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Transcript of Antiretroviral Resistance Testing in the Management of HIV-infected Patients Christopher Behrens, MD...
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
RNA DNA
HIV
Nucleus
Host Cell
Nucleoside Analogues (NRTIs)
Non-Nucleosides (NNRTIs) Protease Inhibitors (PIs)
Reverse Transcriptase
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. Richman, DD. Scientific American , July 1998
How Drug Resistance Arises
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?
Insufficient drug level
Viral replication in the presence of drug
Resistant virus
Poor adherence
Social/personal issuesRegimen issues
ToxicitiesPoor potency
Wrong dose
Host genetics
Poor absorption
Rapid clearance
Poor activation
Drug interactions
True or False?
The patients with the lowest levels of adherence are the most likely to develop resistance to their ARVs
What is the relationship between adherence and resistance?
00.10.20.30.40.50.60.70.80.9
1
0 10 20 30 40 50 60 70 75 80 85 90 95 100
Adherence
Res
ista
nce
Harrigan, JID, 2005• Prospective, observational
study• N = 1191• Predictors of resistance
– High baseline VL
– Good (not great) adherence
What is the relationship between adherence and resistance?
0
5
10
15
20
25
1996-97 1998-99 2000-01
NRTI anyNNRTI anyPI any primarytwo classesthree classes
Is Resistance Becoming More Common?
JAMA. 2002 Jul 10;288(2):181-8.
% o
f re
sist
ant i
sola
tes
Prevalence of resistance among recently-infected patients at San Francisco General Hospital
Is Resistance Becoming More Common?
Little SJ, Holte S, Routy JP, et al. N Engl J Med. 2002;347:385-94
Recently Infected, ART Naïve, United States
How do we test for resistance?
1. Genotype
2. Phenotype
3. Virtual Phenotype
HIV Life Cycle
RNA DNA
HIV
Nucleus
Host Cell
Nucleoside Analogues (NRTIs)
Non-Nucleosides (NNRTIs) Protease Inhibitors (PIs)
Reverse Transcriptase
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
AAA GAC AGTAAA GAC AGTAAA GAC AGTAAA GAC AGT AAAAAA AAACAC AGAGCCAAAAAA AAACAC AGAGCC
LysLysLysLys AspAspAspAsp SerSerSerSer LysLysLysLys AsnAsnAsnAsn SerSerSerSer
Codon Silent MutationMutation Silent Mutation
Adapted from Winters. Reviewed in Wilson. AIDS Read 2000;10:469.
M184V
M = Methionine184 = 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.
Adapted from D’Aquila. Topics in HIV Medicine 2001;9(2):31.
L N R W YF Q
41 67 70
560560
AZTAZT L T(Wild Type)
1 (Mutant)
219215210
KM D K
L M K
ddIddI 65 74 184
V V R
ddCddCT
D
65 74 18469
41 67 70 219215210d4Td4T 75
V
TMSA
Mutation Selected in vitro
ABCABC 74 115
Y
F V
219184 21521041 67 7065
3TC3TC 184
E
118
V
I
44
D VI
Clinical significance under investigation
Reverse Transcriptase Mutations Selected by NRTIs
SA
L K
100
181
100
NVP
DLV
EFV
V V
103
106108
188 190
Y G
I N A I C LH A
L
103
103 108
181
Y
CI
236
P
C
188
L
190 225
P
H
56056011
Adapted from D’Aquila. Topics in HIV Medicine 2001;9(2):31.
Mutation
Reverse Transcriptase Mutations Selected by NNRTIs
K V L
1 99
10
L
IDV 20 24 32
L L M
46
I
54 71
I V G A
82 84 90
54 71 82 84 90
10 48 54 71 82 84 90
71 77 82 88 90
VLILF G
V
D
3630 46
N
84
I
46
I
10
RTV
SQV
NFV
APV
46
32
FIRV
5447 50
I V
10
FI IL
84
AFTS
7773
S A
77
36 73 77
M V
Primary Secondary
M V AFTS IV SAVTIII IIRV MR
20 32 33 36
N D
V VM
844610LPV/RTV 545320 24 71 82 9063
L
P
F
L
10
Adapted from D’Aquila. Topics in HIV Medicine 2001;9:31.
Protease Mutations Selected by PIs
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 10-
20% 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 fold-change in susceptibility to antiretroviral agents
Drug Concentration
Inh
ibit
ion
of
Vir
al
Re
plic
ati
on
(%
) 100
0
ICIC5050
50
ICIC5050
Fold Fold ResistanceResistance
Wild-type strain
Mutant strain
Reviewed in Wilson. AIDS Read 2000;10:469.
Phenotype Resistance Testing
PhenoSense HIV Patient Report
PhenoSense™ HIV ReportPhenoSense™ 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
• More directly estimates net effect of multiple mutations
• Clinically relevant thresholds of resistance not yet determined 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?
Study (year published)
Study Arms Conclusions
VIRADAPT (1999)
Genotype + expert advice vs
usual care (no expert advice)
Genotype with expert advice better than usual care without expert advice
CPCRA 046 (2000)
Genotype + expert advice vs
usual care (no expert advice)
Genotype with expert advice better than usual care without expert advice
Havana (2002)
Genotype +/- expert advice vs
usual care (+/- expert advice)
Genotype and expert advice each helpful; genotype with expert advice resulted in best clinical outcomes
ARGENTA (2002)
Genotype + expert advice vs
usual care (+ expert advice)
Genotype with expert advice not significantly better than standard of care + expert advice
VIRA3001 (2002)
Phenotype (no expert advice) vs
usual care (no expert advice)
Phenotype without expert advice better than usual care without expert advice
Narval (2002)
Genotype (no expert advice) vs
phenotype (no expert advice) vs
usual care (no expert advice)
No signficant advantage of genotype or phenotype over usual care
Published Randomized Controlled Trials of Resistance Testing
% of Patients with HIV-1 RNA <400 copies/mL
wk 12NO G, NO Expert (N = 77) 36.4% NO G, Expert (N = 67) 49.3% G, NO Expert (N = 69) 46.4%G, Expert (N = 65) 69.2%
0
20
40
60
80
100
No G No Expert Op.
No G Expert Op.
G No Expert Op.
G Expert Op.
P = .0206 P = .00132
(ITT)
Tural. 40th IACAC; 2000; Toronto. Presentation LB-10.
BL wk 24
Havana Results:
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
ProteaseRTHIV
Access Data
Genotype & Phenotype Data
Virtual PhenotypeWild-type HIV
Resistant HIV
Illustration by David Spach, MD
The Virtual PhenotypeSample report
When Should a Resistance Assay be Ordered?
Antiretroviral Resistance Testing: Guidelines for Implementation
Clinical Setting/ Recommendation
Rationale
Recommended:
•Virologic failure during ART
•Suboptimal suppression of viral load (VL) after initiation of ART
•Acute (primary) HIV infection
•Chronic HIV infection before starting ART
Determine role of resistance in drug failure and maximize the number of active drugs in the new regimen
Determine the role of resistance in drug failure and maximize the number of active drugs in the new regimen
Determine if resistant virus was transmitted; select regimen accordingly
Assays may not detect minor resistant species, but some 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
10
100
1000
10000
100000
HIV
RN
A
Medications Started
50 50
Illustration by David Spach, MD
Time
Antiretroviral Therapy: Failure to Suppress
10
100
1000
10000
100000
HIV
RN
A
Medications Started
50 50
Illustration by David Spach, MD
Time
0
5
10
15
20
25
1996-97 1998-99 2000-01
NRTI anyNNRTI anyPI any primarytwo classesthree classes
Time Trends in Primary HIV-1 Genotypic Drug Resistance Among
Recently Infected Persons
JAMA. 2002 Jul 10;288(2):181-8.
% o
f re
sist
ant i
sola
tes
Antiretroviral Resistance Testing: Guidelines for Implementation
Clinical Setting/Recommendation Rationale
Recommended Virologic failure during HAART Suboptimal suppression of viral load after initiation of HAART Acute (Primary) HIV Infection
Determine the role of resistance in drug failure and maximize number of active drugs in a new regimen if indicated Determine the role of resistance and maximize number of active drugs in new regimen
Determine if drug resistant virus was transmitted and design initial regimen accordingly
Consider Chronic HIV infection prior to initiation of HAART
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
Not Generally Recommended After discontinuation of drugs Plasma viral load < 1000 copies/mL
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
•Suboptimal suppression of viral load (VL) after initiation of ART
•Acute (primary) HIV infection
Determine role of resistance in drug failure and maximize the number of active drugs in the new regimen
Determine the role of resistance in drug failure and maximize the number of active drugs in the new regimen
Determine if resistant virus was transmitted; select regimen accordingly
Consider:
•Chronic HIV infection before starting ART
Assays may not detect minor resistant species, but consider if significant probability of transmitted drug-resistant virus
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
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)
What is the relationship between adherence and resistance?
00.10.20.30.40.50.60.70.80.9
1
0 10 20 30 40 50 60 70 75 80 85 90 95 100
Adherence
Res
ista
nce
Antiretroviral Resistance Testing: Guidelines for Implementation
Clinical Setting/ Recommendation
Rationale
Recommended:
•Virologic failure during ART
•Suboptimal suppression of viral load (VL) after initiation of ART
•Acute (primary) HIV infection
•Chronic HIV infection before starting ART
Determine role of resistance in drug failure and maximize the number of active drugs in the new regimen
Determine the role of resistance in drug failure and maximize the number of active drugs in the new regimen
Determine if resistant virus was transmitted; select regimen accordingly
Assays may not detect minor resistant species, but some 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
Barbour JD et al. AIDS: Volume 18(12) 20 August 2004 pp 1683-1689
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
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 chronically-infected 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)
• 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
Empiric design of salvage regimens for patients failing ART: key considerations
Time after dose (hours)
0 2 4 6 8 10 12100
1,000
10,000
An Example of Ritonavir Boosting:Indinavir/Ritonavir BID PK Study
IDV/RTV q12h:
800/200 High-fat Meal
800/100 High-fat Meal 400/400 High-fat Meal
IDV q8h: 800 mg Fasted
IndinavirPlasma
Concentration(nM)
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
% of Patients with HIV-1 RNA <400 copies/mL
wk 12NO G, NO Expert (N = 77) 36.4% NO G, Expert (N = 67) 49.3% G, NO Expert (N = 69) 46.4%G, Expert (N = 65) 69.2%
0
20
40
60
80
100
No G No Expert Op.
No G Expert Op.
G No Expert Op.
G Expert Op.
P = .0206 P = .00132
(ITT)
Tural. 40th IACAC; 2000; Toronto. Presentation LB-10.
BL wk 24
Havana Results:
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
0100002000030000400005000060000700008000090000
100000
30 mosago
24 mosago
18 mosago
12 mosago
6 mosago
1 moago
Viral Load
Initiate ARTPancreatitis;lamivudine substituted fordidanosine
Genotype ordered
50
Vira
l Loa
d (c
opie
s/m
L)
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
• 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
Failed AZT/ddI/nevirapine in remote past
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%
Underwood M et al. 12th CROI; 2005, Boston. #674.
Prevalence of resistance among new 787 HIV diagnostic specimens from 899 sites in six states
Categories Participants with HIVDRAny drug class: RTI or primary PI 114 (14.5%)
NRTI 56 (7.1%)
NNRTI 66 (8.4%)
PI 22 (2.8%)
Two or more drug classes 24 (3.1%)