Initiation of Antiretroviral Therapy (ART)
Christopher Behrens, MDNorthwest AIDS Education &
Training CenterUniversity 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?
CD4 cell count
4-8 Weeks Up to 12 Years 2-3 Years
CD
4 C
ell C
oun
t (c
ells
/mm
³)
1,000
500
Asymptomatic HIV Infection AIDS
Acute Infection
HIV Infection is characterized by a steady decline in the number of CD4 cells
Time
200
high risk of opportunistic infections
mm³
Mellors et al. Ann Intern Med 1997;126:946.
(cells/mm³)
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
Egger et al. Lancet 2002; 360:119-30.
Years from starting HAART
Findings: effects of clinical stage on clinical progression
Egger et al. Lancet 2002; 360:119-30.
Years after starting HAART
Findings: effect of baseline HIV Viral Load on response to ART
Egger et al. Lancet 2002; 360:119-30.
Years from starting HAART
• 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
Cohort studies: conclusions
1. Chen RY et al. 8th CROI, Chicago 20012. Hogg RS et al. JAMA. 2001;286:2568-2577
3. Sterling et al, 9th CROI, Seattle 20024. 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 PI-based 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 TuOrB11892. Arribas JR et al. AIDS 2002;16(11):1554-6.3. Walmsley S et al. NEJM 2002 346(26):2039-46.
1
10
100
1,000
10,000
100,000
1,000,000
10,000,000
Pla
sma
HIV
RN
A
Plasma RNA Copies
CD4 Cells
4-8 Weeks Up to 12 Years 2-3 Years
CD
4 Cell C
ount
1,000
500
Intermediate Stage AIDS
Primary Infection
Sero-conversion
CD4 Count, Viral Load, and Clinical Course
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
but < 350 Any value Treatment should be offered
following full discussion of pros and cons with each patient
Asymptomatic > 350/mm3 > 100,000 copies/mL
Most clinicians recommend deferring therapy, but some would treat
Asymptomatic > 350/mm3 < 100,000 copies/mL
Defer therapy
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, October 6, 2005.
When Should ART be Initiated? IAS-USA 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– 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
• Once-daily dosing• 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
Little SJ, Holte S, Routy JP, et al. N Engl J Med. 2002;347:385-94
Recently Infected, ART Naïve, United States
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
•Suboptimal suppression of viral load (VL) after initiation of ART
•Acute (primary) HIV infection
•Chronic HIV infection before starting ART
Determine role of resistance in drug failure and maximize the number of active drugs in the new regimen
Determine the role of resistance in drug failure and maximize the number of active drugs in the new regimen
Determine if resistant virus was transmitted; select regimen accordingly
Assays may not detect minor resistant species, but some 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.
• Which of the following factors in her situation suggests that adherence may be problematic for her?
A. her depressionB. she is already symptomatic with HIV infectionC. her age (less than 30 years old)D. 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. her depressionB. she is already symptomatic with HIV infectionC. her age (less than 30 years old)D. all of the above factors are associated with
reduced adherence to antiretrovirals.
Adherence
Adherence
“Drugs don’t work if people don’t take them.”
- C. Everett Koop
0
20
40
60
80
100
>95 90-95 80–90 70-80 <70
Pat
ient
s w
ith
HIV
RN
A<
400
cop
ies/
mL
, %
PI adherence, % (electronic bottle caps)
Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.
Virologic Control falls sharply with diminished adherence
Self-Adminstered vs Directly Observed Therapy During Incarceration
0
102030405060708090
100
% w
ith
VL
< 5
0 co
pies
/mL
w4 w8 w16 w24 w48 w64 w72 w80 w88
DOT <50
SAT <50
Fischl et al 8th CROI, 2001 abstract 528
p < 0.01
N = 50 in each group
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. 4. Stone VE, et al. JAIDS 2001; 28:124-131
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. 95%
B. 85%
C. 75%
D. Not much better than flipping a coin
Clinicians’ Estimates of Adherence Not Much Better Than Random
Bangsberg 2001 JAIDS ARTPaterson 2000 Annals Int Med ARTHaubrich1999 AIDS ARTSteiner 1995 Arch Int Med AZTBosely 1995 Eur Resp J Inhaled terbutalineCharney 1967 Pediatrics PenicillinCaron 1978 Clin Pharmacol AntacidsGilbert 1980 Can Med Assoc J DigoxinBlowey 1997 Ped Nephrology CyclosporinMushlin 1977 Arch Int Med 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
RNA DNA
HIV
Nucleus
Host Cell
Nucleoside Analogues (NRTIs)
Non-Nucleosides (NNRTIs) Protease Inhibitors (PIs)
Reverse Transcriptase
Fusion Inhibitors
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
Time after dose (hours)
0 2 4 6 8 10 12100
1,000
10,000
An Example of Ritonavir Boosting:Indinavir/Ritonavir BID PK Study
IDV/RTV q12h:
800/200 High-fat Meal
800/100 High-fat Meal 400/400 High-fat Meal
IDV q8h: 800 mg Fasted
IndinavirPlasma
Concentration(nM)
6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.
Preferred Initial ART Regimens:DHHS Guidelines
• NNRTI-based:
• PI-based:
Efavirenz*+
3TC or FTC+
AZT or tenofovir
Lopinavir/ritonavir (Kaletra)+
3TC or FTC+
AZT
* except during first trimester of pregnancy or women with high pregnancy potential
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, October 6, 2005.
• 2 pills once daily• Not associated with
dyslipidemia1 and hyperglycemia2, unlike other PIs
• Case reports of reversal of lipodystrophy when PI switched to ATV
Atazanavir: favorable dosing and toxicity profile
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
• N=810 treatment-naïve 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
0
10
20
30
40
50
60
70
80
90
100
4 8 12 16 24 32 40 48
Efavirenz Atazanavir
Line 4
Week
Squires KE et al. 42nd ICAAC, September 2002. Abstract 1076.
% R
espo
nder
s VL <400 copies/mL
VL <50 copies/mL
p = NS
Initial ART: Practice
• NNRTI-based:
• PI-based:
efavirenz+
3TC or FTC+
AZT or tenofovir
lopinavir/ritonavir (Kaletra) or atazanavir/ritonavir
+3TC or FTC
+AZT or tenofovir
* except during first trimester of pregnancy or women with high pregnancy potential
Initial ART: Practice
Anchor Drug NRTI backbone Dosing Daily pill burden
Efavirenz AZT + 3TC bid 3
TDF + FTC qd 2
Lopinavir/ ritonavir
AZT + 3TC bid 6
TDF + FTC bid 5
Atazanavir/ ritonavir
AZT + 3TC bid 5
TDF + FTC qd 4
Initial HAART: Future?
Anchor Drug NRTI backbone Dosing Daily pill burden
Efavirenz
AZT + 3TC bid 3
TDF + FTC qd 2
ABC + 3TC qd 2
Lopinavir/ ritonavir
AZT + 3TC bid 6
TDF + FTC bid 5
ABC + 3TC bid 5
Atazanavir/ ritonavir
AZT + 3TC bid 5
TDF + FTC qd 4
ABC + 3TC qd 4
ABC hypersensitivity may be more severe with qd versus bid dosing
• 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
9%
5%
2%
7%
2%
0%0%
2%
4%
6%
8%
10%
hyper-sensitivity
severehyper-
sensitivity
severediarrhea
ABC 600mg qd
ABC 300mg bid
% o
f pa
tien
t wit
h re
acti
on
Epzicom package labeling, August 2004
Which ART regimen performs best in clinical trials?
Results from Comparable Trials:ITT analysis of VL <400 c/mL at Week 48
Based on: Bartlett. Presented at: 7th CROI; 2000; San Francisco, Calif. Poster 519.
d4T + 3TC + LPV/RTV (M98-863)
Reg
imen
(tr
ial)
d4T + 3TC + EFV (GS-903)
TDF + 3TC + EFV (GS-903)
0 10 20 30 40 50 60 70 80 90 100
AZT + 3TC + EFV (AI424-034)
AZT + 3TC + IDV (DMP-006)
AZT + 3TC + ABC (CNA3005)d4T + ddI + IDV (START II)
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)
AZT + 3TC + ABC (CNAB3003)
d4T + ddI + IDV (Atlantic)
AZT + 3TC + EFV (DMP-006)
TDF + 3TC + EFV (GS-903)
d4T + 3TC + NFV (M98-863)
% with HIV RNA<50 copies/mL
at 48 Weeks (ITT)
AZT + 3TC + ATV (AI424-034)
d4T + 3TC + EFV (GS-903)
AZT + 3TC + EFV (EPV20001)
AZT + 3TC + IDV (START II)
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
10
100
1000
10000
100000
1000000
0 1 2 3 4 5 6 7 8
Viral Load
ART Initiated
50 50
Time (months)
CD
4 co
unt (
cell
s/m
m3 )
Vir
al L
oad
(cop
ies/
mL
)
10
100
1000
10000
100000
1000000
0 1 2 3 4 5 6 7 8
0
50
100
150
200
Viral Load
CD4 Count
ART Initiated
50 50
Time (months)
CD
4 co
unt (
cell
s/m
m3 )
Vir
al L
oad
(cop
ies/
mL
)
Antiretroviral Therapy: Optimal Response
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
IRD Clinical Manifestations Onset Typical Course
MAC Lymphadenitis, high fever, infiltrates on chest x-ray
1 - 12 wk
Resolves with continued ART and anti-MAC therapy; may require corticosteroid therapy
CMV Retinitis and vitreitis 1 - 2 mo Resolves with continued ART and anti-CMV therapy
Uveitis 2 mo - 2y
Macular edema, epiretinal membrane formation, cataracts
Herpeszoster
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.
Clinical Presentation & Course of Common Immune Reconstitution Syndromes
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
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