WHY IS THIS COMBINATION FAILING HIV RESISTANCE

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WHY IS THIS COMBINATION FAILING?HIV RESISTANCE

• Ernesto J. Lamadrid, MD, AAHIVS
• Director, HIV Services, Alachua County Health
  Department
• Assistant Professor Univ. of Florida College of
  Nursing
• Faculty, Florida/Caribbean AETC

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Disclosure of Financial Relationships
This speaker has no significant financial
relationships with commercial entities to
disclose.
This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
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Antiretroviral Therapy 2008

• 27 antiretrovirals available
• Regimens are easier to use and adhere to
• Lifetime therapy
• Treatment fatigue
• Poor adherence
• Development of resistance

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Antiretroviral Resistance

• Decreased ability of antiretroviral agent to
  suppress replication of patients virus
• Can be transmitted from a patient with a
  drug-resistant strain or can develop under
  selective drug pressure
• Not an all or none phenomenon, can be relative to
  drug concentration

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What is Treatment Failure?

• Treatment failure can be classified as
• Virologic a confirmed HIV RNA level gt400
  copies/mL after 24 weeks, gt50 copies/mL after 48
  weeks, or a repeated HIV RNA level gt400 copies/mL
  after prior
• suppression of viremia to lt400 copies/mL.
• Immunologic persistently decline on CD4 count.
• Clinical viral suppression with intolerable side
  effects of ARVs compromising quality of life.

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Adverse Consequences of Viremia During
Antiretroviral Therapy

• Resistance mutations accumulate, reducing future
  treatment options
• Viral load typically increases over time
• CD4 cell count may remain stable in the
  short-term, but typically declines over time
• Increasing risk of clinical events in viremic vs
  suppressed patients
• Goal of therapy is to achieve sustained
  undetectable viral load
• Achievable for majority of patients with
  currently available agents

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Types of Resistance Tests

• Genotype
• HIV gene sequencing of the patients virus to
  detect mutations known to confer drug resistance
• Phenotype
• Measures ability of a recombinant virus derived
  from the patient sample to grow in different
  concentrations of antiretroviral drugs
• Virtual phenotype
• Use of genotype results to predict phenotypic
  susceptibility based originally on database of
  paired genotype and phenotype data or, more
  recently, through scores derived from linear
  regression analysis

Hirsch MS, et al. Clin Infect Dis.
200337113-128.
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Limitations of Resistance Testing

• Lack of uniform quality controls across different
  laboratories
• High cost compared with other tests routinely
  done in HIV care
• Cannot be reliably performed with HIV RNA lt
  500-1000 copies/mL
• May not be able to detect minority populations of
  resistant virus if they account for lt 20 of the
  sampleespecially common after drug
  discontinuation
• Resistant strains that are in viral reservoirs
  also not detected

DHHS Guidelines, May 2006. Devereux HL, et al.
AIDS 199913F123-F127.
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Interpreting Resistance Tests A Step-by-Step
Approach

• Collect all prior resistance tests for review
• Make sure current treatment, level of adherence,
  HIV RNA, and CD4 cell count are known
• Take each drug class individually
• Start with NNRTIs
• Next is NRTIs M184V alone vs broader resistance
• Finish with PIs Is resistance present at all? If
  so, is cross-resistance minimal, moderate, or
  high?
• Choose new regimen incorporating resistance data,
  treatment history, and results from clinical
  studies

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DHHS Panel Recommendations

• HIV drug resistance testing is recommended for
  persons with HIV infection when they enter into
  care regardless of whether therapy will be
  initiated immediately (AIII). If therapy is
  deferred, repeat testing at the time of
  antiretroviral therapy initiation should be
  considered (CIII).
• A genotypic assay is generally preferred for
• antiretroviral-naïve persons (AIII).
• HIV drug resistance testing should be performed
  to assist in selecting active drugs when changing
  antiretroviral regimens in cases of virologic
  failure (AII).

Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents January
29, 2008
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DHHS Panel Recommendations

• Drug resistance testing should also be performed
  when managing suboptimal viral load reduction
  (AII).
• Drug resistance testing in the setting of
  virologic failure should be performed while the
  patient is taking his/her antiretroviral drugs,
  or immediately (i.e., within 4 weeks) after
  discontinuing therapy (AII).

Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents January
29, 2008
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DHHS Panel Recommendations

• Genotypic resistance testing is recommended for
  all pregnant women prior to initiation of therapy
  (AIII) and for those entering pregnancy with
  detectable HIV RNA levels of viremia
• Drug resistance testing is not advised for
  persons with HIV RNA lt1,000 copies/mL, because
  amplification of the virus is unreliable (DIII).

Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents January
29, 2008
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Resistance Testing Recommended
Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents January
29, 2008
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Resistance Testing Not Recommended
DHHS Guidelines for the Use of Antiretroviral
Agents in HIV-1-Infected Adults and Adolescents.
October 10th, 2006. www.aidsinfo.nih.gov
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International AIDS Society?USA Drug Resistance
Mutations Group
The International AIDS SocietyUSA (IASUSA) is
a not-for-profit, HIV clinical specialist-educatio
n organization. It is entirely different from and
not affiliated with the International AIDS
Society (Stockholm, Sweden).
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Mutations Selected by nRTIs
Emtricitabine
2008 International AIDS Society-USA
Johnson et al Topics HIV Med. April/May 2008
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Mutations Selected by nRTIs
Multi-nRTI Resistance 151 Complex (affects all
nRTIs currently approved by the US FDA except
tenofovir)
2008 International AIDS Society-USA
Johnson et al Topics HIV Med. April/May 2008
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Mutations Selected by NNRTIs
2008 International AIDS Society-USA
Johnson et al Topics HIV Med. April/May 2008
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Mutations Selected by PIs
Fosamprenavir/ritonavir
2008 International AIDS Society-USA
Johnson et al Topics HIV Med. April/May 2008
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Mutations Selected by PIs (cont)
Saquinavir/ritonavir
2008 International AIDS Society-USA
Johnson et al Topics HIV Med. April/May 2008
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Mutations in the Envelope Gene Associated With
Resistance to Entry Inhibitors
Enfuvirtide
2008 International AIDS Society-USA
Johnson et al Topics HIV Med. April/May 2008
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Mutations in the Integrase Gene Associated With
Resistance to Integrase Inhibitors
2008 International AIDS Society-USA
Johnson et al Topics HIV Med. April/May 2008
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Case 1

• 40-yr-old man, new HIV diagnosis, antiretroviral
  therapy naive
• Last negative test in 1999 sexually active with
  other men
• Construction worker with alternating shifts
• CD4 1100 cells/mm3 HIV RNA 5500 copies/mL
• Hepatitis C Ab () w/ normal transaminases
• What is your next step?

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Resistance Issues in Naive Patients

• When should clinicians test for resistance in
  HIV-1-infected treatment-naive patients?
• How often does transmission of resistant variants
  occur?
• What is the best method for testing for resistant
  variants and how to interpret results?
• What benefit is derived from the knowledge gained
  by resistance testing in treatment-naive
  patients?

clinicalcareoptions.com/hiv
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Resistance Issues in Naive Patients

• When should clinicians test for resistance in
  HIV-1-infected treatment-naive patients?
• How often does transmission of resistant variants
  occur?
• What is the best method for testing for resistant
  variants and how to interpret results?
• What benefit is derived from the knowledge gained
  by resistance testing in treatment-naive
  patients?

clinicalcareoptions.com/hiv
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Resistance Testing in Rx-Naive Patients Should Be
Done at Diagnosis
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Re-emergence vs Reversion of Wild-Type Virus
Selected drug resistance
Initial wild-type
Resistant variants selected during therapy
Re-emergence of wild-type when therapy
discontinued

Wild-type HIV
Resistant HIV
Transmitted drug resistance
Initial resistant
Reversion toward wild-type during untreated
chronic infection
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Considerations Regarding Testing for Transmitted
Resistance

• Practice setting
• Lower threshold in urban areas or areas that
  commonly treat HIV
• Patient characteristics
• Infection source and antiretroviral history of
  source
• Duration of infection
• MSM may be more likely to acquire resistant
  variants than women or IDUs
• Travel history
• If CD4 count lt 100 cells/mm3 and infection
  duration gt 10 years, resistance test unlikely to
  guide therapy

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Demographic Differences

• Different prevalence in different populations
• Incidence of resistant virus in SHCS by subgroup
• Women (10.4)
• Men (2.6)
• Heterosexual contact (6.1)
• Homosexual contact (11.3)
• IDU (13)

Yerly S, et al. AIDS. 2001152287-2292.
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Resistance Issues in Naive Patients

• When should clinicians test for resistance in
  HIV-1-infected treatment-naive patients?
• How often does transmission of resistant variants
  occur?
• What is the best method for testing for resistant
  variants and how to interpret results?
• What benefit is derived from the knowledge gained
  by resistance testing in treatment-naive
  patients?

clinicalcareoptions.com/hiv
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Increasing Prevalence of Resistant Virus In Newly
Infected Patients Genotypic Analysis
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22.7
1995-1998
20
1999-2000
15.9
15
Presence of major resistance mutations ()
10.2
9.1
10
8.5
8.0
7.3
3.8
5
1.7
0.9
0
Any ARV
NRTIs
NNRTIs
PIs
MDR
Little SJ, et al. N Engl J Med. 2002347385-394.
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Resistance Issues in Naive Patients

• When should clinicians test for resistance in
  HIV-1-infected treatment-naive patients?
• How often does transmission of resistant variants
  occur?
• What is the best method for testing for resistant
  variants and how to interpret results?
• What benefit is derived from the knowledge gained
  by resistance testing in treatment-naive
  patients?

clinicalcareoptions.com/hiv
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What Resistance Test to Use in Naïve Patients?

• The available resistance tests are genotype and
  phenotype.
• The genotype identifies the mutations present in
  the viral genome
• The phenotype grows the virus in presence of the
  different drugs
• Genotype is the test used to measure resistance
  in naïve patients

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New dx, ART naive
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Resistance Issues in Naive Patients

• When should clinicians test for resistance in
  HIV-1-infected treatment-naive patients?
• How often does transmission of resistant variants
  occur?
• What is the best method for testing for resistant
  variants and how to interpret results?
• What benefit is derived from the knowledge gained
  by resistance testing in treatment-naive
  patients?

clinicalcareoptions.com/hiv
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Impact of Baseline Resistance on Treatment
Outcome FTC-301A Study
Naive pts, baseline VL gt 5000 copies/mL
Incidence of Virologic Failure ()
Any
NNRTI
NRTI
K103N
Any
NNRTI
NRTI
K103N
Mutation type
FTC ddI EFV n 270
d4T ddI EFV n 276
Borroto-Esoda K, et al. CROI 2004. Abstract 672.
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Summary Points

• Up to one quarter of acutely or recently infected
  patients have detectable drug resistance
  mutations
• Among chronically infected patients, detectable
  drug resistance mutations are generally present
  in 5 to 10
• May reflect acquisition of HIV when transmission
  of resistant strains was less common, and/or
  back-mutation of transmitted resistant virus to
  WT
• These rates support the use of resistance testing
  in treatment-naive individuals, particularly in
  recently infected patients
• Prevalence of transmitted resistance varies by
  population, and may have declined in recent years

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NNRTIs Important Mutations

• Most common K103N, Y181C
• These also lead to NNRTI resistance L100I,
  V106A, V108I, Y188L, G190A/S, P225H
• Other substitutions in loci close to the above
  may induce NNRTI resistance

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Clinical Consequences of Resistance to
First-Generation NNRTIs

• Important points about NNRTI resistance
• Extensive cross-resistance between drugs
• No impairment of replication capacity or ongoing
  antiviral effect once resistance develops
• Why resistance reports may be misleading
• NVP failures often select for Y181C EFV still
  active phenotypically
• G190A may lead to DLV hypersusceptibility rarely
  present in isolation

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Clinical Consequences of Resistance to
First-Generation NNRTIs (contd)

• But most studies suggest any prior NNRTI
  resistance reduces subsequent response to current
  NNRTIslow levels of K103N may not be detected by
  current assays
• Therefore, sequencing not a practical option with
  first-generation NNRTIs (EFV, NVP, DLV)
• NNRTIs in a failing regimen should be stopped to
  prevent selection of mutations that may impair
  response to second- generation agents

Palmer S, et al. J Clin Microbiol.
200543406-413. Vingerhoets J, et al. CROI 2006.
Abstract 154.
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Impact of Number of NNRTI Mutations on Response
to Etravirine
ActiveControl
Response to ETV 800 BID by of B/L NNRTI
mutations
ETV800 BID
0
1
2
3
0
n 40
n 14
n 19
n 16
n 30
n 79
n 79
-0.14
-0.5
-0.54
-1.0
Mean Change in VL at Wk 48 (log10 copies/mL)
-0.9
-1.01
-1.5
-1.38
-1.67
-2.0
All patients had confirmed NNRTI mutations
(K101P, V179E, V179F, Y181I, Y181V, G190S,
and/or M230L) at screening or prior genotypic
resistance tests
ITT, NC no change from baseline.
Cohen C, et al. IAC 2006. Abstract TUPE0061.
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Case 2

• 29-yr-old female, hotel employee, with ITP
• Pretreatment lab values CD4 210 HIV RNA
  88,000 PLT 27K
• Antiviral history
• 2000 treated with ZDV/3TC NVP, adherent during
  pregnancy with HIV RNA lt 400 PLT gt 100K
• Started taking ART intermittently after her baby
  was born HIV negative
• Returned for follow-up when she noted new rash
• PE scattered petechiae, otherwise normal
  platelet count 14K CD4 350 HIV RNA 45,000
• Whats the next step?

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Current Rx ZDV/3TC, NVP HIV RNA 45,000, CD4 350
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The Special Case of M184V

• M184V emerges rapidly in nonsuppressive regimens
  containing 3TC or FTC
• Associated with high-level phenotypic resistance
  to 3TC/FTC in vitro but also reduction in
  replication capacity, HIV RNA lt baseline
• Increases susceptibility to ZDV, d4T, TDF
  decreases (slightly) ABC, ddI, but all NRTIs have
  some activity

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M184V Increases Susceptibility to d4T, ZDV, and
TDF
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Accumulation of NRTI Mutations During
Nonsuppressive ZDV/3TC/ABC
M184V any TAM(s)
100
90
M184V only or wild-type
76
75
80
67
60
56
60
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of Patients With Mutation
40
33
40
25
24
20
10
0
0-8 n 39
17-24 n 28
25-32 n 24
33-40 n 20
41-48 n 16
9-16 n 34
Number of Weeks on Therapy After Viral Rebound
Melby T, et al. CROI 2001. Abstract 448.
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Thank you!!!
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