Salvage Antiretroviral Therapy Guiding Principles, Strategies and the Role of Resistance Testing.
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Transcript of Salvage Antiretroviral Therapy Guiding Principles, Strategies and the Role of Resistance Testing.
DHS/ HIV/PP
HIV: Case History
A 26-year-old man with an HIV RNA level of 106,000 and a CD4 count of 121 cells/mm3 is started on a regimen of AZT (zidovudine) plus 3TC (lamivudine) plus Nevirapine. He has an initial excellent response: HIV viral load < 50 at months 3, 6, and 9, and his CD4 count rises to 247. At the 12 month visit, he admits to missing some doses in the past month.
What would you do? Would you change his regimen?
DHS/ HIV/PP
HIV: Case History
You re-address his adherence problems You continue his current regimen but order a viral
load and CD4 count. His 12 month HIV RNA level comes back at 224
copies/mL; CD4 count is essentially unchanged.
What would you do?
HIV Case continued
• The viral load is repeated 2 weeks later and returns at 822 copies/ml.
• Would you change his regimen?• Would you order a resistance test?
Antiretroviral Resistance Testing
• due to HIV’s high transcription error rate and high level of replication, mutant HIV variants constantly generated
• these variants often contain mutations that confer variable levels of resistance to antiretroviral agents
• poor adherence or suboptimal regimens can lead to resistance and ‘viral breakthrough’
HIV Case continued
Wild-type HIV
Resistant HIV
Pre-treatment: wild-type
On Treatment: resistance
Poor Adherence
Antiretroviral Resistance Testing
• Goal of resistance testing is to identify these resistance-conferring mutations in order to more intelligently design a ‘salvage’ regimen
• Studies have documented clinical benefit of resistance testing
• Expert advice on interpretation of the genotype carries a similar and additive benefit as well
Summary of Randomized Controlled Trials of Resistance Testing
Study N Primaryendpoint
Study Arms Change in viralload (log10)
% with undetectable VL
VIRADAPT 108 24 weeks Genotype + expert advicevs
SOC (no expert advice)
-1.15 vs –0.67(p=0.05)
32% vs 14% <200 copies/mL(p=0.67)
GART 153 4-8 weeks Genotype + expert advicevs
SOC (no expert advice)
-1.19 vs –0.61(p < 0.001)
N/A
Havana 274 24 weeks Genotype +/- expert advicevs
SOC (+/- expert advice)
-1.1 vs –0.8(p=0.02)
58% vs 42% <400 copies/mL(p=0.01)
Expert advice +/- genotypevs
SOC (no expert advice) +/-genotype
-1.0 vs –0.9(p=0.03)
59.1% vs 41.1% <400 copies/mL(P = .003)
ARGENTA 174 6 months Genotype + expert advicevs
SOC (no expert advice)
N/A 21% vs 17% <500 copies/mL(p=NS)
VIRA3001 274 16 weeks Phenotype (no expert advice)vs
SOC (no expert advice)
-1.23 vs -0.87(P = .004)
45% vs 34% <400 copies/mL(P = 0.099)
NARVAL 541 12 weeks Genotype (no expert advice)vs
phenotype plus expert advicevs
SOC (no expert advice)
N/A 41% vs 33% vs 34% <200 copies/mL(P =0.249)
Antiretroviral Resistance Testing: Guidelines for Implementation
Clinical Setting/Recommendation Rationale
Recommended Virologic failure during HAART
Suboptimal suppression of viral load after initiation of HAART
Determine the role of resistance in drug failureand maximize number of active drugs in a newregimen if indicated
Determine the role of resistance and maximizenumber of active drugs in new regimen
Consider Acute (Primary) HIV Infection Determine if drug resistant virus was transmitted
and design initial regimen accordingly
Not Generally Recommended Chronic HIV infection prior to initiation of HAART
After discontinuation of drugs
Plasma viral load < 1000 copies/mL
Current assays unlikely to detect minor drugresistant quasispecies
Resistant quasispecies tend to become minorspecies in the absence of selective drug pressure,making detection by current assays unlikely
Current assays unreliable at low viral loads
DHS/ARV Rx/PP
Antiretroviral Therapy: Viral Failure
10
100
1000
10000
100000
HIV
RN
A
Medications Started
50 50
DHS/ARV Rx/PP
Antiretroviral Therapy: Failure to Suppress
10
100
1000
10000
100000
HIV
RN
A
Medications Started
50 50
DHS/HIV/Resistance /PP
HIV Primary Infection Isolates
2
1
7
2
6
0
2
4
6
8
10
Res
ista
nt
Iso
late
s %
NRTI NNRTI PI
1996-1998
1999-2000
3
From: Little SJ. JAMA 1999;282:1142-9.Little SJ. 8th Conf Retrovirus. Abstract 756
N = 108 PatientsNewly HIV-Infected Phenotypic Data: 10-fold Resistance
Resistance Testing: Acute vs. Chronic HIV Infection
Wild-type HIV
Resistant HIV
Acute HIV Chronic HIV
No Therapy
Resistance Testing: On (Failing) Therapy vs Off Therapy
Wild-type HIV
Resistant HIV
On Therapy Off Therapy
ARV Rx stopped
Resistance Testing: Genotypic Assays
Reports mutations in Reverse Transcriptase & Protease genes
Generally require > 1,000 copies/mL Turn-around time of approximately two weeks cost: around $400 several trials have demonstrated clinical
benefit
Resistance Testing: Phenotypic Assays
Determine amount of drug required to suppress HIV replication in vitro
intuitively simpler but less clinical experience, less data demonstrating benefit
Generally require > 1,000 copies/mL turn-around time of approximately four weeks cost: close to $1,000
Genotyping vs Phenotyping
• discordance common between the two assays• genotypic assays suffer from complexity of
interpretation, potentially unknown interactions between various mutations
• phenotypic assays suffer from lack of consensus on susceptibility cut-offs for most agents, inability to delineate mutation patterns underlying resistance, high cost, and lengthy turn-around time
HIV Resistance TestingVirtual Phenotype
Genotype
ProteaseRTHIV
Access Data
Genotype & Phenotype Data
Virtual PhenotypeWild-type HIV
Resistant HIV
HIV Case continued
• You obtain a genotype which shows the K103N mutation in the Reverse Transcriptase Gene
• Would you change the nevirapine in his regimen to efavirenz?
Salvage Antiretroviral Therapy: Guiding Principles
• Always confirm viral failure with repeat viral load measurements
• Re-visit adherence issues
• Try to correct adherence problems before starting a salvage regimen
Salvage Antiretroviral Therapy: Guiding Principles
• for adherence or intolerance problems, can change single agent in the regimen as long as resistance is not suspected
• for cases of viral failure or failure to achieve sustained virologic suppression, must change at least two of the agents; an entirely new regimen is best though not always feasible
• beware of cross-resistance within a class
Salvage Antiretroviral Therapy: Guiding Principles
• trials have demonstrated the clinical benefit of resistance testing in designing salvage regimens, but resistance testing can miss minor resistant variants of HIV
• trials have also demonstrated the clinical benefit of expert assistance in designing salvage regimens
Salvage Antiretroviral Therapy: Guiding Principles
• Many patients have limited salvage options; it is sometimes rational to continue a ‘failing’ regimen in order to maintain partial viral suppression
• discontinuation of HAART should be considered for patients experiencing return to viral baseline and declining CD4 count who do not have rational salvage options
Salvage Regimens & Resistance Testing: Key Points
• Consider salvage regimens for virologic failure, failure to suppress, immune deterioration, or inadherence/toxicity
• resistance testing is indicated for virologic failure, failure to suppress, and acute HIV infection
• expert advice has proven clinical benefit in interpreting resistance tests and designing salvage regimens