NATAP has extensive coverage of Metabolic Changes and Fat Redistribution information reported at the Retrovirus Conference. Graeme Moyle, MD, of the Chelsea and Westminter Hospital in London wrote a report that is available on the NATAP web site. As well, I'm filing this report and expect to follow with an additional report.

Following this brief summary of the study is a detailed report on the study presented by Lydia Ruiz on HIV-infected individuals on HAART with lipodystrophy (fat redistribution and elevations in triglycerides & cholesterol). Study participants were previously taking a PI with d4T/ddI. They had lipodystrophy and were randomized to remain on their regimen or substitute NVP for the PI, but continue the d4t/ddI. Week 48 results are available for 80% of the participants. Ruiz reported viral load suppression was essentially maintained. VL rebounded in 6-10% of study participants: 5/52 (10%) in the NVP arm, 3/54 (6%) in the PI arm. But she said that VL failure was observed in patients who had been exposed to sequential ART therapy. She reported significant improvements in cholesterol and triglycerides for those who switched to NVP. Antihistimines may prevent NVP rash. There were 3 rashes in NVP arm (2/3 stopped NVP). Although, there were no significant changes observed through anthropometric or DEXA measurements at month 12 in body changes, DEXA measurements showed a stabilization in the morphological changes in the NVP group. Ruiz said recovery might require a prolonged period. Ruiz measured L-carnitine and serum lactate at baseline and found them normal. In a subgroup 6-9 months after study started, 17% had L-carnitine deficiency and 8% had lactic acidemia. There were no apparent differences between the 2 treatment groups. Ruiz concluded L-carnitine and serum lactate were not useful as a surrogate marker for lipodystrophy syndrome, but there has been controversy over the reliability of generally available techniques for measuring lactate. In addition, at a Bristol-Myers meeting on Metabolics and Fat redistribution prior to Retrovirus, one researcher said that in 56/60 patients with lipodystrophy he has reviewed, lactate was not elevated. There were 6 (11%) cases of acute hepatitis in the NVP arm (4/6 stopped NVP). Ruiz said that patients reported improved quality of life which she said was due to improved simplicity of regimen. She also said the NVP regimen was 15-25% less expensive than PI regimen.

The primary objectives of this study are to assess the capacity of people switching from a protease inhibitor (PI) regimen to a nevirapine )PI-sparing regimen):

• for maintaining full HIV-RNA suppression
• to allow for immunological improvement

The secondary objectives were:

• to evaluate the body shape changes occurring in HIV patients who suffer clinical lipodystrophy, once PI regimens are substituted by PI-sparing regimens including d4T+ddI+NVP
• to analyze the variations in the metabolism of lipids and glucose observed in patients changing t PI-sparing regimens
• to determine if the modifications made in NRTIs produce any change in plasma L-carnitine and lactic acid over the follow-up
• to evaluate the impact of lipodystrophy and the subsequent treatment with a PI-sparing regimen on quality of life and cost-benefit ratio

Adult patients were included if they had clinicaly evident lipodystrophy; had been on HAART including PI for at least last 9 months; baseline CD4s >100;HIV-RNA <400 at least during 6 months. They were excluded if they had prior NNRTI experience.

Patients randomized in study had been receiving d4T+ddI+PI and were randomized to continue their regimen or switch to NVP with d4T+ddI.Individuals receiving NVP were given 15 day course of antihisatimine in order to prevent rash.

They recruited 106 patients and 80% have reached 48 weeks. The study is randomized, prospective and multi-center. The results below are based on these 80%. Monthly monitoring included plasma HIV-RNA, body shape changes, adherence counseling, adverse events. Every 3 months--CD4/CD8 T-cell counts, biochemistry, hematology, insulin, lactic acid, L-carnitine, dietetic counseling, anthrometric measures. Every 6 months--DEXA, GTT, photograph.

There were no differences in demographics at baseline between the two groups. The prior time that viral load was <400 was about 56± 31 months. The prior time on PI was 90-93 ± 29 months. Ruiz announced that 20% had normal chol. And trig. at baseline but percentages are different below. At baseline, in the NVP group (n-52)--CD4s were on average 650± 270; CD8s 1457± 540; total cholesterol 277± 42 mg/dL; triglycerides 270± 180 mg/dL; patients with normal cholesterol values 30%; patients with normal trig. values 39%; abnormal GGT 2, diabetes 3.

Patients in control PI group (n-54) had baseline measures of-- CD4s 569± 264; CD8s 1257± 436; total chol. 222± 45; patients with normal chol 39%; triglycerides 285 265± 205 mg/dL; 41% had normal trig. values; 4 GGT abnormal; and 5 diabetes.

• Rash-- 3 persons in the NVP arm (2/3 stopped NVP); none in control
• Acute hepatitis--6 in NVP arm (4/6 stopped NVP)
• Pancreatitis-- 1 in NVP arm and none in control am
• Anemia (AZT)-- 1 in NVP arm, none in control
• Polyneuropathy (d4T)-- 1 in NVP arm, none in control
• Nephrolithiasis-- none in NVP arm; 3 in control arm
• Diarrhea (>3)-- none in NVP arm, 4 in control

Viral rebound in 8 patients:

NVP arm 5/52 (10%)

Control group: 3/54 (6%)

Virologic failure was observed in patients who had been exposed to sequential different antiretroviral regimens prior to entry into the study.

About 20% of patients had been naÔve to HAART prior to the PI regimen they were on when they started this study:

• 8/52 (15%) in the NVP group
• 11/54 in control group (20%)

About 80% of patients had 2 or more prior ARTs before HAART:

• 44/52 (85%) in NVP group
• 43/54 (80%) in control group

About 80% of all patients had VL <20 copies/ml at week 48. Almost 70% in NVP group and 60% in the PI group had <5 copies/ml but no statistical differences were found.

The increase in CD4s and CD4% in both groups from baseline reached statistical difference. But the differences between the two groups at week 48 were not statistically different. They observed a significant decrease from baseline to week 36 in CD8s and CD8% in both groups. There was no statistical difference between the two groups at week 36.

From baseline to week 24, they found a slight increase in naÔve CD4s and CD8s (CD45RA+) in NVP-treated patients. But in the control group values remained stable.

When looking at memory CD4s and CD8s (CD45RO+) they observed no changes or slight increases.

• In the NVP group there was a statistical significant decrease in chol. from baseline to week 48. The program reported it to be from 227± 42 to 201± 35 (p<0.05). By week 12 the chol. declined a good deal. In the control group, chol.. value remained the same. There was no statistical difference between the two groups at week 48.
• A statistically significant decline in trig. was observed in the NVP group from 270± 180 to 207± 152 from baseline to week 48. By week 12 there was a nice decline. There were no changes in the control group. Again, there were no statistical significant differences between groups at week 48.

There were no changes in glucose observed. Abnormal fasting glucose (>120 mg/dl) at baseline and at week 24.

There has been some controversy over whether testing methods for lactate are accurate and reliable. Ruiz performed a cross-sectional study at 6-9 months of study (n-53; 28 in NVP group; 25 in control). Overall, mean baseline total L-carnitine was normal (35-66 umol/L) in patients in both groups.

9/53 (17%) of patients had L-carnitine deficiency (<35 umol/L): 4 patients in NVP group and 5 in the PI group.

4/53 (8%) patients had lactic acidemia (lactic acid >2 mmol/l., ratio lactate/pyruvate >20 and pH<7.35: 3 in NVP group and 1 in control group.

Ruiz reported no significant improvement from baseline nor differences between groups at week 48 in the 80% of patients evaluated.

However, Ruiz said patients receiving NVP showed by DEXA measurements a stabilization in the morphologic abnormalities. But there was no significant (statistical) body-shape changes through anthropometric or DEXA measurements at 12-months follow-up. If you look at both the DEXA and anthropometric changes from baseline through follow-up, you will note in a number of cases that the NVP arm showed a stabilization while for the individuals in the PI control arm the trend was a continuing worsening. For example, the waist circumfrance increased more for the control group than the NVP group (+1.09 vs +1.54). For the arm DEXA % - (-0.20± 6.7 in NVP vs -1.92± 5.7 in control). Ruiz and previously Joep Lange have suggested that recovery of altered body-shape changes with PT-sparing regimens might require a prolonged period of time longer than 1 year. In poster 52, Thierry Saint-Marc reported that 9 months after switching from d4T to AZT or abacavir there was a reversal in lipo-atrophy (fat depletion in limbs) improved: abdominal and mid-thigh subcutaneous fat increased by 32% and 36%, respectively (fat mass expressed in %); biceps, triceps, and suprailiac skinfold increased increased in similar proportions; 11 patients reported a major improvement in their fat distribution (4 admitted to have their body-shaped as prior to body changes) and 21 reported partial improvement.

Anthropometric and DEXA Changes

Anthropometric Changes and DEXA Changes

Ruiz reported no significant body-shape changes were found according to:

• baseline CD4 (cut-off: 500 cells/uL and 300 cells u/L)
• baseline Body mass index (BMI)- (cut-off: 22)

Ruiz reported an improvement in quality of life for those in NVP group compared to those remaining on PI. She said this was based mainly on the simplicity of the regimen. The costs for the NVP regimen were lower than for the PI group.

Ruiz concluded:

• viral suppression retained after switch to NVP (<20 copies/ml)
• switch associated with continuous increase in CD4s and decrease in CD8s
• significant improvements in cholesterol and triglycerides after switch
• antihistimines may prevent NVP rash
• Lactic acidemia and L-carnitine are not useful as a surrogate marker for lipodystrophy syndrome (but, as noted above in article some researchers have said they think methods for testing lactate levels are not reliable)
• DEXA measurements showed a stabilization in the morphological changes in the NVP group. So, although there were no significant changes observed through anthropometric or DEXA measurements at month 12, recovery might require a prolonged period
• Depending on PI prescribed cost reduction ranged from 15-15% per patient