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When to StartWhen to Stop?What to Start?
Joseph J. Eron, Jr, MDProfessor of MedicinePrincipal 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
0 10 20 30 40 50 60 70 80 90 100% With VL < 50 at Week 48
Boosted PI
NNRTI
NRTI
Unboosted PI
Collated Results of HAART Studies
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.
Previous analysis emphasized relation b/w pill burden and response
Updated analysis: pill burden less important
Highlights efficacy of boosted-PI and NNRTI regimens
Slide 6
0
15
30
45
60
75
90
105
120
135
150
Med
ian
CD
4 In
crea
se
97
119 120 121127 125
150Median CD4 increase
Treatment Responses in 1st Year of HAARTImproving Over Time
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
» Most “failure” now due to loss to follow-up or treatment discontinuation
Lampe F, et al. CROI 2005. Abstract 593
24.8 23.017.3
12.4 10 8 8.4
0
10
20
30
40
50
1996 1997 1998 1999 2000 2001 2002
% with > 500 copies/mL
60
70
80
90
100
% W
ith
VL
>50
0 o
n A
RT
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
Years Since Initiation of HAART
0 1 2 3 4 5
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Pro
bab
ility
of
AID
S o
r D
eath
101-200 cells/mm3
201-350 cells/mm3
351-500 cells/mm3
Antiretroviral Therapy (ART) Cohort Collaboration. AIDS 2007;21:1185-97.
Slide 10
HOPS Cohort: Early, Uninterrupted ART Associated with Improved Outcomes
CD4 Cell Count Category
Incidence per 1,000 patient years by pre-HAART CD4 count and % time on HAART (n = 4,421)
MortalityOpportunistic Infections80
70
60
50
40
30
20
10
0
80
70
60
50
40
30
20
10
0 0-49 50-199 200-349 350-499 500+ 0-49 50-199 200-349 350-499 500+
CD4 categoryCD4 category
HAART < 95% of time HAART > 95% of time
* P = 0.05 for difference by % HAART use
HAART < 95% of time HAART > 95% of time
* P = 0.05 for difference by % HAART use
Inci
de
nce
pe
r 1
,00
0 P
ers
on
-Ye
ars
Inci
de
nce
pe
r 1
,00
0 P
ers
on
-Ye
ars
71.5
47.8
38.5
25.521.4
15.9 14.211.5
7.2 7.5
*
*
55.9
26.1
37.8
22.3 20.1
10.4
16.2
5.4 7.32.4
*
*
**
Lichtenstein K, et al. CROI 2006. Abstract 769.
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
Moore RD, et al. IAC 2006. Abstract THPE0109.
0
100
200
300
400
500
600
700
800
900
0 Yr 1 Yr2 Yr3 Yr 4 Yr 5 Yr 6
CD
4 ce
lls/m
m³
13%*
12%*
1.5%*†
*% developing AIDS over 6 years of study† P < .05 compared with CD4+ < 200
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–HIV-
related mortality* associated with CD4 depletion
Weber R et al. 12th CROI; 2005; Boston. Abstract 595.
*Liver-related: Chronic viral hepatitis, liver failure (other); malignancy-related: malignancy, non-AIDS hepatitis; heart-related: MI, other CVD, other heart disease
RR
RR of death according to immune function and specific cause
>500
1.0
10
<50 50–99 100–199 200–349 350–499
100
0.1 CD4 count
Overall
HIV
Malignancy
Heart
Liver
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)
Person YearsNon-AIDS defining
malignanciesAIDS-definingmalignancies
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
– Median F/U 5 years
• Higher latest CD4 associated with lower risk of OI and non-OIs
• Tx strategies should minimize time spent at lower CD4 counts
Multivariate HR/100 CD4 Cell Increase*
P value <0.01 <0.01 <0.01 0.06 0.40 0.08Baker 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
Haz
ard
Rat
io
1
0.58
0.810.76 0.78
0.92
0.83
0
0.2
0.4
0.6
0.8
1
1.2
Refer
ence OI
Non-O
ILiv
er CVRen
al
Mali
gnan
cy
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
1. Emery S, et al. 4th IAS, Sydney 2007, #WEPEB018;
Composite endpoint1
0 4 8 12 16 20 24 28 32 38
Months
0
5
10
15
20
25
Cu
m.
pro
bab
ilit
y (X
100
)
HR=5.08 (95% CI: 1.91-13.5) p=0.001
Deferred ART
Immediate ART
Early Therapy
Greater Toxicity?
Greater Resistance?
Risk of Fat Loss/Accumulation with NRTIs + PIs Increases with Time on ARVs
• Prospective study of 494 ARV-naïve patients starting HAART (Oct ’96-Sept ’99)
• 85 subjects (17%) developed fat changes after median of 18 mo.
– 21% central obesity
– 34% subcutaneous lipoatrophy
– 45% mixed
– 11.7 cases per 100 person-years
• Associated laboratory changes*
– CD4 cell count
– Plasma HIV RNA
– Triglyceride level
– Cholesterol level
Martinez E et al. Lancet. 2001;357:592-598.*All P values 0.001.
Kaplan-Meier Curve Showing Progression to Any Lipodystrophy
0 6 12 18 24Time since starting HAART (months)
Numbers at risk 494 433 333 246 136
Any lipodystrophy
Lipodystrophy with subcutaneous lipoatrophy
Lipodystrophy with central obesity
% o
f pa
tient
s
0
5
10
15
20
25
Incidence of Myocardial Infarction Increases with Duration of Combination ART (D:A:D Study)
Friis-Møller N et al. N Engl J Med. 2003;349:1993-2003.
Exposure (y):Exposure (y): NoneNone <1<1 1-21-2 2-32-3 3-43-4 >4 >4 Relative Risk:Relative Risk: 0.240.24 1.01.0 1.341.34 1.731.73 1.981.982.55 2.55
No. of eventsNo. of events 33 99 1414 2222 3131 47 47 No. of person-y 5714No. of person-y 5714 41404140 48014801 58475847 72207220 84778477
Inci
denc
e pe
rIn
cide
nce
per
1000
Per
son-
Yea
rs10
00 P
erso
n-Y
ears
0
1
2
3
4
5
6
7
8
None <1 1-2 2-3 3-4 >40.5
1
2
4
8
NNRTI-Exposure (yrs)
RR
(95
% C
I)
Relative Rate of MI according to NNRTINNRTI Exposure (adjusted for PI exposure)PI exposure)
Adjusted RR* per year of NNRTI: 1.05 [0.98-1.13]
: 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
0
10
20
30
40
50
60
70
EFV
TCDR=1N=227
PY=713 TCDR=0N=116
PY=258
PI/r NFV NVPDLV
IDV PI PI/NNRTI
TCDR=15N=184
PY=756TCDR=2
N=65PY=316
TCDR=2N=110
PY=659
TCDR=4N=34
PY=176
TCDR=0N=53
PY=244
Inci
denc
e ra
te o
f T
C-D
R (
case
s/10
00 P
Y)
First HAART regimen
Triple-class antiretroviral drug resistance (TC-DR) incidence rates (cases/1000 person-years)
stratified by first HAART regimen
HOPS: More Resistance with Later Initiation of Therapy
• Major mutations 50% less likely in pts starting with CD4 >350 vs <200, despite greater treatment exposure
Uy JP, et al. 4th IAS, Sydney 2007, #WEPEB017
0-199 cells/mm3
200-349 cells/mm3
>350 cells/mm3
GT mutations and virologic failure
Any mutation
(n=78)
NRTI mut. among
NRTI-exp(n=77)
NNRTI mut. among
NNRTI-exp(n=37)
PI mut. among PI-exp(n=48)
Pat
ien
ts (
%)
p=0.076 p=0.007 p=0.051 p=0.103
0
10
20
30
40
50
60
Transmission
HIV RNA Level Affects Probability
of HIV Transmission
GUD = genital ulcer disease.Gray R, et al. Lancet. 2001;357:1149-1153.
GUD No GUD
0
.5
1
1.5
2
2.5
3
3.5
4
4.5
5
<1700 1700- 12,500- 38,500+ GUD
Log Viral Load (c/mL)
Pro
bab
ilit
y o
f Tra
nsm
issio
n/1
000 C
oit
al
Acts
Vernazza PL et al. AIDS. 2000;14:117-121.
ART-Induced Reduction in Plasma HIV RNA Associated with Decreased
Levels in Semen
0
20
40
60
80
100
Pat
ient
s (%
) w
ith
dete
ctab
le H
IV in
sem
en
n=55
n=114
Controls (drug naive)
Effective ART
HIV-RNA
P<0.0001
HIV-DNA
P=0.01
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.
12/07
Current DHHS Guidelines for Initiating ART: Chronic Infection
Clinical Category and/or CD4 Count
Recommendation
History of AIDS-defining illnessCD4 <200 cells/mm³CD4 200-350 cells/mm³
Initiate ART
Indications for HAARTRegardless 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
12/07
DHHS Guidelines
Clinical Category and/or CD4 Count
Recommendation
CD4 >350 cells/mm³, asymptomatic, without conditions listed above
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, HPV-
associated 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
Once Treatment is Started, Can We Stop?
Consequences of Stopping ART:
SMART Trial
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)
HIV-1-infected patients with
CD4+ cell count > 350 cells/mm3
(N = 5472)
95.4% treatment experienced
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%.
Favors VS ►(viral suppression)
►
Favors DC(drug conservation)
#Pts w/ EventsEndpoints Relative Risk (95% CI)
Death from any cause or Opportunistic Disease 167
Serious opportunistic disease 15
2.6
6.6Death from any cause 85
1.8
0.1 1 10
Severe Complications* 1041.7
*CVD, Renal, Hepatic Events (fatal/nonfatal)El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.
SMART: Primary Endpoint and Components
SMART: Why Did the “STI” Arm Have More Clinical Progression?
N = 5472; randomized trial comparing continuous treatment (VS) to “STI” arm (DC):
— Stop meds CD4 >350
— Restart CD4 <250
Trial halted Jan 2006
— 2.63 greater risk of OI/death in DC versus VS arm
Greater risk of DC strategy explained by:
— Lower CD4 count
— Higher viral load at higher CD4 counts
Implications for “When to Start?”
0
2
4
6
8
10
12
14
16
<250 250-349 350-499 >499
DC
VS
Event Risk by Time Updated CD4 Count1
Time Spent at Different CD4 Strata2
0
5
10
15
20
25
30
35
< 200
< 250
< 350
Follow
-Up
Tim
e
(%)
VS GroupDC Group
31.7
7.28.2
1.73.1 0.8
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.
OI/
Death
by
Arm
Du
rin
g
Stu
dy (
%)
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
N NIncidence rate ratio
P value
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< 0.001
Continuous CD4 guided
What to Start With?
Initial Treatment: Preferred Components
*Avoid in pregnant women and women with significant pregnancy potential.
**Emtricitabine can be used in place of lamivudine and vice versa.
Efavirenz*
OR
Atazanavir + ritonavir
Fosamprenavir + ritonavir (BID)
Lopinavir/ritonavir (BID)
NNRTI Option
PI Options
Tenofovir + emtricitabine**
Zidovudine + lamivudine**
+
NRTI Options
Initial Treatment: Alternative Components
*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
Nevirapine*
OR
Atazanavir**
Fosamprenavir
Fosamprenavir + ritonavir (1x/day)
Lopinavir/ritonavir (1x/day)
NNRTI Option
PI Options
Abacavir + lamivudine
Didanosine + (emtricitabine or lamivudine)
NRTI Options
Initial Treatment: Other Possible Options
Abacavir + lamivudine + zidovudine (coformulated)
Nelfinavir*
Saquinavir (ritonavir-boosted)
Stavudine + lamivudine
Inferior virologic efficacy
Inferior virologic efficacy
Inferior to lopinavir/ritonavir
Significant toxicities
RationaleARV drugs or regimens
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 5142Study Design
LPV/r + NRTI EFV + NRTI LPV/r + EFV
Primary Study ObjectivesPrimary Study ObjectivesTime to virologic failure*Time to virologic failure*
Time to regimen completionTime to regimen completion††
Major inclusion criteria:ART naïve, Any CD4 or HIV
RNA >2000 c/mL
Major inclusion criteria:ART naïve, Any CD4 or HIV
RNA >2000 c/mL
*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 virologic failure or d/c secondary to any treatment related discontinuation of any componenttreatment related discontinuation of any componentRiddler S, et al. Presented at: XVI IAC; August 13-18, 2006; Toronto, Canada. August 13–18, 2006; Abstract THLB0204.
753 Patients randomized in open label design
ACTG 514296-Week Outcomes (ITT)
75
89
77
67
83
73
0
10
20
30
40
50
60
70
80
90
100
Without Virologic Failure <50 c/mL
Pat
ient
(%)
EFV + 2 NRTI (n = 250) LPV/r + 2 NRTI (n = 253) LPV/r + EFV (n = 250)
Riddler S, et al. Presented at: XVI IAC; August 13-18, 2006; Toronto, Canada. Abstract THLB0204.
EFV vs LPV: P = .006
EFV vs LPV/EFV: P = .5
LPV vs LPV/EFV: P =.13
CD4+ Cell Count Change from BL:+239 vs +285 vs +268 P =.01)
EFV vs LPV: P = .003EFV vs LPV/EFV: P = .123LPV vs LPV/EFV: P = .183
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 TDF-containing regimens
Lipoatrophyby Randomized Group
0 10 20 30 40
48 Weeks
96 Weeks
EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r
Lipoatrophy (>20% Limb Fat Loss) (%)
P Values at Week 96 LPV/EFV vs LPV: .023LPV/EFV vs EFV: <.001LPV vs EFV: .003
P Values at Week 96 LPV/EFV vs LPV: .023LPV/EFV vs EFV: <.001LPV vs EFV: .00321
10
7
3217
9
Haubrich R, et al. Presented at: 14th CROI; February 25–28, 2007; Los Angeles, CA. Abstract 38.
n = 188
n = 197
n = 166
n = 171
n = 173
n = 191
Lipoatrophy by NRTI
0 10 20 30 40 50
48 Weeks
96 Weeks
d4T ZDV TDF
% Lipoatrophy (>20% Limb Fat Loss)
26
168
42
27
9
n = 93
n = 153
n = 117
n = 84
n = 136
n = 133
P Values at Week 96
ZDV vs TDF: <.001
d4T vs TDF: <.001
d4T vs ZDV: .038
P Values at Week 96
ZDV vs TDF: <.001
d4T vs TDF: <.001
d4T vs ZDV: .038
ZVD = ziclovidiine.Haubrich R, et al. Presented at: 14th CROI; February 25–28, 2007; Los Angeles, CA. Abstract 38.
ZDV/3TC/EFV
•Phase III, randomized, double–blind, placebo–controlled study to evaluate Phase III, randomized, double–blind, placebo–controlled study to evaluate a) ZDV/3TC + EFV, b) ZDV/3TC/ABC + EFV and c) ZDV/3TC/ABCa) ZDV/3TC + EFV, b) ZDV/3TC/ABC + EFV and c) ZDV/3TC/ABC
•ZDV/3TC/ABC found to be inferior and discontinuedZDV/3TC/ABC found to be inferior and discontinued
ART-naïve patientsN = 765, Compared for 3 years
ZDV/3TC/ABC/EFV
Virologic Failure99 patients
Virologic Failure94 patients
Baseline Characteristics
240 Median CD4 (cells/mm³) 240
4.9 Mean Viral Load (log10 c/mL ) 4.9
How Many NRTIs?ACTG 5095: Study Design
92% <200 (P= .59)88% <50 (P = 0.39)
90% <200 (P = .59)85% <50 (P = .39)
Results at Year 3Results at Year 3
ABC = abacavir.Gulick R, et al. JAMA. 2006;296:769-781.
ACTG 5095Time to Virologic Response
Time (wk)
Pro
bab
ilit
y o
f N
o R
esp
on
se
0 72 14424 96 16848 1200
0.2
0.4
0.6
0.8
1.0
ZDV/3TC/ABC+EFVZDV/3TC+EFV
Confirmed HIV RNA <200 c/mLConfirmed HIV RNA <200 c/mL
Gulick R, et al. JAMA. 2006;296:769-781.
No difference of probability of not failing among patients with HIV RNA >100,000 c/mL
ACTG 5095 Impact of Baseline Values and Risk of Virologic Failure
at 3 Years on EFV
By Baseline HIV RNA LevelBy Baseline HIV RNA Level
By Baseline CD4 Cell CountBy Baseline CD4 Cell Count
1.0 1.75 2.850.660.35
<50
50-199
200-349
350-499
≥500
≥300,000
100,000-299,999
30,000-99,999
<30,000
Ribaudo H, et al. Presented at: XVI IAC; August 13–18, 2006; Toronto, Canada Abstract THLB0211.
1.0 1.75 2.850.660.35
TDF QDFTC QDEFV QD
(n = 255)
Noninferiority Trial, Primary Endpoint <400 c/mL at Week 96TLOVR
CBV BIDEFV QD
(n = 254)
Week 144
Stratification by
HIV RNA >10,000 c/mL Any CD4 count
Baseline Characteristics86% Male 87%36 Age (Median) 37233 Median CD4
(cells/mm³)241
5.0 Median Viral Load (log10 c/mL )
5.0
Adequate Renal and Hepatic Function at baselineFTC/TDF Fixed dose combination tablet was not used
What NRTIs? GS 934: Study Design
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.
ARV-naïve patientsrandomized 1:1
Week 144
BL 8 16 24 32 40 48 60 72 84 96
Proportion <50 c/mL (TLOVR)
0
10
20
30
40
50
60
70
80
90
TDF+FTC+EFV 67*
CBV+EFV 61*
P = .16
*95% CI: (-2.3%, +15.0%)
Time (wk)
Resp
on
der
(%)
Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.
Mean Absolute Change in CD4 Count From Baseline
0
50
100
150
200
250
300
BL 8 16 24 32 40 48 60 72 84 96
Time (wk)
270 TDF+FTC+EFV
237 CBV+EFV
P = .036
n = 255 238 234 223 218 209 199 177 184 172 166
n = 254 222 216 199 188 175 164 145 149 149 142
Mean
Ch
an
ge (
cells/m
m3)
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).
P =.017
P = .036
Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.
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
Entry criteria
— HIV-1 RNA 1000 c/mL
— No CD4 cell count restrictions
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
ART-naïve subjects
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
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
66 65 63 66 6767 646370666465
0
20
40
60
80
100 FPV/ r BID LPV/ r BID
TLOVR 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
Pro
port
ion
of
Su
bje
cts
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
0
50
100
150
200
250
FPV/ r LPV/ r FPV/ r LPV/ r
mg/d
L
Baseline Wk 48
Cholesterol Triglycerides
Baseline n= 363 377 363 377Wk 48 n= 287 294 287 294
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.
