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

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

Time on HAART (years)

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

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/L)

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/L 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

2.1
0.4

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,
patients 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/L

DHHS guideline for use of ARVs in
HIV-infected adults and adolescents, Jan 2008

Rapid decline in CD4 > 100/ L

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/L

Risk of AIDS-related events and Non-AIDS-defining conditions

is higher in this range than at >350 cells/L

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

Friis-Moller N et al. N Engl J Med 2007;356:1732 4 Weber R.Arch Intern Med 2006;166:1632

Gupta SK, et al. CID 2005;40:1559

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

ds DNA

Integrase

vpr
HIV

SQV,RTV, IDV, NFV, AMV, LPV/rtv,

TPV, DRV

Genomic RNA

Proviral DNA

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

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
.

 10 HIV
NAPHA . 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 Options

EFV*
OR
PI Options

ABC + 3TC
+

TDF + FTC

ATV + RTV
FPV + RTV (BID)
LPV/RTV (BID)

* Avoid

in pregnant women and women with significant pregnancy potential

FTC can be used in place of 3TC and vice versa
For patients who have tested negative for HLA-B*5701
TDF + FTC or 3TC is preferred in patients with HIV/HBV coinfection

Initial Treatment:
Alternative Components (1)
NNRTI Option
NVP*

PI Options
ATV
FPV
FPV + RTV (once daily)
LPV/RTV (once daily)
SQV + RTV

* NVP should not be initiated in women with CD4 counts of >250 cells/L or men
with CD4 counts of >400 cells/L
ATV must be boosted with RTV if used with TDF
May be insufficient if HIV RNA >100,000 copies/mL

Initial Treatment:
Alternative Components (2)
NRTI Options (in order of preference)
ZDV + 3TC
ddI + (FTC or 3TC)

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/L or
ARV-naive men with CD4 counts of
>400 cells/L)

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

Patients 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 36 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/L 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 36 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

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

3
N= 35

51 56

Number of active 0
drugs in OBT*
MOTIVATE 1 & 2-Week 24

44 130 134

59

* 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

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

24.1%

94

0.7
0.6
0.5

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