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12th Conference on Retroviruses and Opportunistic Infections February 22-25, Boston

12th Conference on Retroviruses and Opportunistic Infections February 22-25, Boston.

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12th Conference on Retroviruses and Opportunistic Infections February 22-25, Boston

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  1. 12th Conference on Retroviruses and Opportunistic Infections February 22-25, Boston A randomized open study comparing the impact of reducing stavudine dose vs. switching to tenofovir on mitochondrial function, metabolic parameters, and subcutaneous fat in HIV-infected patients receiving antiretroviral therapy containing stavudine. Milinkovic A,López S, Miro O, Vidal S, Arnaiz JA, Blanco JL, Leon A, Larrousse M, Lonca M, Laguno M, Mallolas J, Miro JM , Gatell JM, MartinezE. Hospital Clínic, Barcelona anamilinkovic@hotmail.com

  2. Background • Peripheral lipoatrophy and dyslipidemia may complicate stavudine-containing antiretroviral therapy. Mitochondrial dysfunction has been suggested as at least one potential underlying mechanism in the pathogenesis of peripheral lipoatrophy and dyslipidemia associated with stavudine. • Available data suggest that tenofovir has little effect on mitochondrial gamma polymerase and a lower risk for peripheral lipoatrophy and dyslipidemia than stavudine. Switching from stavudine to abacavir has shown an improvement on peripheral lipoatrophy without significant effects on plasma lipids. To date, the effects of switching from stavudine to tenofovir are unknown. • Scarce data suggest that reducing stavudine dose may be as effective as standard dose but less toxic, although the effects of reducing stavudine dose on peripheral lipoatrophy and dyslipidemia are unknown.

  3. Patients and methods Type of study Prospective, randomized, open-label study Inclusion criteria Clinically stable HIV-infected patients receiving antiretroviral therapy containing stavudine 40 mg bid with a plasma HIV RNA <200 copies/mL for at least the previous 6 months . Treatment arms (while preserving the remaining drugs unchanged) • d4T dose reduction to 30mg bid d4T 30 arm • Switch d4T to TDF TDF arm • Continue d4T 40mg bid d4T 40 arm

  4. Methods Follow up 6 months Study visits: • Baseline, 1, 3 and 6 months: glucose , triglycerides, total, HDL and LDL cholesterol, plasma HIV–1 RNA, CD4 cells count and lactate. • Baseline and 6 months: mitochondrial analysis and body composition (DEXA). • Statistical analysis: Kruskal-Wallis test, Bonferroni adjustment for the significance level , McNemar test , Fisher Chi-square test .

  5. Methods - mitochondrial function Mitochondrial analysis in PBMCs • Mitochondrial DNA content was determined by quantitative real time PCR. • Mitochondrial Mass was determined through the measurement of Citrate Synthase (CS) Activity by spectrophotometry. • Oxidative activity of intact cells (spontaneous cellular oxidation) was determined by polarography. • Enzyme activity of the mtDNA-encoded complexes of the OXPHOS system (Complex IV and Complex III activity) was determined by spectrophotometry. • Results were expressed as absolute values and as percentages with respect to the baseline value.

  6. Baseline characteristics D4T-40 (n=22)D4T-30 (n=19)TDF (n=17) Age (mean±SD) 45 ± 10 43 ± 7 46 ± 9 CD4 (/mm3) HIV diagnosis 174 ± 120 197 ± 199 246 ± 207 Baseline study 568 ± 245 695 ± 317 529 ± 325 PIs (n, %) 7(32) 1(5) 2(12) NNRTIs (n, %) 13 (59) 17(89) 13(76) ddI (n, %) 6(27) 4(21) 1(6) HIV-1 RNA (copies/mL) HIV diagnosis 278000 273000 202000 Baseline<20 copies/mL 22 (100%) 19 (100%) 17 (100%)

  7. Baseline laboratory dates D4T-40 (n=22)D4T-30 (n=19)TDF (n=17) P Tgl (mg/dL)141 ±116 207 ± 189 242 ± 234 0,15 Chl total (mg/dL) 222 ± 35 227 ± 40 205± 49 0,96 LDL-Chl (mg/dL) 142 ± 29 141 ± 33 137 ± 29 0,87 HDL-Chl (mg/dL) 48 ± 11 47 ±15 47 ± 9 0,65 Lactate (mg/dL) 13 ± 5 15 ±3 13 ±5 0,89

  8. Baseline fat mass(DEXA) D4T-40 (n=22)D4T-30 (n=19)TDF (n=17) P Peripheral (g) Median 3204 3295 4438 0,57 IQR2238-4797 2785-4351 2585-5619 Truncal (g) Median 7510 8220 9107 0,27 IQR5742-10375 6833- 12090 7769-11850 Total (g) Median11843 11459 14000 0,31 IQR 8674-15061 9851-16990 10673-18848

  9. Baseline lean mass(DEXA) D4T-40 (n=22)D4T-30 (n=19)TDF (n=17) P Peripheral (g) Median 25218 24331 25212 0,38 IQR22088-29285 21945-29121 23110-27143 Truncal (g) Median 25184 26205 26652 0,55 IQR 23035-28547 24495-28146 25238-28591 Total (g) Median55008 53896 56134 0,75 IQR 48792-62588 52531-59918 53129-59874

  10. Triglycerides Percentage of change from baseline % d4T 40 d4T 30 TDF At 1 Mo:p-value=0.133 At 3 Mo:p-value=0.093 At 6 Mo: 30 vs.40:p-value=0.638 30 vs.TDF:p-value=0.152 * 40 vs. TDF=0.0390

  11. d4T 40mg d4T 30mg TDF 300mg Cholesterol 30 vs. 40: p-value=0.939 30 vs. TDF: p-value=0.073 *40 vs. TDF: p-value=0.020 6 -month ∆ Chl (mg/dL) Baseline

  12. d4T 40mg d4T 30mg TDF 300mg LDL-Cholesterol Global p-value=0.078 Baseline 6 -month ∆ LDL-Chl (mg/dL)

  13. d4T 40mg d4T 30mg TDF 300mg HDL-Cholesterol Global p-value=0.788 Baseline 6-month ∆ HDL-Chl (mg/dL)

  14. Lactate Percentage of change from baseline d4T 40 d4T 30 TDF * % At 6 Mo: p-value=0.159 At 1 Mo: p-value=0.326 * At 3 Mo: 30 vs.40:p-value=0.466 30 vs.TDF:p-value=0.344 * 40 vs. TDF=0.015

  15. Change in mean CD4 cell count CD4 cell (cells/mm3) d4T 40 d4T 30 TDF p-value=0.134 p-value=0.762 p-value=0.620

  16. % of patients with HIV-1 RNA<20 p-value=0.328 p-value=0.764 p-value=0.134 d4T 40 d4T 30 TDF

  17. d4T 40mg d4T 30mg TDF 300mg Peripheral fat 30 vs. 40: p-value=0.124    30 vs. TDF: p-value=0.902 *40 vs. TDF: p-value=0.003 ∆ weight 6-month (g) Baseline

  18. d4T 40mg d4T 30mg TDF 300mg Peripheral fat  30 vs. 40: p-value=0.097    30 vs. TDF: p-value=0.768 *40 vs. TDF: p-value=0.003 6-month ∆ median (%) Baseline

  19. d4T 40mg d4T 30mg TDF 300mg Total fat 30 vs. 40: p-value=0.168 30 vs. TDF: p-value=0.998 *40 vs. TDF: p-value=0.032 ∆ weight 6- month (g) Baseline

  20. d4T 40mg d4T 30mg TDF 300mg Total fat 30 vs. 40: p-value=0.179  30 vs. TDF: p-value=0.988   *40 vs. TDF: p-value=0.029 6-month median ∆ (%) Baseline

  21. d4T 40mg d4T 30mg TDF 300mg Total lean mass *40 vs. TDF: p-value=0.016*30 vs. TDF: p-value=0.008 30 vs. 40: p-value=1.000 Baseline 6- month median ∆ (%)

  22. d4T 40mg d4T 30mg TDF 300mg Total lean mass   30 vs. 40: p-value=0.995 *40 vs. TDF: p-value=0.013 *30 vs. TDF: p-value=0.007 Baseline ∆ weight 6- month (g)

  23. 120 2.5 100 2.0 80 (ND2/18S rRNA) (nmol/min/mg) Citrate synthase activity 60 1.5 40 1.0 d4T (40 mg) mtDNA / nDNA 20 d4T (30 mg) 0.5 d4T (40 mg) TDF 0 d4T (30 mg) TDF 0 1 2 3 4 5 6 0.0 Months 0 1 2 3 4 5 6 Months 10 9 8 7 /min/mg) 6 Spontaneous cellular oxidation 2 5 (nmol O 4 3 2 d4T (40 mg) d4T (30 mg) 1 TDF 0 0 1 2 3 4 5 6 Months Mitochondrial function

  24. 60 300 50 250 40 200 (nmol/min/mg) Complex IV activity 30 (nmol/min/mg) Complex III activity 150 20 100 d4T (40 mg) 10 d4T (30 mg) d4T (40 mg) 50 TDF d4T (30 mg) 0 TDF 0 1 2 3 4 5 6 0 0 1 2 3 4 5 6 Months Months Complex III activity Complex IV activity 160 160 (100%) (100%) 140 140 120 120 100 100 80 80 Percentage respect to baseline Percentage respect to baseline 60 60 40 40 d4T (40 mg) d4T (40 mg) 20 20 d4T (30 mg) d4T (30 mg) TDF TDF 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Months Months Mitochondrial function

  25. Mitochondrial mass (CS activity) mtDNA content 160 160 (100%) (100%) 140 140 120 120 100 100 80 80 Percentage respect to baseline Percentage respect to baseline 60 60 40 40 d4T (40 mg) d4T (40 mg) 20 d4T (30 mg) 20 d4T (30 mg) TDF 0 TDF 0 0 1 2 3 4 5 6 Spontaneous 0 1 2 3 4 5 6 Months cellular oxidation Months 160 (100%) 140 120 100 80 Percentage respect to baseline 60 40 d4T (40 mg) 20 d4T (30 mg) TDF 0 0 1 2 3 4 5 6 Months Mitochondrial function

  26. Results • Virological safety and Adverse events • Virological rebounds: 2 patient in d4T 40 arm • No significant changes in CD4 cell count • 2 cases of symptomatic hyperlactatemia in d4T 40 arm • 1case at baseline visit, another after 6 months. • Reasons for discontinuation: • Pregnancy -1patient • Lost to follow up-2 patients • Poor adherence-1 patient

  27. Conclusions • In patients receiving d4T 40 mg bid containing antiviral therapy and HIV-1 RNA<20 copies/mL: • Switching from d4T 40 bid to TNF was associated with significant improvement in triglycerides, cholesterol and body fat at 6 months. • Reduction in d4T 40 bid to d4T 30 mg bid was associated with an improvement in triglycerides, cholesterol and body fat at 6 months although the differences did not reached statistical significant. • Both switch arms were at least as virologically effective as d4T 40 arm.

  28. Conclusions • No mitochondrial parameter from PBMCs studied differed among groups either at baseline or at 6 months suggesting either that fat and plasma lipid effects are not mediated via mitochondria, or if mediated by mitochondria not by those from PBMCs, or the mitochondrial tests used are not sensible enough to detect potentially mitochondria-mediated changes.

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