LIPODYSTROPHY WORKSHOP

LIPODYSTROPHY WORKSHOP
Toronto, Canada, September 14, 2000

Reported by Jules Levin, NATAP

Lipodystrophy is catch-all term used to describe body changes, lipid abnormalities (elevated choleterol, triglycerides), glucose increases, and bone mineral density abnormalities persons with HIV are experiencing. The body changes can consist of fat accumulation in the abdomen, breasts for women, on the back of neck (buffalo hump) or in other places. Fat depletion or wasting in the arms, face and/or legs can be seen separately or together with fat accumulation. The body changes are also called fat redistrubtion. This is the first report from the 2^nd Intl Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. This year's meeting is better and more attended than the first meeting last year. At this meeting there have been some interesting basic science talks showing to me that there has been progress in beginning to understand the mechanisms at work here. But it's taken a few years of floundering to get to this point. However, its also quite clear that the mechanisms at work are not yet understood and they are very complicated. Intricate networks of proteins, cytokines, immune system components, and lipid & glucose are potentially involved. As well, HIV and the antiretroviral drug treatments for HIV appear to play roles. Quite a bit of funding is available from the NIH and the pharmaceutical industry for research, so this field ought to yield results from studies in coming years. There appears to be a good deal of basic science research going on in a variety of areas. Hopefully, the results will be increasingly more effective in yielding useful information. One interesting note is an ongoing study of Rosiglytazone at UCSF looking at this antidiabetic drug's potential to improve fat depletion in the arms, legs, and face. The drug may cause increased LFTs for individuals with liver problems or hepatitis so it must be used cautiously in these individuals or possibly not at all for individuals with more advanced liver conditions. The ACTG is planning a combination study of Rosiglytazone and Metformin, which is an antidiabetic drug which can reduce fat accumulation but may cause fat loss in the face, arms, or legs.

Human Growth Hormone Studied in Various Dosing Regimens for Fat Redistribution: preliminary data

There were two interesting study reports today on HGH. Both studies looked at different dosing regimens. And, both studies had different dosing regimens than the study reported by Engelson & Kotler at Durban (see the results of that study below), which showed fat loss in the arms & legs at a dose of 6 mg per day. The first HGH study in Toronto was presented by JC Lo and a group at University of California at San Francisco called "The effects of recombinant human growth hormone on glucose metabolism and body composition in HIV-positive subjects with fat accumulation syndromes". Seven subjects with fat accumulation were enrolled in an open-label study of HGH at a dose of 3 mg per day for 6 months. Insulin sensitivty, oral glucose tolerance, and body composition (DEXA) were measured at baseline, month 1 and month 6. Persons with diabetes and elevated triglycerides were excluded from the study. Individuals with diabetes should probably not use HGH, as it can cause glucose problems. HGH was discontinued in one subject at week 3 due to hyperglycemia (glucose problem). The person's baseline oral glucose tolerance test revealed pre-existing diabetes despite normal fasting glucose, so afterwards persons with glucose intolerance were excluded.

Five persons completed 6 months of HGH, with a dose reduction to 1.5 mg in one patient at month 2 for arthralgias (body aches). All 5 persons experienced a reduction in hump size and/or abdominal girth (stomach): total body fat decreased an average of 4.4 kg (3.7 kg. Of which was trunk fat but 0.5 kg loss was from arm & leg fat). In other words, there was fat loss of 0.5 kg in the periphery. Lo said there was a peripheral fat loss seen in the study and she does not recommend HGH to individuals with lipo-atrophy (peripheral fat loss). In the study, lean body mass increased (5.4 kg) in all subjects at month 6.

Lo concluded that short-term HGH at 3 mg/day reduced buffalo hump and abdominal girth in subjects with HIV-associated fat accumulation. And, although insulin sensitivity and glucose intolerance initially worsened, improvements toward baseline was seen at 6 months, possibly due to body fat. Lo recommended that screening oral glucose tolerance should be obtained to exclude persons at risk for HGH induced hyperglycemia.

Effects of low dose growth hormone therapy for HIV-associated fat accumulation

This study was intended to explore low dose HGH (4 mg every other day) on body changes, safety, and lipid and sugar metabolism. This study was conducted in 14 (of 30) individuals who had participated in the 24 week study reported at Durban and reprinted below. The average age of the participants was 43 (range 30-55). There were 13 Caucasian men and 1 African American woman. They all had enlarged abdomens at study start. This was confirmed by patient report, observation by 2 study doctors and subsequent MRI. They were all clinically stable on antiretrovirals.

The individuals took a 12 week planned washout after receiving 6 mg daily in the previous study before starting this study of 4 mg every other day. Measurements included whole body MRI plus fasting lipids, glucose and insulin. Five subjects did not complete the study. The reasons for dropout were self-perceived lack of efficacy (n=2), scheduling problems (n=1), loss to follow-up (n=1), and an adenocarcinoma probably not related to HGH. Drug was temporarily discontinued for severe pain (n=1) and abnormal LFTs (n=2), but resumed without further problems. Other adverse events included mild joint stiffness or pain (n=1) and rash (n=1). Mean skeletal muscle volume increased from 28.3 to 29.9 (p=0.004). As measured by MRI, subcutaneous fat did not change from baseline to week 24. Subcutaneous fat is just below the surface of the skin. Visceral fat (deep inside the stomach: this is referred to by stomach fat accumulation) decreased from 4.4 to 3.9 (p<0.02) at week 12 and had no further change at week 24. By DEXA, arm fat and leg fat did not change from baseline to week 12 or to week 24, although total trunk fat decreased from 9.2 to 8.4 at week 12 without further change at week 24.(p<0.01). But, even at the lower dose HGH showed adverse events and metabolic abnormal changes, although less troublesome. Mean fasting insulin, cholesterol and triglycerides did not change (n=8).

DURBAN REPORT: The following HGH report was excerpted from the NATAP Reports newsletter and the NATAP web site Durban Summaries. Engelson & Kotler from St Lukes Roosevelt Medical Center in New York City reported on a prospective, open-label trial of 6 mg/day HGH s.c. of 14 HIV-infected individuals with fat redistribution and enlarged abdomen. HGH treatment was for 24 weeks and there was a 12-week follow-up after stopping HGH. There was a fat loss of about 5-kg, overall weight was about the same. Although there was a loss in trunk fat, there was also a loss in arm and leg fat by DEXA. Visceral adipose tissue (deep stomach fat) was reduced as measured by MRI. The effects were complete by week 12. 12 weeks after HGH was stopped 85% of the visceral adipose tissue (deep stomach fat) returned, and the farm & leg at loss returned. Adverse effects were common, especially arthralgias and myalgias that improved or resolved with dose reduction or discontinuation. In addition, at week 12, 3 participants (13%) met American Diabetes Association criteria for diabetes based on a 2-hour oral glucose tolerance test and 9 patients (30%) met the criteria for glucose intolerance. Although all 30 participants had normal fasting glucose at baseline, they also all had elevated fasting insulins (>10 IU/mL). Lower doses and induction-maintenance dosing will be explored in future study.

BRIEFS FROM TODAY'S SESSION

As an introduction, mitochondrial toxicity is a toxicity that occurs to the mitochondria in cells. These mitochondria process fat and protein for energy to the body. It appears as though NRTIs cause mitochondrial toxicity which may be associated with fat redistribution. In today's meeting it was said that mitochondrial DNA deletions and mutations can lead to clinical diseases--deafness, diabetes, myopathy.

Some patients with mitochondrial toxicity do not have lactic acidosis even after exercising.

Ribivarin is not likely to cause mitochondrial toxicity. It has a different mechanism of action (was told this offline at conference by researcher).

Motochondrial toxicity or DNA depletion can cause liver failure, nephropathy, lactic acidosis.

Interactions of drugs, environment and genes may cause mitochindrial toxicity. Genes may predispose a person to susceptibility to toxicity from drugs and environment.

Anti-oxidants might reverse mitochondrial toxicity in mice if the toxicity is due to immune dysfunction.

Toxins can accumulate in mitochondria. It's possible that NRTIs may accumulate in mitochondria. We don't know the answer to this. But it should be studied.