Julio Montaner MD, FRCPC, FCCP

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Antiretroviral Therapy 2006

• Julio Montaner MD, FRCPC, FCCP
• Director, BC-Centre for Excellence on HIV/AIDS
• Professor of Medicine and Chair, AIDS Research
• Co-Director, Canadian HIV Trials Network
• Providence Health Care - University of British
  Columbia

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Objectives

• Recent Developments in ART
• When to Start
• How to Start
• Experienced patients
• New drugs
• Access/Sustainability
• HAART and HIV Transmission

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When to Start Antiretroviral TherapyIAS-USA
International Panel
Hammer et al, JAMA, Aug 16th, 2006. 296 827-843
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Antiretroviral Therapy for HIV Infection in
Adults and Adolescents in Resource-Limited
Settings
2006 revision
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When to Start - Consensus

• Symptomatic Patients
• Treat all
• Asymptomatic Patients
• CD4 Abs before 200/mm3
• Regardless of HIV-1-RNA level
• When the patient is ready to commit

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Recommended initial HAARTAugust 2006
NNRTI component EFV NVP
N-NtRTI component TDF FTC ABC 3TC ZDV
3TC Alternatives d4T 3TC ddI 3TC
In selected patients
PI component LPV/rtv ATV/rtv fosAMP/rtv SQV/rtv

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Treatment Simplification1996 - 2006
Selected regimens
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Treatment Simplification1996 - 2006

• LPV/rtv 4 heat stable tablets/ day
• SQV 500 mg tablet
• ENF Biojector needle free gas powered device
• TI strategies
• Induction and maintenance
• - Number of drugs vs potency genetic barrier

Selected Issues
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Dealing with treatment failure

• Identify and correct the cause
• Aim for a fully suppressive therapy
• - plasma HIV-1 RNA level lt50 copies/ml
• Compensate for partially compromised drugs
• Consider Residual Antiviral Potency (RAP)
• STI not generally recommended

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OPTIMA Predictors of Endpoints
MegaHAART gt 4 drugs
3-month treatment interruption
Standard HAART 4 drugs
Treatment-experienced triple-class failure CD4
300/mm3 HIV-1 RNA 5000 c/mL on failing regimen
MegaHAART gt 4 drugs
Continuation of therapy
Standard HAART 4 drugs
Or lab evidence of triple-class resistance

• N 307 bsl CD4 111/mm³ - Mean follow-up 1.8
  yrs (ongoing)
• 55 had 1 log drop in viral load at 6-24 weeks
• CD4 count or HIV-1-RNA changes, or disease
  progression (pNS)

Endpoints predicted by baseline CD4 count, change
in viral load, and CD4 count at 24 weeks
J Singer, et al. CROI 2006. Abst 526
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Tipranavir/rtv Antiviral effect
ITT NCF
Week 48
Week 24
plt0.0001
plt0.0001
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Darunavir Virologic response

• p-value lt0.001 (multivariate analysis) updated
  data (all patients reached Week 24)
• 1Defined by Antivirogram
• 2TLOVR time to loss of virologic response

DeMeyer S, et al. CROI 2006. Abst 157
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Need 2 active drugs Power 1 2 OB /- T20
/- TMC114
100
No T20
T20
80
67
27
60
of patients with response (lt 50 copies/ml) at
24 weeks
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40
27
16
20
8
25
39
0
Control PI/r
TMC114/r (600 bid)
Katlama et al. CROI 2005. Abst 164LB
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New Drugs in the Pipeline

• NRTIs
• Amdoxovir (DAPD)
• Racivir
• Avexa 754 (-dOTC)
• Dioxolane thymidine (DOT)
• GS 9148
• KP1461
• MIV-210
• NCRTI

• PIs
• Brecanavir
• PPL-100
• SPI-256
• SM-309515l

• Entry Is
• CXCR4 Is
• AMD070
• KRH 3955
• KRH 3140
• CCR5 Is
• Maraviroc
• Vicriviroc
• Fusion Is
• TRI-1144
• TRI-999
• Attachment/CD4 binding Is
• PRO 140
• TNX 355

• Maturation Is
• PA-457
• Integrase Is
• MK-0518
• GS-9137

• NNRTIs
• Etravirine
• TMC278

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Access and Sustainability
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Adherence to ART in Sub-Saharan Africa and North
America A Meta-analysis
E Mills J Nachega I Buchan J Orbinski A
Attaran S Singh B Rachlis P Wu C Cooper L
Thabane K Wilson G Guyatt D Bangsberg JAMA.
2006296679-69
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Effect of HAART on HIV Transmission

• PEP/PrEP
• MTCT
• Discordant Couples
• Ecological Evidence

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MTCT from 25 to lt 1

• Before 1994 25
• 1994 - 1996 8
• 1996 - 1998 2
• Modern HAART lt1 transmission

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Discordant Couples
T Quinn et al, NEJM, 342921-929, 2000
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Effect of HAART on Heterosexual Transmission of
HIV - Spain

• Prospective observational study of heterosexual
  couples in Madrid
• N 393 couples, index case HIV , enrolled
  1991-2003
• HIV infection prevalence of partners of index
  cases without ART 8.6
• HIV infection prevalence of partners of index
  cases on HAART 0

P 0.0129 HAART vs other options
P 0.006 pre-HAART vs late-HAART
Castilla, et al. JAIDS 2005 4096-101
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New HIV and Syphilis in BC
Rate per 100,000 population
M REKART, BC-CDC, 2006
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Cost-Effectiveness of HAART Re-examined BC-DTP
HIV deficit in BC in 2005 400

• Cost of Medical Management of 1 HIV infection
  over a lifetime 250,000

Averted lifetime Rx cost up to 2001 US 96.4M A
total of 3,963 pts were on HAART in BC in
2005 Total actual drug cost (using patented
drugs) in 2005 49 million US
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Cost-Effectiveness of HAARTRe-examined
HIV deficit in North America in 2005 94,741

• Cost of Medical Management of 1 HIV infection
  over a lifetime 250,000

Averted Cost up to 23,685,250,000
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Expansion of HAART for HIV PreventionChallenges
Untested hypothesis Safety/Toxicity Individual
Rights Resistance Hidden Epidemics
Logistics Erosion of Prevention Effort Cost
This hypothesis needs to be explored
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Conclusion

• HAART has evolved dramatically over the last
  decade
• HAART is cost-effective using a traditional
  patient centered model
• - HAART decreases Morbidity/Mortality
• HAART is even more cost-effective when its potent
  effect on secondary HIV prevention is considered

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The impressive clinical impact and
cost-effectiveness of modern HAART provide a very
powerful rationale to urgently expand HAART
programs (at the very least, to those in medical
need, on a world wide basis)
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The impressive clinical impact and
cost-effectiveness of modern HAART provide a very
powerful rationale to urgently expand HAART
programs (at the very least, to those in medical
need, on a world wide basis)
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Acknowledgements

• R Hogg, E Wood, T Kerr, M Tyndall, A Levy, PR
  Harrigan,
• Pedro Cahn, Jose Esparza, Craig Mc Clure
• BC-Centre for Excellence on HIV/AIDS
• HIV/AIDS Program at PHC/UBC
• Canadian HIV Trials Network
• International Collaborators
• ART Guidelines Panel, IAS - USA
• BC-MoH
• SPH Foundation
• International Research-based Pharmaceutical
  Industry
• MSHRF, CIHR and NIH
• HW, Ottawa
• Research Staff and Study Participants