HIV TherapyExperience is the Best Teacher

David K. Stein, M.D.Director, Adult HIV Research Activities

Jacobi Medical CenterAssociate Professor of Clinical Medicine

Albert Einstein College of Medicine

But, It’s a But, It’s a Humbling Way Humbling Way

to Learnto LearnLessons I’ve Learned the Hard

Way!

AssumptionsAssumptions• Most of you will never take the ID Boards

or become Primary Care HIV Providers• Most of you will not be the Primary

manager of HIV infected patients• Most of you don’t speak up when a

question is asked of the audience in a lecture, even if you know the answer.o I have assurances that even if you answer incorrectly you will

probably still have a job tomorrow (although I can’t say what that job will entail)

• My kids think I’m crazy, and they probably are right.

LS

What do all What do all those letters those letters and numbers and numbers

mean?mean?M184M/V

Translation = High level resistance to Lamivudine and Emtricitibine

LS GenotypesLS GenotypesJune 2002•M41M/L•D67N•K70R•K103N•T215F•K219E

February 2005•K65K/R

October 2007•D67N•K70R•K103N•T215F•K219E

September 2006•None

Let’s Go Back to Let’s Go Back to SchoolSchool

Y=mx + bY=mx + b

10101010

10-5

Codon 184Codon 184Normally Methionine

ATG to ATA [methionine to isoleucine] and ATG to

GTA [methionine to valine]

HAART = HAART = Highly Active Highly Active

Anti-Anti-Retroviral Retroviral TherapyTherapy

HAART typically contains 3 or more ACTIVE drugs

1010-5 -5 X X 1010-5 -5 X X 1010-5 -5 = = 1010-15-15

Genetic Genetic BarrierBarrier

Different Drugs have different Genetic Barriers

OK, OK, I’ve been sitting here I’ve been sitting here

for the last few for the last few minutes. What has minutes. What has

this got to do with me?this got to do with me?

HIVNET 012HIVNET 012Neviripine given for Maternal-Fetal HIV

Transmission Prevention

I GOT IT – at I GOT IT – at least 3 least 3 DRUGSDRUGS

BUT 1 can equal 2 or 3 or 4

Drug CombinationsDrug Combinations• Combivir 1=2• Epzicom 1=2• Truvada 1=2

• Kaletra 2=1+

• Trizivir 1=3• Atripla 1=3• Complera

1=3o Complere 1=0

• Stribild 1=3+

Nothing is Not always Nothing is Not always NothingNothing

What to do?What to do?• Patient comes to ER complaining of

stomach upset and nausea after starting a 3 drug combination of Efavirenz, Lamivudine and Zidovudine. He says he is miserable and looks uncomfortable, but not in need of admission.

• He was given Zofran and Omeprazole with no relief.

• He sees his PMD in 10 days but it is the weekend and he is not in the office today.

T 1/2

A Little Bit of A Little Bit of Something can be Something can be

DangerousDangerous

What is wrong with What is wrong with this?this?

• A patient with HIV, Asthma, and a history of a prior UGI bleed comes to the ER with an acute Asthma attack. She is taking Atazanavir and Epzicom for the last 4 years. Nebs are given and the patient is somewhat better, but needs steroids before discharge. In addition to the Prednisone she is given Omeprazole which she received 3 years ago when she had an UGI bleed.

Click!Click!

Giving a Prescription Giving a Prescription is not a Treatmentis not a Treatment

• 1 BID is not 2 pills a day• 1 BID is not 1 at Breakfast, 1 at Lunch

• In This case 1 or 2 is less than 1

Time to Switch GearsTime to Switch Gears

Sometimes the little Sometimes the little things that don’t seem things that don’t seem important at the time important at the time can save a person’s can save a person’s

lifelife• A 27 year old female comes into the ER with burning

on urination for the last week. She is otherwise healthy. Her exam is remarkable for some mild tenderness over the bladder. UA is abnormal and she is given some antibiotics for a UTI

clinicaloptions.com/hivImproving Practical Skills for Primary Care of HIV-Infected Patients

2006 Recommendations From CDC: Routine Opt-Out Testing for HIV

Routine voluntary testing for patients aged 13-64 yrs in healthcare settings—not based on patient risk

Branson BM, et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

Improving Control of HIV Begins With Improving Control of HIV Begins With

Enhanced Detection and Linkage to Enhanced Detection and Linkage to

CareCare• Data from CDC and Prevention National HIV Surveillance

System used to calculate HIV prevalence, undiagnosed HIV prevalence, and linkage to HIV care

Hall HI, et al. AIDS 2012. Abstract FRLBX05.

100

80

60

40

20

0Diagnosed Linked

to CareRetained in Care

Prescribed ART

Viral Suppression

82%

56%89%

25%

Pat

ien

ts (

%)

N = 1,148,200

941,524

757,81280%

424,834378,906

287,05075%

33%37%

66%

82%

When to When to Start ARTStart ART

• Exact CD4 count at which to initiate therapy not known, but evidence points to starting at higher counts

• Current recommendation: ART for all

March 2012www.aidsetc.org34

Potential Benefits of Potential Benefits of Early Therapy Early Therapy

o Untreated HIV may be associated with development of AIDS and non-AIDS-defining conditions

• Earlier ART may prevent HIV-related end organ damage; deferred ART may not reliably repair damage acquired earlier

o Increasing evidence of direct HIV effects on various end organs and indirect effects via HIV-associated inflammation

o End-organ damage occurs at all stages of infection

March 2012www.aidsetc.org35

Drug toxicity Preservation of limited Rx

options Risk of resistance (and

transmission of resistant virus)

↑ potency, durability, simplicity, safety of current regimens

↓ emergence of resistance ↓ toxicity with earlier therapy Risk of uncontrolled viremia Near normal survival if CD4+ count

> 500 ↓ transmission

Early ARTDelayed ART

Risks and Benefits of Risks and Benefits of Earlier Initiation of Earlier Initiation of

ARTART

Current ARV Current ARV MedicationsMedications

NRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV)

NNRTI Delavirdine (DLV) Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV)

PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV)

Integrase Inhibitor (II) Raltegravir (RAL) Elvitegravir* (EVG)

Fusion Inhibitor Enfuvirtide (ENF, T-20)

CCR5 Antagonist Maraviroc (MVC)

37www.aidsetc.org

* EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC

Selected Selected ComplicationsComplications

Mitochondrial Toxicity• Lactic Acidosis• Lipoatrophy

• Metabolic Syndrome• Cardiac Toxicity?• Nephrotoxicity• Other

Adverse Adverse Effects: Effects: NRTIsNRTIs

• All NRTIs: o Lactic acidosis and hepatic steatosis (highest

incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC)

oLipodystrophy(higher incidence with d4T)

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Adverse Adverse Effects: Effects: NNRTIsNNRTIs

• All NNRTIs:oRash, including Stevens-Johnson

syndromeoHepatotoxicity (especially NVP)oDrug-drug interactions

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Adverse Adverse Effects: PIsEffects: PIs

• All PIs: oHyperlipidemia o Lipodystrophy oHepatotoxicityoGI intoleranceo Possibility of increased bleeding risk

for hemophiliacsoDrug-drug interactions

March 2012www.aidsetc.org

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Adverse Adverse Effects: IIEffects: II

• RAL oNauseaoHeadacheoDiarrheaoCPK elevation, myopathy,

rhabdomyolysisoRash

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Adverse Effects: Adverse Effects: CCR5 AntagonistCCR5 Antagonist

• MVC o Drug-drug interactionso Rasho Abdominal paino Upper respiratory tract infectionso Cougho Hepatotoxicityo Musculoskeletal symptomso Orthostatic hypotension,

especially if severe renal disease

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Adverse Effects: Adverse Effects: Fusion InhibitorFusion Inhibitor

• ENF o Injection-site reactionso HSRo Increased risk of bacterial pneumonia

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Opportunistic Opportunistic InfectionsInfections

• PJP• Cryptococcal meningitis• MAC• Cryptosporidiosis• Toxoplasmosis• Esophageal Candidiasis• Histoplasmosis• CMV• TB

Treatment-Treatment-Experienced Patients: Experienced Patients:

ART FailureART Failure• Causes of treatment failure include:

o Patient factors (eg, CD4 nadir, pretreatment HIV RNA, comorbidities)

o Drug resistanceo Suboptimal adherenceo ARV toxicity and intolerance o Pharmacokinetic problemso Suboptimal drug potency

oProvider experience

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A mere one pill once per day….but at what cost?

$2253/month

$2323.84/month

$2810/month

HIV Treatment 2013

Take Home MessageTake Home Message

Unless 1or 2 = 3

3