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  3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Athens, Greece - October 2001
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Amprenavir and Effects on Metabolics & Lipoatrophy
Selected Highlights From Day Two - Wednesday October 24
Written by Jules Levin
  There were 2 interesting studies about amprenavir today. Michael Dube, from the ACTG and Indiana University, reported on "Prospective 48-week Intensive Metabolic Study of Amprenavir-based Therapy in HIV-infected Patients". He reported finding no significant change in fasting glucose, fasting insulin. Insulin sensitivity (resistance) did not fall significantly by week 8 or week 24, but was decreased at week 48. Six patients experienced new or worsening glucose tolerance by week 24, but fasting hyperglycemia (sugar in blood) did not occur. Interestingly, patients did gain a good deal of weight in the trunk as well as in the periphery. He did not measure visceral fat. Most of the patients in the study were hispanic (10 hispanic, 2 black, 2 white). Cholesterol and triglycerides increased, tribglycerides by 90%. These findings, in addition to the findings from the second study Iıll describe below, suggest that amprenavir might be a good regimen option for patients with diabetes or a propensity for diabetes. And also for patients with lipoatrophy or a propensity for lipoatrophy. However, the study was only 48 weeks. Although the data at week 48 is encouraging in terms of not developing lipoatrophy, it is preferable to see longer term data, as lipoatrophy can develop in year two of therapy. Week 48 self-reported body image questionaires showed either no changes or increases in the amount of flesh in the face and limbs. Dube reported insulin resistance appeared late following weight gain, particularly trunk fat, but loss of limb fat or facial lipoatrophy did not occur. Unlike the short-term insulin resistance reported with indinavir at yesterdayıs session & reported in my first report, these late changes appear to be related to increased adiposity (fat in belly) rather than a direct drug effect. Other researchers I spoke with feel the insulin resistance results seen here are encouraging and credible, but preliminary. They would like to see further confirmatory study. They would like to measure amprenavir blood levels to make sure there was enough amprenavir on board when blood work evaluating glucose & insulin resistance was sampled. Amprenavir was administered at 6am and blood work done at 8am. They also were unsure if the insulin resistance testing Dube used was appropriate. Although the study is small the metabolic testing was intensive.
Dube reported the rationale for this study: in vitro data showed amprenavir (APV) had lesser effects on lipolysis (fat breakdown by the body), and pre-adipocyte (fat cells) differentiation (less negative effects on fat cells than other protease inhibitors. Animal data suggested less effects on lipid (cholesterol, triglycerides) and glucose metabolism in mice. APV showed fewer "retinoid symptoms" and fat redistribution compared to indinavir in a human study.
14 stable, non-diabetic, PI-naïve adults (12 men, 2 women) with CD4 >100, HIV-RNA >500, fasting blood sugar <110 mg/dL, no OI, no meds affecting glucose metabolism received APV 1200 mg twice daily + abacavir 300 mg twice daily + 3TC 150 mg twice daily. Two patients with prior 3TC received d4T. Some patients had AIDS. They were prospectively evaluated by oral glucose tolerance test (OGTT) and IV-GTT, lipid profile measures, and DEXA at weeks 0-24-48 weeks after starting therapy. They kept 72-hour diet diaries at weeks 0-8-24-48 and Dube told me that the patients did not eat fatty meals, which could explain why they gained weight.
Baseline demographics- Average age 38, body mass index 25.9, median CD4s at entry 261 (range100-500), median CD4 gain at week 48 (170), median HIV viral load 5.02 log (100,000 copies/ml), proportion <400 HIV-RNA at week 24 12/14 86%, <400 at week 48 11/11 (100%).
  • Fasting glucose was unchanged throughout the study: 95 at baseline and 94 at week 48 (p=.97)
  • Fasting insulin was 9.6 at baseline and 13 at week 48 (p=.08)
  • 120-minute glucose was 114 at baseline, 139 at week 8, 146 at week 24, and 122 at week 48 (p=.35)
  • Insulin sensitivity did not change from baseline (4.9) to week 8 (4.2) and week 24 (4.7), but was significantly less at week 48 (3.0)
  • Free fatty acids increased at week 24 but declined to baseline levels by week 48

Body Composition Changes by DEXA (n=11)
  • Body weight (kg) increased 4.9 from 70.7 to 75.6 (p=0.3); about 2.2 pounds per kg
  • Total body fat (kg) increased 3.4 from 15.7 to 19.1
  • Total body lean (kg) increased 1.5 from 52.6 to 54.1 (p=0.7)
  • Total bone mineral content (kg) increased 0.04 from 2.38 to 2.42 (p=0.2)
  • Trunk fat (kg) increased 2.2 from 8.5 to 10.6 (p=0.1)
  • Limb fat (kg) increased 1.2 from 6.4 to 7.5 (p=0.054)
  • Trunk:limb fat ratio increased 0.09 from 1.40 to 1.49 (p=0.005)

Self-perceived body changes as assessed by standard questionaire
  • At baseline, 6/16 (38%) considered themselves underweight, 8/16 (50%) "just right", and 2/16 (13%) overweight
  • At week 48, no subject considered themselves underweight, 5/11 (45%) considered their weight "just right", 6/11 (55%) considered themselves to be somewhat or very overweight
  • "Do you think that your appearance has changed since you began study treatment": 3/11 (27%) no change in belly size, 8/11 (64%) noticed an increase
  • At week 48, 5/11 (45%) reported no change in the amount of flesh in the face and 6/11 (55%) noticed a gain. Similarly, 7/11 (64%) noted no change in leg size, 4/11 (36%) reported an increase
  • No subject reported a decrease in the size of the legs or a decrease in the amount of flesh (lipoatrophy) in the face since starting study medications

  • Total cholesterol, triglycerides (by 90%), LDL-c (bad Cholesterol), HDL-c (good cholesterol) increased significantly
  • An increase in bone mineral content occurred
  • Insulin resistance appeared late (at week 48), following and probably due to weight gain, particularly trunk fat
  • APV-based HAART did not cause short-term (within 24 weeks) insulin resistance

Differential Effects of 3 Protease Inhibitors (indinavir, nelfinavir, amprenavir) on Insulin Sensitivity, and Fat Cells & Lipoatrophy
Jacqueline Capeau from Faculte de Medecine St-Antoine in Paris reported on -
"Differential in vitro Effects of Indinavir, nelfinavir and Amprenavir on cell differentiation, Insulin Sensitivity, and Apoptosis (cell death) and the Preventive Impact of Rosiglitazone"
Capeau offered the following background: protease inhibitors used in the treatment of HIV have been causally associated with lipodystrophy and insulin resistance both in vitro (in the test tube) and in vivo (humans). We previously showed that indinavir impairs adipocyte differentiation (fat cell production) and induces insulin resistance (through a mechanism that probably involves SREP-1 nuclear entry).
The objective of the study was to examine the relative impact and mechanism of action of indinavir, nelfinavir, and amprenavir on adipogenesis (fat cell production), response to insulin, and apoptosis (cell death).
  • The 3 protease inhibitors inhibited adipocyte differentiation with a rank order gradually decreasing from indinavir to nelfinavir and amprenavir
  • Insulin sensitivity was measured by the activation of MAPK and Akt/PKB. PIs inhibited insulin action on MAP and Akt/PKB kinases with half maximally effective concentrations for indinavir, nelfinavir, and amprenavir. This suggests to me that PIs inhibited insulin effectiveness. In personal conversation, Capeau told me that amprenavir did not lead to insulin resistance.
  • Long-term treatment with indinavir and nelfinavir promoted cell apoptosis
  • Amprenavir did not lead to apoptosis
  • Rosiglitazone prevents the effect of protease inhibitors on cell differentistion, resistance to insulin, and programmed cell death
She summarized by saying that rosiglitazone could represent a therapeutic possibility.