Of the thirty plus abstracts and posters that focused on Lipodystrophy (LD) at the recent Retroviruses Conference, it was repeatedly stated that researchers needed to begin working together at establishing consensus on definitions of LD, and standardizing measurement techniques. Most of the data presented at the conference dealt in some capacity with investigating the causes of LD, or how to slow or halt (and in some cases reverse) the progression of LD, but cross comparison of data collected in the absence of standardized norms makes firm conclusions difficult.

What Is Lipodystrophy?

LD is often associated solely with Fat Redistribution (FR). But definitions of LD have been widening to include several different syndromes that can be classified under two categories, metabolic changes and morphologic changes:

Data released from several studies suggests that at this time there does not seem to be any identifiable relationship between the incidence of LD associated metabolic changes and morphologic changes.

There was much discussion about the need for standardizing tests and measures for the morphological changes associated with LD, for both clinical diagnosis and research purposes. Currently many studies are non-comparable because of the diverse methods of assessment in use.

One technique often used by researchers is observational reporting by patients and/or physicians, of any physical body changes. Reporting changes instead of using absolute measurements is unreliable. Reported changes by patients when compared to a Computed Tomography Scan (CT Scan), shows that patients are more likely to miss or under report FR or FD.

The methods for measuring the physical effects of LD should include:

What Are The Causes Of LD?

Prior to the advent of potent ART, physical body changes were identified as wasting syndrome, which was thought to occur due to HIV itself, and/or as a side effect of Nucleoside Reverse Transcriptase Inhibitors (NRTI) monotherapy. Since 1996 physical body changes that fall under the widening definitions of LD have been hypothesized to occur because people are living longer with HIV, long term exposure to NRTIs, the inclusion of PIs in ART, the inclusion of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), other factors including age, gender, race, family history, associated risk factors, or a combination of any and all of the above.

Data presented from the Australian cohort study, where 1350 participants were followed over 8 months, reveals that patients who have ever taken a PI were much more likely to have LD associated symptoms (81%) over patients who had been on ART that did not include a PI (33%), or patients who had never been on any ART (5%).

These findings were partially supported by others. One study concluded "HIV per se had no apparent effect of FD", that despite a decrease in total body fat of patients who have never taken ART, the "ratio of trunk to appendicular fat was significantly greater" in patients who had ever received ART, with or without a PI. And another study states "Abdominal fat accumulation can occur in patients taking ART independent of PI."

At this stage it is almost impossible to pinpoint the exact causes of LD. Before researchers can begin implicating one drug over another, factors such as the lack of standardized tests and measures and lack of long term data must be taken into account. One pitfall that was highlighted suggests that data currently available on long term exposure tends to implicate the most recent drug(s) in use.

Can The Effects Of LD Be Slowed down, Halted and/or Reversed?

There were several studies that focused attention on substituting one class of drug for another in an attempt to decrease the effects of LD. Unfortunately, for reasons already mentioned, the data is difficult to compare and inconclusive.

PIs have long been associated with LD, and conflicting data from several studies involving the substitution of a PI for an NNRTI were presented. E.Bonnet et al concluded that "no improvement is observed in lipidic abnormalities and LD in patients switching from PI to a NNRTI," S. Gharakhanian et al stated that "PI substitution with Efavirenz does not seem to lead to significant improvement of clinical or biological anomalies."

But two other studies with similar hypotheses concluded that "Hypertriglyceridemia, insulin resistance and abdominal obesity may improve after 6 months of switching from a PI to Efavirenz" and switching patients with LD from PI to Nevirapine shows "continuous improvements in CD4, reduced Cholesterol (CHOL) and Triglicerides (TG)."

A Carr et al "switched heavily ARV-pretreated LD Syndrome patients" from a PI based combination to a regimen of Abacavir-Neviripine-Adefovir-hydroxyurea. "Switching led to reduced central fat and improvement of some lipid parameters, but decline in peripheral fat and overall muscle mass."

Finally, two studies focused attention on D4T (stavudine) in PI naive patients. C. Goujard et al concluded that "typical LD features can be observed in PI-naive patients, and the use of stavudine and duration of previous treatment are associated with lipodystrophy occurrence." Thierry Saint-Marc et al concluded that by stopping D4T in PI naive patients, after 9 months patients showed "improvements in metabolic and body fat abnormalities." I spoke with Saint-Marc who complained that most of the PI switching studies did not factor in the effects of D4T which have long been suspected in LD.

The Future Of Lipodystrophy Research

Two studies that are currently in development were unveiled as models for the future of multi-centered collaborative research. Being two decades into the pandemic it's hard not to become cynical as to why it's taken so long (and for so much money) for researchers to finally come to terms with the need for multi-centered, cross comparative studies.

FRAM, Fat Redistribution And Metabolic Change in HIV Infection, is a US initiative "that will study 75-100 subjects each from 16 HIV treatment sites in the U.S. and as well as in population based controls (Veterans Affairs database). They will be surveyed for changes and have objective measurements including anthropometrics, MRI, DEXA and laboratory analysis of metabolites. Epidemiology of the objective changes as well as subjective reports will be performed."

D.A.D. (Data Collection On Adverse Events Of Anti-HIV Drugs), a large multi-nation study with the participation of pharmaceutical industry, academia, community, and regulatory groups, will "follow over 15,000 HIV positive patients over two years." The control group will consist of "a retrospective analysis of cardiovascular events using a large US hospital database (VA)", and also proposed is "a case definition protocol for fat redistribution."