Sequenced HAART regimens in the resource poor setting

1
Sequenced HAART regimens in the resource poor
setting

• Dr Ian Sanne
• Clinical HIV Research Unit
• International ACTG Site / CIPRA-SA site
• University of the Witwatersrand
• Right To Care

2
Current HIV prevalence worldwide
Eastern Europe Central \Asia 1 200 000
Western Europe 570 000
North America 980 000
East Asia Pacific 1 200 000
North Africa Middle East 550 000
Caribbean 440 000
South South-East Asia 6 000 000
Australia New Zealand 15 000
Sub Saharan Africa 29 400 000
Latin America 1 500 000
Total 42 million
Joint United Nations Programme on HIV/AIDS
(UNAIDS) and World Health Organization (WHO).
AIDS epidemic update Dec 2002
3
Scale-up of HAART

• Implementation in over 400 sites across South
  Africa
• Treatment initiated in over 50,000 patients in 1
  year
• Centralized procurement strategy
• In country manufacture of generic medicines (80
  Aspen, 10 CIPLA, 10 Brand)
• Right To Care responsible for 4575 initiated on
  treatment in 2004

4
Themba Lethu Clinic

• Initiated over 3500 patients since April 2004
• 85 of first line therapy D4T, 3TC, EFV
• 56 Women of child bearing potential
• 12/1276 treatment switch for toxicity
• 88 viral load undetectable at 6 months
• lt2 on second line therapy

5
Overview

• Treatment standardization
• How is ARV resistance informing treatment
  decisions
• First line treatment regimens studies that
  inform decisions
• New drugs registered in 2003

6
The ideal HAART regimen

• Highly effective
• Low toxicity
• Easy to comply with
• Once-daily dosing
• Few pills
• Few or no food restrictions
• High barrier to resistance

7
Public Health Ideal

• Equitable treatment access and distribution
• Low cost
• Simple treatment strategy
• Not too much choice
• Prescribed by Primary Health Care Clinics
• Low monitoring requirements
• Implementation considerationsRefridgeration
• Sequenced treatment for failure

8
National Roll-Out South Africa
9
Treatment adherence

• Pill burden
• Dose interval
• Requirement of dosing with food
• Independent of socio-economic group, education
  status

10
How will the treatment be monitored?

• Clinical Monitoring good for side effects,
  general clinical features good but not sensitive
  enough 75 effective (1)
• CD4 count intra-laboratory variability of 15,
  clinically dependent (eg. TB)
• Opportunistic Infections 5 new AIDS defining
  illness despite maximal viral suppression Immune
  reconstitution syndromes severe potentially
  irreversible immunosuppression

11
HIV resistance how is this informing treatment
options?
12
Antiretroviral drug resistance develops from
incomplete inhibition of viral replication
Weak Drug Pressure
wild type virus(drug susceptible)
mutant virus(drug resistant)
TIME
Contributed by Dan Kuritzkes
13
Better Inhibition of Viral Replication Delays
Drug Resistance
Potent Drug Pressure
TIME
Contributed by Dan Kuritzkes
14
Low Genetic Barrier for ARV resistance (3TC,
NNRTIs)
Relative Resistance
3
4
2
5
1
Number of Mutations
15
High Genetic Barrier for ARV resistance (ZDV,
d4T, TDF, PIs)
Relative Resistance
3
4
2
5
1
Number of Mutations
16
Initial Resistance NNRTI-based Regimens

• NNRTI resistance mutations
• 45 to 80 of early failures
• 3TC resistance
• 30-50 of early failures
• Other resistance mutations e.g. TAMs, K65R
• lt 10

17
Poorer Virologic Response From Delayed Switch
First regimen Second regimen
Late switch
Intermediate switch
Early switch
Viral load
Accumulation of mutations
Time
18
CNA3005 Mutations After Virologic Failureon
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.
19
Effect of Increasing Number of TAMS on NRTI
Susceptibility
10,000
100
100
AZT
TDF
3TC
1,000
10
10
100
Fold Changein NRTI Susceptibility
10
1
1
1
-1
-1
-1
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
100
10
100
d4T
ddI
ABC
Fold Changein NRTI Susceptibility
10
10
1
1
1
-1
-1
-1
0
1
2
3
4
5
6
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Number of TAMs
Number of TAMs
Number of TAMs
Whitcomb JM et al. 9th CROI, Seattle, 2002.
Abstract 569.
20
Selection of NRTI Resistance Mutations

• TAMs (41L, 67N, 70R, 210W, 215Y/F, 219Q/E)
• Uncommon in early virologic failure
• Selected sequentially
• Emergence somewhat delayed if M184V is present
• Modest impact on viral fitness

21
Effect of 184V on response to ddI

• Virus load response in ACTG 307 184V mutation1
• Lack of effect of 184V on ddI response seen in
  other studies2,3

19 7 4 13 17
9 52 24 13
n
Week 8 D plasma HIV-1 RNA (log c/mL)
pNS for all comparisons
1. Eron J. Antiviral Therapy 20027S102 2.
Winters MA. Antiviral Therapy 20027S101 3.
Gazzard B, et al. XIV Int AIDS Conference,
Barcelona 2002, 3144
22
Which nucleoside combination to use in first line
therapy

• ACTG 384

23
ACTG 384 Design

• 980 Antiretroviral naïve subjects (lt7 days prior
  ART)
• HIV-1 viral load gt500 copies/ml
• Stratification
• HIV RNA lt10,000, 10,000-100,000, gt100,000 c/mL
• Country US, Italy

24
(No Transcript)
25
NNRTI which one?

• 2NN study results

26
Treatment success and failure
Success only significant difference EFV vs
NVPEFV, plt 0.001
27
Grade 3 or 4 laboratory toxicities
hepatobiliary only significant difference
NVP-od vs EFV, plt 0.001
28
Overlapping toxicity ddI and d4T
29
Triple nucleoside regimens

• ACTG 5095

30
A5095 Results 32 Weeks F/U
31
A5095 Time to Virol Failure, Baseline VL lt
100,000 copies
Pooled EFV arms
ZDV/3TC/ABC
Probability of Not Failing
Log rank treatment comparisons Z3.30, p0.001
Weeks from Randomization
32
Pros and Cons of Thymidine vs Thymidine-Sparing
First-line Regimens
Thymidine Analogue-Sparing Regimens (TDF/3TC,
ABC/3TC, ddI/3TC)
Thymidine Analogue-Based Regimens (AZT/3TC,
d4T/3TC)

• Best studied
• Low pill burden (AZT/3TC)
• QD therapy (d4T/3TC)
• Established potency
• Gradual resistance (delayedTAMs with M184V)
• Prevention of K65R (AZT)

• Preservation ofthymidine analogues
• Less mitochondrial toxicity
• QD therapy
• Established potency
• Broader cross-resistanceof TAMs
• K65R ? AZT hypersusceptibility

33
Tenofovir

• Nucleotide analogue reverse transcriptase
  inhibitor
• Once daily dosing

34
Study 903 Tenofovir Patients lt 50 Copies/mL at
96 weeks
Intent to Treat (MissingFailure)
TDF3TCEFV d4T3TCEFV

(n299) (n301)
HIV RNA c/mL
? 100,000 128/161 (80) 127/172
(74) gt 100,000 104/138 (75)
95/129 (74) CD4 Cells/mm3 lt 200
87/118 (74) 78/113 (69) ? 200
145/181 (80) 144/188 (77)
Data on file. Gilead Sciences, Inc. February
2003.
35
Atazanavir Clinical Profile

• Once-daily azapeptide PI
• Cmin gt protein-binding adjusted EC50 for gt 36 h
• Low pill burden (2 capsules/day)
• Efficacy and durability of response in
  treatment-naïve and -experienced patients
• Favorable effects on metabolic (lipid) parameters
• I50L is signature mutation in PI-naïve patients1
• Associated with ? in vitro sensitivity to other
  PIs
• May preserve future treatment options

1Colonno et al. XI International HIV Drug
Resistance Workshop. July 25, 2002, Seville,
Spain
36
Public Health Ideal

• Equitable treatment access and distribution
• Low cost
• Simple treatment strategy
• Not too much choice
• Prescribed by Primary Health Care Clinics
• Low monitoring requirements
• Implementation considerationsRefridgeration
• Sequenced treatment for failure

37
Conclusion

• First line therapy?ABC 3TC EFV/NVPTDF FTC
  EFV/NVP(Continued use of NVP for MTCT)
• Resistance second line treatmentDidanosine, AZT
  ltgt TDF
• First Protease InhibitorWhich is best PI
  following an NNRTI regimen failure