THE CHANGING FACE OF LIPODYSTROFHY
Gus Cairns investigates the latest thinking
about this body-morphing side effect
The first wave of lipodystrophy in the UK has probably done its worst. People
starting HIV drugs today probably won’t ever look in the mirror and
see a stick-limbed, pregnant-bellied stranger looking back from a skeletal
face. But those of us who had our bodies distorted by the drugs that saved
our lives are not going to turn back into Michelangelo’s David (or Botticelli’s
Venus) any time soon.
So says Professor David Cooper, the Australian HIV specialist who coined the
word ‘lipodystrophy’ back in 1998. These days, says Cooper, clinicians
are more concerned about the long-term effects of lipodystrophy and whether
it increases heart-attack risk.
The HAART of the matter
Convincing evidence highlighting this risk comes from the large DAD study
that showed people with HIV not on treatment had an annual rate of one in
2,500. After three years on combo therapy this risk rose 10-fold. After four
years the rate was still climbing to one in 190. This rate is not hugely troubling
but the trend is steadily upward. What will happen in 10 or 15 years?
Some specialist like UK Professor Brian Gazzard, argue that if you exclude
the first year on therapy the heart-risk is no worse than that found in an
ageing population who tend to smoke too much. DAD also showed that a large
proportion of the people taking part in the study had modifiable, life-style
risk factors for heart disease like cigarette smoking.
What causes lipodystrophy?
“One mistake we made was to assume it was all caused by the protease
inhibitors (PIs),” explains Cooper. “That was a coincidence. Lipodystrophy
started appearing soon after people were put on combination therapy, and everyone
was on PIs. It took quite a while to work out what was really going on.”
The problem was probably toxicity caused, not just by PIs, but by some nucleoside
drugs, especially the thymidine anagalogues, d4T and AZT.
Researchers eventually found fat cells in people on these antiretrovirals
were shrunken and poorly developed, with lots of gaps between them; not plump
with juicy grease as fat cells should be. And when they looked at the chemistry,
they found out why.
Fat behaving badly
Cooper explains what happened when they gave HIV negative volunteers six weeks
of Combivir [AZT plus 3TC, though 3TC is not strongly implicated] or d4T plus
3TC.
“Within two weeks, the activity of certain genes that govern the way
fat cells develop, and how energy is processed from fat, was massively suppressed
in some or massively switched on in others.”
And most PIs had a similarly swift effect. After four weeks on PIs the cholesterol
content of certain immune cells and, worryingly, of cells lining blood vessels,
rises by factors ranging from 140 per cent (on amprenavir) to 360 per cent
on full dose (400-600g) ritonavir.
Double whammy
HIV drugs disrupt the normal processing of fat. The culprit nucleoside (NRTI)
drugs switch off crucial genes that govern how fat is shunted in and out of
cells so the body no longer knows when to burn it and when to store it.
If you are also taking PIs, these drugs appear to immature fat cells like
naturally-occurring messengers telling them to stay immature. So, already
depleted fat gets no chance to build up. The two drug classes even affect
some of the same genes.
Cooper says: “It’s an incredible coincidence that we developed
two completely different classes of drugs, many of which by different routes
end up having the same effect.”
The upshot is body fat disappears from its normal sites. Mitochondria, the
parts of cells that burn fat as fuel, start to disappear or malfunction. Digested
fat finds no storage place and spills into the bloodstream where it circulates,
as cholesterol and other fats called triglycerides, at far higher levels than
normal, potentially gumming up blood vessels. And the displaced fat gets re-deposited
in odd places: inside the abdomen, between the shoulder blades, or, less disfiguring
but more dangerously, in the liver or pancreas, which may eventually lead
to liver failure and pancreatitis.
This not only raises the risk of heart attacks and strokes, but in many cases
also the risk of diabetes. In one study, PIs reduced the ability of fat cells
to respond to insulin (which processes sugar into fat) by 55 per cent to 80
per cent.
What can be done?
The most important thing is to get treated for your HIV when the time is right.
There are now ways to minimise the risks and there is more scope to tailor
treatments to the person.
By switching lipodystrophy patients from d4T or AZT to abacavir, Cooper’s
patients replaced 1.9 kilos of limb fat within 16 months. But the average
person has 7-8 kilos so at this rate it would take five to six years to get
the fat back on your limbs. And people may never get their cheeks back. Cosmetic
fillers like New-Fill and silicone implants like Bio-Alcamid will probably
remain the only option for facial fat loss.
Drugs that act on fat cells in the opposite way to antiretrovirals seemed
promising, but a recent trial of one, rosiglitazone, made no difference to
limb fat and in some cases added insult to injury by giving men fatty lumps
on their limbs - benign fat deposits or tumours called lipomas.
So, if you have the choice, it is better to switch before you get fat loss.
Luckily, the news is not all gloom. We have other nucleosides; 3TC and its
cousin FTC can be added to abacavir or tenofovir as the NRTI ‘backbone’
of a combination.
On the PI front, Cooper says we at last have a pill that “looks pretty
clean in terms of lipodystrophy” in the shape of atazanavir, though
its potency in people who have tried other PIs is still an on-going question.
Coming along fast are entry inhibitors, with one already here: T-20 (Fuzeon).
Because they act outside the cell they shouldn’t alter fat metabolism.
As for the non-nucleosides (NNRTIs) efavirenz probably has a neutral effect:
it raises blood fats to some extent but also raises the fraction of cholesterol
called HDL (high-density lipoprotein). This actually protects against heart
attacks by acting as a sort of molecular ‘Hoover’ that sweeps
up fat deposits from the blood.
And some scientists think nevirapine might have a protective effect. It improves
the ratio of HDL to all cholesterol to such an extent it may have an anti-lipid
effect, like statins.
People allergic or resistant to nevirapine can take statins that can reduce
the risk of heart attacks somewhat, but not as much as switching drugs, and
certainly not as much as lifestyle changes.
What you can do yourself
Stuff you can do yourself can make a big difference.
Cooper points to factors that can reduce heart attack risk in a ‘typical’
patient: a 39-year-old white male, smoker with lipodystrophy and cholesterol
nudging the upper end of ‘normal’.
Cardiologists give this man a 10 per cent chance of having a heart attack
in his 40s, which is high. If he receives statins, that chance falls to seven
per cent. If you switch his PI to atazanavir or an NNRTI and optimise his
nucleosides, the risk goes down to six per cent. Have him stop smoking...and
the risk goes down to two per cent, or one per cent if he switches his HIV
drugs too.
Exercise works too; not just by burning fat but also by starting to redirect
fat deposition away from the belly and back towards the proper places. In
moderation it also gives you a CD4 boost and improves your mood.
But working against all these are gravity and time. Lipodystrophy looks worse
as you age because you get a middle-aged spread anyway.
Cooper says: “I’ve got all these middle-aged male patients with
lipodystrophy who want to look buffed and beautiful for the bathhouses, and
I honestly can’t look them in the face and say, ‘My dear, there’s
a magic pill to bring your looks back’. There isn’t.
“That’s why it will be so important in future to choose the right
drugs first. At least we now know the ones to avoid.”
What you can do about lipodystrophy
• If you’re on d4T, AZT, ddI or PIs and haven’t got body
shape changes or high blood fats don’t panic. You may simply be less
susceptible.
• A diet low in saturated fats and carbohydrates and high in unsaturated
fats like fish oils can reduce heart attack risk.
• Over-the-counter supplements like vitamin E, acetyl-l-carnitine and
niacin may help reduce lipid levels.
• If you smoke, the single best thing you can do is stop.
• Exercise, in moderation.
• Get your cholesterol and triglycerides measured regularly. An ‘upper
limit of normal’ 5-6 mmol/Lfor cholesterol and 1.7mmol/L for triglycerides.
LDL or ‘bad’ cholesterol should be below 2.5 mmol/L , and HDL
or ‘good’ cholesterol above 1.04 mmol/L
• Ask your doctor about drug switching, but be aware not all options
may be possible.
• Ask your doctor whether you need statins (for high cholesterol), fibrates
(for high triglycerides) and human growth hormone (for wasting).
• Consider face-fillers. New-Fill face-filler is available in five clinics
in London and in Manchester, Portsmouth, Brighton and Birmingham. The London
HIV commissioners are working to make it equally accessible across London,
at least. New-Fill and another face-filler, Bio-Alcamid, are available privately.
