Transcript Guidelines for Antiviral Treatment of HIV

Guidelines for Antiviral
Treatment of Adults and
Adolescents with HIV-1
(including 2011-2013 changes, and a little extra on what
else is new and current)
• Ronald P. Hattis, MD, MPH
– Associate Clinical Prof. of Preventive Medicine, Loma
Linda University
– AAHIVM HIV Specialist
– President, Beyond AIDS
• December 5, 2013
On behalf of Beyond AIDS Foundation
1
Objectives
• The participant will be able to apply recent
treatment guidelines for HIV in the care of
HIV/AIDS, and will be aware of other
recent developments in HIV care
• The participant will be able to explain to
patients the importance of viral load
suppression to help prevent transmitting
the virus to partners, and the advantages
of early onset of antiretroviral treatment
2
Sources and acronyms
• Presentation includes summaries of recent
changes in recommendations on ART
(antiretroviral therapy) of two key advisory
groups sponsored by:
– IAS-USA: International Antiviral Society – USA
division
• Published in JAMA 7/25/12, hereafter referred to as IAS
or IAS-USA guidelines
– DHHS: U.S. Dept. Health and Human Services,
which includes National Institutes of Health
• Published on NIH Website 1/10/11, 3/27/12, and
2/12/13, hereafter referred to as DHHS guidelines
• CDC and NIAID (the part of NIH dealing with infectious
3
diseases) are sources of further information
Evolution of guidelines on when
to start treatment for HIV/AIDS
• 1996-2000 “hit early, hit hard” often
advocated
• 2001-2012 treatment guidelines advised
delaying antiretroviral therapy (ART) until
CD4* cell counts <200, then <350, more
recently <500/ml
– Delayed due to concerns about toxicity, resistance
– Cell count drop usually took 5-10 years to occur
– Most of HIV transmission occurred before
treatment
* CD4 cell = type of white blood cell critical to immune system,
4
and preferentially attacked by HIV
2012 ART guidelines introduced a
radical change, not fully adopted
• 2012 guidelines expanded offering of
treatment to anyone with HIV
• This major change has been incompletely
adopted so far by providers or publicized
to patients
• Early and continuous treatment can
reduce morbidity and mortality and also
can be the key to controlling the U.S. HIV
epidemic
5
6
“Treatment as prevention”
• Meanwhile, research has proven that ART
can reduce HIV transmission by up to 96%
– Concept first proposed 1996 by Hattis and Jason
http://www.beyondaids.org/articles/1996MA~1.PDF,
http://www.beyondaids.org/articles/WillNewMedicationsReduceInfec
tiousnessofHIV-1997.pdf
– Confirmed effective in series of studies 2010-2011
• HPTN 052 clinical trial showed reduction of
transmission to sexual partners of 96% in
combination with prevention counseling
– Cohen, M. S.; McCauley, M.; Sugarman, J. (2012),
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3200068/
7
“Treatment as Prevention”: 2011
“Science Breakthrough of the Year”
(also featured at
International
AIDS Conference,
7/12, Washington,
DC)
8
Potential to expand treatment
Study based on CDC’s National HIV
Surveillance system (Hall, I 7/27/12 using 2009 data)
– 83% of est. 1.15 million infected persons in U.S.
have been tested
– 66% are linked to care (lower if black, young)
– Only 33% have received ART (1/2 of those in care)
– Only 25% have very low viral loads (VL, copies of
virus per ml) (3/4 of those receiving ART)
– Separate study by CDC in 2011 came up with
similar figures: 80% of infected tested, 62% in
care, 36% on ART, 28% virologically controlled
– http://blog.aids.gov/2012/07/hivaids-treatment-cascade-helps-identify-gaps-in9
care-retention.html
Potential to control epidemic:
additional opportunities
(assuming about 5% uncooperative)
• Percentage of infected persons tested diagnosis
•
•
•
could be increased about 15%, from 83% to 95%
95% of the 95% knowing diagnosis could be linked
to care, increasing care by 36%, from 66% to 90%
of total
95% of the 90% in care could get ART, increasing
treatment 58%, from 33% to 85% of total
If virological control rate could be increased from
75% to 80% of those treated, patients who are
almost non-infectious could be increased by 2.76
times, from current 25% to 69% of total
10
Potential to control epidemic:
additional opportunities, contd.
• 44% more of currently infected persons (69%-
25%) would be only 4% as likely to transmit HIV,
once VL controlled
– A theoretical potential of 42% decrease in
infectious persons, with similar incidence drop, just
to start with
– As fewer new infected people gradually replace
greater numbers now alive (R0, viral reproductive
rate <1) , incidence rate of HIV infections will
exponentially drop to lower and lower levels
• Actual rate reduction depends on achieving virological
control before most transmission occurs
• Prevalence drop depends on life expectancy
11
Potential to control epidemic:
additional opportunities, contd.
• However: just applying new guidelines, to offer
ART treatment to all already in care, even
without increasing testing, linkage to care, or %
of patients with low VL, could achieve:
• Using low estimate of 62% in care, and only 90%
•
acceptance, could treat another 23% of all infected
persons, and control viral load in ¾ of them
This would mean 17% more of total infected persons
would become non-infectious (a 2/3 increase from
current number) and incidence rates would drop
accordingly
12
Categories of evidence used in
DHHS guidelines
• Ratings of recommendations
A = Strong
B = Moderate
C = Optional
• Ratings of evidence
I = data from randomized controlled trials
II = data from well-designed nonrandomized
trials or observational cohort studies with
long-term clinical outcomes
III = expert opinion
13
Concise summary of Changes,
from IAS-USA Guidelines, contd.
• Recommended initial regimens should include 2
•
nucleos(t)ide reverse transcriptase inhibitors (NRTIs:
tenofovir/emtricitabine or abacavir/lamivudine)
Also include one of the following:
– a nonnucleoside reverse transcriptase inhibitor (NNRTI: efavirenz)
– a ritonavir-boosted protease inhibitor (PI: atazanavir or darunavir), or
– an integrase strand transfer inhibitor (INSTI: raltegravir)
• Alternatives:
–
–
–
–
–
For the NRTI: zidovudine (with lamivudine) (esp. in pregnancy)
For the NNRTI: nevirapine or rilpivirine
For the PI: ritonavir-boosted lopinavir, fosamprenavir, or saquinavir
For the INSTI: cobicistat-boosted elvitegravir
Rarely, a CCR5 attachment inhibitor: maraviroc.
14
Concise summary of Changes,
from IAS-USA Guidelines, contd.
• “CD4 cell count and HIV-1 RNA level should be
•
•
•
monitored, as should engagement in care, ART
adherence, HIV drug resistance, and quality-ofcare indicators.”
Reasons for regimen switching include virologic,
immunologic, or clinical failure and drug toxicity or
intolerance
Confirmed treatment failure should be addressed
promptly and multiple factors considered
Comment: Psychological and cultural factors need
to be addressed, affect adherence
15
Concise summary of Changes,
from IAS-USA Guidelines 7/25/12
IAS, published in JAMA (Journal of the American Medical Association)
http://jama.jamanetwork.com/article.aspx?articleid=1221704
• Treatment now recommended for all adults with HIV
•
infection; strength of recommendation and quality of
evidence increase with decreasing CD4 cell count
and presence of certain concurrent conditions
Clinical benefit is unknown for
• Elite controllers (viral load undetectable without
treatment)
– DHHS 2/13: Treat if CD4 counts decrease, or symptoms
• Long-term nonprogressors (stable CD4 cell counts
>500/μL and HIV-1 RNA <1000 copies/mL while not
taking ART)
– DHHS 2/13: Consider treatment if VL >200
16
DHHS Guidelines 1/10/11
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf
• Benefits to patient of earlier treatment:
– Increasing evidence demonstrates benefits of
viral suppression and immunologic responses
on reducing mortality and non-AIDS-related
complications in patients with higher
pretreatment CD4 counts.
• NA-ACCORD study observed…adjusted mortality
rates significantly higher among the 6,935 patients
who deferred therapy until CD4 count fell to <500
compared with rates in the 2,200 patients who
started therapy while CD4 count was > 500 (risk
ratio: 1.94, 95% CI: 1.37 to 2.79)
17
Evolution of DHHS recommendations on when to start
• In 1/10/11 guidelines, half of panel
•
recommended treating everyone regardless of
CD4 count
In 3/27/12 guidelines, entire panel
recommended treatment at any CD4 count
based on emerging evidence:
– Harmful impact of ongoing HIV replication on AIDS
and non-AIDS disease progression
– Benefit of effective ART in preventing secondary
transmission of HIV
18
When to start treatment, DHHS
3/27/12 guidelines
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf
• ART is recommended for all HIV-infected individuals.
• Strength of this recommendation varies with
•
pretreatment CD4 cell count:
– CD4 count <350 cells/mm3 (AI)
– CD4 count 350 to 500 cells/mm3 (AII)
– CD4 count >500 cells/mm3 (BIII)
Regardless of CD4 count, initiation of ART strongly
recommended for:
– Pregnancy (AI)
– History of an AIDS-defining illness (AI)
– HIV-associated nephropathy (HIVAN) (AII)
19
Additional priority indications for
treatment (IAS-USA 7/25/12)
• Hepatitis C virus (HCV) coinfection: CIII (however, if CD4 cell
•
count >500/μL may delay ART until after completion of HCV
treatment)
Chronic hepatitis B virus (HBV) coinfection: AII
– Both HBV and HIV respond to tenofovir combined with either lamivudine
or emtricitabine
• Age older than 60 years: BII
• During acute phase of primary HIV infection, regardless of
symptoms: BIII
• ART should be started as soon as possible, preferably within
the first 2 weeks of diagnosis, in patients with most
opportunistic infections (AI)
20
When to start treatment, DHHS
3/27/12 guidelines, contd.
• Patients who are at risk of transmitting HIV to sero•
•
negative sexual partners (AI [heterosexuals] or AIII
[other transmission risk groups])
Patients starting ART should be willing and able to
commit to treatment and should understand the benefits
and risks of therapy and the importance of adherence
(AIII)
Patients may choose to postpone therapy, and providers,
on a case-by-case basis, may elect to defer therapy on
the basis of clinical and/or psychosocial factors
– However, ART should be offered and discussed with all patients
21
Drug selection and initiation of
treatment in special situations
• HIV-2 (not covered by this presentation) may not
respond to same drugs
– Resistant to NNRTIs; darunavir, lopinavir, and saquinavir are
most effective PIs
http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/24/hiv-2infection
• Timing and choice of ART may be modified with
cryptococcal disease and tuberculosis
(IAS-USA 7/25/12)
– For Cryptococcus, death rates lower when ART delayed till
after 10 weeks of antifungal treatment
– For TB, adverse events lower for patients with CD4 counts
over 50, when ART delayed for 8-12 weeks after starting TB
therapy
• NIH 3/27/12 recommended delay of only 2 weeks if low BMI, 22
When to Start Treatment: Lack of
International Consensus (courtesy of E. Daar, UCLA, 11/21/13)
Clinical
Category
CD4 Count
(cells/mm3)
DHHS
2013
IAS-USA
2012
EACS
2012
BHIV
2012
WHO
2013
AIDS/Severe Sx
Any value
R
R
R
R
R
Asymptomatic
≤350
R
R
R
R
R
350 to ≤500
R
R
C
D
R
>500
R
R
D
D
D
Pregnant
women
Any value
R
R
R
R
R
HIV-associated
nephropathy
Any value
R
R
R
R
R
HIV/HBV
Any value
R
R
R
R
R
HIV-neg partner
Any value
R
R
C
C
R
DHHS Mar 2013: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf;
IAS-USA: Thompson MA, et al. JAMA. 2012; 308: 387-402;
EACS Nov 2012. http://www.eacsociety.org/Portals/0/files/pdf%20files/EacsGuidelines-v6.1-2edition.pdf;
BHIV 2012: http://www.bhiva.org/TreatmentofHIV1_2012.aspx;
WHO June 2013: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf
23
Treating HIV/HCV coinfection in
DHHS guidelines (3/27/12)
Note: Expect major changes as new oral drugs are approved, starting with
simepravir 11/22/13, sofosbuvir pending
• Hepatitis C section includes bocepravir and
telaprevir, add one as 3rd drug (with interferon and
ribavirin) for patients with genotype 1 hepatitis C
–
–
–
–
–
Both can be used with raltegravir
Telaprevir but not bocepravir can be used with ATV/r
Telaprevir at increased dose can be used with EFV
Avoid DRV/r, LPV/r, EFV with bocepravir
Avoid DRV/r, FPV/r, or LPV/r with telaprevir
• Interferon and ribavirin may be coadministered with
ART but drug interactions, hepatotoxicity additive
– This is rationale for delay in initiating ART if VL >500 and
24
plan immediate hepatitis C treatment, till it is completed
What else was added in 3/27/12
DHHS guidelines?
• New section on HIV and the older patient, including
comorbidities and their treatment
– Non-AIDS morbidities; inflammation speeds chronic diseases
• Wholesale cost table included (and updated 2/12/13)
– Wholesale cost of most approved regimens is still over
$2,000/mo (AIDS Drug Assistance Plan needed by many)
• Section on women has expanded discussion of
interactions of hormonal contraceptives with ARVs
– Injectable Depo-Provera associated in 1 study with double
risk of acquiring or transmitting HIV
25
What’s new in 2/12/13 and
10/30/13 DHHS Guidelines?
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf
http://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv-guidelines/0
• Stribild (Elvitegravir/cobicistat/tenofovir/emtricitabine
(EVG/COBI/TDF/FTC) as a fixed-dose combination
product) is recommended as an alternative regimen
for ART-naive patients, then 10/30/13 as a preferred
initial complete regimen for treatment-naïve patients
– Should have pre-treatment creatinine clearance >70
mL/min (BI).
• Dolutegravir (alternative INSTI to raltegravir)
recommended 10/30/13 as a preferred initial drug for
treatment-naïve patients
• http://aidsinfo.nih.gov/news/1392/hhs-panel-on-antiretroviral-guidelines-for-adults-and-
26
adolescents-updates-recommendations-on-insti-based-regimens-for-art-naive-individuals
What’s new in 2/12/13 DHHS
Guidelines, contd.
• Early HIV, or having a seronegative partner, are
•
•
special indications for urgent initiation of ART
Genotypic tropism assay (cheaper) now available as
alternate to favored but expensive phenotypic
assay, before starting maraviroc (CCR5 antagonist)
Genotype for INSTI’s (integrase inhibitors) is
recommended if failure of a regimen containing one
– Not part of standard genotype panels
– Not a requirement before initial treatment
• Efavirenz does not need to be discontinued in
pregnancy if it is maintaining undetectable VL
– Avoid in females if pregnancy is planned or risk (no contraception)
– By 5-6 wks., 2-3x estimated risk of neural tube defects is over
27
What’s new in 2/12/13 DHHS
Guidelines, contd.
• Treatment should be discussed starting at first
clinical contact
• If ARV treatment is started before receiving a
genotype, use a PI-based regimen
• More drug interactions listed, incl. with INSTIs
• Additional measures needed in labor and
delivery
– Intravenous ZDV if viral load 400 or greater
28
ARV drug classes and how they
are combined (adapted from multiple sources)
• NRTIs (Nucleoside or nucleotide reverse transcriptase
inhibitors): 2 used together as “backbone” of standard
regimens; 7 available, 5 used
– These are typically combined with one additional drug from any of
following classes:
• NNRTIs (Non-nucleoside reverse transcriptase
•
inhibitors): 5 available, 3 used
PIs (protease inhibitors): 9 available, 4 used
– Typically need to be “boosted” by a small dose of ritonavir, a fifth
member of same drug class
• INSTIs (Integrase strand transfer inhibitors): 3 available
•
and used, one only in a combination and needs “booster”
Fusion or attachment inhibitors: 2 available, 1 used
29
How the 5 main classes of HIV
antiretroviral drugs work
Source: http://i-base.info/guides/starting/hiv-lifecycle
For more technical explanation see http://www.touchbriefings.com/pdf/3024/biswas.pdf
30
Review of currently available
antiretroviral drugs (following tables adapted with edits
from http://aidsinfo.nih.gov/contentfiles/ApprovedMedstoTreatHIV_FS_en.pdf)
• Of 27 drugs on market, only 18 are in
recommended and 11 are in first-line regimens
– 2 of these are used only to increase blood levels of PIs, or
of an INSTI, by inhibiting CYP3A (ritonavir, cobicistat)
– 2 only available in a combination product (Stribild)
– Combination pills provide convenience, reduce pill burden
• Drugs still currently recommended as primary,
•
alternative, or booster drugs highlighted in bold
below
Those available as generics (5 early NRTIs and one
early NNRTI) have asterisks (*) after brand names
31
below
NRTIs
(“nukes,” block reverse transcriptase, an enzyme
HIV needs to make DNA copies of its RNA for reproduction)
Date of
FDA
Generic
Abbreviation
name
Brand
name
Food restrictions and
dosage
3TC
lamivudine
Epivir*
Take with or without
food 1x300 mg tab qd
17-Nov-95
ABC
abacavir
Ziagen*
Take with or without
food 2x300 mg tabs qd
17-Dec-98
AZT or ZDV
zidovudine
Retrovir*
Take with or without
food 1x300 mg tab bid
19-Mar-87
d4T
stavudine
Zerit*
Take with or without food
24-Jun-94
Take on an empty stomach
30 mins before, or 2 hours
after meal 1x250-400 mg cap qd
31-Oct-00
Videx EC*
1x30-40 mg cap bid
approval
ddI
didanosine
FTC
emtricitabine Emtriva
Take with or without
food
1x200 mg cap qd
02-Jul-03
TDF
tenofovir
Take with or without
food
1x300 mg tab qd
26-Oct-01
32
Viread
NNRTIs
(“non-nukes,” bind to reverse transcriptase, an
enzyme HIV needs to make DNA copies of its RNA in cell)
Generic
Abbreviation
name
Brand
name
Food restrictions and
dosage
Date of
FDA
approval
DLV
Rescriptor
Take with or without food
04-Apr-97
Take on an empty
stomach 600 mg
17-Sep-98
etravirine
(IAS: occas. Intelence
salvage use)
Take following a meal
18-Jan-08
nevirapine
Take with or without
food 1x200 mg tab qd x 14d 21-Jun-96
EFV
ETR
NVP
delavirdine
efavirenz
Sustiva
(US)
Stocrin
(Europe)
Viramune*
2x200 mg tabs tid
1x 600 mg tab qd (pref. qhs)
2x100 mg tabs bid
then bid
RPV
rilpivirine
Edurant
Take with food
1x 25 mg tab qd
20-May-11
33
PIs
(block protease, an enzyme HIV needs to assemble
new viral components into complete copies of itself)
Abbreviation Generic name
FPV
fosamprenavir
Brand name
Food
restrictions and
dosage
Lexiva (US)
Take with or
without food, 4x
Telzir (Europe)
700 mg tabs /r qd
or 2 bid (or 1 bid /r
Date of FDA
approval
20-Oct-03
PI Tx exp)
ATV
atazanavir
Reyataz
Take with food
1x300 mg tab /r qd
20-Jun-03
Take with food
DRV
IDV
darunavir
indinavir
Prezista
Crixivan
1x800 mg /r tab qd
(new; or 2x400 mg /r
or 1x600 mg /r bid Tx
experienced)
Take on empty
stomach w fluids
1 hour before, or 2 hours
after, a meal, 2x400 mg
caps q8h (or bid /r, nonFDA)
23-Jun-06
13-Mar-96
34
PIs, contd.
Abbreviation
Generic name
LPV/RTV
lopinavir +
ritonavir
(favored in
pregnancy)
NFV
RTV
SQV
TPV
nelfinavir
ritonavir
(used only as
booster)
saquinavir
(occasionally
used)
tipranavir
Brand name
Kaletra9
Aluvia
(developing
world)
Food
restrictions
and dosage
Take with or
without food
4x250/50 mg
tabs qd, or 2 bid
Date of FDA
approval
15-Sep-00
(Tx exp or preg.)
Swallow whole
Viracept
Take with food
14-Mar-97
Norvir
Take with
food if
possible
01-Mar-96
gel capsule)
Take within two
hours of food
06-Dec-95
Aptivus
Take with or
without food
22-Jun-05
2x625 mg tabs bid
/r means 100 mg,
/rr means 200 mg
Invirase (hard
2x500 mg caps bid/r
2x250 mg caps bid /rr
35
Entry/fusion /attachment inhibitors
(block entry of virus into cells)
Abbreviation
T-20
MVC
Generic
name
enfuvirtide
maraviroc
Brand Name
Food restrictions Date of FDA
and dosage
approval
Fuzeon
Prepared from powder,
injected into thigh, arm,
abdomen
90 mg (1 ml) bid
Celsentri (Europe)
Take with or
without food
Selzentry (US)
INSTIs
Abbreviation
RAL
13-Mar-03
18-Sep-07
1-4x150 mg tab bid
(inhibit enzyme integrase, block integration of HIV copy into DNA)
Generic
name
raltegravir
Brand Name
Food restrictions
and dosage
Date of FDA
approval
Isentress
Take with or
without food
12-Oct-07
(Stribild taken
with food) 1 daily
27-Aug-12 only
as component
Take with or
without food
12-Aug-13
1x400 mg tab bid
EVG
elvitegravir
Component
of Stribild
DTG
dolutegravir Tivicay
36
Combination pills
(not incl. LPV/RTV)
Multi-class 1/day
Brand name
Combinations
Food restrictions
and dosage
Date of FDA
approval
EFV + TDF + FTC
Atripla
Take on an empty
stomach 1 qd
12-Jul-06
RPV + TDF + FTC
Complera
Take with food 1 qd
10-Aug-11
EVG + cobicistat
+ TDF + FTC
Stribild
Take with food 1 qd
27-Aug-12
NRTI
Combinations
Brand name
Food restrictions
and notes
Date of FDA
approval
Kivexa (Europe)
Take with or
without food 1 qd
02-Aug-04
ABC + AZT + 3TC
Trizivir (no longer
recommended)
Take with or without
food 1 bid
14-Nov-00
AZT + 3TC
Combivir
Take with or
without food 1 bid
27-Sep-97
TDF + FTC
Truvada
(also for PrEP)
Take with or
without food 1 qd
02-Aug-0437
ABC + 3TC
Epzicom (US)
How do I keep all these straight?
Common complaints by clinicians
• Too many “–virs”
– Names of 12 drugs from 3 classes end with “vir”
• 3-digit acronyms don’t help
– Not always easy to associate generic names and
acronyms with brand names
• Suggestions:
– Take advantage of lists from pharmaceutical
companies, some with pictures, dosages, etc.
– Become familiar with 4 (of 7) two/three-drug
combination pills, plus 4 more: darunavir,
atazanavir, raltegravir; and ritonavir as booster38
The “nuke” dependence problem
• All recommended regimens include choice of only 4
NRTIs combos: lamivudine (3TC) or emtricitabine
(FTC), combined with either tenofovir (TDF) or
abacavir (ABC)
– TDF precautions: nephrotoxic, avoid or give alternate days if
CrCl<50, twice weekly if CrCl 20-29; increased bone loss
– ABC precautions: Pre-screen with HLA-B*5701, must be neg.;
M.I. risk in one study, more virological failure if baseline VL
>100,000
• No guidelines are provided (due to lack of data)
when neither TDF or ABC can be used
– No “Nuke-free” regimens are discussed in DHHS guidelines
– See table on next slide for recent studies of such regimens
• “Warmline” suggests can add FTC or 3TC even if mutations found
39
NRTI-sparing options
Courtesy of E. Daar, UCLA, 11/21/13
Strengths
LPV/r + EFV (A5142)
Weaknesses
Good efficacy
High pill count
Large study
Poor tolerability
Lipid elevation
LPV/r monotherapy
Simplicity
Tolerability
Concerns regarding efficacy
DRV/r monotherapy
Simplicity
Tolerability
Mixed results for efficacy
LPV/r + 3TC
Decrease toxicity
Efficacy
No data with preferred PI/r
DRV/r + RAL
Good tolerability
Twice daily
Concerns regarding efficacy in naive
Large study nearly complete
ATV bid + RAL
No booster
Poor tolerability
Poor efficacy
PI/r + MVC (R5 only pts)
INSTI-sparing
Concerns regarding efficacy
Study recently stopped
•
40
The ART-ful Restaurant
Some selections will be served together as one combo dish.
This menu not available if fewer than 3 selections ordered.
Chef’s recommendations in orange.
• Select two items from list A (the NRTIs)
– One from these 2: emtracitabine, or lamivudine
– One from these 3: tenofovir, abacavir, zidovudine (“AZT”)
• Warning: must have been tested for allergy to abacavir; AZT
recommended only for experienced palates, not for the faint of heart
• Add one item from any of the following groups:
– NNRTIs: efavirenz, rilpivirine (latter if baseline VL<100,000)
– Protease inhibitors: atazanavir, darunavir, fosamprenavir,
lopinavir (a perennial favorite for expecting ladies)
• This group will be garnished with a little ritonavir for enhancement
– Integrase inhibitors: raltegravir, dolutegravir, elvitegravir
• Latter in combo only, the Stribild Special
41
– Entry inhibitor: maraviroc (pre-ordered, requires special eligibility)
What to start, commentary on
individual and cultural factors
• “Selection of a regimen should be individualized on
the basis of virologic efficacy, toxicity, pill burden,
dosing frequency, drug-drug interaction potential,
resistance testing results, and comorbid conditions”
(DHHS 3/27/12)
• Patient should be committed to adherence to
treatment before starting
(DHHS 2/12/13)
• Cultural competence is important
– Patient must be approached with sensitivity when
recommending onset of therapy
42
What to start, per DHHS
recommendations
Preferred Regimens (Regimens with optimal and durable efficacy, favorable
tolerability and toxicity profile, and ease of use)
TDF/FTC “backbone” or EFV/TDF/FTC can be one pill (Truvada or Atripla)
NNRTI-Based Regimen
• EFV/TDF/FTC (AI)
EFV should not be used during first
trimester of pregnancy or in women
trying to conceive or not using effective
contraception. 1 tablet once/day
PI-Based Regimens (in alphabetical
/r means boosted with ritonavir.
Both regimens require 3 pills once/day
ATV/r should not be used in patients
who require >20 mg omeprazole
equivalent per day
ATV/r associated with cholelithiasis
Start with PI if no genotype first
(2/12/13 DHHS recommendation)
order)
• ATV/r + TDF/FTC (AI)
• DRV/r (once daily) + TDF/FTC (AI)
PI-Based Preferred Regimen for
Pregnant Women
• LPV/r (twice daily) + ZDV/3TC (AI)
Based on long experience of safety
Kaletra 2 tabs and Combivir 1 tab, both
taken twice/day in pregnancy
43
What to start, per DHHS
recommendations, contd.
Preferred Regimens, contd. (Regimens with optimal and durable efficacy,
favorable tolerability and toxicity profile, and ease of use)
TDF/FTC “backbone” or EFV/TDF/FTC can be one pill (Truvada or Atripla)
ABC/3TC “backbone” can also be one pill (Epzicom)
INSTI-Based Regimens
• RAL + TDF/FTC (AI)
• DTG + TDF/FTC
• DTG + ABC/3TC
• EVG/COBI/TDF/FTC
RAL is taken twice/day, Truvada
once/day
DTG and EVG were approved as
preferred initial therapy components
10/30/13, both in once/day tablets
EVG/COBI/TDF/FTC is available as a
single pill containing entire regimen,
once daily
DTG + ABC/3TC is only preferred
starting regimen containing abacavir,
which is otherwise an alternative NRTI
44
44
What to start, per DHHS, contd.
Alternative Regimens (Regimens that are effective and tolerable but have
potential disadvantages compared with preferred regimens. An alternative
regimen may be the preferred regimen for some patients.)
NNRTI-Based Regimens (in alphabetical order)
• EFV + ABC/3TC (BI)
• RPV/TDF/FTC (BI)
• RPV + ABC/3TC (BIII)
PI-Based Regimens (in alphabetical order)
• ATV/r + ABC/3TC (BI)
• DRV/r + ABC/3TC (BIII)
• FPV/r (once or twice daily) + ABC/3TC or TDF/FTC (BI)
• LPV/r (once or twice daily) + ABC/3TC or TDF/FTC (BI)
45
What to start, per DHHS, contd.
Acceptable Regimens (CI) (Regimens that may be selected for some patients
but are less satisfactory than preferred or alternative regimens) and
Regimens that may be acceptable but more definitive data are needed (CIII)
NNRTI-Based Regimen
• EFV + ZDV/3TC (CI)
• NVP + (TDF/FTC or ZDV/3TC) (CI)
• NVP + ABC/3TC (CIII)
• RPV + ZDV/3TC (CIII)
Comments:
• NVP should not be used in patients with
moderate to severe hepatic impairment, in
women with pre-ART CD4 count >250 or
men with pre-ART CD4 count >400.
• RPV virologic failure more common if
PI-Based Regimens
• ATV + (ABC or ZDV)/3TC (unboosted, CI) baseline VL >100,000. Don’t use with PPIs.
• Use NVP and ABC together with
• ATV/r + ZDV/3TC (CI)
caution, both can cause HSRs within the
• DRV/r + ZDV/3TC (CIII)
first weeks after initiation of therapy.
• FPV/r + ZDV/3TC (CI)
• ZDV can cause bone marrow
• LPV/r + ZDV/3TC (CIII) (non-pregnant)
suppression, lipoatrophy, and rarely lactic
INSTI-Based Regimen
acidosis with hepatic steatosis.
• RAL + ZDV/3TC (CIII)
• Unboosted ATV may be used but only
when RTV boosting is not possible.
CCR5 Antagonist-Based Regimens
• MVC requires prior tropism testing;
• MVC + ZDV/3TC (CI)
patient must have only CCR5-tropic
• MVC + TDF/FTC or ABC/3TC (CIII)
virus. (Added 1/10/11 by NIH) 46
Summary of what to start per DHHS
courtesy of E. Daar, UCLA, 11/21/13
Preferred
Regimens
• EFV/TDF/FTC
• ATV/r + TDF/FTC
• DRV/r (once daily) + TDF/FTC
• RAL + TDF/FTC
• EVG/COBI/TDF/FTC
October 30, 2013
• DTG + TDF/FTC
• DTG + ABC/3TC
[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]
Alternative
Regimens
•
•
•
•
•
Acceptable
Regimens
• EFV or RPV + ZDV/3TC
• NVP + TDF/FTC or ZDV/3TC or ABC/3TC
• ATV + (ABC or ZDV)/3TC
• ATV/r, DRV/r, LPV/r, FPV/r , RAL + ZDV/3TC
• MVC + ZDV or ABC/3TC
• SQV/r + TDF/FTC or ABC/3TC or ZDV/3TC (with caution)
EFV + ABC/3TC
RPV + (TDF or ABC)/(FTC or 3TC)
ATV/r or DRV/r + ABC/3TC
FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC
RAL + ABC/3TC
Individualizing First-line Therapy:
Specific Circumstances
courtesy of E. Daar, UCLA, 11/21/13
Circumstance
Agents
No genotype
 Use boosted PI
High HIV-1 RNA
 Caution with ABC, RPV
Renal disease
 Caution with TDF, ATV/RTV; monitoring complicated with
COBI and DTG
Dyslipidemia
 RAL, DTG, RPV most lipid neutral
CV risk factors
 Possible association with ABC, ddI, LPV/RTV
 No data for DRV/RTV, INSTIs, MVC
Pregnancy
 Preferred: ZDV/3TC + NVP, LPV/RTV, or ATV/RTV
 EFV can be used after first 5-6 wks
Chronic HBV
 Preferred TDF + 3TC or FTC
 Alternative is entecavir
Decreased BMD
 Caution with TDF
CNS effects
 Caution with EFV for at least first month
Newest ARV drugs
• Rilpivirine: NNRTI with fewer CNS side
effects than efavirenz
– Approved separately as Edurant 5/20/11
– Approved as component of Complera 8/10/11
• Formulated in once-daily tablet with FTC/TDF
– Should not be used with proton pump
inhibitors
– Pregnancy category B (vs. D for efavirenz)
– Taken with food (vs. without for efavirenz)
– Not recommended due to virological failures if
baseline VL >100,000 (similar to abacavir) 49
Newest ARV drugs, contd.
• Dolutegravir (DTG, 50 mg/day)
– Approved by FDA 8/12/13, brand name Tivicay
– Recommended by HHS 10/30/13 in preferred
initial therapy for treatment-naïve patients
– IAS-USA: An INSTI with good activity against RAL
and EVG-resistant strains
– Does not require boosting; one dosage (50 mg/d)
– Faster and superior VL suppression when
combined with ABC + 3TC, compared with Atripla
(EFV + FTC + TDF) in one trial, with similar
toxicity, less CNS side effects and rash
• Walmsley et al., ICAAC 2012
50
Newest ARV drugs, contd.
• Stribild: combination of 4 drugs, sometimes
referred to as “quad”
– Approved 8/27/12, after both NIH and IAS-USA
guidelines issued
– Recommended 10/30/13 by HHS as a preferred
initial regimen for treatment-naïve patients
• Faster VL suppression than ATV/r regimen, slightly
superior to EFV regimen with same NRTIs
– Formulated as tablet with 2 old drugs (FTC/TDF)
and 2 new ones
• Elvitegravir (EVG), a new INSTI not used separately
– Requires boosting, but low-dose RTV without another PI was
considered a risk for PI resistance
• Cobicistat, a new CYP3A booster without ART effect
51
Lab monitoring schedule (DHHS 1/10/11)
Care
entry
f/u
before
ART
ART start
or change
CD4 count
Y
Every 3-6
months
Y
Viral load
(VL)
Y
Every 3-6
months
Y
Genotype
Y
Y
HLAB*5701
If
considering
abacavir
CCR5
tropism
If
considering
maraviroc
2-8 wks
after
start or
change
Every
3-6
mos.
Y
Y
Y
Every
6-12
mos.
(IAS:
6 mos)
Stable
w VL
suppr.
Treatment
failure
Y
Y
Y
If
maraviroc
considered
52
or is failing
Less frequent CD4 counts needed
if VL undetectable (DHHS 1/10/11)
• “Poor CD4 response is rarely an indication for modifying a
virologically suppressive ARV regimen…for the patient on a
suppressive regimen whose CD4 cell count has increased well
above the threshold for opportunistic infection risk, the CD4
count can be measured less frequently than the viral
load…every 6 to 12 months, unless there are changes in the
patient’s clinical status, such as new HIV-associated clinical
symptoms or initiation of treatment with interferon,
corticosteroids, or anti-neoplastic agents (CIII).”
• IAS-USA goes along with this up to every 6 months, not 12
• Comments:
– Aim for VL and CD4 every 3 months; if CD4 high and stable and
VL undetectable, do CD4 every 2 visits
– Steadily decreasing CD4 count may be indication for modifying regimen
53
Virologic definitions (DHHS 1/10/11)
• Virologic suppression: A confirmed HIV RNA level
•
•
below the limit of assay detection
Virologic failure: The inability to achieve or maintain
HIV RNA level <200 copies/mL)
Incomplete virologic response: Two consecutive
plasma HIV RNA levels >200 copies/mL after 24
weeks on ARV regimen
– Baseline HIV RNA and regimen may affect timing of
response
– Determine whether failure is do to adherence
• Repeat genotype (while on failing regimen, per UCSF)
•
– Dilemma if 200-1000, lab may not be able to do
Change 2-3 drugs (never only 1) if failing regimen 54
Treatment-experienced patients,
salvage regimens
• Give DRV, LPV, FPV bid; increase ritonavir dose
•
•
•
with DRV, FPV for experienced patients
Consider third-line drugs not on the “starter” list
If can’t find 3 drugs without resistance, use 4-5
If expert consultation not locally available, or for
rapid advice, nationally-funded services at UCSF:
– “Warmline” (HIV management) (800) 933-3413
• Only number really needed, others go to same staff
– “PEPline (occup. exposures) (888) 448-4911
– Perinatal hotline (prevention of transmission to
55
newborn) (888) 448-8765
HIV and Chronic Disease
• HIV care includes chronic disease prevention and
management
– Not emphasized in the presentation in proportion to
importance in overall treatment
• Body is in a state of chronic inflammatory response
– Increased rates of diabetes, hyperlipidemia, renal disease,
and other chronic diseases
– Many non-AIDS-defining conditions due to HIV infection
• HIV itself and some ART drugs can increase
metabolic risks
– Lower HDL, raise triglycerides, or cause neuropathy,
nephropathy, lipodystrophy
• Common co-morbidities including psychiatric,
56
substance abuse, hepatitis C, etc. complicate therapy
Prevention of opportunistic
infections (OIs) Last updated by CDC 4/10/09
• http://www.aidsinfo.nih.gov/contentfiles/Adult_OI.pdf
Prophylaxis to prevent first episode of opportunistic disease
DISEASE TO
PREVENT
PROPHYLAXIS
INDICATION
Pneumocystis CD4 <200 (or
(now reclassi- oro-pharyngeal
fied as a
Candida)
fungus,
Pneumocystis
jirovecii)
DRUGS OF FIRST
CHOICE
ALTERNATE REGIMENS
Trimethoprimsulfamethoxazole
(TMP-SMX), 1 DS
PO daily (AI); or
1 SS daily (AI)
• TMP-SMX 1 DS PO tiw (BI); or
• Dapsone 100 mg PO daily or 50
mg PO bid (BI); or Dapsone 50 mg
PO daily + pyrimethamine 50 mg
PO weekly + leucovorin 25 mg PO
weekly (BI); or
• Aerosolized pentamidine 300 mg via
Respigard II™ nebulizer every month
(BI); or
• Atovaquone 1,500 mg PO daily • (BI);
or Atovaquone 1,500 mg +
pyrimethamine • 25 mg + leucovorin 10
mg PO daily (CIII)
57
Prophylaxis to prevent first episode of opportunistic disease, contd.
DISEASE TO
PREVENT
PROPHYLAXIS
INDICATION
DRUGS OF FIRST
CHOICE
ALTERNATE REGIMENS
Toxoplasmosis
CD4 <100
Toxoplasma
IgG positive
(AII)
TMP-SMX, 1 DS PO
daily (AII)
•TMP-SMX 1 DS PO tiw (BIII); or
TMP-SMX 1 SS PO daily (BIII);
•Dapsone 50 mg PO daily + pyrimethamine 50
mg PO weekly + leucovorin 25 mg PO weekly
(BI); or (Dapsone 200 mg + pyrimethamine 75
mg + leucovorin 25 mg) PO weekly (BI);
•(Atovaquone 1,500 mg +/- pyrimethamine 25
mg + leucovorin 10 mg) PO daily (CIII)
Tuberculosis
PPD or
Quantiferon
positive
Isoniazid (INH) 300
mg PO daily (AII) or
•Rifampin (RIF) 600 mg PO daily x 4 months
(BIII); or
•Rifabutin (RFB) (dose adjusted based on
concomitant ART) x 4 months (BIII)
CD4 <50
Azithromycin 1,200
mg PO once weekly
(AI); or Clarithromycin
•Rifabutin (RFB) 300 mg PO daily (BI) (dosage
adjustment based on drug-drug interactions
with ART); rule out active TB before starting
RFB
Mycobacterium
avium complex
(MAC)
900 mg PO biw (BII) for
9 months –
both plus pyridoxine
50 mg PO daily (BIII);
or if exposed to drugresistant TB,
consultation with public
health (AII)
500 mg PO bid (AI); or
Azithromycin 600 mg PO
twice weekly (BIII)
58
Pediatric DHHS guidelines (11/1/12)
http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf
• Recommend treatment of all infants <12
months old and for all children with symptoms
• Generally recommend treatment of children
>1 yr without symptoms, with strength of
recommendation based on CD4 counts
– <1000 for ages 1-3 (AII)
– <750 for ages 3-5 (AII)
– <500 for age 5 and older (AI)
• Some drugs approved only above certain ages
• Not all drugs have liquid or chewable versions
• Dosages based on weight
59
PrEP (Pre-exposure prophylaxis)
http://www.cdc.gov/hiv/prep/pdf/PrEPfactsheet.pdf
• 7/16/12: FDA approved Truvada for PrEP, based on 2 studies a
year earlier, showing “strong evidence that PrEP is effective
and safe among heterosexually-active men and women”
– TDF2 study: once-daily tenofovir plus emtricitabine reduced risk of acquiring HIV
infection by roughly 62 percent of heterosexually-active men and women.
– Partners PrEP study: daily tenofovir plus emtricitabine reduced HIV transmission
among heterosexual serodiscordant couples by 75%
• Before initiating PrEP (From CDC Interim Guidelines 8/12):
– Document negative HIV antibody test immediately before starting PrEP medication.
– Test for acute HIV infection if patient has symptoms consistent with acute HIV infection or
reports unprotected sex with an HIV-positive person in the preceding month.
– Determine if women are planning to become pregnant, are currently pregnant, or are
breastfeeding.
– Confirm that patient is at ongoing, very high risk for acquiring HIV infection.
– If any sexual partner is known to be HIV-infected, determine whether receiving
antiretroviral therapy; assist with linkage to care if not in care or not receiving antiretroviral
therapy.
– Confirm that calculated creatinine clearance is ≥60 mL per minute (Cockcroft-Gault
60
formula).
PrEP
(pre-exposure prophylaxis) contd.
• Follow-up while PrEP medication is being taken (CDC 8/12):
– Every 2–3 months, perform an HIV antibody test (or fourth generation antibody/antigen
test) and document negative result.
– At each follow-up visit for women, conduct a pregnancy test and document results; if
pregnant, discuss continued use of PrEP with patient and prenatal-care provider.
– Evaluate and support PrEP medication adherence at each follow-up visit, more often if
inconsistent adherence is identified.
– Every 2–3 months, assess risk behaviors and provide risk-reduction counseling and
condoms. Assess STI symptoms and, if present, test and treat for STIs as needed.
– Every 6 months, test for bacterial STIs even if asymptomatic, and treat as needed.
– Three months after initiation, then every six months while on PrEP medication, check
serum creatinine and calculate creatinine clearance.
• Comments:
– HIV viral load before initiation would confirm patient not already infected. Truvada is not
adequate therapy for infected persons, and if infection has already occurred, or occurs
during treatment, this could lead to increased population resistance to a “backbone” drug
– FDA and CDC did not clearly limit indications. Three logical ones exist, but first 2 were not
included in studies, so unknown how much they add to effectiveness of prevention:
• Bridging gap till infected partner’s VL is reduced to very low levels
• PrEP for uninfected partner + ART for infected partner, when pregnancy intended
• In a marriage or committed relationship, if infected partner refuses to take ART 61
PrEP: Concerns of Beyond AIDS
http://www.beyondaids.blogspot.com/2012_07_01_archive.html
• Toxicity and cost of treatment justified for persons who
are actually infected, but more problematic for persons
who might merely be exposed.
– Treatment of a defined population of already-infected
persons should logically be much more cost-effective, and
should have a higher risk-benefit ratio, than treating a
larger, ill-defined population of persons, including many who
will not even become exposed.
• PrEP may be substituted by some people for regular
condom use in spite of counseling (motive for PrEP use)
• Episodic use (effectiveness not studied) can lead to
acquisition and potential drug resistance due to suboptimal two-drug treatment
62
What about vaginal microbicides?
• The Microbicide Pipeline (sources: NIAID, Wikipedia):
– A number of active components, including proteins, small molecule
inhibitors, and natural products that being developed as microbicide
candidates
– Surfactants/Detergents to inactivate virus unfortunately damage
mucosa
• Nonoxynol-9, still on some condoms, should not be used)
• Most promising:
– tenofovir (TDF) 1% gel, 39% effective; CAPRISA 004 was 12th
microbicide-efficacy study completed, and first to demonstrate a
significant reduction in HIV transmission in humans
• But concern about development of drug resistance to a key
“backbone” drug
– ViraGel, a nanoscale dendrimer to bind to virus and prevent entry into
cells, 85% effective in preventing both HIV and HSV in macaque
monkeys; human studies pending
63
History of HIV Vaccine Research: long, slow slog
(NIAID Web site)
2003
•U.S. and Royal Thai governments jointly initiated RV144, a
Phase III trial to evaluate a novel HIV vaccine strategy
commonly referred to as "prime-boost."
•Formation of Global HIV Vaccine Enterprise proposed in
Science
2004
VaxGen candidate failed in Phase III trials.
2009
Results of Phase III Thai Trial (RV144) show vaccine
combination is first to demonstrate modest preventive effect
(31%) in humans. Trial enrolled more than 16,000 volunteers.
Over six months, volunteers received a prime-boost vaccination
including six injections of a vaccine called ALVAC HIV (vCP1521) with
the last two of the six injections being a combination of that vaccine
and another one called AIDSVAX B/E (gp120).
ALVAC‐HIV (vCP1521) consists of a viral vector (inert form of
canarypox) containing genetically engineered versions of three HIV
genes (env, gag and pro). AIDSVAX B/E is composed of genetically
engineered gp120, a protein on the surface of HIV.
2010
•Two potent antibodies that prevent most strains of HIV identified by
the VRC (VRC01 and VRC02).
64
•Establishment of Pox-Protein Public-Private Partnership (P5)
Summary
• Almost all HIV-infected patients should be offered
•
ART, which can benefit them and also serve as the
most effective strategy for preventing transmission
and controlling the epidemic
Current treatment recommendations cover most
aspects of effective care
– 15 recommended and 2 new drug components, and 6
combination pills (5 recommended, 1 new) provide a wide
range of options for once and twice daily dosing
• However, all recommended regimens rely on only 4 NRTI
combinations, only 1 alt.; insufficient data on NRTI-free regimens
– No recent changes in antimicrobial prophylaxis
– Pre-exposure prophylaxis: concerns, limited indications
– Recent modest progress on vaginal microbicides, vaccines
65