Antiretroviral Therapy Administration and Adherence

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Antiretroviral Therapy Administration and
Adherence

• 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
• Funding NIMH (Project Officer Christopher
  Gordon, PhD)
• April, 2007

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Will widespread, unregulated access to
antiretroviral drugs in sub-Saharan Africa, lead
to the rapid emergence of drug resistant viral
strains, spelling doom for the individual,
curtailing future treatment options, and
leading to transmission of resistant virus?
Preventing antiretroviral anarchy in sub-Saharan
Africa Harries et al Lancet 2001 358410-4.
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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
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MEMS Adherence and Viral Suppression
?
?
?
?
Paterson DL, et al. Ann Intern Med.
200013321-30.
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Ritonavir Boosted PIs Lead to Better Viral
Suppression at Moderate Adherence LevelsViral
Suppression lt50 Copies for RTV Boosted and
Unboosted PI
P0.04
N67
N46
N83
n71
Bangsberg et al Int Conference on Adherence to
HIV Treatment 2007
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NNRTI Lead to Better Viral Suppression (lt400
copies/ml) than Unboosted PIs at Moderate
Electronic Medication Monitor Adherencen65
p0.01
Bangsberg CID 200643939-41
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Prevalence of NNRTI and PI Resistance by
AdherenceBangsberg AIDS 2006 20223-232
N107
Unboosted PI
NNRTI
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Why NNRTI Might Have A Different
Adherence-Resistance Relationship

• NNRTI potent and exert high selective pressure
• NNRTI act distant to the active site little
  impact on fitness
• NNRTI resistance seen with single dose therapy

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Resistance Risk by Adherence and Regimen Class
Bangsberg et al J. Antimicrob Chem 2002
53(5)696-9.
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Replicative Capacity
HIV PR and RT Sequences
Purify Viral RNA
AAAA
RT-PCR
AAAA
AAAA
Patient Plasma
PR-RT
Transfection
Luciferase
Luciferase


Pool of Patient-Derived Recombinant Viruses
Containing Luciferase
A-MLV env
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Luciferase Activity (Replication) of Sensitive
Wild-Type Virus Decreases at Higher Drug Levels
10,000,000
1,000,000
100,000
Luciferase
10,000
1,000
100
0
1
10
100
1,000
Drug concentration, nM
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Replication of Sensitive vs. Resistant Virus
10,000,000
WT Control (NL4-3)
Resistant (pt-derived)
1,000,000
100,000
Luciferase
10,000
1,000
100
0
1
10
100
1,000
Drug concentration, nM
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Sensitive HIV is More Fit than Resistant HIV at
Lower Drug Concentrations and Becomes Less Fit at
Higher Drug Concentration
Comparing Resistant Subject Isolates With
Sensitive Reference Strain
Resistant Wildtype Replication Ratio
Bangsberg et al AIDS 2006 20223-232
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Methods Derive average resistant/WT fitness
curve Convert adherence adjusted predicted in
vivo concentrations to comparable in vitro
concentrations
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Level of adherence above which the resistant
virus is more fit than the wild-type virus is
2 for efavirenz and nevirapine and 85 for
nelfinavir
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Antiretroviral therapy in Africa Warren Stevens,
Steve Kaye, Tumani Corrah BMJ  2004328280-282

• In sub-Saharan Africa.the potential short term
  gains from reducing individual morbidity and
  mortality may be far outweighed by the potential
  for the long term spread of drug resistance. In
  Africa, a higher proportion of patients are
  likely to fall into the category of potential
  poor adherers unless resource intensive adherence
  programmes are available.

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Adherence to HIV Therapy in the Industrialized
North
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Mbarara, Uganda
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Adherence in Patients Purchasing Generic
D4T/3TC/NVP in UgandaN36
Oyugi et al JAIDS 2004 361100-1102
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Meta-Analysis of Barriers to Adherence in Africa
and North AmericaMills and Bangsberg JAMA
2006296679-690

• Systematic review of adherence
• 28,689 patients in 228 studies
• North America
• Brazil, Uganda, Cote dIvoire, South Africa,
  Malawi, Bostwana, Costa Rica, Romania

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Resource-Rich Country Summary 54.7 (95CI
48.0-61.3)
Resource-Poor Country Summary 77.1
(95CI67.3-85.6)
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Adherence Declines Over Time in A
Resource-Limited SettingOyugi AIDS (in press)
N97
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D4T/3TC/Nevirapine17 USD per month
Triomune
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Stopping drugs with different half lives
Last Dose
Day 1
Day 2
Drug concentration
IC90
Zone of potential replication
IC50
12
0
24
48
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Time (hours)
S. Taylor et al. 11th CROI Abs 131
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Genetic polymorphisms and EFV metabolismHaas D,
et al. JID 2005192(11)1931-42

• Homozygous T/T genotype common in
  African-Americans (20) than Caucasians (3)

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Genetic polymorphisms and EFV metabolismHaas D,
et al. JID 2005192(11)1931-42

• Homozygous T/T genotype common in
  African-Americans (20) than Caucasians (3)
• TT genotype 50 prevalence in Ghana (Klein, Pharm
  Genomic 2005)

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NNRTI Resistance and Treatment DiscontinuationPar
ienti et al CID 2004381311-6
No. patients at Risk 1 drug holiday 52 47 38 30 1
9 4 gt 2 drug holidays 19 17 13 10 6 1
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Patient reported 48 hr treatment interruptions
are associated with virologic failure in
UgandaSpacek CID 2006 15252

• 23 of patients
• 63 due to financial difficulty
• Median duration 30 days
• Association with virologic failure
• OR 0.2, 95CI 0.1-0.5

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Frequency and Duration of Treatment
Interruptions gt48hrs over 24 weeks on Self-pay
ARTOyugi and Bangsberg AIDS (in press)
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Frequency and Duration of Treatment
Interruptions gt48hrs over 24 weeks on Self-pay
ARTOyugi and Bangsberg AIDS (in press)
Correlates Financial difficulty securing ARVs
and pharmacy stockouts
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Frequency and Duration of Treatment
Interruptions gt48hrs over 24 weeks on Self-pay
ARTOyugi and Bangsberg AIDS (in press)
Correlates Financial difficulty securing ARVs
and pharmacy stockouts 90 of all missed doses
occur during an interruption
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MEMS-Defined 48 Hour Treatment Interruptions
Predict Resistance to Self-pay ART in
UgandaOyugi and Bangsberg AIDS (in press)
P0.04
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• Africans dont know what Western time is,and
  do not know what you are talking about, when
  asked to take drugs at specific times.
• Andrew Natsios USAID Administrator

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How to Take ARVs on Time Rural Uganda Without a
Watch Johns Adherence StoryMaier, Mwebesa,
Emenyonu, Pepper, BangsbergPLOS 2006

• No education
• Works as a farmer.
• Lives with his brother, sister-in-law, and three
  nieces in a three room mud-walled house without
  electricity.
• Owns a lantern, bed, sofa, bike, and a radio, but
  no watch.
• HIV in April 2005 and started generic D4T/3TC/NVP
  (Triomune) after disseminated herpes zoster and
  Kaposis sarcoma
• CD4 count of 151

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Electronic medication monitor record of time of
bottle openings for am and pm doses.
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Adherence

• 90 of doses within 10 minutes of 720
• 90 of doses within 17 minutes of 720 pm
• Overall adherence 98.9

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Johns Adherence 0-9 and 10-18 months
Subsequent MEMS assessment (May 2006 to January
2007 (9 months))
Initial MEMS assessment (August 2005 to April
2006 (9 months))
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Obstacles to Adherence in RLC

• Distance from health center/transport costs
• Stock-outs
• Stigma/disclosure
• Long waiting lines at the clinic
• feel rushed in conversations with the doctors
  because of the other people waiting
• Adverse effects

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Summary

• Most resistance has occurred in highly adherent
  patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels
  of adherence
• NNRTI resistance low adherence and treatment
  discontinuation
• Internationally stable drug supply and
  distribution

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Summary

• Most resistance has occurred in highly adherent
  patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels
  of adherence
• NNRTI resistance low adherence and treatment
  discontinuation
• Internationally stable drug supply and
  distribution

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Summary

• Most resistance has occurred in highly adherent
  patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels
  of adherence
• NNRTI resistance low adherence and treatment
  discontinuation
• Internationally stable drug supply and
  distribution

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Summary

• Most resistance has occurred in highly adherent
  patients on partially suppressive regimens
• Potent regimens reduce resistance at all levels
  of adherence
• NNRTI resistance low adherence and treatment
  discontinuation
• Internationally stable drug supply and
  distribution

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