“The TOP TEN”Important Issues of HIV Medicine in 2006
2
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Faculty
Editor and Course DirectorEditor and Course Director
Harold A. Kessler, MDHarold A. Kessler, MDAssociate Dean, Post-Graduate Medical Associate Dean, Post-Graduate Medical
Education Director, Office of Continuing Medical Education Director, Office of Continuing Medical Education Rush University Medical CenterEducation Rush University Medical Center
Chicago, IllinoisChicago, Illinois
Presenter
Cyril K. GoshimaCyril K. Goshima, M.D, M.D
Director, AIDS Education ProjectDirector, AIDS Education ProjectHawaii AIDS Education & Training CenterHawaii AIDS Education & Training Center
Honolulu, HawaiiHonolulu, Hawaii
Learning Objectives (CME, CE, CPE)
At the completion of this educational activity, participants should be able to:
— Describe the most important recent developments regarding HIV treatment
— Identify key studies that can improve outcomes with HIV treatment
— Summarize the clinical data supporting methods for improving the health and management of HIV-infected patients
Disclosure Information
It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME. Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months. If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content.
Disclosure Information
Cyril K. Goshima, M.D.
Grants/Research Support: Abbott, Agouron, BI, BMS, Gilead, GSK, DuPont, Pfizer, Serono, Tibotec
Speakers’ Bureau: GSK, Gilead
Opinions & Off Label Discussion
The opinions or views expressed in this educational program are those of the participants and do not
necessarily reflect the opinions or recommendations of Gilead Sciences, Rush University Medical Center, University of Florida College of Pharmacy, ANAC or CCMC. The faculty may have included discussion on
unlabeled uses of a commercial product or an investigational use of a product not yet approved for
this purpose.
Please consult the full prescribing information before using any medication mentioned in this program.
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10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
Developing WorldTreatment and Prevention 10
A Global View of HIV Infection38.6 million people living with HIV, 2005
UNAIDS Report on the global AIDS epidemic, 2006
"I just don't believe we can reverse this if we keep having more people infected every year than we are
increasing the number of people on medication.”
~William Jefferson Clinton, Head of Clinton Foundation
Survival in Africa with ART
HIV+ cohort followed since 1995 ART available since 2003 ART impact on mortality and causes of death assessed
Munderi P, et al. XVI IAC (2006). Abst. THLB0208
2003-20061995-20001819658Pt-yrs of F/U
Median CD4 cells at enrollment
Survival Probability after 2 yearsSurvival Probability after 1 yearMortality/1000 pt-yrsDeaths (%)
9375
93.8%27.5%95%54.7%34.1577.26%74%
Survival in Africa with ART
With ART there is a decrease in death With ART there is an increase in survival
Rapid Scale Up in India
Estimated 5.2 million people living with HIV/AIDS in India
April 2004: Free ART program started at 8 centers
June 2006: 34,620 pts on ART at 54 centers
Planned— 2007: 100,000 pts on ART— 2011: 300,000 pts on ART
at 250 centers
1%
73%
13%
13%
LTFU Died Stopped On ART
Outcomes at 24 mos. for Patients Started on ART
Khera A, et al. XVI IAC (2006). Abst. WEPE0096
Trials in Developing World
Open label, single arm study of TDF + FTC + EFV in Senegal1
40 ARV naïve pts: — median CD4 122/mm3
(3-310)— VL 5.3 log10 c/ml
At month 9:— 87.5% <400 c/ml— 77.5% < 50 c/ml— Median CD4 +242
cells/mm3
Safe and well tolerated— 3 Pts developed TB— 3 deaths (all with CD4 <5);
none drug related
0102030405060708090
100
%<400 c/mL %<50 c/mL
Month 1 Month 3 Month 6 Month 9
Landman R, et al. 13th CROI (2006). Abst. 543
TDF + FTC + EFV: HIV RNA Suppression
% P
atie
nts
Trials in Developing World
Success rates in developing countries are similar to those in the developed world
Promising HIV prevention approaches
1. Male circumcision: several consistent study results
2. Treatment as Prevention?
- ARVs to lower viral burden, decrease transmission
- Treat all infected patients?
- Post Exposure prophylaxis?
- PreExposure prophylaxis?
"A vaccine's going to be critical in the long run to containing the epidemic. Unless there's some striking
breakthrough that we're not aware of, it's likely to be another 10 years before one is commercially available."
~Cate Hankins, chief HIV scientist at the United Nations
Developing WorldTreatment and Prevention
Continued transmission vexing across the world— Multiple reasons cited
Vaccines – still no leading candidate Treatment more available, consistent
responses Circumcision data consistently protective
"I just don't believe we can reverse this if we keep having more people
infected every year than we are increasing the number of people on medication.”
~William Jefferson Clinton, Head of Clinton Foundation
7.0
20.0
0
5
10
15
20
25
2003 2005
%
UNAIDS Report on the global AIDS epidemic, 2006
Coverage of ARV therapy
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9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
Resistance in Naïve Patients
“Drug resistance testing is recommended
for persons with chronic HIV infection prior
to initiation of therapy.”
~DHHS Guidelines for the Use of ARV Agents in HIV-1-Infected Adults and Adolescents, October, 2006
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Resistance in Naïve Patients: A Global Study
WATCH: Worldwide Analysis of resistance Transmission over time of Chronically and acute infected HIV-1 Patients
6,054 naïve pts Country (n):
— Europe 3,252— Africa 1,162— Asia 653— Latin America 806— N America 290
Results: 8.9% ≥1 mutation0%
1%
2%
3%
4%
5%
6%
7%
8%
PI NRTI NNRTI
Bowles E, et al. XVI IAC (2006). Abst. MOPE0388
Resistance by ARV class
9Resistance in Naïve Patients
Pre treatment genotypic mutations Important in drug selection / options Noted worldwide Rates and trends vary across continents Especially high rate of NNRTI resistance in
recently infected US youth
“Drug resistance testing is recommended for persons
with chronic HIV infection prior to initiation of therapy.”
~DHHS Guidelines for the Use of ARV Agents in HIV-1-Infected Adults and Adolescents, October, 2006
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8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
The SMART Study
“It was hypothesized that, over the longer term, a stratified treatment interruption will results in a
significant lower rate of serious toxicities than an uninterrupted treatment, while maintaining a low rate of disease progression.”
~http://www.smart-trial.org
Can We Ever Stop Treatment? Yes, but…
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Continuous ARV
(Viral Suppression)
Defer ARV until CD4 <250, then treat until CD4 >350,
then stop
(Drug Conservation)
N = 5,472Eligibility: CD4 >350
SMART Study: Design
Primary Endpoint: Powered to detect Clinical events / death
SMART Study Results:HIV and Clinical Events
Is stopping for < four months safer? Unclear yet.
Viral Suppression Group
Drug Conservation Group
444036322824201612840
Months
0.00
0.05
0.10
0.15
0.20
Hazard ratio, 2.6; 95% CI, 1.9-3.7; P<0.001
Cum
ulat
ive
Prob
abili
ty o
f Eve
nt
Opportunistic Disease or Death from Any Cause
No. at Risk
16228037244454068987010401301166620742720
17328838847457272490610771310169520812752
Drug conservation
Viral suppression
Drug Conservation Group
444036322824201612840
Months
0.00
0.05
0.10
0.15
0.20
Hazard ratio, 1.7; 95% CI, 1.1-2.5; P=0.009
15727337544354369386710411292166320742720
16528238046256371389910701307169220772752
Major Cardiovascular, Renal or Hepatic Disease
Viral Suppression Group
SMART Study Group NEJM 2006;355:2283-2296
The SMART Study: Conclusions
Stopping Suppressive ARVs – at any CD4 cell count – carries greater risk of OIs and other illnesses
Not just HIV-related OIs; — Other clinical conditions and all cause mortality were at higher rates
Increased risk explained by current CD4 cell counts— 250-350 has greater risk compared to >350
Increased Risk > 350 CD4 cell counts explained by viremia— Implications for when to start?
“It was hypothesized that, over the longer term, a stratified treatment interruption will results in a significant lower rate of serious toxicities than an
uninterrupted treatment, while maintaining a low rate of disease progression.”
~http://www.smart-trial.org
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SMART Study Group NEJM 2006;355:2283-2296
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7. CCR5 Inhibitors
8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
CCR5 Inhibitors:The Good, The Bad, The Unknown
CXCR4 CCR5CD4
T-cell lines Lymphocytes Monocyte/macrophages
Coreceptor Usage of HIV-1 Variants
Based on slide from D. Kuritzkes.
R5(NSI)
X4(SI)
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The Good
The Bad
The
Two agents on Phase III development; MVC on EAP 1st QTR 2007Short-term activity clear New class: no cross resistance to existing classesCD4 stability even in viremic dual tropic pts
Activity tied to tropism phenotype assay – unknown costTropism appears related to disease stagePotency and PK may present challenges
Uncertainty regarding safety of CCR5 inhibition Uncertain risk/benefit in patients with mixed infectionOptimal clinical use not defined Timing of FDA approval unclear
Unknown
CCR5 Inhibitors:The Good, The Bad, The Unknown 7
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6. Efavirenz Potency Further Validated ACTG 5095 and 5142
7. CCR5 Inhibitors
8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
ACTG 5095 and ACTG 5142:Efavirenz Potency Further Validated
What is the role of EFV + 2 NRTIs:— Compared to newer boosted PIs— At very high viral load levels / very low CD4 counts
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ACTG Protocol A5095
ZDV/3TC/ABC ZDV/3TC + EFVZDV/3TC/ABC
+ EFV
HIV+, ARV-naïve subjects, n=1,147
A phase III randomized, double-blind, placebo-matched, multicenter study with duration of follow-up planned for approximately 2 years after enrollment of last subject.
Baseline Characteristics
Median CD4+: 238 cells/mm3
Median HIV-1 RNA viral load: 78,825 copies/mL
<100,000 copies/mL 57%
100,000 copies/mL 43%
Gulick R, et al. 45th ICAAC (2005). Abst. H-416a
ACTG 5095: Similar Risk of Virologic Failure Across VL / CD4 Strata at Year 3
Ribaudo H, et al. XVI IAC (2006). Abst. THLB0211
By Baseline CD4 Cell Count
1.0 1.75 2.850.660.35
<50
50-199
200-349
350-499
≥500
By Baseline HIV RNA Level≥300,000
100,000-299,999
30,000-99,999
<30,000
1.0 1.75 2.850.660.35
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152
1.0
0.8
0.6
0.4
0.2
0.0
ACTG 5142:Time to Virologic Failure
Adjusted p values (threshold for significance <0.016)LPV/EFV vs LPV: 0.13LPV/EFV vs EFV: 0.5LPV vs EFV: 0.006
Pro
po
rtio
n N
ot
Fai
led
Time in Weeks From Randomization
LPV
EFV
LPV/ EFV
Riddler S, et al., XVI IAC (2006). Abst THLB0204
ACTG 5142:ARV Resistance Mutations (Preliminary Analysis)
Patient Samples LPV EFV LPV/ EFV
Observed VF 94 60 73
Genotypic assays+ 52 33 39
Any PI mutations 20 13 18
Major PI mutations++ 0 0 2
NNRTI mutations 2** (4%) 16 (48%) 27*
NRTI mutations 8 (15%) 11*** (33%) 4
Mutations in 2 classes 2** (4%) 10*** (30%) 2+some genotype assays pending++30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V,82A/F/L/S/T, 84V, 90M
*P < 0.05 compared to LPV; ** P<0.05 compared to EFV;*** P<0.05 compared to LPV/ EFV
% of Genotype results
Riddler S, et al., XVI IAC (2006). Abst THLB0204
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5. New Data with Boosted Protease Inhibitors: Naïve Patients
6. Efavirenz Potency Further Validated ACTG 5095 and 5142
7. CCR5 Inhibitors
8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
New Data with Boosted Protease Inhibitors:Clinical Trials in Naïve Patients
Hyperbilirubinemia
Separate timing of ARA use
Do not use with PPI
Decreased risk hyperlipidemia
QD
Lowest pill burden
ATV/r
Interim Data set presentedFewer lipid effects than LPV/rSQV/r
Rash
Dose flexibility
No food restrictions
QD or BID for Tx naïve
FPV/r
Hyperlipidemia
Insulin Resistance
Substantial clinical trial data
Heat stable reformulation
QD or BID for Tx naïve
LPV/r
Component Considerations Major Toxic Effects and Cautions
Note: TPV/r NOT recommended for use in ARV naïve pts Adapted from Hammer S, et al. JAMA 2006;296:827-843.
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Parade of Boosted Protease InhibitorsClinical Trials in Naïve Patients
More PI options to select from Similar Efficacy data for most boosted PIs
— Hepatic Safety data avoid TPV use (naïve pts)
Promising initial data: lower RTV dose— Tradeoff of rare PI resistance?— Lipid data show small differences remain
Induction maintenance promising for— Boosted PIs (LPV) without NRTIs— Unboosted ATV with NRTIs
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4. Newest Protease Inhibitors: Experienced Patients
5. New Data with Boosted Protease Inhibitors: Naïve Patients
6. Efavirenz Potency Further Validated ACTG 5095 and 5142
7. CCR5 Inhibitors
8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
Newest Protease Inhibitorsfor Experienced Patients
Two new boosted PIs available in the past year Which one do we pick? And with what regimen?
4
50
1
(94)
42
2
(113)
22
3
(58)
10
≥4
(41)
42
All
(373)
Virologic Response by DRV Associated Mutations
De Meyer S, et al. XV Int’l HIV Drug Resistance Wkshp (2006). Poster 73
Number of TMC114 mutations(Number of Patients)
Patie
nts
with
VL
HIV
RN
A <
50 c
opie
s/m
L at
Wee
k 24
(%)
64
0
(67)
100
80
40
60
20
0
* V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V
7 8 8 9 10 8
Median number of IAS-USA PI resistance-associated mutations
Treatment Response by TPV Resistance
Number of PI Mutations (TPV list)
BaselineTPV Susceptibility
(Q25,Q75)
Change in VL*at 2 Weeks(Q25,Q75)
0 to 10.8
(0.5, 1.1)
-1.25
(-0.91, -1.78)
2 to 31.2
(0.7, 2.2)
-1.37
(-0.79, -1.83)
4 to 52.4
(1.2, 5.0)
-1.40
(-0.57, -1.87)
6 to 73.6
(2.1, 12.0)
-1.27
(-0.23, -1.81)
8+16.3
(4.9, 50.3)
-0.33
(+0.11, -0.83)
*Change in HIV RNA from baseline through week 2 (OT) or week 24 (LOCF) in log10 copies/mL.Tipranavir FDA Review (May 19, 2005); Available at www.fda.govValdez H et al. Antiviral Ther 2005;10:S29
Change in VL*at 24 Weeks(Q25,Q75)
-2.10
(-0.82, -2.77)
-0.89
(-0.21, -2.35)
-0.45
(-0.03, -2.15)-0.49
(-0.03, -1.60)-0.08
(+0.01, -0.18)
How to Pick a PIRole for Resistance Testing
REDUCED RESPONSE96.93.471.5Darunavir/r
REDUCED RESPONSE5.41.21.5Tipranavir/r
RESISTANT2.449.0Atazanavir
MINIMAL RESPONSE56.19.783.6Lopinavir/r
RESISTANT2.277.4Fosamprenavir
MINIMAL RESPONSE9.61.277.4Amprenavir/r
MINIMAL RESPONSE2.00.977.4Amprenavir
REDUCED RESPONSE26.57.19.0Saquinavir/r
MINIMAL RESPONSE7.31.334.7Nelfinavir
MAXIMAL RESPONSE40.110.69.7Indinavir/r
MINIMAL RESPONSE4.50.99.7Indinavir
PI mutations: 10I, 13V, 32I, 33F, 46I/L, 54L, 63P, 71V, 76wt/V, 82I, 84V, 90M
PI
Newest Protease Inhibitorsfor Experienced Patients
Two new boosted PIs available in the past year— Which one do we pick?— Resistance pattern can guide choice
And with what regimen?— At least one fully active drug from a new ARV class
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1.
2.
3. Integrase Inhibitors
4. Newest Protease Inhibitors: Experienced Patients
5. New Data with Boosted Protease Inhibitors: Naïve Patients
6. Efavirenz Potency Further Validated ACTG 5095 and 5142
7. CCR5 Inhibitors
8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
Integrase Inhibitors
Initial data sets of these drugs show great promise
What lessons are we learning?
3
MK-0518: A Novel HIV-1 Integrase Inhibitor
HIV integrase inhibition: a new mechanism of action— Active against WT, MDR HIV, CCR5 and CXCR4
Potent activity in ART-naive pts after 10 days of monotherapy
— HIV RNA of 1.7 – 2.2 log10 copies/mL
Predominantly metabolized via glucuronidation (UGT1A1)
— No (known) ARV drug interactions
— Not an inhibitor/inducer of CYP3A4
— No RTV boosting
Integrase Inhibitors
Initial Data Sets Show Great PromiseWhat lessons are we learning?
1. Highly active across naïve and experienced pt spectrum
2. Encouraging safety profile in short term use3. However, observe incomplete suppression at week 244. An important component to a new regimen
— But must still avoid functional monotherapy (EAP?)
5. Unknowns:— Future implications of faster suppression?— Cost?
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1.
2. Single Tablet Therapy: EFV/FTC/TDF
3. Integrase Inhibitors
4. Newest Protease Inhibitors: Experienced Patients
5. New Data with Boosted Protease Inhibitors: Naïve Patients
6. Efavirenz Potency Further Validated ACTG 5095 and 5142
7. CCR5 Inhibitors
8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
Single Tablet Therapy(EFV/FTC/TDF)
Yes, it’s a single pill How strong are the data versus other options?
2
GS 934:Proportion < 400 c/mL (TLOVR)
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
10 0
Weeks
TDF+FTC+EFV 75%*
ZDV/3TC+EFV 62%
p = 0.004
*95% CI: (+4.3%, +21.1%)% R
espo
nder
Gallant J, et al. XVI IAC (2006). Abst. TUPE0064
BL 8 16 24 32 40 48 60 72 84 96
BL 8 16 24 32 40 48 60 72 84 96
GS 934:Proportion < 50 c/mL (TLOVR)
0
10
20
30
40
50
60
70
80
90
TDF+FTC+EFV 67%*ZDV/3TC+EFV 61%*
p = 0.16
*95% CI: (-2.3%, +15.0%)
Weeks
% R
espo
nder
CD4 Mean Change: 270 TDF+FTC+EFV 237 ZDV/3TC+EFV p = 0.036
Gallant J, et al. XVI IAC (2006). Abst. TUPE0064
GS 934:Resistance Development through Week 96
TDF+FTC+EFV(n = 244)
ZDV/3TC+EFV(n = 243)
Viremic / Genotype 14 (6%) 29 (12%)
Wild Type 4 7
Any Resistance 10 (4%) 20 (8%)
EFV-R 10 (4%) 18 (7%)
M184V/I 2 (1%) 9 (4%)
TAMs 0 1
K65R 0 0
Excludes patients with baseline NNRTI-R mutations (n = 487)Gallant J, et al. XVI IAC (2006). Abst. TUPE0064
p = 0.017
p = 0.036
% of total enrolled
P<0.001
5.5
8.1
Week 96
GS 934:Week 96 Total Limb Fat (DXA)*
*For subset who had week 48 DataGallant J, et al. XVI IAC (2006). Abst. TUPE0064
P=0.034
Tota
l Lim
b Fa
t (K
g)
6
7.4
0
1
2
3
4
5
6
7
8
9
10
Week 48
EFV + ZDV/3TC
EFV + TDF + FTC
P=0.001
P=0.01
N 49 51 44 49
Single Tablet Therapy(EFV/FTC/TDF)
Yes it’s a single pill
How strong are the data versus other options?
Unsurpassed Efficacy Unique in simplicity Supportive Long term safety data
— ~2% have increases in Creatinine – stable over years
— Small degree of hip demineralization
2
1. The Progress of Initial Treatment
2. Single Tablet Therapy: EFV/FTC/TDF
3. Integrase Inhibitors
4. Newest Protease Inhibitors: Experienced Patients
5. New Data with Boosted Protease Inhibitors: Naïve Patients
6. Efavirenz Potency Further Validated ACTG 5095 and 5142
7. CCR5 Inhibitors
8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006
The Progress of Initial Treatment
An abundance of data over a decade narrows down our choices to a few best
Within these few, are there ways to distinguish the “front runners”?
1
Recommended ComponentsNRTI NNRTI PITDF or AZT and FTC or 3TC
FTC and ddIEFVor NVP*
LPV/r SQV/rATV/r IDV/r
Alternate ComponentsABC and 3TC
ddI and TDF
ddI and 3TC
AZT and ABC
d4T and 3TC
FPV/rATVNFV
Special Circumstances Only (3-NRTI Regimen)AZT-3TC-ABC**
*In selected patients** No longer recommended for initial therapy except when use of NNRTIs or PIs is precludedAdapted from Yeni PG et al. JAMA 2004;292:251-265.
Initial ARV Regimens:IAS-USA Treatment Guidelines (2004)
Initial ARV Regimens:IAS-USA Treatment Guidelines (2006)
Recommended
NRTI NNRTI PI
TDF/FTC or ZDV/3TC or ABC/3TC EFV(or NVP†)
LPV/r SQV/rATV/r FPV/r
Alternate
No specific alternatives listed‡
†In selected patients‡Triple-NRTI regimens are no longer recommended as initial therapy because of insufficient antiretroviral potency compared with a regimen containing efavirenz. However, for patients requiring treatment with regimens that preclude use of NNRTIs or protease inhibitors, a combination consisting of zidovudine, abacavir, and lamivudine may be considered.
Adapted from Hammer S, et al. JAMA 2006;296:827-843.
Preferred regimens
PI-basedATV + (3TC or FTC) + (AZT, d4T, ABC or ddI) or (TDF+RTV
100mg/d)
FPV + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)
FPV/r + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)
IDV/r + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)
LPV/r + (3TC or FTC) + (d4T, ABC, TDF or ddI)
NFV + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)
SQV/r + (3TC or FTC) + (AZT, d4T, ABC, TDF or ddI)
Alternative regimens
EFV +(3TC or FTC) + (AZT or TDF)
LPV/r +(3TC or FTC) + AZT
3 NRTI-basedABC + AZT + 3TC – only when a preferred or an alternative NNRTI- or PI-based regimen
cannot or should not be used
DHHS Recommended Regimens forTreatment-Naїve Patients (2005)
NNRTI-based
EFV + (3TC or FTC) + (ABC, ddI or d4T)
NVP + (3TC or FTC) + (AZT, d4T, ddI, ABC or TDF)
DHHS Guidelines for the Use of ARV Agents in HIV-1-Infected Adults and Adolescents, July, 2005.
1 Efavirenz is not recommended for use in the 1st trimester of pregnancy or in sexually active women with child-bearing potential who are not using effective contraception.2 The pivotal study that led to the recommendation of lopinavir/ritonavir as a preferred PI component was based on twice-daily dosing [NEJM 2002]. A smaller study has shown
similar efficacy with once-daily dosing but also showed a higher incidence of moderate to severe diarrhea with the once-daily regimen (16% vs. 5%) [JAIDS 2006].3 Emtricitabine may be used in place of lamivudine and vice versa.4 Nevirapine should not be initiated in women with CD4+ T cell count >250 cells/mm3 or in men with CD4+ T cell count >400 cells/mm3 because of increased risk of symptomatic
hepatic events in these patients.5 Atazanavir must be boosted with ritonavir if used in combination with tenofovir.
Select 1 Component from Column A + 1 from Column B
Column A (NNRTI or PI) Column B (Dual-NRTIs)
Preferred components
NNRTI or PIEFV1 ATV/r
FPV/r (BID)LPV/r2 (BID)
TDF/FTC3 (co-formulated); orAZT/3TC3 (co-formulated)
Alternative Components
NNRTI or PINVP4 ATV5
FPVFPV/r (QD)LPV/r (QD)
ABC/3TC3 (co-formulated)DDI + (FTC or 3TC)
www.aidsinfo.nih.gov DHHS Guidelines, October 10, 2006
DHHS Recommended Regimens forTreatment-Naїve Patients (2006)
The Progress of Initial Treatment
An abundance of data over a decade narrows down our choices to a few best
Within these few, are there ways to distinguish the front runners?
Balancing Success / Simplicity / Safety getting easier to do…
1
1. The Progress of Initial Treatment
2. Single Tablet Therapy: EFV/FTC/TDF
3. Integrase Inhibitors
4. Newest Protease Inhibitors: Experienced Patients
5. New Data with Boosted Protease Inhibitors: Naïve Patients
6. Efavirenz Potency Further Validated ACTG 5095 and 5142
7. CCR5 Inhibitors
8. The SMART Study
9. Resistance in Naïve Patients
10. Developing World Treatment and Prevention
“The TOP TEN”Important Issues of HIV Medicine in 2006