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4th Lipodystrophy Workshop: metabolic abnormalities, HCV/HIV coinfection, fat loss, HCV/HIV coinfection
Michael Dube, MD, Indiana University School of Medicine, ACTG researcher
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The 4th International Workshop on Adverse Drug Reactions and Lipodystrophy (Sept 2002) in HIV was encouraging in that additional insights were presented that further our knowlege of how lipid disorders and insulin resistance come about. It was however, discouraging that few new therapeutic options were described. Clearly, insight into these mechanisms should ultimately lead to identifying effective interventions, and perhaps more importantly the development of antiretrovirals that lack these effects. The day of the kinder, gentler regimen appears to be approaching. If we know HOW a drug affects metabolism in a cell, looking for similar drugs that still work against HIV but lack these effects on metabolism in the cell, will enhance our ability to identify drugs that are easier on the system.
Leptin is a hormone that is produced by adipocytes (fat cells) that improves many metabolic problems (such as elevated lipids, insulin resistance, and accumulation of fat in the liver) when given to non-HIV-infected patients with certain forms of lipodystrophy. Such patients tend to have very low levels of leptin. Because patients with HIV-related lipodystrophy (particularly those with extensive loss of subcutaneous fat, the fat beneath the skin which when lost leads to facial thinning and prominent veins and muscles in the arms and legs) tend to have lower leptin levels, leptin may be a potentially useful intervention. Leptin's benefits though may be limited to those with only very low leptin levels. Currently, only injectable forms of leptin are available. Notably, leptin treatment is not expected to result in improvement in loss of fat (lipoatrophy), only replace the leptin that the lost adipocytes are no longer making. So, while it may improve cardiovascular risk and lessen the chances of developing diabetes, it probably won't change people's appearances.
When given to mice receiving ritonavir, leptin resulted in lowered cholesterol and less liver fat (Riddle et al, abstract #5). They also reported that feeding a diet rich in polyunsaturated fats (PUFA), ritonavir-fed mice unexpectedly had even greater increases in cholesterol and triglycerides. These resutls suggest that leptin administration may be helpful in reversing PI-induced lipid disorders and provide a potential rationale to try this intervention in humans. Studies of leptin treatment are starting in individuals with HIV lipodystrophy. It may be that only those with very low leptin levels to begin with will have much benefit, but studies are clearly needed.
Problems with the amount of, the production of, or the function of, the intracellular protein SREBP-1 (sterol regulatory element binding protein) continues to receive a great deal of attention. This protein is important because increased levels of it in the cell generally lead to increased activity of PPAR-gamma (a protein that aids insulin sensitivity and is important to the development of fat cells, ie the conversion from a pre-adipocyte to a fully functioning adipocyte) and enzymes that synthesize lipids in the liver. So, on one hand decreased activity of SREBP-1 could lead to problems in development of normal fat cells, and increased activity may lead to increased production of cholesterol and triglycerides in the liver.
Capeau (abstract #1) reported that the lamin proteins (which are important in certain forms of non-HIV lipodystrophy) were disturbed in adipocytes exposed to indinavir. These lamin proteins are important in getting SREBP-1 to its active site inside the nucleus of the cell. While this finding doesn't necessarily lead to an intervention that can fix the lamins, if we know how and where the protease inhibitors or other drugs are affecting the cell, it will aid in identifying drugs that do not have this effect.
Yaresheski (abstract #7) treated rats who are normally destined to develop diabetes (Zucker diabetic fatty rats) with nucleosides (NRTI), indinavir, or both. The development of diabetes was accelerated by indinavir and adding NRTI tended to accelerate this tendency further. These results suggest that there are additive, or synergistic effects of the different HAART components in predisposing to diabetes. It will be interesting to apply this rat model to a variety of HAART regimens to determine which components facilitate the development of diabetes the most.
Koster (abstract #6) showed that the PI indinavir reduced the pancreatic B-cell's ability to take up glucose, which is necessary to induce the cell to release insulin, and thus reduced insulin release by the cells. Reduced insulin release, or insulin secretion, also occurred in rats treated with indinavir, in a manner similar to what occurs in type 2 diabetes. In most people with type 2 diabetes, insulin resistance occurs, but an inadequate response of the pancreas to secrete sufficient insulin to overcome insulin resistance must also occur in order for the blood sugar to be elevated. The diabetes that can be seen during PI use thus could be promoted by both reduced insulin secretion and increased insulin resistance that could be a direct effect of the drugs. Indinavir was the most potent PI studied at reducing glucose uptake by B-cells, with nelfinavir followed by amprenavir as being progressively less potent. As other studies have shown, the PI drugs clearly have different metabolic effects in humans and in various in vitro and animal models. The search for the "metabolically clean" PI continues, but data presented at this conference and other recent meetings suggest that the investigational BMS PI atazanavir might ultimately be shown to be that PI.
Parker (abstract #10, first author Wang), a scientist from BMS, reported the metabolic effects of the new BMS PI atazanavir in a variety of in vitro models. In general, atazanavir tended to lack or have lesser effects on metabolism in these assays. Not all PIs were reported in every experiment, and in several instances the in vitro study results did not seem to correlate well with what is known about drugs' clinical effects in humans. Nonetheless, these results provide a rationale to further study the metabolic effects of atazanavir in humans, in the hopes that this PI may be proven distinct from the available agents.
Along those lines, several clinical studies have now reported lesser or no lipid effects with atazanavir. In contrast to nelfinavir, naive subjects initiating atazanavir-based ART did not develop elevations in total cholesterol, LDL-cholesterol, or triglycerides. Murphy (abstract #15) reported a follow-up study where subjects initially assigned to nelfinavir treatment were switched to atazanavir. Elevated lipid levels among these subjects tended to normalize upon switching to atazanavir. If similar results occur with regards to insulin resistance and other adverse metabolic effects, then perhaps atazanavir may lack the adverse effects of other PIs. A poster from Sension (abstract 36) reported the effects of atazanavir-AZT-3TC and efavirenz-AZT-3TC on about 800 ART-naive subjects. Fasting glucose, insulin, and C-peptide increased at week 24 in both groups. Although the absolute changes appeared small, statistics were not reported and the customary measure of insulin resistance (HOMA-IR, which is calculable using these fasting values and involves the product of glucose X insulin) was also not reported. While there appeared to be no difference between the glucose metabolism measures between efavirenz (which is generally held to lack effects on glucose metabolism) and atazanavir, more data are needed. While atazanavir appeared to have lesser effects on total and LDL-cholesterol and triglycerides, efavirenz appeared to have greater effects on increasing HDL-cholesterol. Again, statistical comparisons of the lipid results was not provided in this BMS-sponsored study.
Editorial note: Sension reported that before starting study drugs fasting glucose for the patients receiving atazanavir was 90 mg/dL and it was 92 mg/dL after 24 weeks. Fasting insulin was 11 uU/mL at baseline and 12 after 24 weeks. C-peptide was 2.2 ng/mL at baseline and 2.4 at week 24. Link to article on this study in Lipodystrophy Workshop Reports on NATAP website:
www.natap.org/2002/lipoWorkshop/day2.htm
While hepatitis C is generally considered to cause insulin resistance and thus predispose to diabetes mellitus, data presented by Hadigan (abstract #34) suggest that hepatitis B may predispose to insulin resistance and diabetes mellitus. Data are needed to see if there is an independent role of hepatitis viruses in these disorders, or whether insulin resistance is primarily mediated by viral hepatitis-associated lipoatrophy. It will be of great interest to see if successful treatment of hepatitis B or C results in amelioration of metabolic disturbances. (editorial note: HCV therapy should in theory improve the liveršs functioning and metabolic abnormalities. Small studies suggest that due to an impaired liver associated with HCV or HCV/HIV coinfection HCV treatment could result in increased cholesterol and triglycerides while prior to HCV treatment lipids and glucose were lower (ICAAC 2002 abstract H-1723).
Editorial Note: Hadigan found HIV+/HCV+ and HBV/HIV coinfected patients were more likely to have glucose abnormalities than HIV+ patients without hepatitis. Link to NATAP report on this study: http://www.natap.org/2002/lipoWorkshop/day9.htm
A variety of circulating substances have been found to correlate with insulin resistance in subjects with lipodystrophy. The problem with many of these correlations is that, as is the case with leptin (see above), while it may be abnormal in an individual it may only be a marker for some other disturbance that is really the problem. For example, if leptin is low in patients with loss of subcutaneous fat and insulin resistance, is the low leptin responsible for the insulin resistance, or is loss of fat responsible for the insulin resistance and the low leptin is just a result of fat loss? Vigouroux (abstract #33) reported leptin, adiponectin (another adipocyte-derived hormone with systemic effects on glucose metabolism), and measures of the TNF-alpha system (TNF-alpha is an inflammatory cytokine that has been implicated in insulin resistance and lipoatrophy) in men with lipohypertrophy, lipoatrophy, and mixed hypertrophy/atrophy. Correlations were found between insulin resistance and lower leptin and higher adiponectin, for the group as a whole. But if the assertions of Carl Grunfeld and the FRAM study are correct, and only lipoatrophy is associated with HIV and its treatment in men and fat accumulation is not increased and only reflects what normally occurs in the general population, then dividing groups based on the presence/absence of lipohypertrophy becomes somewhat artificial. Thus, looking at a group with lipoatrophy alone (or lipoatrophy without regard to lipohypertrophy) becomes the most "pure" way to isolate HIV- and HIV treatment-specific abnormalities. So, when Vigouroux looked at only those with lipoatrophy, she reported that leptin, adiponectin, and metabolic parameters were not different and insulin resistance only mildly increased. Thus, it remains unclear the associations of leptin and adiponectin to HIV-specific metabolic problems. The most significant alterations in that study were among those with both lipoatrophy and lipohypertrophy. Since many studies of "lipodystrophy" focus on subjects with both manifestations, care must be taken not to generalize results from studies of these mixed disorders to the more HIV-specific lipoatrophy disorders.
CONCLUSIONS
We are beginning to understand the mechanisms leading to drug- and disease-induced insulin resistance and the closely associated lipoatrophy. This understanding should eventually lead to interventions to test and ARV drugs that lack these effects. Unfortunately, progress has been slow and the relative lack of treatment trials underscores this fact. Hopefully trials with leptin will prove successful but are unlikely to affect lipoatrophy itself. Further data are needed with atazanavir to confirm promising initial results.
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