When to Start
When to Stop?
What to Start?
Joseph J. Eron, Jr, MD
Professor of Medicine
Principal Investigator
AIDS Clinical Trials Unit
School of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, NC
Benefits and Risks of
Deferred ARV Therapy
 Potential benefits of
deferred therapy
— Avoidance of toxicity, improved
quality of life
— Preservation of future
treatment options
— Delayed development of
drug resistance
— Decreased total time on
drug therapy
— Increased time for patient
education
— More time for development of
more potent, less toxic, and
better studied combinations
 Potential risks of deferred
therapy
— Potential for irreversible immune
damage
 Is immune recovery the same
as immune preservation
— Increased possibility of clinical
progression
 HIV related
— Malignancy and cognitive
disorder
— Non-HIV clinical events.
— Increased risk for HIV transmission
Adapted from DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov.
Accessed December 13, 2006.
The Case for Earlier Initiation of Therapy
 Availability of more potent, easier, and less
toxic regimens
 Cohort studies showing benefit with earlier
therapy
 Better response to therapy
 Decreased transmission
 Cost-effectiveness
The Case for Earlier Initiation of Therapy
 Easier, more potent, and less toxic therapy
Collated Results of HAART Studies
 Previous analysis emphasized
relation b/w pill burden and
response
 Updated analysis: pill burden less
important
 Highlights efficacy of boosted-PI
and NNRTI regimens
Unboosted PI
NNRTI
NRTI
Boosted PI
0
10
20
30
40
50
60
70
80
90
% With VL < 50 at Week 48
Bartlett JA, Fath MJ, Demasi R, et al. An updated systematic overview of triple combination therapy in
antiretroviral-naive HIV-infected adults. AIDS 2006;20:2051-64.
100
Slide 6
Treatment Responses in 1st Year of HAART
Improving Over Time

» Most “failure” now due to loss to follow-up or treatment discontinuation
90
70
127
121
120
119
80
150
Median CD4 increase
% with > 500 copies/mL
100
150
135
125
120
105
97
60
90
50
75
40
60
30
24.8
45
23.0
17.3
20
10
12.4
30
10
8
8.4
15
0
0
1996
1997
Lampe F, et al. CROI 2005. Abstract 593
1998
1999
2000
2001
2002
Median CD4 Increase

4143 subjects from 5 clinic cohorts in Europe and Canada
Treatment-naive; started HAART from 1996-2002
 risk of virologic failure,  med. CD4 count increase in later years
% With VL >500 on ART

Slide 7
Unadjusted and adjusted risk ratios of virological failure by year of starting
cART
1999 is reference category. Unadjusted*=adjusted for cohort only; Adjusted 1#=adjusted for cohort, age,
risk group, pre-HAART VL and CD4 count, previous AIDS; Adjusted 2$ =adjusted for all above factors plus
starting regimen as defined by 3rd drug and nucleoside combination.
Lampe et al, Arch Intern Med 2006;166:521-528
Slide 8
Cohort Data
Improved outcomes with earlier antiretroviral
therapy
HIV and non-HIV clinical events associated with
CD4 cell counts above 200
Slide 9
HAART and Survival Based on Initial
CD4 Cell Count



Modeled data from ART Cohort
Collaborative
10,855 pts, >61,000 person-years
of F/U
934 progressed to AIDS or died
IDUs excluded from model
< 200 vs
201-350
< 350 vs
351-500
Hazard ratio for
AIDS (95% CI)
3.68
(3.01-4.51)
1.52
(1.10-2.10)
Hazard ratio for
AIDS or death
(95% CI)
2.93
(2.41-3.57)
1.26
(0.94-1.68)
Cumulative Probability of AIDS/Death by CD4
Count at Initiation of ART
Probability of AIDS or Death

101-200 cells/mm3
201-350 cells/mm3
351-500 cells/mm3
0.12
0.10
0.08
0.06
0.04
0.02
0.00
Antiretroviral Therapy (ART) Cohort Collaboration. AIDS 2007;21:1185-97.
0
1
2
3
4
Years Since Initiation of HAART
5
Slide 10
HOPS Cohort: Early, Uninterrupted ART
Associated with Improved Outcomes
Incidence per 1,000 patient years by pre-HAART CD4 count
and % time on HAART (n = 4,421)
Opportunistic Infections
HAART < 95% of time
HAART > 95% of time
70
60
80
55.9
Incidence per 1,000 Person-Years
Incidence per 1,000 Person-Years
80
* P = 0.05 for difference by % HAART use
50
40
30
37.8
*
26.1
*
22.3
20
20.1
*
16.2
10.4
10
*
5.4
0
0-49
50-199
200-349
350-499
7.3
2.4
500+
Mortality
71.5
HAART < 95% of time
HAART > 95% of time
70
60
50
*
* P = 0.05 for difference by % HAART use
47.8
38.5
40
*
30
25.5
20
21.4
15.9 14.2
10
7.2 7.5
0
0-49
50-199
CD4 category
200-349
CD4 category
CD4 Cell Count Category
Lichtenstein K, et al. CROI 2006. Abstract 769.
11.5
350-499
500+
Slide 11
Pre-HAART CD4 Predicts Progression to
AIDS: Johns Hopkins Cohort
Johns Hopkins HIV Cohort

Patients with virologic
suppression for up to 6 yrs
(N=280)


Only patients with baseline
CD4 >350 returned to near
normal CD4 count levels
Rate of progression to AIDS
or death significantly higher
over time in patients with CD4
<200 and 201-350 vs. >350
900
800
1.5%*†
700
CD4 cells/mm³

600
12%*
500
13%*
400
300
200
100
0
0
Yr 1 Yr2 Yr3 Yr 4 Yr 5 Yr 6
*% developing AIDS over 6 years of study
† P < .05 compared with CD4+ < 200
Moore RD, et al. IAC 2006. Abstract THPE0109.
Slide 12
Caveat

Remember Bias of Cohort Studies
» Complex or non adherent patient may
have therapy delayed
– Bias by indication
» Lead time bias
Slide 13
HIV-Associated Complications that
are Less CD4-Dependent
Neurocognitive impairment
 Non-Hodgkin’s lymphoma
 Peripheral neuropathy
 HPV-associated dysplasia/cancer
 Kaposi’s sarcoma
 HIV-associated nephropathy

Slide 14
D:A:D Study: CD4 Count Associated with Risk
of Non-HIV Related Death


>23,000 pts in Europe,
Australia, USA
1248 (5.3%) deaths
2000–2004 (1.6/100
person-years)
» Of these, 82% on ART
Both HIV- and non–HIVrelated mortality*
associated with CD4
depletion
Weber R et al. 12th CROI; 2005; Boston. Abstract 595.
100
Overall
HIV
Malignancy
RR

RR of death according to immune
function and specific cause
Liver
Heart
10
1.0
<50
0.1
50–99 100–199 200–349 350–499 >500
CD4 count
*Liver-related: Chronic viral hepatitis, liver failure
(other); malignancy-related: malignancy, non-AIDS
hepatitis; heart-related: MI, other CVD, other heart
disease
CD4+T-cell Count Associated with Risk of AIDS
and Non-AIDS-related Malignancies
• Risk factors for fatal AIDS-defining malignancies (ADM) and
non-ADM in the D:A:D study
– Of 1246 deaths, 112 ADM and 193 non-ADM related
• 4 most common non-ADM: lung, GI, hematologic, anal
• Risk of ADM and non-ADM increased as CD4 cells decrease
• Additional risk factors
– ADM: Prior AIDS event (RR 2.43, P<0.0001)
– Non-ADM: Older age (RR 1.53/5 years older, P<0.0001),
current smoking (RR 2.42, P<0.0001),
active HBV (RR 1.89, P=0.008)
D’Arminio Monforte A et al. 14th CROI; 2007; Los Angeles. Abstract 84.
Malignancies and CD4+ T-cell Count
Latest CD4
(cells/mm3)
Non-AIDS defining
malignancies
Person Years
AIDS-defining
malignancies
Rate
(/1000 p-y)
n
RR
(P)
Rate
(/1000 p-y)
n
RR
(P)
<50
2335
6.0 (14)
15 (<0.001)
20.1 (47)
175 (<0.001)
50-99
2295
9.6 (22)
19 (<0.001)
4.8 (11)
41 (<0.001)
100-199
8097
6.8 (55)
10 (<0.001)
2.8 (23)
24 (<0.001)
200-349
21048
2.0 (43)
3 (<0.001)
0.7 (14)
6 (<0.001)
350-499
24052
1.1 (27)
2 (0.3)
0.3 (7)
3 (0.09)
≥500
46903
0.6 (27)
1
0.1 (5)
1
D’Arminio Monforte A et al. 14th CROI; 2007; Los Angeles. Abstract 84.
CD4+ T-Cell and Risk of Clinical events
•
Evaluation of impact of CD4+
count on OI and non-OI events
– Compared latest CD4 count
in FIRST study (n=1397)
with risk
– Median BL CD4 163 cells/uL,
mean increase of 238
cells/uL
Multivariate HR/100 CD4
Cell Increase*
1.2
1
1
0.92
0.81
0.8
0.6
0.76
0.78
<0.01
0.06
0.83
0.58
0.4
– Median F/U 5 years
•
•
Higher latest CD4 associated
with lower risk of OI and non-OIs
0.2
0
Tx strategies should minimize
time spent at lower CD4 counts
P value
Baker J et al. 14th CROI; 2007; Los Angeles. Abstract 37.
*Adjusted for: age, sex, race, prior AIDS, hepatitis B and C, baseline CD4 & RNA, and latest RNA
<0.01
<0.01
0.40
0.08
CASCADE: Sero-conversion Cohort
• N=9,858; med. F/U 8 yrs post-seroconversion
• 597 deaths, >50% non-AIDS-related
• Current & nadir CD4 and time with CD4 <350 assoc.
with:
– AIDS deaths
– Non-AIDS deaths: Infections, liver disease, malignancy
Marin B, et al.Sydney 2007, #WEPEB019
Randomized Studies
There are none!
Slide 20
Clinical Trial Data Supporting Earlier
Therapy
SMART1


Subset: ART-naïve or not on ART at
randomization
» Immediate ART: n=249 (131
naïve)
» Deferred ART: n=228 (118
naïve)
Greater risk of OI, OI/death, serious
non-AIDS event with deferred ARV
>5-fold increased risk with deferred
ARV
25
Cum. probability (X100)

Composite endpoint1
HR=5.08 (95% CI: 1.91-13.5)
p=0.001
20
Deferred ART
15
1
0
Immediate ART
5
0
0
4
8
12 16 20 24 28 32 38
Months
1. Emery S, et al. 4th IAS, Sydney 2007, #WEPEB018;
Early Therapy
Greater Toxicity?
Greater Resistance?
Risk of Fat Loss/Accumulation with
NRTIs + PIs Increases with Time on ARVs
•
•
Kaplan-Meier Curve Showing
Progression to Any Lipodystrophy
Prospective study of 494 ARV-naïve
patients starting HAART (Oct ’96-Sept
’99)
Any lipodystrophy
Lipodystrophy with subcutaneous lipoatrophy
Lipodystrophy with central obesity
85 subjects (17%) developed fat
changes after median of 18 mo.
25
– 34% subcutaneous lipoatrophy
– 45% mixed
– 11.7 cases per 100 person-years
•
Associated laboratory changes*
– CD4 cell count 
% of patients
– 21% central obesity
15
10
5
– Plasma HIV RNA 
– Triglyceride level 
0
– Cholesterol level 
Martinez E et al. Lancet. 2001;357:592-598.
*All P values 0.001.
20
0
6
12
18
24
Time since starting HAART (months)
Numbers at risk
494
433
333
246
136
Incidence of Myocardial Infarction Increases with
Duration of Combination ART (D:A:D Study)
8
Incidence per
1000 Person-Years
7
6
5
4
3
2
1
0
Exposure (y):
Relative Risk:
No. of events
No. of person-y
None
0.24
3
5714
Friis-Møller N et al. N Engl J Med. 2003;349:1993-2003.
<1
1.0
1-2
1.34
2-3
1.73
3-4
1.98
>4
2.55
9
4140
14
4801
22
5847
31
7220
47
8477
Relative Rate of MI according to NNRTI Exposure
(adjusted for PI exposure)
8
RR (95% CI)
Adjusted RR* per year of NNRTI: 1.05 [0.98-1.13]
4
2
1
0.5
None <1 1-2 2-3 3-4 >4
NNRTI-Exposure (yrs)
: Adjusted for sex, age, cohort, calendar year, prior CVD, family history of
CVD, smoking, body-mass index, PI exposure
Friis-Moller et al, CROI 2006, oral 144
HOPS: More Toxicity with Later Initiation of
Therapy
• More NRTI toxicity (anemia, neuropathy, renal
insufficiency) with initiation of ART at lower CD4
counts
Lichtenstein CROI 2005
UNC CFAR DB Triple Class Resistance
Incidence rate of TC-DR (cases/1000 PY)
70
60
Triple-class antiretroviral drug resistance (TC-DR)
incidence rates (cases/1000 person-years)
stratified by first HAART regimen
TCDR=4
N=34
PY=176
50
TCDR=15
N=184
PY=756
40
TCDR=2
N=65
PY=316
30
20
10
TCDR=1
N=227
PY=713
TCDR=2
N=110
PY=659
TCDR=0
N=53
PY=244
TCDR=0
N=116
PY=258
0
EFV
PI/r
NFV
NVP
DLV
IDV
First HAART regimen
PI
PI/NNRTI
HOPS: More Resistance with Later Initiation of
Therapy
GT mutations and virologic failure
60
p=0.076
p=0.007
Any
mutation
(n=78)
NRTI mut.
among
NRTI-exp
(n=77)
p=0.051
p=0.103
50
Patients (%)
• Major mutations 50% less likely
in pts starting with CD4 >350 vs
<200, despite greater treatment
exposure
40
30
20
10
0
NNRTI mut.
among
NNRTI-exp
(n=37)
0-199 cells/mm3
200-349 cells/mm3
>350 cells/mm3
Uy JP, et al. 4th IAS, Sydney 2007, #WEPEB017
PI mut.
among
PI-exp
(n=48)
Transmission
Probability of Transmission/1000
Coital Acts
HIV RNA Level Affects Probability
of HIV Transmission
5
GUD
No GUD
4.5
4
3.5
3
2.5
2
1.5
1
.5
0
<1700
GUD = genital ulcer disease.
Gray R, et al. Lancet. 2001;357:1149-1153.
1700-
12,500-
Log Viral Load (c/mL)
38,500+ GUD
ART-Induced Reduction in Plasma HIV RNA
Associated with Decreased Levels in Semen
Controls (drug naive)
n=55
Effective ART
n=114
detectable HIV in semen
Patients (%) with
100
P<0.0001
80
60
P=0.01
40
20
0
HIV-RNA
Vernazza PL et al. AIDS. 2000;14:117-121.
HIV-DNA
The Impact of ART on HIV Transmission
Among HIV Serodiscordant Couples
 ART offered in Kigali, Rwanda since 2003
 1034 serodiscordant couples followed
 248 “index cases” receiving ART (CD4<200)
 In spite of counseling, 42 seroconversions
 Only 2/42 seroconversions with partner on ART
 HIV-negative individuals whose partners are on ART
are less likely to seroconvert compared with those
whose partners are not on ART
(OR = 0.19; 95% CI:0.05-0.80)
Kayitenkore K et al. XVI IAC; 2006; Toronto. Abstract MOKC101.
Current DHHS Guidelines for
Initiating ART: Chronic Infection
Clinical Category and/or CD4
Count
History of AIDS-defining
illness
CD4 <200 cells/mm³
CD4 200-350 cells/mm³
Recommendation
Initiate ART
12/07
Indications for HAART
Regardless of CD4 Cell count
• HBV co-infection that requires therapy
– Entecavir not longer an option
• HIV Associated Nephropathy
• Pregnancy
• Discordant couples?
– Perhaps if fully informed
DHHS Guidelines
Clinical Category and/or CD4
Count
CD4 >350 cells/mm³,
asymptomatic, without
conditions listed above
Recommendation
Optimal time to initiate ART
is not well defined. Consider
individual patient
characteristics and
comorbidities.
12/07
Potential Benefits of Early Therapy
(CD4 >350 cells/mm³)
 Maintain higher CD4; prevent irreversible
immune system damage
 Decrease risk of HIV-associated complications
 eg, TB, NHL, KS, peripheral neuropathy, HPVassociated malignancies, HIV-associated cognitive
impairment
 Decrease risk of nonopportunistic conditions
and non-AIDS associated conditions
 eg, CV, renal, and liver disease; malignancies;
infections
 Decrease risk of HIV transmission
12/07
Potential Risks of Early Therapy
(CD4 >350 cells/mm³)
 ARV-related side effects and toxicities
 Drug resistance (due to ART failure)
 Inadequate time to learn about HIV, treatment, and
adherence
 Increase in total time on ART; greater chance of
treatment fatigue
 Current ART may be less effective or more toxic
than future therapies
 Transmission of ARV-resistant virus, if incomplete
virologic suppression
12/07
Once Treatment is Started,
Can We Stop?
Consequences of Stopping ART:
SMART Trial
HIV-1-infected
patients with
CD4+ cell count
> 350 cells/mm3
(N = 5472)
95.4% treatment
experienced
Continuous antiretroviral therapy
throughout follow-up*
(n = 2752)
ART stopped/deferred† until CD4+
<250 cells/mm3 then started to
increase CD4+ to >350 cells/mm3
(n = 2720)
El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.
*Mean follow-up 16 months
†The protocol also permitted antiretroviral therapy to be initiated/reinitiated if symptoms of disease from HIV infection developed or the percentage of CD4+ lymphocytes
(CD4+ percentage) was less than 15%.
SMART: Primary Endpoint and
Components
Endpoints
#Pts w/ Events
Relative Risk (95% CI)
2.6
Death from any cause or
Opportunistic Disease
167
Death from any cause
85
Serious opportunistic disease
15
1.8
6.6
1.7
104
0.1
*CVD, Renal, Hepatic Events (fatal/nonfatal)
El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.
1
Favors DC
Favors VS ►
(drug conservation)
(viral suppression)
►
Severe Complications*
10
SMART: Why Did the “STI” Arm Have More
Clinical Progression?
— Stop meds CD4 >350
— Restart CD4 <250
 Trial halted Jan 2006
16
14
OI/Death by Arm
During Study (%)
 N = 5472; randomized trial
comparing continuous treatment
(VS) to “STI” arm (DC):
Event Risk by Time Updated CD4 Count1
12
10
6
4
2
0
— 2.63 greater risk of OI/death
in DC versus VS arm
— Lower CD4 count
— Higher viral load at higher
CD4 counts
 Implications for “When to Start?”
<250
250-349
350-499
>499
Time Spent at Different CD4 Strata2
35
Follow-Up Time (%)
 Greater risk of DC strategy
explained by:
DC
VS
8
31.7
30
25
20
15
8.2
10
5
0
3.1
DC Group
7.2
0.8
1.7
VS Group
1. Lundgren J, et al. Presented at: XVI IAC; August 13-18, 2006; Toronto, Canada. Abstract WEAB 0203;
2. El Sadr W, et al. Presented at: XVI IAC; August 13-18, 2006; Toronto, Canada. Abstract WEAB0204.
< 200
< 250
< 350
Trivacan Study
• Treatment Naïve patients in Abidjan
• Randomized to continuous ARV treatment or
CD4 guided interruption or timed interruption of
therapy
• Therapy held for CD4 > 350 and resumed
when CD4 < 250
• CD4 guided arm stopped on DSMB review
– 110 received continuous treatment
– 216 received CD4 guided therapy
Lancet. 2006 Jun 17;367(9527):1981-9
Trivacan: Time to severe Morbidity or Death
Trivacan Study
Continuous CD4 guided
N
N
Incidence
rate ratio
Overall severe
morbidity
13
85
0.38
< 0.001
Death
1
4
.048
0.57
TB
4
12
0.65
0.47
Bacterial Diseases
1
31
0.06
< 0.001
Bacteremia
0
17
0.00
P value
< 0.001
What to Start With?
Initial Treatment:
Preferred Components
NNRTI Option
NRTI Options
Efavirenz*
OR
PI Options
Atazanavir + ritonavir
+
Tenofovir +
emtricitabine**
Zidovudine +
lamivudine**
Fosamprenavir + ritonavir (BID)
Lopinavir/ritonavir (BID)
*Avoid in pregnant women and women with significant pregnancy potential.
**Emtricitabine can be used in place of lamivudine and vice versa.
Initial Treatment:
Alternative Components
NNRTI Option
Nevirapine*
OR
NRTI Options
Abacavir +
lamivudine
PI Options
Atazanavir**
Fosamprenavir
Fosamprenavir + ritonavir (1x/day)
Didanosine +
(emtricitabine
or lamivudine)
Lopinavir/ritonavir (1x/day)
*Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 counts
>400 cells/mm³
**Atazanavir must be boosted with ritonavir if used in combination with tenofovir
Initial Treatment:
Other Possible Options
ARV drugs or regimens
Rationale
Abacavir + lamivudine +
zidovudine (coformulated)
Inferior virologic efficacy
Nelfinavir*
Inferior virologic efficacy
Saquinavir (ritonavir-boosted) Inferior to lopinavir/ritonavir
Stavudine + lamivudine
Significant toxicities
These are considered acceptable but inferior to preferred
or alternative components. They may be used in special
circumstances.
*Should not be given to pregnant women.
ARVs Not Recommended in Initial
Treatment (1)
High rate of early
virologic failure
 Didanosine + tenofovir
Inferior antiviral activity  Delavirdine
 Saquinavir as sole PI
(unboosted)
High incidence of
toxicities
 Indinavir + ritonavir (boosted)
 Ritonavir used as sole PI
ARVs Not Recommended in Initial
Treatment (2)
High pill burden/
Dosing inconvenience
Indinavir (unboosted)
 Nelfinavir + saquinavir
Lack of data in initial
treatment
 Darunavir
 Enfuvirtide
 Tipranavir
No benefit over
standard regimens
 3-class regimens
 3 NRTIs + NNRTI
ARV Medications: Should Not
Be Offered at Any Time
 ARV regimens not recommended:
— Monotherapy (except possibly zidovudine used to prevent
perinatal HIV transmission)
— Dual NRTI therapy
— 3-NRTI regimen (except abacavir/lamivudine/
zidovudine and possibly lamivudine/zidovudine +
tenofovir
— NRTI-sparing regimens
ARV Medications: Should Not
Be Offered at Any Time
 ARV components not recommended:
— Didanosine + stavudine
— Stavudine + zidovudine
— Emtricitabine + lamivudine
— Atazanavir + indinavir
— Saquinavir as single PI (unboosted)
ARV Medications: Should Not
Be Offered at Any Time
 ARV components not recommended:
— Efavirenz in pregnancy and in women with significant
potential for pregnancy*
— Nelfinavir in pregnancy and in women with significant
potential for pregnancy*
— Nevirapine initiation in women with CD4 >250 cells/mm³
or men with CD4 >400 cells/mm³
* Women who are trying to conceive or who are not using
effective and consistent contraception.
ACTG 5142
Study Design
Primary Study Objectives
Time to virologic failure*
Time to regimen completion†
753 Patients randomized in
open label design
Major inclusion criteria:
ART naïve, Any CD4 or HIV
RNA >2000 c/mL
LPV/r + NRTI
EFV + NRTI
LPV/r + EFV
*Virologic failure defined as early (rebound or lack of suppression by 1 log10) or late (failure to suppress to <200 c/mL
or rebound); †Regimen Completion defined as virologic failure or d/c secondary to any treatment related
discontinuation of any component
Riddler S, et al. Presented at: XVI IAC; August 13-18, 2006; Toronto, Canada. August 13–18, 2006; Abstract THLB0204.
ACTG 5142
96-Week Outcomes (ITT)
EFV + 2 NRTI (n = 250)
LPV/r + 2 NRTI (n = 253)
100
89
90
Patient (%)
80
70
75
67
73
50
30
20
77
83
CD4+ Cell Count Change from BL:
+239 vs +285 vs +268 P =.01)
60
40
LPV/r + EFV (n = 250)
EFV vs LPV: P = .006
EFV vs LPV/EFV: P = .5
LPV vs LPV/EFV: P =.13
EFV vs LPV: P = .003
EFV vs LPV/EFV: P = .123
LPV vs LPV/EFV: P = .183
Without Virologic Failure
<50 c/mL
10
0
Riddler S, et al. Presented at: XVI IAC; August 13-18, 2006; Toronto, Canada. Abstract THLB0204.
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
NRTI mutations
8
11‡
4
NNRTI mutations
2§
16
27¶
Mutations in 2 classes
2§
10‡
2
*Some genotype assays pending.
†30N, 321, 33F, 46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V, 90M.
‡P <.05 vs LPV/EFV.
§ P <.05 vs EFV.
¶ P <.05 vs LPV.
Riddler S, et al. Presented at: XVI IAC; August 13-18, 2006; Toronto, Canada. Abstract THLB0204.
Haubrich R, et al. CROI; 2007.
Abstract 38 (ACTG 5142)
 Significantly lower incidence of lipoatrophy at 96 weeks for
NRTI-sparing vs NRTI-containing regimens
 Lipoatrophy incidence comparable with TDF-containing vs
NRTI-sparing regimen
 Incidence of lipoatrophy in NRTI arms lower with LPV/r vs
EFV regardless of NRTI used
 Total cholesterol, high density lipoprotein (HDL), and
non-HDL increases similar between LPV/r and EFV + 2 NRTI
arms
 Triglycerides at 96 weeks significantly higher with LPV/r vs
EFV + 2 NRTIs
 Serum lipid changes greater with stavudine (d4T) - vs TDFcontaining regimens
Lipoatrophy
by Randomized Group
EFV + 2 NRTIs
n = 173
96 Weeks
LPV/r + 2 NRTIs
9
17
n = 166
n = 171
32
n = 197 7
48 Weeks
n = 191
10
21
n = 188
0
EFV + LPV/r
10
20
P Values at Week 96
LPV/EFV vs LPV: .023
LPV/EFV vs EFV: <.001
LPV vs EFV:
.003
30
Lipoatrophy (>20% Limb Fat Loss) (%)
Haubrich R, et al. Presented at: 14th CROI; February 25–28, 2007; Los Angeles, CA. Abstract 38.
40
Lipoatrophy by NRTI
d4T
ZDV
9
n = 136
27
n = 117
96 Weeks
TDF
42
n = 84
P Values at Week 96
ZDV vs TDF: <.001
n = 153 8
16
n = 133
48 Weeks
26
n = 93
0
10
20
30
d4T vs TDF: <.001
d4T vs ZDV: .038
40
% Lipoatrophy (>20% Limb Fat Loss)
ZVD = ziclovidiine.
Haubrich R, et al. Presented at: 14th CROI; February 25–28, 2007; Los Angeles, CA. Abstract 38.
50
How Many NRTIs?
ACTG 5095: Study Design
• Phase III, randomized, double–blind, placebo–controlled study to evaluate
a) ZDV/3TC + EFV, b) ZDV/3TC/ABC + EFV and c) ZDV/3TC/ABC
• ZDV/3TC/ABC found to be inferior and discontinued
ART-naïve patients
N = 765, Compared for 3 years
ZDV/3TC/ABC/EFV
240
4.9
Virologic Failure
94 patients
90% <200 (P = .59)
85% <50 (P = .39)
ABC = abacavir.
Gulick R, et al. JAMA. 2006;296:769-781.
Baseline Characteristics
Median CD4 (cells/mm³)
Mean Viral Load (log10 c/mL )
Results at Year 3
ZDV/3TC/EFV
240
4.9
Virologic Failure
99 patients
92% <200 (P= .59)
88% <50 (P = 0.39)
ACTG 5095
Time to Virologic Response
Probability of No Response
Confirmed HIV RNA <200 c/mL
1.0
ZDV/3TC/ABC+EFV
ZDV/3TC+EFV
0.8
0.6
0.4
0.2
0
0
24
48
72
96
120
Time (wk)
144
168
No difference of probability of not failing among patients
with HIV RNA >100,000 c/mL
Gulick R, et al. JAMA. 2006;296:769-781.
ACTG 5095 Impact of Baseline Values and
Risk of Virologic Failure at 3 Years on EFV
By Baseline HIV RNA Level
≥300,000
100,000-299,999
30,000-99,999
<30,000
0.35
0.66
1.0
1.75
2.85
1.75
2.85
By Baseline CD4 Cell Count
≥500
350-499
200-349
50-199
<50
0.35
0.66
1.0
Ribaudo H, et al. Presented at: XVI IAC; August 13–18, 2006; Toronto, Canada Abstract THLB0211.
What NRTIs?
GS 934: Study Design
Noninferiority Trial, Primary Endpoint <400 c/mL at Week 96
TLOVR
ARV-naïve patients
randomized 1:1
TDF
FTC
EFV
Stratification by
QD
QD
QD
CBV
EFV
HIV RNA >10,000 c/mL
Any CD4 count
(n = 255)
86%
36
233
Baseline Characteristics
Male
Age (Median)
Median CD4 (cells/mm³)
BID
QD
(n = 254)
87%
37
241
5.0
Median Viral Load
5.0
(log
c/mL
)
Week 144
Week 144
10
Adequate Renal and Hepatic Function at baseline
FTC/TDF Fixed dose combination tablet was not used
CBV = carbovir.
*FDA-required endpoint, similar to ITT Missing = Failure, Switch = Failure.
Requires confirmation for success, used by FDA for presentation in U.S. Prescribing Information of newly approved
antiretrovirals.
Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.
Proportion <50 c/mL (TLOVR)
90
Responder (%)
80
TDF+FTC+EFV 67*
70
r 60
e
d
CBV+EFV 61*
50
pon40
30
P = .16
*95% CI: (-2.3%, +15.0%)
Res
% 20
10
0
BL
8
16
24
32
40
48
60
72
84
Time (wk)
Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.
96
Mean Absolute Change
in CD4 Count From Baseline
Mean Change (cells/mm3)
270 TDF+FTC+EFV
300
3)
m 250
m
200
237 CBV+EFV
150
100
P = .036
50
0
Mean Change (cells/
BL
8
16
24
32
40
48
60
72
84
96
Time (wk)
n = 255
238
234 223
218
209
199
177
184
172
166
n = 254
222
216
188
175
164
145
149
149
142
199
Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.
Resistance Development Through Week 96
TDF+FTC+EFV
(n = 244)
CBV+EFV
(n = 243)
Genotypes
14
29
Wild Type
4
7
Any Resistance
10
20
EFV-R
10
18
M184V/I
2
9
TAMs
0
1
K65R
0
0
Excludes patients with baseline NNRTI-R mutations (n = 487).
Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.
P =.017
P = .036
Initial Treatment Strategies:
PI-based Regimens
KLEAN Study: LPV/r vs FPV/r, Both
With 3TC and ABC QD
Phase IIIb, randomized (1:1), open-label, 48-wk study conducted at 131 sites
in the US, Europe, and Canada
ART-naïve
subjects

Entry criteria
—
HIV-1 RNA 1000 c/mL
—
No CD4 cell count restrictions
FPV/r 700 mg/100 mg
BID + ABC/3TC
(600 mg/300 mg) FDC QD
n = 434
LPV/r 400 mg/100 mg
BID + ABC/3TC
(600 mg/300 mg) FDC QD
n = 444

Stratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mL

KLEAN had 90% power to detect noninferiority of FPV/r to LPV/r within a 12% difference
FDC = fixed-dose combination.
Eron J, et al. Presented at: 16th IAC; August 13–18, 2006; Toronto, Canada. Abstract THLB0205.
KLEAN Study: HIV-1 RNA <50 c/mL at Wk
48
Proportion of Subjects
100
80
FPV/r BID
66 65
67
70
66 63
LPV/r BID
67 64
64
65 66
HIV-1 RNA
<100,000
c/mL
HIV-1 RNA
≥100,000
c/mL
CD4+ <50
cells/mm3
CD4+ 50-199
cells/mm3
CD4+ ≥200
cells/mm3
63
60
40
20
0
TLOVR
FPV/r
n=
434
197
237
67
163
204
LPV/r
n=
444
209
235
80
152
212
Eron J, et al. Presented at: 16th IAC; August 13–18, 2006; Toronto, Canada. Abstract THLB0205.
KLEAN Results: Median Fasting Lipids
(mg/dL) at Baseline and Wk 48
Cholesterol
Triglycerides
250
Baseline
Wk 48
mg/dL
200
150
100
50
0
Baseline
Wk 48
n=
n=
FPV/r
LPV/r
363
287
377
294
FPV/r
363
287
Use of lipid-lowering medications was similar in the FPV/r and LPV/r groups (11%).
Eron J, et al. Presented at: 16th IAC; August 13–18, 2006; Toronto, Canada. Abstract THLB0205.
LPV/r
377
294