Transcript HIV and primary Care

Antiretroviral
therapy and
Primary Care
Chris Boyle, MD
9/8/2011
Case
56 yo man tests positive for HIV after you
initiate routine HIV testing during your first
clinic visit. He feels well. He has a PMH of
hyperlipidemia, GERD and seasonal allergies.
He is highly motivated to initiate ARVs. Do
you
a) Refer him to a HIV specialist
b) Take care of him yourself.
Katz, MH. Human Immunodeficiency Virus Is (Once Again) a Primary Care Disease. Arch Intern
Med. 2011;171(8):719-720.
HIV Screening and Access to Care: Health Care System Capacity for
Increased HIV Testing and Provision of Care (2011)
“Increased use of strategies such as task shifting, comanagement, and care
coordination can help to maximize the ability of the current health care workforce to
accommodate an increased number of HIV-positive individuals. In addition, these
strategies may result in improved patient care and increased provider satisfaction,
which, in turn, may increase the retention of HIV/AIDS care providers in the field.”
“...the emergence of HIV as a chronic medical condition...infectious disease
specialists and primary care providers who are HIV experts due to substantial patient
care experiences, formal training, or both, are generally better-prepared to manage
HIV disease than are primary care generalists....However, most HIV-positive patients
can benefit greatly from the broader skills of primary care providers in addressing
their other health care needs.”
Committee on HIV Screening and Access to Care; Institute of Medicine. “HIV Screening and Access to Care:
Health Care System Capacity for Increased HIV Testing and Provision of Care.” The National Academies Press,
2011.
Case
56 yo man tests positive for HIV after you
initiate routine HIV testing during your first
clinic visit. He feels well. He has a PMH of
hyperlipidemia, GERD and seasonal allergies.
He is highly motivated to initiate ARVs.
You keep him!
Case
56 yo man tests positive for HIV after you
initiate routine HIV testing during your first
clinic visit. He feels well. He has a PMH of
hyperlipidemia, GERD and seasonal allergies.
He is highly motivated to initiate ARVs. You
check HIV intake labs, including a CD4, viral
load and resistance panel. Labs are
significant for a CD4=496 and VL=6500, with
wild type virus.
When to Start
a) Initiate ARVs - everyone should be on treatment
b) Initiate ARVs - His CD4 count is <500
c) Do not initiate ARVs until his CD4 is <350
d) Do not initiate ARVs until his CD4 count is <200
e) Do not initiate ARVs until he has an opportunistic infection
When to Start
There are two major organizations that periodically make
updates regarding when and what to start.
The Department of Health and Human Services (DHHS) last updated in 01/2011 and The International Antiviral
Society - USA (IAS-USA) - last updated in 07/2010
When to Start
Historical Perspective
1996 - treat for a CD4<500, consider treatment in all
Mantra “Hit Early, Hit Hard”(N Engl J Med. 1995;333(7):450.)
however drugs had multiple side effects, difficult to adhere to
regimens, which led to...
2001 - treat for a CD4<200 and consider treatment if 200-350
however regimens became better tolerated, easier to administer
and there was increasing evidence that treating earlier improved
mortality, which led to...
2007 - treat for a CD4<350, several caveats of when to treat earlier
2009 - treat for a CD4<500, consider treatment in all.
When to Start 2011
Cohort study from 19962004 using a large data
registry with 3,851 HIV
and 1,044,589 non-HIV
patients at Brigham and
Women’s Hospital (BWH)
or Massachusetts General
Hospital (MGH)
The primary outcome was
myocardial
infarction,
identified by International
Classification of Diseases
coding criteria
J Clin Endocrinol Metab. 2007 Jul;92(7):2506-12
When to Start 2011
A, Myocardial infarction rates and corresponding adjusted RR.
HIV
Non-HIV
J Clin Endocrinol Metab. 2007 Jul;92(7):2506-12
When to Start 2011
Patel P, et al. Incidence of Types of Cancer among HIV Infected Persons Compared with the General Population in the United States, 1992–2003.
When to Start 2011
SMART
Randomized controlled study evaluating
continuous use of antiretroviral therapy vs
scheduled drug interruptions in
management of HIV
5472 participants with 2720 assigned to
drug conservation (scheduled
interruptions) and 2752 to viral
suppression arms (continuous therapy)
Medial CD4 count at entry was 597.
The primary end point was the
development of an opportunistic disease or
death from any cause.
The secondary end point was major
cardiovascular, renal, or hepatic disease.
El-Sadr WM, et al. CD4+ Count–Guided Interruption of Antiretroviral Treatment The Strategies for
Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-96.
El-Sadr WM, et al. CD4+ Count–Guided Interruption of Antiretroviral Treatment The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med
2006;355:2283-96.
Whn to Start - 2011
El-Sadr WM, et al. CD4+ Count–Guided Interruption of Antiretroviral Treatment The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med
2006;355:2283-96.
When to Start 2011
NA-ACCORD
N Engl J Med. 2009 Apr 30;360(18):1815-26
Art-CC
Lancet. 2009 Apr 18;373(9672):1352-63.
The HIV-CAUSAL Collaboration
Ann Intern Med. 2011 Apr 19;154(8):509-15.
When to Start 2011
NA-ACCORD
Observational study of 17,517
asymptomatic HIV infected patients
in the United States and Canada
from1996 through 2005.
All patients were ARV naive and
were stratified according to the
CD4, either >500 or 351-499 at
initiation or ARVs.
Primary endpoint was relative risk
of death for patients who initiated
treatment with those that deferred.
N Engl J Med. 2009 Apr 30;360(18):1815-26
When to Start 2011
N Engl J Med 2009;360:1815-26
When to Start 2011
N Engl J Med. 2009 Apr 30;360(18):1815-26
When to Start 2011
N Engl J Med. 2009 Apr 30;360(18):1815-26
When to Start 2011
HPTN - 052
Multi-national randomized
controlled trial which enrolled 1763
ART naïve HIV positive patients
with CD4 counts of 350-500 who
were in sero-discordant couples.
The primary end point was linked
HIV transmission in HIV negative
partners.
N Engl J Med 2011; 365:493-505
Study halted early, and data
analyzed found that early initiation
of ART had a 96% relative
reduction in linked HIV
transmissions
DHHS guidelines
ss
Department of Health and Human Services, 2011
What to Start
You review his HIV genotype and he has wild type virus. What do
you want to start?
a) Tenofovir + Emtricitabine (Truvada) + Lopinavir/Ritonavir
(Kaletra)
b) Abacavir + Lamivudine (Epzicom) + Atazanavir/Ritonavir
c) Combination Tenofovir + Emtricitabine + Efavirenz (Atripla)
d) Combination abacavir, zidovudine, lamivudine (Trizivir)
What to Start
http://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf
http://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf
+ Rilpivirine
http://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf
What to Start
Combination NRTIs
Protease Inhibitors
NNRTIs
Integrase Inhibitors
http://depts.washington.edu/nwaetc/Pill_Chart_2010.pdf
What to Start
Concepts in antiretroviral treatment
Always have three active drugs
Whenever possible those should include a “preferred” or
“alternative” regimen which includes
2 nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs) AND
1 active protease inhibitor (PI), non-nucleoside reverse
transcriptase inhibitor (NNRTI), or an integrase inhibitor
NOTE: Protease inhibitors should almost always be coadministered with ritonavir
What to Start
DHHS graphic of the Preferred and
alternative regimens
Department of Health and Human Services, 2011
Thompson, M.A. et al. JAMA 2010;304:321-333
+
or
or
with
=
HAART
http://depts.washington.edu/nwaetc/Pill_Chart_2010.p
What to Start
Choosing a regimen
1) Based on resistance profile
2) Prior ARV exposure
3) side effects
4) pill burden
5) potential drug-drug interactions
6) patient co-morbidities
What to Start
56 yo man tests positive for HIV after you initiate routine HIV
testing during your first clinic visit. He feels well. He has a PMH
of hyperlipidemia, GERD and seasonal allergies. He is highly
motivated to initiate ARVs. You check HIV intake labs, including
a CD4, viral load and resistance panel. Labs are significant for a
CD4=496 and VL=6500, with wild type virus.
...you discuss his options as TDF/FTC/EFV (Atripla), TDF/FTC
(Truvada) + Atazanavir/ritonavir, TDF/FTC (Truvada) +
Darunavir/ritonavir, and TDF/FTC (Truvada) + Raltegravir. He
prefers a once-a-day regimen, but doesn’t otherwise care if he
has to take multiple pills. He is worried about that pill that makes
you “go crazy”.
What to Start
...you probe his PMH a bit more and find out that his GERD quite
severe and is taking daily Omeprazole and he is on Simvastatin
40mg PO daily for an LDL of 160 with multiple CAD risk factors.
What do you choose?
a) Tenofovir + Emtricitabine (Truvada) + Atazanavir/Ritonavir
b) Tenofovir + Emtricitabine (Truvada) + Darunavir/Ritonavir
c) Combination Tenofovir + Emtricitabine + Efavirenz (Atripla)
d) Tenofovir + Emtricitabine (Truvada) + Raltegravir
Side effects
58 yo woman with pancreatitis, neuropathy,
lipodystrophy and lactic acidosis. What ARV
is she on?
Stavudine or didanosine (no longer used in the US, or most
of the world)
Side effects
30 yo man on ARVs with an elevated
creatinine seen on routine labs. What ARV is
he on?
Tenofovir
renal insufficiency (0.5% of patients)
fanconi syndrome
Side effects
23 yo woman who started ARVs two weeks ago and now
feels “flu-ish”, along with diarrhea, nausea, vomiting and
new dyspnea on exertion for the past week. Also for the
past 2 days she has noticed a new rash. On exam she has
a fever to 39.5 celsius and blood pressure of 95/50
(baseline is 120/75). What ARV is she on?
Abacavir
Abacavir hypersensitivity (3-5% of patients)
screen with HLA-B*5701 testing prior to initiation
also caution in patients with CAD or CAD risk factors
Side effects
NRTIs
lactic acidosis (very very very rare with current NRTIs …mostly from stavudine,
didanosine and AZT)
nausea/vomiting
HBV flare if discontinued
Abacavir
Abacavir hypersensitivity (3-5% of patients)
screen with HLA-B*5701 testing
also caution in patients with CAD or CAD risk factors
Tenofovir
fanconi syndrome
renal insufficiency (0.5% of patients)
Stavudine and didanosine (no longer used in the US, or most of the world)
pancreatitis
lactic acidosis
lipodystrophy
neuropathy
Side effects
28 yo man whose skin
looks like this. What ARV
is he on?
Atazanavir
commonly causes an indirect
hyperbilirubinemia
rarely causes jaundice
entirely harmless and goes away
with discontinuation
http://optimismandwhitepaint.blogspot.com/2009/08/house-beautiful-color-q
Side effects
34 yo man started on ARVs 2 weeks ago who
has been hanging out with this guy for the
past 10 days.
Side effects
What class of ARVs is he on?
http://horizoncomfortzone.blogspot.com/2011/01/amazing-toilet-facts.html
Side effects
PIs (all cause nausea, vomiting and diarrhea
and dyslipidemia)
Atazanavir
jaundice (elevated indirect bilirubinemia)
excellent lipid profile
Darunavir
caution in sulfa allergic patients
excellent lipid profile
Ritonavir
reputation for bad nausea, vomiting,
diarrhea
Side effects
56 yo man started on ARVs 6 months ago.
Since starting ARVs he has had nightly vivid
nightmares. Additionally he now feels kind of
depressed. What ARV is he on?
Efavirenz
Side effects
NNRTIs
Efavirenz
headaches, nightmares, depression/mood disorders, feeling
"hung over" or "disassociated" (23% will have some CNS
effects; generally goes away with time)
rash (up to 25%, usually goes away)
dyslipidemia
hepatotoxicity
teratogenic (neural tube disorders), don’t use in the first
trimester
Nevirapine
hepatic necrosis (idiosyncratic, and increased risk at higher
CD4 counts)
Side effects
45 year old man recently started on ARVs
and is experiencing no side effects, but is
realizing that twice daily meds is harder than
expected
Raltegravir
very well tolerated
occasional nausea, vomiting, headache,
diarrhea, but usually no side effects.
BID dosing
Drug-Drug
Interactions
1) Acid suppressants
2) Anticonvulsants
3) Statins
4) TB medications
5) Methadone
6) Antidepressants
7) Oral Contraceptives
Drug-Drug
Interactions
1) Acid suppressants
atazanavir requires a acidic environment
and should not be coadministered with a
PPI and should be separated from a H2
blocker by 12 hours
Drug-Drug
Interactions
Antidepressants –
Interact with protease inhibitors, and
NNRTIs and generally DECREASE antidepressant levels.
Bupropion + Efavirenz (decreases bupropion)
Sertraline + Efavirenz (decreases sertraline)
Paroxetine + Darunavir/r (decreases paroxetine)
Sertraline + Darunavir/r (decreases sertraline)
Trazadone + all ritonavir boosted PIs (increases trazadone)
TCAs + all ritonavir boosted PIs (increases TCA)
Drug-Drug
Interactions
Anticonvulsants
Phenytoin - DO NOT use with PIs or
NNRTIs (decreases ARV serum levels)
Carbamezapine - DO NOT use with Pis
(decreases ARV serum levels)
Lamotrigine - Avoid with PIs (decreases
lamotrigine drug levels)
Drug-Drug
Interactions
Statins
NNRTIs (namely Efavirenz)
will decrease the serum concentration of nearly all
statins, adjust statin to meet LDL goal
PIs
Simvastatin CONTRAINDICATED with all PIs as it can
increase serum concentrations up to 3000%
Atorvastatin and Rosuvastatin, increased statin
concentrations, but OK to use
Pravastatin - very little interaction with most PIs
Drug-Drug
Interactions
TB medications
Rifampin is CONTRAINDICATED with all
PIs as it will decrease PI serum
concentrations.
Efavirenz should be dose adjusted.
Drug-Drug
Interactions
Methadone
PIs and NNRTIs may decrease
methadone serum concentrations
Drug-Drug
Interactions
http://reference.medscape.com/druginteractionchecker
http://hivinsite.ucsf.edu/InSite
Case
56 yo man tests positive for HIV after you initiate routine HIV testing
during your first clinic visit. He feels well. He has a PMH of
hyperlipidemia, GERD and seasonal allergies. He is highly motivated
to initiate ARVs. You check HIV intake labs, including a CD4, viral load
and resistance panel. Labs are significant for a CD4=496 and
VL=6500, with wild type virus. You discuss his options and he prefers a
once-a-day regimen, but doesn’t otherwise care if he has to take
multiple pills. He is worried about that pill that makes you “go crazy”.
He is taking daily Omeprazole and Simvastatin 40mg PO daily for an
LDL of 160 with multiple CAD risk factors.
What do you choose?
Darunavir/ritonavir +
Tenofovir/Emtricitabine!!
Exciting New Directions
New (possibly 1st line) ARVs
Dolutegravir (next generation highly potent, mutation resistant,
integrase inhibitor)
Elvitegravir (once-a-day integrase inhibitor which is just around the
corner)
Will be coformulated with TDF/FTC and new boosting agent
cobisistat into a once-a-day “quad pill”
Rilpivirene (new FDA approved once-a-day NNRTI without the bad
CNS side effects) Also, rilpivirene coformulated with Truvada (Btripla!)...it’s actually called Complera
Randomized trial of when to start
Strategic Timing of Antiretroviral Treatment (START) trial…however
becoming a moot point as we move towards treatment for all.
Pre-exposure prophylaxis
Summary
1) Why primary care doctors should care about HIV care
2) The important societies making the rules for ARV management
3) Historical context to “when to start”
4) Reviewed the studies which are pushing the field towards earlier treatment
5) Important drugs to know
6) Important concepts on “what to start”
6) major ARV side effects
7) major drug-drug interactions, and where to quickly trouble-shoot ARV interaction questions
8) Future directions
Thank you!