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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,

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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
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
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
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

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 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 TuftsSQ thigh adipose tissue

Subcutaneous thigh adipose tissue

Week 0

Week 48

abdominal vat and sat
Abdominal VAT and SAT
  • All CTs centrally analyzed at Tufts

Subcutaneous adipose tissue (SAT)

Visceral adipose tissue (VAT)

Week 0

Week 48

sq thigh adipose tissue median iqr
SQ thigh adipose tissuemedian (IQR)

p=0.02*

p=0.06*

* within arm change

abdominal sq adipose tissue median iqr
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
Visceral adipose tissue (VAT)median (IQR)

p<0.01*

p<0.01*

* Within arm change

vat tat ratio median iqr
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

early discontinuation reasons
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
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.

Acknowledgments