Multi-Center, Randomized, Open-label, Comparative Trial of the Clinical Benefit of Switching the Protease Inhibitor To Nevirapine in HAART-Experienced Patients Suffering Lypodystrophy

Multi-Center, Randomized, Open-label, Comparative Trial of the Clinical Benefit of Switching the Protease Inhibitor To Nevirapine in HAART-Experienced Patients Suffering Lypodystrophy
authors: LRuiz and others for the Spanish Lipodystrophy Study Group

This study was presented at the final session at the Thursday Late Breaker Sesssion. It compares a group of patients who reported lipodystrophy while taking a PI regimen and had undetectable viral load by either the standard viral load test (Roche Amplicor <400 copies/ml) or the Roche ultrasensitive test (<50 copies/ml). Patients were randomized to remain on their current regimen or switch to a nevirapine regimen with d4T+ddI. Ruiz reported preliminary results at the 12 week point in the study which is planned to continue for 48 weeks. Although the follow-up time of 12 weeks is short, the results are promising. Reductions in HIV RNA have been maintained, cholesterol and triglycerides are reduced for those who switched to the nevirapine regimen, and patients and doctors report improved lipodystrophy. The following tests were given at baseline and every 3 months- CD4s, DEXA, triglycerides, cholesterol, AST/ALT, fasting glycemia, BIA (bioelectric impedance), anthropometric changes.

All patients who received the nevirapine regimen were given antihistimines to prevent the NVP rash. Investigators reported there was no evidence of rash in either randomized group.

The primary objectives of this study are: (1) to evaluate the body-shape changes occurring in HIV patients suffering from clinical lipodystrophy, once protease inhibitor containing regimens are substituted by PI-sparing regimens (PISRs) including d4T+DDI+NVP (nevirapine or Viramune- brand name); and (2) to assess the capacity of the PISR (containing NVP) to maintain plasma HIV RNA fully suppressed.

The secondary objectives were - (1) to evaluate the clinical utility of different techniques used to measure the body fat composition (DEXA, bioelectric impedance -BIA, anthropometric measurements, etc); (2) analysis of the variations in the metabolism of lipids and carbohydrates in patients changing to PISRs; and (3) impact of lipodystrophy and subsequent treatment with a PISR on the quality of life, drug adherence and cost-benefit ratio.

The planned enrollment is for 100 patients (50 per arm) and at present 62 patients have been enrolled. Investigators used separate questionaires for patients and their treating physicians to get both perspectives. The patient questionaire asked about any changes in body appearance without reference to PI therapy. Questions focused also on specific changes in the regions involved in lipodystrophgy (LPD). The physician questionaire asked if the patient suffered fat wasting in the face, buttocks, arms or legs, with or without abnormal fat deposits in the abdomen, interscapsular region ("buffalo hump"), perotid glands or breasts.

Patients qualified for study if they had clinically evident lipodystrophy, had been on a PI regimen for at least 9 months, had a baseline CD4 count >100, and their HIV-RNA was <400 copies/ml for at least 6 months. Patients were excluded if they had experienced an opportunistic infection within the prior 4 weeks, and if they had previous NVP experience. Patients were randomized to receive DDI+D4T+NVP or to continue their current PI containing regimen (D4T+3TC+PI).

Baseline Characteristics
no major differences between two groups

Nevirapine PI Regimen

N 15 14

Current Follow-Up 12 weeks 12 weeks

Time taking PIs (months) 23 ± 7 24 ± 8

Time VL<400 copies/ml 17 ± 7 14 ± 8

CD4 count 632 ± 200 574 ± 233

HIV-RNA <400 <400

Total Cholesterol 222 ± 51 201 ± 37

Triglycerides 266 ± 138 256 ± 163

**Baseline Characteristics**
no major differences between two groups
	Nevirapine	PI Regimen
N	15	14
Current Follow-Up	12 weeks	12 weeks
Time taking PIs (months)	23 ± 7	24 ± 8
Time VL<400 copies/ml	17 ± 7	14 ± 8
CD4 count	632 ± 200	574 ± 233
HIV-RNA	<400	<400
Total Cholesterol	222 ± 51	201 ± 37
Triglycerides	266 ± 138	256 ± 163

Of the so far randomized patients most had been on an indinavir regimen (20/29). Six had been on a nelfinavir regimen, and 3 were taking RTV+SQV. They were relatively evenly dispersed between the two arms.

Twenty-one patients (11 in NVP group, 10 in PI group) completed 12 weeks and their data was available for this analysis. Plasma HIV-RNA was maintained <400 copies for patients in both groups during the 12 week follow-up. 17/21had plasma VL <50 copies/ml and this was sustained for the 12 week follow-up. Regarding changes in cholesterol and triglycerides, individuals receiving the nevirapine regimen had their cholesterol significantly reduced from a baseline value of 230 ± 46 to 196 ± 54 (P<0.05). 7 out of the 11 in the NVP group normalized their cholesterol and 1/10 normalized it in the PI group. Triglycerides levels decreased in the NVP group but the changes did not reach statistical significance. Abnormal fasting glucose (>120 mg) was seen in one person in the NVP group both at baseline and week 12. AST/ALT did not show significant changes. Ruiz reported the quality of life (p=0.017) and both the physician's and patients estimation of body shape changes improved siginficantly (P=<0.05) in the NVP group. Although it did not reach statistical significance at week 12, improvements were reported in BIA, DEXA, and anthropometric measures.

Again, 12 weeks is premature to draw too many conclusions. It is important to see if these preliminary positive results will be maintained over the longer term. Of particular importance is--will viral load reductions continue to be maintained for all? And, will improvements in LPD and reduced lipids be maintained?