Title: WHY IS THIS COMBINATION FAILING HIV RESISTANCE
1WHY IS THIS COMBINATION FAILING?HIV RESISTANCE
- Ernesto J. Lamadrid, MD, AAHIVS
- Faculty Florida/Caribbean AETC
2Disclosure 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.
3Antiretroviral Therapy 2008
- 27 antiretrovirals available
- Regimens easier to use and adhere to
- Lifetime therapy
- Treatment fatigue
- Poor adherence
- Development of resistance
4Antiretroviral 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
5What 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 persistent decline or lack of rise
in CD4 count above a certain threshold over a
period of time - Clinical viral suppression with intolerable side
effects of ARVs compromising quality of life.
Also defined as occurrence of HIV-related
clinical events after 3 months on therapy
6Types 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.
7Limitations 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.
8Interpreting 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
9Resistance Testing Guidelines Treatment-Naive
Patients
10DHHS Panel Recommendations
- 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) - 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
11DHHS Panel Recommendations (cont)
- 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) - 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
Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents January
29, 2008
12Resistance Testing Recommended
Guidelines for the Use of Antiretroviral Agents
in HIV-1-Infected Adults and Adolescents January
29, 2008
13Resistance 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
14Mutations Selected by nRTIs
2006 IAS
15Mutations Selected by NNRTIs
2006 IAS
16Mutations Selected by PIs
82
2006 IAS
FIRV
17Mutations Selected by PIs (cont)
2006 IAS
18Case 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?
19(No Transcript)
20Resistance 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
21Resistance 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
22Resistance Testing in Rx-Naive Patients Should Be
Done at Diagnosis
2002 New Dx
2005 Still Rx Naive
23Re-emergence vs Reversion of Wild-Type Virus
Initial wild-type
24Considerations 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
25Demographic 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.
26Resistance 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
27Increasing Prevalence of Resistant Virus In Newly
Infected Patients Genotypic Analysis
25
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.
28Resistance 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
29What 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
30New dx, ART naive
31Resistance 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
32Impact 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.
33Summary 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
34New dx, ART naive
35NNRTIs 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
36Clinical 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
37Clinical 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.
38Case 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?
39Current Rx ZDV/3TC, NVP HIV RNA 45,000, CD4 350
40The 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
41M184V Increases Susceptibility to d4T, ZDV, and
TDF
42Which NRTI Combinations Should Be Used After
M184V?
- No prospective data on the optimal NRTI choice
- Based on results of 3TC discontinuation studies
and resistance testing, the following are likely
to be most active
-TDF/ABC - -TDF/FTC/ZDV
- -TDF/ZDV
- If above cannot be used, these combinations would
also retain activity - DDI/TDF
- ZDV/3TC/ABC
- TDF/ddI should be avoided even though both retain
activity vs M184V-containing viruses
43Case 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?
44What Combination will you Choose?
- Tenofovir emtricitabine efavirenz
- Tenofovir emtricitabine atazanavir/ritonavir
- Zidovudine abacavir fosamprenavir/ritonavir
- Tenofovir emtricitabine abacavir
- atazanavir/ritonavir
- e) Tenofovir didanosine lopinavir/ritonavir
45(No Transcript)
46Thank you!!!
?