January 1998
The Eyes Have It?
by Mark Mascolini
The protease era brings PWAs less CMV retinitis ? and a shortsighted slowdown in research to fight it
You can make one sure bet about CMV. After that, all bets are off.
Here’s the sure bet: If you’re old enough to have sex, you’re
probably infected with CMV – that’s short for cytomegalovirus, which can
cause blindness, brain infections and other evil things in people with
derelict immune systems. If you’re gay, HIV positive and sitting in a
room with nine other gays with HIV, nine of you have CMV infection too.
But you 10 HIV negative gay guys in the next room, don’t get smug" Eight
of you are CMV positive. And in that other room with 10 people who
shoot up, seven or eight are a swim with CMV. How about the room with 10
folks who aren’t HIV positive and never injected drugs or had gay sex?
Six have CMV.
But HIV negative guys and gals, straight or gay, have an advantage:
If they don’t do something that wastes their immune system – like get
cancer or have an organ transplant – their CMV will never cause disease.
Meanwhile, people with AIDS, especially when their CD4 counts slide
below 50, run a big risk that CMV will start burning up cells at the
back of the eyeball – the retina – causing CMV retinitis. Or CMV may
torch cells in the gut, lung, liver, esophagus or brain.
Now here are some things about CMV you can’t bet on, unless you like
long odds: That a whopping CD4 boost from protease inhibitor
combinations protects you from CMV retinitis. That the recent plummet in
new cases of CMV disease won’t bounce back up in another year. That the
one drug approved to prevent CMV disease will do that. That another
anti-CMV drug doctors rave about, or blood test to help tell who’s at
risk, will be approved any time soon.
Protease inhibitors did much more than make lots of sick people feel
better. They also changed the way everyone thinks about CD4 counts. Two
years ago, if your CD4 count dipped under 100, you had to start worrying
about CMV disease. If it skidded below 50, you worried more. Doctors
routinely scheduled regular exams with an eye specialist for people
whose CD4 counts fell below 100, because almost everyone who got
retinitis got it with CD4 counts way down in the double digits.
Things are no longer so simple. Last year, AIDS docs began seeing
scattered cases of full-fledged CMV disease in people whose CD4 counts
had rocketed form 50 or lower into the 200s after taking protease
combinations called HAART – highly active antiretroviral therapy. How
good can these protease combos be if people are getting retinitis
despite plummeting viral loads and soaring CD4 counts? What’s going on?
Eleven CMV savants interviewed for this article gave the same answer:
They don’t know. But they all have good ideas. These surprising cases
don’t mean protease inhibitors spark CMV disease, they all said – not
exactly, anyway. You can look at it two ways.
First, maybe the CMV disease was already there when these people
started taking protease inhibitors. Michael Polis, MD, of the National
Institute of Health, notes that four of five people in one report hadn’t
had an eye exam before HAART started. So no one would know if retinitis
was already smoldering, because signs of disease are subtle – or
nonexistent – in its early stages.
Rich Pollard, MD, of Galveston, Texas, a co-author of the report on
the five cases Polis mentioned, adds another reason that the "smoldering
disease" scenario might make sense: Doctors detected retinitis in all
five people in the first weeks after they started HAART. Eye experts
figure that a few weeks pass between the time that CMV gets into the eye
and when they can spot retinitis. So, if CMV had slithered into these
people'’ eyes just before protease combos began recharging their immune
batteries, retinitis would have showed up exactly when it did – a few
weeks into the new therapy. And once people have been taking protease
combinations for more than two months, Pollard adds, new retinitis no
longer appears – as long as CD4s stay high.
There’s another way to explain CMV disease after HAART hikes low CD4
counts: The new CD4 cells don’t work. Different crews of CD4 cells have
different jobs. Some learn – and remember – how to grabble only with TB,
while others can waylay a certain flu virus, a toenail fungus or CMV.
When CD4 counts tumble, whole CD4 crews may be nearly, perhaps
completely, wiped out. If HAART jacks up CD4 counts, it does so by
multiplying the CD4 crews still left. And if HIV decimated the CMV crew,
it could take moths for a person’s new CD4 cells to relearn their
anti-CMV stratagems. And it’s possible they never would.
This explanation ticks off Larry Drew, MD, PhD, and a CMV ace in San
Francisco. He calls the idea that new CD4 cells are wimps "a complete
misinterpretation." Those cells may not be ready to take on CMV two
minutes after people pop their first protease pills, says Drew. But
given time, protease combos show a flair for anti-CMV bondage and
discipline.
Drew’s argument looks good for two reasons. First, the five people
Pollard described all had remarkably well-controlled retinitis: Using
anti-CMV drugs, they got no worse for up to a year, compared to the
usual five months. Second, Polis and others published a report last year
of four people whose retinitis cleared up and stayed controlled during
HAART – even when three of them stopped taking their anti-CMV drugs. The
fourth person never started anti-CMV therapy.
Douglas Jabs, MD, an eye specialist in Baltimore, isn’t surprised.
He’s found that even fairly feeble anti-HIV therapy like solo AZT
sometimes bucks up the immune system enough to corral CMV. But Jab’s
isn’t convinced that HAART solves the CMV problem. He points to another
part of the Pollard report that catalogued CD4 counts of people with new
retinitis before and after widespread use of protease drugs. Almost
everyone in the "before" group got retinitis with a CD4 count below 50.
But seven of the 49 in the "after" group had CD4 counts over 100 when
their retinitis surfaced. And the CMV Hotline of the National
Association of People With AIDS (NAPWA) reports plenty of calls from
people whose CMV got worse despite HAART and anti-CMV drugs.
But to get a better fix on whether CMV disease is coming or going in
the protease era, you have to look at the big picture. Sizing up CMV
from sea to sea, do you count more or fewer cases since Crixivan made
Merck investors richer?
Fewer – by a lot. Only a year ago, CMV experts routinely wrote 25
percent to 40 percent of people with AIDS get retinitis. No more.
Comparing notes with CMV colleagues across the country, Atlanta’s Dan
Martin, MD, figures the number of new cases has dropped at least 50
percent, maybe 70 percent. In New York City, the picture may be even
rosier. Early last year Murk Heinemann, MD, began trooping to local
clinics and AIDS residences, peering into the eyes of a hundred people
with low CD4s. His goal is to find candidates for CMV drug trials. So
far he’s found just one.
But Martin, Heinemann and the others aren’t celebrating yet. Everyone
worries about what Martin calls "a CMV honeymoon." Indeed, Judith
Currier, MD, in San Diego sees signs of what could be "a beginning of a
resurgence" in CMV disease, though she doesn’t have hard numbers.
Douglas Jabs does. His numbers don’t show CMV on the rebound, but they
do show the decrease may have bottomed out. In the Baltimore area, new
CMV cases plunged 55 percent from their peak. But in the first half of
1997, jabs counted the same number of new cases as in the first half of
1996.
Besides what they may say about how long HAART works, these CMV ups
and downs directly influence the development of new anti-CMV drugs. If
Heinemann and Jabs can’t find enough people for trials, new therapies
won’t get studied. And if drug makers see a dwindling market, they’ll
slow down – or stop – testing new products.
We’re not talking hypotheticals here. Hoffman-La Roche, which makes
intravenous (IV) ganciclovir and ganciclovir capsules (also called
Cytovene) for CMV, has what most CMV wonks rate as a potentially potent
new drug: Progan (or valganciclovir) is similar to ganciclovir, but
could work better than oral ganciclovir. Why? When you drip ganciclovir
straight into a vein, you get high drug levels in blood – but you need a
permanent hole in your chest. Even if you take 12 ganciclovir capsules a
day, the standard dose, you don’t get as much into your blood. Four
Progan caps a day equals a day’s worth of IV ganciclovir.
Sound promising? Want to find out about Progan trails? Not so fast.
Roche was planning three Progan trials – two for people who already have
CMV disease, and one to prevent disease in people at high risk. Michael
Marco of the Treatment Action Group, who studies these things, says the
trials looked well designed. Then, after reports circulated about
plummeting rates of CMV disease, word came from Roche headquarters in
Basel, Switzerland: Kill two of the studies, including the prevention
trial.
"Dumbfounded" is the word Dan Martin uses to describe the reaction of
most CMV experts. He, Marco and others pleaded with Roche to push
ahead with all three trials. Numbers of new cases may be falling, they
concede. But that’s now. Like Currier, martin fully expects to see a CMV
rebound in 1998 as HAART fails in more people. Even if the market stays
smaller than it was, Martin thinks Roche has a "moral obligation" to
develop Progan – not just for PWAs, but for everyone who gets CMV
disease.
Roche’s U.S, point man, Dan O’Day, MD, vows the company is
"absolutely committed" to getting Progan licensed. Trial planners are
redesigning the scrapped studies, which O’Day predicts will begin again
"most likely in early 1998." But according to Roche, the prevention
trial, which needs 600 participants to show valid results, may be too
big. Currier disagrees: "They can get 600."
While awaiting for new drugs for CMV-disease prophylaxis
(prevention), people with low CD4 counts face tough decisions about the
one such drug already approved, oral ganciclovir. Let’s say protease
inhibitors didn’t work for you and your CD4 count’s under 100. Or maybe
HAART did work – for a while – but you’re losing CD4s again. If you’ve
never had CMV disease, should you try to prevent it with oral
ganciclovir? Or should you just get eye checkups every three or four
months and watch for early signs of retinitis – fuzzy vision, blind
spots, bright flashes, "floaters"? (See "When Irish Eyes Are Smiling".)
Last summer, a government panel said adults with CMV in their blood
and CD4s under 50 "may" consider oral ganciclovir to prevent disease.
They gave four reasons why people may not want to take it: Serious side
effects, like drops in red or white blood cells, "limited efficacy," no
evidence that it prolongs life, stratospheric cost ($18,000 a year
wholesale). This is like Dad giving you the keys to the Firebird on prom
night and saying, "By the way, kid, it’s missing four wheels."
The panel didn’t even mention a possible fifth flaw: Resistance.
Based on preliminary data, CMV expert Larry Drew expects to find
resistant virus in about five percent of people who’ve taken the drug
for 18 to 24 months. Others worry this could be a wild underestimate,
because resistance can only be measured in urine or blood, not where it
matters most – in the eye. If CMV is resistant to oral ganciclovir, it’s
also resistant to IV ganciclovir – making the latter worthless. Worse,
there’s good evidence that two other CMV therapies – foscarnet and
cidofovir – don’t work as well in people with ganciclovir-resistant CMV.
Kevin Frost, director of clinical research at the American Foundation
for AIDS Research, who knows CMV inside-out, scoffs at the new
guidelines for offering oral ganciclovir with one hand, then taking it
back with the other. He calls the blanket recommendation to use
ganciclovir as prophylaxis "a mistake" because of the drug’s many
disadvantages. Even Michael Polis, who sat on the panel, says he feels
"lukewarm" about the guidelines and adds: "There was a lot of
disagreement about how strongly to recommend oral ganciclovir." Debate
ended, though when one panelist asked the 80 or so AIDS specialists in
attendance how many routinely use the drug to prevent CMV disease. Only
two raised their hands. And no one interviewed for this article touts
ganciclovir as prophylaxis, although most say they’ll consider it for
people at highest risk of CMV disease – those with CMV in blood, CD4
counts under 50 and no response to HAART (especially if they’ve had MAC,
indicating seriously compromised immune function).
One Roche-sponsored study showed that oral ganciclovir cut CMV
disease rates by half – although by current estimates of annual
incidence, for every 100 PWAs with CD4s below 50 who take Cytovene, only
ten would be protected. And 31 percent of those at highest risk (shown
by measurable CMV in the blood) developed the disease despite taking the
drug. Meanwhile, a federally funded community study found that the drug
provided no protection at all.
The federal panel’s clearest finding was that "the most important
method for preventing severe CMV disease" is early detection and
treatment. To learn more about early signs, you cam call NAPWA’s
Roche-funded CMV Hotline (800.838.9990) or Roche itself (800.624.CHECK),
which will send you a "screening kit" with a video and a self-testing
grid.
But buyer beware: These "educational" campaigns are riddled with
blunt reminders that (expensive) ganciclovir capsules can save your
sight. Roche’s striking posters widespread in some urban neighborhoods
(blaring "Don’t let CMV leave you in the dark" on a window shade
half-covering an eye), like its Cytovene and in POZ and
elsewhere, use very old data to scare you about the rate of CMV disease –
the references are from pre-HAART 1983, 1987 and 1993. And – surprise –
nether the ads nor the posters mention the conflicting study results,
the federal panel’s reservations or even its guideline to consider the
drug only after dipping below 50 CD4 cells.
There’s another early-warning system for CMV disease. For years,
researchers have been fine-tuning tests that count CMV copies in blood –
viral load assays. Early data suggest that doctors will be able to use
such tests, just as they use now HIV viral load assays, to predict a
person’s risk of worsening disease and chart responses to therapy. Such
CMV assays could help in deciding whether to start CMV prophylaxis.
But development of CMV assays is creeping along. Roche Diagnostics
says its test will be ready for research use in 1998 but can’t say when,
or if, they’ll have a test your doctor can use. Researchers already use
Chiron’s CMV assays, but the company has no immediate plans for an
office kit. In fact, Chiron’s David Chernoff, MD, points to the scuttled
Progan studies as evidence of an evaporating market.
Some might call this development sluggish. A less patient Michael
Marco calls it dicking around. The Progan and CMV-assay stories offer
chilly reminders of how much market forces – not altruism – drive AIDS
industry. Are drug boardroom captains being penny-wise and
pound-foolish? Some CMV experts think so. Three interviewed for this
article, with no coy intent, used the same adjective to describe Roche’s
Progan procrastination: Shortsighted.
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