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)
March 2012www.aidsetc.org
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Adverse Adverse Effects: Effects: NNRTIsNNRTIs
• All NNRTIs:oRash, including Stevens-Johnson
syndromeoHepatotoxicity (especially NVP)oDrug-drug interactions
March 2012www.aidsetc.org
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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
March 2012www.aidsetc.org
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Adverse Effects: Adverse Effects: Fusion InhibitorFusion Inhibitor
• ENF o Injection-site reactionso HSRo Increased risk of bacterial pneumonia
March 2012www.aidsetc.org
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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