When Less is More: Transmission of Drug-Resistant
HIV in Canada
STIRRHS ConferenceMontreal, Quebec
June 3, 2006
Why do this project?
• HIV challenge
• 5000 new cases annually
• Living long with HIV through HAART
Who is Spreading HIV ?
75/333 (23%)Unprotected Intercourse
18/75 (24%)Drug Resistant HIV
333 HIV Positive Patients
155/191 Partners HIV Negative
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
Barriers to Reducing Spread
1. Drugs are not “user-friendly”
2. Adherence is not optimal
3. Not all sex is safe
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
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
Objectives
ADHERENCETO
HAART
DEVELOPMENT OFRESISTANCE
SPREAD OFRESISTANT HIV
RISK BEHAVIOUR
Objective 1 Influence
adherence
Objective 2 Influence
development ofresistance
Objective 3 Modify
risk behaviour
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
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)
Design (2)
• Development of an intervention
• Information-motivation-behavioural skills model
• Specific intervention…
Design (3)
• Stratify in three groups: <80%, 80-95% and >95% adherence to HAART
• Evaluation of intervention– RCT
Primary Health Outcome Measures
Level of Adherence
Level of Drug-resistant HIV
Number of New Cases of Drug-Resistant HIV
The Problem of Side Effects
• Cluster randomized, controlled trial
• HIV positive patients
• Clinic waiting rooms
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
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
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
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
HAART NON-ADHERENCE RESISTANCE
SPREAD
Complex regimenToxicity Mechanisms of resistance
HIV INFECTION
The aims of this project are
1. to simplify drug regimen by developing new drug delivery methods
2. reduce toxicity by using newer agents
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
Methods to Improve Adherence
• New Drug Delivery Methods
• Transdermal patch
• Reduce toxicity
• Combination of drugs A1, B2 and C3
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
New Drugs
Patients will be randomized to receive either1. A1, B1, C12. A1, B2, C3As transdermal patches
Outcomes:Side effect profileViral loadCD4 counts
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
• 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
• 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
• 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
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
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
• 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
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
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
