Preliminary Study on Changes in Lipids, Insulin and Body Changes During 12-Week STI: triglycerides & cholesterol declined but CD4s decreased, viral load increased, some developed clinical decline (1 person had PCP)
     R Hoh(1), J Troiano(2), M Christiansen, SG Deeks(1), MK Hellerstein(3) Univer of Cal-SF(1), Gladstone Institute of Virology & Immunology-SF(2), Univer of Cal at Berkely(3)

This study was presented at the Lipodystrophy Workshop in Toronto in September 2000. The study was designed to look at STIs, and so it was not designed to see if stopping therapy for HIV improves body changes (lipoatrophy & fat accumulation in abdomen) and metabolic changes (cholesterol, triglycerides, glucose, insulin). Therefore, the patients who entered the study did not have very high lipid values or high fasting insulin & glucose. And on a whole the study population did not have a high incidence rate of lipoatrophy & abdominal fat accumulation. Given these limitations triglycerides improved appreciably within the first 4 weeks of stopping therapy. Cholesterol clearly improved 16-20%. Glucose & fasting insulin were on average normal in patients before the study started. The study investigators did not see improvements in body changes but only 6/17 patients had lipoatrophy at baseline, and only 7/19 had abdominal fat accumulation. In addition, the authors said evaluation is limited also because of the difficulty in finding objective measures of body changes. Using waist:hip ratio, they saw no improvement on average but waist:hip ratio has limitations discussed below. And since so few patients in the study had body changes mean values of overall study population may not identify improvements. This study did not report 12-week measures on the individuals who had lipoatrophy or fat accumulation at baseline. In addition, important potential risks of stopping therapy were seen: on average CD4s decreased 30% during the STI, and on average viral load increased from 4.4 log (about 25,000 copies/ml) to 5.1 log (about 125,000 copies/ml). In addition, although patients were reported to be clinically stable before stopping therapy several patients developed clinical complications, which are briefly enumerated below (1 person developed PCP).

The 19 male subjects selected for the study had on average 135 years of documented HIV infection and were an older group of men (427 years age). Patients were heavily pre-treated with an average of 73 years of NRTI & 31 years of protease inhibitor therapy use. Initially 23 patients were enrolled into study--4 patients were excluded one due to high dose androgen therapy started during study, 3 due to pre-existing IDDM; one person stopped his PI therapy but decided to continue his NRTIs.

Prospective measurements were obtained at San Francisco General Hospital from patients entering a STI study. Eligible patients had taken a PI based regimen for at least 12 months and had viral load above 2500 copies/ml. Fasting blood tests were taken at baseline and every 4 weeks for 12 weeks. Body composition measured by single frequency bioelectrial impedance analysis (BIA, RJL Systems, Inc), and anthropometrics (performed by the same examiner) were measured at baseline and at 12 weeks off therapies.

RESULTS

Rapid improvements in fasting triglycerides, total cholesterol and LDL cholesterol (bad cholesterol) were seen with significant improvements occurring within first 4 weeks after stopping.

Cholesterol decreased by 16% by week 4 (from 19442 to 16724 mg/dl; p<0.001, n=18), and by 20% by week 12 (15526; p<0.0001, n=19).

Fasting insulin: 6/17 patients (35%) were hyperinsulinemic (>20 mU/ml) at baseline. Mean fasting insulin did not change significantly (19.6-19.5 mU/ml, n=17), probably because so few patients had elevated fasting insulin.

Fasting glucose: average baseline fasting blood glucose measures were also within normal range (8712 mg/dl, n=19) and did not change during the study).

Body composition: 6/19 patients self-reported abdominal fat gain and 7/19 reported peripheral lipo-atrophy. Average waist hip ratio was elevated at baseline (0.970.07). This is a ratio of the waist measure to the hip and suggests a fatter stomach. The effectiveness of this measure has been questioned because a person could have lost fat in the hip area and therefore would show a greater waist:hip ratio suggesting a fatter stomach which could be due to fat depleted hip area.

Weight gain: patients gained an average of 1.30.5 kg (p=0.04, n=19). By BIA, 77% of the weight gain was from lean body mass (1.00.7 kg, p=0.02, n=19). Body fat increased 0.3 kg, but was not significant.

Conclusions  
Since average waist:hip ratio did not change in 12 weeks off therapy this suggests the abdominal fat accumulation did not improve. But, as mentioned above using BIA has limitations. The authors concluded that objective assessments of body composition changes are difficult to assess. Improvements in body changes may take longer than 12 weeks. In a number of switch studies in which patients with lipoatrophy & fat accumulation were not to show improvements by objective measures after being followed for 1 year+ after switching from a PI to PI-sparing regimen. This suggests 1 year or longer after a switch is not long enough to see an improvement or that in general body changes may not be reversible just by switching therapy. However, those studies looked at individuals who did not stop therapy, they just switched therapy. It's possible stopping for longer than 12 weeks might improve body changes. In addition, drug therapy interventions such as antidiabetic drugs are being researched with the hope that they may help improve body changes. Continuing lipodystrophy research may be able to uncover therapeutic interventions that reverse body changes. Research appears to have picked up momentum and funding. Although it appears to be a very complex situation, ongoing research may be able to sort out the causes for the various manifestations of lipodystrophy.

You can see additional reports from the Lipodystrophy Workshop on the NATAP web site. These reports include special reports written by Graeme Moyle - "Perspectives on Lipodystrophy--what have we learned about the cause" and by Carl Fichtenbaum on: "Evaluation & Management of Hyperlipidemia in HIV Infection". Soon to come--special report by Andrew Carr on bone problems.

Here's the link: Selected Reports from The Lipodystrophy Workshop in Toronto

This paper did not report final patient self-report on if they saw any improvements. The authors stressed that study patients were selected for STI and not for study of body composition and metabolic change. That's why only 6/19 had abdominal fat accumulation, only 7/19 had lipoatrophy, average fasting glucose was normal, and only 6/17 had elevated fasting insulin. The average baseline cholesterol & triglycerides levels were not very elevated (343 triglycerides, 194 cholesterol).

Still, interrupting therapy led to a rapid decline in triglycerides and a clear improvement in total and bad (LDL) cholesterol.