Template

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Strategies for Antiretroviral Therapy Case-based
Discussion
Joseph J. Eron, Jr. MDProfessor of
MedicineUniversity of North Carolina
The International AIDS SocietyUSA
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Initiation of Antiretroviral Therapy
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Case 1

• Patient is 42 yo white woman recently diagnosed
  with HIV
• Partner died 5 years ago of unknown causes
• She has hypertension and type II Diabetes
• Has taken your adherence tutorial and HIV 101
  training. She appears ready for therapy.
• Her viral load is 35,000 and her CD4 cell count
  is 330 repeat measures are similar

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Case 1 Question 1

• At this point you would
• Defer therapy and follow the patient every 6
  months
• Defer therapy and follow the patient every 3
  months
• Begin the process of therapy initiation

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Guidelines for Initiation of ART
except TB
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Observational cohort data supporting earlier
therapy

• SMART1
• Subset of patients ART-naïve or not on ART at
  randomization
• Immediate ART n249 (131 naïve)
• Deferred ART n228 (118 naïve)
• Greater risk of OI, OI/death, serious non-AIDS
  event with deferred ARV
• gt5-fold increased composite risk with deferred
  ARV
• CASCADE2
• N9,858 median F/U 8 years post-seroconversion
• 597 deaths, gt50 non-AIDS-related
• Current CD4, nadir CD4, and time with CD4 lt350
  cells/mm3 associated with
• AIDS deaths
• Non-AIDS deaths Severe infections, liver
  disease, malignancy

1. Emery S, et al. 4th IAS, Sydney 2007,
WEPEB018 2. Marin B, et al. ibid, WEPEB019
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Case 1 Question 2

• Would you order a resistance test prior to
  therapy initiation?
• Yes
• No

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How Common is Drug Resistance at Diagnosis?

• US Variant, Atypical and Resistant HIV
  Surveillance System (VARHS)
• Estimate prevalence of transmitted resistant
  mutations
• Determine distribution of HIV subtypes
• March 2003 to October 2006 11 states, 409 sites,
  n3130

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6.9
M41L 45.1 of NRTI K103N 70.1 of NNRTI L90M
40.0 of PI 95 Subtype B
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3.6
2.4
1.9
MDR
Any
NRTI
NNRTI
PI
Wheeler et al. 14th CROI. Los Angeles, 2007. Abs
648
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In resource rich world, transmitted resistance
appears to be stabilising or even reducing
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Chronic infection
12
10
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Samples with IAS mutation(s) ()
6
4
Acute infection
2
0
1997
1998
1999
2000
2001
2002
2003
2004
2005
Year of sample
UK Collaborative Group on HIV Drug
Resistance. AIDS 2007211035-9.
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Case 1 Question 3

• Which resistance test would you order?
• Genotype
• Phenotype
• Geno/Pheno Assay

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Case 1

• You decide to initiate therapy
• Prior to initiating therapy you obtain the
  following information
• Genotype shows wild-type virus
• HbA1C is 6.9 on oral therapy and diet
• Fasting cholesterol is 280 with HDL of 38
• Weight is 58 kg and creatinine is 1.5
• She has had a tubal ligation
• The patient desires simple once daily therapy

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Case 1 Question 3

• Which initial therapy would you choose?
• Fixed dose combination TDF/FTC/EFV
• FDC ZDV/3TC plus EFV
• FDC ABC/3TC plus EFV
• FDC TDF/FTC every other day plus EFV
• FDC TDF/FTC and atazanavir all once daily
• FDC ABC/3TC plus atazanavir
• FDC ABC/3TC plus once daily lopinavir/ritonavir
• Something else

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Case 1

• Your medical student calculates her creatinine
  clearance
• 44.7 cc/min by Cockcroft Gault
• 40 mL/min/1.73 m2 by MDRD
• You decide to begin ABC/3TC FDC with atazanavir
  all once daily

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Case 1 Question 4

• Prior to starting ABC/3TC and EFV what additional
  tests would you obtain
• Tropism Assay
• HLA B5701 Assay
• Hep B sAg, HepB sAb and HepB core Antibody
• 2 and 3

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PREDICT-1 Prospective study of HLA-B5701
screening to reduce ABC HSR

• ABC-naive starting ABC randomized (11) to SOC
  /- HLA-B5701 testing
• B5701 pts excluded. Physicians blinded to
  B5701- or untested
• Co-primary endpoints ABC HSR
• Clinically suspected
• Clinically suspected with skin patch confirmation
• 1650 evaluable patients completed 6 weeks or
  stopped due to HSR
• Multivariate predictors of HSR
• Clinically suspected HLA screening, white race,
  use of NNRTIs, concurrent PIs (not ARV naive)
• Skin patch confirmed HLA screening only

Clinically suspected and immunologically
confirmed HSP in ITT evaluable population
Mallal S, et al. 4th IAS, Sydney 2007, WESS101
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Prospective ABC Genetic ScreeningRauch et al CID
20064399-102
Proportion of patients stopping ABC in first 6
wks. The upper line patients who stopped ABC
because of any symptoms. The bottom line
definitive ABC hypersensitivity reactions
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Case 1

• The patient is HLA B5701 negative
• Her HepB surface Ab, IgG Core
• Consistent with past infection
• Treatment with ABC/3TC and atazanavir results in
  an HIV RNA lt 50 c/mL and an increase in CD4 to
  400 after 6 months of therapy

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Case 2 Highly Treatment Experienced

• J. R. is a 50 yo AA man HIV 1994
• CD4 nadir 49 with history of PCP
• Past Medical History
• Pancreatitis, DM, Elevated Triglycerides,
  Hypertension, Obesity
• Treatment history
• NRTI ZDV, 3TC, d4T, ddI
• PI full dose RTV, IDV, SQV/r, LPV/r
• NNRTI EFV, NVP (virologic failure documented on
  NVP)
• Enfuvirtide for 6 months 2005 stopped 2o ISR
  with low level viremia

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Case 2 Highly Treatment Experienced

• Since Jan 2005 regimen ATZ/r TDF, 3TC -gt FTC,
  abacavir
• 7/20/05 CD4 150 (12), VL 18,200 copies/ml
• 6/12/07 CD4 114 (14.2) , VL 5,185 copies/ml
• Most recent genotype
• NRTI mutations M41L, E44D, L74V, M184V, L210W,
  T215Y
• NNRTI mutations K103N, Y181C
• Protease mutations L10V, I13V, K20R, L33F,
  M36L, M46L, I54V, A71V, V82A, I84V L90M

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Case 2 Question 1

• Is zidovudine likely to have antiretroviral
  activity in this patient?
• Yes
• No
• I dont know
• RT mutations M41L, E44D, L74V, M184V, L210W,
  T215Y, K103N, Y181C

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Mutations Associated with Increased
Susceptibility to ZDV

• M184V
• Y181C
• L74V
• K65R

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TPV Score and Treatment Response
10V, 13V, 20R, L33F, 36L, 46L, 54V, A71V, V82A,
I84V L90M
TPV Score
0-1
2-3
4-5
6-7
8-9
Median FC
0.7-0.9
1.1-1.4
2.0-3.1
3.3-3.9
14.7-52.5
0
-0.08 (n 4)
-0.45 (n 260)
-0.49 (n 68)
-1
-0.89 (n 242)
Median Change in VL at Wk 24 (log10 copies/mL)
TPV Score Mutations10V, 13V, 20M/R/V, 33F, 35G,
36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P,
82L/T, 83D, 84V
-2
-2.10 (n 144)
-3
24-week data from patients in RESIST-1 and -2
given TPV/r
Valdez H, et al. Resistance Workshop 2005.
Abstract 27. Baxter JD, et al. J Virol.
20068010794-1080
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Baseline Resistance and Response to DRV/r
10V, 13V, 20R, L33F, 36L, 46L, 54V, A71V, V82A,
I84V L90M
Baseline DRV FC

• Baseline fold-change was strongest predictor of
  Week 24 response
• 11 mutations associated with reduced response
• V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S,
  L76V, I84V and L89V
• 73 of pts had ? 2 of these mutations

FC ? 10 (n 255) (70 of pts)
FC 11-40 (n 65) (17 of pts)
FC gt 40 (n 48) (13 of pts)
0
-0.5
-0.78
? VL at Wk 24, (NC F)
-1.0
-1.08
-1.5
-2.0
-2.04
-2.5
VL lt 50 c/mLat Wk 24
50
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DeMeyer S, et al. Resistance Workshop 2006.
Abstract 73.
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Case 2 Question 2What would you do at this
point?

• Continue current therapy
• Change therapy to ZDV, TDF/FTC, DRV/RTV, and ENF
• Use an NRTI-only or 3TC-only holding regimen
• Stop all therapy
• Get more information and use novel agents

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Emergence of ENF Resistance
While ENF resistance fades post D/C it rapidly
re-emerges with ENF therapy
Maroldo L, et al. CROI 2005. Abstract 717.
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IAS-USA Guidelines Updated Goals of Therapy in
Experienced Patients

• Viral suppression to lt 50 copies/mL is achievable
  and should be a goal of therapy in
  treatment-experienced patients

IAS-USA Guidelines. JAMA. 2006296827-843.
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Case 2 Question 3

• Would you like to order a phenotype?
• Yes
• No
• Are you kidding even Dan Kuritzkes gets
  phenotypes in this setting

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Case 2 NRTI and NNRTI
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Case 2 Protease Inhibitors
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Case 2

• Current regimen ATZ/r TDF/FTC, abacavir
• 7/20/05 CD4 150 (12), VL 18,200 copies/ml
• 6/12/07 CD4 114 (14.2) , VL 5,185 copies/ml
• You now have maraviroc approved. Raltegravir and
  etravirine are available thru expanded access
• Resistance Summary
• Sensitive to DRV and TDF (though 7-fold increase
  in IC50 to DRV and TAMs are present)
• ZDV just above cut-off
• ENF experienced

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Case 2 Question 4

• Would you get a tropism assay?
• Yes
• No
• Not sure

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Maraviroc MOTIVATE 1 and 2 Triple Class
Resistance R5 only virus
MVC BID OBR (n 191)
Placebo OBR (n 91)
MVC QD OBR (n 182)
100
100
MOTIVATE 1
MOTIVATE 2
90
90
80
80
70
70
60
60
P lt .0001
P lt .0001
50
50
Patients,
Patients,
48.5
45.6
42.2
40
40
40.8
P .0005
P .0006
30
30
24.6
20.9
20
20
10
10
0
0
16
20
24
0
4
8
12
2
16
20
24
0
4
8
12
2
Time (Weeks)
Time (Weeks)
P values vs placebo at Week 24
Nelson M, et al. CROI 2007. Abstract 104aLB.
Lalezari J, et al. CROI 2007. Abstract 104bLB.
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The Importance of Active Drugs in OBR Patients
With VL lt 50 c/mL at Wk 24
MVC QD OBR
MVC BID OBR
Placebo OBR
100
90
Combined Analysis MOTIVATE 1 and 2
80
70
61
58
55
53
60
52
Patients,
43
43
50
40
29
30
19
18
20
9
10
3
0
51
56
44
N
35
130
134
59
104
64
132
121
88
Number of active drugs in OBR
0
1
2
3
Nelson M, et al. CROI 2007. Abstract 104aLB.
Lalezari J, et al. CROI 2007. Abstract 104bLB.
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Prevalence of Coreceptor Tropism

• Demarest J, et al. ICAAC 2004. Abstract H-1136.
  2. Brumme ZL, et al. J Infect Dis.
  2005192466-474. 3. Moyle GJ, et al. J Infect
  Dis. 2005191866-872. 4. Melby T, et al. J
  Infect Dis. 2006194238-246. 5. Wilkin T, et al.
  Clin Infect Dis. 200744591-595. 6. Nelson M,
  et al. CROI 2007. Abstract 104aLB. 7. Lalezari J,
  et al. CROI 2007. Abstract 104bLB.

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Case 2 Question 5

• Tropism result shows Dual/Mixed virus.
• In your new regimen would you use
• Raltegravir
• Etravirine
• Maraviroc
• Raltegravir and Etravirine
• All three agents

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BENCHMRK 1 and 2 HIV-1 RNA lt 50 copies/mL (ITT,
NC F)
Raltegravir OBR
Placebo OBR
BENCHMRK-2
BENCHMRK-1
61
62
Percent of Patients withHIV RNA lt50 Copies/mL
P lt .001 at Week 16
P lt .001 at Week 16
36
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Weeks
Weeks
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
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BENCHMRK 1 and 2 HIV-1 RNA lt 400 c/mL at Wk 16
by Agents in OBR
Raltegravir OBR
Placebo OBR
n
of Patients
Overall Efficacy Data
447
79
230
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Efficacy by Agents in OBR
Enfuvirtide
Darunavir








First use in OBR No use in OBR
0
20
40
60
80
100
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
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Integrase Inhibitor Resistance

• Raltegravir two major pathways (N155 or
  Q148)Q148H/G140S most common.
• Most have multiple mutations
• In Phase II study majority of failures had GSS 0

1Hazuda DRW 2007 Grinsztejn et al. Lancet 2007
369 1261-69, 2Steigbigel CROI 2007 LB 105b,
3McColl et al DRW 2007
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Mutations can confer cross resistance to
structurally diverse integrase inhibitors
399 / 838 / 2194X
502X
IC50 ratio of mutants vs. WT HIV-1 in
infectivity assay
Wei et al CROI 2007, Hazuda etal DRW 2007
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Etravirine Phase IIIDUET-1 and -2 study lt50
copies/mL at Week 24 (TLOVR)
DUET-1
p0.0050
56
Responders () 95 CI
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Time (weeks)
CI confidence interval intent-to-treat (ITT)
populationTLOVR time to loss of virological
response imputation algorithm
Madruga et al and Lazzarin et al Lancet 2007
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Response according to number of active
background ARVs
DUET-1
47
0
9
59
1
24
Number of active background ARVs (PSS)
68
2
61
66
?3
65
0
20
40
60
80
100
Patients with viral load lt50 copies/mL at Week
24 ()
Darunavir and enfuvirtide are counted as active
if FClt10 or used de novo, respectively PSS
phenotypic sensitivity score
Madruga et al and Lazzarin et al Lancet 2007
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The number of baseline ETR RAMs correlated with
the virological response to ETR
ETR RAMs V90I, A98G, L100I, K101E/P, V106I,
V179D/F Y181C/I/V, G190A/S
Proportion of patients with confirmed viral load
lt50 HIV-1 RNA copies/mL
0
1
2
3
4
5
Overall placebo group
Overall TMC125 group
No mutation(reference)
Number of ETR RAMs (13)
161
9
Patients (n)
52
121
64
32
19
414
406
16
2
Patients ()
40
30
8
5
86
no detectable baseline NNRTI RAMs from the list
of 44 n406 (100)
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Case 2 Question 6

• You choose to use raltegravir and etravirine.
  Will you add
• Darunavir/r
• Tipranavir/r
• Neither drug

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Case 2 Question 7

• You choose raltegravir, etravirine and DRV/r.
  Will you add NRTI?
• 3TC or FTC only
• 2 or more NRTI
• No NRTI

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Case 2

• The patient is started on raltegravir,
  etravirine, DRV/r, ZDV and FDC TDF/FTC
• Three months later the HIV RNA is lt 50 c/mL and
  CD4 cell count is 150 cells/mm3