When Less is More: Transmission of Drug-Resistant HIV in Canada
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When Less is More: Transmission of Drug-Resistant
HIV in Canada
STIRRHS ConferenceMontreal, Quebec
June 3, 2006
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Why do this project?
• HIV challenge
• 5000 new cases annually
• Living long with HIV through HAART
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Who is Spreading HIV ?
75/333 (23%)Unprotected Intercourse
18/75 (24%)Drug Resistant HIV
333 HIV Positive Patients
155/191 Partners HIV Negative
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So what’s the problem?
• HAART regimen is demanding
• Adherence must be >95%
• 57-77% of patients cannot adhere optimally
• At 80% adherence drug resistance develops
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Barriers to Reducing Spread
1. Drugs are not “user-friendly”
2. Adherence is not optimal
3. Not all sex is safe
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Hypothesis
• The spread of drug-resistant HIV virus can be reduced by redesigning the strategy of treatment targeted towards one of these three pillars:– Improving adherence– Reducing the development of drug-resistance– Reducing risk sexual and drugs-associated
behaviour
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Objectives
This collaborative group will use a transdisciplinary approach to improve patient adherence to HAART and prevent the spread of drug-resistant HIV by:– Optimizing drug combinations/delivery– Alleviating side effects to treatment– Identifying factors associated with decreased
adherence specific to the Canadian population
– Furthering “safe-sex” techniques
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Objectives
ADHERENCETO
HAART
DEVELOPMENT OFRESISTANCE
SPREAD OFRESISTANT HIV
RISK BEHAVIOUR
Objective 1 Influence
adherence
Objective 2 Influence
development ofresistance
Objective 3 Modify
risk behaviour
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Objective 1: Adherence
a. Understand the problems of adherence to HAART
b. Design, implement and evaluate a computer-based tool designed to improve management of drug side effects
c. To modify the influence of side-effects of therapy on drug adherence by designing alternative drug delivery methods
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Design (1)
• Understand the problem of adherence and barriers related to HAART
• 1st year: Qualitative study: understand point of view, motivation, psychological concerns of patient and health professionals, study of barriers to therapy adherence (implementation, analysis)
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Design (2)
• Development of an intervention
• Information-motivation-behavioural skills model
• Specific intervention…
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Design (3)
• Stratify in three groups: <80%, 80-95% and >95% adherence to HAART
• Evaluation of intervention– RCT
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Primary Health Outcome Measures
Level of Adherence
Level of Drug-resistant HIV
Number of New Cases of Drug-Resistant HIV
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The Problem of Side Effects
• Cluster randomized, controlled trial
• HIV positive patients
• Clinic waiting rooms
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The Problem of Side Effects
• Half of treatment centers will complete a computer based survey– Length of illness– Adherence to treatment– Side effect profile– Risky sexual behavior
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The Problem of Side Effects
• The computer will provide a print out of the side effect profile
• Pharmacists will review the profile and determine the likely causal agents
• Physicians will use the information to give patients coping strategies and/or prescriptions to abate side effects
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The Problem of Side Effects
• Additionally, the computer will provide the patient with information regarding adherence and risk of drug resistant HIV as well as decreasing transmission as the survey is being completed
• Issues can then be further discussed with the clinician
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The Problem of Side Effects
At the completion of the study, we will compare the control and intervention groups to determine if there is a difference in adherence between the groups
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HAART NON-ADHERENCE RESISTANCE
SPREAD
Complex regimenToxicity Mechanisms of resistance
HIV INFECTION
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The aims of this project are
1. to simplify drug regimen by developing new drug delivery methods
2. reduce toxicity by using newer agents
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Complex Regimen
Three classes of drugsA, B & C : A1,B1 and C1Some in empty stomach / others in full stomachMultiple pills, large sizeToxicity
New drug delivery methods such asTransdermal patchNew combination of drugs – for example A1, B2
and C3
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Methods to Improve Adherence
• New Drug Delivery Methods
• Transdermal patch
• Reduce toxicity
• Combination of drugs A1, B2 and C3
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New Drug Delivery MethodsStudy DesignRandomized control trialParticipants : non-adherent patientsThe usual oral regimen (n=50)Transdermal patch (n=50)Adherent patients (>95%) (n=50)For three months
Outcomes:Drug concentrationsViral loadCD4 countsPatient compliance – side effects
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New Drugs
Patients will be randomized to receive either1. A1, B1, C12. A1, B2, C3As transdermal patches
Outcomes:Side effect profileViral loadCD4 counts
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Objective 2Mechanisms of Resistance
• Non- adherence (50%) patients
• Mutations in viral enzymes & proteins
• The aim of this study will be to elucidate the mechanisms of drug resistance to HAART
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• Study DesignHIV will be cultured from non-adherent (50%) patients
• Mutations in the viral enzyme and proteins to be determined using DNA
• 3-D structure of the proteins determined
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• In vitro cell culture studies
• to compare the efficacy of the usual and the new combinations of drugs
• To compare the development of drug resistance
Outcome:
Drug resistance – viral counts
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• Experimental Design• Cultured HIV will be incubated with
increasing concentrations (1uM to 1mM) of either the usual or new combinations of drugs for 24 hours to 72h
• Different regimens of failing drug adherence• At the end of treatment period perform – viral counts and examine for
mutations in HIV
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Bench to Bedside
• RCT to compare drug resistance in the usual and the new combination of drugs
• Newly identified HIV patients will be randomized to receive either
• Usual drug combination or the new drug combinations for 1 year
• Examine viral load, CD4 counts, mutations in HIV
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Objective 3: Reduce risk behaviour
• Assessment of risk behaviour – Survey– Correlate risk-behaviour with adherence, viral load
and resistance
• Intervention– Educate – show movie, talk to clinic nurse, doctor,
educate doctor– Provide needles and condoms
• Test intervention with questionnaire• Evaluate intervention efficiency
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• Objective: to reduce spread of HIV by risk behaviour
• Research design: case-control, prospective
• Primary measure of health outcome: risk behaviour after intervention
Objective 3: Reduce risk behaviour
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Members• HIV-positive patients and
partners• Doctors• Psychologists• Anthropologist/
Sociologist • Basic scientist/
pharmacologist, virologist• Epidemiologist• Computerperson
ContributionTo adhere or not to adhere
and behave Clinical perceptionTheoretical conceptsUnderstand determinant
factorsResistance development
studies bghjewlfbywObviousSoftware design
Team members and their contributions
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The real team members
• Nils Chaillet• Li Chen• Barbra de Vrijer• Pia Elustondo• Laura Gaudet• Sownd
Sankaralingam
• Dr William Fisher• Dr Robert Platt• Dr Lise Goulet