Resistance Primer

1

Managing Antiretroviral Failure and the Use of
Resistance Testing
Paul E. Sax, MD
The International AIDS SocietyUSA
2
What You Need to Know

• Resistance testing is complicated
• Resistance criteria are changing all the time
• Once resistant, always resistant, but resistance
  often isnt absolute
• Certain key mutations are worth memorizing
  (sorry)
• Practice, practice, practice

3
Clinical situations in which resistance testing
is recommended (IAS-USA)

• Acute or recent (lt12 months) HIV infection
• Before initiation of antiretroviral therapy in
  established HIV infection
• Patients infected within previous 2 years and
  possibly longer
• Regimen failure
• Pregnancy (if detectable plasma HIV-1 RNA level)

DHHS guidelines recommend if gt5 prevalence of
resistance in community
Hirsch MS, et al. Clin Infect Dis
200337113-128 DHHS Guidelines, July 14, 2003,
www.hivinfo.nih.gov
4
Limitations of Prevalence Data onPrimary Drug
Resistance

• Review of 12 studies on prevalence of primary
  drug resistance
• 1993 to 2002, n80-1092
• Range 5 to 30 (largest studies 10)
• Trend data on prevalence of resistance highly
  variable
• Lack of consistency of sampling
• Variability of sample size
• However Data likely exclude a major increase or
  decrease in resistance rates during the past 3-4
  years

Kaplan J. XV IAC, Bangkok 2004, TuBs194
5
Relative Cost-Effectiveness of Genotype
Resistance Testing
2800
PCP/toxoplasmosis prophylaxis1
13,000
Antiretroviral therapy2
16,500
Resistance testing after failure
28,600
MAC prophylaxis3
31,700
Resistance testing first regimen
77,200
Fungal prophylaxis4
1,452,500
PCP prophylaxis5
Cost ()/QALY
QALFquality adjusted life-year
saved. 1Co-trimoxozole 2AZT/3TC/EFV
3azithromycin 4fluconazole 5atovaquone. Sax
P, et al. XIV IAS. Barcelona, 2002. Abstract
MoPeB3129.
6
Primary Resistance Increases the Risk of
Virologic Failure

• Prospective, international study of 571 ARV-naïve
  pts
• 95 (546/571) had baseline resistance testing
• 16 (90/546) showed baseline NRTI and/or NNRTI
  resistance

Borroto-Esoda K, et al. 11th CROI, San Francisco
2004, 672
7
NNRTIs Mutations You Need to Know

• Extensive cross-resistance between efavirenz,
  nevirapine, and delavirdine
• Remember K103N, Y181C
• For experts L100I, V106A, V108I, Y188L G190S,
  P225H
• More being discovered all the time

8
Protease Inhibitors Distinctive Resistance
Patterns

• Certain selected mutations associated with little
  PI cross resistance
• nelfinavir and D30N
• atazanavir and I50L
• fosamprenavir and I50V or I54V
• When these mutations are selected, other PIs
  retain activity, but
• NRTI resistance is often present as well
• NFV and FPV (?ATV) may select for broader
  resistance in certain settings

9
Key PI resistance mutations and high-level PI
resistance

• All PIs will have activity reduced by the
  presence of substitutions at 46, 54, 82, 84, and
  90
• More mutations (including minor mutations) more
  resistance
• Resistance to boosted PIs is relative, not
  absolute

10
Approach to PI Resistance

• Look for key mutations
• D30N, I50L or V, I54V
• Count of key protease mutations at 46, 54, 82,
  84, and 90
• Get a sense of resistance density

11
Approach to PI Resistance -- Continued

• Classify as none, low-level, moderate, or
  high-level resistance
• Low level 1 of the friendly mutations
• Moderate 1 or 2 (maybe 3) of the common
  PI-associated mutations
• High-level 4 or more of the common
  PI-associated mutations
• For patients with any PI resistance, a boosted PI
  should be at least part of any subsequent regimen

12
NRTIs Resistance Patterns You Need to Know

• 3TC and FTC and M184V
• TDF, ABC, ddI and K65R or L74V
• AZT and d4T and TAMS M41L, L210W, T215Y vs.
  D67N, K70R, and K219Q

13
3TC or FTC and M184V

• M184V emerges rapidly (days-weeks) in
  non-suppressive regimens
• Associated with high level phenotypic
  resistance in vitro, but also reduction in
  replication capacity, HIV RNA lt baseline
• Increases activity of AZT, d4T, TDF decreases
  (slightly) ABC, ddI, but all NRTIs have some
  activity
• When to stop?

14
Continuing 3TC Despite Resistance Documented
Benefit (E-184V Study)

• Randomized study in patients with virologic
  failure on 3TC-containing ART (n50) and M184V
  mutation all had CD4 gt 500
• Replication capacity increased in interruption
  group and remained low in 3TC monotherapy group

Castagna A, et al. XV IAC, Bangkok 2004,
WeOrB1286
15
Tenofovir, abacavir, ddI and K65R

• Patients treated with TDF 3TC/FTC EFV may
  develop one or all of K65R, M184V, and NNRTI
  mutations
• K65R induces broad NRTI resistance potentially
  the cause of poor ABC/3TC/TDF and ddI/3TC/TDF
  performance
• Also selected by ABC, ddI, d4T other mutational
  patterns appear more common
• AZT remains active vs K65R mutants

16
NRTI Resistance Mutations and Replication Capacity
(n 130)
57
(n 8)
56
(n 3)
29
(n 60)
80
(n 36)
73
(n 9)
82
(n 61)
66
(n 68)
N 1040 Excludes samples with PI-resistance
55
(n 21)
47
(n 2)
30
(n 3)
29
0
10
20
30
40
50
60
70
80
90
100
Median Replication Capacity ( of WT Reference)
P lt .05 P lt .001 (vs no NAMs/no TAMs group)
Miller MD, et al. 10th CROI, Boston 2003.
Abstract 616.
17
NNRTIs Is sequencing an option?

• NVP failures often select for Y181C EFV still
  active phenotypically
• G190A may lead to delavirdine hypersusceptibility
• Clinical significance of above unclear most
  studies suggest any prior NNRTI resistance
  reduces subsequent NNRTI response

18
AZT and d4T and TAMS

• Thymidine-associated mutations, emerge
  sequentially with AZT and d4T containing regimens
• More TAMS more cross resistance 3 or more a
  typical cutoff for ddI and ABC
• Two pathways (overlap occurs)
• M41L, L210W, T215Y (bad, knocks out TDF)
• D67N, K70R, and K219Q (less bad, TDF still active)

19
Change in NRTI Susceptibility and Number of TAMs,
With and Without M184V
Whitcombe JM, et al. J Infect Dis.
2003188992-1000.
20
Change in NRTI Susceptibility and Number of TAMs,
With and Without M184V
Whitcombe JM, et al. J Infect Dis.
2003188992-1000.
21
4 Week HIV RNA Response After Adding ddI to a
Failing Regimen
Molina J, et al. 43rd ICAAC, Chicago 2003, H-447
22
TDF Resistance and Virologic Response
222
42
57
68
55
n

Mean DAVG24 (log10 c/mL)

plt0.0001 p0.013



All patients
No TAMs
1 or 2 TAMs
gt3 TAMs with M41L or L210W
gt3 TAM no M41L or L210W
Miller M, et al J Infect Dis. 2004 Mar
1189(5)837-46.
23
Approach to NRTI Resistance

• Look for key mutations
• M184V
• TAMS of two pathways
• K65R
• L74V (ddI, ABC resistance -- AZT still active)
• Get a sense of resistance density

24
Approach to NRTI Resistance -- Continued

• Classify as none, low-level, moderate, or
  high-level resistance
• Low level M184V alone (all commonly-used NRTIs
  have some activity)
• Moderate M184V with lt3 TAMS
• High-level M184V with 3 or more TAMS (esp with
  210) or K65R
• Continue 3TC/FTC? Why not?

25
TORO Studies Predictors of HIV RNA lt 400
VL lt 400 by Number of Positive Prognostic Factors
(Simplified Model)
100
ENFOB
OB
80
80
P lt .05
59
60
50
of patients
47
34
40
19

• If all 4 predictive factors present, 80 reach
  VL lt400 c/mL at Week 24

23
20
15
3
2
0
0
1
2
3
4
Number of positive prognostic factors
n 140 61 188 93 192 100 101 56
40 24
Montaner J, et al. 2nd IAS, Paris 2003, Abstract
116.
26
Early Antiviral Activity in BI 1182.51
0
-0.2
-0.4
-0.6
HIV RNA (log10 copies)
-0.8
-1
-1.2
Functional Monotherapy
TPV added to LPV/APV/SQV
-1.4
0
2
4
6
8
Weeks of Treatment
Walmsley S, et al. XV IAC, Bangkok 2004,
WeOrB1236
27
Low-level Viremia Associated with a Low
Short-term Risk of Disease Progression
Slide 27

• CHORUS database n3009
• Entry stable VL for 6 months
• Stratified into 3 groups
• VL lt400K c/mL
• VL 400K20K c/mL
• VL gt20K c/mL
• Endpoints Death or AIDS event
• Mean follow-up 3 years
• Results independent of pretreatment CD4

• Conclusion
• Low to moderate viremia not associated with
  clinical progression if VL is below pre-treatment
  baseline and CD4 is preserved

Raffanti SR, et al. J Acquir Immune Defic Syndr
2004371147-1154
28
STI prior to Salvage may Lead to Permanent Loss
of CD4 cells
Lawrence J, et al. N Engl J Med. 2003 Aug
28349(9)837-46.
29
The Most Important Slide

• Deciding whether to switch, and what to switch
  to, depends on multiple factors
• Patient clinical status, including CD4/HIV RNA
• Patient adherence
• Patient ability to tolerate complex regimens
• Antiretroviral history
• Availability of new options, both now and on the
  immediate horizon
• Resistance testing offers some guidance for this
  very tough decision

30
http//www.hardballtimes.com/main/authors/studes/