Executive Summary

Primary HIV Infection Research Agenda -- Executive Summary

The following is an excerpt from the executive summary of the proceedings of a meeting entitled "Primary HIV Infection: Developing a Research Agenda," sponsored by the Universitywide AIDS Research Program of the Office of Health Affairs of the University of California on February 28, 1997.

Introduction

Primary or initial HIV infection (PHI) has recently emerged as an important target for research. Until recently, there have been no sensitive measures for detecting primary infection nor any potentially effective treatments for early HIV disease. With the advent of HIV RNA assays (viral load testing), it is now possible to detect HIV infection during its initial phase, immediately following infection and before antibodies to the virus are detectable. Advances in drug development have led to a new standard of multidrug therapy, which has been effective in suppressing viral replication in the early stages of infection and may ultimately prove effective in eradicating the virus before it can begin the long process of immune system destruction.

These advances have led to an increased understanding of HIV viral dynamics during the period of primary and early HIV infection, including an increased understanding of the emergence of antiviral drug resistance, and of the human immune responses to HIV. These findings have important implications for HIV-related clinical and preventative intervention strategies. Clinical researchers are poised to determine whether multidrug combination therapy initiated during primary infection can confer long-term benefits. Social/behavioral scientists and epidemiologists, working in conjunction with clinicians and community organizations, will need to examine strategies to identify and recruit individuals with primary HIV infection, make therapies available to persons from diverse populations, to assess whether persons with primary HIV infection can adhere to complex therapeutic regimens administered over long periods of time, and to evaluate the impact of early therapy on HIV transmission. Increasing our knowledge of the events that occur during and immediately following HIV infection promises to have a significant impact on the disease, both at the individual and societal levels.

At a conference convened by the Universitywide AIDS Research Program (UARP) in San Francisco on February 28, 1997, HIV/AIDS researchers in the basic, clinical, epidemiological, social and behavioral sciences and representatives of community organizations and public health agencies met to discuss the development of a statewide research agenda focused on primary HIV infection and to begin the process of networking among potential collaborators for such studies.

Recommendations for Research

The conferees were charged with developing research priorities for each of five topic areas: epidemiology and detection; pathogenesis; treatment and adherence; recruitment and retention of research participants; and prevention. During the course of the meeting several key issues emerged. Highlights from the discussions that took place during the meeting and selected areas for research in each topic area are summarized below.

Detection of Primary HIV Infection

The availability of sensitive assays to quantitate HIV RNA, including polymerase chain reaction, now permits the detection of HIV and measurement of viral replication during the primary infection window period before antibody production has begun. These assays, used in combination with other available tests, have the potential for being used to stage primary and early HIV infection into distinct time periods, based on the viral dynamics and the emergence of the immune response. These powerful tests have applications for detection, prevention and early treatment of HIV disease. They also have an immediate relevance for the development of a standardized testing protocol for the identification of primary HIV infection, a necessary first step if researchers from throughout California are going to collaborate on primary infection research.

Recognizing the need for uniform testing standards for primary HIV infection, the meeting participants proposed:

Standardizing the Definition of Primary HIV Infection

A standardized definition for primary and early HIV infection needs to be developed that is applicable to both epidemiological and clinical studies. A simple screening system for detection of primary and early HIV infection is proposed which uses a three-test strategy to confirm both the presence of the virus and the relative stage of the immune response. The existence of these new tests have made it necessary to reconsider the manner in which HIV testing and counseling currently takes place.

Revising Statewide HIV Testing and Counseling Protocols

New protocols need to be developed for anonymous and confidential testing and counseling sites. Counselors must be trained to identify individuals with recent exposures to HIV who may be in the primary or early infection stages. Clinical sites providing treatment for primary HIV infection must be able to accept referrals and treat all individuals who meet the screening criteria.

Early HIV Pathogenesis

The extent of virus replication and the severity of symptoms during primary infection may be important determinants of the subsequent course of HIV disease. Despite advances in the elucidation of the structure of HIV, its genetics and its mechanisms of replication and survival in human immune system cells, few individuals have been identified and studied during the course of primary infection.

The dynamics, timing and specificity of how the immune response affects the virus and viral properties can only be better understood by identifying individuals who are undergoing acute infection and studying these dynamics prior to the emergence of the initial immune response.

Important topics for pathogenesis research related to primary HIV infection include:

Effects of Early Antiviral Treatment on Host Immune Response, Viral Set Point and Drug Resistance

Whether early antiviral treatment affects the viral set point and whether it delays the onset of host immune responses needs to be determined. Whether early treatment and the timing of the onset of treatment increases or decreases the risk of later drug resistance also needs to be examined.

Differences in Virus Phenotype

Continued research is needed to understand the patterns of transmission of viral phenotypes, including transmission of the more pathogenic T-cell tropic phenotype versus the less virulent macrophage tropic phenotype of HIV. Studies are also needed to examine the interaction between patient genotype and virus phenotype. The role of co-receptors on the selection of viral phenotype during transmission needs to be explored.

Susceptibility

Further research is needed to study the relationship of co-receptors to an individualÕs susceptibility to HIV infection. Important information on susceptibility also can be gleaned by comparing virology and immunology in recently exposed, but uninfected individuals, with individuals who have just become infected.

Treatment and Adherence

The goal of treatment for primary HIV infection should be the identification of safe and tolerable regimens which produce complete and sustained viral suppression. New drugs have been shown to completely suppress HIV RNA in the plasma and lymphoid tissue for a select group of clinical trial participants. However, treatment failure and drug resistance in the non-adherent patient must be considered realistic possibilities even if optimal treatment regimens are identified. The risks of non-adherence to drug therapies are great and cannot be avoided given the physical, psychosocial and financial constraints faced by most individuals with HIV infection. Even the most highly motivated and well educated patients are likely to experience episodes of non-adherence which will probably result in increased HIV RNA levels.

Critical questions for treatment research on primary HIV infection include:

Treatment Effect on Immune Response

Does immediate therapy prior to an HIV antibody response pose a risk for developing drug resistance if complete virus suppression cannot be achieved?

Optimal Treatment Regimens

Are there safe and tolerable antiretroviral regimens that result in sustained virologic suppression and or viral "eradication" in all tissue reservoirs? Can such regimens be identified for pregnant women?

Tissue Reservoirs

What are the viral dynamics in tissue reservoirs (including brain and lymphoid tissue) during primary infection? Is eradication of HIV from tissue reservoirs more feasible if antiretroviral therapy is initiated during primary HIV infection? What strategies will address the challenge of eliminating HIV DNA, or provirus, in resting host immune cells?

Recruitment and Retention of Research Participants

To increase the recruitment and retention of newly infected individuals from hard to reach and underserved popu-lations, the following strategies were recommended:

Target Non-traditional Locations and People

In order to correct the underrepresentation of individuals from communities and risk groups most often neglected by clinical research, these populations need to be targeted for inclusion in primary HIV infection studies.

Compress the Time Period from Outreach to Testing to Treatment

Reduce the amount of time it takes for individuals who are identified as having been recently exposed to HIV infection to be tested, counseled about treatment options, and referred to appropriate health care providers.

Prevention

The HIV epidemic has time and again presented in microcosm all the contradictions that confront this society with regard to its attitudes toward health and its approach to the delivery of health care. The current situation with respect to potential treatments for primary HIV infection is no exception. There is the danger that the availability of triple combination therapy as prophylaxis or treatment against a new exposure to HIV will "medicalize" HIV prevention, much as advanced surgical techniques and drug treatments have medicalized the prevention of cardiovascular disease. This phenomenon poses two distinct problems: as the epidemic moves increasingly to the less advantaged sectors of our society, costly treatments for HIV are likely to be far less accessible than they are to the more advantaged sectors of society, and the great lessons about risk reduction and behavior change that have been learned over the course of the HIV epidemic are in danger of being lost.

Two distinct questions emerged for prevention research regarding primary HIV infection:

Does treatment of primary HIV infection reduce transmission of HIV?

Innovative research designs must be developed to determine the relative public health impact of treatment for primary infection on the transmission of new HIV infections. Key methodological approaches include partner studies, long-term follow-up studies of viral shedding among individuals treated during primary infection, and epidemic modeling.

Does treatment for primary HIV infection result in increased risk behaviors?

There is strong reason to hypothesize that awareness of post exposure prophylaxis and treatment for primary HIV infection will result in adverse changes in risk-taking behavior at both the individual and community levels. Questions need to be asked and answered regarding the responses of individuals and communities to the availability of treatment for primary HIV infection. Will certain individuals who are receiving this treatment engage in more risk-taking behavior? Will certain communities respond by spreading the message that it is acceptable to revert back to higher risk sexual and drug-use activities now that options for treatment exist?

The hypothesis that links these two issues is whether participation in primary infection treatment programs will change behavior in the direction of higher risk taking. Studies involving patients who are infected and receiving therapy and their uninfected partners represent the best method to determine whether adherence or non-adherence to therapy results in new infections. Behavioral intervention strategies need to be developed now to moderate these anticipated effects. The standard of counseling needs to be reevaluated to ensure that the individual who is participating in treatment does not change risk behavior for the worse.

Discussion

Two major differences of opinion emerged during the course of the meeting. The first difference concerned whether the studies funded by this research initiative should be small and focused or whether they should be more broadly based and inclusive. The second difference concerned whether treatment for all individuals with primary HIV infection or a known recent exposure to HIV is appropriate at this time or whether there should be more study of long-term treatment effects before a standard of care is established.

Many community advocates and clinical researchers believe that treatment for primary HIV infection should be made available immediately to all individuals with primary HIV infection or a known recent exposure. Knowledgeable community members suggest that such widespread administration of therapy during early infection is already occurring. However, many important questions about the short- and long-term effects of such treatment remain unanswered. Small scale, Phase I and II clinical trials are appropriate for answering many of the basic questions about the safety and efficacy of therapy begun during primary infection. Nevertheless, it was strongly recommended that all research participants be offered the option of treatment.

Conclusion

The meeting participants recognized that in order to devise scientifically justified approaches to the identification, treatment and prevention of primary HIV infection, considerably more information is needed about the events that occur during the time interval between infection and the development of an immune response. In addition only limited information is currently available about the long-term effects of early treatment. Because studies on these topics are so vital and are expensive to conduct, the meeting participants recommended that funding be directed toward small studies focused primarily on pathogenesis and the clinical course of early infection.

However, the participants agreed that significant effort should be made to recruit participants from a broad range of affected communities, particularly individuals from populations at highest risk for HIV infection. It is also critical that study participants be recruited and enrolled into clinical studies as soon as possible after primary HIV infection is confirmed. New assay techniques should be tested for their utility in detecting individuals with primary and early HIV infection among those screened in the affected communities. Alternative and confidential test site staff and primary care providers should be trained to identify the symptoms of acute retroviral syndrome (ARS) and also to identify high risk individuals with likely recent exposure to the virus, but who do not exhibit ARS.

Multidisciplinary collaboration is encouraged in all appropriate aspects of this work, especially in the design of recruitment and retention strategies for research participants, treatment protocols that maximize the participants' ability to adhere to complex treatment regimens, and studies to determine the impact of early treatment on transmission. Researchers are strongly encouraged to utilize the availability of UARP funds as seed monies to plan and obtain funding for a comprehensive research agenda focused on primary infection, including the clinical, psychosocial and preventive aspects of this field. Collateral studies need to be designed to complement the research sponsored by the UARP to ensure that all of the important questions related to primary and early HIV infection, especially as it affects California's most vulnerable and hard to reach populations, are addressed.

Copies of the proceedings are available at www.ucop.edu/srphome/uarp or by calling 510-987-9855.