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HIV Treatment 101

C. Ryan Tomlin, Pharm.D., BCPS, AAHIVPClinical Pharmacist – HIV Medicine

Outline

• What is HIV?• Common Labs• Life Cycle and Medication Targets• Building an HIV regimen• HIV Guidelines

– When to start treatment– What medications to start– When to change therapy

2

What is HIV?

• Human – Only found in humans• Immunodeficiency – Weakens immune system by destroying

CD4 cells• Virus – Reproduces by taking over a host cell

3

Common HIV Labs

• Viral Load– How much HIV is in the blood– Lower the better

• CD4 Count– How strong the immune system is– Higher the better

• Genotype– Has HIV found ways to avoid certain medications?– Resistance test

4

HIV Time Course

5

Goals of Therapy

• Increase the CD4– Above 200, preferably above 500

• Decrease the VL– Non-detectable

• Improve quality of life• Reduce secondary HIV related disease• Reduce transmission

– (Undetectable = Untransmittable)

6

HIV Life Cycle

NRTIs NNTRIs PIs Single TabletRegimens

Entry/Fusion Inhibitors

Combivir® Edurant® Aptivus® Atripla® Fuzeon®

Descovy® Intelence® Crixivan® Biktarvy® Rukobia®

Emtriva® Pifeltro® Evotaz® Complera® Selzentry®

Epivir® Rescriptor® Invirase® Delstrigo® Trogarzo®

Epzicom® Sustiva® Kaletra® Dovato®

Retrovir® Viramune® Lexiva® Genvoya®

Trizivir® Norvir® Juluca®

Truvada® INSTIs Prezcobix® Odefsey®

Videx® Isentress® Prezista® Stribild®

Viread® Tivicay® Reyataz® Symtuza®

Zerit® Vitekta® Viracept® Triumeq®

Ziagen®

FDA Approved Antiretrovirals

8

Building an HIV Regimen for a New Patient

• Three medications from at least 2 different classes (usually…)– Never mono therapy– NRTIs are the only class we routinely use more than 1 at a time– Ritonavir and Cobicistat do not count

• Number of medications does not have to match the number of pills

9

Example Single Tablet Regimens

• Biktarvy – 2018– Tenofovir alafenamide/Emtricitabine/Bictegravir– NRTI/NRTI/INSTI

• Symtuza – 2018– Tenofovir alafenamide/Emtricitabine/Darunavir/Cobicistat– NRTI/NRTI/PI/Booster

The Two Drug Rule Exceptions

• Juluca – 2017– Rilpivirine/Dolutegravir– NNRTI/INSTI– Only used in someone stable on another regimen for 6 months

• Dovato – 2019– Dolutegravir/Lamivudine– INSTI/NRTI

Simpler Regimens Over Time

Regimen Dosing Pill Burden

1996: q8h: 10 pills/d / /

1998 q12h: 5 pills/d /

2002 q12h: 3 pills/d /

2003 qd : 3 pills/d

2004 qd: 2 pills/d

2006 qd: 1 pill/d

12

Available Guidelines

• US DHHS : Department of Health and Human Services• IAS-USA : International AIDS Society• BHIVA : British HIV Association• EACS: European AIDS Clinical Society• WHO: World Health Organization

1

What the Guidelines Address

• Laboratory testing• When to start treatment• What medications to start• When to change therapy• Treatment of special populations• Treating co-infected patients• Medication side effects and drug interactions

1

When to Start Therapy

What to Start

When to Change Therapy

1

Treatment Initiation Over Time

1998 2001 2002 2004 2007 2009 2012

CD4 Count

Treat: <500

Treat: <200Offer:<350Indiv.>350

Treat: <200Offer:<350Indiv.>350

Treat: <200Offer:<350Indiv.>350

Treat:<350Indiv.>350

Treat:<350Rec:<500Indiv.>500

Treat everyone<350 (AI)<500 (AII)>500 (BIII)

VL >20,000 >55,000 >100,000

Other factors

PregnantHBVHIVAN

PregnantHBVHIVAN

PregnantHBVHIVANHigh risk of transmitting

1

START Study

• International Study– 215 sites in 35 countries

• 4,685 patients with CD4 counts above 500 enrolled– Half started medications right away– Half waited till CD4 dropped below 350

1http://www.niaid.nih.gov/news/newsreleases/2015/Pages/START.aspx

START Study Results

41

86

0102030405060708090

100

Start right away Start at 350

AIDS, Serious Non-AIDS Events, or Death

18http://www.niaid.nih.gov/news/newsreleases/2015/Pages/START.aspx

Benefits of Early Treatment

• Maintain higher CD4 count to prevent damage to the immune system

• Decrease risk of HIV associated complications– Opportunistic infections– Underlying inflammation

• Decrease risk of transmission– Undetectable = Untransmittable

19

Increase in CD4 Count

Gras L et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Median CD4 Response in Patients ≥50 Years at the Start of ART

Years from Starting ART0 1 2 3 4 65 7

11001000

900800700600500400300200100

0Mea

n CD

4 Ce

ll Co

unt (

cells

/mm

3 )

<50 cells/mm3

50-200 cells/mm3

200-350 cells/mm3

350-500 cells/mm3

≥500 cells/mm3

Control (male, <50 years at start of ART)

≥ 50 years at start of ART

20

When to Start Therapy

What to Start

When to Change Therapy

21

Building An HIV Regimen

2 NRTIs

1 NNRTI

1 Protease Inhibitor

1 Integrase Inhibitor

or

or

Example Regimens

Abacavir Lamivudine Dolutegravir

Triumeq

NRTI NRTI Integrase Inhibitor

Tenofovir AF Emtricitabine Darunavir

Descovy

NRTI NRTI Protease Inhibitor

Cobicistat

Prezcobix

Booster

First Line Regimens For Most People

Tenofovir Emtricitabine RaltegravirNRTI NRTI Integrase Inhibitor

Tenofovir Emtricitabine DolutegravirNRTI NRTI Integrase Inhibitor

Abacavir Lamivudine DolutegravirNRTI NRTI Integrase Inhibitor

Tenofovir Emtricitabine BictegravirNRTI NRTI Integrase Inhibitor

Truvada®/Descovy® + Isentress®

Truvada®/Descovy® + Tivicay®

Biktarvy®

Triumeq®

Lamivudine DolutegravirNRTI Integrase Inhibitor

Dovato®

The Rational For Unboosted Integrase Inhibitors

• Fewer drug interactions than NNRTIs, PIs and Elvitegravir• No food requirement• Good tolerability• Reduce the HIV viral load very quickly

The differences between recommended regimens is getting more and more subtle…

Treatment Naïve – Treatment Selection Factors

• Baseline resistance testing and viral load• Patient anticipated adherence• Other health conditions

– Kidney disease, heart disease– Pregnancy– Hepatitis co-infections

• Side Effects• Drug interactions• Patient’s daily schedule and meal times

26

Treatment Experienced

• Resistance testing• Antiretroviral medication history

– Side effect history– Allergies– Adherence/possible resistance

• All treatment naïve factors

27

Building an HIV Regimen for a New Patient

• Three medications from at least 2 different classes (usually…)– Never mono therapy– NRTIs are the only class we routinely use more than 1 at a time– Ritonavir and Cobicistat do not count

• Two exceptions to the three medication rule – Juluca, Dovato• Number of medications does not have to match the number of

pills

28

Building A Salvage Regimen

• Three medications, each from a different class– Medications selected based on viral resistance– Can still use more than 1 NRTI

• Can have more than 3 medications if there are not enough fully active medications left

Medication 1Partial resistance

Medication 2Partial resistance

Medication 3No resistance

Medication 4No resistance

½ ½ 1 1 = 3Active

Medications

Appropriate or Not? Question #1

Tenofovir DF Emtricitabine Elvitegravir

Stribild

NRTI NRTI Integrase Inhibitor

CobicistatBooster

Yes Probably Not

Appropriate or Not? Question #2

Yes Probably Not

Tenofovir DF Darunavir

Viread

NRTI Protease Inhibitor

Cobicistat

Prezcobix

Booster

Only 2 Active Medications

Appropriate or Not? Question #3

Yes Probably Not

Abacavir Lamivudine Zidovudine

Trizivir

NRTI NRTI NRTI

Only 1 Class

Appropriate or Not? Question #4

Juluca

Rilpivirine Dolutegravir

NNRTI Integrase Inhibitor

Yes Probably Not

Two Drug-Rule Exception

When to Start Therapy

What to Start

When to Change Therapy

34

Reason For Therapy Changes

• Viral Failure• Side Effects• Drug Interactions• Comorbidities• Reduce Pill Burden• Pregnancy• Cost/Insurance

35

Viral Failure

• Possible Causes– Suboptimal adherence– Pharmacokinetic issues– Possible drug resistance

• New regimen selection is based on cause of regimen failure and remaining antiretroviral options

36

Can I Go Back To My Old Regimen?

• Resistance/Viral Failure– No

• Side Effects, Drug Interactions, Comorbidities– Depends on the clinical picture

• Pill burden, Pregnancy, Cost/Insurance– Likely

37

Interruptions in Therapy

• Stop all antiretrovirals at once– Spacing them out only leads to resistance

• In patients with hepatitis B, treatment interruptions can lead to a hepatitis flare

• Always refer patient back to their medication provider

38

Drug Holidays

• If a patient's immune system is strong is it possible to stop medication for a period of time to decrease medication side effects?

• Short answer: No

39

SMART Study

• 5,472 patients enrolled– Half took medications continuously– Half took medications till their CD4 count was >350, then stopped till

<250

• Results– Those who took medication holidays were 2.5x more like to have a

clinical event or death

40N Engl J Med. 2006;355:2283-96.

Summary

• All patient should be offered medications regardless of CD4 count

• Initial treatment regimens should have 2 or 3 active medications

• Regimens should be designed to fit the patient• Interruptions in therapy should be avoided

41

HIV Treatment 101

C. Ryan Tomlin, Pharm.D., BCPS, AAHIVPClinical Pharmacist – HIV Medicine