Update of Antiretroviral Agents in Adults and Adolescents 2008

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

diseaseby 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

0.001

0.01

0.1

1

10

100

1000

10000

100000

1000000

0 100 200 300

Pla

sma

HIV

RN

A (

cop

i es /

ml)

Time on HAART (days)

Limit ofDetection

(50 copies/ml)

Eradication in 2 to 3 years

t1/2 < 1 day

t1/2 ~ 14 days

Start HAART

Viral dynamics in pts on HAART

0.001

0.01

0.1

1

10

100

1000

10000

100000

1000000

0 100 200 300

Time on HAART (days)

Start HAART

Limit ofDetection

(50 copies/ml)

Below limit of detection

t1/2 < 1 day

t1/2 ~ 14 days

Pla

sma

HIV

RN

A (

cop

i es /

ml)

0.0001

0.001

0.01

0.1

1

10

100

1000

10000

0 1 2 3 4 5 6 7Time on HAART (years)

Fre

qu

ency

(p

er 1

06 c

ells

)Slow decay of latently infected

CD4+ T cells

-

Time to eradication> 73.4 years

0.00001

Chun et al., Nature Med., 1995Chun et al., Nature, 1997

Finzi et al., Science, 1997Wong et al. Science, 1997Chun et al., PNAS, 1997

Finzi et al., Nature Med., 1999Siliciano et al., Nature Med., 2003

HAART < 50 copies/ml

•HAART reduces viremia to below 50 copies/ml

Ag†

•HIV persists in a reservoir in resting T cells

•Patients on HAART have residual viremia

HAART < 50 copies/ml

Dornadula et al., JAMA, 1999Palmer et al., PNAS, 2008

0.001

0.01

0.1

1

10

100

1000

10000

100000

1000000

Pla

sma

HIV

RN

A (

cop

i es /

ml)

0 1 2 3

Time on HAART (years)

Limit ofDetection(50 c/ml)

Start HAART

Release from stable reservoirs

ART Goals & Tools to Achieve Them

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

Goals



Goals




Goals





Goals

SMART: Inflammatory Markers StronglyAssociated 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


Selection of ARV regimen

Preservation of future treatment options

Rational sequencing of therapy

Maximizing adherence Use of resistance

testing in selected clinical settings

Goals Tools




Normalize survival Improve QOL Prevention of vertical

transmission Prevention of

transmission to sexual partners

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: Baseline Evaluation

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

5

10

15

20

Pat

ien

ts w

ith

tra

nsm

itte

d

resi

stan

ce (

%)

0

NRTIAny Resistance PINNRTI MDR

1998[1] (n = 257)

5.5

0.4

5.1

0 0

1999[1] (n = 239)

8.8

2.1

7.1

0.8 1.3

2000[1] (n = 299)

10.7

1.7

7.7

3.0

2003-2006[2] (n = 3130)

10.4

6.9

3.62.4 1.91.3

1. Bennett D, et al. CROI 2002. Abstract 372. 2. Wheeler W, et al. CROI 2007. Abstract 648.

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) USDHHS (Oct 04)

symptomatic treat treat treatasymptomaticCD4<200 treat treat treatCD4 200-350 consider therapy should be should be offered

depending on rate considered treatmentof CD4 decline, patient’s wishes and viral load

CD4>350 defer defer defer if VL< 100,000may consider if

VL>100,000

What is the best time to start ARV? 2008

DHHS guideline for use of ARVs in

HIV-infected adults and adolescents, Jan 2008

High viral load >100,000 HIV RNA cop/μL

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/µLRisk 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 2 Patel P et al. Ann Intern Med 2008;148:728

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 6 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 Clinical Staging of HIV Disease in Adults and Adolescents (cont.)


Major Targets of Antiretroviral AgentsMajor Targets of Antiretroviral Agents

HIV

RNARNA

DNA

ds DNAds DNA

RT

Integrase

Transcription

Proviral DNA

Spliced mRNA

mRNA

Genomic RNA

PolyproteinProtein

Protease

Protease InhibitorsSQV,RTV, IDV, NFV, AMV, LPV/rtv,

TPV, DRV

RT Inhibitors

NRTI: AZT, ddI, ddC, d4T, 3TC, ABC

NNRTI: NVP, DLV, EFV, ETV

NTRTI: Tenofovir

1 223

4

55

6

Entry Inhibitors

CXCR4: AMD3100, T22

CCR5: MVC, SCH-C, D;

TAK779

Fusion gp41: T20

vpr

Integrase Inhibitors

RAL

ETV = Etravirine (Intelence )

MVC = Maraviroc (Selzentry )

RAL = Raltegravir (Isentress)

Antiretroviral Drug FDA Approval: Antiretroviral Drug FDA Approval: 1987 - 20041987 - 2004

0

5

10

15

20

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005

AZTddI

ddC d4T

3TCSQV(h)

RTVIDVNVP

NFVDLV

SQV (s)AZT+3TC

EFVABC

APV

LPV/r ddI-EC

AZT+3TC +ABC

TDF

T-20 ATV FTC

ABV+3TCTDF+FTC

NsRTINsRTI NNRTINNRTI PIPIzidovudine (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 atazanavir (ATV)

emtricitabine (FTC) enfuvirtide (T20) fosamprenavir

NtRTI amprenavir (APV)

tenofovir tipranavir (TPV)

FDA-Approved Antiretroviral Drugs June 2005 (21 ARVs)

FDA Approved Antiretroviral DrugsFDA Approved Antiretroviral DrugsOctober 2008 October 2008 (25 ARVs)(25 ARVs)

FDA Approved Antiretroviral DrugsFDA Approved Antiretroviral DrugsCombination Drugs Combination Drugs (5 drugs)(5 drugs)

October 2008October 2008Combination DrugCombination Drug Drug component Drug component Date of approvalDate of approval

AtriplaAtripla TDF (300)+ FTC(200) TDF (300)+ FTC(200) + EFV+ EFV (600)(600)

July 12,2006July 12,2006

EpzicomEpzicom ABC (600)+3TC (300)ABC (600)+3TC (300) Aug 2,2004Aug 2,2004

TruvadaTruvada TDF (300)+ FTC(200)TDF (300)+ FTC(200) Aug 2,2004Aug 2,2004

TrizivirTrizivir ABC (300)+3TC(150)ABC (300)+3TC(150)

+ ZDV (300)+ ZDV (300)

Nov 14,2000Nov 14,2000

CombivirCombivir 3TC(150) + ZDV (300)3TC(150) + ZDV (300) Sep 27,1997Sep 27,1997

AZT 300 mg tablet plus

lamivudine 150 mg/tab

ZILAVIR

Combination drugs, Thailand (1)

Stavudine 30,40 mg plus lamivudine 150 mg

plus nevirapine 200 mg

GPO-VIR S 30, S40.


Zidovudine 250 mg plus lamivudine 150 mg

plus nevirapine 200 mg

GPO-VIR Z 250 .


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โครงการ 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

* Avoid in pregnant women and women with significant pregnancy potential¹ FTC can be used in place of 3TC and vice versa² For patients who have tested negative for HLA-B*5701³ TDF + FTC or 3TC is preferred in patients with HIV/HBV coinfection

EFV*

OR

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

NNRTI Option

PI Options

ABC + 3TC²

TDF + FTC³+

NRTI Options¹

Initial Treatment: Alternative Components (1)

* 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 TDF² May be insufficient if HIV RNA >100,000 copies/mL

• NVP*

• ATV¹ • FPV• FPV + RTV (once daily)• LPV/RTV (once daily)²• SQV + RTV

NNRTI Option

PI Options

Initial Treatment: Alternative Components (2)

¹ FTC can be used in place of 3TC and vice versa

ZDV + 3TC¹

ddI + (FTC or 3TC)

NRTI Options (in order of preference)

ARVs Not Recommended in Initial Treatment (1)

High rate of early virologic failure

• ddI + TDF

Inferior virologic efficacy • ABC + 3TC + ZDV (as 3-NRTI regimen)• DLV• NFV• SQV as sole PI (unboosted)• TPV

No benefit over standard regimens

• 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


Higher incidence of adverse events

• ddI + d4T • ATV + IDV • 2-NNRTI combinations

Potential teratogenicity: avoid during pregnancy (especially 1st trimester) and in women with significant potential for pregnancy*

• EFV

No potential benefit;similar resistance profile

• 3TC + FTC

* Women who are trying to conceive or who are not using effectiveand consistent contraception.


Antagonistic effects • d4T + ZDV

Poor bioavailability • SQV (unboosted)



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 CommentPatients noton therapy

Every 3–6 mos Decision to start treatment and OI prophylaxis

Baseline Before starting ART

Indication for ARV

After starting or changing therapy

6 mos 50/mm3 at 4 mos with successful HAART

Chronic therapy

Every 6-12 mos Expect 50-100/mm3/yearDiscordant results for CD4 and VL in 20%

Adapt from DHHS Guideline

Monitoring: Viral Load

When Comment

Patients noton therapy

Necessary??? Not use for decision to start treatment

Baseline Before starting ART (if available)

Predict probability of viral suppression and durability of response

After starting or changing therapy

6 (12) mos Aim <50 cps/mL

Chronic therapy

Every 6-12 mos Confirm <50 cps/mL “blips”: more frequent monitoring

DHHS: Department of Health and Human Services, IAS: International AIDS society

Treatment Failure Virologic 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 Immunologic failure

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, clinicalprogression

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

Cooper D, et al. CROI 2007. Abstract 105aLB. Steigbigel R, et al. CROI 2007. Abstract 105bLB.

• Randomized, double-blind, placebo-controlled, parallel phase III studies

Raltegravir 400 mg twice daily + OBRBENCHMRK-1 (n = 232)BENCHMRK-2 (n = 230)

Placebo + OBRBENCHMRK-1 (n = 118)BENCHMRK-2 (n = 119)

HIV infected;triple-class resistant; VL > 1000 copies/mL

BENCHMRK-1 (N = 350)(Europe, Asia/Pacific, Peru)

BENCHMRK-2 (N = 349)(North, South America)

Primary endpoints: Week 16

Planned duration: Week 48

Percent of Patients with Virologic Response <50 c/mL (NC=F)

* + OBT p<0.001 at Week 16 for both parameters

BENCHMRK-1 BENCHMRK-2

0 2 4 8 12 16 24Weeks

0

20

40

60

80

100

Per

cent

of P

atie

nts

with

HIV

RN

A <

50 C

opie

s/m

LProtocol 018

Number of Contributing Patients

0 2 4 8 12 16 24

Protocol 019

232 230 158118 118 81

Raltegravir*Placebo*

230 229 128119 119 69

m518p18p19r50a Feb. 16, 2007

Cooper and Steigbigel CROI 2007 LB 105 a+b

61%

36%33%

62%

Maraviroc: MOTIVATE 1 and 2: Trial Design Patients with 3 class resistance or experience

48w

* 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

Randomization 1:2:2

MOTIVATE 1 N = 601MOTIVATE 2 N = 475

OBT* + maraviroc (150 mg† BID)

OBT* + maraviroc (150 mg† QD)

OBT* + placebo

Plannedinterim

analysis

0 24w6 weeks

Patients were stratified by enfuvirtide use and HIV-1 RNA < and ≥ 100,000 copies/mL

R5 HIV-1 infection by Tropism Assay

No DRVr in OBT

Pat

ien

ts (

%)

MOTIVATE 1 and 2: 24 Week VL < 50 copies/mL (ITT, NC = F)

48.5%42.2%

24.6% 20.9%

40.8%45.6%

P = .0005*

P < .0001*P < .0001*

P = .0006*

16 20 240 4 8 12Time (Weeks)

2

20

10

0

30

40

50

60

70

80

90

100

6 10 14 18 22

Pat

ien

ts (

%)

16 20 240 4 8 12Time (Weeks)

2

20

10

0

30

40

50

60

70

80

90

100

6 10 14 18 22

MOTIVATE 1 MOTIVATE 2

Nelson M, et al. CROI 2007. Abstract 104aLB. Lalezari J, et al. CROI 2007. Abstract 104bLB.

*P values vs placebo at Week 24.

Placebo + OBR (n = 209) MVC QD + OBR (n = 414) MVC BID + OBR (n = 426)

MOTIVATE 1 and 2: Percentage of Patients with HIV-1 RNA < 50 copies/mL by Number of Active Drugs in OBT*

0

10

20

30

40

50

60

70

80

90

100

35 51

56 44

130

134

59

88

104

64 132 121

3

18

29

9

43 43

19

52 53 5561 58

0 1 2 ≥ 3Number of active drugs in OBT*

* Based on overall susceptibility score LOCF

Patie

nts

(%)

N=

MOTIVATE 1 & 2-Week 24

MVC QD + OBTMVC BID + OBT

Placebo + OBTIncludes all patients who received at least one dose of study medication

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.

Study Design


-14

Study day

0 2 28 42 84 224

48wks

48wks

Enrollment

Deferred ArmStart ART

Opportunistic Infection

TreatmentStarts

ImmediateArm

Start ART

RecommendedStart window

A5164

Median 12 daysMedian 12 days

Median 45 daysMedian 45 days

Results Through 48 Weeks

• No difference in primary endpoint of virologic suppression• No difference in IRIS (10 immediate, 13 deferred) or need for ART changes

Pro

bab

ilit

y o

f su

rviv

ing

w

ith

ou

td

eath

/new

AID

S d

efin

ing

ev

en

t

Immediate ARTDeferred ART

00.0

0.2

1.00

4 8 12 16 20 24 28 32 36 40 44 48

0.1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

116

94

HR=0.5399%CI (0.25,1.09)P=0.023


A5164

Progress to

AIDS Progress to

AIDS

14.2%14.2%

24.1%24.1%

Websites to Access the Guidelines

http://www.aidsetc.org http://aidsinfo.nih.gov www.hopkins-aids.org

www.medscape.com/hiv

Documents

Update of Antiretroviral Agents in Adults and Adolescents 2008