Switching to a Thymidine Analog-Sparing or a Nucleoside-Sparing Regimen Improves Lipoatrophy: 24 Week Results of a Prospective Randomized Clinical Trial: AACTG A5110 Robert Murphy, Jiameng Zhang, Richard Hafner, Abby Shevitz, Karen Tashima, Kevin Yarasheski, Baiba Berzins, Susan Owens, Jodi Forand, Scott Evans, Pablo Tebas and the AACTG A5110 Study Team

Objectives Primary Objectives: –To investigate effects of change in peripheral fat wasting of thymidine-sparing regimen and NRTI-sparing regimen Secondary Objectives: –To investigate the effect of changes on subcutaneous and visceral fat tissue distribution in the abdomen –To investigate the effect of change on safety and virologic activity. –To investigate the effect of change on glucose and lipid metabolism –To investigate the effect of change on serum and urine markers of bone mineral metabolism –To investigate the effect of treatment change on quality of life

Inclusion criteria HIV-1 infection Self-reported peripheral fat wasting including atrophy of the extremities, since starting ARV therapy Fat wasting confirmed on a physical examination On HAART including either ZDV or d4T, for  24 weeks Plasma HIV-1 RNA < 500 copies/mL CD4+ cell count  100 cells/mm 3 Labs –Creatinine  3 x ULN –AST (SGOT) and ALT (SGPT)  5x ULN –Lipase  1.5 x ULN

Exclusion criteria Initiation of oral hypoglycemic agents, Use of insulin, megestrol, rhGrowth hormone, supraphysiologic doses of corticosteroids, or hydroxyurea * Initiation of androgen therapy* Hyperthyroidism or hypothyroidism * Systemic chemotherapy within 6 months Pregnancy and breast-feeding Drug abuse that could interfere with adherence to study Serious illness Current use of investigational agents Documented or suspected acute hepatitis within 60 days of entry * Stable physiologic replacement was allowed

A5110 Schema Clinical Lipoatrophy >24 wks ZDV or d4T HIV RNA <500 c/ml “Readable” CT N = ACTG sites A1: Thymidine-sparing Switch d4T or ZDV to ABC A2: Nucleoside-sparing Switch to LPV/r + NVP B1: Delayed B2: Delayed Switch d4T or ZDV to ABC Switch to LPV/r + NVP O 24w 48w 72w n=37 n=40 n=13 Primary endpoint  Original 2:2:1:1 randomization. Delayed arms were discontinued after MITOX was presented  Patients restrictively randomized based on ARV history and genotype; 80% eligible for all arms  Stratification by current d4T or ZDV use Secondary endpoint (combined arms) n=11

Primary endpoint Primary: Change in thigh subcutaneous (SQ) adipose tissue at 24 weeks for all 3 arms Secondary: –Change in thigh SQ adipose tissue after 24 weeks of intervention (combined arms) –Change in abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), glucose, lipid, bone, quality of life at 24 and 48 weeks Power: 50 patients per group, 80% to detect a 30% difference within arms

SQ thigh adipose tissue All CTs centrally analyzed at Tufts Week 0 Week 48 Subcutaneous thigh adipose tissue

Abdominal VAT and SAT Week 0Week 48 All CTs centrally analyzed at Tufts Visceral adipose tissue (VAT) Subcutaneous adipose tissue (SAT)

Baseline characteristics Delayed (n=24) ABC (n=37) LPV/r + NVP (n=40)p value Male % NS White % NS Hx IVDU % 2158 NS Age y (median) NS CD4/ml (median) NS % HIV RNA >200 c/ml 436 NS % on D4T NS

Baseline characteristics median (IQR) Delayed (n=24) ABC (n=37) LPV/r + NVP (n=40)p value Thigh SQ adipose tissue (cm 2 ) 19 (7, 27)15 (7, 29)20 (11, 29)ns SAT(cm 2 )78 (34,111)60 (39,170)85 (53,121)ns VAT(cm 2 )94 (50,146) 142 (82,195) 115 (71,160) 0.04 VAT:TAT ratio 0.53 (0.45, 0.70) 0.64 (0.46, 0.77) 0.57 (0.44, 0.68) ns

SQ thigh adipose tissue median (IQR) * within arm change p=0.02* p=0.06*

Abdominal SQ adipose tissue median (IQR) p<0.01* *Within arm change † Between arm p<0.01 p<0.01* p=0.04* †

Visceral adipose tissue (VAT) median (IQR) * Within arm change p<0.01*

VAT:TAT ratio median (IQR) * Within arm change † Between arms p<0.01 p<0.01* p=0.08* p<0.01* †

CD4 and HIV RNA at 24 weeks Delayed (n=24) ABC (n=37) LPV/r + NVP (n=40) % HIV RNA <200c/ml NS (486, 946, 706, 15211, 96805) CD4 count Median % change IQR , , ,25 NS P=0.03

Early Discontinuation Reasons ABC LPV/+NVP Study discontinuations Unable to contact patient 10 Patient withdrawal 12 Severe debilitation, unable to continue 01 Study drug discontinuations 6 6 ABC: fever, nausea, hepatitis, rash/allergic reaction (3) LPV/r+NVP: rash/allergic reaction, hyperlipidemia (3), hepatitis (2)

Conclusions Switching d4T or ZDV to lopinavir/r + nevirapine, an NRTI-sparing regimen. is associated with significant improvement in SQ extremity fat at 24 weeks. Switching d4T or ZDV to abacavir, a non-thymidine analog, or lopinavir/r + nevirapine, an NRTI-sparing regimen, is associated with significant improvements in abdominal SAT, VAT and VAT:TAT Both interventions appear safe immunologically and virologically, the NRTI-sparing increased CD4 counts significantly Longer follow up is needed to better understand the long term implications of both interventions Central lipid, glucose, bone metabolism and quality of life studies and 48 week analyses are ongoing

Acknowledgments Team members –Robert L. Murphy, M.D. –Pablo Tebas, M.D. –Richard Hafner, M.D. –Mira Madans –Scott Evans, Ph.D. –Jiameng Zhang, Ph.D. –Susan Owens, R.N., M.S. –Paul Tran, R.Ph. –Robert W. Coombs, M.D., Ph.D. –Karen T. Tashima, M.D. –Kevin E. Yarasheski, Ph.D. –Abby Helen Shevitz, M.D., M.P.H. –Jane Baum, B.S.N., –Baiba Berzins, M.P.H. –Carolyn Schnizlein-Bick, Ph.D. –Melvin Littles. A.A. Participants Sites Quest Diagnostics Pharmaceutical Partners –Abbott Kevin Garren Scott Brun –Boehringer-Ingelheim Doug Ferriman Pete Piliero –GlaxoSmithKline Irene Gray Gary Pakes Tufts reading center –Jodi Lee Forand, B.S. –Abby Shevitz, M.D.