Transcript Management of Treatment-Experienced HIV+ Patients

HAART for the treatment
experienced patient
Prema Menezes PA-C
Treatment Failure
Definition and Reasons
 Immunologic
 No increase in CD4
 Decrease in CD4
 Clinical
 HIV related event at
least 3 months after
ART
 Virologic
 HIV RNA >400
(24wks), >50 (48
weeks)
 Virus
 Resistant
 Drug Therapy
 Sub optimal
 Sub therapeutic
 Patient
 Non adherence
DHHS Treatment Guidelines
Managing virologic failure: make a distinction
between limited, intermediate, and extensive
prior treatment exposure and resistance
Goal of treatment: re-establish maximal
virologic suppression
 March 2004: Preservation of immune function and
prevention of clinical progression
 May 2006: Re-suppress HIV RNA levels maximally and
prevent further selection of resistance mutations
New Agents
 Protease Inhibitors
 Tipranavir
 Darunavir
 NNRTIs
 Etravirine
 Integrase Inhibitor
 Raltegravir
 CCR5 Inhibitor
 Maraviroc
Limited Treatment Failure
Case 1: First Line Virologic Failure
 31 yo woman s/p bilateral tubal ligation began




[fdc ZDV/3TC] + EFV 36 months ago
Initial CD4 = 162; VL = 56,000
After starting HIV therapy, CD4 increased to 365
and VL fell to 340 and then to < 50 c/mL
Difficulty taking medication over the past 2
months due to relapse of substance abuse
Now returns with weight loss and thrush
What is your next step?
1.
2.
3.
4.
5.
Obtain HIV RNA, CD4, continue therapy and
have her return within a month
Obtain HIV RNA, CD4, stop therapy and have
her return within a month
Obtain a resistance test
Choice 1 and 3
Choice 2 and 3
GS934: Resistance Development
Through Week 96
Patients genotyped, n
Wild-type, n
Any resistance, n
EFV resistance
mutations, n
M184V/I, n
TAMs, n
K65R, n
TDF + FTC
(n = 244)
14
4
10
ZDV/3TC
(n = 243)
29
7
20
10
18
2
0
0
9*
1
0
Comparative trial of ZDV/3TC/EFV vs. TDF/FTC/EFV
in treatment naïve patients
Gallant J, et al IAC 2006. Abstract TUPE0064.
KLEAN: Resistance FPV/r vs. LPV/r
(with ABC/3TC FDC)
FPV/r,
n
LPV/r,
n
Confirmed virologic failures
16
24
Unable to sequence
2
3
No treatment-emergent mutations
9
14
TAMs (M41M/L)
0
1
3TC-associated mutations (M184I, M184V, M184M/V)
3
4
NNRTI-associated mutations (V106V/A)
0
2
PI-associated mutations: all minor (I54I/L, I93I/L,
K20K/R, I62I/V)
3
2
Treatment-emergent mutations
Eron JJ Jr, Lancet 2006.
Case 1: First Line Virologic Failure
 CD4 now = 98 and VL = 29,000
 Genotype reveals 184V and 103N mutations
 ART is discontinued and PCP prophylaxis


prescribed. The patient enters in-patient detox
and 6 weeks later returns to restart HIV
medications.
She begins a series of adherence counseling
sessions
What ART to use?
Case 1: First Line Virologic Failure
1. Atazanavir + NRTIs
2. Atazanavir/ritonavir + NRTIs
3. Lopinavir/ritonavir + NRTIs
4. Fos-Amprenavir/ritonavir + NRTIs
5. [fdc ZDV/3TC/ABC] + tenofovir
6. Other
If you chose NRTI + PI – which NRTIs
1. Abacavir + 3TC or FTC
2. Abacavir + tenofovir
3. Didanosine plus 3TC or FTC
4. Didanosine plus tenofovir
5. Tenofovir + 3TC or FTC
6. Tenofovir, ZDV + 3TC or FTC
7. Something else
3TC Alone vs Treatment Interruption
Mean CD4+ Decrease (ITT)
0
BL
-50
4
8
Weeks
12
16
20
Mean VL Increase (ITT)
24
3TC
TI
1.4
3TC
TI
1.2
1.0
0.8
-100
0.6
-150
0.4
-200
0.2
0
BL
-250
4
8
12
Weeks
16
20
24
In contrast to treatment interruption arm, 3TC alone
resulted in:
 No recovery in RC
 No increase in RT mutations
 No reversion of PR mutations
Castagna et al. AIDS 20:795 2006
Effects of M184V on other NRTI
 Increases in susceptibility
 Zidovudine
 Stavudine
 Tenofovir
 Minimal Change or decrease in susceptibility
 Abacavir
 Didanosine
− Both of these agents can select for M184V in vivo.
First Line Virologic Failure
 Good news
 Lots of treatment options
 Considerations
 Keep 3TC/FTC in new regimen
 Genotype
 Resistance appears to be limited in first
HAART failure
ART Options for Extensively
Treatment Experienced Patients
Newer Agents
Darunavir
Tipranavir
POWER 1 and 2 trials: design
Randomization
Investigator-selected
CPI(s) + OBR
• PI-, NRTI- and NNRTIexperienced
• ≥1 PI mutation*
• PI-based regimen
• VL >1,000 copies/mL
Investigatorselected CPI(s)
+ OBR (without
NNRTIs)
TMC114/r 400/100mg qd
+ OBR
TMC114/r 800/100mg qd
+ OBR
TMC114/r 400/100mg bid
+ OBR
TMC114/r 600/100mg bid
+ OBR
•
The highest dose of TMC114/r (600/100mg bid) provided the greatest
virologic response in the Week 24 analysis and is the selected dose for
treatment-experienced patients
•
The combined 48-week efficacy and safety interim analysis at this dose
versus CPI(s) is reported here
*Based on IAS-USA March 2003 at start of studies; updated to October 2004 list during studies
VL = viral load, OBR = optimized background regimen (NRTIs ± enfuvirtide [ENF])
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
POWER 1 and 2: BL characteristics
TMC114/r
600/100mg bid
n=131
CPI(s)
n=124
89
44
88
44
36
12.0
4.61 (0.69)
153 (3–776)
43
12.9
4.49 (0.78)
163 (3–1,274)
Previous ARV experience
Mean duration (months; SD)
NRTI
NNRTI
PI
Fusion inhibitor (ENF)
100 (48)
28 (24)
65 (29)
14 (11)
106 (45)
23 (15)
65 (28)
11 (9)
Genotypic and phenotypic information
Median primary PI mutations* (n; range)
Median PI resistance-associated mutations* (n; range)
≥1 sensitive† PI available (%)
≥1 sensitive† NRTI in OBR (%)
3 (0–5)
8 (0–12)
36
72
3 (0–5)
8 (1–13)
39
73
Demographics
Gender (% male)
Mean age (years)
Disease characteristics
CDC class C (%)
Mean duration of infection (years)
Mean VL (log10 copies/mL; SD)
Median CD4 count (cells/mm3; range)
*IAS-USA October 2004,
ARV = antiretroviral; SD = standard deviation
was determined by Antivirogram®
†susceptibility
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
POWER 1 and 2: patients with VL <50 copies/mL
over time to Week 48 (ITT-TLOVR)
100
TMC114/r 600/100mg bid
CPI(s)
Patients (%)
80
60
45%*
(n=59/131)
46%*
(n=50/110)
12%
(n=15/124)
10%
(n=12/120)
40
20
0
0 12 4
8
12
16
20
24
28
32
36
40
44
48
Weeks
TMC114/r n= 131
CPI(s)
n= 124
131
124
131
124
130
124
120
121
110
120
*p<0.001 vs CPI(s)
ITT = intent-to-treat, TLOVR = time to loss of virologic response
Not all patients had reached Week 48 at the time of analysis; patients
who had not reached Week 48 were censored at their last available visit
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
POWER 1 and 2: virologic response defined as VL
<50 copies/mL by BL subgroups at Week 48 (ITT-TLOVR)
TMC114/r 600/100mg bid
CPI(s)
70
44/82
27/61
50
21/36
40
11/100
30
0/18
5/25
7/70
1/15
10
2/13
20
4/35
Patients (%)
60
0
ENF used
(naïve)
ENF used
(non-naïve)
ENF
not used
0 sensitive
ARV
in OBR
≥1 sensitive
ARV
in OBR
ARV = antiretroviral drug; OBR = optimized background regimen; ENF = enfuvirtide.
Use of ENF was not randomized in POWER 1 and 2.
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
POWER 1 and 2: mean change from BL in CD4
count over time to Week 48 (LOCF)
TMC114/r 600/100mg bid
CPI(s)
Mean change in CD4 count
(cells/mm3)
140
102*
120
92*
100
80
60
40
19
17
20
0
0 2 4
8
12
16
20
24
28
32
36
40
44
48
Weeks
TMC114/r n= 131
CPI(s)
n= 124
131
124
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
131
124
130
124
120
121
110
120
*p<0.001 vs CPI(s)
LOCF = last observation carried forward
Baseline Resistance and Response to DRV/r
 Baseline fold-change was strongest
No. of BL
mutations
% with VL
< 50, Wk 24
0
1
2
3
4
Baseline DRV FC
0
Δ VL at Wk 24, (NC = F)
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
FC 11-40
FC > 40
(n = 255)
(70% of pts)
(n = 65)
(17% of pts)
(n = 48)
(13% of pts)
-0.5
-0.78
-1.0
-1.08
-1.5
-2.0
64
50
42
22
10
-2.04
-2.5
DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.
VL < 50 c/mL
at Wk 24
50%
25%
13%
POWER 1 and 2: observed incidence of the
most common treatment-emergent AEs*
during treatment, regardless of severity and
80
causality TMC114/r 600/100mg bid
70
CPI(s)
Patients (%)
60
50
40
30
20
10
0
Diarrhea
Nausea
Headache
Nasopharyngitis
Fatigue
Upper
respiratory
tract infection
Herpes
simplex
Pyrexia
*AEs = adverse events reported in ≥10% of patients and excluding
ENF-associated injection site reaction (TMC114/r: 28%; CPI: 22%)
Lazzarin A, et al. XVI IAC 2006. Abstract TUAB0104
TITAN
DRV/RTV vs LPV/RTV in
Tx-Experienced, LPV-Naive Patients
 Intermediate treatment experience
 Stratified by treatment site, NNRTI in OBR, HIV
RNA > or < 50,000 c/mL
 Darunavir/ritonavir met criteria for superiority to
lopinavir/ritonavir in proportions with HIV-1 RNA
< 400 copies/mL and < 50 copies/mL at week 48
 Safety comparable between darunavir/ritonavir
and lopinavir/ritonavir
The Randomized Evaluation of
Strategic Intervention in Multidrug
Resistant Patients With
Tipranavir (RESIST)
Resist 1 and 2 – 96 weeks
Proportion of patients with viral load <400 and <50 copies/ml at week 96
Resist 1 and 2 – 96 weeks
Proportion of patients who took Enfuvirtide as a new drug and achieved
virologic suppression.
Safety - laboratory
abnormalities
TPV/r (%)
CPI/r (%)
Grade 3/4 AST
6.1
1.8
Grade 3/4 ALT
9.7
4.2
Grade 3/4 total cholesterol
2.1
0.4
24.9
13.0
Grade 3/4 triglycerides
 Patients with Grade 3/4 elevations in liver enzymes or lipids
were able to continue TPV/r therapy without developing
clinical AEs
Highly
Treatment
Experienced
Patients
Highly Treatment Experienced
 48 yo white man HIV + since 1991 (CD4 180)
 Received ZDV from 1994 to 1996, added 3TC



then indinavir
VL on this regimen was initially BDL and CD4
rose to 300 cells over two years.
VL rose to 5,600 then 10,100, CD4 was 390.
In 2000 treatment was interrupted VL peaked at
386,000 and CD4 fell to 220
Case: Multi-drug Resistance
 Over several years he was on a series of
regimens:




EFV, SQV/RTV, d4T
Abacavir, ddI, LPV/r
TDF, FTC, LPV/r plus SQV
HIV RNA rebound was eventually observed on each regimen
 He feels well and has had no AIDS defining
illness. His current CD4 is 310 and his VL
repeated several times is between 10,000 and
15,000 on therapy
Case: Multi-drug Resistance
 Given long treatment history with only
intermittent suppression of HIV RNA to BDL you
order a genotype
 This is the test available to you
 RT mutations include:
 41L, 74V, 118I, 184V, 215Y and 219Q
 Protease mutations include:
 10V, 20R, 33F, 46L,54V, 82A, 84V and 90M
Case: Multi-drug Resistance
What will you do at this point?
1.
2.
3.
4.
5.
Change to > 1 NRTI, tipranavir/r and enfuvirtide
Change to > 1 NRTI, darunavir/r and enfuvirtide
Interrupt therapy and after 6 months begin > 1
NRTI, darunavir/r and enfuvirtide
Continue current therapy
Holding regimen
Need to Know Likelihood of
Success
CD4 310, clinically stable
Let’s Look at Genotype
RT mutations include:
 41L, 74V, 118I, 184V, 215Y and 219
 Resistance predicted to 3TC, FTC, ddI, ABC,
ZDV
 Intermediate activity to TDF and d4T
Protease mutations include:
 10V, 20R, 33F, 46L,54L, 82A, 84V and 90M
TPV Score and Treatment Response
10V, 20R, 33F, 46L,54L, 82A, 84V, and 90M
TPV Score
Median Change in VL at
Wk 24* (log10 copies/mL)
0-1
Median FC: 0.7-0.9
2-3
1.1-1.4
4-5
2.0-3.1
6-7
3.3-3.9
8-9
14.7-52.5
0
-1
-0.89
(n = 242)
-0.45
(n = 260)
-0.49
(n = 68)
-0.08
(n = 4)
TPV Score Mutations
10V, 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.
Baseline Resistance and Response to DRV/r
10V, 20R, 33F, 46L,54L, 82A, 84V, and 90M
 Baseline fold-change was strongest
0
 V11I, V32I, L33F, I47V, I50V, I54L,
I54M, G73S, L76V, I84V and L89V
 73% of pts had  2 of these
mutations
No. of BL
mutations
% with VL
< 50, Wk 24
0
1
2
3
4
Δ VL at Wk 24, (NC = F)

predictor of Week 24 response
11 mutations associated with
reduced response
Baseline DRV FC
FC  10
FC 11-40
FC > 40
(n = 255)
(70% of pts)
(n = 65)
(17% of pts)
(n = 48)
(13% of pts)
-0.5
-0.78
-1.0
-1.08
-1.5
-2.0
64
50
42
22
10
-2.04
-2.5
DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.
VL < 50 c/mL
at Wk 24
50%
25%
13%
Multi-Drug Resistance
 This case illustrates several points to
consider when making the difficult decision
of when to switch
 This patient is in no clinical danger.
 His CD4 cell count is above 300
 His viral load is over 1 log10 lower than a peak off
therapy.
 He has had no AIDS defining illness and feels well
 On the other hand his current therapy is
not optimal with sustained viral replication
 Continued current therapy may lead to CD4 cell
decline and further accumulation of resistance
Case: Multi-drug Resistance
 There is no clinical urgency; what are treatment
options?
 He is naïve to T-20 therefore likely very active initially
− T-20 low barrier to resistance; incomplete suppression
leads to rapid resistance evolution
 He has no NNRTI mutations
− By history he had previous viral rebound while on EFV
− NNRTI may add modest activity,
− NRTI will likely have modest ADDITIONAL activity
 There are substantial PI mutations limiting PI options
− He has 5 TPV-associated mutations decreasing the
likelihood of a sustained response
− He has 3 DRV mutations which will impact activity
Should He Wait for New
Agents?
How quickly will new mutations
evolve?
Risk of Delayed Switch on Stable HAART
 SCOPE cohort of ART-experienced
subjects (n = 106)[1]
HIV-1 RNA > 1000 c/mL
 1 resistance mutation
Resistance testing every 4 mos
until HAART modification
 Emergence of new mutns at 1 yr
 Any: 44% (95% CI: 33%-56%)
 NAMs: 23% (95% CI: 15%-34%)
 PI: 18% (95% CI: 9%-34%)
 Those with persistent viremia on
HAART run risk of limiting future
treatment options
 Other
studies show similar results[24]
Proportion Without
New Mutation
Stable HAART for  120 days
1 new major PI mutation
1 new NRTI mutation*
Any new mutation
1.00
0.75
0.50
0.25
*PI-treated subjects (n = 71)
0
0
Proportion Without
Loss of 1 Drug




4
8
12
16
20
24
1.00
Time to loss of
1 drug equivalent
0.75
0.50
0.25
Number of available antiretrovirals from the following: ZDV,
3TC, ddI, ABC,TDF, EFV, IDV, NFV, SQV, RTV, APV, LPV
0
0
4
1. Hatano H, et al. CROI 2006. Abstract 615. 2. Lafeuillade A, et al. IAC 2004. Abstract WeOrB1293.
3. Margot NA, et al. JAIDS. 2003;33:15-21.
4. Napravnik S, et al. JAIDS. 2005;40:34-40.
8
12
16
Time (Mos)
20
24
Case 1
 Patient now has CD4 cell count of 120
 VL is 15,000
 Repeat Genotype – virtual phenotype
show no new mutations




DRV fold change = 45 (cut-offs 3.4 – 96.8)
TPV fold change = 4.0 (cut-offs 1.2 – 5.4)
Intermediate susceptibility to TDF resistant to all NRTI
No NNRTI mutations (failed EFV in the past)
Case 1
 If you were to start the patient on new drugs
which would you use?
A. Maraviroc
B. Raltegravir
C. Etravirine
D. Raltegravir/Etravirine
E. Maraviroc/Etravirine
F. Maraviroc/Raltegravir
DUET-1 and -2: Etravirine + DRV/RTVContaining OBR Phase III Trials
Week 24†
HIV-infected patients with VF
on current HAART regimen,
history of ≥ 1 NNRTI resistance
mutations, ≥ 3 primary PI mutations,
HIV-1 RNA > 5000 copies/mL
(DUET-1: N = 612;
DUET-2: N = 591)
Etravirine 200 mg BID
+ DRV/RTV-containing OBR*
(n = 599)
Placebo
+ DRV/RTV-containing OBR*
(n = 604)
*Investigator-selected OBR to consist of DRV/RTV (600/100 mg/mL) + ≥ 2 NRTIs ± enfuvirtide.
†Planned Week 24 analysis: primary endpoint HIV-1 RNA < 50 copies/mL (TLOVR).
Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48.
Mills A, et al. IAS 2007. Abstract WESS204.1. Katlama C, et al. IAS 2007. Abstract WESS204.2.
Cahn P, et al. ICAAC 2007. Abstract H-717.
Week 48
DUET-1 and -2: Pooled Virologic and
Immunologic Responses
Outcome at Week 24
Etravirine
(n = 599)
Placebo
(n = 604)
P Value
59
41
< .0001
Mean change in HIV-1
RNA from baseline, log10
copies/mL
-2.4
-1.7
< .0001
Mean change in CD4+
cell count from baseline,
cells/mm3
+86
+67
< .0001
HIV-1 RNA < 50
copies/mL, %
 In patients using enfuvirtide for the first time (n = 201), the difference between treatment
arms (67% and 62% for etravirine vs placebo, respectively) was not significant (P = .427)
Cahn P, et al. ICAAC 2007. Abstract H-717.
DUET-1 and -2: Response Based on
Active Agents in OBR
Etravirine + OBR
HIV-1 RNA < 50 copies/mL at
Week 24 (%)
100
Placebo + OBR
74
80
67
60
60
45
40
30
20
0
n=
88
8
91
199
211
258
0
1
≥2
No. of Fully Active Agents in OBR (assessed by PSS)
Cahn P, et al. ICAAC 2007. Abstract H-717.
257
DUET-1 and -2: BL ETR Mutations and
Virologic Response at Week 24
V90I
A98G
L100I
K101E/P
V106I
V179D/F
Y181C/I/V
G190A/S
 Presence of ≥ 3 ETR mutations
associated with response
similar to placebo + OBR
– 70% of patients had 0 or 1 ETR
resistance mutations at BL
Patients With HIV-1
RNA < 50 copies/mL (%)
 13 mutations associated with
ETR resistance
100
90
80
70
60
50
40
30
20
10
0
0
– 14% of patients had ≥ 3 ETR
resistance mutations at BL
– Response diminished by ~ 20% in
presence of 1 or 2 mutations
Katlama C, et al. IAS 2007. Abstract WESS204.2.
1
2
3
4
5
No. of BL ETR Mutations
Patients (%)
40
30
16
8
5
1
DUET-1 and -2: Study Conclusions
 Proportion of patients achieving HIV-1 RNA


< 50 copies/mL significantly greater in etravirine arms
CD4+ cell count increase from baseline significantly greater in ETR arm in
DUET-1
 DUET-1: 89 vs 64 cells/mm3 (P = .0002)
 DUET-2: 78 vs 66 cells/mm3 (P = .3692)
Presence of ≥ 3 mutations from list of 13 ETR RT mutations associated with
decreased response
 K103N not associated with ETR resistance
 Incidence of adverse events and laboratory abnormalities similar to placebo
arm
BENCHMRK-1 and -2: Raltegravir in
Treatment-Experienced Pts
 Randomized, double-blind, placebo-controlled,
parallel phase III studies
Primary endpoints:
Week 16
HIV infected;
triple-class resistant;
VL > 1000 copies/mL
BENCHMRK-1 (N = 350)
(Europe, Asia/Pacific, Peru)
BENCHMRK-2 (N = 349)
(North, South America)
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
Planned duration:
Week 48
Raltegravir 400 mg twice daily + OBR
BENCHMRK-1 (n = 232)
BENCHMRK-2 (n = 230)
Placebo + OBR
BENCHMRK-1 (n = 118)
BENCHMRK-2 (n = 119)
Benchmark 1 and 2
Patient Disposition at study entry
BENCHMRK 1 and 2: HIV-1 RNA < 50
copies/mL (ITT, NC = F)
Raltegravir + OBR
Percent of Patients with
HIV RNA <50 Copies/mL
100
Placebo + OBR
100
BENCHMRK-1
80
BENCHMRK-2
80
61%
62%
60
60
P < .001 at Week 16
P < .001 at Week 16
40
20
40
20
33%
0
36%
0
0 2 4
8
12
Weeks
16
24
0 2 4
8
12
Weeks
Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.
16
24
BENCHMRK 1 and 2: HIV-1 RNA < 400
c/mL at Wk 16 by Agents in OBR
Raltegravir + OBR
Placebo + OBR
n
% of Patients
447
230
Overall Efficacy Data
79
43
Efficacy by Agents in OBR
Enfuvirtide
Darunavir
+
+
44
23
+
–
42
24
–
+
80
47
–
–
191
90
+ : First use in OBR
– : No use in OBR
98
87
90
63
90
55
74
29
0
20
40
60
Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.
80
100
BENCHMRK 1 and 2: HIV-1 RNA < 400
c/mL at Wk 16 by PSS/GSS of OBR
Raltegravir + OBR
Placebo + OBR
n
Overall Efficacy Data
(PSS)
0
1
2 or more
(GSS)
0
1
2 or more
% of Patients
447
230
79
43
62
44
141
68
222
110
61
5
76
41
87
57
57
111
63
170
93
159
70
10
85
43
89
71
0
20
40
60
Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.
80
100
Case Summary
CD4 now 200 cell/mm3, VL is 65,000; patient is symptomatic
RT mutations include:
 41L, 74V, 118I, 184V, 215Y and 219
 Resistance to 3TC, FTC, ddI, ABC, ZDV
 Intermediate activity to TDF and d4T
Protease mutations include:
 10V, 20R, 33F, 46L,54L, 82A, 73S, 84V and 90M
 Predicted phenotype TPV = 4.0 (1.2, 5.4) DRV 64 (3.4,
96.9)
 above upper cut-off for all other PI.
Previous NNRTI experience
Raltegravir, etravirine and maraviroc are now available.
 Entry phenotype is dual-mixed
Summary
Treatment experienced patients
 Re-suppress HIV RNA levels maximally
and prevent further selection of resistance
mutations
 Need to know likelihood of success
 Must have at least two active drugs
World AIDS Day
2006
What Is the “Resistance Penalty” of
Continued Nonsuppressive Therapy?
 Studies of resistance accumulation in states of
“incomplete viral suppression”
 68% with new mutations after median of 22 mos[1]
 33% with new TAMs, 2% K65R during 96 wks of FU[2]
 60% with new mutations after median of 9.3 mos, but no shift on
virtual phenotype[3]
 Studies lack results of subsequent switches
 No fully powered randomized studies of early vs deferred
switching
1. Lafeuillade A, et al. IAC 2004. Abstract WeOrB1293.
2. Margot NA, et al. J Acquir Immune Defic Syndr. 2003;33:15-21.
3. Napravnik S, et al. J Acquir Immune Defic Syndr. 2005;40:34-40.