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?

DHS/ARV Rx/PP

HIV Case continued

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

HIV Case continued

• The viral load is repeated 2 weeks later and returns at 822 copies/ml.

DHS/ARV Rx/PP

HIV Case continued

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50

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