clinical trials is gone. 

"Compassion burnout," used to describe declining volunteerism and donations to charitable organizations, may translate into "altruism burnout" with regard to clinical trials. People with HIV who for many years volunteered for research studies to further the fight against AIDS may feel that they have already given enough of their time, and now want to return to the business of living their lives. Those who do want to continue to participate in clinical trials often find that strict entry criteria make them ineligible, sometimes because of the very treatments they have tried in the past. In addition, now that there are reasonably effective treatments, people doing well on them are unlikely to want to assume the risks that clinical trials often involve.

The issue of risk is important. Most clinical trials require accepting a certain degree of risk, which may be significant, or at least relinquishing some control over which drugs one takes. While altruism may play a part in the decision to enroll in research, people are unlikely to accept risk or loss of control unless they feel they might benefit somehow in return.

Before effective treatment strategies became available, clinical trials often provided the only access to promising new therapies, so the hazards seemed balanced by the potential for exposure to a beneficial treatment. It is not surprising that the few clinical trials that continue to enroll quickly are frequently those that evaluate "salvage regimens." These trials provide access to otherwise unavailable medications to patients who have few options left.

A Role for Health-Care Practitioners

People with HIV do not join clinical trials without input from others. Doctors and other clinical providers are often instrumental in facilitating enrollment into clinical research. Both patients and researchers depend upon

health-care providers to discuss clinical trials with their eligible patients, answer questions, and make referrals to appropriate studies. In some cases community-based trials are conducted within a provider's practice. If providers are not committed to working with researchers or not interested in a particular trial, recruiting and retaining patients in studies can become very difficult.

For many providers, shifts in HIV treatment coupled with changes in managed care have created an environment in which clinical trials may be less of a priority than they once were. Practitioners who in the past may have routinely referred patients to clinical trials because of a lack of available treatments may no longer do so if they are relatively satisfied with the options at hand.

And while providers may recognize the importance of trials in answering questions like What is the best treatment to switch to after failing an initial HAART regimen?, they may also feel confident about their own knowledge and choose not to have their patients randomized in a clinical trial to answer such a question. Given the time constraints most providers face, clinical trials may simply not compete with the other priorities. Unless a provider is genuinely excited by a particular study, he or she may not remember to talk about it with patients who may be eligible.

Without referrals from providers, researchers must rely on advertisements or other means to find participants. While this approach may work for trials of new drug candidates, it is less likely to work for strategy trials that test treatment approaches with licensed and available agents.

The Researchers' Dilemma

Ultimately, researchers are left on their own to determine how to recruit and retain participants in studies. Despite the fact that researchers are often at the forefront of HIV treatment, the changes in the epidemic have caught some off-guard. Many researchers were accustomed to years of doing research in a climate of desperation, in which HIV trials often had waiting lists even before they opened. It has been difficult for many to adjust to a climate in which researchers seem to need participants more than vice versa.

Research has always been a challenging discipline, but today even the best researchers may have difficulty designing HIV trials that can both satisfy the rigorous statistical requirements of research as well as enroll enough participants. (Large numbers of people are often required in order for studies to have sufficient statistical power to answer the questions being asked.)

Further, in order to apply the results of clinical trials to women and people of color who are increasingly affected, it is crucial that adequate numbers of women and people of color enroll in the studies. Funded by the National Institutes of Health (NIH), the ACTG and CPCRA networks have a mandate to enroll women and people of color in numbers that reflect the demographics of the HIV epidemic in the areas in which individual units are located.

While a great deal of progress has been made in enrolling underserved populations into HIV research, much work remains to be done. Researchers will need to redouble their efforts to build trust within disenfranchised communities that are often extremely suspicious of research and medical institutions.

The legacy of the Tuskegee trials (federally funded syphilis studies that enrolled adult African-American men whose researchers failed to offer them treatment when it became available, choosing instead to observe the complications of the disease) has not been forgotten, especially among people of color and youth. The atmosphere of mistrust that exists will improve only if researchers commit themselves to the time and energy that the slow process of gaining trust requires by working effectively with a diverse range of community-based organizations.

As younger people become infected with HIV, generational issues arise as well. Adolescents and young adults are of a different generation and mind-set than people infected with HIV in the epidemic's early years. For many young people, HIV has always been an issue, so they may not respond to it with the same crisis mentality that earlier generations did.

Their more relaxed attitudes affect not only their risk-taking behaviors in regard to preventing HIV but also their willingness to volunteer for clinical trials if they are infected. In order for researchers to enroll younger participants now and in the future, they need to understand and respond to the needs of youth.

Overcoming Barriers to Enrollment

HIV research will continue to face significant barriers unless solutions to enrollment problems are found. Certainly, working to build trust among the populations most affected by HIV is a good start. Since the incentives for joining clinical trials may not be as strong today as in the past, finding ways to increase interest and retention in studies is also important. For instance, researchers are re-examining methods to ensure that participants are sufficiently compensated for their time and effort.

This often means reimbursing participants a modest amount for each study visit they make. In addition, clinics and providers are increasingly being compensated for each person they enroll in trials, as a way to reimburse them for the extra time and possible expense involved.

To promote awareness about the importance of clinical trials among people with HIV and their providers, the use of creative, targeted media campaigns alert the community that without their continued involvement, the future of HIV research and the treatment benefits it promises are in jeopardy.

Overcoming the obstacles will not only involve education and outreach, but also changing the way that research is done. Innovative research models are currently being implemented to deal with enrollment problems. In these new models, data can be collected in large numbers of people who belong to cohorts (study groups) that are more loosely defined than in the past, while using the strict criteria of typical clinical trials. Participants might then be enrolled in strategic trials that examine the impact of various treatment decisions. As treatments change, participants could be "rolled over" into new studies or followed clinically in an observational cohort if they do not wish to enroll in a particular trial.

How successful these models will be remains to be seen. As HIV becomes more manageable, strategies used to conduct research during the height of the crisis clearly will not continue to work. Evaluating how researchers who work with other chronic illnesses operate--noting what works for them and what does not--may help generate new approaches to HIV research. Fresh ideas about designing and implementing HIV clinical trials should be a top priority, as continued improvements in HIV treatment are critically needed.

Taking Action

People with HIV and their providers can help researchers by routinely discussing clinical trials with one another. There are also excellent resources available for people who wish to become more involved in the research process. "Open Clinical Trials for HIV/AIDS Treatments," a selection of currently enrolling studies, is a regular BETA feature. Trials Search, a service listing all of the open HIV clinical trials in the U.S. by geographic area, is available online and as a printed guide in some areas. Trials Search is accessible on the Internet at hivinsite.ucsf.edu/tsearch, or can be contacted at 415-476-5777 or 1-800-492-5777. The AIDS Clinical Trials Information Service (ACTIS), which offers information on all government-funded trials, can be found on the Internet at www.actis.org or reached at 1-800-TRIALS-A.

Most publicly funded research institutions welcome community input through advisory boards. Joining a community advisory board can be an excellent way to learn more about the research process while providing valuable feedback and influencing the way research is conducted.

Page last updated 1 June 1999