Management of MultiDrug Resistant HIV When to Switch and How to Wait

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Management of Multi-Drug Resistant HIV When to
Switch and How to Wait

• Steven G. Deeks, MD
• University of California, San Francisco

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Transitional HAART Era (1996-2000)

• Sequential exposure to effective monotherapy in
  a population of largely adherent, aggressively
  treated patients created a cohort of individuals
  with highly-resistant HIV

ZDV 3TC SQV NVP EFV LPV ddI
RTV ABC TNF d4T IDV NFV
1996 1997 1998 1999 2000
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Modern HAART Era

• New drugs continue to emerge in a sequential
  manner, forcing patients to use these drugs as
  they become available or remain on a stable
  partially suppressive regimen

T20 TPV TMC114 R5 TMC 125 Integrase
Inhibitors D-d4FC
Inhibitors
2004 2005 2006 2007 2008 2009
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Questions When should new drugs be used in the
setting of triple-class MDR HIV (when to
switch)? And, if a decision is made not to
switch, what to do in the meantime (how to
wait)?
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When to Switch Limited Data and No Clear
Consensus

• There is no consensus on the optimal time to
  change therapy for virologic failure. The most
  aggressive approach would be to change for any
  repeated, detectable viremia . . .
• However
• . . . a decision to change regimens might
  reduce future treatment options for that patient
  . . .

DHHS Guidelines, released October 29, 2004
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RESIST Studies New goal of therapy for heavily
pre-treated patient?
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RESIST Enfuvirtide plus tipranavir/ritonavir (lt
400 at week 24)
Caveat T20 treated patients had advanced disease
(median CD4 72-77 median VL log 5.1, median
prior exposure of 13-14 drugs)
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Use of resistance testing for the when to
switch rather than how to switch question
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When not to use tipranavir/r with T20?
BI 1182.52 change in HIV RNA at week 2
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When not to use tipranavir/r?
VIRCO Lower threshold lt 3 fold Upper threshold
gt 10 fold
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When not to switch?

• Tipranavir Proportion Baseline
  Fold Change Responders TPV-mutations
• 0-3 45 (74/163) 0-4
• 3-10 21 (10/47) 5-7
• gt10 0 (0/8) 8

Tipranavir-associated mutations L10V, I13V,
K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V,
I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or
I84V Outcome confirmed gt 1 log decrease at week
24 (in absence of T20)
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Wait for more options?
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POWER Enfuvirtide plus TMC114/ritonavir (lt 50
at week 24)
Caveat Interim analysis on a small
subset Enfuvirtide-naïve TMC 114 600 BID
Katlama et al CROI 2005
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Risk of waiting
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For any given level of viremia, CD4 T cell loss
is slower in patients with drug-resistant HIV
that those with wild-type HIV
Drug Resistant
Wild-type
JID 2000 181946-53
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CD4 Decline after onset of continuous virologic
failure (n291)
However, risk of disease progression (AIDS/death)
for any given CD4 T cell count or HIV RNA level
in setting of MDR has not been defined
AIDS 2002 16201-207
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Response rates to salvage therapy are predicted
by disease stage
Montaner J, et al. 2nd IAS, Paris 2003, 116
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CD4 T cell count is a consistent predictor of
virologic response to salvage therapy
Virologic response to tipranavir/r is
significantly reduced in patients with very low
CD4 T cell count at time of treatment
modification (but remains higher than comparator
PI)
Hicks et al IAS 2005
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Resistance increases over time (at a slow rate)

• Mutation rate in patients remaining on stable
  HAART (n98)
• 60 selected for new mutations at rate of
  1.5/year
• Rate is not defined in patients with multiple
  mutations and prolonged treatment failure

Napravnik/Eron JAIDS, 2005 (in press)
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Risk of WaitingUnique Issues Regarding R5
Inhibitors
100
80
60
Prevalence of X4 or R5/X4
40
20
0
gt 300 248
201-300 104
101-200 81
51-100 31
lt 50 50
n
Moyle G, et al. Journal of Infectious Diseases,
2005
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Summary When to switch

• If two (or preferably) three well-tolerated and
  effective drugs are available then an early and
  aggressive switch should be considered
• When to switch requires access to resistance
  test with well defined genotypic and/or
  phenotypic cut-offs
• If not, benefits of preserving novel treatment
  classes may outweigh benefits of switching,
  particularly if
• CD4 T cell counts gtgt 100
• Substantial resistance to existing classes
  already exists
• Virus is already dual tropic/X4
• The question then becomes how to wait

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How to Wait? Which drugs should be maintained
and why?
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Complete Treatment Interruption vs. 3TC
Monotherapy (n 50)
Interruption of all drugs in patients with
drug-resistant HIV results in rapid increase in
viremia
Detectable viremia on 3TC-based regimen, CD4 gt 500
Castagna et al. International AIDS Conference,
Bangkok, 2004 (Abstract WeOrB1286.)
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Complete Treatment Interruption vs. 3TC
Monotherapy (n 50)
3TC monotherapy exerts a persistent anti-HIV
effect (even in presence of M184V) . . . This may
be due to fitness or residual drug effect
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Selective Interruption of 3TC (n6)
0.8
0.6
Interruption of 3TC results in an increase in
HIV RNA (before loss of M184V), indicating
residual antiviral activity
0.4
0.2
0.0
-0.2
-0.4
-0.6
-0.8
0
2
4
6
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Weeks after 3TC Discontinuation
Campbell et al CID 2005
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Complete Treatment Interruption of ZDV/3TC (n
16)
Interruption of ZDV/3TC in patients receiving
long-term therapy was associated with rapid
increase in viremia in all subjects (median
increase 0.54 log, range 0.31 to 1.71)
Eron et al JAIDS 2005
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Reverse Transcriptase Inhibitor Interruption
(continued Protease Inhibitor Therapy)
7 of 7 patients had an immediate and durable
increase in viremia (gt 0.5 log) with no early
change in genotype
All patients had M184V and TAMS
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• Major Mutations Change in HIV RNA (wk 2)
• M41L, D67N, T69D, M184V, L210W, T215Y 1.00
• none 0.79
• D67N, K70R, M184V,T215T/S, K219Q 0.94
• M41L, T69T/A, K70R, V75A, M184V 0.62
• M41L, D67N, K70R, V75M, V118I, M184V,
  L210W,T215F 0.46
• M184V 0.78
• D67N, K70R, M184V, K219Q 0.80
• M41L, E44D, D67D/N, V118V/I, M184V, L210W,
  T215Y 0.42

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Treatment Interruptions of Individual Therapeutic
Drug Classes (N 53) (Week 2
change in Viral Load)
Residual Activity Against Resistant
Variant NRTIs gtgt gt T20, PI gt NNRTI
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Summary Maintaining partial viral suppression

• NRTIs often have residual activity against
  resistant HIV
• Implications
• NRTIs should be maintained pending availability
  of more effective regimens
• NRTIs should remain backbone of salvage
  regimens (additive effect?)
• Other drugsparticularly protease inhibitors
  and/or enfuvirtidemay no longer exert a direct
  antiviral impact, yet still have residual benefit
  via its impact on the maintenance of mutations
  that reduce fitness and/or virulence

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How to Wait? Unresolved issues regarding a
unique role of protease inhibitor therapy and
perhaps other drugs in reducing virulence
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Definitions

• Fitness the ability of a virus to replicate in
  a given environment typically implies
  competition between two species
• Virulence/Pathogenicity Capacity of a virus to
  cause disease independent of viremia, often
  defined based on rate of CD4 decline

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PLATO CD4 decline slower with MDR vs. Wild-type
HIV
CD4 Slope (cells/year)
Steady State Viral Load (copies/mL)
Lancet 2004
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PLATO Change (95 CI) in CD4 cell count slope

• Univariate Multivariate
• Age (per 10 yr) -5.6 -6.7
• Female 25 16
• Current VL (per Log) -28 -25
• Current CD4 (per 100) 8.2 NS
• of drugs (per drug) 4.9 4.8
• Boosted PI 33 (22 to 43) 18 (7 to 28)
• NNRTI -24 (-35 to 13) -23 (-35 to 11)

Robust linear regression 9173 observations from
1848 patients on-treatment with stable viral load
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How to wait Maintaining CD4 T cells

• Factors associated with persistent immunologic
  and clinical benefit in setting of drug resistant
  HIV have not been defined
• Observational data suggest durable CD4 T cell
  count benefits are due in part to continued use
  of protease inhibitors, and this effect is
  independent of viral load
• Implications
• Continued protease inhibitor therapy and perhaps
  T20 should be considered in advanced
  immunodeficiency
• Will patients failing NRTI-based therapy in
  regions that lack access to these drugs
  experience durable clinical benefit commonly
  observed in the modern HAART era?

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