Transcript Managing Antiretroviral Failure in Treatment

Managing Antiretroviral Therapy in
Treatment-Experienced Patients:
Multiple Regimen Failures
MATEC
Catherine Creticos, M.D.
Medical Director
Case Study 1

D.R. is a 42 yo male HIV+ for 12 years on
multiple HIV treatment regimens, starting
with Combivir (ZDV/3TC) in the mid-1990s
& including Crixivan (IDV) and Lexiva (APV).
Most recently he has been on a combination
of Trizivir (ZDV/3TC/ABC), Videx (DDI), and
boosted Reyataz (ATV/r). His viral load =
33,000 and CD4 = 355.
Case Study 2

S.F. is a 31 yo female HIV+ for past 10 yrs.
She has been on ARV therapies but nonadherent. Her CD4 is repeatedly <100. At
her most recent visit she was on Epzicom
(3TC/ABC), Invirase (SQV), & Kaletra
(LPV/r). Labs show her viral load = 55,600
and CD4 = 73. She returns to discuss
changing her therapy and tells you that she
is again off her ART for the past 2 weeks.
DHHS and IAS-USA Guidelines:
Goals of Therapy

Evolving goal of antiretroviral therapy for all
HIV-positive patients regardless of the
extent of previous treatment experience
Achieve and maintain undetectable VL
 Now applies to an increasing number of
treatment-experienced patients

Hammer SM, et al. JAMA. 2006;296:827-843.
DHHS guidelines, May 2006. Available at: http://aidsinfo.nih.gov.
Goals of Therapy in Patients
With Access to < 2 Active Agents
Reduce VL by ≥ 1 log10
 Stabilize CD4 count
 Minimize drug toxicity
 Prevent clinical progression and death
 Avoid new resistance mutations that
could reduce future options
 Avoid “monotherapy” with new drugs

RESIST: Phase 3 Study of
Boosted Tipranavir (TPV/r)
Patients failing
PI-containing
HAART
VL > 1000
Any CD4+
HIV resistance
expert panel
Best PI
choice
TPV/r arm
Preselection of
regimen
by investigator:
CPI + OBR †
(± enfuvirtide)
Baseline
genotypic
resistance
testing*
†
*
CPI, comparator PI
OBR, optimized background
Computerized
randomization
to OBR plus:
CPI arm
LPV/r, IDV/r,
SQV/r, APV/r
Failures in CPI arm after Wk 8
eligible for TPV/r in rollover study
Entry criteria:
≥ 1 primary PI mutation: 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M
≤ 2 mutations: 33, 82, 84, or 90
Farthing C, et al. ICAAC 2006. Abstract H-1385. Hicks CB, et al. Lancet. 2006;368:466-475.
RESIST:
VL<50 copies/mL at wk 96
Patients With HIV-1 RNA
< 50 copies/mL (%)
100
TPV/r (n = 746)
CPI/r (n = 737)
80
ITT: NC = F
60
40
P < .0005
22.8%
20.4%
20
0
9.1%
10.2%
0
8
16
24
32
Farthing C, et al. ICAAC 2006. Abstract H-1385.
40
48
56
64
72
80
88
96
RESIST 1 and 2:
TPV/r Results at 96 wks
TPV/r
80
60
p < .0002
p < .0005
40
20
0
20.4
9.1
n =746
All Patients
100
Control
34.7
14.4
Patients With VL
< 400 copies/mL (%)
Patients With VL
< 50 copies/mL (%)
100
80
60
40
20
0
First-Time
ENF Use
TPV/r
Control
p < .0001
p < .0001
44.4
26.9
14.4
10.9
n =746
All Patients
First-Time
ENF Use
TPV/r similar toxicity profile to comparator PIs at wk 48, except:
Grade 3/4 ALT (10.1% vs 3.3%), AST (6.3% vs 2.9%)
 Grade 3/4 TGs (30.8% vs 23.1%), TC (4.3% vs 0.7%) (p < .0001 for all
comparisons)

Farthing C, et al. ICAAC 2006. Abstract H-1385. Hicks CB, et al. Lancet. 2006;368:466-475.
Patients With  1 log10
Reduction in VL (%) Week 24
RESIST: Greater Response at wk 24
With More Active Agents in OBR
100
TPV/r
CPI/r
80
60
54.7
46.2
40
20
41.2
37.4
13.1
34.3
19.9
12.9
9.1
0
0
1
2
18.9
3
Number of Sensitive Background ARVs
Cooper D, et al. CROI 2005. Abstract 560.
Overall
Relationship of TPV Score to TPV
Phenotype Results and Response
TPV Score*
Median Change in VL at
Wk 24* (log10 copies/mL)
Median FC:
0
0-1
2-3
4-5
6-7
8-9
0.7-0.9
1.1-1.4
2.0-3.1
3.3-3.9
14.7-52.5
-1
-0.89
(n = 242)
-0.45
(n = 260)
-0.49
(n = 68)
Distribution of patients in
RESIST-1 & -2 by BL TPV score
-2
-2.10
(n = 144)
-3
*10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V,
58E, 69K, 74P, 82L/T, 83D, 84V
Valdez H, et al. Resistance Workshop 2005. Abstract 27.
-0.08
(n = 4)
20% 1% 9%
36%
34%
TPV Mutation Score vs IAS-USA
Protease Gene Resistance Mutations
TPV L I K
Score 1013 20
V V M
R
V
IAS- L
USA 10
F
I
R
V
L E M K M I
33 35 36 43 46 47
F G I T L V
K L D V L
20 24 30 32 33
R I N I I
M
F
I
V
M
36
I
L
V
I Q
54 58
A E
M
V
M I G I F I
46 47 48 50 53 54
I V V L L V
L A
V
L
A
M
C
S
H
69
K
L
63
p
T
74
P
A C
71 73
V C
T S
T
A
V N I
82 83 84
L D V
T
V V
77 82
I A
F
T
S
I N L
84 88 90
V D M
S
 Many mutations (13, 35, 43, 58, 74, 83) have not been associated with

resistance to other PIs
Major mutations (D30N, G48V, N88D, L90M) associated with other PIs
do not contribute to Tipranavir (TPV) mutation score
Kohlbrenner VM et al. HIV-DART 2004. Abstract 40.
Adverse Effects of Boosted
Tipranavir: Black Box Warnings
TPV/r associated with reports of

Fatal and nonfatal hepatitis and hepatic decompensation


More hepatotoxicity in patients on TPV/r in RESIST 1 and 2;
patients with chronic HBV or HCV coinfection have increased risk
Fatal and nonfatal intracranial hemorrhage

13 patients receiving TPV/r experienced intracranial hemorrhage;
use with caution in patients at risk of increased bleeding from
trauma, surgery, or other medical conditions, or those receiving
medications known to increase risk of bleeding
Aptivus [package insert]. Ridgefield, Conn: Boehringer Ingelheim; June 2006.
POWER 1 and 2: Boosted
Darunavir (DVR) Study Design
Investigator-selected
CPI(s) + OBR
• PI-, NRTI- and NNRTIexperienced
•  1 PI mutation (IAS-USA)
• PI-based regimen
• VL > 1000 copies/mL
Investigatorselected CPI(s)
+ OBR (without
NNRTIs)
DRV/r 400/100 mg QD
+ OBR
DRV/r 800/100 mg QD
+ OBR
DRV/r 400/100 mg BID
+ OBR
DRV/r 600/100 mg BID
+ OBR

DRV/r 600/100 mg BID provided greatest virologic response in
Wk 24 analysis; FDA-approved dose for treatment-experienced pts
VL, viral load; OBR, optimized background regimen (NRTIs ±
enfuvirtide)
Lazzarin A, et al. IAC 2006. Abstract TUAB0104.
Patients With VL< 50 c/mL (%)
POWER 1 and 2:
VL<50 at wk 48 (ITT-TLOVR)
100
DRV/r 600/100 mg BID
Control
80
*P < .001 vs comparator PI/r.
60
45*
46*
12
10
40
20
0
012 4
8
12
16
20
24
Weeks
28
32
36
40
44
48
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. IAC 2006. Abstract TUAB0104.
POWER 1 and 2:
VL<50 at wk 48 by Baseline Group
Overall
46
n = 110
10
n = 120
ENF Used
(Naive)
n = 36
ENF Not
Used
n = 61
≥ 3 Primary
PI Mut
n = 55
No Sensitive
ARVs in OBR
n = 25
≥ 1 Active
Agent in OBR
n = 44
58
11
n = 35
44
10
n = 70
n = 74
n = 18
n = 11
0
DRV/r 600/100 BID
CPI/r
44
5
20
0
54
11
20
40
60
80
Patients With VL < 50 copies/mL at wk 48 (ITT, NC = F) (%)
Lazzarin A, et al. IAC 2006. Abstract TUAB0104.
100
POWER 3:
VL<50 at wk 24 by ITT-TLOVR
 POWER 3: ongoing phase III open-label study, DRV/r 600/100 mg[1]
 Safety analysis similar to POWER 1 and 2[2]
Patients With VL
< 50 copies/mL (%)
70
POWER 1 (n = 65)
60
POWER 2 (n = 66)
50
53
POWER 3 (n = 327)
40
39
40
30
20
10
0
B/L
2
4
8
1. Molina JM, et al. IAC 2006. Abstract TUPE0060.
2. Madruga V, et al. IAC 2006. Abstract TUPE0062.
12
Weeks
16
20
24
Effect of Baseline Darunavir FoldChange on Response to Darunavir

Baseline fold-change to DRV (by Antivirogram) was strong
predictor of Week 24 response in POWER 1, 2, and 3
Patients With VL < 50
copies/mL at Wk 24 (%)
100
Distribution of pts
by baseline DRV FC
80
13%
60
50
40
17%
25
13
20
n=
0
255
65
48
FC ≤ 10 FC 11-40 FC > 40
Baseline DRV FC
DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.
70%
Effect of Baseline DRV-associated
Mutations on Response to DRV

11 PI mutations associated with reduced response

V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V
Patients With VL < 50
copies/mL at Wk 24 (%)
100
Distribution of pts by
baseline # of DRV mutations
80
64
60
50
18%
42
11%
16%
40
22
20
0
10
n=
67
94
113
58
41
0
1
2
3
≥4
Baseline No. of DRV Mutations
DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.
25%
30%
POWER 1, 2, and 3:
Effect of Fuzeon (ENF) by Baseline Fold
Change to Darunavir (ITT-TLOVR)
N (%)*
FC > 40
FC 10-40
Response (< 50 c/mL)
n = 11
n = 17
28 (9%)
18%
12%
59%
n = 17
50 (17%)
n = 33
Controlling for # of active
NRTIs in OBR, # of primary
PI mutations, DRV FC, and
ENF use (naive/not used)
15%
53%
n = 64
FC  10
Adjusted estimate
49%
P = .32
223 (74%)
52%
n = 159
0
*Patients reaching Wk 24 or D/C earlier, excluding
those who had previously used ENF
Data on file. Tibotec Therapeutics. 2006
20
40
60
Subjects using ENF naively
39%
80
100
Subjects not using ENF
Relationship Between Activity of OBR
and Response to DRV/r 600/100 mg




Subgroup analyses of pooled
POWER 1, 2, and 3 data
Highest rates of VL<50 in pts
with ≥ 2 active agents in OBR[1]
No incremental benefit of active
ENF if ≥ 1 active NRTI in OBR[1]
Phenotypic susceptibility score
(PSS) of OBR also predicted VL
< 50 at Wk 24[2]
 PSS ≤ 0.5: 34%
 PSS 0.5-1.5: 49%
 PSS > 1.5: 52%
Characteristic of OBR
VL < 50 at
Wk 24, %
# of active agents

0
26

1
46

≥2
49
Type of active agent

Active ENF only
43

≥ 1 active NRTI, no ENF
51

≥ 1 active NRTI + active ENF
53
1. Pozniak A, et al. BHIVA, 2006. Abstract P3.
2. Vangeneugden T, et al. Resistance Workshop, 2006. Abstract 1138.
FDA Indications for New PIs
Boosted Tipranavir (TPV/r)
 “Adult patients with evidence of viral replication,
who are highly treatment-experienced or have
HIV-1 strains resistant to multiple PIs”
Boosted Darunavir (DRV/r)
 “Antiretroviral treatment-experienced adult
patients, such as those with HIV-1 strains resistant
to more than one protease inhibitor”
Most Clinical Isolates Are Maximally
Susceptible to Both TPV and DRV

Analysis of 56,018 samples submitted for routine
resistance testing
DRV
0.2%
TPV
1.5%
5.0%
8.7%
Susceptibility
Maximal
Reduced
Minimal
94.8%
Picchio G, et al. ICAAC 2006. H-999.
89.8%
Tipranavir and Darunavir
Mutations and Phenotypic Cutoffs
Similarities and Differences in Key Mutations
TPV
10V
DRV
20M/R/V
11I
TPV
DRV
13V
54A/M/V 58E
50V
33F
32I
69K
54L/M
35G
43T
46L
33F
82L/T 83D 84V
76V
84V
Phenotypic Cutoffs
PhenoSense: FC
for Reduced
Activity
PhenoSense: FC
for No Response
VircoTYPE: FC for
Maximal
Response
VircoTYPE: FC for
Minimal Response
TPV[1,2]
≥2
≥8
< 1.2
≥ 5.4
DRV[3,4]
≥ 10
≥ 40
< 3.4
≥ 96.9
Assay/
Cutoff
47V
47V
74P
73S
36I
1. Oakley E, et al. Resistance Wkshp 2006. Abstract 71. 2. Bacheler L, et al. Euro
Resistance Wkshp 2006. Abstract 40. 3. De Meyer S, et al. Resistance Wkshp 2006.
Abstract 73. 4. Winters B, et al. Resistance Wkshp 2006. Abstract 160.
89V
Susceptibility to Tipranavir or Darunavir
After Failure of Each Other
Limited data suggest both agents may retain
activity after failure of the other


Among 39 patients with virologic rebound on
DRV/r[1]; median 8.14 fold-change loss of DRV
susceptibility from baseline; however, no decrease
in susceptibility to TPV
In POWER 3, 51 patients (11%) were failing TPV/r
at entry[2]; 44% achieved VL<50 copies/mL at wk
24, similar to overall response to DRV/r in POWER
1, 2, and 3 (42%)
1. De Meyer S, et al. CROI 2006. Abstract 157.
2. Lefebvre E, et al. ICAAC 2006. Abstract H-1387.
Key Steps to Regaining
Virologic Suppression
Aim for undetectable viral load
 Use cumulative results from current and
prior resistance tests along with treatment
history to assess drug susceptibility
 Select a new regimen containing at least 2
fully active agents

Use of New Agents:
Too Soon, Too Late, or Just Right?

Too soon


Too late


New drug used in combination with inactive or partially
active drugs despite relatively preserved CD4 cell count
New drug deferred until the patient’s virus is resistant to
all other available drugs
Just right

New drug combined with other active agents or use
deferred until other new agents available
What to Combine With the New PIs
in Treatment-Experienced Patients





NNRTIs: most patients have resistance to first-generation
NNRTIs at this stage
Assess NRTI resistance carefully, considering all resistance
test results and treatment history
Other PIs: cannot be combined with tipranavir (TPV);
limited data with darunavir (DRV); minimal data supporting
dual-boosted PIs
Fuzeon (ENF): often the best choice in patients with
extensive 3-class resistance
New agents
Expanded Access Availability

Etravirine (TMC125): available since August 2006


MK-0518: available since September 2006


www.clinicaltrials.gov/ct/show/NCT00354627?order=2
www.benchmrk.com/secure/earmrk/earmrk.html
Maraviroc: expected to be available Q1 2007
Combining New Agents
With the New PIs

Etravirine (TMC125): second-generation NNRTI



Integrase inhibitors


DUET study in progress (DRV ± ETV)
EAP available
MK-0518: EAP available, BID, no RTV boosting effect
Entry inhibitors

Maraviroc (MVC): CCR5 inhibitor, EAP available soon


199 patients w/NNRTI resistance
and ≥ 3 primary PI mutations
 Median NNRTI Fold Change
 NVP: 61.3
 EFV: 41.4
 ETV: 1.6
Randomized to
 ETV (400mg or 800mg BID)
+ NRTIs ± LPV/r ± ENF
 Active control: best available
regimen from approved
agents (NNRTIs excluded)
VL < 50 copies/mL at Wk 48 (%)
TMC 125-C223: Response to
Etravirine (ETV) at wk 48
100
80
60
40
23
22
20
0
0
ETV
ETV
400mg BID 800mg BID
Cohen C, et al. IAC 2006. Abstract TUPE0061.
Control
TMC 125-C223: Baseline NNRTI
Mutations and Response at wk 48
Response to ETV 800 BID by
Each of the following
ETV
Active
# of B/L NNRTI mutations
800 BID Control
mutations, always in
0*
1
2
≥3
combination with up to
0
n = 79
n = 40
n = 14
n = 19
n = 16
n = 30
4 other mutations was
-0.14
associated with a mean
-0.5
Fold Change > 10
-0.54
 K101P, V179E, V179F,
-1.0
-0.9
Y181I, Y181V, G190S,
-1.01
M230L
-1.5
-1.38
 For 179E, G190S, or
M230L, the additional
-1.67
mutations always included
-2.0
Y181C when FC > 10
*All patients had confirmed NNRTI mutations
from prior genotypic resistance tests
Mean Change in VL Log10

ITT, NC = no change from baseline
Cohen C, et al. IAC 2006. Abstract TUPE0061.
Pilot Data on DRV/r Plus Etravirine



Combination DRV+ETV associated with 30%  in ETV
levels vs controls; not judged to be clinically significant[1]
3-class resistant patients treated with DRV/r 600/100mg
BID + ETV 200mg BID + NRTIs ± ENF
Montaner et al.[2]


4/5 patients achieved VL < 50 copies/mL at wks 20-24
Boffito et al.[3]




10/12 patients completed 24 weeks of therapy
9/10 achieved VL<50, 1/10 = 722 copies/mL
Median VL decline, -2.7 log10; CD4 increase: 113 cells/mm3
No serious adverse events or changes in laboratory safety
1. Boffito M, et al. CROI 2006. Abstract 575c. 2. Montaner J, et al. IAC 2006. Abstract THPE0136.
3. Boffito M, et al. ICAAC 2006. Abstract H-1000.
Raltegravir (MK-0518):
Integrase Inhibitor BENCHMRK Trials



BENCHMRK-1 and -2: parallel randomized, double-blind,
placebo-controlled phase III studies BENCHMRK-1 and -2
designed to evaluate efficacy and safety of raltegravir +
OBR in triple-class–resistant patients
Raltegravir (MK-0518) with optimized background regimen
[OBR] demonstrated superior virologic efficacy vs placebo
at wk 16 in patients with triple-class resistance
Safety and tolerability of raltegravir appeared comparable
to placebo
Cooper D, et al CROI 2007, Abstracts 105aLB
Steigbigel R, et al CROI 2007, Abstract 105bLB
Raltegravir (MK-0518): Virologic
Suppression Through Week 24 (NC=F)
MK-0518 200 mg BID (n = 43)
MK-0518 400 mg BID (n = 45)
100
Patients With VL
< 50 copies/mL (%)
Patients With VL
< 400 copies/mL (%)
100
MK-0518 600 mg BID (n = 45)
OBR alone (n = 45)
80
60
40
20
80
60
40
20
0
0 2 4
8
12
16
Week
Grinsztejn B, et al. ICAAC 2006. Abstract H-1670b.
24
0 2 4
8
12
Week
16
24
Maraviroc (MVC) CCR5 Inhibitor:
MOTIVATE Trials


Randomized, double-blind, placebo-controlled, phase
IIb/III clinical studies: Maraviroc + Optimized
Background Therapy in Viremic, ART-Experienced
Patients (MOTIVATE) 1 and 2
Maraviroc plus optimized background therapy [OBT]



MVC associated with significantly greater viral suppression
than placebo
Similar activity in MVC once-daily and twice-daily arms
In combined analysis, higher rate of viral suppression with
twice-daily MVC in patients with no active drugs in OBT
Lalezari J, et al CROI 2007 Abstract 104bLB
Nelson M, et al CROI 2007 Abstract 104aLB
Maraviroc (MVC) CCR5 Inhibitor:
MOTIVATE Trials (cont.)

Maraviroc plus OBT associated with significantly
greater CD4 cell count increase vs placebo

Among patients with tx failure, MVC recipients more
likely to exhibit shift in detected tropism to X4 or
dual/mixed-tropic R5/X4
Fewer patients receiving MVC experienced tx
failure compared with those receiving placebo
 Safety profiles similar between MVC & placebo

Lalezari J, et al CROI 2007 Abstract 104bLB
Nelson M, et al CROI 2007 Abstract 104aLB
MVC Safe in Experienced
Patients With Detectable X4 HIV

No difference in mean VL ↓ between MVC + OBR vs placebo + OBR




-0.97, -0.91, -1.20 log10 for placebo, MVC QD, and MVC BID at wk 24
No major AEs; no hepatotoxicity, lymphoma, or adenocarcinoma
Higher CD4+ cell counts at wk 24 with MVC vs placebo
Detection of only X4-tropic HIV more common at tx failure with MVC
vs placebo; however, similar CD4 cell count increases in pts with
detection of only X4 virus vs overall MVC-treated population,
suggesting no impact on immunologic recovery
Change in CD4+ Cell Count
Population
Placebo + OBR
(n = 58)
MVC QD + OBR
(n = 57)
MVC BID + OBR
(n = 52)
+36
+60
+62
-104 (n = 2)
+48 (n = 12)
+33 (n = 12)
All treated patients
Patients with only X4 virus
detected at time of VF
Mayer H, et al. IAC 2006. Abstract THLB0215.
Other New Agents in
Advanced Clinical Trials

Integrase inhibitor


Maturation inhibitor


GS-9137: QD, boosted by RTV
Bevirimat (PA-457)
Entry inhibitors

Vicriviroc: CCR5 inhibitor
Guidelines for Choosing a
Nonsuppressive “Holding Regimen”

Do not use an NNRTI if resistant



Use Epivir (3TC) or Emtriva (FTC) even if resistant



NNRTI mutations have no beneficial impact on fitness
Accumulation of additional mutations may result in
cross-resistance to second generation NNRTIs
Simple and well-tolerated drugs
M184V  fitness, increases activity of ZDV, D4T, TDF
Choose PIs and/or NRTIs based on resistance and
tolerability/toxicity considerations
Estimated Timeline for Availability
of New Antiretrovirals
CXCR4
inhibitors
Entry inhibitors
(anti-gp120, CCR5)
GS-9137
Maraviroc
MK-0518
2006
2007
Etravirine
Vicriviroc
Maturation inhibitors
TNX-355
Integrase inhibitors
Bevirimat
2008
2009
2010
TMC278
PIs
Brecanavir
NNRTI
Apricitabine
NRTI
Case Study 1

D.R. is a 42 yo male HIV+ for 12 years on
multiple HIV treatment regimens, starting
with Combivir (ZDV/3TC) in the mid-1990s
& including Crixivan (IDV) and Lexiva (APV).
Most recently he has been on a combination
of Trizivir (ZDV/3TC/ABC), Videx (DDI), and
boosted Reyataz (ATV/r). His viral load =
33,000 and CD4 = 355.
Case Study 1:
Resistance Mutations

RT mutations:


PR mutations:


M41L, E44D, D67N, V118I, M184V, L210W, T215Y
L10I, K20I, M36I/M, M46I, I54V, L63P, G73T, A71T, I84V,
L90M
Interpretation of Genotype (GT):

By Quest


Sensitive to all NNRTIs and TPV
Resistant to all NRTIs
Drug Resistance Interpretation
Stanford Database Website
Major PI Mutations:
M46I, I54V, I84V, L90M
Minor PI Mutations:
L10I, A71T, G73T
Other Mutations:
K20I, M36I, L63P
Protease Inhibitors
 ATV: High-level resistance
 DRV: Intermediate resistance
 FPV: High-level resistance
 IDV: High-level resistance
 LPV: Intermediate resistance
 NFV: High-level resistance
 SQV: High-level resistance
 TPV: Intermediate resistance
NRTI Mutations:
M41L, E44D, D67N, V118I,
M184V, L210W, T215Y
NNRTI Mutations: None
Nucleoside RTI
 3TC: High-level resistance
 ABC: High-level resistance
 AZT: High-level resistance
 D4T: High-level resistance
 DDI: High-level resistance
 FTC: High-level resistance
 TDF: Intermediate resistance
Non-Nucleoside RTI
 DLV: Susceptible
 EFV: Susceptible
 NVP: Susceptible
Clinical Decisions and Questions
What about the lack of resistance to the NNRTIs?
 Can an effective regimen be constructed for this
patient? What if you think the regimen would be
effective but not completely suppressive?
 How do you feel about combining agents that
have not been combined in clinical studies?
 Would this patient benefit from drug interruption?
 How do you deal with the discordance between
interpretations?
 What antiretroviral combinations would you
consider for this patient?

Case Study 2

S.F. is a 31 yo female HIV+ for past 10 yrs.
She has been on ARV therapies but nonadherent. Her CD4 is repeatedly <100. At
her most recent visit she was on Epzicom
(3TC/ABC), Invirase (SQV), & Kaletra
(LPV/r). Labs show her viral load = 55,600
and CD4 = 73. She returns to discuss
changing her therapy and tells you that she
is again off her ART for the past 2 weeks.
Case Study 2
Do you obtain a resistance assay at this
time?
 What issues do you discuss at this visit?

Case Study 2:
Resistance Assays

RT mutations


M41L, l74V, Y115F, M184V, T215Y, Y181C
PR mutations

L10F, K20I, V32I, M46I, I47V, I54V, L63P, A71T,
G73S, I84V, L90M
Case Study 2:
Resistance Assessment

By Quest Genotype (GT):
Sensitive to Viread (TDF), Sustiva (EFV),
Tipranavir (TPV)
 Partially sensitive to Zerit (D4T)


By Quest Phenotype (PT):


Sensitive to Zerit (D4T), Retrovir (ZDV), Viread
(TDF); Sustiva (EFV); and Tipranavir (TPV)
Replication capacity: 5.5%
Drug Resistance Interpretation
Stanford Database Website
Major PI Mutations:
V32I, M46I, I47V, I54V, I84V, L90M
Minor PI Mutations:
L10F, A71T, G73S
Other Mutations:
K20I, L63P
Protease Inhibitors
 ATV: High-level resistance
 DRV: High-level resistance
 FPV: High-level resistance
 IDV: High-level resistance
 LPV: High-level resistance
 NFV: High-level resistance
 SQV: High-level resistance
 TPV: High-level resistance
NRTI Mutations:
M41L, L74V, Y115F, M184V, T215Y
NNRTI Mutations: Y181C
Nucleoside RTI
 3TC: High-level resistance
 ABC: High-level resistance
 AZT: Intermediate resistance
 D4T: Intermediate resistance
 DDI: High-level resistance
 FTC: High-level resistance
 TDF: Low-level resistance
Non-Nucleoside RTI
 DLV: High-level resistance
 EFV: Low-level resistance
 NVP: High-level resistance
Clinical Decisions and Questions
What are the risks and benefits of continuing the
current regimen?
 Is this patient a candidate for a treatment
interruption?
 What antiretrovirals would you possibly combine
for this patient to construct an effective regimen?
 What additional measures would you undertake in
this patient’s HIV therapy?
