THE SALVAGE MIRAGE
Top HIV doctor Mike Youle tells Gus Cairns how the workings of big pharma and EU red tape are hindering development of effective salvage therapy for people who have burned through their treatment options
In September four HIV clinicians and researchers, including the UK’s
Mike Youle, wrote to the top medical journal The Lancet highlighting “a
major clinical problem in the treatment of highly antiretroviral drug-experienced
individuals”.
The problem, they said, was HIV had to be treated with drug combinations,
but drug research and development is geared towards evaluating and marketing
just one drug at a time. This means patients who have failed multiple regimes,
with resultant highly drug-resistant HIV, only ever get offered ‘serial
monotherapy’. They get put on each new drug as it appears. But that
drug soon fails because it is unsupported by other drugs that work, and HIV
has proved capable of developing resistance to every treatment thrown at it
so far.
Bad medicine and drug failure
Mike Youle is keen to stress that the majority of his patients are doing fine.
“Perhaps only one in a 100 patients treated at the Royal Free Hospital
falls into the category our letter talked about. But that’s a problem
in itself. HIV treatment is so successful it has become increasingly difficult
to find enough patients to do a clinical trial for drugs designed to help
that minority.”
Do people get into this situation because they don’t take their
drugs properly?
“Not always. Some catch a multi-drug-resistant virus, of course, but
that’s usually weakened virus. I have a patient who on paper is resistant
to everything, but is doing fine with a CD4 count of 800 and a low viral load.
“Unfortunately bad medicine is a major reason. At least half the Royal
Free salvage patients got inappropriate care elsewhere.
“Take one patient, previously treated in a small clinic outside London.
He was given two nucleoside drugs, which he failed on, and probably became
resistant to. They gave him nelfinavir and two new nucleosides. Nelfinavir-based
regimes don’t have a great record, and he failed on that. Then they
gave him Kaletra which can work for resistant patients, but gave him the two
original nucleosides. So he failed on that.
“He still had a chance, because he’d never taken any of the non-nucleosides.
And what did they do? They just added nevirapine to his failing regime. As
any doctor should know, this meant he developed NNRTI resistance almost instantly
and blew his one chance of those drugs.
“When he turned up here he had a rock-bottom CD4 count and a serious
AIDS-defining illness. I put him on tenofovir, tipranavir and T-20 and he’s
doing fine.
“Luckily for him, the only two new options around worked. If only T-20
or only tipranavir had worked, he’d have failed, and then we’d
have had nothing.”
Why only one drug turns up at a time
Mike says the barriers to new combination therapies are not scientific, but
political and economic. They are bound up in how the pharmaceutical industry
and its regulators are geared towards producing single ‘blockbuster’
drugs.
He says if people really worked towards developing combinations of new drugs,
they’d have to test them in combination. And that creates all sorts
of difficulties. Drugs interact in unpredictable ways which means your two
‘miracles’ might lower each other’s levels in the body,
cancelling out each other’s effects. This already happens if you combine
fosamprenavir and lopinavir (Kaletra’s active ingredient), or tipranavir
and any other PI.
“What you could do at a very early stage is agree to test your two drugs
in HIV-negative volunteers. That can be done fast.”
But the biggest barrier, he says, is the attitude of the pharmaceutical companies.
“Drugs are not developed, in their minds, to be ‘salvage’
drugs. Take tipranavir (Boehringer Ingelheim’s new protease inhibitor
(PI), designed to work with HIV resistant to other PIs). Boehringer are doing
a head-to-head study with Kaletra (Abbott’s widely-used PI) to see if
there’s a chance it could be a good first-line drug. That’s just
the way the market works. But it means companies are petrified of sharing
knowledge about drugs in development. One company with a salvage drug approached
another with one in development about sharing knowledge to see if they’d
work better together. But the other company, whose drug wasn’t so far
advanced in development, wasn’t playing ball.”
However, on some occasions, two new drugs are being developed by the same
company, he explains.
“Johnson and Johnson has two salvage drugs in its development ‘pipeline’;
TMC 114, a protease inhibitor, and TMC 125, a non-nucleoside. Both work against
highly resistant virus, and when used together could pack a knockout punch
against resistant HIV.
“But even here the pharmaco people who design trials are scared that
if they tested the two drugs together, some unexpected interaction or toxicity
would be discovered that would stymie their development as individual drugs.
“HIV treatment activists are at fault too because they tend to push
too hard for investigatory salvage drugs to be available to anybody when this
could be quite damaging. This in itself makes the pharma researchers dig their
heels in.
“Access should be tightly monitored and restricted to the minority of
patients who desperately need them. I’d say the definition of ‘desperate
need’ is someone resistant to virtually all licensed drugs with a CD4
count of under 50.”
Blairite bungling and EU obstruction
In the absence of drug company-sponsored combo trials, researchers like Mike
have done their own trials. He’s an Aids physicians with a reputation
for backing hunches and getting patients undetectable with unorthodox regimes
where conventional ones have failed.
But new EU regulations are set to end these trials. Events like the Alder
Hey Hospital babies-brains-in-jars scandal have led to much tighter EU regulations.
“Previously researchers took responsibility for the ethical conduct
of their studies. But now their NHS trust managers have to carry the can,
and they are unwilling to take responsibility. There’s also vastly more
bureaucracy and paperwork, which increases costs.
“We’re doing a study on Kaletra to see if liver damage alters
the level of the drug in the body. These are patients who’ve been on
the drug for six months. All you’re doing is taking two extra blood
samples.
“But the new regulations say because it’s a study we have to label
the Kaletra separately as a study drug, we have to get patients to bring back
bottles to check adherence, and we have to report every single side-effect
even though it’s not a study to establish safety. If we were studying
two drugs, the amount of paperwork involved would make it impossible to do
the study without drug company sponsorship.”
This is the nub of the problem. The other major UK research clinic, the Chelsea
and Westminster hospital, has already announced it is stopping research unsupported
by pharmacos; not because they want to, but because only drug companies have
the money and staff to make it work.
Mike says the Kaletra study is the last his team will do. So the kind of ‘quick-n-dirty’
small study an inspired researcher might run, to find if an unconventional
combo might just pull a salvage patient out of no-CD4-land, becomes exactly
the kind of study no one will sanction.
“It’s only the UK that rigidly interprets these regulations with
Blairite relish. When I asked colleagues in France, Italy and Spain what they
were doing they said ‘Pah! We ignore them.’
“This EU directive is playing directly into the hands of Big Pharma.
Any semblance of independence from the industry is being destroyed in the
name of protecting the individual.”
