Download Initiation of Antiretroviral Therapy (ART)

Initiation of Antiretroviral Therapy
(ART)
Christopher Behrens, MD
Northwest AIDS Education &
Training Center
University of Washington
When Should Patients with HIV be
Treated with ART?
• Benefits
– reduced morbidity &
mortality
– immune system recovery
• Drawbacks
– toxicities
– lifestyle changes
– potential for developing
resistance
Initiation of Antiretroviral Therapy:
Key Considerations
• Symptoms & Opportunistic Infections
• CD4 count
• Viral Load
• Anticipated Adherence - patient ‘readiness’
Initiation of ART: Case
 A 29-year old woman comes to the clinic for routine
HIV care; she has been HIV-infected for about 4 years,
and has never received antiretroviral treatment. Her
most recent CD4 count is 330 cells/mm³ and her viral
load is 88,000 copies/mL.
 Would you suggest she start antiretroviral therapy?
What does a CD4 count of 330
cells/mm³ mean?
HIV Infection is characterized by a steady
decline in the number of CD4 cells
CD4 Cell Count (cells/mm³)
Acute
Infection
Asymptomatic HIV Infection
AIDS
1,000
CD4 cell count
500
200
high risk of opportunistic infections
4-8 Weeks
Up to 12 Years
Time
2-3 Years
mm³
(cells/mm³)
Mellors et al. Ann Intern Med 1997;126:946.
When Should ART be Initiated?
An analysis of prospective studies
• 13 cohort studies from Europe & North America
• 12,574 patients initiating ART
–
–
–
–
–
Median age 38; mostly men
Median baseline CD4 count 250; VL 74,000
Median month of ART initiation: 12/1997
Mostly PI-based regimens
24,310 person-years of followup
Egger et al. Lancet 2002; 360:119-30.
Analysis of 13 cohort studies: effect of baseline
CD4 count on response to initial ART
Years from starting HAART
Egger et al. Lancet 2002; 360:119-30.
Findings: effects of clinical stage on
clinical progression
Years after starting HAART
Egger et al. Lancet 2002; 360:119-30.
Findings: effect of baseline HIV Viral
Load on response to ART
Years from starting HAART
Egger et al. Lancet 2002; 360:119-30.
Cohort studies: conclusions
• Initiation of ART after HIV-related symptoms had
developed was associated with a less durable
response to ART
• For the asymptomatic patient, CD4 count at initiation
of ART carried strongest prognostic significance,
corroborating findings from other studies1-4
• Age, infection via IDU, history of AIDS-related
illness also appeared to affect durability of clinical
response to ART
1. Chen RY et al. 8th CROI, Chicago 2001
2. Hogg RS et al. JAMA. 2001;286:2568-2577
3. Sterling et al, 9th CROI, Seattle 2002
4. Palella et al, 9th CROI, Seattle 2002
Caveats
• High VL (>100,000 copies/mL) also carried
prognostic significance, but
– few patients initiated on efavirenz or ritonavir-boosted
regimens
– other recent studies have not demonstrated a clear
correlation between baseline viral load and efficacy of
ART1,2
• Observational study: other potential confounding
factors (e.g., adherence, hemoglobin) could have
affected results
1. Philips AN et al. JAMA 2001;286:2560-2567.
2. Hogg RS et al. JAMA 2001;286:2568-2577.
Implications for Clinical Practice
• Ideally, initiate ART before CD4 count drops below
200 cells/mm³ and before clinical symptoms develop
• A benefit for treatment before CD4 count falls below
350 may exist, but the small risk of clinical
progression if therapy is deferred must be balanced
against drawbacks of ART
• If CD4 already less than 200 or clinical progression
has occurred, ART is clearly indicated as soon as
patient is ready to start
Implications for Clinical Practice:
Significance of Baseline Viral Load
• Initiation of ART before VL >100,000 copies/mL may
allow for more therapeutic options and greater
clinical success
• However, highly potent efavirenz- or boosted PIbased regimens may be equally effective in patients
with high baseline viral loads1-3
• VL is a marker for rate of CD4 decline: more
frequent monitoring in patients with high VL?
1. XIV International AIDS Conference, July 2002. Abstract TuOrB1189
2. Arribas JR et al. AIDS 2002;16(11):1554-6.
3. Walmsley S et al. NEJM 2002 346(26):2039-46.
CD4 Count, Viral Load, and Clinical Course
Primary
Infection
Seroconversion
10,000,000
AIDS
Plasma HIV RNA
1,000,000
100,000
10,000
Plasma RNA Copies
1,000
CD4 Cell Count
Intermediate Stage
1,000
CD4 Cells
100
500
10
1
4-8 Weeks
Up to 12 Years
2-3 Years
When Should ART be Initiated?
DHHS Guidelines
Clinical Category
CD4 count Viral Load
Recommendation
Symptomatic (AIDS,
severe Sx)
Any value
Any value
Treat
Asymptomatic, AIDS
< 200/mm3 Any value
Treat
Asymptomatic
> 200/mm3 Any value
but < 350
Asymptomatic
> 350/mm3 > 100,000
copies/mL
Asymptomatic
> 350/mm3 < 100,000
copies/mL
Treatment should be offered
following full discussion of pros
and cons with each patient
Most clinicians recommend
deferring therapy, but some
would treat
Defer therapy
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and
Adolescents, October 6, 2005.
When Should ART be Initiated? IASUSA Guidelines
Yeni et al. JAMA. 2004;292:251-265.
Recent Advances in Antiretroviral
Therapy
incremental gains in convenience,
tolerability, and insights into toxicity have
added up to significant improvements in
management of HIV disease
Advances in Antiretroviral Therapy:
Easier Regimens
• Lower pill burden
• Once-daily dosing
– Fixed dose combinations
•
•
•
•
TDF/FTC (Truvada)
ABC/3TC (Epzicom)
AZT/3TC (Combivir)
AZT3TC/ABC (Trizivir)
– Fewer pills for same effect
•
•
•
•
•
efavirenz
nelfinavir
fosamprenavir
lopinavir/ritonavir
saquinavir
•
•
•
•
•
•
•
•
•
tenofovir
3TC, FTC
abacavir
ddI
efavirenz
atazanavir
fosamprenavir (w/ ritonavir)
saquinavir (w/ ritonavir)
lopinavir/ritonavir
• Fewer food restrictions with newer agents and with
ritonavir boosting of protease inhibitors
Advances in Antiretroviral Therapy:
Improvements in Toxicity
• New drugs with less toxicity
– Tenofovir: no dyslipidemia compared with d4T
– Atazanavir: no dyslipidemia compared with other PIs
• Improved Understanding of Toxicities
– Nevirapine toxicity: identification of high-risk groups
• women CD4 >250 cells/mm³
• men CD4 >400 cells/mm³
– Mitochondrial toxicity as basis for many long-term
toxicities
– Clarification of which NRTIs are most likely to cause
mitochondrial toxicity (d4T, ddI, ddC)
– Partial clarification of lipodystrophy
Timing of Initiation of
ART
Is the Pendulum
Swinging Back to
Earlier Treatment?
Before you start…
Resistance Testing
Adherence Issues
Resistance in treatment-naïve
individuals is becoming more common
Recently Infected, ART Naïve, United States
Little SJ, Holte S, Routy JP, et al. N Engl J Med. 2002;347:385-94
Persistence of Resistant Strains
Following Primary HIV Infection
•
11 subjects with primary HIV infection who deferred ART and who had at least
one major drug resistance mutation identified at presentation, followed with serial
resistance assays.
–
–
–
–
7 subjects with NNRTI resistance
2 with NRTI and PI resistance
1 with NNRTI and PI resistance
1 with resistance to all three classes of drugs
• NNRTI resistance was lost slowly: the average time to reversion of 103N
variants to mixed 103N/K populations was 196 days following the estimated date
of infection (153 to 238 days, 95%CI).
• PI resistance was not lost at all: In the 4 patients with protease resistance
mutations, no reversion was detected at 64, 191, 327, and 342 days after infection.
• Complete reversion of genotypic resistance was observed in only one
patient, at 1019 days after infection.
Little SJ. 11th CROI, February 2004, Abstract 36LB
Antiretroviral Resistance Testing: Guidelines
for Implementation
Clinical Setting/
Recommendation
Rationale
Recommended:
•Virologic failure during ART
Determine role of resistance in drug failure and maximize
the number of active drugs in the new regimen
•Suboptimal suppression of viral load Determine the role of resistance in drug failure and
maximize the number of active drugs in the new regimen
(VL) after initiation of ART
Determine if resistant virus was transmitted; select
•Acute (primary) HIV infection
regimen accordingly
•Chronic HIV infection before
Assays may not detect minor resistant species, but some
starting ART
resistance mutations may persist for years. Consider
testing early after diagnosis of HIV infection.
Usually not recommended:
•After discontinuation of drugs
•Plasma VL <1,000 copies/mL
Resistance mutations may become minor species in the
absence of selective drug pressure
Resistance assays unreliable if VL is low
Adapted from DHHS, Antiretroviral Guidelines, October 6, 2005
Initiation of Antiretroviral Therapy:
Key Considerations
• Symptoms & Opportunistic Infections
• CD4 count
• Viral Load
• Anticipated Adherence - patient ‘readiness’
Adherence: Case 1
• A 23 year old single woman with HIV infection
diagnosed two years ago.
• No history of antiretroviral therapy.
• Current CD4 count is 230 cells/mm³.
• Her physical exam is remarkable only for oral
candidiasis (thrush).
• Review of her past medical history includes
depression, which she admits has been worse lately.
• Current medications include nortriptyline and oral
contraceptives.
Adherence
•
Which of the following factors in her
situation suggests that adherence may be
problematic for her?
A.
B.
C.
D.
her depression
she is already symptomatic with HIV infection
her age (less than 30 years old)
all of the above factors are associated with
reduced adherence to antiretrovirals.
Adherence
•
Which of the following factors in her
situation suggests that adherence may be
problematic for her?
A.
B.
C.
D.
her depression
she is already symptomatic with HIV infection
her age (less than 30 years old)
all of the above factors are associated with
reduced adherence to antiretrovirals.
Adherence
“Drugs don’t work if people don’t
take them.”
- C. Everett Koop
Virologic Control falls sharply with
diminished adherence
Patients with HIV RNA
<400 copies/mL, %
100
80
60
40
20
0
>95
90-95
80–90
70-80
<70
PI adherence, % (electronic bottle caps)
Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.
Self-Adminstered vs Directly Observed
Therapy During Incarceration
% with VL < 50 copies/mL
N = 50 in each group
100
90
80
70
60
50
40
30
20
10
0
DOT <50
SAT <50
w4
w8
w16
w24
w48
w64
w72
w80
w88
p < 0.01
Fischl et al 8th CROI, 2001 abstract 528
Predictors of Poor Adherence
•
•
•
•
•
•
•
active alcohol1 or substance2 abuse
work outside the home for pay1
depressed mood1
lack of perceived efficacy of ART3
lack of advanced disease4
concern over side effects4
regimen complexity5
1. Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281.
2. Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407.
3. Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588.
4. Wenger N, et al. 6th CROI, 1999, Abstract 98.
5. Stone VE, et al. JAIDS 2001; 28:124-131
Factors Associated with Higher
Levels of Adherence
•
•
•
•
•
twice-daily or once-daily regimens1,4
belief in own ability to adhere to regimen1
not living alone2
dependent on a significant other for support2
history of opportunistic infection or advanced
HIV disease3
1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125.
2. Morse EV et al, Soc Sci Med 1991;32:1161-1167.
3. Singh N, et al, AIDS Care 1996;8:261-269.
Factors Associated with Higher
Levels of Adherence
• Belief in efficacy of antiretroviral therapy
• Belief that non-adherence will lead to viral
resistance
Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.
How good are clinicians at predicting
their patients’ adherence?
A.
B.
C.
D.
95%
85%
75%
Not much better than flipping a coin
Clinicians’ Estimates of Adherence
Not Much Better Than Random
Bangsberg
Paterson
Haubrich
Steiner
Bosely
Charney
Caron
Gilbert
Blowey
Mushlin
2001
2000
1999
1995
1995
1967
1978
1980
1997
1977
JAIDS
Annals Int Med
AIDS
Arch Int Med
Eur Resp J
Pediatrics
Clin Pharmacol
Can Med Assoc J
Ped Nephrology
Arch Int Med
ART
ART
ART
AZT
Inhaled terbutaline
Penicillin
Antacids
Digoxin
Cyclosporin
Hypertensive
Improving Adherence:
Before Initiation of Therapy
 Assess patient's understanding and acceptance
of the regimen: negotiated plan
 Investigate and manage medical barriers to
adherence
• Try to use simple regimens
– Twice-daily or better
– Without food requirements if possible
Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.
Improving Adherence: After
Initiation of Therapy
• Close follow-up
• Ask patient to verbalize treatment regimen
• Education about adherence
• Consider cues, alarms to remind patients of
dosing
• Referral to community support groups
• Involve other members of the health care team
Back to Case 1
• You confirm her viral load and CD4 count; she
keeps her follow-up appointments and appears
to understand the importance of adherence.
You start her on an antidepressant medication
and refer her for counseling. 3 months later
her depression is significantly improved and
she feels ready to initiate ART.
• What regimen would you recommend?
Selecting the Initial ART Regimen
Combination Antiretroviral
Therapy (ART)
• Combination of at least 3 drugs, usually:
– 2 NRTIs (the “NRTI backbone”), plus:
– 1 NNRTI or 1-2 PIs
• Therapy with only one or two agents allows
HIV to overcome therapy through resistance
mutations
HIV Life Cycle and Classes of ARVs
HIV
Nucleoside Analogues (NRTIs)
Reverse Transcriptase
RNA
DNA
Nucleus
Fusion Inhibitors
Host Cell
Non-Nucleosides (NNRTIs)
Protease Inhibitors (PIs)
FDA-Approved ARVS: NRTIs
FDA-Approved ARVS: NNRTIs and PIs
FDA-Approved ARVS: PIs (cont.) and
Fusion Inhibitor
Ritonavir intensification of other
Protease Inhibitors (PIs)
• PIs, like many medications, are metabolized in the
liver by the cytochrome P450 enzyme complex
• Ritonavir inhibits this complex, thereby boosting
serum levels of co-administered PIs
• Low doses of ritonavir can be used to increase the
potency and simplify the dosing of PI-based regimens
An Example of Ritonavir Boosting:
Indinavir/Ritonavir BID PK Study
10,000
IDV/RTV q12h:
800/200 High-fat Meal
Indinavir
Plasma
Concentration
(nM)
800/100 High-fat Meal
1,000
400/400 High-fat Meal
IDV q8h:
800 mg Fasted
100
0
2
4
6
8
Time after dose (hours)
10
12
6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.
Preferred Initial ART Regimens:
DHHS Guidelines
• NNRTI-based:
Efavirenz*
+
3TC or FTC
+
AZT or tenofovir
* except during first trimester of pregnancy or women with high pregnancy potential
• PI-based:
Lopinavir/ritonavir (Kaletra)
+
3TC or FTC
+
AZT
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents,
October 6, 2005.
Atazanavir: favorable dosing and
toxicity profile
• 2 pills once daily
• Not associated with
dyslipidemia1 and
hyperglycemia2,
unlike other PIs
• Case reports of
reversal of
lipodystrophy when
PI switched to ATV
1. Piliero P et al. 9th CROI, Seattle, February 2002. Abstract 706-T.
2. Sension M et al, 4th Intl Lipodystrophy Workshop, San Diego, 2002. Abstract 36.
AI424-034: Atazanavir vs Efavirenz
100
90
% Responders
• N=810 treatmentnaïve patients
randomized to
AZT/3TC plus
either efavirenz or
atazanavir
• Mean baseline viral
load 4.85 log
copies/mL
• Mean baseline CD4
count 320 cells/mm³
80
Efavirenz
Atazanavir
70
Line 4
VL <400 copies/mL
60
50
p = NS
40
30
VL <50 copies/mL
20
10
0
4
8
12
16
24
32
Week
Squires KE et al. 42nd ICAAC, September 2002. Abstract 1076.
40
48
Initial ART: Practice
• NNRTI-based:
efavirenz
+
3TC or FTC
+
AZT or tenofovir
* except during first trimester of pregnancy or women with high pregnancy potential
• PI-based:
lopinavir/ritonavir (Kaletra)
or atazanavir/ritonavir
+
3TC or FTC
+
AZT or tenofovir
Initial ART: Practice
Anchor Drug
NRTI backbone
Dosing
Daily pill burden
Efavirenz
AZT + 3TC
bid
3
TDF + FTC
qd
2
AZT + 3TC
bid
6
TDF + FTC
bid
5
AZT + 3TC
bid
5
TDF + FTC
qd
4
Lopinavir/
ritonavir
Atazanavir/
ritonavir
Initial HAART: Future?
Anchor Drug
Efavirenz
Lopinavir/
ritonavir
Atazanavir/
ritonavir
NRTI backbone
Dosing
Daily pill burden
AZT + 3TC
bid
3
TDF + FTC
qd
2
ABC + 3TC
qd
2
AZT + 3TC
bid
6
TDF + FTC
bid
5
ABC + 3TC
bid
5
AZT + 3TC
bid
5
TDF + FTC
qd
4
ABC + 3TC
qd
4
ABC hypersensitivity may be more
severe with qd versus bid dosing
10%
% of patient with reaction
• CNA30021: n = 770
treatment naïve patients
randomized to ABC
300mg bid versus ABC
600mg qd
• Combined with 3TC
plus efavirenz (each
once daily)
• Equivalent treatment
efficacy
• ? More severe
hypersensitivity with qd
dosing
8%
9%
ABC 600mg qd
ABC 300mg bid
7%
6%
5%
4%
2%
2%
2%
0%
0%
hypersensitivity
Epzicom package labeling, August 2004
severe
hypersensitivity
severe
diarrhea
Which ART regimen performs
best in clinical trials?
Regimen (trial)
Results from Comparable Trials:
ITT analysis of VL <400 c/mL at Week 48
AZT + 3TC + IDV (START II)
AZT + 3TC + ATV (AI424-034)
AZT + 3TC + EFV (AI424-034)
AZT + 3TC + ABC (CNA3005)
d4T + ddI + IDV (START II)
AZT + 3TC + IDV (DMP-006)
AZT + 3TC + IDV (AVANTI 2)
AZT + ddI + NVP (INCAS)
AZT + 3TC + NFV (AVANTI 3)
AZT + 3TC + IDV (CNA3005)
AZT + 3TC + IDV (START I)
d4T + ddI + 3TC (Atlantic)
d4T + 3TC + IDV (START I)
d4T + ddI + NVP (Atlantic)
2 NRTIs + SQV-SGC (NV-15355)
d4T + 3TC + NFV (M98-863)
AZT + 3TC + ABC (CNAB3003)
d4T + ddI + IDV (Atlantic)
AZT + 3TC + EFV (EPV20001)
AZT + 3TC + EFV (DMP-006)
% with HIV RNA
<50 copies/mL
at 48 Weeks (ITT)
d4T + 3TC + LPV/RTV (M98-863)
d4T + 3TC + EFV (GS-903)
TDF + 3TC + EFV (GS-903)
d4T + 3TC + EFV (GS-903)
TDF + 3TC + EFV (GS-903)
0
10
20
30
40
50
Based on: Bartlett. Presented at: 7th CROI; 2000; San Francisco, Calif. Poster 519.
60
70
80
90
100
Selection of the Initial ART regimen:
Summary
• Regimen potency
• Patients’ preference regarding pill burden, dosing
frequency, and food and fluid considerations
• Potential adverse effects
• Baseline antiretroviral resistance profile
• Co-morbidity or conditions such as tuberculosis, liver
disease, depression or mental illness, cardiovascular
disease, chemical dependency, pregnancy, and family
planning status
• Potential drug interactions with other medications
DHHS Antiretroviral Therapy Guidelines, July 2003, p. 14.
Case 1, continued
 You decide to start her on AZT (zidovudine) plus 3TC
(lamivudine) plus efavirenz.
 What are your goals of therapy?
 What follow up labs do you arrange, and when?
Antiretroviral Therapy: Optimal Response
ART Initiated
CD4 count (cells/mm3)
Viral Load (copies/mL)
1000000
Viral Load
100000
10000
1000
100
50
50
10
0
1
2
3
Time (months)
4
5
6
7
8
Antiretroviral Therapy: Optimal Response
ART Initiated
200
Viral Load
100000
CD4 Count
150
10000
100
1000
50
100
50
50
10
0
0
1
2
3
4
Time (months)
5
6
7
8
CD4 count (cells/mm3)
Viral Load (copies/mL)
1000000
Follow-up Laboratory Testing
• Viral load & CD4 counts, initially once
monthly after starting therapy; can space out to
every 3 months if doing well
• Goals are undetectable viral load (<50 or 75
copies/mL) and rise in CD4 count
• CBC, electrolytes, LFTs at regular intervals to
monitor for toxicity, also when signs or
symptoms develop
Case 2
• A 33 year old woman with a CD4 count of 30
cells/mm³ initiates antiretroviral therapy with a
regimen of AZT + 3TC + nevirapine (NVP)
• Initially she feels better, but 3 weeks later she
returns complaining of fevers, night sweats, and
swollen lymph nodes
• Physical examination is remarkable for:
– Fever of 38.7 C
– Bilateral axillary enlarged, tender lymph nodes
– Weight 120 lbs (unchanged from when she initiated ART)
What is likely responsible for her
symptoms?
A. She is having a toxic reaction to her ART
medications
B. Her ART regimen is not working, as evidenced by
development of a new opportunistic infection
C. Her ART regimen is working so well that her newly
strengthened immune system is reacting against a
previously unrecognized infection
D. I have no idea what is going on with her
Case continued
•
You order diagnostic tests including blood
cultures and a biopsy and culture of her
enlarged lymph nodes
Gram stain of lymph node: acid-fast bacilli in macrophages.
www.med.sc.edu:85/fox/mycobacteria.htm
Immune Reconstitution Syndrome
• Reflects newly invigorated immune system mounting
an inflammatory response against an infection that
was previously clinically silent in the face of severe
immunodeficiency
• Common among patients with robust rise in CD4
count (e.g., over 100 cells/mm³) in the first several
weeks following initiation of ART
• Typically managed by continuing ART and
administering anti-inflammatory medications to
control symptoms, such as NSAIDS and/or steroids
• Occasionally discontinuation of antiretrovirals is
necessary
Clinical Presentation & Course of Common
Immune Reconstitution Syndromes
IRD
Clinical Manifestations
Onset
Typical Course
MAC
Lymphadenitis, high fever, infiltrates
on chest x-ray
1 - 12 wk
Resolves with continued ART and antiMAC therapy; may require
corticosteroid therapy
CMV
Retinitis and vitreitis
1 - 2 mo
Resolves with continued ART and antiCMV therapy
Uveitis
2 mo - 2y
Macular edema, epiretinal membrane
formation, cataracts
Herpes
zoster
Localized
1 - 4 mo
Resolves with acyclovir therapy
TB
Fever, worsening infiltrates/effusion
on chest film, mediastinal and
peripheral lymphadenopathy
1 - 6 wk
Resolves with continued ART and
antituberculous therapy; may require
corticosteroid therapy
Cryptococcal
meningitis
New headache, meningismus,
increased number of white
blood cells in cerebrospinal fluid
1 wk - 8
mo
Resolves with continued ART and
antifungal therapy
IRD, immune restoration disease; MAC, Mycobacterium
avium complex; CMV, cytomegalovirus.
Qazi NA et al. AIDS Reader 12(10):452-457, 2002.
Initial Antiretroviral Therapy:
Summary
• ART has made HIV a treatable and manageable chronic
disease for many patients
• ART consists of at least 3 drugs, generally from 2 or more
classes
• When to initiate therapy remains controversial, but
probably best to start before CD4 falls below 200
cells/mm³
• Consider adherence and baseline viral load when
designing initial regimen
• Goal is undetectable viral load (<50 copies/mL) and rise
in CD4 count
• Monitor closely after initiation of therapy