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Antiretroviral Drug Resistance

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Title: Antiretroviral Drug Resistance


1
Antiretroviral Drug Resistance
  • Basic Knowledge
  • Global Impact
  • Utility of Global Surveillance
  • Anthony Amoroso, MDAssistant Professor of
    MedicineUniversity of Maryland School of
    MedicineInstitute of Human VirologyChief of
    Infectious Diseases, VA Maryland Health Care
    System

2
Living with HIV used to be like playing
checkers and now its like playing chess.
Becky Trotter, POZ
3
HIV-1 Viral Dynamics Basis of resistance
  • In an HIV-1 infected individual, it is estimated
    that
  • 10.3 x 109 virons are produced each day
  • Average life span of an HIV-1 viron in plasma is
    5.6hours
  • Average HIV-1 generation time is 2.6 days

4
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5
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6
HIV-1Viral Dynamics - Mutations
  • Genome Size - 104 base pairs
  • Mutation rate of HIV-1 is estimated to be 3.4 x
    105 per base pair per replication cycle
  • If true, then every mutation at every position on
    the genome would occur numerous times each day

7
How Quickly Resistance Can Occur Depends on the
Viral Load
Adapted from Siliciano, 2002
8
Development of Viral Resistance
mutations
  • VIRUS
  • High replication rate
  • Error prone
  • Latent reservoir
  • PATIENT
  • Non adherence
  • Side effects
  • DRUG
  • Subtherapeutic concentrations
  • Selective pressure of less potent ARV therapy
  • Ctrough
  • Intrinsic activity

9
Viral Resistance is the Outcome of Viral
Replication, Mutation and Selection
New Virus Quasispecies
Original Virus Quasispecies
Selection Pressure exerted by Drugs
HIV RNA Level
Minority Quasispecies with reduced susceptibility
Resistant virus
Time
10
HIV-1 RNA Response in Subjects With M184V (M184V
Present by Week 12)
300 mg BID (n14)
Kuritzkes D, et al. AIDS 199610975-81.
11
HIVNET-012 Prevalence of NVP Resistance
Mutations at 6 to 8 Weeks Postpartum
60
46
40
with resistance mutations
19
20
0
Mothers(n111)
Infected infants(n24)
Eshleman SH, et al. 8th CROI February 4-8, 2001
Chicago, IL. Abstract 516.
12
Case 9 Gulu, Uganda
  • 16 year old female

13
Pre-ARV HX
  • No previous ARV exposure
  • OIs prior to ARV Diarrhea and wasting, Genital
    ulcerative disease
  • Baseline weight 35 kg
  • WHO stage III
  • Baseline CD4 37 c/mm3 (11/2004)
  • ARV start date 22/12/04
  • Baseline labs Hb 10.3g/dl, AST 22, ALT 18,
    Cr 0.7

14
ARV therapy
  • 14 month duration of therapy
  • Start 22/12/04 TDF/3TC/EFV
  • Switch 21/07/0 TDF/FTC/EFV (current)

15
OIs since ARV start
  • Herpes Simplex
  • Genital Ulcerative Disease
  • Tonsillitis 22/02/05
  • Anal sores 16/11/05
  • Perinatal viral warts 14/03/06

16
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18
Adherence
  • Patient had treatment preparation, home visits
    and DOT
  • Dispensing frequency Monthly
  • No subjective history of missed doses in the past
    6 months
  • No history of missed refills in past 6 months
  • No history of missed appointments in past 6 months

19
Viral Load?
  • gt750,000 copies/ml

20
Why?
  • Poor adherence to safe sexual practices is been
    closely linked to poor adherence to ARVs.
  • Adolescents are notoriously horrible at taking
    chronic medications

21
What is major concern in this case?
  • This pt is at high risk for spreading resistance
    virus.
  • Is secondary prevention counseling going to have
    any effect on this patients behavior?

22
Surveillance
23
Rise in ARV Resistance Among Treatment-Naive
Patients
Patients With gt10-Fold Resistance N 408
gt10-Fold Resistance
1 drug
1996-1998
10
?2 drugs
1999-2000
8
P .05
P .001
6
Patients ()
4
2
0
NNRTIs
PIs
1999-2000
Little. 8th CROI 2001 Chicago. Abstract 756
24
Reduced Susceptibility (gt10 Fold) of Transmitted
HIV during Primary Infection
20
NRTI
NNRTI
PI
15
Percentage
10
5
0
1996
1997
1998
1999
2000
15
71
88
106
32
n

Year
Little SJ. 8th CROI, Chicago, 2001. 756
25
Prevalence of Drug Resistance1080/1906 patients
Assumes no resistance in samples with HIV RNA
lt500 copies/mL Represents 63 of total study
population
Richmond
26
Causes of Resistance Lessons Learned
  • Learning curve during applications of consensus
    treatment guidelines
  • AZT monotherapy
  • Sequential monotherapy
  • 2NRTI and PI ( i.e. AZT, 3TC and non-boosted
    PI)
  • Borderline therapeutic drug levels and
    significant drug interactions
  • High Adherence Requirements

27
Global resistance in naïve patients study
  • WATCH Worldwide Analysis of resistance
    Transmission over time of Chronically and acute
    infected HIV-1 Patients1
  • RT PI mutations from 6,054 naïve pts
  • Source Europe 3252, Africa 1162, Asia 653, Latin
    America 806, North America 290
  • Results 8.9 gt1 mutation
  • Europe 11.3 NA 9.3, Africa 5.7, Latin
    America 5, East Asia 9.4, S/SE Asia 5.3, 1.8
    multiclass resistance

Resistance by ARV class
1. Bowles E, et al. XVI IAS, Toronto 2006,
MOPE0388 2. Bowles E, et al. 4th EHDRW, Monte
Carlo 2006, 7
28
Primary resistance in ARV-naïve adolescents
  • Study of resistance in pts age 12-24 from 15 US
    cities (n55)
  • HIV-infected w/in 180 days using detuned assay
  • Genotype (GT) and Phenotype (PT) obtained
  • Major mutations defined by IAS-USA Drug
    Resistance Mutations Group
  • 1 pt had GT PT resistance to ARV in all 3
    classes

Viani R, et al. 13th CROI, Denver, CO, February
5-8, 2006. Abst. 21
29
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30
The HIV Family
HIV-1
HIV-2
HIV-1
less pathogenic
Group O M N
(Cameroon)
Clade A,C,F B E Others
(Africa) (US, Europe) (SE Asia)
Levy JA. HIV and the Pathogenesis of AIDS. 2nd
ed. Washington, DC American Society for
Microbiology 1998152-158.
31
Distribution of HIV-1 Subtypes in Africa
32
Can Resistance Testing Be Used forNon-Clade B
HIV-1 Subtypes?
  • Do the assays yield any results?
  • Yes, at least for kit-based genotyping assays
  • Do the results have the same interpretation?
  • Mostly yes
  • Exception
  • Some secondary PI mutations are more common in
    non-clade B viruses
  • M36I, for example, is wild type for clade C

33
SDNVP and Resistance2005
  • Resistance in child 13 - 52
  • Resistance in mothers 39 - 75 resistance
  • Clade A 19
  • Clade D 36
  • Clade C 69

34
Conclusions
  • Different HIV-1 subtypes seem to possess distinct
    potentials for drug related resistance mutation
    acquisition, including alternative routes and
    substitutions.
  • This may affect the future design of
    antiretroviralregimens and salvage regimens in
    distinct areas of the world where non-B isolates
    dominate the HIV/AIDS epidemic.

35
Why new strategies are needed to avoid
resistance
  • The mainstream strategy of sequencing, as a
    whole, has not been successful.
  • Cross-resistance is a major problem and can
    prevent rational sequencing of drugs
  • Novel drugs or new drugs in a class may not be
    available or effective once resistance develops

36
The Impact of Cross Resistance First shot is
your best shot
Rate of Treatment Failure in EuroSIDA Cohort (n
8507)
Mocroft, et al, Antivir Ther, 2000.
37
Viral Suppression by Country (by Year 1 Sites)
38
ART drug resistance mutations in ART experienced
patients in Nigeria E. Idigbe, T. Salawu, B.
Osotimehin, B. Chaplin,J-L Sankalé, J Idoko, E
Ekong, R Murphy , PJ Kanki
Nigerian Institute of Medical Research (NIMR),
Lagos Nigeria Federal Ministry of Health, Abuja,
Nigeria National Action Committee AIDS, Abuja,
NigeriaHarvard School of Public Health, Boston,
MA, USAJos University Teaching Hospital, Jos,
NigeriaHarvard PEPFAR (APIN Plus), Lagos,
Nigeria. Northwestern University, Chicago USA
Supported by AIDS Prevention Initiative Nigeria
funded by the Bill Melinda Gates Foundation,
DAIDS-NIAID/NIH, the Federal Ministry of Health
and NACA.
39
Resistance Patterns to the Baseline Regimen of
Patients with viral loads greater 3000 c/ml .
40
Response to d4T/3TC/NVP in mothers based on
previous history of single-dose NVP
68
52
38
With Virologic Suppression
N47
N143
N66
N40
N61
N119
significant
Joudain et al. NEJM 4/04
41
What will we do with surveillance information?
42
DHHS Guidelines Recommendations for Using
Drug-resistance Assays (Updated 5/04/06)
New recommendations as of DHHS Guidelines update
5/04/06.
Adapted from DHHS Guidelines (5/04/06). Available
at http//aidsinfo.nih.gov. Accessed May 9, 2006.
43
Regimen Selection by Line of Therapy
Percentage
n951 n601 n369
n451
Line of Therapy
Base All treated patients Q1 2006 data
Line of therapy change defined as a switch of any
component of the patients ARV regimen.
ISIS market research data, Synovate US HIV
Monitor Q1 2006.
44
Public Health Approach to Treatment
  • Utilize 1st line regimens with predictable
    mutations and dead end mutational pattern
  • Utilize 1st line regimens which allow for
    rational 2nd line therapies
  • Be willing to change 1st line therapeutic
    approach based on resistance data despite costs
  • Invest more heavily on community treatment
    support/adherence programs to ensure high level
    initial adherence
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