Primary HIV Infection Research
Agenda -- Executive Summary
Universitywide AIDS
Research Program
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 by calling 510-987-9855.
Page last updated 2 July 1997
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