Options for Deep Salvage Therapy: Now and in the Future A Clinical Perspective on the Management of - PowerPoint PPT Presentation

1 / 44
About This Presentation
Title:

Options for Deep Salvage Therapy: Now and in the Future A Clinical Perspective on the Management of

Description:

Response to NNRTI-HAART in women who received SD-NVP (MTCT) ... higher' - FC at which response is essentially gone (80% in response) Step 4: Validation ... – PowerPoint PPT presentation

Number of Views:61
Avg rating:3.0/5.0
Slides: 45
Provided by: yeni2
Category:

less

Transcript and Presenter's Notes

Title: Options for Deep Salvage Therapy: Now and in the Future A Clinical Perspective on the Management of


1
Options for Deep Salvage Therapy Now and in the
FutureA Clinical Perspective on the Management
of Experienced Patients
  • 3rd IAS Pathogenesis and Treatment Conference
  • Rio de Janeiro, July 2005
  • Julio Montaner MD, FRCPC, FCCP
  • Director, BC Centre for Excellence on HIV/AIDS
  • Professor of Medicine and Chair, AIDS Research
  • Providence Health Care - University of British
    Columbia

2
Outline
  • Why does HAART fail?
  • Resistance
  • TDM - IQ
  • Dealing with treatment failure

3
Why does HAART fail?
Failing HAART
Drug
Patient
Virus
Potency
Toxicity
Resistance
Non-adherence
Interactions
4
Effect of adherence on Survival
High Adherence
Incomplete Adherence
Probability of Survival ()
Probability of Survival ()
Time Since Start of ARVs
Time Since Start of ARVs
Wood et al. AIDS, 2003
5
HIV/HCV and mortality
Probability of Survival ()
log rank p lt 0.001
Time from Start of Antiretrovirals (mos)
Co-morbidities represent a poorly recognized
cause of non-adherence
R Hoog et al, MTEP 2002
6
Physician Experience
Probability of Survival
Probability of Survival
Experienced MD
Non-experienced MD
Time Since Start of ARVs
Time Since Start of ARVs
Wood et al, CROI 2002
7
Why does HAART fail?
  • HAART is highly effective
  • Access remains a major challenge
  • Barriers to HAART poorly understood
  • North vs South
  • Among those who access HAART
  • Co-morbidities
  • Adherence
  • MD Experience
  • Resistance

8
Outline
  • Why does HAART fail?
  • Resistance
  • TDM - IQ
  • Dealing with treatment failure

9
BSL genotype predicts failure
  • FTC 301A Prospective study of 571 ARV-naive
    patients
  • 16 (90/546) had baseline NRTI and/or NNRTI
    resistance

Borroto-Esoda K, et al. 11th CROI, 2004 672
10
Primary Resistance Frequency
  • CASCADE 22 sero-converter cohorts in 10
    countries (Europe, Australia Canada)
  • 467 sero-coverters between 1987 - 2002
  • 13 patients had drug-resistant virus (mostly
    NRTI resistance)

Masquelier B, et al. 11th CROI, 2004, 683
11
HIV super-infection
  • Documented HIV superinfection1-4
  • Low Prevalence to date
  • 3 of 78 (4) pts in the first 6 to 20 months of
    infection in SD and LA5
  • 1 of 32 (3) newly infected subjects from MACS6

Mean change in HIV RNA and CD4 after
superinfection
These findings have important implications ?
pVL and ?CD4 Counseling strategies Vaccine
development
Change in RNA (log10 c/mL)
Change in CD4 (/mm3)
p0.05 vs controls without superinfection
1. Altfeld M, et al. Nature 2002420434 2. Jost
S, et al. NEJM 2002347731 3. Koelsch K, et al.
AIDS 200317F11 4. Ramos A, et al. J Virol
2002767444 5. Smith D, et al. 11th CROI, 2004,
21 6. Gottlieb G, et al. 11th CROI, 2004, 454
12
PART Resistance and STIs
Frequency () of mutations according to drug class
  • 136 patients on 1st HAART
  • HIV RNA lt400 c/mL (6-48 mo) and CD4 gt350/mm3
    (nadir gt100/mm3 )
  • 4 cycles 3 mos of Rx with STIs of 1, 1, 2, and 2
    months
  • Mutations in 39/136 (29) pts
  • Virological failure (gt400 c/mL)
  • With mutations 33
  • No mutations 12
  • p0.004 (95 CI 4.5- 37.3)

Palmisano L, et al. 11th CROI, 2004, 552
13
Reversion of mutations with TICPCRA 064
  • Randomized, prospective clinical endpoint trial
  • 4 months TI in multi-class failure
  • Study closed due to safety concerns in the TI arm
  • 97/137 patients had planned TI of gt 4 months

Lawrence J, et al. 11th CROI, San Francisco 2004,
665
14
Impact of Minor Resistant VariantsSingle-genome
sequencing (SGS) in ACTG 398
Mean change (95 Cl)
Naive - Exp SGS- Exp SGS
Weeks from randomization
N Initial End Naive- 235 186 Exp 156
114 Exp- 48 34
Kearney M, et al. 11th CROI, 2004, 695
Mellors J, et al. 11th CROI, 2004, 39
15
Response to NNRTI-HAART in women who received
SD-NVP (MTCT)
Subsequent response to triple therapy 3 and 6
month responders (50 c/mL)
  • 255 women started d4T, 3TC, NVP postpartum
  • 213 NVP-exposed, 42 not NVP-exposed intrapartum
  • Genotype post partum
  • K103N (21)
  • G190A (9)
  • Y181C (2)
  • 61 patients had detectable NVP levels up to 24
    days post partum

Chi2 for linear trendplt0.001
No NVP 42 37 28NVP no MUT 139 112 110 NVPMUT 61
58 50
Jourdain G, et al. 11th CROI, San Francisco 2004,
41LB
16
Incorporating Resistance Testing in the
Management of Experienced Patients
17
Virtual Virus
Baseline resistance
Virtual Virus
Resistant calls ()
Genotype with Stanford interpretation
Harrigan, et al. MTEP 2002 Harrigan et al. JID
2005
18
Resistance Test Interpretation Estimation of
phenotypic clinical cutoffs (CCO)
  • 13,026 patients records reviewed
  • 3,156 treatment regimens met all inclusion
    criteria
  • 2/3 of treatment regimens from cohort data
  • Separate data sets created for each drug
  • Each regimen contributed to data sets for
    multiple drugs
  • Boosted and non-boosted PIs modeled separately

Step 1 Collect clinical outcome data create
analysis dataset Step 2 Develop model of
virologic response as function of BL FC as
predicted by VircoType and other
variables Step 3 Define clinical cutoffs -
lower - FC at which response begins to be lost
(20 ? in response) - higher - FC at which
response is essentially gone (80 ? in
response) Step 4 Validation
Bootstrapping Test performance of model
on unseen data
Bacheler L, et al. 44th ICAAC, Washington 2004,
H-1133
19
Resistance Test Interpretation Estimation of
phenotypic clinical cutoffs (CCO)
Bacheler L, et al. 44th ICAAC, Washington 2004,
H-1133
20
Resistance
  • Resistant HIV continues to expand
  • Primary, Secondary, Super-infection
  • Baseline resistance predicts outcome
  • Even in first line HAART
  • Minority species can affect HAART efficacy
  • May be relevant re STIs or Salvage
  • Virtual Virus incorporates cumulative resistance
    Hx
  • CCO facilitates resistance test interpretation
    and development of a treatment strategy

21
Resistance testing must take into account
  • All prior drug exposure
  • Viral load response
  • Duration of exposure
  • Timing of the test
  • Heterogeneity of the viral populations
  • Across patients
  • Within patients (Virtual Virus)
  • PS Keep in mind what are the treatment options
    available

22
Outline
  • Why does HAART fail?
  • Resistance
  • TDM - IQ
  • Dealing with treatment failure

23
Inhibitory Quotient (IQ)
Inhibitory quotient characterizes the
relationship between drug exposure and drug
susceptibility

Neu, JAMA 1980
24
CONTEXT Impact of IQ
GIQ24 and virologic response at 24 and 48 wks
Virologic response defined as lt400 c/mL and/or gt1
log10 c/mL decrease from baseline
  • In contrast to GIQ, APV levels was not an
    independent predictor of virological response

Xu F, et al. HIV 7, Glasgow 2004, P141
25
Normalized IQ and response to RTV-boosted PIs
with HIV RNA lt400 c/mL at Week 48 by
interquartile CCO-NIQ
  • CREST Experienced subjects (n87)
  • NRTI (100)
  • NNRTI (68)
  • PIs (93)

Predictors of response in MV analysis Baseline
HIV RNA (p0.012) Changes in PI during study
(p0.034) Clinical cutoff-NIQ (p0.003) Biologic
cutoff-NIQ (pgt0.05)
Winston A, et al. HIV 7, Glasgow 2004, PL6.6
26
Resistance Drug Exposure IQ
Resistance ? Decreased Susceptibility
Decreased susceptibility is a relative
concept, which must be interpreted in the context
of a regimens potency and the drug exposure that
can be achieved in vivo
27
Outline
  • Why does HAART fail?
  • Resistance
  • TDM - IQ
  • Dealing with treatment failure

28
Multiple Drug (2 Class) Failure
  • Avoid continued exposure to a failing regimen to
    minimize resistance evolution which will further
    compromise the entire drug class(es)
  • Change whenever a new regimen with 2 active
    drugs can be constructed (GSS or PSS 2)
  • If such a regimen cannot be constructed, change
    can be deferred unless imminent risk of OI/death
    is high

IAS-USA Guidelines, JAMA 2004
29
Multidrug Rescue Therapy (MDRT)
J Montaner et al, MTEP 2002.
30
MDRT Durability of ResponseAmong pts achieving
2 consecutive BQL on MDRT
Probability of Remaining BLQ ()
J Montaner et al, MTEP 2002
31
Survival of HAART/Naive vs MDRT
P value NS After adjusting for age, prior AIDS
Dx, CD4, pVL
Lee et al, JID, 2003
32
TORO Virologic Responses
Lalezari et al, NEJM, 2003 Lazzarin et al, NEJM,
2003
Montaner et al. 2nd IAS, Paris, 2003 116
33
Needle-free injection system
Montaner et al, DART, 2004
34
RESIST-1 and 2
  • Primary endpoint of pts with HIV RNA reduction
    gt1 log10 at Week 24
  • R-1 TPV/RTV 41.5 CPI 22.3
    (plt0.0001)
  • R-2 TPV/RTV 41.0 CPI 14.9
    (plt0.0001)
  • Toxicity
  • Subjective side effects NS
  • Higher rates of ALT, TC, and TG with TPV/rtv

(CPI comparator PI)
1. Hicks C, et al. 44th ICAAC, Washington 2004,
H-1137a 2. Cahn P, et al. HIV 7, Glasgow 2004,
PL14.3
35
TMC114/rtv in Experienced Patients
300/100 bid
900/100 qd
600/100 bid
Control
0.0
plt0.001
change in viral load
-0.5
(log cps/mL)
-1.0
-1.5
0
2
4
6
8
10
12
14
time (days)
Katlama et al, CROI, 2005
36
TMC125 in NNRTI-Resistant Individuals
Mean SE (n 16) PVL decrease by day 7 -0.9
log10
37
Reverset a Cytidine Analog Inhibitor Active in
Naive Patients
Courtesy of Incyte Corporation and Pharmasset, Inc
38
Reverset a Cytidine Analog Inhibitor Active
Against Drug Resistant HIV In Vitro
Geleziunas,et al. Antiviral Chemistry
Chemotherapy, 2003
39
ENF PI/r PVL lt50 c/ml
100
80
67
60
of patients with response (lt50 copies/ml) at 24
weeks
37
37
40
No ENF
ENF (naive only)
17
20
0
LPV/r1 (naive)
TMC114/r3
1. Courtesy of Roche 3. Katlama et al. CROI 2005.
Abstract 164LB
40
Investigational drugs
41
Managing Experienced PatientsThe Bottom Line
  • Assess the virological failure
  • Confirm virological failure
  • Identify the cause of failure
  • Correct the determinants of failure
  • Evaluate con-meds
  • Define The Enemy
  • Geno/Phenotype
  • Construct a virtual virus
  • Add to it using probabilistic approach

42
Managing Experienced PatientsThe Bottom Line
  • Identify unacceptable drugs
  • Careful review of past drug exposure
  • PK interactions
  • Past and additive toxicities
  • Develop a menu of viable drugs
  • Review available and acceptable list of ARVs
  • Consider experimental-expanded access drugs
  • Rank them based on their residual antiviral
    activity
  • (Potency against WT/CCO) x Exposure factor
  • Consider potential efficacy interactions

43
Managing Experienced PatientsThe Bottom Line
  • Construct the maximally active drug regimen
    possible
  • Aim for a GSS or PSS gt2
  • A new drug from a new class has a GSS or PSS 1
  • Make the new active drug(s) the backbone of the
    regimen
  • A new drug from a failed class has a GSS or PSS
    lt1
  • Consider residual antiviral potency of recycled
    drugs
  • Monitor safety and efficacy very closely
  • Use Lab monitoring and TDM (IQ) liberally
  • Be ready to compromise
  • FST vs PST
  • STI not generally recommended

44
Acknowledgements
  • BC-Centre for Excellence on HIV/AIDS
  • HIV/AIDS Program at PHC/UBC
  • Canadian HIV Trials Network
  • International Collaborators
  • IAS - USA
  • International Research-based Pharma
  • MSHRF
  • CIHR
  • BC-MoH and HW, Ottawa
  • PHC, SPH Foundation and UBC
  • Research Staff and Study Participants
Write a Comment
User Comments (0)
About PowerShow.com