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Past Issues
Volume 19, number 9/10/11
September–November 2005
Satellite of Lore
Pharma-sponsored sessions spread the gospel of viral suppression
Long-Term Coming
early suppression predicts seven-year survival
Shy and Retiring
Joe Sonnabend on avoiding the need for salvage therapy
How to Switch
When to switch from a failing regimen may not be as crucial
as where you switch
The Church of Viral Suppression
By Bob Huff
There is something Old World about the biannual European AIDS
Conference. The two I have attended were held in cold, northern
towns where fuels like peat and coal are still used to heat rooms.
This year's meeting, in Dublin, Ireland, was sponsored by the European
AIDS Clinical Society (EACS) and offered two full days of scientific
talks and poster presentations to doctors and researchers from
around the continent. But unlike the Annual Retrovirus Conference
in the US, which primarily attracts scientists and physicians with
a strong interest in research, the European conference is also
attended by a substantial number of everyday, working clinicians
who come to get a refresher course in state-of-the-art HIV care.
As at most medical conferences, outside of the hushed meeting
rooms more festive attractions await, including a forest of posters
and a colorful exhibition hall where pharmaceutical companies set
up tents to woo doctors who wander into camp. This is the village
marketplace, a swirling festival of lights and video screens where
the throng mingles beneath giant logos amid laughter and the hiss
of espresso makers.
At EACS, though, more than any conference I've been to, it is
the pharmaceutical company-sponsored satellite session that seems
to be the central attraction. Not exactly an official part of the
scientific program, satellite sessions are granted to the drug
makers in return for significant financial support of the conference.
Not surprisingly the companies use these events to feature their
latest products and to promote recent data that has appeared in
proper science sessions. In Dublin, nine companies held satellite
sessions over a three day span, beginning at 7:30 in the morning
and ending well after dark.
These sessions began to feel a bit like church services, packed
with pilgrims come to witness eminent doctors uphold enduring truths
and argue the nuances of contending theologies. In honor of the
tenth anniversary of the advent of truly effective HIV treatment,
almost every company's satellite presentation began with a ritual
recitation of the miracle of HAART. In Dublin we gathered to hear
the ancient faith affirmed: "The goal of antiretroviral therapy
is to achieve maximum virologic suppression."
They Love to Tell the Story
The Concert Hall of the Royal Dublin Society has a reverential
air to it, made a bit musty by shelves of thick Gaelic books
that line the hall. At nearly every session a hushed congregation
fills the great room, rising to the rafters and spilling into
the nave aisles. Onstage, sponsors' crusade banners flank a large
central screen that displays an endless procession of PowerPoint
slides. The high priests of European AIDS medicine preside over
these sessions and bid for the hearts of the multitude with impeccably
reasoned logic that leads from point-to-point and slide-to-slide,
arriving at a version of truth the sponsors hope will prove undeniable.
Their presentations are as finely honed as a Jesuit's tract.
Often they are scripted by third-party medical communications
firms, and the presenters are well compensated for their aura
and expertise. The arguments are crafted to lead — not push — the
learned audience to the desired epiphany. But free will is respected
and the audience is never bullied and rarely cajoled, although
sometimes in the hands of a less skilled presenter the pitch
becomes too obvious and clangs like a cracked bell.
The topics of these sessions are like parables that reveal the
patron's underlying message. If the theme is lipoatrophy and how
to avoid it, you know you are in the church of Gilead to learn
about the demons of thymidine analog NRTIs. The sermon is subtle
and you may hear the virtues of Viread invoked only once or twice
during the hour; yet to those with eyes that can see, the path
is clear: Truvada will set you free. If the devil is lurking in
the lipids, then this morality play is about the evil Kaletra,
and rescue by good King Reyataz or Sir Viramune is certain. But
if you are called to worship time and tradition by the old sage
Abbott, then it's mighty Kaletra reciting the ancient mystery of
virologic failure without PI resistance.
In a kind of communion ritual, attendees sometimes receive small
devices that allow them to register their opinions on formal questions
posed by the presenters. Within seconds the collective responses
are displayed on the big screen for all to behold and wonder at.
In these moments the secret heart of the congregation is revealed.
Often responses seem preordained, such as when a question points
to an obvious choice that reinforces the sponsor's message. This
is a pedagogic exercise and seems very effective. But the beliefs
of the mob can be frightening too. In a catechism sponsored by
the makers of efavirenz (Sustiva, Stocrin), the limits and dangers
of nevirapine were drilled unmercifully, yet a sizeable minority
of respondents never quite seemed to grasp that they risked a case
of liver failure by prescribing nevirapine to a woman with more
than 250 T cells (over 400 for men).
These errant answers are a sobering reminder of why satellite
sessions are so useful. Despite how complex treating HIV can be
in day-to-day practice, the dos and don'ts must be made sufficiently
simple so that garden variety doctors — the parish priests
of medicine — can keep the message straight and tend their
flocks without losing any sheep to the wolves of toxicity, resistance,
or lipodystrophy. When the guidelines are made clear, adherence
to the faith is more likely.
There were no apostates or freethinkers in the big hall. No heretics
hailing hydroxyurea, immune modulation, or other theories that
stray from the central doctrine of everlasting viral suppression.
Although Merck allowed a peak behind the veil to suggest a coming
paradise of therapeutic vaccines and integrase inhibitors, most
companies offered redemption here on earth, available now (or soon)
at your local pharmacy. The sponsors' prize for mounting this pageant
is a buttressed position in the minds of Europe's doctors — and
a possible up-tick in market share. The doctors get a renewed awareness
of the complexities of treating HIV and some measure of comfort
knowing they are in touch with the mainstream.
No Room at the In
Pfizer: Viral Entry Denied: The Promise of CCR5 Antagonists
Pfizer opened its set of early morning sermons with a review of
antiretroviral fundamentals by Jonathan Schapiro from the USA.
Pfizer currently markets nelfinavir, a protease inhibitor, but
is also deeply invested in developing a new HIV drug from an emerging
class of antiretroviral compounds called entry inhibitors. Pfizer's
experimental CCR5 antagonist, called maraviroc, is currently in
Phase III trials.
Truly, Schapiro said, sounding a universal theme, AIDS treatments
have gotten better, with around 77% of patients achieving virologic
suppression within the first year. But this still leaves many who
are not undetectable, and as resistance mutations accumulate over
time eventually all treatment options will be exhausted. The sad
fact is that people are still dying of AIDS in the US and Europe.
Patients with multiclass-resistant HIV are especially hard to treat
and transmitted drug resistance in newly infected people is a continuing
problem.
Schapiro invoked the well-known limitations of the current classes
of drugs: non-nucleoside reverse transcriptase inhibitors (NNRTIs)
have a relatively low barrier to resistance, there are few choices,
and cross resistance is common. There are many nucleoside reverse
transcriptase inhibitors (NRTIs), but again cross resistance limits
the number of effective options. Even among the protease inhibitors
(PIs) with higher barriers to resistance, cross resistance can
limit selection. The choices shrink further when tolerability and
toxicity are factored in. Once resistance to the most tolerable
regimen has developed then second- and third-line choices begin
to put a greater burden on the patient in terms of increased toxicity
and diminished convenience. The cycle of treatment failure is accelerated
as adherence to a suboptimal regimen declines. Fuzeon (T-20, enfuvirtide)
is available to help these patients, but it comes with the millstone
of twice-daily injection. New drugs in the three main classes are
on the way, but at best they offer incremental improvements or
are intended to patch over resistance problems after treatment
failure has occurred.
At this point it should be clear to all that we need a new drug
from a new class with a new mechanism of action that is free from
the old toxicity and resistance problems. So what would a truly
new drug look like? First it must reduce viral load as well or
better than drugs from the current classes. Then it must have no — or
at least manageable — tolerability issues and minimal long-term
toxicity. It should have a unique resistance profile and pose a
high barrier to developing resistance in the first place. Finally,
it should be an oral drug, ideally taken only once a day. Shapiro's
presentation didn't reveal the identity of this savior drug, but
it did create a hunger in the hearts of the audience for what was
to come.
Daniel Kuritzkes from the USA next reviewed the process of HIV
entry, paying particular attention to the role of the human CCR5
receptor, how HIV uses this cellular protein to infect target cells,
and what happens when HIV switches from using CCR5 and starts using
a similar receptor called CXCR4, an event associated with more
rapid disease progression. There has been concern that if the CCR5-using
form of HIV is blocked then the virus will start using CXCR4 to
gain entry to cells, and some worry this might speed up the pace
of immune damage, although in clinical trials to date this hasn't
been reported.
Finally Graeme Moyle from the UK took the stage to survey what
we currently know about the drugs that deny HIV entry into virginal
lymphocytes. Until recently, three companies were developing competing
versions of CCR5 antagonists, although in the weeks before this
conference one competitor had been swallowed by the whale of toxicity
and another had been lured astray by the glittering temptation
of once-a-day dosing. All studies of aplaviroc, GSK's CCR5 candidate,
were terminated after several cases of severe liver toxicity began
to appear among study subjects. Fortunately, the liver problems
abated when the drug was removed but this unforeseen safety problem
proved fatal to the drug's future and it was dropped. A few weeks
later, Schering announced that it was canceling clinical trials
of its CCR5 blocker in treatment-naïve patients due to low
potency and an inability to compete with efavirenz in reducing
viral load. Schering's drug, called vicriviroc, benefits from boosting
with ritonavir, and trials of the drug in treatment-experienced
patients who are taking it in combination with boosted protease
inhibitors will continue. It appears likely that blood levels of
unboosted vicriviroc, especially when dosed once per day, were
not reliable in all patients. This study seems to have been a gamble
on Schering's part, since it did not test the once-a-day dose in
the initial trial that proved that vicriviroc worked. It's possible
that the temptation of achieving the holy grail of one-pill-a-day
led to a leap of faith that vicriviroc's long half-life in the
blood could carry it through. Alas, whether precipitated by greed
or by pride, expectations for vicriviroc have been diminished.
Later in the conference fears about the viability of this entire
class of compounds were heightened when word came that there had
been a case of serious liver toxicity in a patient taking Pfizer's
maraviroc. After the aplaviroc experience, some wondered if this
was a problem with all CCR5 blockers. But as details filtered out,
it appeared likely that other liver toxic drugs were responsible
for this incident and no other cases involving maraviroc have been
reported. Still, this one case, coming on the heels of the other
disasters, has put everything to do with vicriviroc and maraviroc
under closer scrutiny.
Pick Up Your Beds
Boehringer-Ingelheim: Classic and Modern ART
Boehringer Ingelheim has become adept at the confessional style
of data presentation. Their satellite session focused on the proper
use of nevirapine and tipranavir, two drugs with problematic side
effect profiles. For nevirapine, which can kill if improperly used,
the only ethical approach is to tell the story clearly, without
spin, which is what William Powderly did. Powderly, formerly of
St. Louis, USA, has lately removed to Dublin where he now heads
the School of Medicine, and served as one of the conference hosts.
Nevirapine, he reminded his audience, has good efficacy but its
safety issues require physicians to learn how to use it correctly.
The drug should not be initiated in women with more than 250 CD4+
T cells/mm3 or in men with over 400 CD4+ T cells/mm3. All patients
should be instructed to be watchful for signs or symptoms of rash
and hepatitis during the first six weeks after starting nevirapine.
Once nevirapine has been successfully initiated, CD4 counts that
rise above these levels are not a problem.
Results from the Boehringer-sponsored 2NN study, which demonstrated
statistical equivalence between nevirapine and efavirenz, have
never seemed as compelling as the company would like because of
a five percentage point gap between the drugs in the main efficacy
result. A presentation in one of Dublin's scientific sessions might
help explain this gap. Storfer et al reported on the high rate
of liver toxicity seen in 2NN subjects from Thailand who received
once-daily nevirapine. The association between higher CD4 counts
and liver toxicity was not understood at the time 2NN was designed.
When patients with CD4 counts exceeding the current cutoffs were
excluded from the 2NN analysis, not only were adverse event rates
comparable between the twice-daily nevirapine and efavirenz groups,
but the efficacy gap narrowed as well.
Another important use for nevirapine is to help prevent mother-to-child
HIV transmission during childbirth. In resource-poor settings the
use of a single dose of the drug at the time of delivery had been
advocated until evidence began to accumulate that nevirapine resistance
was common in mothers when they subsequently began continuous therapy.
The very long half-life of the drug in the blood after a single
dose allows HIV to replicate and select a nevirapine-resistant
strain, which persists. A solution, now being tested, is to cover
this "tail" of dwindling nevirapine concentration with a few days
of Combivir to keep HIV down until the nevirapine is gone.
Tipranavir (Aptivus) is a recently US-approved protease inhibitor
that has been targeted for salvage therapy. Jurgen Rockstroh from
Germany reviewed the results from the RESIST studies of tipranavir
versus best available therapy in highly treatment-experienced individuals.
At 24 weeks, 34% of patients in the tipranavir group had HIV RNA
below 400 copies/mL compared to only 15% of those in the comparison
group. Subsequently, during a scientific session at the conference,
48 week RESIST results were reported that continued this theme,
with about 30% of the tipranavir group below 400 copies versus
13.8% in the comparison group. Clearly there is an advantage to
having tipranavir on board, but these low numbers speak to the
pressing need for overall improvements in salvage therapy. For
patients who included Fuzeon in their regimens, the prospect of
success was brighter, with 50% of those on tipranavir having a
protocol-defined treatment response. This demonstrates the importance
of including at least two active drugs when constructing a salvage
regimen; if only one active drug is added to a failing regimen,
then the benefit will likely be short lived.
Most dropouts in this study were due to viral failure in the comparison
arm and were switched to tipranavir after 8 weeks, which necessarily
limits any comparative safety data after that point. The selection
of Jurgen Rockstroh, widely known as a hepatitis expert, to present
the tipranavir data speaks to concerns about the drug's potential
for liver toxicity. In the 24-week RESIST data, grade 3 or 4 ALT
elevations were reported in 5.9% of those receiving tipranavir
and in 1.8% of those in the comparison arm. Rockstroh acknowledged
that the risk of liver toxicity is higher in patients receiving
tipranavir, especially those with HBV or HCV coinfection. He recommends
routine monitoring and discontinuation if elevated liver enzymes
are accompanied by symptoms. Aside from this issue, Rockstroh said,
the safety profile of tipranavir was comparable to other PIs used
in RESIST.
David Back from the UK addressed one of the other difficulties
with boosted tipranavir: how to use it in combination with other
drugs. An early study of tipranavir in combination with several
protease inhibitors revealed that it could dramatically lower the
levels of saquinavir, amprenavir, and Kaletra, which effectively
ruled it out for use in a dual boosted-PI strategy. Back, one of
the world's experts in drug interactions walked through what else
is known about how tipranavir interacts with others. There seems
to be no relevant interaction between tipranavir and efavirenz
or nevirapine or with the NRTIs, including tenofovir. Coadministration
with the PIs, of course, is not recommended. There are also likely
significant interactions with certain TB drugs, some statins, some
antifungals, and probably other drugs. The bottom line is that
the net effect of tipranavir is difficult to predict and clinicians
should be mindful of other, unrecognized potential interactions.
Eye of a Needle
Hoffman LaRoche: Rewriting the Book on Optimum Treatment
Strategies for HIV-infected Patients
Julio Montaner from Canada focused on the problematic state of
salvage therapy as evidenced by the RESIST trials and highlighted
the role that Roche's Fuzeon can play in the salvage setting. Several
additional trials have confirmed that response rates in difficult-to-treat
patients can be doubled by using Fuzeon in combination with another
active agent. Montaner reminded us that there is no systemic toxicity
with Fuzeon, and that injection site reactions, the most common
side effect, may be soon mitigated by a new mode of administration
that shoots the drug past the skin in a blast of compressed gas.
The device that does this, the Biojector 2000, has shown good patient
acceptance in clinical trials, achieving significantly better scores
for tolerability and ease of use than injections. Unfortunately
a few days after Montaner spoke, the FDA asked Roche to provide
more data on the bioavailability of Fuzeon delivered via the device
before they will approve its use. This setback means that Fuzeon
users are stuck using needles for perhaps another year.
Christine Katlama from France then took the podium to implore
the audience to never give in to viral replication. There are risks
to allowing HIV to run free at every stage of the disease, she
said. The accumulation of resistance mutations can affect future
treatment options and this means that even patients with high CD4
counts and moderate viral loads are at risk when virologic failure
is allowed to occur. One blessing: The availability of new drugs
means that no one should go unsuppressed.
She recommends that patients invite Fuzeon into their lives for
three months to see if it works for them. Results are seen quickly,
she said, and this often motivates patients to keep going, especially
when they become undetectable for the first time ever. Katlama
also reviewed a study on the acceptability of injectable ARVs that
found patients were much more willing to try Fuzeon than their
doctors thought they were. At this point she could have called
for converts to come forward and be anointed, but she didn't.
Sharon Walmsley of Canada next sang the praises of Roche's boosted
Invirase (saquinavir), which in the odd play of history was first-born
among protease inhibitors, then exiled to wander in the wilderness,
but is now born again in a convenient new 500mg tablet. Ten years
ago, when Invirase became the first PI approved in the US, it seemed
miraculous that an effective treatment for AIDS had finally been
found. But a high pill burden and poor efficacy meant Invirase
was soon eclipsed by other PIs and even a new formulation of saquinavir.
Eventually, as ritonavir boosting of PIs became standard, Invirase
was rediscovered as a highly effective and quite tolerable alternative
to Kaletra. Roche hopes that the new 500mg tablet removes one of
the remaining barriers to its wider use. While older studies show
acceptable efficacy compared to its rivals, a study of the new
formulation versus Kaletra now in progress in France may help clarify
the issue. Importantly, Walmsley noted, is that, similar to Kaletra,
no significant PI mutations are found after virologic failure on
Invirase, thus leaving future treatment options relatively intact.
Invirase does affect blood lipid levels, although differently from
Kaletra, tending toward lower triglycerides and higher total cholesterol,
according to one study. Another study found its lipid profile similar
to that of efavirenz.
At this point Marta Boffito of the UK jumped into to discuss what
is known about drug interactions with Invirase, focusing on a significant
increase in saquinavir exposure when used with omeprazole. Finally,
Mike Youle of the UK presented some clinical data on the new formulation
and suggested that once-daily saquinavir/ritonavir at a dose of
2000/100mg may be equivalent to twice daily 1000/100mg.
Roche followed its HIV satellite with another session dedicated
to treating HIV/HCV coinfected patients, but we shall not stray
into such esoteric knowledge here.
Revelations
Merck: Current and New Anti-Viral Therapies
Jose Gatell from Spain organized his talk for Merck in a novel
and thoughtful way that stressed the need for new interventions
to address several common situations encountered throughout the
spectrum of clinical practice. Merck has plans to thwart HIV even
before infection occurs and is working on a vaccine candidate that
is currently in phase II clinical trials. The potential for an
HIV vaccine appeared again, this time in a therapeutic context,
when Gatell speculated about a potential role for immune stimulation
during treatment interruption. Most patients who stop therapy do
so because they are no longer able to either physically or mentally
tolerate taking drugs with no end in sight. Since life-long treatment
is a necessity and viral rebound the inevitable result of stopping,
simplification strategies that use less toxic or less burdensome
regimens remain a critical unmet need. Finally, when treatments
fail—for whatever reason—and CD4 counts decline to dangerous
levels, then the need for salvage therapy — and the paucity
of options must be confronted. One possibility for simplifying
salvage therapy may involve new drugs from new therapeutic classes
that attack new HIV targets, such as the promising sounding integrase
inhibitor that Merck is developing.
Next, Margaret Johnson from the UK broke out the electronic confessionals
and took the congregation down a rocky path of clinical quandaries
where all roads seemed to lead to efavirenz. This was the session
in which 10% to 20% of responders voted to prescribe nevirapine
to women with CD4 counts above the recommended range. Merck was
the discoverer of efavirenz and licensed it to Bristol Myers-Squibb
for the US market and a few other places where it is sold as Sustiva.
It may sound odd to American ears, but in much of the rest of the
world efavirenz is known as Stocrin and is marketed by Merck.
David Cooper of Australia presented a familiar sounding, but no
doubt useful session on factors to consider when choosing between
an NNRTI and a PI for an initial drug regimen. Since there is not
a lot of comparative data, Cooper reprised the main considerations:
PIs are attractive for being slow to allow resistance and NNRTIs
have a relatively low barrier to resistance. PIs avoid the risk
of initial toxicity to nevirapine, and PIs may also be a better
choice for women of child bearing age. On the other hand, NNRTIs
are easy to use, avoid the long term toxicity of PIs, are highly
potent, and are cheaper.
Get Thee Behind Me!
Bristol-Myers Squibb (BMS): Countering Complexity, Curbing
Complications: Advances in Antiretroviral Treatment Strategies
This session began with a review of advances in ARV simplicity
and convenience presented by Ian Sanne of South Africa — and
in this context S&C means once-daily dosing, the hallmark of BMS's
efavirenz and atazanavir (Reyataz). But this session took a different
tack by using case-based panel discussions as a break from back-to-back
slide lectures. One case focused on the metabolic complications
of protease inhibitors, which, in this context, is code for saying
that Kaletra raises blood lipids (and by implication the risk of
cardiovascular disease) and Reyataz doesn't. Of course it's far
more complicated than that and a presentation by Peter Reiss of
the Netherlands provided a balanced overview of the metabolic mysteries,
including the latest news from the lipodystrophy workshop that
concluded just before this conference opened. But despite evidence
that HIV itself raises lipids, which can be managed with medication,
discussants kept returning to the theme of switching to a less
offending drug (Reyataz) to avoid toxicity.
BMS gains a bit of credibility for promoting the concept of switching
because the only evidence that switching can be beneficial comes
from studies that switched Zerit (stavudine, d4T) to either AZT
or tenofovir to prevent body fat wasting. Of course BMS makes Zerit,
and although they have all but abandoned efforts to market the
drug, it is still useful as a sacrificial lamb. If switching from
d4T minimizes toxicity, then wouldn't switching from Kaletra to
Reyataz also be a good idea? As panel members admitted, there is
not yet enough evidence to support voicing that strategy but the
group did seem to agree that atazanavir has a neutral effect on
lipids. One panel member raised the interesting question of whether
the 100mg boosting dose of ritonavir used with atazanavir could
be responsible for lingering metabolic problems after the switch.
Another considered it possible, but thought it risky to use atazanavir
unboosted unless he was able to monitor the drug's levels in the
blood. Worries about Kaletra-associated increases in lipids have
apparently touched a nerve in many physicians, if not in patients,
and sales of Reyataz in the US are said to have nearly caught up
to those of Kaletra.
How Great Thou ART
Abbott: Long-term Data, Long-term Security?
Any
newcomer drug hoping to win converts is going to have to face the
deep and broad experience that so many physicians have using Kaletra.
Although they may worry about their patients' lipid levels and
the possibility of increased cardiovascular disease (CVD) risk,
many are comfortable with the durability and reliable viral control
they get from Kaletra. With a new formulation rolling out that
should increase convenience and possibly help with the diarrhea
(but not the lipids), Kaletra's seven years of data are hard to
ignore.
Fiona Mulcahy, one of the conference's Irish hosts, opened this
symposium by polling the audience via the electronic butter boxes
about their goals and experiences with antiretroviral therapy.
To the question of what characteristic was most important for an
ARV regimen, 59% answered immune recovery; 21% thought a high barrier
to resistance was supreme; and 18% selected tolerability. Only
1.4% thought lack of cross-resistance was most important. Asked
if they noticed a plateau in immune recovery in their patients
after three or four years on treatment, 52% said this was common
and 34% said they see it sometimes. Only 8% said they never saw
such a plateau and 5% said it was rare.
Joep Lange from the Netherlands then took the stage to describe
results from the Kaletra 720 study, which has now reached seven
years and is the longest running prospective study of an ARV regimen.
To date, viral suppression below 50 copies/mL has been sustained
in 59% of the original participants. He did not dwell on the 41%
who didn't fare so well. Building on the question asked earlier,
Lange reviewed results from two observational studies that found
a "plateau" in CD4 count benefits after three or four years of
therapy. In contrast, the Kaletra 720 study shows CD4 counts increasing
steadily over the seven year period for all patients, regardless
of at what stage they started. At seven years, the mean CD4 cell
count increase was +501 cells/mm3. Evidence is accumulating that
maintaining a higher CD4 count can help avoid disease progression,
improve the tolerability of therapy, and possibly minimize long-term
side effects such as lipoatrophy. To address concerns about Kaletra-associated
increases in cholesterol and triglycerides, Lange showed a slide
that suggested patients in the 720 study who switched from d4T
to tenofovir (d4T was state of the art seven years ago) experienced
significant decreases in lipid values while remaining on Kaletra.
Jose Arribas from Spain covered several issues concerning drug
resistance in current HIV therapy including transmitted drug resistance,
which appeared in 10–20% of newly infected people in several
studies. But mainly he was there to distinguish between the resistance
profiles of the NNRTI class and the PIs, and to guide our attention
to the resistance benefits offered by Kaletra. To date, no primary
Kaletra resistance mutation has been detected in trials, possibly,
Arribas says, because the drug is so rapidly cleared from the blood
after a missed dose, thus avoiding putting the virus under pressure
to replicate in the presence of subtherapeutic concentrations of
the drug.
With the audience softened up by Lange and Arribas, Barry Peters
of the UK took on the great looming unknown about Kaletra: Will
Kaletra-associated lipid increases eventually translate into an
increased risk for cardiovascular disease? First he reviewed the
known CVD risk factors; including male sex and older age, then
went on to high blood pressure, insulin resistance, smoking, and
HIV itself. There is no clear cut answer at this point and the
one large study that found an increased risk of CVD in people with
HIV on therapy is contradicted by another large study that did
not. This is all enough to muddy the waters around Kaletra and
conclude that the benefits of an efficacious ARV regimen are so
great that the potential CVD risk should not cause an ill-considered
switch. Besides, if you want to dramatically lower your risk of
heart and vascular problems, then you really should stop smoking.
You know who you are.
Finally, George Hanna of Abbott introduced the audience to the
new tablet formulation of Kaletra that offers a lighter pill burden,
no food restrictions, and requires no refrigeration. In healthy
subjects, a lower rate of diarrhea was reported than had been seen
in historical studies of the old Kaletra. Whether this benefit
will be seen in HIV-positive patients with touchy GI tracts remains
to be seen.
New Deity on the Block
Tibotec: TMC114, A New PI — A New Paradigm?
Tibotec
doesn't have a drug in the market yet, but TMC114, its protease
inhibitor compound now in phase III clinical trials, is already
becoming well known as a promising PI for the salvage setting.
The generic name for the drug, darunavir, also surfaced at this
conference, although Tibotec seemed unwilling to embrace the unfortunate
denomination. Ritonavir-boosted TMC114 is now available though
an expanded access program and shows enough potential that this
session dared ask if a new paradigm was in the offing.
Schlomo Staszewski from Germany reviewed the treatment options
for patients with multi-drug resistance. It is generally accepted
that simply adding one new drug to a failing regimen is a recipe
for failure and that at least two drugs with activity against an
individual's virus should be added if a switch is to be made. For
some patients, sticking with a failing regimen, particularly one
containing lamivudine, may help minimize viral replication capacity
and thus be preferable to stopping all drugs. Of course for many,
toxicity and tolerability problems are responsible for the need
to switch or stop therapy. There is increasing evidence that NRTI
resistance mutations can be managed to reawaken sensitivity to
previously used drugs, such as zidovudine, and sequencing of NRTIs
should be considered. For protease inhibitors, although there is
a high initial barrier to resistance, once PI mutations have started
to accumulate, even double-boosted PIs can be unsatisfactory. This
background set up the undeniable need for new drugs with activity
against HIV that has lost susceptibility to the existing PIs. Tipranavir
is one newly approved drug that attempts to address this problem,
although there are concerns with tolerability. TMC114, though not
yet approved, has performed well in the limited data shown so far
and initial reports say it is well tolerated.
Paul Stoffels of Tibotec reviewed the discovery and development
of TMC114. He said the company's criteria required that any successful
drug must be active against existing drug-resistant HIV, be resistant
to the development of resistance itself, and be as good as or better
than the competition in terms of tolerability, toxicity, and convenience.
That Tibotec has been successful, he said, is demonstrated by the
extraordinary decision of the US FDA to allow the company to file
for new drug approval based upon Phase II data — before the
large Phase III trials are completed. Approval in the US could
be seen by June 2006.
Christine Katlama from France reviewed 24-week results of the
318-person Phase IIb POWER 1 study that compared several doses
of TMC114 plus optimized background therapy (OBT) to OBT alone
in highly treatment-experienced patients. In the 600mg dose that
was selected for further study, 59% of patients with more than
three primary PI mutations who received TMC114 had viral load below
50 copies/mL compared to only 9% of those on OBT alone. Overall,
53% of the TMC patients versus 18% of the controls achieved viral
load below 50 copies/mL. Mean CD4 counts increased by 124 cells/mm3
in the TMC group compared to 20 cells/mm3 in the comparison group.
Discontinuations due to adverse events and the incidence of serious
adverse events were similar between the groups. These results are
impressive and they certainly impressed the FDA, but whether TMC114
can produce a shift in the treatment paradigm remains to be seen.
(Efficacy results from the POWER 2 study presented at the ICAAC
conference the following month generally supported what was seen
in this study, although safety and tolerability results from that
trial were not as rosy.)
Smart Balm
Gilead: Facing the Future: Evolving Strategies to Manage
Lipodystrophy Risk
The "face" in this symposium's title is a code word for lipoatrophy,
particularly the most visible and troubling consequence of treatment-associated
toxicity, facial wasting. Coming on the heels of the Lipodystrophy
Workshop, held in Dublin just before the conference, Gilead's symposium
offered a concise review of what we know about the underlying causes
of body fat alterations in HIV disease. Of significance to Gilead,
one thing we know, or at least strongly suspect, is that tenofovir
is not implicated in facial fat wasting and switching from thymidine
analog NRTIs (d4T, AZT) to tenofovir can mitigate and possibly
allow for the restoration of lost fat in the face.
Conference host Bill Powderly introduced the session by reviewing
the range of possible risk factors for lipodystrophy before zeroing
in on thymidine analogs and how they may be causing mitochondrial
toxicity in fat cells that leads to depletion of fat tissue.
Peter Reiss from the Netherlands sharpened the attack on thymidine
analogs by reviewing clinical data on fat loss under different
NRTI regimens. The detrimental role of stavudine (d4T) is now widely
accepted but it increasingly seems that over a longer time period,
zidovudine (AZT) can eventually cause many of the same problems.
The non-thymidine NRTIs, which include tenofovir, ddI, and abacavir,
have not been shown to significantly affect limb fat or total body
fat when compared to thymidine analogs. Although facial fat loss
is the most visible and most psychologically damaging manifestation
of lipoatrophy, accurate facial fat measurements are difficult
to perform and limb fat is generally considered a surrogate.
Finally, Joel Gallant of the USA reviewed the range of treatments
for existing fat wasting and concluded that the best strategy is
to prevent it from happening in the first place by avoiding thymidine
NRTIs. In a hopeful note, there is now some evidence that fat repletion
can occur naturally, albeit very slowly, once the offending thymidine
analogs have been removed.
The First Shall be Last
Glaxo-Smith Kline (GSK): Planning Today for Tomorrow's
Success
It's a bit sad that GSK is lately reduced to promoting abacavir
as its most promising product. Coming off the crash of its entry
inhibitor hopeful, aplaviroc; the erosion of Combivir use in favor
of once-daily Truvada; and a lackluster protease inhibitor, the
company has evidently turned to abacavir as having the greatest
potential for growth in sales. The drug is probably underutilized,
primarily due to physician fears of hypersensitivity reactions
(HSR) when initiating use, which occurs in 5–8% of patients.
But HSR can be recognized and managed, and after the drug is on
board, there is remarkably little toxicity to a once-daily abacavir/lamivudine
NRTI combo. Jens Lundgren from Copenhagen introduced GSK's satellite
by reviving an old discussion about drug sequencing and set up
the case for anticipating resistance patterns when choosing a first
NRTI combination.
Vincent Calvez from France offered a presentation designed to
position abacavir as a more logical first choice over GSK's arch
foe, Gilead's tenofovir. The strategy is to sequence abacavir before
tenofovir to minimize potential resistance issues. All three available
dual NRTI combos (based on abacavir, tenofovir, or AZT) also contain
either lamivudine or emtricitabine, similar drugs that lose potency
when faced with the fairly easy-to-get M184V resistance mutation.
Resistance to abacavir or tenofovir is more difficult to produce
and generally only occurs after M184V has appeared. Calvez argued
that abacavir is a more rational choice for first-line therapy
because L74V, the most common abacavir-associated resistance mutation,
when it occurs in combination with M184V, actually tends to boost
the virus's sensitivity to subsequent use of tenofovir, whereas
M184V in combination with the K65R mutation that can cause tenofovir
resistance prevents subsequent use of abacavir. The message: To
keep your options open, use abacavir first. Um, it's a lot to digest,
but it might tip the balance for some doctors.
Simon Mallal from Australia then addressed the abacavir hypersensitivity
issue with a discussion of a possible genetic marker that may one
day identify individuals most likely to be affected. But the real
key to identifying abacavir HSR is clinical vigilance, which means
distinguishing it from a reaction to another drug, an unrelated
illness, or symptoms of immune reconstitution disease. If a true
HSR to abacavir has occurred, the drug must be stopped and never
taken again to avoid severe and possibly fatal consequences. It's
this last bit that no doubt tempers physician enthusiasm for using
abacavir. But for those concerned about long-term mitochondrial
toxicity associated with other NRTIs, the extra vigilance at the
outset may be worth the effort.
Finally Lynn Marks of GSK addressed the perception that the company's
pipeline is sputtering and focused on the pressing need for better
therapies in both the developed and developing worlds. As the creator
of the world's first AIDS drug in 1987 and the maker of treatment
guidelines mainstay, Combivir, GSK has come to seem like a permanent
fixture in HIV therapy. But the bar for safety, efficacy, and convenience
has been set higher in recent years and it will take a stunningly
effective and problem-free new drug from GSK, or indeed any of
these companies, to capture an honored spot in the HIV therapeutic
pantheon. (The following month at the ICAAC conference in Washington,
DC, GSK gave an impressive first look at their new PI candidate,
brecanavir, which they hope will return them to greatness.)
Go in peace.
The Long-term Impact
of Early Virologic Control
Nicolai Lohse and colleagues from Odense University Hospital
in Denmark have been analyzing patient records from Denmark's
HIV Cohort, a nation-wide study of nearly every person on
antiretroviral (ARV) therapy in that country. They have previously
reported that virologic failure among patients who first
started triple combination ARV therapy before 1999 was far
more common than in those who began therapy after 1999. This
finding is probably due to the advanced stage of disease
in the earlier group, and due to preexisting NRTI resistance
caused by prior use of one- and two-drug regimens.
A new report by Lohse et al finds that maintaining virologic
control during the one-year period after the first six months
of therapy (months 6 to 18) is predictive of improved CD4
cell count, survival, and the likelihood of successful viral
suppression after follow up out to 7.5 years. Six months
on therapy was chosen as a starting point for this study
because by that point most patients will have gotten over
the initial side effects of treatment and will have settled
into a pattern of good adherence and sustained viral suppression.
The study cohort of 2046 patients was divided into three
groups according to the success of viral suppression during
the yearlong period from 6 to 18 months after starting triple
drug therapy. Group 1 (1,173 pts) had HIV RNA < 400 copies/mL
throughout the entire year. Group 2 (546 pts) were below
400 copies/mL only part of the time; and Group 3 (327 pts)
had detectable HIV RNA at every measurement during the year.
At 72 months of follow-up, 92.7% of patients in Group 1 were
still alive compared to 76.1% of patients in Group 3. Survival
in Group 2, those with partial suppression, was 85.6%. Viral
load was suppressed in 96% of those in Group 1, 83% in Group
2, and in only 57% of those in Group 3. CD4 counts improved
in all groups, but were significantly higher in Groups 1
and 2 than in Group 3. A subgroup of unsuppressed patients
who took a treatment interruption during the first 18 month
of therapy had a higher death rate than patients in Group
3. The most common reasons for interruption were adherence
difficulties (30%), patient choice (25%), and drug intolerance
(27%).
The initial characteristics of members of the three groups
may have bearing on their success at long-term viral control.
While baseline age, sex, race, and viral load were comparable
among the groups, Group 3 patients had lower CD4 counts,
were more likely to have injected drugs and have hepatitis
C, and had much greater prior exposure to ARVs. In reference
to the earlier research by Lohse et al on the timeframe for
starting treatment, 47% of Group 1 started therapy after
1998 compared to only 16% of those in Group 3 and 27% in
Group 2. This suggests that underlying factors such as prior
resistance, hepatitis C coinfection, social and economic
status, and generally poorer immunological and clinical condition
may have contributed to inferior long-term outcomes for many
patients in this cohort. These factors may also affect individuals'
ability to practice the perfect adherence required to maintain
viral suppression.
Lohse N, Kronberg G, Gerstof J, et al. Virologic control
during the first 6–18 months of initiating highly
active antiretroviral therapy as a predictor for outcome
in HIV-infected patients: A Danish, population-based, 6-year
follow-up study. Clinical Infectious Diseases. 2006;42:136–44.
|
Treating HIV is Rarely
an Emergency
An Interview with Joseph Sonnabend
By Bob Huff
Dr. Joseph Sonnabend was one of the earliest AIDS clinicians
and researchers. He helped introduce the concept of safer sex
and was a pioneer in establishing community-based research. He
was mentor to many of the first generation of AIDS activists
and is famous among patients for being the first doctor who treated
them as equals. He recently retired from medical practice in
New York and now lives in London.
BH: When you hear the term "salvage therapy," what does that mean
to you?
JS: I'm personally distant from it in the sense that it's not
an issue that has arisen much in my years of practice. I haven't
taken a great deal of interest when there have been meetings or
sessions on salvage therapy. I have not taken a great deal of interest
because I have only rarely been in the situation where I have had
patients whom I've started on therapy who have reached the point
of requiring salvage therapy.
I've had patients in clinics and people who've come to me from
other doctors, so I've had a few of those patients whose treatment
options were very limited, but not many. I really can not recall
ever having prescribed T-20, for example. I would have if that
situation had ever arisen, but it never has. And I've had thousands
of patients. And I'm obviously speaking about patients who started
therapy during the protease inhibitor era.
I know that treatment can fail, of course. Certainly I've had
failures; one patient just wasn't very mentally reachable; another
decided she had found another source of salvation. But by and large,
they've done really well.
So I've had to think about why I have been so fortunate. It's
partly what I have done, and partly what I haven't done, and another
part is the kind of practice I've had: a private practice consisting
largely of gay men; patients who are better educated; better motivated,
maybe; more knowledgeable about the medications and probably more
likely to stick to their drugs. So, credit goes there, but on the
other hand I know there are many patients of this kind who really
are in trouble.
BH: This is surprising since the conventional wisdom says that
if you've been treating gay men for a long period of time, they've
gone through a lot of different regimens and they end up resistant
to everything. So what was different about the way you were treating
them?
JS: It may have to do with what I have not done. First, I have
not started people on treatment too early. When the original version
of the treatment guidelines came out I thought they were very,
very wrong headed. I wrote a response — I suggested that the
way we resolve clinical uncertainly is by doing proper trials,
not by issuing guidelines. HIV medicine had already moved somewhat
away from the traditional way of trying to find answers by doing
many well-designed trials and was moving toward relying on the
consensus of a panel of experts.
I thought they seemed to be gazing into a crystal ball as to the
long-term effects of therapy. If these drugs were known to be completely
non-toxic, it wouldn't be a problem. But the potential toxicities
could not have been known then, and of course since then problems
have come up; lipodystrophy, diabetes, etc.
So the drugs are quite potent. And the one thing an experienced
doctor would think about, I believe, in deciding whether or not
to intervene in a patient is the rate of progress of the disease
in that particular patient. One of the striking things about HIV
is the huge variation in the rates of disease progression. But
what those guidelines did was to ask one to make a decision based
on a snapshot. Well, we know about blips in viral load; fluctuations
in CD4 counts; we know about all sorts of things that say a snapshot
does not provide enough information.
The fact is there are no emergencies in HIV medicine — with
the exception of people with very low T-cells, of course. But if
you're dealing with anybody above 200, there's no emergency; it's
not life and death, and you can wait a little while to get a fuller
picture. So I think what may have been important in my practice
was that I didn't follow the guidelines as they were written when
they first came out. As it turns out, more recent revisions of
the guidelines seem to be a little bit more in accord with what
I actually did.
BH: What would you do?
JS: I would suggest starting treatment at a time when there was
a consistent increase in viral load over maybe six or nine months;
a decline in CD4 cells; or development of symptoms, whether it
be thrush or some other. So it was individualized, and I think
it is very important to individualize treatment to the rate of
progress. In effect that translates into not staring early. I would
start patients where there were stable signs of progression. There
were other cases where people were worried and wanted to start
treatment and of course I didn't withhold it.
BH: If you saw a change in the rate of progress would you start
sampling that person's viral load and CD4 count more frequently?
JS: Yes, I would.
BH: In New York City, nearly 30% of people with an HIV diagnosis
also receive an AIDS diagnosis within one month and I imagine many
of these patients present as emergencies. It seems your practice
was not exactly a cross-section of all the patients who are out
there in New York today.
JS: No, as I said, most of the patients I'd been seeing had followed
me from my private practice to the clinics at Cabrini and St. Lukes.
But that doesn't mean I didn't have experience with the clinic
patients as well, and if I had more of them I might have a different
story to tell. But on the other hand there are some things I did
that were different from what many other people do.
The second thing that I didn't do was switch drugs at the drop
of a hat. And I have a sense that that may be quite important.
I tended to keep people on the same treatment even if they had
detectable viral loads — as long as there was not a consistent
increase in the viral loads. As a result, a good number of patients
in my practice did have detectable viral loads while on treatment
but they didn't increase and they did just fine. Not everybody;
some of them did start to increase and that's another matter.
This, again, was against the dogma. You open a manual of HIV medicine
education for physicians and you will see: "What are the goals
of antiretroviral therapy?" Well, "the goal of antiretroviral therapy
is to produce an undetectable viral load using the most sensitive
assay available." And that's based on all the theories of viral
evolution. But we assume too much and we don't know the whole complexity
of this: we don't know about mutations that compensate; mutations
that resensitize.
I should also say, as far as viral load goes, on principle I never
used the under-50 assay. I wouldn't do it unless people asked for
it. I didn't use it because what am I going to do if it is 200
or 300? I'm not going to do anything.
BH: Let's say you saw two in a row at 1,000 copies.
JS: Nothing.
BH: Okay, one's at 1,000 and the next one is at 5,000.
JS: I'd wait a little bit more. It kind of depends on what the
CD4 count is and what the clinical stage is, too. There are people
who will tolerate 100,000, actually.
BH: Well, doesn't the probability of developing resistance mutations
go up as the rate of replication goes up?
JS: Well, that's true, but you have to rely on empirical stuff,
too. And what we ought to do is recognize that there are people
around with detectable viral loads of 20,000–30,000 on treatment
ever since these drugs became available and they are not going
up. Now, what is it? They are full of mutations. We could learn
something from these people and recognize that the phenomenon exists.
It's easy to go along with the Darwinian thing and selection and
escape, and of course I believe all of that, but there are complexities
in there that are not taken into account. We don't know enough
about mutations that may compensate; that may have an effect on
fitness; that may resensitize the virus to other drugs. It's something
that you have to learn from real life, and we do have these patients
with detectable viral loads and they're full of TAMS and they're
with us and doing just fine. I've had patients with a viral load
continue on treatment and it hasn't gone up, but everybody is different.
I think every patient will contribute some degree of viral control
themselves; it's variable; it's more or less; so you have to tailor
things to each person.
I've said there is a gulf between academic doctors working from
the book, who only see patients in the clinic once or twice a week
and don't deal with patients at the end of the telephone because
they've got residents to do that. They're not field doctors. On
the other hand there are on-the-ground doctors who have observations.
I've been told it's just a question of time and don't be silly.
I've been at meetings when I said I had patients with viral loads
who've been stable for years and I've been told I was lying.
So I can say that part of it is because I didn't change regimens
quickly. I know others will change on a single viral load increase
before seeing if it was a blip or if it was sustained. Their idea
is to keep people 100% undetectable, and I think that has hurt
people. That is my own belief. Of course there are instances when
you have to change. But where do doctors get their information?
They are instructed by academic doctors and this is common dogma:
you've got to get undetectable, and you've got to stay undetectable,
and if the viral load creeps up...do something. This was more in
the earlier days. I think people are much more tolerant about this
now because they've seen what the effect was.
BH: Did you use resistance assays?
JS: I did use them. Not all that much, but there were times when
they were important, for example with the NNRTIs — if you
get a K103N, that's bad news.
Another thing I know I did differently is that I had a predilection
for using nevirapine (I didn't care for Sustiva because of its
neurologic side effects, which I think are much worse that they
tell us.) At that time I was doing clinical research at CRI (Community
Research Initiative), and I was the principal investigator for
trials for nevirapine and delavirdine, so I became familiar with
NNRTIs and nevirapine in particular, so I stuck with what I knew.
I have had a few rashes, but it wasn't so terrible; and I have
had a few liver problems, but it was alright; we just stopped and
that was that. But by and large I had a good experience with nevirapine.
So in those days in 1996, I did things differently, because I tended
to start people on an NNRTI, rather than a protease inhibitor.
I went to one of these company marketing meetings once at the
Waldorf Astoria where they give you a little box and everyone in
the audience votes their choices to various clinical dilemmas.
Press "A" if you'd do this, etc. They'd present you with a patient
and give you five options and ask what you'd start them with. Once
choice was an NNRTI and two nukes, so I pressed that button, and
when they showed the results I think 2% chose what I chose and
everybody else was choosing Crixivan and whatever else. And the
moderator said, "I wonder who those one or two people are?" And
I felt like ducking under the desk. About five years later I went
to another meeting and the same question was asked and this time
about 60% of them chose an NNRTI and two nukes. Now, nevirapine
is an unforgiving kind of drug because you can lose the whole class
if adherence isn't good, so that brings in another aspect of what
I did differently.
I really think an essential ingredient for success is the relationship
between the doctor and the patient. I have come to the view that
in HIV medicine more than any other field, the nature of the doctor-patient
relationship is absolutely key, particularly with people who are
on treatment. When adherence became a big issue, a lot of money
was available, and people were hired as adherence counselors, and
it was all for the patients. It was all crap. They should have
had counseling for the doctors. Maybe you wouldn't call it adherence
counseling, but I'm not joking. In order to be an HIV physician
there are certain attributes you should have or you should think
about doing something else! It's labor intensive and if you choose
this profession you ought to be willing to give up a bit of doctor
sanctity, if you will, and make yourself available to your patients
to a greater extent than in other fields. That's awfully important.
You're actually endangering people if you don't have these qualities.
How you present the ARV regimen and how you choose it together
with the patient is very important. Don't present it in a threatening
way. I've heard of doctors who said, "If you don't do this you're
going to die." If you hear something like that and you aren't taking
your pills regularly, you're not going to tell your doctor. What
you really want to do is let the patient feel that you are working
together as a team — as best you can; you can't always achieve
this, and maybe not even that often, but do as best as you can.
And don't make the disease sound trivial either; it's not a chronic
manageable anything. Tell your patient that there is work involved,
and that their life is never going to be the same again but we're
going to try to make it okay. But let's not kid ourselves that
this is a walk in the park, you know. Despite all those ads, you're
not going to turn into a mountain climber.
BH: So you tried to make them feel like it was a mutual journey.
JS: What I really tried to do was make it possible for patients
to tell me if they were having any trouble with the medicines.
Everybody is different as far as far as side effects go: some people
will swallow Norvir like water; there are other people who just
sniff it and can't stand it. Some people get Viracept diarrhea
which is horrible; and others just get a little. Some people can
take a million pills without thinking about it and they stick to
it; and others can't deal with it. So when it comes to the number
of pills or the side effects profile, it's good to work out with
the patient what they can live with. So you just have to try the
regimen. If they have a reaction with diarrhea or nausea, then
you try to keep away from what is causing that. But the most important
thing is they have no hesitation in telling you what their situation
is. How many patients don't tell their doctors the truth? It's
a lot.
The objective is you want to be able to relate to the patient
in such a way that if that patient has a problem — say, nausea — that
you may not think is terrible (but it doesn't matter what you think)
then one should be in the kind of relationship with that person
that they can call you and actually get through to you — not
an office person or not get a return call or something. That's
not for HIV medicine. That may be okay for other things, but it's
not for HIV.
So you have to get to understand your patient a bit — unless
you have to start treating them because they are really sick with
PCP or something — but the more usual thing is that you get
to know them first. And you might find that some people are better
left untreated because it's going to be a disaster story if you
try to treat them.
You have to get patients to have some sort of trust. I can think
of one clinic patient, he was declining and it just seemed awful,
and it involved a 15 minute discussion. I remember we made a deal
and I said I'm going to put you on some heavy duty stuff — we've
got to get your T-cells back — but I promise you that within
three or four months I'm going to make it easier for you. Now,
I don't know about induction/maintenance; it hasn't been sufficiently
studied, but in this disease you just have to do it; you can't
wait for the studies. So there's every reason to think that this
concept of induction/maintenance may be perfectly viable, and as
far as this gentleman was concerned, it was the only viable thing
because he was not going to stick on the Kaletra and whatever else
I gave him forever. And when the time came, he opted to change
and I said I think we'll need another month, but after that I did
change him to an easier regimen and he did okay. So building up
that kind of relationship where you can discuss these things is
time consuming, it's a little bit labor intensive, and it may not
be entirely practical, given the volume of patients, the reimbursement
situation, and the need to see many patients. But it's so important.
BH: So in an initial conversation with a patient, you'd talk about
much of what we've been talking about here?
JS: Yes, although it depends. If someone just had PCP as their
first diagnosis, I'd have a different conversation. But part of
the conversation with a person who is feeling well, is telling
them there is no urgency; there are really no emergencies in HIV
medicine — with some obvious exceptions. But otherwise there
are no emergencies, so you can afford to look and see what is happening.
So I would ask people to let me observe them. I would say that
everybody progresses at a different rate. I would say, maybe you're
a fast progressor; maybe you're a slow progressor. I have no idea,
but we'll find out. And mostly they've been comfortable with that.
Sometimes they were anxious and wanted to be on treatment. And
other people didn't want to be on treatment; they hated the idea,
so they were quite willing to go along with this kind of thing.
But when they finally did go on treatment, they knew that they
had to. So when the time comes and it looks like things are going
wrong the whole compliance issue is a little better.
So, just to go back again, I don't know why I've had the success
I've had — and I'm not bragging or boasting — but I do
know that I've had a very loyal group of patients. Also I think
part of it is that I have had some disregard for official recommendations.
I'm not suggesting that people do that, but I had been an academic
physician, I was in the virus lab for 15 years, an associate professor
for eight years, I had a very traditional infectious diseases upbringing,
including in immunocompromised hosts in the transplant field before
HIV. So I think I'm capable of making some judgments and I'm not
saying one should in principle not listen to authorities — that's
not the point I'm making. But in my particular case, I haven't
respected some of the advice that's out there and I haven't followed
it, and I think my patients have done better. But that's sort of
selective and we need to have some research.
Another thing, and this is just a personal opinion, but I don't
think it is reasonable to expect young people to be on these potent
drugs for the rest of their lives uninterrupted. Therefore the
need to develop strategies of interruption is absolutely critical
and I can't see where the opposition comes in because, if you don't
accept that, then you accept the principle that a young person
is going to be 30 or 40 years (we hope) on drugs, the full toxicity
of which is not known. So I don't know what form the treatment
interruptions will take, but that seems to me to be such an obvious
thing to do.
The other thing that I have done with a few patients is cycling
the drugs — actually it was Mike Mullen who first suggested
it and I thought it was a great idea, and I believe there are some
studies on it now. The theory is that since the drugs have different
toxicities, if you go off a combo that makes you undetectable,
you can always come back to it. So if you have a liver-related
toxicity, it might be reasonable to give the liver a rest every
year or so as a way of toxicity management. Of course, these need
to be studied. And when people are used to something, they are
very reluctant to change. I've tried, and sometimes I've succeeded,
but people are reluctant to change.
The issue of salvage treatment should be discussed in a different
way, because it tends to boil down in the discussions to adherence: "You
failed because you didn't take your drugs properly." I think that
is valid, but it is begging the questions underneath that. That
just dumps everything on the patient, but it is the patient, it
is the doctor; the economy, the economics of practice; the traditions
of practice; it's the communication between patient and doctor;
the need to see a certain number of people; clinic structures;
managerial interference. We've tended to put it all on the patient
and think we can solve the problem by hiring an adherence counselor.
And the thing about salvage is that it may be the person who reaches
salvage is not going to succeed because there's something about
that individual where nothing works.
I've thought we should look at people in the database who'd reached
the point of salvage and try and see what it is about them: how
many different drugs; what was the trigger for changing; adherence
issues? So I think it should be looked into as more than as just
a case of a bad patient; a naughty patient who is not taking his
drugs.
BH: Did you observe a lot of lipoatrophy or facial wasting in
your patients?
JS: Well, yes I did, unfortunately. I tended to shy away from
the full dose of AZT more that most, and I'm happy to say that
I never have written a ddC prescription in my life. But I did use
ddI, d4T, 3TC, because that's what we had at the time, and of course
AZT, and abacavir when that came out. So with the d4T, there was
lipoatrophy, but I didn't know it at the time; and who did know
it? So, sad to say, I've seen a fair amount.
BH: How concentration conscious are you? Do you think about all
the factors that can affect drug concentration?
JS: I think that's important. I know there are huge variations
in some of the drugs. But I don't think about concentration problems
very frequently. Not with the standard dose. I think there is a
bit of overkill in the standard doses. I think one tries to aim
for a very comfortable level above the minimum inhibitory concentration.
You want leeway, and of course people metabolize things differently;
and there's not much you can do with the nukes because serum levels
don't tell you a whole lot.
BH: Did you use atazanavir unboosted?
JS: No. I wonder if people do? I don't know. I never do. I had
one person who wouldn't take it because a friend said, "Oh you're
going to turn yellow!" Well, you've got to listen to that. I could
have talked him into it, and I can't remember whether I did or
I didn't.
BH: Did you have many turn yellow?
JS: I had some, but the same thing happened with Crixivan. But
it bothers some and others couldn't care less. So what I take home
from this and all my experience, which is coming to an end now,
is that, more than any other kind of medicine, HIV medicine involves
a closer, more intimate kind of relationship with one's patient,
and that may not be attainable given the economics of practice.
But if you go into that branch of medicine you should accept that
and be willing to try.
The compliance problem underscores the complexity of it all; not
these simple minded solutions, these mems-caps and hiring an adherence
counselor and beating on the patients: "Studies have proven that
if you're not compliant you will fail!" That leads to a punitive,
coercive approach: "You're going to die unless you take your pills!" Instead
of saying, "Okay these pills aren't working; you're not taking
them. Let's talk about it. We have something else for you. We'll
find something for you. Give me a call if it is bothersome."
BH: I wonder if it is practical to conduct a practice this way
any longer.
JS: I gave up my private practice because of financial reasons.
I was doing clinical research at CRI and I was only seeing patients
half time, and with the managed care and the billing, I just couldn't
afford to keep it open; it was more than I could deal with. So
I went to work in the clinic, but my patients came with me. Most
of the clinic patients were originally my private patients. About
70% I'd say came with me. So, again, it may not be me as much as
the practice and the patients that had that relationship with me
that they would follow me from my practice to Cabrini then to St.
Lukes. Not all of them liked it but they did it, so that is a factor.
BH: Have all of your patients found new doctors now that you are
retiring?
JS: No, some are still calling me. But they need to find a new
doctor. I'm almost 73 and it's no good. I can't tell you how difficult
it was trying to match people up with new doctors. And the anger
some people felt towards me was very hurtful, actually. Well they
trusted me. You spend so much time with a doctor and you have to
go through the process of finding someone else...
BH: I imagine a lot of people just won't go to the doctor again
for a long time.
JS: Yes, there's one guy who called me a few months ago and asked
me for new prescriptions because he hadn't been to see anybody.
I see doctors and I see the barriers they put up. Maybe it is
necessary for the economics or maybe for the doctor's emotional
protection. But I've certainly gone to visit people in their homes.
And maybe it has a kind of ripple effect, because people hear that
you do that, they'll know that you'll come. Maybe it adds to the
way that people trust you, even though they don't require you to
visit, they know that you would do so.
Maybe there are some patients who would feel uncomfortable with
somebody who was not gay, but not all gay men. There are women
doctors and some gay men feel comfortable with them. It's as if
you're in this disease and you have to undergo a kind of obstacle
course. It needn't be charitable, but nobody should make the mistake
of saying it's going to be alright and you're going to climb mountains.
It's the same thing about safe sex, I believe. If you try to eroticize
safe sex you're actually defeating yourself. I think the thing
to do is be upfront and honest and people will listen to you. So
you say, it's not as good as the real thing, unless you're into
rubber, but this is reality. That's it. Life sucks. We can make
the best of it, but don't pretend that it's actually a turn-on,
because that becomes absurd. And it's the same with this: taking
pills everyday; having to go to the doctor; having to know your
viral load: it's another way of life. The anxiety you feel every
few months waiting for your results; stuff like that affects people
in different ways but nobody can pretend it's easy. It's a different
life. It's not the same any longer. The idea is to recognize that
and be supportive and not exaggerate.
I feel blessed that I don't have to do these things. I have high
blood pressure and I have to take pills but they have no side effects
and I'm very compliant — because I know that I ought to be
and I see the consequences of high blood pressure — but the
pills don't have any side effects.
If HIV medicines were like that there would be no problem. Just go on
them. There's not a downside, other than the cost. That's why I feel that if
the answer remains only in drugs, then were going to have to work out some
different forms of treatment that involves interruptions, where someone
may manage to do nine months out of each year.
When To Switch Depends on What You Can
Switch To
By Bob Huff
There is an open question about how to monitor antiretroviral
(ARV) therapy in the developing world. In rich countries, HIV RNA
and CD4+ cell counts are routine. RNA tells the amount of virus
detectable in the blood, and it gives a rapid readout on the success
of therapy. CD4 count tells about the health of the immune system
and usually responds in a positive direction after a period of
successful ARV treatment. These tests — and others — are
routinely done before starting therapy and every few months thereafter.
They are performed in central laboratories and cost hundreds or
thousands per year.
But for resource limited settings, where spending even $100 per
year on drugs is a burden, such complete monitoring of therapy
is not affordable. Efforts are being made to reduce the cost of
diagnostic tests and make them more practical, but for the near
future, most agree that only limited monitoring is feasible. The
question for the authors of simplified treatment guidelines is:
what should be monitored when you can only monitor one parameter?
Theoretically, any amount of viral replication allows the risk
of a random drug resistance mutation to occur, which in turn allows
more replication, thus increasing the chances that resistance mutations
accumulate, ultimately leading to complete loss of suppression
by the initial drug regimen. If the increasing viral load can be
detected soon enough, then one or more drugs in the regimen can
be switched and the virus resuppressed. The most sensitive viral
load assay in common use detects HIV RNA starting at 50 copies
per mL of blood. Because of the phenomenon of transitory but harmless
blips in viral load up to 1,000 copies, most clinicians who take
this aggressive approach would want to confirm a viral breakout
above several hundred copies with two HIV RNA determinations a
few weeks apart. At this point they might perform a genetic or
phenotypic resistance assay and either intensify the regimen or
switch one or more drugs. More conservative physicians may prefer
to intensify adherence education and wait until they see a sustained
trend of detectable virus approaching or passing 1,000 copies before
making a change. With over 20 approved ARV agents in the US, there
are options to explore.
But treatment options in the developing world are limited, and
the question of "when to switch" may ultimately be determined by
what is available to switch to. There may be one first-line regimen
that is routinely prescribed because it is generally safe and effective,
easy to dispense, and affordable to use in mass treatment programs.
A second-line therapy, if one is available, will likely be much
more expensive, and may be withdrawn due to futility once it has
failed. For patients in these settings a second chance could be
their last chance.
Diagnostic assays are likely to be limited also. An ideal product
for the developing world might be a disposable, point-of-care dipstick
that only returns a semi-quantitative result, say green if above
200 CD4+ cells and red if below. The assay would be used by workers
in the field to make treatment decisions according to guidelines.
So what are the likely long-term outcomes of using various decisions
points for switching under these circumstances? Using a highly
sensitive HIV RNA assay will force the earliest regimen switch.
While this may avert HIV resistance, the patient will also be consuming
additional resources. Viral load determinations must be performed
fairly frequently to catch early failures, and if the expensive
second-line therapy also fails, then therapy may be withdrawn and
clinical deterioration will progress to mortality.
Using a less sensitive cut-off point for viral load (say 1,000
or 5,000) will require fewer determinations, delay triggering an
initial switch, extend the time—and the number of patients
on their initial regimen, and preserve resources. Since disease
progression rarely tracks viral replication closely, overall survival
may be significantly extended compared to using an earlier switch
point under these resource-limited circumstances.
Using CD4 count to guide regimen switching is yet less sensitive
to regimen failure than using HIV RNA but some would argue that
it is a more direct marker of the health of the patient. CD4 counting
may also be cheaper and more feasible to deploy than RNA tests.
Switching is delayed until immune deterioration is evident, although
at a cost of the likely accumulation of multiple resistance mutations.
But if the second regimen can suppress the virus for a second round
of immune recovery, then the overall time to clinical failure may
be much longer than that obtained by aggressively switching based
on viral load.
The least sensitive method for determining when to switch would
depend solely on diagnosing clinical symptoms. In some settings,
and on a population basis, this might be effective, although it
appears likely that immune recovery is often less successful after
symptoms have appeared. Since clinical trials are unlikely, perhaps
modeling these scenarios with an eye to maximizing long-term survival
can offer some guidance.
Finally, if monitoring and switching rules tailored to available
resources are able to produce better long-term outcomes than those
based on virologic abstractions, then universal treatment guidelines
for resource-limited settings may not be advisable. "When to switch" may
be best decided by program and national policy makers based on
what is available, what is affordable, what produces the best outcome
for the greatest number of people under those specific conditions.
© 2006 Gay Men's Health Crisis
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