Effect of Raltegravir Intensification on LowLevel Residual Viremia in HIVInfected Patients on Antire

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Effect of Raltegravir Intensification on
Low-Level Residual Viremia in HIV-Infected
Patients on Antiretroviral Therapy Results from
ACTG A5244Gandhi R, Zheng S, Bosch R, Chan E,
Margolis D, Read S, Kallungal B, Sprenger H,
Janik J, Jacobson J, Wiegand A, Kearney M, Palmer
S, Coffin J, Mellors J, Eron J on behalf of the
AIDS Clinical Trials Group A5244 team
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Background and Rationale

• Most patients on combination ART with HIV RNAlt50
  c/mL will have detectable viremia using a single
  copy assay (SCA)
• More likely to have detectable viremia if
  pretreatment HIV RNA gt100,000 c/mL
• Level does not seem to decay even after up to 7
  years of ART
• Palmer et al, PNAS 1053879
• Residual viremia (RV) may reflect ongoing
  low-level replication, virus release from stable
  reservoirs, or both
• Ongoing replication may replenish the latent
  reservoir and prevent eradication of HIV
• If this is the case, intensification with an
  agent that acts by an alternative mechanism, e.g.
  an integrase inhibitor, may reduce RV lead to
  more rapid decay of latent reservoir

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Study Design

• Randomized cross-over trial of RAL
  intensification in patients with HIV RNA lt50 c/mL
  on currently recommended ART
• Subjects randomized 11 to add either RAL 400 mg
  bid (immediate-intensification, arm A) or placebo
  (deferred-intensification, arm B) for 12 wks. At
  wk 12, subjects crossed-over to other arm while
  continuing their background regimen
• Primary objective To compare HIV RNA level by
  SCA averaged between wks 10/12 in subjects who
  add RAL to subjects who do not add RAL to their
  background regimen

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Study Population

• HIV-infected subjects on PI- or NNRTI-containing
  ART for at least 12 months
• HIV RNA lt50 c/mL for 6 months
• CD4 cell count 200/mm3
• Pre-treatment HIV RNA level gt100,000 c/mL
• Screening HIV RNA 1 copy by SCA

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Sample Size and Power

• Sample size of 50 (25 per arm) provides 80 power
  to detect 0.5 log10 difference between arms in
  HIV RNA level by SCA averaged at weeks 10 and 12

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Baseline Characteristics of Enrolled Subjects
Arm A RAL first (immediate intensification). Arm
B Placebo first (deferred intensification)
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Safety and tolerability

• Of 53 subjects who initiated study treatment, 49
  (92) contributed data to the primary endpoint at
  weeks 10/12 and 46 (87) completed all 24 weeks
  of the study
• Pill counts showed that 94-97 of doses taken
• No difference between arm A and B in the rate of
  grade 2 or higher signs and symptoms or grade 3
  or higher lab abnormalities
• Overall, the study drug was well-tolerated

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Effect of RAL Intensification on HIV RNA

• HIV RNA at week 10/12 did not differ between the
  RAL-intensified (n25) and the placebo group
  (n24) (median 1.1 vs. 1.7 c/mL or 0.05 vs. 0.23
  log10 c/mL, p0.80)
• 95 confidence interval for the difference
  between the arms -0.37 to 0.37 log10 c/mL
• Change in HIV RNA from baseline to weeks 10/12
  did not differ between the two groups (median
  -0.3 and -0.1 c/mL, p0.52)
• No significant change in HIV RNA after subjects
  crossed-over from RAL to placebo or from placebo
  to RAL

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No Reduction in Low-Level Residual Viremia after
Raltegravir Intensification
? Arm A RAL first (immediate intensification) ?
Arm B Placebo first (deferred intensification)
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Effect of RAL Intensification on CD4 Cell Count

• Trend towards greater CD4 cell count increase
  from baseline to wk 12 in immediate-intensificatio
  n group compared with the deferred-intensification
  group, which reversed after the cross-over
• Combining groups A and B, median change in CD4
  count after RAL intensification was 42 cells/mm3
  (95 C.I., -2 to 57, p0.066)
• No significant change in CD8 cell count after RAL
  intensification

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Conclusions

• In this randomized, double-blind cross-over
  study, 12 weeks of RAL intensification did not
  reduce low-level residual plasma viremia in
  patients on currently recommended combination ART
• Trend towards a greater CD4 cell count increase
  during RAL intensification, which reversed after
  the drug was stopped.
• Studies of the effect of RAL on T cell activation
  are ongoing

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Implications

• Our findings argue against the hypothesis that
  ongoing, complete cycles of replication and
  integration are the main source of residual
  plasma viremia
• New therapeutic strategies to eliminate
  reservoirs that produce residual viremia are
  needed to eradicate HIV infection, and should be
  urgently evaluated
• Activation-elimination strategies that stimulate
  HIV expression from latently-infected cells, e.g.
  IL-7, prostratin, HDAC inhibitors, SAHA
• Strategies that interfere with self-renewal and
  persistence of memory T cells that harbor latent
  virus Chomont et al Nat Med, published online
  June 21, 2009

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Acknowledgements
Additional members of the ACTG A5244 Team Carla
Pettinelli Ana Martinez Richard DAquila Lisa
Demeter Barbara Philpotts Betty Donoval Robert
Levaro Randi Leavitt
Finally, we would like to thank all the patients
who participated in this study.
The hard work of the study staff at the many
AIDS Clinical Trials Group sites who participated
in this trial