Robert Murphy, Jiameng Zhang, Richard Hafner, Abby Shevitz, Karen Tashima, Kevin Yarasheski,

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+ cellcount  100 cells/mm3 • 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 A1: Thymidine-sparing Switch d4T or ZDV toABC n=37 A2: Nucleoside-sparing Switch to LPV/r + NVP n=40 Secondary endpoint (combined arms) n=11 Clinical Lipoatrophy >24 wks ZDV or d4T HIV RNA <500 c/ml “Readable” CT N = 101 15 ACTG sites B1: Delayed Switch d4T or ZDV to ABC n=13 B2: Delayed Switch toLPV/r +NVP O 24w 48w 72w 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

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

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

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

Baseline characteristics

Baseline characteristicsmedian (IQR)

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

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

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

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

CD4 and HIV RNAat 24 weeks

Early Discontinuation Reasons ABCLPV/+NVP Study discontinuations Unable to contact patient 1 0 Patient withdrawal 1 2 Severe debilitation, unable to continue 0 1 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

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. Acknowledgments

Robert Murphy, Jiameng Zhang, Richard Hafner, Abby Shevitz, Karen Tashima, Kevin Yarasheski,