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TOOLS AND PRINCIPLES FOR

OPTIMIZING ADHERENCE TO HIV REGIMENS

Edric Paw Cho Sing, Pharm. D. 2015 CandidateUniversity of Toronto Faculty of PharmacyAdvanced Pharmacy Practice Experience

Novack’s Rexall Drug Store

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PRESENTATION OVERVIEW• HIV/AIDS Today• HIV Drug Resistance• Mechanism of Drug Resistance• Impact of Adherence• Clinical Tools for Every Day Practice

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HIV/AIDS TODAY

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HIV/AIDS TODAY

www.unaids.org

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1 in 10 ART-naïve patients carried HIV with ≥1 drug resistance mutation.

Rates of drug resistant HIV in ART-naïve patients have been rising, from 3.4% during 1995-1998, to 12.4% by 1999-2000.

North America was found to have the highest prevalence of transmitted resistance (12.9%)

HIV/AIDS TODAY

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HIV/AIDS TODAY

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HIV DRUG RESISTANCE

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HIV resistance can arise in 3 ways:

① Sloppy replication (infidelity)

HIV RESISTANCE

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HIV RESISTANCEHIV replication is sloppy!

≥1 mutation per genome transcribed ~20 billion mutations/day

HIV replication is high volume!

~10 billion copies/day 107-108 infected cells/day

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HIV RESISTANCEHIV resistance can arise in 3 ways:

① Sloppy replication (infidelity)

② Through transmission (transmitted resistance)

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HIV RESISTANCEHow is HIV transmitted?

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HIV RESISTANCEHIV resistance can arise in 3 ways:

① Sloppy replication (infidelity)

② Through transmission (transmitted resistance)

③ Selective pressures (acquired resistance)

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WHAT IS DRUG RESISTANCE?Drug Resistance – Ability of disease-causing microorganisms (e.g. bacteria or viruses) to continue multiplying despite the use of otherwise effective drugs.

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WHAT IS DRUG RESISTANCE?

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WHAT IS DRUG RESISTANCE?

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THE MECHANISM OF DRUG RESISTANCE

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MOR: Viral RT Discrimination M184V, Q151M complex, K65R

MECHANISM OF DRUG RESISTANCE: NRTI

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MOR: Excision of incorporated NRTI

“Thymidine Analogue Mutations”

MECHANISM OF DRUG RESISTANCE: NRTI

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MOR: Reduction of NNRTI affinity to allosteric site Drug-dependent mutations (K103N efavirenz,

Y181C nevirapine)

MECHANISM OF DRUG RESISTANCE: NNRTI

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MOR: Enlargement of catalytic site, reduction of PI affinity to the enzyme

MECHANISM OF DRUG RESISTANCE: PI

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MUTATIONS AND RESISTANCELow Genetic Barrier – Single mutations which cause complete resistance

Ex. All NNRTI, 3TC

High Genetic Barrier – Multiple step-wise mutations needed to cause resistance

Ex. Protease Inhibitors, most NRTI

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DISTRIBUTION OF DRUG RESISTANCE

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DISTRIBUTION OF DRUG RESISTANCEReduced susceptibility more common for NNRTI’s compared to NRTI’s or PI’s

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THE IMPACT OF ADHERENCE

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95% ADHERENCEIt is recommended that adherence be maintained above 95% to achieve optimal outcomes

Level of Adherence Once-Daily Regimen Twice-Daily Regimen

>95% Adherence No more than 1 dose per month

No more than 3 doses per month

>90% Adherence No more than 3 doses per month

No more than 6 doses per month

>80% Adherence No more than 1 dose per week

No more than 3 doses per week

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95% ADHERENCEExample #1: Once-daily regimen

FTC/TDF (Truvada)Raltegravir (Isentress)

FTC/TDF/ELV/c (Stribild)

Example #2: Twice-daily regimen

Miss no more than 1 dose per month

Miss no more than 3 doses per month

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THE BRITISH COLUMBIA STUDYObjective: To examine long-term effects of adherence on virologic and immunologic response

Primary Outcome: Immunologic response (CD4+): ≥145 cells/uL Virologic response (pVL+): 65% of the time with VL<50 copies/mL

Stratification of Responses: Best response (CD4+/pVL+) Incomplete response (CD4+/pVL- or CD4-/pVL+) Worst response (CD4-/pVL-)

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THE BRITISH COLUMBIA STUDYHighly adherent patients (>95%) achieved a median viral

load suppression 78.8% of the follow-up time.

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THE BRITISH COLUMBIA STUDYAfter adjustment for certain baseline characteristics,

the probability for “best” response was higher for highly adherent patients (>95%)

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THE BRITISH COLUMBIA STUDY

Worst response associated with higher mortality (OR 6.09), progression to AIDS/death (OR 3.25),

and emergence of drug resistance (OR 10.56) compared to best response

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THE BRITISH COLUMBIA STUDY

Conclusion: Adherence is a key feature influencing both virologic and

immunologic responses. When adherence < 95%, patients were more likely to experience

poor responses to treatment. When adherence > 95%, NNRTI and PI/r –based regimens

provided the highest likelihood of virologic and immunologic response.

Poor virologic and immunologic response led to negative health outcomes.

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CLINICAL TOOLS FOR EVERY DAY

PRACTICE

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ASSESSING ADHERENCE

1. Acknowledge the difficulties of adherence

“Taking pills every day is hard. Most people have problems taking their pills at some point during treatment. I am going to ask you about problems that you may have had taking your pills. Please feel comfortable telling me about pills you may have missed or taken late. I am asking because I want to make it easier for you to take them.”

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ASSESSING ADHERENCE

2. Confirm understanding of the regimen

• “How many of [Drug A] are you taking per day?”

• “How often do you take [Drug A] per day?”

• “Are there any special instructions that you follow?”

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ASSESSING ADHERENCE

3. Self-Assessment of Adherence

• Over the past 3 days

• Over the past week

• Over the past month

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ASSESSING ADHERENCE

4. Reasons for Missed Doses

• Forgetful

• Away from home

• Too busy

• Side effects

• Feeling sick or depressed

• Ran out of pills

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ASSESSING ADHERENCE

5. Ask about side effects or other problems

• “Do you have any difficulty swallowing the medications?”

• “Do the medications upset your stomach?”

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ASSESSING ADHERENCE

6. Collaborate with the patient to facilitate adherence

• Review the potential risks of poor adherence

• Set goals (≥ 95% adherence)

• Offer specific suggestions

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PROMOTING ADHERENCE

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PROMOTING ADHERENCE: MEDISAFE

Visual, easy-to-use pill reminder and medication management app

• Free

• iTunes and Google Play

MediSafe reminds patient to take their pillMed-Friend (family member/care-taker) is notified if patient forgets to take pill.

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PROMOTING ADHERENCE: MEDISAFE

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PROMOTING ADHERENCE: HIVPLUS

Comprehensive HIV treatment resource with daily pill and appointment reminders

• Free

• iTunes and Google Play

Additional features: VL/CD4 tracker, pharmacy finder, health articles, treatment guidelines, clinical trials, complementary and alternative medicine information

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PROMOTING ADHERENCE: HIVPLUS

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PROMOTING ADHERENCE: GLOWCAP

Gadget fitting over prescription bottle and lights and beeps when dose is due. Sends alert to family members if bottle is not opened.

• $80 + $15/month (AT&T)

• American productAdditional features: Adherence reports, refill request button

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PROMOTING ADHERENCE: GLOWCAP

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PROMOTING ADHERENCE: GLOWPACK

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GENERAL PRINCIPLES Successful adherence is an on-going effort Positive reinforcement Maintain open lines of communication Identify barriers to adherence Individualize strategies Non-judgmental approach

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SUMMARY• Drug resistance hinders optimal HIV

management

• Transmitted HIV resistance is an on-going issue

• Different ARV drug classes have different genetic barriers to resistance

• ≥95% adherence is optimal

• Pharmacists are in a position to assess adherence and recommend tools to promote adherent behaviours

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THANK YOU FOR LISTENING.QUESTIONS?