Antiretroviral Drug Resistance

1
Antiretroviral Drug Resistance

• Richard T. DAquila, MD
• Vanderbilt University Medical Center and the
  Vanderbilt Meharry Center for AIDS Research
• Nashville, TN
• February 8, 2005

2
Antiretroviral Drug Resistance

• Has it reversed the hard-fought gains of
  antiretroviral chemotherapy?
• Is it a threat for the future?
• What action is required?
• Footnote
• Most often-used word in HIV research and care may
  be Multifactorial

3
HIV Replication Chemotherapy
NFV, SQV, IDV, APV, r/LPV, ATV(r), fAPV(r),
r/TPV
Proteae Inhibitors
EntryInhibitors
T-20 (fusion inhib), Others (CD4 coreceptor
inhib) in development
Reverse Transcriptase Inhibitors
NRTIs ZDV, d4T, ddI, 3TC, FTC, ABC,
TDF NNRTIs EFV, NVP, DLV
Integrase Inhibitors
In develpment
Current drugs act at RT and Protease, One blocks
fusion
4
HIV Adapts (best variant selected)

• Immunity selects (amplifies) escape mutant
• Consensus HIV sequence in a population reflects
  the escape mutants selected by the most common
  HLA alleles
• Drugs also select resistant mutants
• More ongoing replication on drug - greater
  chance of resistance
• In past selection by sequential mono/dual Rx
  (adding one new drug) maximized amplification of
  resistance
• Resistance is relative, not absolute

5
Does HIV resistance cause drug failure?

• Early cautious approach because it was known that
  acyclovir-resistant HSV does not always cause
  drug failure
• High level zidovudine resistance associated with
  failure, after controlling for other poor
  prognostic factors (1995)

6
Does HIV resistance cause drug failure?

• Studies of resistance genotyping at regimen
  failure
• Slightly better response to salvage if identified
  mutations before choosing next drug regimen

7
Failure of HIV Rx usually partial
Deeks, et al AIDS 199913F35
Generally, CD4 count declines slowly during Rx
failure
8
J Acquir Immune Defic Syndr 20043711471154
Effect of Persistent Moderate Viremia on Disease
Progression During HIV Therapy Stephen P.
Raffanti, MD, Jennifer S. Fusco, BS,Beth H.
Sherrill, MS, Nellie I. Hansen, MPH, Amy C.
Justice, MD, PhD, Richard DAquila, MD, Wendy J.
Mangialardi, MD,and Gregory P. Fusco, MD, MPH for
the Collaborations in HIV Outcomes
Research/United States Project
Conclusions These data suggest that
maintenance of moderate viremia may confer
clinical benefit not seen when viremia exceeds
20,000 copies/mL, and this should be taken into
account when considering the risks and benefits
of continuing failing therapy.
9
Resistance Tests in Rx-experienced patients
Failing Rx

• In our local Nashville experience (at
  Comprehensive Care Center), resistance and drug
  side effects (especially body shape changes and
  lipid problems) drive decision making
• ART Management Conf multi-disciplinary
• Time to discuss, test, teach
• Expert management of resistance critical

10
Why do failing drugs sustain benefit?

• Drug activity against wild-type HIV (wild type
  stays suppressed)
• Partial drug activity against resistant HIV
  (continues some suppression)
• Decreased replication capacity of resistant HIV
• Immune response against antigens in replicating
  (resistant) virus
• Decreased CD4 cell activation by resistant virus
• Statins inhibit HIV by decreasing cell
  proliferation
• Under study as adjunct w ARVs

11
Fitness Phenotype Competitive Cultures
WT
MT
20 TCID50
80 TCID50
MOI 0.001
MT2
Day Postinfection 0, 1, 7, 14, (17), 21 DNA
PCR
UDG-Cloning
Site-Specific Sequencing 30, 63, 46, 82, 84, 90,
p1p6 ( control)
Martinez-Picado. J Virol 1999733744.
12
Relative Fitness of Drug-Resistant HIV Mutants
D30N vs WT
WT
100
75
Mutant ()
50

25

D30N
0
0
2
4
6
8
10
12
14
16
18
Day
Starting with 85 D30N mutant, depicting the
percentage of D30N mutant over time.
Statistically significant difference from day 0
(P
J Virol 1999733744.
13
Relative Fitness of Drug-Resistant HIV Mutants
D30N vs L90M
L90M
100
75
Mutant ()
50
25
D30N


0
0
2
4
6
8
10
12
14
16
18
Day
Starting with 80 D30N mutant, depicting the
percentage of D30N mutant over time.
Statistically significant difference from day 0
(P
J Virol 1999733744.
14
Relative Fitness of Drug-Resistant HIV Mutants
L63P/L90M vs WT and D30N/L63P vs WT
WT
100
L63P/L90M
75
Mutant ()
50
25
WT

D30N/L63P


0
0
2
4
6
8
10
12
14
16
18
20
22
0
2
4
6
8
10
12
14
16
18
20
22
Day
Starting with 87 L63P / L90M mutant, depicting
the percentage of L63P / L90M mutant over
time. Statistically significant difference from
day 0 (P
Martinez-Picado. J Virol 1999733744.
15
Replicative Fitness of PI-Resistant HIV

• NFV-selected D30N mutations may require more
  compensation than initial mutants selected by
  other PIs
• Future role for fitness phenotype testing in
  addition to current genotyping and drug
  susceptibility phenotyping?
• Replicative capacity (RC) offered by ViroLogic

16
Pie in the Sky Rx that selects for
persistently low fitness HIV

• Resistance mutations impair fitness in absence of
  drug (Nature 1993, many others)
• Will additional compensatory mutations that
  accumulate later offset this effect?
• On continued failing drugs gradual increase in
  both resistance and replicative capacity

17
Why do partially suppressive drugs sustain
benefit?

• Drug activity against wild-type HIV (wild type
  stays suppressed)
• Partial drug activity against resistant HIV
  (continues some suppression but more resistance
  evolves slowly)
• Decreased replication capacity of resistant HIV
• Immune response against antigens in replicating
  (resistant) virus
• Decreased CD4 cell activation by resistant virus
• Statins inhibit HIV by decreasing cell
  proliferation
• Under study as adjunct w ARVs

18
Evolution On-Drugs and Off-Drugs

• On continued failing drugs gradual increase in
  both resistance and replicative capacity
• Off-drugs Abrupt change in CD4 count and viral
  load frequently associated with a shift to
  wild-type (drug-susceptible) virus

19
Case 1

• 32 yr old male presents with fever and sore
  throat to a walk-in clinic
• PMH neg
• Rapid strep test (and throat culture) positive
  for gp A strep
• PCN prescribed
• Need to ask about HIV risks
• He had one recent risk

20
Case 1

• Acute HIV infection seen in 2001
• Viral load 750,000 c/ml
• 399 CD4 T lymphocytes/ml

Gandhi, et al CID 2003
21
Gandhi, et al CID 2003
22
Gandhi, et al CID 2003
23
Gandhi, et al CID 2003
24
Gandhi, et al CID 2003
25
Persistence of Infecting MutantsPI Resistance

• NRTI and PI cross-resistant mutant acquired at
  infection
• Highly resistant to RTV/LPV (75-fold) and all
  earlier PIs
• Not treated because only NNRTIs would be fully
  active
• Rapid CD4 cell count decrease and viral load
  increase associated with increase in HIV
  replicative capacity
• Coincident with loss of RT 184V
• Worsening immunodeficiency was temporally related
  to emergence of less-resistant virus
• Persistence of almost all resistance mutations
  off-drugs supports screening resistance genotype
  tests for all new HIV diagnoses
• Now could use fully-active NNRTI T20, as well
  as partially active drugs (TDF, ?upcoming PIs)

Gandhi, et al. CID 2003
26
What is prevalence of resistant virus among
treated patients in North America?

• Richman, et al. (HCSUS, AIDS 2004, n2864) 50
  of all, and 87 of ARV Rxed patients with
  detectable viremia
• Prior mono/dual Rx before HAART
• Harrigan, et al. (HOMER, BC, JID Feb 2005,
  n1191) 25 of all with viral load 1000 at q 3
  mo visits over first 30 mos of Rx
• Drug naïve before starting HAART (1996-00) - 75
  started with single PI (IDV mostly), 25 with
  NNRTI (NVP)
• No data yet on starting todays even better
  regimens

27
Incidence of resistant virus among newly infected
patients in US and Europe

• Not all studies show increases in incidence of
  resistance over time
• Is resistant virus less transmissible than
  wild-type?
• Need to keep monitoring
• Will starting Rx with triple combos, and always
  using best available options slow spread?

28
Bell-shaped Adherence and Resistance Curve
Inadequate Drug Pressure To Select Resistant
Virus
Complete Viral Suppression
Drug Pressure Selects Resistant Virus
Increasing probability of selecting mutation
Increasing Adherence
29
MEMS Adherence and Incomplete Viral Suppression
?
?
?
?
Paterson DL, et al. Ann Intern Med.
200013321-30.
30
Resistance Risk by Adherence and Regimen Class
Bangsberg et al J. Antimicrob Chem 2002
53(5)696-9.
31
Why do first regimens including boosted PIs fail?

• 80 no resistance or only resistance to most
  resistance-vulnerable NRTI
• Adherence
• Minor subpopulation not detected early
• Cellular drug transporters that may efflux drugs
  out of cells
• Concern about measuring blood drug levels that it
  does not measure intracellular levels where drug
  needs to be to act

32
Adherence to HIV Therapy in the Industrialized
North
33
Prevalence of ARV Resistance
Holodniy Int J HIV STD 2004151241
Richman AIDS. 2004181393
34
Adherence in Patients Purchasing Generic
D4T/3TC/NVP in Kampala, UgandaN36
Oyugi et al JAIDS 2004 361100-1102
35
Adherence Studies in Resource Constrained Settings

• Orrel C, Bangsberg, Badri, Wood. Adherence is not
  a barrier to successful antiretroviral therapy in
  South Africa. AIDS 2003
• Laurent C, Diakhate N, Gueye NF, Toure MA, Sow
  PS, Faye MA, et al. The Senegalese government's
  highly active antiretroviral therapy initiative
  an 18-month follow-up study. Aids
  2002,161363-1370.
• Byakika-Tusiime J, Oyugi J, Tumwikirize W,
  Katabira E, Mugyenyi P, Bangsberg D. Ability to
  Purchase and Secure Stable Therapy are
  Significant Predictors of Non-adherence to
  Antiretroviral Therapy in Kampala, Uganda. 10th
  Conference on Retroviruses and Opportunistic
  Infections. Boston 2003.
• Leon MP Niccolal L Determining risk factors
  associated with nonadherence in HIV patients in
  Costa Rica IAS 2003 675
• May SB, Cardoso GCP, Costa ER, Barroso PFHUCFF
  High adherence in a resource poor seting in Bazil
  IAS 2003 657

36
(No Transcript)
37
Matching Regimen, Resistance and Adherence
Distribution in Kampala
38
Laurent et al Effectiveness and safety of a
generic fixed-dose combination of nevirapine,
stavudine, and lamivudine in HIV-1-infected
adults in Cameroon open-label multicentre trial.
Lancet. 2004 Jul 3364(9428)29-34
39
Adherence to HIV Therapy in the Industrialized
North
40
Is Average Adherence Enough?Bangsberg and Deeks
JGIM 200417812-13
41
Summary

• Most resistance has occurred in highly adherent
  patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels
  of adherence
• Poverty is not an international risk factor for
  incomplete adherence
• Average adherence is sufficient to impact
  morbidity and mortality

42
Views on ARV Adherence in Promoting Domestic and
International Health Disparities
Thanks to David Bangsberg for prior slides. His
entire presentation (title below) to 2004
Workshop on Disparities and the HIV Epidemic
(held in Nashville, Nov 18-19, 2004) is
available at http//www.mc.vanderbilt.edu/root/vu
mc.php?siteWorkshopdoc4557

• David Bangsberg, MD, MPH
• Associate Professor of Medicine
• Epidemiology and Prevention Interventions Center
• Division of Infectious Diseases
• The Positive Health Program
• San Francisco General Hospital
• AIDS Research Institute, UCSF
• November, 2004

43
Antiretroviral Drug Resistance

• Has it reversed the hard-fought gains of
  antiretroviral chemotherapy?
• My answer No
• Is it a threat for the future?
• My answer Yes
• Does it require action?
• My answer Yes
• All antiretroviral drugs must be available to
  every patient
• Each virus has unique exposure Hx need to
  individualize drugs
• More RD - HIV drugs and diagnostics
• Top priority New drugs inhibiting different
  targets in HIV replication
• Continue current priorities
• HIV pathogenesis research, observational cohort
  research, montioring for resistance, clinician
  and patient education re expert management of
  resistance

44
Is need for new drugs endless?

• Hope for better potency of new combos
• New tools to synergize blocking HIV replication
• Further slow resistance emergence
• Hope for eradication

45
HIV Replication Chemotherapy
NFV, SQV, IDV, APV, r/LPV, ATV(r), fAPV(r),
r/TPV
Proteae Inhibitors
EntryInhibitors
T-20 (fusion inhib), Others (CD4 coreceptor
inhib) in development
Reverse Transcriptase Inhibitors
NRTIs ZDV, d4T, ddI, 3TC, FTC, ABC,
TDF NNRTIs EFV, NVP, DLV
Integrase Inhibitors
In develpment
Current drugs act at RT and Protease, One blocks
fusion
46
Acknowledgements

• David Bangsberg, Steve Deeks, and the entire
  community of physicians and scientists studying
  antiretroviral resistance
• The Comprehensive Care Center
• Nashville, TN following 2100 HIV pts
• Adult AIDS Clinical Trials Group (AACTG)
• National network and Vanderbilt ACTU
• Centers for AIDS Research (CFAR)
• National network and Vanderbilt Meharry CFAR
• Organizers of the 2004 Workshop on Disparities
  and the HIV Epidemic (the Vanderbilt Meharry
  CFAR, the Meharry Center for Health Disparities
  Research in HIV, the Meharry Vanderbilt
  Alliance), and its supporters including the NIH
  Office of AIDS Research
• IAS-USA, HIVMA
• Pharmaceutical companies working on HIV and
  companies working on resistance testing