Many people are
suffering with peripheral fat wasting (arms, legs, butt, face) often accompanied
by elevated lipids (cholesterol & triglycerides) & glucose, and fat
accumulation in the stomach. Women can experience enlarged breasts.
Metabolic changes and body changes observed also include: impaired
glucose tolerance (inadequate levels of insulin in response to consumed
glucose); high fasting blood sugar; insulin resistance (high levels of blood
glucose & insulin at the same time). Fat accumulation in several
locationsóabdomen, back of neck (buffalo hump), lipomas (bumps of fat that can
This June in San Diego
the First Lipodystrophy Conference was held. This conference and follow-up
meetings highlight to me that we now know less about the causes of this
syndrome, which includes fat redistribution, than we thought we knew last year.
We continue to learn how little we know, and it appears a difficult task to get
an understanding of the mechanisms and causes. One of the problems highlighted
at this conference was that there is not a generally accepted definition of this
syndrome. Various studies appear to be using different definitions of
lipodystrophy. But, it appears difficult to put together a general definition.
Last year research from
the Australian research group implicated protease imhibitors, and it was widely
accepted that protease inhibitors were the sole cause of lipodystrophy or fat
redistribution. This year, starting with reports at the February í99 Human
Retrovirus Conference followed by reports at many conferences since, weíve
seen studies reporting individuals who have never taken protease inhibitors but
have taken dual NRTIs have experienced fat redistribution or lipodystrophy. Don
Kotler has reported that he observed similar symptoms in individuals in the
earlier years after HIV was discovered who had never taken any HIV drugs. A
small study from the Australians reported seeing lipodystrophy in individuals
treated during acute infection after 12 months on therapy.
research groups have conducted preliminary research and claim to have some
understanding of the mechanism of action causing lipodystrophy or fat
redistribution, I think their findings appear preliminary and inconclusive.
Limited and inconclusive success appears from therapeutic interventions so far.
Switching from a PI regimen to a nevirapine regimen may improve cholesterol and
triglycerides. Patient and doctor observations reported some individuals
body changes improved following switch to nevirapine. Itís been observed in
preliminary studies that Human Growth Hormone can reverse fat accumulations but
do not appear to nor is it expected to reverse fat redistribution: wasting in
the face, arms or legs. One study
reported high prevalence of lipid abnormalities associated with PI use. I
donít know of evidence that steroids reverse or prevent fat redistribution.
Increasingly I think doctors are concerned that long-term steroid use may have
long-term harmful effects.
In a small study from
the same Australians (A Carr, D Cooper), patients who had only taken NRTIs
developed lipodystrophy but did not report lipid elevations. NRTI lipodystrophy
may have different clinical and metabolic features, and result from a different
cause than from PIs. Kees Brinkman has suggested that mitochondrial toxicity
associated with NRTIs may be associated with the development of this syndrome.
Mitochondrial toxicity may cause cells, including fat cells, to be
dysfunctional. This can lead to neuropathy and myopathy. A personís genetics
can play a role in developing mitocondrial toxicity. In his report on the
Australian paper Dr Abhimanyu Garg said the patients in this study developing
lipodystrophy after only NRTI use (n=14) were characterized by recent onset of
fatigue, elevated serum lactate levels (4.6 vs. 1.2 mmol/l), nausea, weight
loss, abdominal dystension, and elevated liver enzymes. As well, they did not
have hypertriglyceridemia but had low serum albumin concentrations. Metabolic
alterations reportedly improved after cessation of NRTIs but weight gain was
limited. Thus, HIV-infected patients who developed body fat changes on NRTIs had
a syndrome that is distinguishable from the lipodystrophy syndrome developing
with PI-containing HAART use. Constitutional symptoms, lactic acidemia and
hepatic dysfunction and recent weight loss characterize the syndrome with NRTI
use. However, because significant weight loss occurred in these patients with
NRTI use, it appears that this study cannot rule out wasting as a cause of the
observed body fat loss.
There has been much
discussion about what may be causing fat redistribution? Associations have been
Duration of NRTI
Duration of total
therapy followed by PI therapy
restoration of immune system by HAART
diabetes and heart disease in family, genetics related to disposition to
The cause for
lipodystrophy may be multi-factorial for a person. As well, the causes for
lipodystrophy may be different for one person than another. HIV causes immune
dysregulation and immune deficiency. Either or both may play a role in fat
redistribution. It could be due to the partial immune reconstitution that occurs
from successful therapy, or there may be an abnormal immune response to therapy.
For example, when CD4s start to return to normal after effective HIV therapy,
the immune system is not normalized. Some people still experience an OI. Another
suggestion by Kathleen Mulligan is perhaps an immune system that continues to be
'turned on', to respond to HIV that is no longer present, and instead attacks
and kills subcutaneous fat cells. Many potential explanations are being offered,
but research has yet to make clear headway in understanding this phenomenon.
Kotler and others have
said they see the syndrome more often in people whoíve had HIV for a while,
and have had the best responses to HAART with undetectable viral loads and
significantly increased CD4s. It may be that several years of double NRTIs may
start the process of lipodystrophy but after adding a PI this could lead to more
including the Australianís more recent paper implicating NRTIs, have reported
associations, not causation, between d4T and lipodystrophy. But these studies
appeared not designed adequately to sort out various factors such as duration
and type of prior therapy, exposure to AZT prior to d4T, and reasons for
discontinuing AZT. In fact, many of the studies at the Lipodystrophy Conference
appeared flawed by the same types of problems. Sometimes study results appeared
inconsistent, possibly because various potentially contributing factors were not
characterized. Ongoing research is trying to sort out contribution of individual
NRTIs to lipodystrophy.
Julian Falutz of
Montreal reported in study presented at Lipodystrophy Conference that men (n=21)
on long-term saquinavir HAART with a mean viral load of 1400 copies/ml were less
likely to develop "HIV/HAART associated lipodystrophy" than a
comparable group of men (n=23) on indinavir HAART. A separate study shows only
minor changes in lipids and glucose to individuals taking Fortovase regimen at
24 weeks.. The SALSA study found women were more likely than men to have truncal
obesity (98% vs 76%), and less likely to have peripheral wasting (e.g. limb
lypodystrophy 68% vs 54%; butt LP 59% vs 44%). Men were more likely to have
elevated triglycerides (84% vs 32%) and cholesterol (53% vs 29%). 98% of
individuals in this study were receiving combination therapy with a PI, and
51/210 had <500 copies/ml viral load. M Galli study reported higher incidence
of "altered fat tissue distribution" in women than men (26% vs 6.5%).
Individuals with elevated cholesterol and triglycerides may be at risk for
premature heart disease. Lipids and glucose should be monitored. Lipids can be
lowered with lipid lowering drugs. Glucose can also be managed. Insulin
resistance can be treated in individuals without HIV with troglitazone
(associated with liver side effects) and rosiglitazone. But these drugs have not
yet been tested in HIV lipodystrophy. The ACTG is planning such studies. Doctors
express concern about placing individuals on poly pharmacies (various drugs for
various syndromes) without clear evidence of success. Diet and exercise can
control lipids, glucose and slim down a protruding stomach for some individuals.
Exercise can also enhance oneís self of well-being, improve overall health,
prevent premature heart disease, and tighten oneís muscles. In preliminary
studies, Human Growth Hormone (HGH) reduced fat deposits but did not and are not
expected to reverse fat redistribution. As well, in Kotlerís preliminary study
of HGH fasting glucose increased. Follow-up studies are planned. In some studies
described in this newsletter, switching individuals to PI-sparing regimens have
shown partial improvements. Switching may entail what appears to be a low risk
of losing control of viral suppression. This may depend on a personís
treatment history. Some doctors have anecdotally reported seeing improvement
following switch to amprenavir in some individuals but not in others. Some
researchers say they need more objective data, not observations by doctors and
patients, confirming that switching from a PI to a PI-sparing regimen can
improve body shape alterations.
Metformin is an
anti-diabetic drug that improves insulin sensitivity. Abnormal lipids and
glucose improved in a small study but no improvement was seen in fat
redistribution. Studies are ongoing. Some people opt for cosmetic surgery. Kees
Brinkman has suggested that riboflavin, L-carnitine, and co-enzyme Q may improve
cell dysfunction due to mitochondrial toxicity and thus fat redistribution, but
there is little evidence yet supporting this.