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Achy
Breaky HAART
by
Linda Grinberg
The hottest buzz in HIV/AIDS circles is Structured Treatment
Interruptions. The eradication bubble began to burst when
researchers discovered latent, replication-competent viral
reservoirs, capable of persisting for over 60 years. Despite
immeasurable virus in the bloodstream by the most sensitive
laboratory assays, these hidden sanctuaries were found to
harbor virus impervious to highly active anti-retroviral therapy
("HAART"). The prospect of a lifetime of drugs began losing
its luster. Thus began the search for new approaches and the
concept of drug holidays caught fire.
Interest
in structured treatment interruptions (STI) may partially
be fueled by wishful thinking, as patients grow ever weary
of the dreary prospect of never-ending pill-popping. With
missed doses leading to drug resistance, non-adherence is
the single most important reason for clinical failure. Growing
concerns about long-term toxicities and lack of access to
expensive regimens for millions of impoverished AIDS-sufferers
in developing nations lend a sense of urgency to finding viable
alternatives. Among the many compelling rationales for STI
research, the most basic raison d'�tre is simply the need
for a brief respite from unrelenting drug regimens and intolerable
side effects.
One
rationale for STIs is that the very success of HAART, ironically,
may be its flaw. Based on the observations of Bruce Walker,
HAART decreases HIV-specific cellular immunity by lowering
the amount of HIV antigen. A treatment interruption, allowing
a controlled amount of virus to be re-introduced to the immune
system might, theoretically, provide sufficient antigen stimulation
to trigger stronger HIV-specific and lympho-proliferative
responses.
The Berlin and Washington Patients
The
initial excitement began with the report by Franco Lori and
of the famous Berlin patient, who cycled on and off treatment
twice, prompting HIV to re-emerge, and then subsequently re-suppressing
it with treatment. After the last interruption, the Berlin
patient's virus became undetectable and has remained so for
nearly three years, without treatment. Replication-competent
virus can still be found in latent cells, so he's not considered
"cured", yet he continues to baffle experts.
Lori,
Julianna Lisciewisz and colleagues then theorized that exposing
the immune system to HIV in a highly controlled manner might
stimulate the body's innate ability to fight back. To test
this, they attempted to replicate the process in three treatment-na�ve
individuals. After a second interruption, the first patient's
viral load remained below 5,000 for six months. A second patient's
viral load quickly rebounded with each interruption. But in
the third patient-- "the Washingtonian"- the time to viral
rebound became increasingly prolonged. After the last treatment
interruption, he went 150 days before resuming treatment.
"We
are working on a predictive assay that can be performed from
the same blood sample that is used for a CD4 analysis," states
Lisziewicz. "This assay is called VIR, because it quantifies
virus-specific immune responses. Our data suggest that CD3VIR
(percentage of HIV-specific T cells) determines the duration
of control of HIV after a treatment interruption. We urgently
need to run clinical trials to understand the predictive value
of VIR assays."
A
Walk on the Wild Side
Veronica
Miller J.W. Goethe-Universitat in Frankfurt submitted an abstract
at the 1999 Retrovirus Conference, that received scant attention,
but later that year dazzled participants at the 2nd International
Salvage Therapy Workshop with her description of a chronically-infected,
multi-drug resistant cohort on megaHAART (5-9 drugs). Thirty-nine
patients with confirmed phenotypic resistance at baseline
discontinued HAART after experiencing virologic failure. Following
the STI, two-thirds appeared to shift toward a more drug sensitive
"wild-type" virus. Upon treatment resumption, these patients
were more responsive than the non-shifters. Miller's observations
were riveting, and Pandora's box was opened�
I
Left My HAART in San Francisco
Steven
Deeks and colleagues at the University of California San Francisco
confirmed and expanded upon Miller's observations. Patients
failing a protease inhibitor-based regimen were randomized
into two groups: 18 patients underwent a 12-week treatment
interruption; the others remained on failing regimens. After
eight weeks, 16 of 17 evaluable patients underwent a shift
from drug-resistant to protease inhibitor-sensitive virus.
However, resistant virus identical to samples collected pre-STI
were later found post-STI in peripheral blood mononuclear
cells (PBMCs) -- one reservoir of drug-resistant mutants --
suggesting that low-level drug resistant virus had been archived
in proviral DNA in half the cases measured.
The
Calvez Cohort
Attempting
to duplicate Miller's results, Vincent Calvez of the Piti�-Salp�tri�re
Hospital in Paris conducted a small study that enrolled 20
advanced-stage patients with triple-class drug resistant virus.
Having previously failed a median of nine agents in over 6
years of treatment, these patients had a median CD4+ count
of 77 cells/mm3 and a median viral load of 160,932 copies/mL.
After undergoing an STI of eight weeks, but prior to the initiation
of a 5-9 drug MegaHAART salvage regimen, genotypic assays
revealed that the virus in 55% of the participants appeared
to have shifted: five patients lost mutations to one drug
class, two patients to two drug classes, and three to all
three drug classes. However, six months later, the shifters
were unable to maintain an immunologic or virologic advantage
over the non-shifters. Though not considered statistically
significant, the non-shifters gained an average of 30 CD4+
cells/mm3 compared to the shifters, whose CD4+ counts remained
near baseline. An average of 2-log drops in viral RNA through
six months of follow-up were observed in both groups.
The
Boston Seven
In
Bruce Walker's Massachusetts General Hospital acute infection
study, seven patients underwent treatment interruptions and
weekly tracking of viral load, CD4+ cell counts, and T-lymphocyte
proliferative responses. After the first interruption, virus
rebounded within one to eight weeks with a simultaneous increase
in HIV-specific immune responses. After the second STI, HIV-RNA
remained <5,000 copies/mL. Though the study was small, these
results suggest that cellular immunity might be boosted in
recently infected patients.
Spanish
Collaboration
Delayed
viral rebounds, lowered set-points and enhanced immune responses
were also observed in a collaborative study conducted by researchers
in Spain, Switzerland, and the Aaron Diamond AIDS Research
Center in New York. Felipe Garcia and colleagues reported
on ten chronically-infected, treatment-naive patients with
high CD4+ counts who, after initiating a triple-combination
regimen, sustained undetectable plasma RNA levels for a year.
These patients then underwent three interruption cycles: The
first two were four weeks, separated by six months of treatment.
The third interruption continued until viral loads rose >10,000
copies/mL.
During
each treatment interval, virus became undetectable. Following
each interruption, viral rebound was detected in all cases
with a mean doubling time of 2.23, 3.38, and 3.25 days, respectively.
But by the second interruption, 4/9 patients had initial viral
rebounds at pre-HAART levels, which then diminished to 120
copies/mL in one patient, to 20 copies/mL in another, and
to about 6 copies/mL in the other two. None of the four had
measurable HIV-specific responses prior to the STIs, but all
four developed strong responses to a broad panel of HIV antigens.
With the third STI, measurable virus remained <10,000 copies/mL
for 32 weeks in the same four who achieved viral control during
the second STI. These new viral set-points ranged from 4-32
copies/mL.
The
Philadelphia Story
In
the September issue of the Journal of Infectious Diseases,
Luis Montaner of the Wistar Institute in Philadelphia reported
the first documented case of a chronically-infected patient
who has completely stopped therapy for over four months, mounting
an immune response sufficient to maintain low-level HIV-RNA
in his bloodstream. Five patients were monitored during an
interruption for a median period of eight weeks and compared
to five untreated controls. All five STI patients showed significant
increases in anti-HIV immune responses. Upon treatment re-initiation,
the patients' CD4+ and CD8+ killer cells quickly recovered.
Two months later, when the Philadelphia patient stopped therapy
for good, his immune system responded even more powerfully,
suggesting that even in chronic infection, the body may be
capable of fighting back. If validated by further studies,
Montaner's research will prove to be "quite significant and
encouraging," says Franco Lori.
Embarking
on a controlled clinical trial with 42 patients funded by
the National Institute on Allergies and Infectious Diseases
(NIAID), Montaner states, "While many patients would benefit
from occasional breaks from drug therapy and its side effects,
we are pursuing whether short interruptions can instruct the
immune system to control the virus to a point where treatment
will not need to be reinitiated,'' Montaner stated.
The
Largest Study
Preliminary
results of the largest study yet initiated suggest that responses
are highly variable. Bernard Hirschel recently reported preliminary
observations on a study involving 122 patients. The treatment
strategy involves four cycles consisting of eight weeks on
treatment, followed by two-week breaks or until viral thresholds
of 5000 copies/mL are reached. Hirschel could detect no consistent
pattern in the 56 patients who completed four STIs. Nineteen
patients failed to get their viral loads <50 copies/mL after
therapy resumption, though this was probably due to poor adherence.
Evidence of resistance mutations to two drugs in the study
regimen -- an apparent first in STI research - was reported
in one patient. One explanation is that immune responses in
chronically-infected patients differ, while another may be
attributable to poor study design. Experts have suggested
that a two-week STI may not be long enough to elicit adequate
immune responses.
The
Longest Study
Studies
at NIAID under Mark Dybul and Anthony Fauci are seeking to
determine whether the benefits of HAART can be preserved,
while minimizing side effects and reducing the overall cost
of treatment. The following strategies are being studied:
two months on treatment/one month off; one week on/one week
off; and two days on/five days off. Reporting on the longest
trial to date at the World AIDS Conference in Durban on the
longest trial to date -- the two-months on/one month off regimen
-- Dybul reported that nine of 70 recruits made it through
either two or three STI cycles. While the first nine experienced
viral rebounds with each interruption, virus was subsequently
re-suppressed with treatment. Three of the nine had smaller
rebounds during the second interruption, while one had a higher
rebound. During the first STI, CD4+ cells counts decreased
by almost 20%, but after the initial dip, they remained relatively
stable throughout subsequent breaks. This third strategy was
determined ineffective and subsequently abandoned. While it
is far too early to evaluate whether the first two strategies
will be successful, without harmful loss of viral control
or seriously reduced CD4+ counts, such approaches could dramatically
cut the cost of treatment in developing nations.
The
Lurking Enemy
In
the past, treatment interruptions were considered anathema,
for fear that reemerging virus would mutate into drug-resistant
forms. Such worries have been partially allayed, as there
have been few well-documented cases of new mutations arising
as a direct result of STIs. But re-emergence of drug-resistant
mutants has been observed. One critical unanswered question,
whether on or off treatment, is how long resistant viruses
persist at low levels or archived in long-lived cells.
A
year after presenting her initial results, Dr. Miller presented
a sobering update. Almost three-quarters of the original cohort
eventually experienced virologic rebound and one quarter were
unable to recover their pre-STI CD4+ counts, underscoring
the potential risks of stopping therapy in the setting of
virologic failure. As suspected, resistant virus lurked at
undetectable levels even in the shifters and later resurfaced.
Because virus rebounded even more rapidly in patients whose
virus did not shift, treatment interruptions may not be advisable
in all heavily pre-treated patients before instituting a multi-drug
salvage regimen and also points up the need for predictive
assays.
Barcelona
Five
Lidia
Ruiz and colleagues from Barcelona reported on the return
of virus with mutations related to previous drug exposure
upon treatment cessation. Ruiz's study followed five patients
who had maintained viral suppression for over two years on
potent antiretroviral regimens. Proviral DNA in PBMCs showed
no evidence of mutations pre-STI, but NRTI-associated mutations
cropped up in the virus of three of the five during interruptions.
In one person who had previously been on AZT monotherapy for
24 months, AZT mutations reemerged during all three STIs and
the 3TC mutation resurfaced in another two, who had previously
taken 3TC. Despite the inclusion of 3TC in the antiretroviral
regimens following STIs, all three patients were still able
to regain viral control.
Reemergence
or Selective Reversion?
Using
an ultrasensitive, PCR-based resistance assay, Allan Hance
of Xavier Bichat Hospital in Paris identified more than one
primary protease mutations, in what appeared to be wild-type
virus, after a three-month STI. In a presentation at the Resistance
Workshop in Spain earlier this year, Hance amplified two mutations
shared by several PIs, and zeroed in on virus isolated from
13 patients who had stopped treatment for two months or more.
While conventional genotyping interpreted the virus as "wild-type",
Hance's assay found mutations in nine of the 13 individuals
-- one whom had not been on antiretrovirals for five months.
Further analysis of secondary mutations in these viral isolates
led Hance to propose that mutant virus observed during STIs
might have two possible origins: one may be the reemergence
of mutants derived from previous treatment; the second, that
a new viral species may have emerged resulting from the recombination
of mutant populations by "selective reversion".
A Matter of Semantics
Reversion
to wild-type is a misnomer. According to Veronica Miller,
"A lot of confusion stems from mixing up different mechanisms
of changes in viral susceptibility after treatment discontinuation.
The phenomena we observed within a few weeks, also confirmed
by Steve Deeks, is simply a shift in the dominant population
at defined points in time. Perhaps we were all a bit careless
at the beginning, and words like 'reversion' and 'switch'
were used to describe the phenomena," Miller explains. Reversion
also occurs, but by a different mechanism than the shift we
described. Reversion is the reverse process of development
of resistance under drug pressure. Since reverse transcription
is error-prone, even with the removal of drug pressure, mutations
still emerge. Sometimes these will be backward mutations,
i.e. toward the original wild-type or some other phenotypically
wild-type form. We also know that viral recombination does
take place and may be used in a viral population to adapt
to the environment. To what extent this plays a role in the
emergent virus population, I cannot presently say."
Cautionary
Notes
Other
worrisome observations reported by Miller were the development
of new AIDS-defining events. In an expanded cohort of 165
patients, 17 new opportunistic infections were documented.
Without a non-STI comparison arm, the impact on disease progression
remains unclear; however, if treatment failure can be delayed,
then STIs may provide benefit in advanced disease.
Corroborating
Miller's findings in an late-stage population, Calvez also
recorded four new clinical events during treatment breaks.
Fortunately, the drops in CD4+ cell counts were not as precipitous
as in Miller's cohort -- five patients lost more than 50 cells/mm3
-- but there was no difference between the shifters and the
non-shifters. Results in the Calvez study differed from Miller's
in one important way: Miller's shifters lost mutations to
all antiretrovirals, whereas only three of 20 people in the
Calvez study did. Calvez also reported that longer STIs led
to a greater shift toward wild-type, but due to the risk of
opportunistic infections, the inherent dangers of longer interruptions
in advanced patients are obvious. STIs may only prove feasible
in those who can regain viral control under HAART. However,
if treatment failure is delayed, this may represent progress.
Given
the markedly prolonged plasma half-life of non-nucleoside
reverse transcriptase inhibitors (nNRTIs) relative to other
drugs, their rates of clearance from the plasma will differ.
Therefore, stopping all drugs simultaneously instead of in
a staggered fashion could put people at risk of being on monotherapy,
if that drug is still present at a significant level in plasma
after the other agents have been cleared.
Hope
Amidst Uncertainties
While
STIs may hold promise, many unknowns remain. There is a small,
but vocal chorus of scientific naysayers who still cling dearly
to lifelong antiretrovirals as the Holy Grail. Thus far, the
data on STIs are inconclusive and in the end, there may be
no single answer to the question, "What is the best strategy?"
The issues involved may ultimately turn out to be multi-factorial,
hinging on such variables as immune status, host and viral
factors. Or this avenue may prove to be a dead-end. But most
patients and clinicians would agree that, out of necessity,
this approach must be explored. Numerous "proof of concept"
studies are underway in virtually every patient population,
addressing safety, efficacy, optimal on/off schedules and
which markers may be predictive of outcome. "We still have
a number of questions to answer," states Dr. Miller, "and
are collectively analyzing data from several cohorts with
well-documented databases to answer these and other questions."
"The
simple fact of the matter is that, from a hard-headed scientific
perspective, the STI concept is still unproven. It is presently
founded on theory and anecdotes - good theory and impressive
anecdotes, to be sure, but ones not yet proven," states John
Moore, Professor of Microbiology and Immunology at Cornell
University Medical School. A supporter of STI research, Moore
emphasizes the need to thoroughly evaluate this approach through
controlled clinical trials.
As eradication has all but evaporated into yesterday's elusive
dream, scientists must unflinchingly face an age of treatment
uncertainties, a tragic global pandemic and the inescapable
reality that growing numbers of patients are stopping therapy.
No one can deny the undeniable - lifelong treatment, as we
now know it, is untenable and fast becoming an anachronism.
Innovative strategies, Moore further states, which "harness
the power of the immune system in combination with effective
antivirals are likely to be essential to properly control
HIV infection in the long-term".
Author
Linda Grinberg, President of the Foundation for AIDS and Immune
Research (FAIR) in Los Angeles, was a sponsor of the 1st STI
Workshop in July, 1999 and is currently organizing the 2nd
STI workshop for Fall, 2000. She is also a member of the Board
of Directors of Project Inform.
References
Altfeld
M, Rosenberg ES, Eldridge RL, et al. Increase in Breadth and
Frequency of CTL Responses after Structured Therapy Interruptions
in Individuals Treated with HAART during Acute HIV-1 AIDS
Infection. 7th Conference on Retroviruses and Opportunistic
Infections; January 31 - February 2, 1999; San Francisco,
Calif. [Abstract 357].
Deeks
SG, Wrin T, Hoh R, Troiano J, et al. Virologic and immunologic
evaluation of structured treatment interruptions (STI) in
patients experiencing long-term virologic failure. 7th CROI,
January 2000; [Abstract LB10].
Dybul
M, Yoder C, Belson M, et al. A randomized, controlled trial
of intermittent versus continuous highly active antiretroviral
therapy (HAART); July 2000; XII International World AIDS Conference,
Durban, South Africa [Late-Breaker].
Garcia
F, Plana M, Ortiz GM, et al. Structured Cyclic Antiretroviral
Therapy Interruption (STI) in Chronic Infection May Induce
Immune Responses Against HIV-1 Antigens Associated with Spontaneous
Drop in Viral Load. 7th CROI, January 2000 [Abstract LB11].
Hirschel
B, Fagard C, Lebraz M, et al. The Swiss-Spanish Intermittent
Trial (SSITT); July 2000; XII International World AIDS Conference,
Durban, South Africa [Abstract ThOrB747].
Lisziewicz
J, Rosenberg E, Lieberman J, et al. Control of HIV despite
the discontinuation of antiretroviral therapy. N Engl J Med
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Lori
F, Foli A, Maseratt R, et al. Control of viremia after treatment
interruption. 7th CROI, January 2000; [Abstract 352].
Miller
V, Rottmann C, Hertogs K, et al. Mega-HAART, resistance and
drug holidays Second International Workshop on Salvage Therapy
for HIV Infection, Toronto, May 1999. [Abstract 030].
Miller
V, Rottmann C, Hertogs K, et al. Antiretroviral treatment
interruptions in patients with treatment failure: analyses
from the Frankfurt HIV Cohort. 3rd International Workshop
on Salvage Therapy for HIV Infection, Chicago, April 2000.
[Abstract 25]
Papasawas,
Ortiz GM, Gross R, et al. Enhancement of Human Immunodeficiency
Virus Type-1 Specific CD4 and CD8 T Cell Responses in Chronically
Infected Persons after Temporary Treatment Interruption; J
Inf Diseases 2000;182:766-775; September, 2000
Ruiz
L, Martinez-Picado J, Romeu J, Negredo E, Tuldra A, Tural
C, and Clotet B. Structured Treatment Interruption in Chronically
HIV-1-Infected Patients after Long-Term Viral Suppression.
7th CROI, January 2000; [Abstract 354].
Walker
BD, Rosenberg ES, Hay CM, Basgoz N, Yang OO. Immune control
of HIV-1 replication. Adv Exp Med Biol 1998; 452:159-67.
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