backdrop

1

Management of Late Virologic Failure and Viral
Fitness
Steven G. Deeks, MD
SG Deeks, MD.Presented at IASUSA/RWCA Clinical
Conference, August 2004.
The International AIDS SocietyUSA
2
Why not Switch?
Slide 2
TORO 995 three-class experienced subjects
randomized to optimized back-ground (OB) vs.
enfuvirtide (T20) plus OB
Plt0.0001
lt 400 copies/mL
30
12
OB T20
OB
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
3
When To Switch Who Does Well and Who Does Not?
Slide 3
Montaner J, et al. 2nd IAS, Paris 2003, 116
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
4
When to Switch in Patients with MDRThe Clinical
Dilemma
Slide 4

• Enfuvirtide or any potentially effective drug
  should be deferred until at least two additional
  effective agents are available
• Therapy should be modified before the development
  of advanced immunodeficiency and before the
  development of high-level resistance to existing
  drugs

SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
5
When will patients with MDR and limited options
have at least 2 effective agents?The question
is when to switch, not how to switch
Slide 5
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
6
Tipranavir/ritonavir in deep salvage
Slide 6
Amprenavir/r (n74)
Saquinavir/r (n74)
Lopinavir/r (n78)
HIV RNA (log10 copies)
Tipranavir/r (n66)
Curry K, et al. 5th International Workshop on
Clinical Pharmacology of HIV Therapy April 1-3,
2004 Rome, Italy
Median CD4 T cell count 140, viral load 5.0 log
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
7
Slide 7
R5 viruses Macrophage-tropic Non-syncytium
inducing Associated with slow progression
(causality not clear) Prevalent in early
disease Transmitted variants

• X4 viruses
• T-cell tropic
• Syncytium-inducing
• Associated with rapid progression
• (causality not clear)
• Emerge in late disease
• R5 62 (n378)
• X4 4 (n23)
• Dual 34 (n211)

TORO
X4/R5 viruses Mixtures vs. Dual Tropic
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
8
Co-receptor Tropism (X4/R5) Do X4 (SI)
variants cause rapid disease progression?
Slide 8
R5 Virus
R5/X4 or X4 Virus
207 HIV-infected hemophiliacs (age 6-19) enrolled
in the HGDS natural history cohort, 1989-1990
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
9
Can partially effective drugs (or drug classes)
become fully effective by increasing exposure?
Slide 9
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
10
Abbott 049 Steady-State Lopinavir Mean (SD)
Concentrations
Slide 10
Flexner C, et al., Poster 843, 2nd IAS Conf,
Paris, July 2003
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
11
Abbott 049 Predictors of a viral load lt 400
(week 48)
Slide 11

• Predictor Unadjusted Adjusted
• Baseline VL 0.01 NS
• Fold change IC50 0.02 NS
• Number of LPV mutations 0.04 NS
• Active NRTIs 0.02 0.04
• LPV IQ 0.002 0.007

SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
12
What about dual boosted protease inhibitors?
Slide 12
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
13
Tipranavir BI 1182.51 Controlled study of Dual
Boosted PIs
Slide 13
RCT (n296) 3 mutations at protease codons 33,
82, 84, 90
LPV/r OBR (400 mg/100 mg)
SQV/r OBR (1000 mg/100 mg)
APV/r OBR (600 mg/100 mg)
TPV/r OBR (500 mg/200 mg)
TPV/r 500/100 mg added at 2 weeks Final RTV dose
200 bid in all arms
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
14
Slide 14
Dual boosted PI therapy vs. RTV/TPV in deep
salvage
Monotherapy
TPV added to LPV/APV/SQV
HIV RNA (log10 copies)
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
15
Why not switch?

• Salvage regimens are often complex, with
  significant short-term and long-term
  complications
• Risk may outweigh benefit in elderly or patients
  with advanced co-morbid conditions (renal, liver
  disease)
• Patients are often doing well (or are progressing
  slowly)
• Costs of treatment
• Aggressive switch strategies risk future
  therapeutic options

16
PLATO Steady State Viremia and Rate of CD4
Cell Decline
Slide 16
CD4 Slope (cells/year)
Steady State Viral Load (copies/mL)
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
17
Slide 17
Resistance
Replicative Capacity
Viremia
HIV may be constrained in its ability to become
highly resistant and highly fit, thus resulting
in durable partial suppression
J Virology 2002 7611104-12
SG Deeks, MD. Presented at IASUSA/RWCA Clinical
Conference, August 2004.
18
Summary Pathogenesis of Drug-Resistant HIV
Despite emergence of drug-resistance, plasma HIV
RNA levels often remain below the off-treatment
set-point as long as treatment is maintained
Persistent antiviral activity against resistant
variant Reduced viral fitness (replicative
capacity) Enhanced HIV specific immune
responses
Rate of CD4 T cell decline delayed in presence
of MDR compared to WT Predicted by delta VL (
gt 0.7 log?) Predicted by a steady-state viral
load lt 10 to 30K Mediated by reduced T cell
activation