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