Transcript Plasma HIV RNA

Update of Antiretroviral Agents in
Adults and Adolescents 2008
NOV 17, 2008
Management of HIV/AIDS (1)

During past 27 years, HIV/AIDS has
been transformed from
almost fatal disease
manageable disease
by Antiretroviral Therapy (ART) (12 years)
and Optimal Rx of HIV-related
Opportunistic Infections and Malignancies
HIV/AIDS 27 years
Management of HIV/AIDS (2)

Optimal ART can provide
-durable virologic, immunologic and clinical benefits
-minimal toxicities and drug resistance
-potentially normal life span
Recent Issues Influencing
ART in HIV/AIDS 2008

Recent approval of 3 novel ARVs
- CC chemokine receptor antagonist
: Maraviroc (CCR5 antagonist)
- Integrase strand transfer inhibitor
: Raltegravir
- 2nd generation NNRTI
: Etravirine
Recent Issues Influencing
ART in HIV/AIDS 2008



Recent approval of 3 novel ARVs
New data that better inform the choice of
ARV for initial Rx and Mx of treatment failure
New pathogenetic insights into the role of
HIV in previously considered non-AIDS
related conditions
Goals of ART

Eradication of HIV?
Not possible with currently
available ARV medications
What do we need to do to cure
HIV infection?
• Stop ongoing viral
replication
• Identify all stable
reservoirs
• Find a way to
eliminate each one
Viral dynamics in pts on HAART
Start HAART
1000000
100000
10000
1000
100
10
1
0.1
0.01
0.001
t1/2 < 1 day
t1/2 ~ 14 days
Limit of
Detection
(50 copies/ml)
0
Eradication in
2 to 3 years
100
200
Time on HAART (days)
300
Viral dynamics in pts on HAART
Below limit of detection
Start HAART
1000000
100000
10000
1000
100
10
1
0.1
0.01
0.001
t1/2 < 1 day
t1/2 ~ 14 days
Limit of
Detection
(50 copies/ml)
0
100
200
Time on HAART (days)
300
Slow decay of latently infected
CD4+ T cells
Frequency
(per 106 cells)
10000
Time to eradication
> 73.4 years
1000
100
10
1
-
0.1
0.01
0.001
0.0001
0.00001
0
1
2
3
4
5
6
7
Time on HAART (years)
Chun et al., Nature Med., 1995
Chun et al., Nature, 1997
Finzi et al., Science, 1997
Wong et al. Science, 1997
Chun et al., PNAS, 1997
Finzi et al., Nature Med., 1999
Siliciano et al., Nature Med., 2003
•HAART reduces viremia to below 50 copies/ml
HAART
< 50 copies/ml
•HIV persists in a reservoir in resting T cells
Ag
†
•Patients on HAART have residual viremia
HAART
< 50 copies/ml
Dornadula et al., JAMA, 1999
Palmer et al., PNAS, 2008
1000000
100000
10000
1000
100
10
1
0.1
0.01
0.001
Start
HAART
Limit of
Detection
(50 c/ml)
Release from stable reservoirs
0
1
2
Time on HAART (years)
3
ART Goals & Tools to Achieve Them
Goals







Maximal and durable
suppression of HIV-RNA
Restore CD4 number and
function
Reduce inflammation and
immune activation
Normalize survival
Improve QOL
Prevention of vertical
transmission
Prevention of transmission
to sexual partners
ART Goals & Tools to Achieve Them
Goals

Maximal and durable
suppression of HIV-RNA
ART Goals & Tools to Achieve Them
Goals


Maximal and durable
suppression of HIV-RNA
Restore CD4 number and
function
ART Goals & Tools to Achieve Them
Goals



Maximal and durable
suppression of HIV-RNA
Restore CD4 number and
function
Reduce inflammation and
immune activation
SMART: Inflammatory Markers Strongly
Associated With Mortality and CVD Events
Biomaker
All-Cause Mortality
(N=85)
Fatal or Nonfatal CVD
(N=136)
OR
P value
OR
P value
hs-CRP
3.5
0.004
1.6
0.2
IL-6
12.6
<.001
2.8
0.003
Amyloid A
2.3
0.08
1.6
0.12
Amyloid P
1.1
0.09
2.8
0.002
D-dimer
13.3
<.001
2
0.06
F1.2
1.4
0.45
0.8
0.56
ART Goals & Tools to Achieve Them
Goals







Maximal and durable
suppression of HIV-RNA
Restore CD4 number and
function
Reduce inflammation and
immune activation
Normalize survival
Improve QOL
Prevention of vertical
transmission
Prevention of transmission
to sexual partners
Tools





Selection of ARV regimen
Preservation of future
treatment options
Rational sequencing of
therapy
Maximizing adherence
Use of resistance testing
in selected clinical
settings
Before Initiating ART:
Evaluation


Baseline
Complete History and Physical examination
Laboratory testing:









HIV antibody
CD4 cell count
Plasma HIV RNA
Resistance test (genotype)
CBC, chemistry profile, BUN, Cr, transaminase
Fasting glucose and lipids
RPR or VDRL
Hepatitis A, B, C serology
Toxoplasma IgG
Before Initiating ART:
Additional Tests





Tuberculin skin test
Chest X ray (if clinically indicated)
Gynecologic exam with Pap smear
Testing for chlamydia and gonorrhea
Ophthalmology exam
(CD4 cell count <100 cells/µL)
Considerations in Initiating ART (1)





Willingness of patient to begin and the
likelihood of adherence
Degree of immunodeficiency
(CD4 cell count)
Plasma HIV RNA
Risk of disease progression
Potential benefits and risks of therapy
Considerations in Initiating ART (2)


ART should be considered lifelong therapy
Interruption of ART is not recommended,
except for serious toxicities or inability to take
oral medications

Usually causes immediate virologic rebound, with
CD4 decline
Use of CD4 Cell Levels to Guide
Therapy Decisions

CD4 count




The major indicator of immune function
Most recent CD4 count is best predictor of
disease progression
CD4 count usually is the most important
consideration in decision to start ART
Important in determining response to ART


Adequate response: CD4 increase 100-150 cells/µL per
year
CD4 monitoring

Check at baseline (x2) and at least every 3-6
months
Use of HIV RNA Levels to Guide
Therapy Decisions

HIV RNA:


Less important than CD4 count, but may
influence decision to start ART and determine
frequency of CD4 monitoring
Critical in determining response to ART


Goal of ART: HIV RNA below limit of detection
(ie, <40 to <80 copies/mL, depending on assay)
HIV RNA monitoring:



Check at baseline (x2) and at least every 3-4
months in stable patients
Immediately prior to initiating therapy
2-8 weeks after start or change of ART
Testing for Drug Resistance

Before initiation of ART:





Resistance testing (genotype) recommended for all at
entry to care, and for all pregnant women
Transmitted resistance in 6-16% of HIV-infected patients
Identification of resistance mutations may optimize
treatment outcomes
In absence of therapy, resistance mutations may decline
over time and become undetectable by current assays,
but may persist and cause treatment failure when ART is
started
Patients with virologic failure:


Perform while patient is taking ART, or ≤4 weeks after
discontinuing therapy
Interpret in combination with history of ARV exposure
and ARV adherence
CDC Survey: Patterns of
Transmitted Drug Resistance
Any Resistance
NNRTI
NRTI
MDR
PI
Patients with transmitted
resistance (%)
20
15
10.7
8.8
10
7.7
7.1
6.9
5.1
5.5
5
2.1
0.4
0
10.4
0.8 1.3
1.7
3.6
3.0
1.3
2.4 1.9
0 0
1998[1]
(n = 257)
1999[1]
(n = 239)
1. Bennett D, et al. CROI 2002. Abstract 372.
2. Wheeler W, et al. CROI 2007. Abstract 648.
2000[1]
(n = 299)
2003-2006[2]
(n = 3130)
Other Studies: Before
Treatment with Specific ARVs

HLA-B 5701 screening





Recommended before starting abacavir, to reduce risk of
hypersensitivity reaction (HSR)
HLA-B 5701-positive patients should not receive ABC
Positive status should be recorded as an ABC allergy
If HLA-B 5701 testing is not available, ABC may be initiated, after
counseling and with appropriate monitoring for HSR
Coreceptor tropism assay


Should be performed when CCR5 antagonist is being considered*
Consider for patients with virologic failure on a CCR5 antagonist
* Not FDA approved for initial ARV therapy.
Guidelines for initiation of ARV in chronic HIV-1 infection
Disease stage
BHIVA (Jul 03)
IDSA (July 04)
symptomatic
asymptomatic
CD4<200
CD4 200-350
treat
treat
CD4>350
treat
consider therapy
depending on rate
of CD4 decline,
patient’s wishes
and viral load
defer
treat
should be
considered
defer
USDHHS (Oct 04)
treat
treat
should be offered
treatment
defer if VL< 100,000
may consider if
VL>100,000
What is the best time to start ARV? 2008
High viral load >100,000 HIV RNA cop/μL
DHHS guideline for use of ARVs in
HIV-infected adults and adolescents, Jan 2008
Rapid decline in CD4 > 100/ μL
ARV treatment of adult HIV infection 2008 IAS-USA panel.
JAMA 2008;300:555-570
Indications for ART
Treat all:

CD4 counts of 200-350 cells/µL
Risk of AIDS-related events and Non-AIDS-defining conditions
is higher in this range than at >350 cells/µL
Non-AIDS cancer: lung, anal, head and neck, NHL
1,2
End organ damage: CVS 3, hepatic 4, and renal dysfunction 5,6
1
Grulich AE et al. Lancet 2007;370:59
3
Friis-Moller N et al. N Engl J Med 2007;356:1732 4 Weber R.Arch Intern Med 2006;166:1632
5
Gupta SK, et al. CID 2005;40:1559
2
6
Patel P et al. Ann Intern Med 2008;148:728
Choi AI et al. J Am Soc Nephrol 2007;18:2968
WHO Classification of
HIV-Associated Clinical Diseases
WHO ARV Guidelines 2006
WHO Clinical Staging of HIV
Disease in Adults and
Adolescents
WHO ARV Guidelines 2006
WHO Clinical Staging of HIV
Disease in Adults and
Adolescents (cont.)
WHO ARV Guidelines 2006
Major Targets of Antiretroviral Agents
Protease Inhibitors
RT Inhibitors
Integrase Inhibitors
NRTI: AZT, ddI,
RAL
ddC, d4T, 3TC, ABC
NNRTI: NVP, DLV, EFV, ETV
NTRTI: Tenofovir
DNA
1
2
6
ds DNA
Integrase
vpr
HIV
SQV,RTV, IDV, NFV, AMV, LPV/rtv,
TPV, DRV
3
Genomic RNA
Proviral DNA
5
Protease
RT
RNA
Transcription
4
mRNA
Spliced mRNA
Entry Inhibitors
Polyprotein
Protein
CXCR4: AMD3100, T22
CCR5: MVC, SCH-C, D;
TAK779
Fusion gp41: T20
ETV = Etravirine (Intelence )
MVC = Maraviroc (Selzentry )
RAL = Raltegravir (Isentress)
Antiretroviral Drug FDA Approval:
1987 - 2004
LPV/r
ddI-EC
EFV AZT+3TC
ABC +ABC
TDF
20
NFV
DLV
SQV (s)
AZT+3TC
15
ABV+3TC
TDF+FTC
T-20
ATV
FTC
APV
RTV
IDV
NVP
10
3TC
SQV(h)
ddC
5
d4T
ddI
AZT
0
1987
1989
1991
1993
1995
1997
1999
2001
2003
2005
FDA-Approved Antiretroviral Drugs
June 2005 (21 ARVs)
NsRTI
NNRTI
PI
zidovudine (ZDV) nevirapine (NVP)
saquinavir (SQV)
didanosine (ddI)
efavirenz (EFV)
ritonavir (RTV)
zalcitabine (ddC)
delavirdine (DLV)
indinavir (IDV)
stavudine (d4T)
nelfinavir (NFV)
lamivudine (3TC)
lopinavir/r (LPV/r)
abacavir (ABC)
Entry inhibitor
emtricitabine (FTC) enfuvirtide (T20)
NtRTI
tenofovir
atazanavir (ATV)
fosamprenavir
amprenavir (APV)
tipranavir (TPV)
FDA Approved Antiretroviral Drugs
October 2008 (25 ARVs)
FDA Approved Antiretroviral Drugs
Combination Drugs (5 drugs)
October 2008
Combination Drug
Drug component
Date of approval
Atripla
TDF (300)+ FTC(200)
+ EFV (600)
July 12,2006
Epzicom
ABC (600)+3TC (300)
Aug 2,2004
Truvada
TDF (300)+ FTC(200)
Aug 2,2004
Trizivir
ABC (300)+3TC(150)
+ ZDV (300)
Nov 14,2000
Combivir
3TC(150) + ZDV (300)
Sep 27,1997
Combination drugs, Thailand (1)
AZT 300 mg tablet plus
lamivudine 150 mg/tab
ZILAVIR 
Combination drugs, Thailand (2)
Stavudine 30,40 mg
plus lamivudine 150 mg
plus nevirapine 200 mg
GPO-VIR  S 30, S40
.
Combination drugs, Thailand (3)
Zidovudine 250 mg
plus lamivudine 150 mg
plus nevirapine 200 mg
GPO-VIR  Z 250
.
สู ตรยาที่นิยมใช้ 10 อันดับแรกในผูป้ ่ วยที่ติดเชื้อHIV
ในประเทศไทยในโครงการ NAPHA มค. 2550
Components of Initial ART:
DHHS Categories
• Preferred
– Clinical data show optimal efficacy and durability
– Acceptable tolerability and ease of use
• Alternative
– Clinical trial data show efficacy but also show
disadvantages in ARV activity, durability, tolerability,
or ease of use (compared with “preferred”
components)
– May be the best option in select individual patients
• Other possible options
– Inferior efficacy or greater or more serious toxicities
Initial Treatment:
Preferred Components
NNRTI Option
NRTI Options¹
 EFV*
OR
PI Options
 ABC + 3TC²
+
 TDF + FTC³
• ATV + RTV
• FPV + RTV (BID)
• LPV/RTV (BID)
* Avoid
in pregnant women and women with significant pregnancy potential
¹ FTC can be used in place of 3TC and vice versa
² For patients who have tested negative for HLA-B*5701
³ TDF + FTC or 3TC is preferred in patients with HIV/HBV coinfection
Initial Treatment:
Alternative Components (1)
NNRTI Option
• NVP*
PI Options
• ATV¹
• FPV
• FPV + RTV (once daily)
• LPV/RTV (once daily)²
• SQV + RTV
* NVP should not be initiated in women with CD4 counts of >250 cells/µL or men
with CD4 counts of >400 cells/µL
¹ ATV must be boosted with RTV if used with TDF
² May be insufficient if HIV RNA >100,000 copies/mL
Initial Treatment:
Alternative Components (2)
NRTI Options (in order of preference)
 ZDV + 3TC¹
 ddI + (FTC or 3TC)
¹ FTC can be used in place of 3TC and vice versa
ARVs Not Recommended in
Initial Treatment (1)
High rate of early virologic • ddI + TDF
failure
Inferior virologic efficacy
No benefit over standard
regimens
• ABC + 3TC + ZDV
(as 3-NRTI regimen)
• DLV
• NFV
• SQV as sole PI
(unboosted)
• TPV
• 3-class regimens
• 3 NRTIs + NNRTI
ARVs Not Recommended in
Initial Treatment (2)
High incidence of
toxicities
• d4T + 3TC
• IDV + RTV
• RTV used as sole PI
• NVP (initiated in ARV-naive women
with CD4 counts of >250 cells/µL or
ARV-naive men with CD4 counts of
>400 cells/µL)
High pill burden/
Dosing inconvenience
• IDV (unboosted)
• NFV + SQV
Lack of data in initial
treatment
• DRV
• ENF
• ETV
• MVC
• RAL
ARV Medications: Should Not
Be Offered at Any Time (1)
• ARV regimens not recommended
– Inferior virologic efficacy, rapid development of
resistance:
• Monotherapy with NRTI*
• Dual-NRTI therapy
• 3-NRTI regimen (except ABC+3TC+ZDV or possibly
TDF + 3TC + ZDV, when other regimens are not desirable)
* For pregnant women, see Public Health Service Task Force Recommendations
for the Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal
Health and Interventions to Reduce Perinatal HIV Transmission in the United
States
ARV Medications: Should Not
Be Offered at Any Time (2)
Higher incidence of
adverse events
Potential teratogenicity:
• ddI + d4T
• ATV + IDV
• 2-NNRTI combinations
• EFV
avoid during pregnancy
(especially 1st trimester) and in
women with significant potential
for pregnancy*
No potential benefit;
similar resistance profile
• 3TC + FTC
* Women who are trying to conceive or who are not using effective
and consistent contraception.
ARV Medications: Should Not
Be Offered at Any Time (3)
Antagonistic effects
• d4T + ZDV
Poor bioavailability
• SQV (unboosted)
WHO ARV Guidelines 2006
WHO ARV Guidelines 2006
Change in Future Thai ARV
Guidelines






Initiate ARV when CD4 < 250 or < 350 cells/mm3
EFV as preferred NNRTI (than NVP)
AZT+3TC and d4T+3TC as alternatives or used
for one year then switch to TDF+3TC
TDF+3TC in HIV-HBV co-infection
LPV/r as preferred PI (than IDV/r)
No more NFV
Monitoring

Clinical monitoring

Adherence assurance/assessment

Immunological monitoring

Virological monitoring

Drug resistant testing

Therapeutic drug monitoring
Clinical Monitoring



Patient’s perception of how he/she is feeling on
treatment
Body weight
General appearance





Chronic ill appearance
Fat distribution
Vital signs esp. BT,BP
Clinical of HIV-associated symptoms or
AIDS-defining illness
ARV adverse events/toxicities
ART-Associated Adverse Effects








Lactic acidosis/hepatic steatosis
Hepatotoxicity
Insulin resistance, diabetes melitis
Fat maldistribution
Hyperlipidemia
Increased bleeding in hemophiliacs
Osteonecrosis, osteopenia, osteoporosis
Rash
Common ARV Toxicities
Adherence



High adherence rates associated with virologic
suppression, low rates of resistance, and improved
survival
Important to assess readiness for ART prior to
initiating therapy, and to assess adherence at each
clinic visit
Suboptimal adherence is common
Monitoring: CD4
When
Patients not
on therapy
Baseline
After starting or
changing therapy
Chronic therapy
Comment
Every 3–6 mos

Before starting ART

6 mos

Every 6-12 mos





Decision to start
treatment and OI
prophylaxis
Indication for ARV
 50/mm3 at 4 mos
with successful HAART
Expect  50100/mm3/year
Discordant results for
CD4 and VL in 20%
Adapt from DHHS Guideline
Monitoring: Viral Load
When
Patients not
on therapy
Baseline
Necessary???

Before starting ART
(if available)

After starting or
changing therapy
Chronic therapy
Comment
Not use for decision to
start treatment
Predict probability of viral
suppression and durability
of response

6 (12) mos

Every 6-12 mos



Aim <50 cps/mL
Confirm <50 cps/mL
“blips”: more frequent
monitoring
DHHS: Department of Health and Human Services, IAS: International AIDS society
Treatment Failure

Virologic failure




Immunologic failure



HIV RNA >400 copies/mL after 24 wks or
>50 copies/mL after 48 wks or
Repeated HIV RNA > 50 copies/mL after viral
suppression
Increase <25-50 cells/µL in first year of therapy or
Decline in CD4 count to below baseline
Clinical progression

Occurrence of HIV-related events (after >3 months on
therapy; excludes immune reconstitution syndromes)
Treatment-Experienced Patients:
ART Failure

Causes of treatment failure include:

Patient factors
(eg, CD4 nadir, pretreatment HIV RNA, co-morbidities)
Drug resistance
Suboptimal adherence
ARV toxicity and intolerance
Pharmacokinetic problems

Suboptimal drug potency




Treatment Regimen Failure:
Assessment





Review antiretroviral history
Physical exam for signs of clinical progression
Assess adherence, tolerability, pharmacokinetic
issues
Resistance testing (while patient is on therapy or
recent cessation within 4 weeks)
Identify treatment options
Treatment-Experienced Patients:
Virologic Failure


Assess drug resistance:
 Drug resistance test
 Prior treatment history
 Prior resistance test results
Drug resistance usually is cumulative –
consider all previous treatment history and test
results
Treatment-Experienced Patients:
Virologic Failure

Management:


Clarify goals: aim to reestablish maximal virologic
suppression (eg, <50 copies/ML)
Evaluate remaining ARV options



Newer agents have expanded treatment options
Base ARV selection on medication history, resistance
testing, expected tolerability, adherence, and future
treatment options
Avoid treatment interruption, which may cause viral
rebound, immune decompensation, clinical
progression
Virologic Failure:
Changing an ARV Regimen

General principles:

Add at least 2 (preferably 3) fully active agents to an
optimized background ARV regimen




Determined by ARV history and resistance testing
Consider potent RTV-boosted PIs, drugs with new
mechanisms of action (eg, fusion inhibitor, CCR5
inhibitor, integrase inhibitor, 2nd generation NNRTI) +
optimized ARV background
In general, 1 active drug should not be added to a failing
regimen (drug resistance is likely to develop quickly)
Consult with experts
BENCHMRK-1 and -2: Raltegravir in
Treatment-Experienced Pts
• Randomized, double-blind, placebo-controlled,
parallel phase III studies
Primary endpoints:
Week 16
HIV infected;
triple-class resistant;
VL > 1000 copies/mL
BENCHMRK-1 (N = 350)
(Europe, Asia/Pacific, Peru)
BENCHMRK-2 (N = 349)
(North, South America)
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
Planned duration:
Week 48
Raltegravir 400 mg twice daily + OBR
BENCHMRK-1 (n = 232)
BENCHMRK-2 (n = 230)
Placebo + OBR
BENCHMRK-1 (n = 118)
BENCHMRK-2 (n = 119)
Cooper and Steigbigel CROI 2007 LB 105 a+b
Percent of Patients with Virologic Response
<50 c/mL (NC=F)
Protocol 018
Protocol 019
Percent of Patients with
HIV RNA <50 Copies/mL
BENCHMRK-1
BENCHMRK-2
100
61%
80
62%
60
33%
40
36%
20
0
024
8 12 16
Number of Contributing Patients
Raltegravir* 232
230
Placebo*
118
118
24 0 2 4
Weeks
158 230
81 119
8 12 16
24
229
119
128
69
m518p18p19r50a Feb. 16, 2007
* + OBT
p<0.001 at Week 16 for both parameters
Maraviroc: MOTIVATE 1 and 2: Trial Design
Patients with 3 class resistance or experience
OBT* + placebo
Randomization
1:2:2
MOTIVATE 1 N = 601
MOTIVATE 2 N = 475
OBT* + maraviroc (150 mg† QD)
OBT* + maraviroc (150 mg† BID)
6 weeks
48w
0
Patients were stratified by enfuvirtide use
and HIV-1 RNA < and ≥ 100,000 copies/mL
24w
Planned
interim
analysis
R5 HIV-1 infection by Tropism Assay
No DRVr in OBT
* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV)
† Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC,
all other patients received 300 mg dose of MVC
MOTIVATE 1 and 2: 24 Week
VL < 50 copies/mL (ITT, NC = F)
Placebo + OBR (n = 209)
100
MOTIVATE 1
90
90
80
80
70
70
60
50
P < .0001*
48.5%
42.2%
40
30
P = .0006*
20
24.6%
Patients (%)
Patients (%)
100
MVC QD + OBR (n = 414)
50
P < .0001*
40
30
0
0
45.6%
40.8%
P = .0005*
20.9%
20
10
Nelson M, et al. CROI 2007. Abstract 104aLB.
Lalezari J, et al. CROI 2007. Abstract 104bLB.
MOTIVATE 2
60
10
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (Weeks)
*P values vs placebo at Week 24.
MVC BID + OBR (n = 426)
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (Weeks)
MOTIVATE 1 and 2: Percentage of Patients with
HIV-1 RNA < 50 copies/mL by Number of Active Drugs in OBT*
Includes all patients who received at least one dose of study medication
Placebo + OBT
MVC QD + OBT
MVC BID + OBT
100
90
80
Patients (%)
70
60
50
52 53
88 104
64 132 121
29
30
19
18
20
0
58
55
43 43
40
10
61
9
3
N= 35
51 56
Number of active 0
drugs in OBT*
MOTIVATE 1 & 2-Week 24
44 130 134
1
59
2
≥3
* Based on overall susceptibility score
LOCF
ACTG 5164: Early vs. Deferred ART
with Acute OIs
• Assessment of optimal timing of ART
– Should ART be started during the treatment of an acute OI?
-or– Should ART be deferred until after treatment of an acute OI is completed?
•
N= 282; 85% men; 92% treatment-naive
– Median CD4+ count 29 cells/mm3, HIV RNA 5.07 log10 c/ml
•
OIs with effective antimicrobial therapy only
– PCP (63%), bacterial infections, cryptococcal disease, MAC, toxoplasmosis
– TB excluded
•
Any antiretroviral regimen allowable; d4T XR, TDF/FTC, LPV/r
provided
Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142.
A5164
Study Design
Median 12 days
48
wks
Immediate
Arm
Start ART
Opportunistic
Infection
Treatment
Starts
Median 45 days
48
wks
Deferred Arm
Start ART
Recommended
Start window
-14
0
2
28 42
Study day
Enrollment
Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142.
84
224
A5164
Results Through 48 Weeks
Probability of surviving without
death/new AIDS defining event
Progress to
AIDS
1.00
0.9
0.8
116
14.2%
HR=0.53
99%CI (0.25,1.09)
P=0.023
0.4
0.3
0.2
0.1
0.0
Immediate ART
Deferred ART
0
•
•
24.1%
94
0.7
0.6
0.5
4
8
12
16
20
24
28
32
36
40
44
48
No difference in primary endpoint of virologic suppression
No difference in IRIS (10 immediate, 13 deferred) or need for ART changes
Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142.
Websites to Access the
Guidelines

http://www.aidsetc.org
http://aidsinfo.nih.gov
www.hopkins-aids.org

www.medscape.com/hiv

