update of antiretroviral agents in adults and adolescents 2008
DESCRIPTION
Asso.Prof. Narin Hiransuthikul MD, MPH, PhD Dep. of Preventive & Social Medicine Faculty of Medicine Chulalongkorn UNiversity. Update of Antiretroviral Agents in Adults and Adolescents 2008. NOV 17, 2008. Management of HIV/AIDS (1). - PowerPoint PPT PresentationTRANSCRIPT
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
ART Goals & Tools to Achieve Them
Maximal and durable suppression of HIV-RNA
Goals
ART Goals & Tools to Achieve Them
Maximal and durable suppression of HIV-RNA
Restore CD4 number and function
Goals
ART Goals & Tools to Achieve Them
Maximal and durable suppression of HIV-RNA
Restore CD4 number and function
Reduce inflammation and immune activation
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
ART Goals & Tools to Achieve Them
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
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
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 ARV Guidelines 2006
WHO Clinical Staging of HIV Disease in Adults and Adolescents (cont.)
WHO ARV Guidelines 2006
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.
Combination drugs, Thailand (2)
Zidovudine 250 mg plus lamivudine 150 mg
plus nevirapine 200 mg
GPO-VIR Z 250 .
Combination drugs, Thailand (3)
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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
ARV Medications: Should Not Be Offered at Any Time (2)
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.
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 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
Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142.
-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
Zolopa A, et al. 15th CROI; Boston, MA (2008); Abst. 142.
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