Durability of Initial ARV Induced Viral Suppression: Key to Long Term Access, Scalability and Sustai

1
Durability of Initial ARV Induced Viral
Suppression Key to Long Term Access,
Scalability and Sustainability of Comprehensive
HIV care and Treatment in Resource Constraint
CountriesRobert R. Redfield MDInstitute of
Human Virology Abuja, NigeriaMay 4, 2004
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Global Antiretroviral TherapyOpening Thought

• How do we optimally balance the need to rapidly
  eliminate the ARV treatment inequity worldwide
  with the compelling need to implement programs
  which will provide a durable benefit to today's
  patients as well as patients a decade or more
  into the future?

3
Term Definition

• Branded Drugs
• Generic Drugs
• Non Branded Drugs
• Fixed Dose Combination
• Branded
• Generic
• Non Branded

4
FDC Considerations

• Chemical equivalence of active ingredients
• Bioactivity equivalence when co-formulated
• Formulation material impact on drug component
  activity and its bio-availability
• PK profile of components and overall FDC
• Food restrictions or requirements of components

5
Impact of Anti-retroviral Therapy in the US

• Positive Impact
• Major impact on mortality of advanced HIV
  infection
• Major impact on morbidity secondary to HIV
  infection
• gt90 reduction in perinatal HIV infection
• Coupled with the prevention of complicating
  O.I.s using prophylactic antibiotics, many HIV
  patients living in the US and Western World may
  now
• live a natural life time.

6
Impact of Anti-retroviral Therapy in the US

• Negative Impact
• Increased treatment failure secondary to the
  development of drug resistance
• Increase dependency on high cost and high tech
  diagnostics for routine clinical management
• Increase dependency on high cost and experimental
  drugs to maintain clinical benefit
• Increase morbidity secondary to drug induced
  toxicities
• Increase transmission of anti-retroviral drug
  resistant virus
• Significant swings in consensus recommendation
  related to use of anti-retroviral therapy

7
Antiretroviral Drugs 2004

• NRTIs NNRTIs PIs
• Zidovudine Nevirapine Saquinavir
• Didanosine Delavirdine Ritonavir
• Stavudine Efavirenz Indinavir
• Lamivudine Nelfinavir
• Zalcitabine Amprenavir
• Abacavir Lopinavir/r
• Combivir Atazanavir
• Trizivir Fosamprenavir
• Didanosine EC
• Stavudine SR
• FTC

Nucleotide RTI Tenofovir Entry Inhibitors
T20

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Real Life Settings Demonstrates Limited
Durability in Clinical Cohort Studies(1 year
Antiretroviral Treatment Success Rates)

• Baltimore (JHU) 37
• Cleveland Clinic 47
• San Francisco (UCSF) 50
• Amsterdam 60
• Ref Lucas Annal 1999, Deeks AIDS 1999 ,
  Casado AIDS 1998)
• Baltimore (JHU) 36 (18 months)
• 1999-2003 ARV naïve
• Ref Lucas JAIDS 2003

9
Prevalence of Drug Resistance1080/1906 patients
Assumes no resistance in samples with HIV RNA
lt500 copies/mL Represents 63 of total study
population
10
Increasing Frequency of Primary Drug Resistance
Treatment-Naive Patients (N 377)
P .002
P lt .001
P .03
P .07
P .01
Isolates with gt10-foldreduced susceptibility
Little SJ, et al. N Engl J Med. 2002347385-394.
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Durability of Viral Suppression in Key Clinical
Trials
d4T ddI EMV (MKC-302)
AZT 3TC APV (PROAB 3301)
AZT 3TC IDV (START II)
with HIV RNAlt50 copies/mL at 48 Weeks (ITT)
AZT 3TC ABC (CNA3005)
d4T ddI IDV (START II)
AZT 3TC IDV (DMP-006)
AZT 3TC IDV (AVANTI 2)
AZT ddI NVP (INCAS)
AZT 3TC NFV (AVANTI 3)
AZT 3TC IDV (CNA3005)
AZT 3TC IDV (START I)
Regimen (trial)
d4T 3TC EMV (MKC-302)
d4T ddI 3TC (Atlantic)
d4T 3TC IDV (START I)
d4T ddI NVP (Atlantic)
2 NRTIs NVP qd or BID (2NN)
d4T 3TC NFV (M98-863)
AZT 3TC ABC (CNAB3003)
d4T ddI IDV (Atlantic)
d4T 3TC LPV/RTV (M98-863)
(AZT 3TC EFV DMP-006)
d4T 3TC EFV (DMP-043)
d4T 3TC EFV (GS-903)
TDF 3TC EFV (GS-903)
0
10
20
30
40
50
60
70
80
90
100
Based on Bartlett. Presented at 7th CROI 2000
San Francisco, Calif. Poster 519.
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Scaling up Western ARV Derived Treatment
Approach in Brazil

• Brazil has approximately 150,000 patients on
  ARVs via National program
• Significant positive impact on AIDS related
  hospitalization and deaths observed within 2
  years
• 44 resistance in patients on therapy after 2 yrs
• 6-7 of newly diagnosed pts have primary ARV
  resistance
• ARV formulary expanded to 15 ARV drugs
• Expanded need for increase viral diagnostic
  assays for patient management
• Cost per patient under treatment increasing
• Concerns increasing that National commitment to
  provide ARV to all Brazilian will either be
  difficult to maintain or negatively impact other
  health care programs

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Drug Resistance Status and Implications

• Increasing patient with drug resistance
• patients under treatment in clinic setting 30-50
• patients with MDRV requiring deep salvage
  therapy 10-15
• primary drug resistance in new HIV infections
  8-12
• high rates of resistance to cytosine analog and
  NNRTIs gt25
• loss of drug antiviral potency
• cross class resistance
• Increasing dependency on
• sophisticated diagnostic technology,
• clinical expertise,
• management of drug toxicity as a chronic disease
• non cytosine analog and non NNRTI ARVs for long
  term therapy
• need for experimental therapies and new drug
  development
• increasing cost of patient management

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Non-branded FDC (Triommune (D4T, 3TC, Nev)
Scientific Consideration

• Potency of primary regimen
• Limited efficacy of branded FDC
• Limited efficacy of co-administration of potent
  branded drugs
• Cell cycle restriction of thymine analog activity
• Low mutation threshold of 3TC and Nevirapine
• Background Resistance (Neviripine,3TC thymine
  analogs)
• PK profile of regimen
• Significantly different pk profile of active
  drugs
• Changing toxicity profile
• Nevirapine hepatotocity
• D4T lipodystropy, lipoatropy and mitochondrial
• toxicity

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Triple NRTIS strategies
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CNA3005 Mutations After Virologic Failure on
AZT/3TC/ABC
Increasing NRTI cross-resistance
Patients ()
9-16
(n 16)
(n 39)
(n 34)
(n 28)
(n 24)
(n 20)
Weeks On Therapy After First Genotype Test
Melby T et al. 8th CROI, Chicago, 2001. Abstract
448.
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Success of Nucleoside/tide Regimens
Jemsek et al. 11th CROI, 2004 Gallant JE, et al.
43rd ICAAC 2003, Presentation H-1722a Farthing
C, et al. Antiviral Therapy 2003 8 (Suppl. 1)
S195, Abstract 43. Roge BT, et al. Antiviral
Ther 20038173-182 and Gerstoft J, et al. AIDS
2003172045-2052 Melby T, et al. 7th CROI,
Abstract 750.
Adapted from Elion R, et al. 11th CROI, San
Francisco 2004, Abstract 53.
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Non-branded FDC (Triommune (D4T, 3TC, Nev)
Scientific Consideration

• Potency of primary regimen
• Limited efficacy of branded FDC
• Limited efficacy of co-administration of potent
  branded drugs
• Cell cycle restriction of thymine analog activity
• Low mutation threshold of 3TC and Nevirapine
• Background Resistance (Neviripine,3TC thymine
  analogs)
• PK profile of regimen
• Significantly different pk profile of active
  drugs
• Changing toxicity profile
• Nevirapine hepatotocity
• D4T lipodystropy, lipoatropy and mitochondrial
• toxicity

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HIV infection occurs inactivated and resting
PMBC. Does state of cell cycle impact antiviral
activity of approved antiretroviral drug?
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Role of Cell Cycle Agents What is the Impact of
Cell Cycle on the Anti-Viral Activity of RT
Inhibitors?
HIV-1 p24 antigen (ng/ml)
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Role of Cell Cycle AgentsAZT has limited
antiviral Activity in resting HIV infected cells
800
600
400
HIV-1 p24 antigen (ng/ml)
200
0
0
0.03
0.1
0.3
1
4
AZT - Resting Cell Infection
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Non-branded FDC (Triommune (D4T, 3TC, Nev)
Scientific Consideration

• Potency of primary regimen
• Limited efficacy of branded FDC
• Limited efficacy of co-administration of potent
  branded drugs
• Cell cycle restriction of thymine analog activity
• Low mutation threshold of 3TC and Nevirapine
• Background Resistance (Neviripine,3TC thymine
  analogs)
• PK profile of regimen
• Significantly different pk profile of active
  drugs
• Changing toxicity profile
• Nevirapine hepatotocity
• D4T lipodystropy, lipoatropy and mitochondrial
• toxicity

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Low Mutation Threshold Drugs

• Cytosine analogs
• 3TC
• FTC
• NNRTI
• Nevirapine
• Efavirenz

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Resistance and Transmission following Single dose
NVP for PMTCT in Recently Presented Studies

• Multiple studies performed evaluating NVP for
  PMTCT
• Maternal Resistance 17-39
• Higher rates with gt 1 dose
• K103N, Y181C, Y188C
• Infant Resistance 20-45
• Resistance has been associated with
• CD4
• Viral load
• doses of NVP
• time from labor NVP dose to postpartum blood draw

1. Martinson, et al, 11th CROI 2004, Abstract
38. 2. Chalermchokcharoenkit, et al,
11th CROI 2004, Abstract 96 3. Jourdain, et al,
11th CROI 2004, Abstract 41LB
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Response to d4T/3TC/NVP in mothers based on
previous history of single-dose NVP
90
60
With Virologic Suppression
30
0
Baseline
3 months
6 months
42
37
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No NVP
NVPNo Mutation
139
112
110
NVP Mutation
81
58
50
Jourdain G, et al. 11th CROI 2004 Abstract 41
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ACTG 398 HIV-1 RNA response (log10 copies/ml) by
NNRTI Experience and NNRTI mutations
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Non-branded FDC (Triommune (D4T, 3TC, Nev)
Scientific Consideration

• Potency of primary regimen
• Limited efficacy of branded FDC
• Limited efficacy of co-administration of potent
  branded drugs
• Cell cycle restriction of thymine analog activity
• Low mutation threshold of 3TC and Nevirapine
• Background Resistance (Neviripine,3TC thymine
  analogs)
• PK profile of regimen
• Significantly different pk profile of active
  drugs
• Changing toxicity profile
• Nevirapine hepatotocity
• D4T lipodystropy, lipoatropy and mitochondrial
• toxicity

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Stopping drugs with different half lives
Last Dose
Day 1
Day 2
Drug concentration
IC90
Zone of potential replication
IC50
12
0
24
48
36
Time (hours)
S. Taylor et al. 11th CROI Abs 131
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Nelfinavir plasma concentration profiles
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Non-branded FDC (Triommune (D4T, 3TC, Nev)
Scientific Consideration

• Potency of primary regimen
• Limited efficacy of branded FDC
• Limited efficacy of co-administration of potent
  branded drugs
• Cell cycle restriction of thymine analog activity
• Low mutation threshold of 3TC and Nevirapine
• Background Resistance (Neviripine,3TC thymine
  analogs)
• PK profile of regimen
• Significantly different pk profile of active
  drugs
• Changing toxicity profile
• Nevirapine hepatotocity
• D4T lipodystropy, lipoatropy and mitochondrial
• toxicity

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Nevirapine label change for hepatotoxicity

• Severe, life-threatening hepatotoxicity
• Often associated with rash
• Greatest risk in women with CD4 gt250 cells/mm3
  (12-fold ? risk)
• Increased risk for men with CD4 gt400 cells/mm3
  (3-fold ? risk)
• Greatest risk during first 6 weeks (continued
  risk through 18 weeks)
• Symptoms often non-specific, including fatigue,
  malaise, anorexia, nausea, jaundice
• Hepatic injury may progress despite drug
  discontinuation
• Monitoring
• Transaminases at baseline, 2 weeks, 4 weeks, and
  regularly thereafter
• Draw transaminases with any rash
• Dont escalate NVP dose until rash resolved

Nevirapine package insert, January 23, 2004
32
(No Transcript)
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Non-branded FDC (Triommune (D4T, 3TC, Nev)
Scientific Consideration

• Potency of primary regimen
• Limited efficacy of branded FDC
• Limited efficacy of co-administration of potent
  branded drugs
• Cell cycle restriction of thymine analog activity
• Low mutation threshold of 3TC and Nevirapine
• Background Resistance (Neviripine,3TC thymine
  analogs)
• PK profile of regimen
• Significantly different pk profile of active
  drugs
• Changing toxicity profile
• Nevirapine hepatotocity
• D4T lipodystropy, lipoatropy and mitochondrial
• toxicity

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Lipodystrophy
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Inhibition of Polymerase Gamma
Higher value greater inhibition
Relative potency of inhibition of
polymerase gamma (? )
Nucleoside analog
1/Ki/Km
Martin et al. AAC 1994 38 2743. Chen et al. Mol
Pharm 1991 39 625. Daluge et al, AAbC 1997 41
1082.
36
Effect of NRTIs on mtDNA Content in Human
Skeletal Muscle Cells

• Primary human SkMC
• 9-day incubation with the drugs
• Southern-blot analysis of mitochondrial DNA vs.
  chromosomal DNA

140
120
TDF
100
3TC
d4T
80
ddI
Relative mtDNA Content
ddC
60
AZT
40
20
0
0.01
0.1
1
10
100
1000
NTRI Concentration ?M
Birkus and Cihlar, unpublished data (2001)
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What Impact will rapid scale up of D4T, 3TC and
Nevirapine based regimen have on future
treatment options for patients treated in 3 by 5
scale up.?
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Implications of Stages of Treatment Failure with
D4T, 3TC and Nev
Remaining Treatment Options
NRTIs ABC, AZT, ddI, d4T, TDF NNRTIs
None PIs All
Early Virologic Failure
d4T, 3TC, Nevirapine
Clinical Failure (Late Virologic Failure)
NRTIs None NNRTIs None PIs All
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Current Limitations

• Limited Safety and Efficacy of FDC in populations
  proposed for rapid scale up (3 million by 2005)
• Bioequivalence data of FDC formulation in terms
  of drug activity and drug absorption poorly
  defined in target populations to date
• Co-formulation of drugs of different Pk profiles
• Drugs involved in co-formulation recently
  recognized to cause significant toxicity ( D4T
  and Nev) which has modifed use in Europe and US

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Central to Long Term Success Durability of
Viral Suppression will Ultimately Define Access
to Efficacious ARV therapy

• Durability of Viral Suppression
• Preservation of Potency of Cytosine analog and
  NNRTI drugs
• Integration of evidence based data driving ARV
  scale up decisions

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Closing Questions for Reflection

• Is the wide-scale use of FDC Triomune (D4T, 3TC
  Nevirapine) or equivalent based regimen the best
  regimen for National scale up?
• Has adequate safety and efficacy data been
  obtained to warrant use in wide-scale AVR
  scale-up?
• Has its durability threshold been validated in
  countries to be used wide scale expansion in WHO
  3 by 5 program?
• Has adequate post marketing system been
  established to monitor for post marketing safety
  concerns related to drug toxicity or efficacy?
• If wide scale use of Triomune go forward in
  global ARV programs, what will be its ultimate
  impact on access to treatment, scalability, and
  long term sustainability of HIV treatment and
  care programs in the developing world?
• Is there any lessons to be learn from wide scale
  implementation of Nevirapine based PMTCT programs