|
|
 |
Immune-Based Therapies at
the Retrovirus Conference
by Daniel Raymond
|
|
The relatively low profile
of immune-based therapies (IBTs) at this year’s Retrovirus
Conference reflects the current state of the field. While
we have nearly 20 antiretroviral drugs that attack HIV replication,
we have no approved therapies directed at the immune system.
In theory, IBTs could offset the damage to the immune system
done by HIV, improve the quality and strength of the immune
response, or help the immune system control HIV without antiretrovirals.
The field of IBTs offers hope that researchers can develop
strategies allowing people with HIV to delay or interrupt
antiretroviral therapy, ideally reducing drug resistance problems
and side effects due to HAART (highly active antiretroviral
therapy).
Despite the potential for
changing HIV treatment, only one IBT—interleukin-2 (IL-2)—is
currently in phase III trials; the results from the IL-2 trials,
SILCAAT and ESPRIT, won’t be available for years. Therapeutic
vaccines, designed to improve the immune system’s ability
to control HIV in people who are chronically infected, are
still in the early stages of development. The therapeutic
vaccines furthest along are being researched in small studies
designed to determine safety and measure changes in the immune
response to HIV.
An oral abstract session
dedicated to IBTs focused primarily on two therapeutic vaccine
candidates—MVA-BN-Nef and ALVAC. MVA-BN-Nef is the Bavarian
Nordic version of modified Vaccinia Virus Ankara that expresses
HIV’s nef gene; MVA-BN (without the nef gene) will soon enter
trials as a stand-alone smallpox vaccine for people with HIV.
Dr. Harrer from the University of Erlangen, Germany, presented
safety and immunogenicity data from a Phase I study of MVA-BN-Nef
vaccine. The vaccine was safe in a group of 14 people on HAART
with CD4 counts over 400. Subjects received three immunizations,
and then interrupted HAART. While measurements of immune response
to nef improved after vaccination, all 14 subjects experienced
viral rebound within weeks of interrupting treatment. Vaccination
did not lead to immune control of HIV in the absence of antiretroviral
therapy, although five subjects appeared to maintain viral
loads at lower levels than their original viral setpoint—the
viral load at the time when HAART was first initiated.
|
|
|
|
Results from two ALVAC studies—VACCITER
(ANRS 094) and VACCIL-2 (ANRS 093)—conducted in France similarly
failed to generate much enthusiasm. ALVAC is a recombinant
form of the canarypox virus that contains several HIV genes;
ALVAC vCP1433, the version of ALVAC used in these studies,
expresses genes for HIV’s env, gag, and sections of pol and
nef. Dr. Tubiana reported on ANRS 094, in which a group of
48 people (on stable HAART, with CD4 counts above 400) received
a series of four vaccinations. In order to assess whether
ALVAC could help the immune system control HIV without medication,
all participants discontinued HAART four weeks after their
last ALVAC immunization. After 44 weeks of follow-up, only
four subjects (8%) maintained a viral load below 10,000 copies
and CD4 counts above 250 without restarting HAART—results
no better than in other treatment interruption studies that
do not use vaccines. Dr. Tubiana suggested that the series
of four ALVAC immunizations may have been too many, exhausting
the HIV-specific immune response, but results from other ALVAC
trials have generally been underwhelming.
Another French study, ANRS
093, also used a treatment interruption to explore the effects
of vaccination on HIV-specific immune control, this time in
a controlled trial of ALVAC vCP1433 in combination with Lipo-6T,
followed by 3 cycles of IL-2. Lipo-6T is another vaccine construct
made up of a set of HIV lipopeptides (sections of HIV proteins
attached to a fat molecule, or lipid tail), while IL-2 is
an immune modulator that raises CD4 counts. Dr. Levy reported
that subjects who received the vaccines and IL-2 had better
HIV-specific immune responses and somewhat better viral control
off treatment than a control group. Overall, only 10 subjects
showed immune control of HIV during the treatment interruption—29%
of the vaccine/IL-2 group vs. 5% of the control group—and
results were only reported through the 12th week off treatment.
Therapeutic vaccines against
HIV face a number of obstacles discussed during the immunology
and pathogenesis sessions at the conference. Dr. Bruce Walker
from Harvard University and others described the dynamics
of immune escape, the development of viral mutations that
allow HIV to evade the immune system—a process similar to
the emergence of drug resistance through the accumulation
of viral mutants. Walker described a group of patients treated
with HAART during acute infection who then interrupted therapy,
in the hope that early HAART treatment might preserve an HIV-specific
immune response strong enough to control HIV without medication.
Despite lengthy periods where subjects maintained low viral
loads off treatment, over the first few years a progressively
increasing number of subjects experienced viral breakthrough
(detectable viral load). In many cases, loss of viral control
was associated with the development of escape mutations.
While immune escape may contribute
to loss of viral control in early HIV infection, mounting
evidence indicates that people with chronic infection have
a flawed HIV-specific immune response—their HIV-specific T-cells
have functional defects. Dr. Rika Draenert reported that a
cohort of untreated people with chronic HIV infection had
CD8 responses to HIV that were fairly broad and strong in
magnitude, not significantly different than the CD8 responses
of long-term non-progressors. These CD8 T-cells were ultimately
ineffective at controlling viral load, despite little evidence
of viral escape mutations in preliminary analyses. However,
many of the HIV-specific CD8 cells had not fully matured,
and would be ineffective at viral control. Chronic HIV infection
is commonly thought of in terms of a quantitative deficiency—progressively
fewer T-cells available to fight infections. New research
suggests that the qualitative defects in immune response are
receiving more attention, and appear to play a key role in
determining the failure of immune control of HIV.
|
 |
|
The implications of
immune escape and qualitative defects for the development
of therapeutic vaccines are unclear, and the current pessimism
in some quarters about the prospects of therapeutic vaccines
may be premature. Unfortunately, few other approaches to immune-based
therapies are in active development at this time. A pilot
study of Peg-Intron (pegylated interferon alfa-2b, approved
for the treatment of hepatitis C) saw benefits in CD4 gains
and viral load decreases in early infection, though the number
of subjects was small (five persons were treated). Audience
members noted that these findings contrasted with the clinical
experience of people co-infected with HIV and hepatitis C,
who generally experience a temporary decline in CD4 counts
during Peg-Intron treatment.
Several posters from European
researchers looked at mycophenolate mofetil in combination
with HAART. Mycophenolate mofetil (MMF) is an immunosuppressant
used to prevent organ rejection in kidney, liver, and heart
transplants. Preliminary studies had suggested that MMF might
indirectly prevent HIV replication, and act synergistically
with abacavir (Ziagen). MMF could also potentially reduce
the viral reservoir of HIV-infected cells by inhibiting the
proliferation of CD4 cells, the cells most susceptible to
HIV infection. The results from these studies were mixed and
inconclusive; the AIDS Clinical Trials Group is currently
studying MMF in combination with DAPD (amdoxovir), an experimental
nucleoside analog, in treatment-experienced patients.
Immune-Based Therapy research
was largely eclipsed at this year’s conference by new antiretroviral
compounds (see page 14) and new insights into immunology and
virology. Immunologists have identified compounds which can
modulate aspects of the immune system, and vaccines which
can show increases in various measures of HIV-specific immune
response, but to date we have little information about whether
these agents will actually help people with HIV stay healthier
and live longer. Ironically, the success of HAART may have
slowed down IBT research—SILCAAT and ESPRIT, the large IL-2
studies, will continue for years because the endpoints are
incidence of disease and death, relatively rare occurrences
in the HAART era. Many IBTs may not directly increase CD4
counts or lower HIV viral loads, making it difficult to assess
their impact. Nor is there consensus on which measures of
HIV-specific immune response are the best ones to guide further
research.
These factors have led to
a reluctance among pharmaceutical companies to invest in IBT
research for HIV. Similarly, advances in immunology have largely
failed as yet to produce effective therapies for autoimmune
diseases, cancers, allergies and asthma. However, the promise
of IBTs should not be discarded—early attempts at IBTs suffered
from being too crude, too toxic, or too risky before the availability
of HAART, while the therapeutic vaccine candidates that have
been most thoroughly studied to date may not be the most immunogenic.
As scientists expand and refine our knowledge of the course
of HIV disease, newer methods and approaches to research may
begin to bear fruit. This will require a concerted effort
among industry, academia and government, and the HIV community
can play a vital role in urging the research process forward.
Daniel Raymond is a HIV/AIDS
treatment activist who writes about hepatitis C, tuberculosis,
and immunology. He lives in New York City. He can be contacted
at daniel.raymond@verizon.net.
|
|
|
