Transcript Antiretroviral Resistance Testing in the Management of HIV

Antiretroviral Resistance Testing in
the Management of HIV-infected
Patients
Christopher Behrens, MD
Amy Kindrick, MD
Robert Harrington, MD
Overview of Antiretroviral
Resistance Testing
• How does resistance develop?
• What is the relationship between adherence and
resistance?
• How much resistance is out there?
• How do we test for resistance?
• How do we interpret the results of a resistance test?
• Does resistance testing improve care?
• When should you order resistance tests?
• Can a single dose of nevirapine for Prevention of
Mother to Child Transmission (PMTCT) result in
clinically significant resistance?
How Does HIV Develop
Resistance to Antiretrovirals?
HIV Life Cycle
HIV
Nucleoside Analogues (NRTIs)
Reverse Transcriptase
RNA
DNA
Nucleus
Host Cell
Non-Nucleosides (NNRTIs)
Protease Inhibitors (PIs)
How does HIV Develop Resistance to
Antiretrovirals?
• HIV reverse transcriptase is a low-fidelity enzyme,
i.e., transcription mistakes are common
• Mistakes (mutations) lead to mutant strains of HIV
• Most mutations are inconsequential or result in
incompetent strains of HIV, but certain mutations
confer resistance to currently available
antiretroviral drugs (ARVs)
• Administration of antiretrovirals in an insufficiently
potent manner exerts reproductive pressure that
selects for resistance-bearing strains which then
become the majority strain of HIV in that patient
How Drug Resistance Arises
How drug resistance arises. Richman, DD. Scientific American , July 1998
How does resistance develop?
Continuation of a failing ART regimen after early resistance has
developed selects for expansion of resistance
How does resistance develop?
Poor Adherence
Drug Resistance
Regimen Failure
How does resistance develop?
Social/personal issues
Regimen issues
Toxicities
Poor potency
Wrong dose
Host genetics
Poor adherence
Poor absorption
Insufficient drug level
Rapid clearance
Viral replication in the
presence of drug
Poor activation
Drug interactions
Resistant virus
True or False?
The patients with the lowest levels of
adherence are the most likely to
develop resistance to their ARVs
Resistance
What is the relationship between adherence
and resistance?
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
10
20
30
40
50
60
70
75
Adherence
80
85
90
95 100
What is the relationship between adherence
and resistance?
Harrigan, JID, 2005
• Prospective, observational
study
• N = 1191
• Predictors of resistance
– High baseline VL
– Good (not great) adherence
Is Resistance Becoming
More Common?
Prevalence of resistance among recently-infected patients at San Francisco General Hospital
% of resistant isolates
25
NRTI any
NNRTI any
PI any primary
two classes
three classes
20
15
10
5
0
1996-97
1998-99
JAMA. 2002 Jul 10;288(2):181-8.
2000-01
Is Resistance Becoming
More Common?
Recently Infected, ART Naïve, United States
Little SJ, Holte S, Routy JP, et al. N Engl J Med. 2002;347:385-94
How do we test for resistance?
1. Genotype
2. Phenotype
3. Virtual Phenotype
HIV Life Cycle
HIV
Nucleoside Analogues (NRTIs)
Reverse Transcriptase
RNA
DNA
Nucleus
Host Cell
Non-Nucleosides (NNRTIs)
Protease Inhibitors (PIs)
Genotypic Resistance Assay
• Sequences relevant portions of the HIV
genome coding for Reverse Transcriptase
and Protease enzymes
• Detects and reports variations in the
sequences of these genes that are known or
suspected to confer antiretroviral resistance
Codon
Mutation
AAA GAC AGT
AAA AAC AGC
Lys Asp Ser
Lys Asn Ser
Adapted from Winters. Reviewed in Wilson. AIDS Read 2000;10:469.
Silent Mutation
M184V
M = Methionine
184 = the codon #
V = Valine
A mutation at codon
#184 in the gene
Reverse Transcriptase
codes for a Valine
residue where
normally a Methionine
residue is found.
Reverse Transcriptase Mutations
Selected by NRTIs
(Wild Type)
AZT
M
D K
41
1 (Mutant)
67
L
L
70
210 215
W
N R
K
ddI
YF Q
560
184
74
R
219
M
L
65
TK
V
V
T
ddC
65
184
74
69
D
V
E
3TC
44
118
184
I
D
VI
V
d4T
41
67
70
75
210 215
219
210
219
TMSA
Y
ABC
41
65
67 70
74
115
184
F
Mutation
Clinical significance
under investigation
Adapted from D’Aquila. Topics in HIV Medicine 2001;9(2):31.
215
V
Selected in vitro
Reverse Transcriptase Mutations
Selected by NNRTIs
L KV V
NVP
Y
106
108
100
103
181
I NAI
1
Y G
CI C LH
188
190
A
560
P
DLV
103
236
181
L
C
P
EFV
100
103
108
188
190
L SA
Mutation
Adapted from D’Aquila. Topics in HIV Medicine 2001;9(2):31.
225
H
Protease Mutations Selected by PIs
L
10
IDV
1
L
K
20
IRV
V
24
32
I
MR
36
I
I
M
M
46
AG
54
I
I
73 77
71
V
V I
V
VT SA
82
L
84
90
99
M
I AFTS V
L
RTV
10
32
20
33 36
46
F
54
IL
71
77
82
84
90
71
73 77
82
84
90
VL
G
SQV
10
48
54
V
S
A
D
NFV
10
30
FI
N
36
46
71
I
APV
10
32
LPV/RTV
10
I V
20
24
84 88
90
D
I
47
46
FIRV
82
AFTS
IL
N
77
46
V
84
54
50
VM
F
53
L
54
63
L
Primary
Adapted from D’Aquila. Topics in HIV Medicine 2001;9:31.
Secondary
71
P
82
84
90
Interpretation of
the results: what
are the clinical
implications of
these mutations in
terms of resistance
to antiretroviral
agents?
Interpretation of the Genotypic
Resistance Assay
• The genotype report typically includes an interpretation
of the clinical implications of the identified mutations
• However:
– The exact significance of many mutations remains
controversial
– Interactions between mutations further complicate estimation
of the clinical impact of a given set of mutations
– Interpretation of genotypic resistance assays is not
standardized across different laboratories
– Assays will not detect minority resistant strains (less than 1020% of the viral population)
Phenotypic
Resistance
Testing
• Tests viability of a synthetic
version of the patient’s HIV
in the presence of
antiretroviral agents
• Similar to traditional
bacterial antibiotic
susceptibility assays
• Results reported as foldchange in susceptibility to
antiretroviral agents
Inhibition of Viral
Replication (%)
Phenotype Resistance Testing
100
Fold
Resistance
50
Wild-type strain
Mutant strain
0
IC50
IC50
Drug Concentration
Reviewed in Wilson. AIDS Read 2000;10:469.
PhenoSense HIV Patient Report
PhenoSense™ HIV Report
Which Resistance Assay is Better?
Pros
Cons
Genotypic
assay
• More clinical experience
and evidence of clinical
utility
• Less expensive (~$400)
• Results available in 1-2
weeks
• Results difficult to interpret
• Does not directly measure net
effect of multiple mutations
Phenotypic
assay
• Simpler to interpret
• Clinically relevant thresholds
• More directly estimates net of resistance not yet determined
effect of multiple mutations for many agents
• Less evidence of clinical
utility
• More expensive (~$1000)
• Results in 3-4 weeks
Does the use of resistance assays
improve clinical results?
Published Randomized Controlled Trials
of Resistance Testing
Study
(year published)
VIRADAPT
(1999)
CPCRA 046
(2000)
Havana
(2002)
ARGENTA
(2002)
VIRA3001
(2002)
Narval
(2002)
Study Arms
Conclusions
Genotype + expert advice
vs
usual care (no expert advice)
Genotype + expert advice
vs
usual care (no expert advice)
Genotype +/- expert advice
vs
usual care (+/- expert advice)
Genotype + expert advice
vs
usual care (+ expert advice)
Phenotype (no expert advice)
vs
usual care (no expert advice)
Genotype (no expert advice)
vs
phenotype (no expert advice)
vs
usual care (no expert advice)
Genotype with expert advice better
than usual care without expert advice
Genotype with expert advice better
than usual care without expert advice
Genotype and expert advice each
helpful; genotype with expert advice
resulted in best clinical outcomes
Genotype with expert advice not
significantly better than standard of
care + expert advice
Phenotype without expert advice
better than usual care without expert
advice
No signficant advantage of genotype
or phenotype over usual care
Havana Results:
% of Patients with HIV-1 RNA <400 copies/mL
100
(ITT)
No G No Expert Op.
80
60
40
P = .0206
P = .00132
No G Expert Op.
G No Expert Op.
G Expert Op.
20
0
BL
wk 12
NO G, NO Expert (N = 77)
NO G, Expert (N = 67)
G, NO Expert (N = 69)
G, Expert (N = 65)
Tural. 40th IACAC; 2000; Toronto. Presentation LB-10.
wk 24
36.4%
49.3%
46.4%
69.2%
Expert Consultation Resources
• National Clinicians’ Telephone Consultation
Service (Warmline): 800-933-3413
• Internet:
– http://hivdb.stanford.edu
– www.hivresistance.com
• Others?
The Virtual Phenotype
Genotype
HIV
Access Data
RT
Proteas
e
Virtual Phenotype
Wild-type HIV
Resistant HIV
Illustration by David Spach, MD
Genotype & Phenotype
Data
The Virtual Phenotype
Sample report
When Should a Resistance Assay
be Ordered?
Antiretroviral Resistance Testing: Guidelines
for Implementation
Clinical Setting/
Recommendation
Rationale
Recommended:
•Virologic failure during ART
Determine role of resistance in drug failure and maximize
the number of active drugs in the new regimen
•Suboptimal suppression of viral load Determine the role of resistance in drug failure and
maximize the number of active drugs in the new regimen
(VL) after initiation of ART
Determine if resistant virus was transmitted; select
•Acute (primary) HIV infection
regimen accordingly
•Chronic HIV infection before
Assays may not detect minor resistant species, but some
starting ART
resistance mutations may persist for years. Consider
testing early after diagnosis of HIV infection.
Usually not recommended:
•After discontinuation of drugs
•Plasma VL <1,000 copies/mL
Resistance mutations may become minor species in the
absence of selective drug pressure
Resistance assays unreliable if VL is low
Adapted from DHHS, Antiretroviral Guidelines, October 6, 2005
Antiretroviral Therapy:
Virologic Failure
100000
Medications Started
HIV RNA
10000
1000
100
50
10
50
Time
Illustration by David Spach, MD
Antiretroviral Therapy:
Failure to Suppress
100000
Medications Started
HIV RNA
10000
1000
100
50
10
50
Time
Illustration by David Spach, MD
Time Trends in Primary HIV-1
Genotypic Drug Resistance Among
Recently Infected Persons
% of resistant isolates
25
NRTI any
NNRTI any
PI any primary
two classes
three classes
20
15
10
5
0
1996-97
1998-99
JAMA. 2002 Jul 10;288(2):181-8.
2000-01
Antiretroviral Resistance Testing:
Guidelines for Implementation
Clinical Setting/Recommendation
Recommended
Virologic failure during HAART
Rationale
Determine the role of resistance in drug failure
and maximize number of active drugs in a new
regimen if indicated
Suboptimal suppression of viral load after Determine the role of resistance and maximize
initiation of HAART
number of active drugs in new regimen
Acute (Primary) HIV Infection
Consider
Chronic HIV infection prior to initiation
of HAART
Not Generally Recommended
After discontinuation of drugs
Plasma viral load < 1000 copies/mL
Determine if drug resistant virus was transmitted
and design initial regimen accordingly
Minor drug-resistant species might not be
detected, but consider testing if significant
probability that patient may have been infected
with a drug-resistant virus
Resistant quasispecies tend to become minor
species in the absence of selective drug pressure,
making detection by current assays unlikely
Current assays unreliable at low viral loads
DHHS. Antiretroviral Guidelines, July 14, 2003, Table 3.
Antiretroviral Resistance Testing: Guidelines
for Implementation
Clinical Setting/
Recommendation
Rationale
Recommended:
•Virologic failure during ART
Determine role of resistance in drug failure and maximize
the number of active drugs in the new regimen
•Suboptimal suppression of viral load Determine the role of resistance in drug failure and
maximize the number of active drugs in the new regimen
(VL) after initiation of ART
Determine if resistant virus was transmitted; select
•Acute (primary) HIV infection
regimen accordingly
Consider:
•Chronic HIV infection before
starting ART
Usually not recommended:
•After discontinuation of drugs
•Plasma VL <1,000 copies/mL
Assays may not detect minor resistant species, but
consider if significant probability of transmitted drugresistant virus
Resistance mutations may become minor species in the
absence of selective drug pressure
Resistance assays unreliable if VL is low
Adapted from DHHS, Antiretroviral Guidelines, October 6, 2005
Reversion to Predominant Wild-Type Virus After
Discontinuing ART
Illustration by David Spach, MD
Drug resistance is Significantly Correlated
with Reduction in Replication Capacity
Wrin T, et al. 5th International Workshop on HIV Drug Resistance and Treatment Strategies. Scottsdale, AZ: June 2001 (Abstract 24)
Resistance
What is the relationship between adherence
and resistance?
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0
10
20
30
40
50
60
70
75
Adherence
80
85
90
95 100
Antiretroviral Resistance Testing: Guidelines
for Implementation
Clinical Setting/
Recommendation
Rationale
Recommended:
•Virologic failure during ART
Determine role of resistance in drug failure and maximize
the number of active drugs in the new regimen
•Suboptimal suppression of viral load Determine the role of resistance in drug failure and
maximize the number of active drugs in the new regimen
(VL) after initiation of ART
Determine if resistant virus was transmitted; select
•Acute (primary) HIV infection
regimen accordingly
•Chronic HIV infection before
Assays may not detect minor resistant species, but some
starting ART
transmitted resistance mutations may persist for years.
Consider testing early in the course of HIV infection.
Usually not recommended:
•After discontinuation of drugs
•Plasma VL <1,000 copies/mL
Resistance mutations may become minor species in the
absence of selective drug pressure
Resistance assays unreliable if VL is low
Adapted from DHHS, Antiretroviral Guidelines, May 4, 2006
Persistence of Resistant Strains
Following Primary HIV Infection
•
11 subjects with primary HIV infection who deferred ART and who had at least
one major drug resistance mutation identified at presentation, followed with serial
resistance assays.
–
–
–
–
7 subjects with NNRTI resistance
2 with NRTI and PI resistance
1 with NNRTI and PI resistance
1 with resistance to all three classes of drugs
• NNRTI resistance was lost slowly: the average time to reversion of 103N
variants to mixed 103N/K populations was 196 days following the estimated date
of infection (153 to 238 days, 95%CI).
• PI resistance was not lost at all: In the 4 patients with protease resistance
mutations, no reversion was detected at 64, 191, 327, and 342 days after infection.
• Complete reversion of genotypic resistance was observed in only one
patient, at 1019 days after infection.
Little SJ. 11th CROI, February 2004, Abstract 36LB
Persistence of
Resistant Strains
Following Primary
HIV Infection
N = 6 patients infected with
resistant strains of HIV;
none reverted to wild-type
over the course of several
months of observation
Barbour JD et al. AIDS: Volume 18(12) 20
August 2004 pp 1683-1689
Persistence of Resistant Strains after
Primary HIV Infection?
Illustration by David Spach, MD
Persistence of Some Resistant Strains after
Primary HIV Infection?
Illustration by David Spach, MD
Testing for Antiretroviral Drug
Resistance: Conclusions
• The proportion of new HIV infections that involve resistant
strains tends to increase with increasing availability of ART
• Initial ART is more likely to fail in patients with a resistant strain
• In patients treated with ART, resistance mutations, especially
those affecting the NNRTIs and PIs, have been found to persist
for up to two years after discontinuation of ART
• Resistance testing is becoming more common in chronicallyinfected patients in North America who acquired their infection
in the past few years
What if you cannot obtain a
resistance assay for your patient who
is failing therapy?
Empiric sequencing of ART regimens
Empiric design of salvage regimens for
patients failing ART: key considerations
• The genotypic barrier to resistance varies
across different antiretroviral agents
– For some ARVs, a single mutation can induce
high-level resistance (e.g., lamivudine, efavirenz,
nevirapine)
– For other ARVs, resistance generally does not
develop until multiple mutations accumulate (eg,
AZT, stavudine, tenofovir)
Empiric design of salvage regimens for
patients failing ART: key considerations
• The phenotypic barrier to resistance can vary for
different ARVs as well
– High serum levels can help to prevent or even overcome
resistance mutations
• Ritonavir boosting of protease inhibitors will increase
their phenotypic barrier to resistance
– PIs, like many medications, are metabolized in the liver by
the cytochrome P450 enzyme complex
– Ritonavir inhibits this complex, thereby boosting serum
levels of co-administered PIs
– Low doses of ritonavir can be used to increase the potency
and simplify the dosing of PI-based regimens
An Example of Ritonavir Boosting:
Indinavir/Ritonavir BID PK Study
10,000
IDV/RTV q12h:
800/200 High-fat Meal
Indinavir
Plasma
Concentration
(nM)
800/100 High-fat Meal
1,000
400/400 High-fat Meal
IDV q8h:
800 mg Fasted
100
0
2
4
6
8
Time after dose (hours)
10
12
6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.
Implications of varying genotypic and
phenotypic barriers to resistance
• Resistance develops initially to NNRTIs (efavirenz,
nevirapine) and lamivudine
• If treatment is continued, resistance can subsequently
develop to other NRTIs such as AZT, stavudine,
didanosine, abacavir, tenofovir
• Protease inhibitors:
– Variable, but generally resistance develops more slowly
than to lamivudine and NNRTIs
– Ritonavir boosting significantly delays development of
resistance to protease inhibitors
Havana Results:
% of Patients with HIV-1 RNA <400 copies/mL
100
(ITT)
No G No Expert Op.
80
60
40
P = .0206
P = .00132
No G Expert Op.
G No Expert Op.
G Expert Op.
20
0
BL
wk 12
NO G, NO Expert (N = 77)
NO G, Expert (N = 67)
G, NO Expert (N = 69)
G, Expert (N = 65)
Tural. 40th IACAC; 2000; Toronto. Presentation LB-10.
wk 24
36.4%
49.3%
46.4%
69.2%
Should we discuss resistance
with patients?
Factors Associated with Higher
Levels of Adherence
•
•
•
•
•
Twice-daily or once-daily regimens1,4
Belief in own ability to adhere to regimen1
Not living alone2
Dependent on a significant other for support2
History of opportunistic infection or advanced
HIV disease3
1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125.
2. Morse EV et al, Soc Sci Med 1991;32:1161-1167.
3. Singh N, et al, AIDS Care 1996;8:261-269.
4. Stone VE, et al. JAIDS 2001; 28:124-131.
Factors Associated with Higher
Levels of Adherence
• Belief in efficacy of antiretroviral therapy
• Belief that non-adherence will lead to viral
resistance
Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.
Teaching the concept of
resistance to patients
A cartoon metaphor
How Resistance Develops
to HIV
 This is the virus known as HIV. The only
thing that matters to him in his short,
nasty life is to destroy T-Cells. To do this,
he must somehow get over this wall.
 The wall is created by taking anti-HIV
medications. When the medicines are
taken correctly, the virus is unable to
climb over the wall to get to your T-cells.
Sometimes the Wall Comes
Down
 When you forget to take your
evening dose, or only take 2 of your
anti-HIV medicines, the strong wall
comes down.
 The virus breaks free and is able to
get over the wall.
 When he gets to the other side, he
discovers a way to get over the wall
in the future. This is called
resistance. He finds a spring that will
give him a little more bounce.
The Wall Goes Back Up
 When you start taking the medicine
regularly again, the wall goes back
up.
 Sometimes, it’s too late and the
virus uses the spring to jump over
the wall. At this point, it is a
resistant virus The drugs may not be
able to keep the wall high enough to
stop the springing virus.
Lessons to Be Learned
It is better to not take anti-HIV drugs at all than to
take them only some of the time.
If you think you may be missing doses often,
please tell your health care provider or
pharmacist! We promise not to tell your mother.
Antiretroviral Resistance
Summary & Conclusions
Summary & Conclusions
• Resistance develops in the setting of an inadequately
suppressive ART regimen
• Educating patients about resistance may promote
better adherence
• For the patient who is failing therapy:
– Revisit adherence issues
– Consider obtaining a resistance assay
– Resistance assay results need to be interpreted with caution,
and ideally with expert assistance
– Salvage regimens can be designed empirically without the
assistance of a resistance assay
Cases
In which of these situations is
resistance testing clearly indicated?
• A 28 yo male just diagnosed with acute HIV infection
• A 38 yo woman on d4T/3TC/indinavir who had
enjoyed full virologic suppression but whose last two
HIV viral loads were 72 and 110 copies/mL
• A 41 yo man on AZT/3TC/nelfinavir whose last three
viral loads were 256, 865, and 1838 copies/mL
• A 35 yo woman with a history of spotty adherence
and a viral load of 20,000 copies/mL while on
d4T/3TC/efavirenz one year ago. She discontinued
all antiretrovirals shortly thereafter, but now wants to
restart ART and appears highly motivated.
In which of these situations is
resistance testing clearly indicated?
• A 28 yo male just diagnosed with acute HIV infection
• A 38 yo woman on d4T/3TC/indinavir who had
enjoyed full virologic suppression but whose last two
HIV viral loads were 72 and 110 copies/mL
• A 41 yo man on AZT/3TC/nelfinavir whose last three
viral loads were 256, 865, and 1838 copies/mL
• A 35 yo woman with a history of spotty adherence
and a viral load of 20,000 copies/mL while on
d4T/3TC/Efavirenz one year ago. She discontinued
all antiretrovirals shortly thereafter, but now wants to
restart HAART and appears highly motivated.
Case 1
• A 33 yo woman with a baseline CD4 count of 260
cells/mm³ and a viral load of 90,000 copies/mL
initiates ART with a regimen of d4T/ddI/nelfinavir.
She achieves virologic control with a viral load <50
copies/mL and her CD4 count rises to 420.
• 6 months later, she develops pancreatitis; 3TC is
substituted for ddI, and her viral load remains <50
copies/mL on d4T/3TC/nelfinavir
• 4 months later her viral load rises to 25,000
copies/mL, and her CD4 count drops to 320.
Case 1: Figure
Viral Load (copies/mL)
Initiate ART
100000
90000
80000
70000
60000
50000
40000
30000
20000
10000
50
0
Genotype ordered
Pancreatitis;
lamivudine
substituted for
didanosine
30 mos 24 mos 18 mos 12 mos 6 mos
ago
ago
ago
ago
ago
Viral Load
1 mo
ago
Case 1 continued
• You order a genotypic resistance assay, which
reveals the following mutations:
– Reverse transcriptase: M184V
– Protease: D30N
• Which of the following regimens is/are
reasonable options for this patient?
–
–
–
–
ddI/abacavir/efavirenz
AZT/3TC/nevirapine
d4T/abacavir/ritonavir/saquinavir
d4T/tenofovir/efavirenz
Case 1 continued
• You order a genotypic resistance assay, which
reveals the following mutations:
– Reverse transcriptase: M184V
– Protease: D30N
• Which of the following regimens is/are
reasonable options for this patient?
–
–
–
–
ddI/abacavir/efavirenz
AZT/3TC/nevirapine
d4T/abacavir/ritonavir/saquinavir
d4T/tenofovir/efavirenz
Case 2
• A 37 yo male initiated ART 5 years ago
• Initial regimen: AZT/ddI/nevirapine
• Responded well initially with VL drop to
undetectable, rise in CD4 from 240 to 400 cells/mm³
• However, experienced virologic failure within one
year with rise in viral load to 12,000 copies/mL
• Regimen changed to d4T/3TC/indinavir; change
made without using a resistance assay
Case 2 continued
• He again achieved an undetectable viral load,
on his new regimen of d4T/3TC/indinavir
• 6 months ago lost to follow-up
• One month ago returned to clinic, describing
recent depression and spotty adherence (both
of which improved in past month)
• labs reveal CD4=320, viral load=10,000.
Case 2 continued
Failed AZT/ddI/nevirapine in remote past
• You order a genotypic resistance assay while he is
still taking d4T/3TC/indinavir, which reveals:
– Reverse transcriptase: M41L, M184V, T215Y
– Protease: I84V
• Which regimen(s) would you recommend?
–
–
–
–
–
ddI/nevirapine/nelfinavir
AZT/3TC/tenofovir/lopinavir+ritonavir
AZT/tenofovir/efavirenz
d4T/abacavir/ritonavir/saquinavir
AZT/d4T/lopinavir+ritonavir
Case 2 continued
• You order a genotypic resistance assay while he is
still taking d4T/3TC/indinavir, which reveals:
– Reverse Transcriptase: M41L, M184V, T215Y
– Protease: I84V
• Which regimen(s) would you recommend?
–
–
–
–
–
ddI/nevirapine/nelfinavir
AZT/3TC/tenofovir/lopinavir+ritonavir
AZT/tenofovir/efavirenz
d4T/abacavir/ritonavir/saquinavir
AZT/d4T/lopinavir+ritonavir
Extra slides
How much resistance is out there?
• 89 diagnostic and clinical sites in 6 U.S. states
• 828 newly diagnosed patients, 95% genotyped
• Overall prevalence of resistance was 14.5%
Prevalence of resistance among new 787 HIV diagnostic specimens from
899 sites in six states
Categories
Any drug class: RTI or primary PI
Participants with HIVDR
114 (14.5%)
NRTI
56 (7.1%)
NNRTI
66 (8.4%)
PI
22 (2.8%)
Two or more drug classes
24 (3.1%)
Underwood M et al. 12th CROI; 2005, Boston. #674.