HIV Therapy
Experience is the Best Teacher
David K. Stein, M.D.
Director, Adult HIV Research Activities
Jacobi Medical Center
Associate Professor of Clinical Medicine
Albert Einstein College of Medicine
But, It’s a
Humbling Way
to Learn
Lessons I’ve Learned the Hard
Way!
Assumptions
• 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
those letters and
numbers mean?
M184M/V
Translation = High level resistance to
Lamivudine and Emtricitibine
LS Genotypes
June 2002
• M41M/L
• D67N
• K70R
• K103N
• T215F
• K219E
February 2005
• K65K/R
September 2006
• None
October 2007
• D67N
• K70R
• K103N
• T215F
• K219E
Let’s Go Back to School
Y=mx + b
10
10
10-5
Codon 184
Normally Methionine
ATG to ATA [methionine to isoleucine] and ATG to GTA
[methionine to valine]
HAART =
Highly Active
Anti-Retroviral
Therapy
HAART typically contains 3 or more
ACTIVE drugs
10-5 X 10-5 X 10-5 = 10-15
Genetic Barrier
Different Drugs have different Genetic
Barriers
OK,
I’ve been sitting here for
the last few minutes.
What has this got to do
with me?
HIVNET 012
Neviripine given for Maternal-Fetal HIV
Transmission Prevention
I GOT IT – at
least 3 DRUGS
BUT
1 can equal 2 or 3 or 4
Drug Combinations
• Trizivir 1=3
• Combivir 1=2
• Atripla 1=3
• Epzicom 1=2
• Complera 1=3 • Truvada 1=2
o Complere 1=0
• Stribild 1=3+
• Kaletra 2=1+
Nothing is Not always
Nothing
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 Something
can be Dangerous
What is wrong with 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!
Giving a Prescription is
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 Gears
Sometimes the little
things that don’t seem
important at the time can
save a person’s life
• 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
Improving Practical Skills for Primary Care of HIV-Infected Patients
clinicaloptions.com/hiv
2006 Recommendations From CDC:
Routine Opt-Out Testing for HIV
 Routine voluntary
testing for
patients aged 1364 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
Enhanced Detection and Linkage to Care
• Data from CDC and Prevention National HIV Surveillance
System used to calculate HIV prevalence, undiagnosed HIV
prevalence, and linkage to HIV care
N = 1,148,200
100
82%
941,524
80
Patients (%)
82%
60
80%
757,812
66%
56%
424,834
40
37%
20
89%
378,906
33%
75%
287,050
25%
0
Diagnosed
Linked
to Care
Hall HI, et al. AIDS 2012. Abstract FRLBX05.
Retained
in Care
Prescribed
ART
Viral
Suppression
When to
Start ART
• Exact CD4 count at which to initiate therapy
not known, but evidence points to starting at
higher counts
• Current recommendation: ART for all
34
www.aidsetc.org
March 2012
Potential Benefits of
Early Therapy
o Untreated HIV may be associated with
development of AIDS and non-AIDSdefining 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
35
www.aidsetc.org
March 2012
Risks and Benefits of
Earlier Initiation of ART
Delayed ART
 Drug toxicity
 Preservation of limited Rx
options
 Risk of resistance (and
transmission of resistant virus)
Early ART
 ↑ 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
Current ARV Medications
NRTI
PI
 Abacavir (ABC)
 Didanosine (ddI)
 Emtricitabine (FTC)
 Lamivudine (3TC)
 Stavudine (d4T)
 Tenofovir (TDF)
 Zidovudine (AZT, ZDV)
 Atazanavir (ATV)
 Darunavir (DRV)
 Fosamprenavir (FPV)
 Indinavir (IDV)
 Lopinavir (LPV)
 Nelfinavir (NFV)
 Ritonavir (RTV)
 Saquinavir (SQV)
 Tipranavir (TPV)
NNRTI
 Delavirdine (DLV)
 Efavirenz (EFV)
 Etravirine (ETR)
 Nevirapine (NVP)
 Rilpivirine
(RPV)
www.aidsetc.org
Integrase Inhibitor
(II)
 Raltegravir (RAL)
 Elvitegravir* (EVG)
Fusion Inhibitor
 Enfuvirtide (ENF, T-20)
CCR5 Antagonist
 Maraviroc (MVC)
* EVG currently available
only in coformulation with
cobicistat (COBI)/TDF/FTC
37
Selected Complications
Mitochondrial Toxicity
• Lactic Acidosis
• Lipoatrophy
•
•
•
•
Metabolic Syndrome
Cardiac Toxicity?
Nephrotoxicity
Other
Adverse
Effects: NRTIs
• 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)
39
March 2012
www.
aidset
c.org
Adverse Effects:
NNRTIs
• All NNRTIs:
o Rash, including Stevens-Johnson
syndrome
o Hepatotoxicity (especially NVP)
o Drug-drug interactions
40
March 2012
www.
aidset
c.org
• All PIs:
Adverse
Effects: PIs
o Hyperlipidemia
o Lipodystrophy
o Hepatotoxicity
o GI intolerance
o Possibility of increased bleeding risk
for hemophiliacs
o Drug-drug interactions
41
March 2012
www.
aidset
c.org
Adverse Effects: II
• RAL
o Nausea
o Headache
o Diarrhea
o CPK elevation, myopathy,
rhabdomyolysis
o Rash
42
March 2012
www.
aidset
c.org
Adverse Effects: CCR5
Antagonist
• MVC
o
o
o
o
o
o
o
o
43
Drug-drug interactions
Rash
Abdominal pain
Upper respiratory tract infections
Cough
Hepatotoxicity
Musculoskeletal symptoms
Orthostatic hypotension, especially
if severe renal disease
March 2012
www.
aidset
c.org
Adverse Effects:
Fusion Inhibitor
• ENF
o Injection-site reactions
o HSR
o Increased risk of bacterial pneumonia
44
March 2012
www.
aidset
c.org
Opportunistic Infections
•
•
•
•
•
•
•
•
•
PJP
Cryptococcal meningitis
MAC
Cryptosporidiosis
Toxoplasmosis
Esophageal Candidiasis
Histoplasmosis
CMV
TB
Treatment-Experienced
Patients: ART Failure
• Causes of treatment failure include:
o Patient factors
(eg, CD4 nadir, pretreatment HIV RNA,
comorbidities)
o Drug resistance
o Suboptimal adherence
o ARV toxicity and intolerance
o Pharmacokinetic problems
o Suboptimal drug potency
o Provider experience
46
March 2012
www.
aidset
c.org
HIV Treatment 2013
$2323.84/month
$2810/month
$2253/month
A mere one pill once per day….but at what cost?
Take Home Message
3
Unless 1or 2 = 3