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00002-E-1 – 1 December 2003
Anti-HIV drugs 2010-2011
Andrea De Luca, M.D.
Institute of Clinical Infectious Diseases. Catholic University, Rome
2nd Division of Infectious Diseases, University Hospital of Siena,
Italy
CD4 +
HIV RNA
time
HAART
MortalityOpportunistic infections
Goals of antiretroviral therapy
00002-E-3 – 1 December 2003
Probability (%) to develop full blown AIDS in the subsequent 3 years by CD4 counts and HIV RNA levels before and after the introduction
of antiretroviral therapy
Without therapy
With therapy
00002-E-4 – 1 December 2003
New AIDS cases per year of diagnosis in Italy
Limitations of antiretroviral therapy
morbidity and mortality but…
Eradication impossible because of latently infected CD4+ memory T cells
Emergence of drug resistance
LIFE-LONG CHRONIC TREATMENT NECESSARY
TolerabilityAdherence
00002-E-6 – 1 December 2003
Antiviral potency and developmentof drug-resistance
Antiviral potency
Ris
k of
dev
elop
men
t of
dru
g-re
sist
ance
poor suboptimal high
Poor pharmacokineticsSuboptimal adherence
Drug pressure selects
resistant virus
Inadequate drug pressure to select
resistant virus
Complete viral suppression
Increasing adherence
RT
Provirus
ProteinsRNA
DNA
RNA
DNA
DNA
RT Viral regulatoryproteins
Viral protease
Reversetranscriptase
Viral integrase
RNA
RNA
Attachment, fusion and entry
DNA
DNA
DNA
Viral zinc-fingernucleocapsid
proteins
00002-E-8 – 1 December 2003
Antiretroviral drugs and classes licensed for use in developed countries
Nucleoside/
nucleotide RT
inhibitors
Non-nucleoside
RT inhibitors
Protease inhibitors Fusion
inhibitors
Integrase
inhibitors
CCR5
antagonists
Zidovudine Nevirapine Saquinavir/rit Enfuvirtide Raltegravir Maraviroc
Didanosine Efavirenz (Ritonavir)
(Zalcitabine) (Delavirdine) Indinavir/rit
Lamivudine Etravirine Nelfinavir
Stavudine Fosamprenavir/(rit)
Abacavir Lopinavir/rit
Tenofovir Atazanavir/ (rit)
Emtricitabine Tipranavir/rit
Darunavir/rit
00002-E-9 – 1 December 2003
NRTI
Historical ARV drugs. Still difficult to avoid
Essential component of ART regimens (2 NRTI+ x)
Alone: Low/intermediate potency, intermediate genetic barrier
Class-toxicity: mitochondrial toxicity (lipoatrophy, peripheral
neuropathy, pancreatitis, hyperlipemia)
Individual components related to organ-specific toxicities (bone
marrow, renal/bone, cardiovascular)
00002-E-10 – 1 December 2003
NNRTI
High potency, low genetic barrier to resistance (except 2nd
generation)
Toxicity: cutaneous (rash, SJS), liver, lipid (modest)
Individual components: organ-specific (EFV: CNS, teratogenicity;
NVP: liver)
00002-E-11 – 1 December 2003
PI
Potent, high genetic barrier (ritonavir-boosted)
Class-toxicity: metabolism (lipid, glicidic, lipodystrophy, cardiovascular)
Ritonavir toxicity (gastrointestinal, lipids)
Lopinavir and fosamprenavir probably cause diarrhea per se
Specific toxicities: hyperbilirubinemia (atazanavir), cutaneous reactions
(sulpha component of fosamprenavir and darunavir), nephrolithiasis
(indinavir>atazanavir)
00002-E-12 – 1 December 2003
FI, INSTI, CCR5 antagonists
All potent drugs but low/intermediate genetic barrier to
resistance
FI: injection site reactions
Other drugs: very modest toxicity – Raltegravir: CNS/psychiatric, muscle– Maraviroc: liver
00002-E-13 – 1 December 2003
ART: Recent /Future developments
Goal (virologic suppression) achieved in 85-90% of patients in trials and
clinical practice (drug naive and experienced patients)
Towards more simple regimens (one pill/day)
Increased genetic barrier
Improved tolerability
Further improvements: – Less medium-long term toxicity (metabolic, cardiovascular, renal/bone)– PK boosting without ritonavir
00002-E-14 – 1 December 2003
New treatments and strategies for naive patients
00002-E-15 – 1 December 2003
ARTEMIS: Wk 96 Lipid and Anthropometric Substudy
Randomized noninferiority trial of
DRV/RTV vs LPV/RTV, both with
TDF/FTC, in naive pts– DRV/RTV noninferior to LPV/RTV at Wk
48. At Wk 96, DRV/RTV met superiority criteria vs LPV/RTV
In anthropometric analysis at Wk 96,
no increase in median midwaist:midhip
ratio in either study arm
Changes in BMI, body weight,
midwaist, chest, hip, and
circumferences similar between arms
and not clinically relevant
DRV/RTV
LPV/RTV
TC LDL-C HDL-C TG 0
10
20
30
40
50
26
35
17 15
5 8
18
56
Med
ian
Incr
ease
at W
k 96
(m
g/dL
)
Baraldi E, et al. IAS 2009. Abstract MOPEB034.
Statistically greater % increases in TC, TG in
LPV/RTV arm than DRV/RTV arm (P < .001)
60
00002-E-16 – 1 December 2003
STARTMRK: Metabolic, Body Composition Changes at Wk 96 With RAL vs EFV
DeJesus E, et al. CROI 2010. Abstract 720. Adapted with permission of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. All Rights Reserved.
Mea
n C
hang
e (m
g/dL
)
0
40
50
20
30
10
-10TC HDL-C LDL-C TG Glucose
App
endi
cula
r F
at M
ean
Per
cent
(S
E)
Cha
nge
40
20
30
10
0
0 48 96Wks
56 46 38
55 40 37
EFV
RAL
Contributing Patients, n
18.1
17.7 17.0
18.2P < .001
P < .001
P < .001
P < .001
P = .025
RAL
EFV
00002-E-17 – 1 December 2003
MERIT: Wk 96 Response With MVC vs EFV in Naive Pts
MERIT-ES: reanalysis of MERIT trial using enhanced phenotypic tropism assay suggested noninferiority of MVC to EFV when additional pts with D/M-tropic virus identified by enhanced assay excluded[1]
Wk 96 efficacy analysis included only MERIT-ES population[2]
Similar proportions in MVC and EFV with VL < 50 copies/mL at Wk 96
CD4+ increase at Wk 96 greater with MVC vs EFV (+212 vs +171 cells/mm³)
EFV more likely discontinued for AEs: 15.5% vs 6.1% on MVC
MVC more likely discontinued for insufficient response: 12.5% vs 5.9% on EFV
EFV + ZDV/3TC MVC + ZDV/3TC
MERIT MERIT-ES
0
20
40
60
80
100
HIV
-1 R
NA
< 5
0 c/
mL
(%
)
69.3 65.3 68.3 68.5
Wk 48
62.458.5
Wk 96
MERIT-ES
60.7 60.5
n 361 360 303 311 203 210 303 311
ITT, NC = F Modified ITT
TLOVR
1. Saag M, et al. ICAAC/IDSA 2008. Abstract 1232a. 2. Heera J, et al. IAS 2009. Abstract TUAB103. 3. Nelson M, et al. IAS 2009. Abstract MOPEB040.
Higher levels of dyslipidemia on EFV
5/15 pts who discontinued EFV for tolerability developed NNRTI mutations in follow-up[3]
00002-E-18 – 1 December 2003
Rilpivirine 25 mg QD+ TDF/FTC 300/200 mg QD
(n = 346)
EFV 600 mg QD+ TDF/FTC 300/200 mg QD
(n = 344)
*THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC.
Stratification by BL HIV-1 RNA < 100,000
vs ≥ 100,000 copies/mL, NRTI use*
Wk 96final analysis
Wk 48primary analysis
Rilpivirine 25 mg QD+ 2 NRTIs†
(n = 340)
EFV 600 mg QD+ 2 NRTIs†
(n = 338)
ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
Randomized, double-blind phase III trials
Cohen C, et al. AIDS 2010. Abstract THLBB206.
ECHO(N = 690)
THRIVE(N = 678)
Treatment-naive, HIV-1 RNA ≥ 5000 copies/mL
no NNRTI RAMs,susceptible to NRTIs
00002-E-19 – 1 December 2003
ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48
*P < .0001 for noninferiority at -12% margin.
Rilpivirine EFV
Cohen C, et al. AIDS 2010. Abstract THLBB206. Graphics used with permission.
HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL
40
0
100
20
8082.384.3
60
682686n =
ECHO THRIVEPooled
Pat
ient
s (%
)
82.882.9 81.785.6
338340344346
-3.6 (-9.8 to +2.5)-3.6 (-9.8 to +2.5)
6.6 (1.6-11.5)6.6 (1.6-11.5)
> 100,000 copies/mL
125/165
121/153
246/318
149/181
136/171
285/352
7781 79 8076 82
Pat
ient
s (%
)
40
0
100
20
80
60
Pooled THRIVEECHO
≤100,000 copies/mL
162/181
170/187
332/368
136/163
140/167
276/330
9083
9184
9084
Pat
ient
s (%
)
40
0
100
20
80
60
ECHO THRIVEPooled
00002-E-20 – 1 December 2003
ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events
Wk 48 Outcome Rilpivirine(n = 686)
Efavirenz(n = 682)
VF with resistance data, n 62 28
No NNRTI or NRTI RAMs,% 29 43
1 Emergent NNRTI RAM,% 63 54
Most frequent NNRTI RAM E138K K103N
1 Emergent NRTI RAMs, % 68 32
Most frequent NRTI RAM M184I M184V
Cohen C, et al. AIDS 2010. Abstract THLBB206. Table used with permission.
Treatment Failure in ECHO and THRIVE
Adverse Events and Discontinuation
Resistance at Virologic Failure
6
0
15
3
12
94.8
346n =
VF
9.0
682686
6.7
AE
2.0
682686
Pat
ient
s (%
)
Wk 48 Outcome, % Rilpivirine(n = 686)
Efavirenz(n = 682)
P Value
DC for AE 3 8 .0005
Most Common AEs of Interest, %
Any neurologic AE 17 38 < .0001
Any psychiatric AE 15 23 .0002
Any rash 3 14 < .0001
Rilpivirine
EFV
00002-E-21 – 1 December 2003
GS-9350–Boosted Elvitegravir + FTC/TDF Noninferior to EFV/FTC/TDF in Naive Pts
Cohen C, et al. CROI 2010. Abstract 58LB. Reproduced with permission.
Wk 24 stratum-weighted difference: +5%
(95% CI: -11.0% to 21.1%)HIV
-1 R
NA
< 5
0 c/
mL
(%
)
100
80
60
40
20
0
Wk0 4 8 12 16 20 24
GS-9350/EVG/FTC/TDFEFV/FTC/TDF
8390
ITT, M = F
Cobicistat (GS-9350): investigational CYP3A
inhibitor (boosting agent)
GS-9350/EVG/FTC/TDF(n = 48)
EFV/FTC/TDF (n = 23)
Treatment-naive pts with CD4+
≥ 50 cells/mm3, HIV-1 RNA
≥ 5000 c/mL, no NRTI, NNRTI, or PI
resistance
(N = 71)
Wk 24 primary endpoint
analysis Wk 48
Elvitegravir: investigational integrase inhibitor
00002-E-22 – 1 December 2003
GS-9350–Boosted ATV Virologic Efficacy Similar to ATV/RTV in Naive Pts
Cohen C, et al. CROI 2010. Abstract 58LB. Reproduced with permission.
Wk 24 stratum-weighted difference: -1.9%
(95% CI: -18.4% to 14.7%)HIV
-1 R
NA
< 5
0 c/
mL
(%
)
GS-9350–Boosted ATV + FTC/TDF
(n = 50)
RTV-Boosted ATV + FTC/TDF
(n = 29)
Treatment-naive pts with CD4+
≥ 50 cells/mm3, HIV-1 RNA
≥ 5000 c/mL, no NRTI, NNRTI, or PI
resistance
(N = 79)
Wk 24 primary endpoint Wk 48 100
80
60
40
20
0
Wk
0 4 8 12 16 20 24
RTVGS-9350
8684
ITT, M = F
Phase II study comparing cobicistat (GS-9350) vs ritonavir as
boosting agent for atazanavir
00002-E-23 – 1 December 2003
Wk 16
Treatment naive,HIV-1 RNA
> 1000 copies/mL,no CD4+ cell count
restriction
(N = 205)
*NRTIs individually selected by trial investigators (TDF/FTC, 67%; ABC/3TC, 33%).†After Wk 48, all patients continue at dose selected for phase III trial.
S/GSK1349572 10 mg QD+ 2 NRTIs QD*
(n = 53)
S/GSK1349572 25 mg QD+ 2 NRTIs QD*
(n = 51)
S/GSK1349572 50 mg QD+ 2 NRTIs QD*
(n = 51)
EFV 600 mg QD+ 2 NRTIs QD*
(n = 50)
Arribas J, et al. AIDS 2010. Abstract THLBB205.
Dose-ranging, partially blinded phase IIb trialWk 48
SPRING-1: S/GSK1349572 vs EFV in Treatment-Naive Patients
00002-E-24 – 1 December 2003
SPRING-1: Virologic Response to S/GSK1349572 vs EFV at Wk 16
CD4+ cell count increases 153-176 cells/mm³ on S/GSK1249572 vs 116 cells/mm3 on EFV
No serious adverse events related to S/GSK1349572
Arribas J, et al. AIDS 2010. Abstract THLBB205. Graphic used with permission.
Wks
HIV
-1 R
NA
< 5
0 co
pie
s/m
L (T
LOV
R),
%
96%92%90%
60%
Time to < 50 copies/mL shorterfor S/GSK1349572 dose than EFV(P < .001 for each comparison)
100
80
60
40
20
0
BL 1 2 4 8 12 16
50-mg dose chosen for phase III trial
572 10 mg572 25 mg
572 50 mgEFV 600 mg
00002-E-25 – 1 December 2003
ARTEN: Wk 48 Response to NVP vs ATV/RTV in Naive Pts
NVP either once daily or twice daily
noninferior to ATV/RTV at Wk 48
Rates of AEs similar overall but higher rate
of discontinuation due to toxicity in NVP
arms (13.6% vs 3.6%)
HIV
-1 R
NA
< 5
0 c/
mL
at W
k 48
(%
)
40
0
100
20
80
Any NVP
65.366.8
60
P = .63
ITT, NC = F
NVPQD
NVPBID
67.0 66.5
Outcome at Wk 48, %
NVP QD(n = 188)
NVP BID(n = 188)
ATV/RTV(n = 193)
Virologic failure 11.2 12.8 14.0
Investigator-defined virologic failure
5.9 11.2 1.6
No confirmed response at Wk 48
5.3 1.6 12.4
Soriano V, et al. IAS 2009. Abstract LBPEB07.
ATV/ RTV
n = 376 193 188 188
00002-E-26 – 1 December 2003
VERxVE: Extended-Release NVP vs Standard NVP in Naive Patients at Wk 48
Multicenter, randomized, double-blind,
noninferiority study in treatment-naive
patients– NVP XR 400 mg QD (n = 508) vs
– NVP IR 200 mg BID (n = 505)
– Both combined with TDF/FTC
Inclusion criteria– HIV-1 RNA > 1000 copies/mL
– CD4+ cell count < 400 cells/mm3 if male or < 250 cells/mm3 if female
Similar safety and tolerability for both arms
AEs included
– Stevens-Johnson (n = 5)
– Hepatitis (n = 14)
– Rash (n = 21)
0
20
40
60
80
100
NVP IR NVP XR
81.075.9
HIV-1 RNA < 50 copies/mL (TLOVR)
Gathe J, et al. AIDS 2010. Abstract THLBB202.
Adjusted difference 4.92% (95% CI: -0.11 to 9.96)
00002-E-27 – 1 December 2003
PROGRESS: LPV/RTV + RAL vs LPV/RTV + NRTIs in Treatment-Naive Patients
Randomized, open-label, multicenter phase III trial in treatment-naive patients with HIV-1 RNA > 1000 copies/mL
– LPV/RTV 400 mg BID + RAL 400 mg BID (n = 101) vs
– LPV/RTV 400 mg BID + TDF/FTC 300/200 mg QD (n = 105)
Relatively low mean
baseline HIV-1 RNA
– 4.25 log10 copies/mL
Reynes J, et al. AIDS 2010. Abstract MOAB0101. Graphic used with permission.
Similar CD4+ cell count gain at Wk 48
– LPV/RTV + RAL: 215 cells/mm³
– LPV/RTV + NRTIs: 245 cells/mm³
0
20
40
60
80
100
Wks
0
HIV-1 RNA < 40 copies/mL (ITT-TLOVR)
8 16 24 32 40 48
83.2%
84.8%
Difference: -1.6% (95% CI: -12.0% to 8.8%)
*Statistically significant difference between arms:Wks 2, 4, 8 P < .002Wk 16 P = .038
**
*
*
Pat
ient
s (%
)
LPV/RTV + RAL
00002-E-28 – 1 December 2003
Mean increases in TC, TG, and HDL-C
from BL to Wk 48 significantly greater in
RAL arm vs NRTI arm
Reynes J, et al. AIDS 2010. Abstract MOAB0101.
Resistance Development at VF
LPV/RTV + RAL
LPV/RTV + NRTIs
Met criteria for resistance testing
4 3
INSTI mutation (N155H)
1 0
NRTI mutations (M184V)
0 1
0
20
40
60
80
100
TC TG HDL-C
Mea
n C
hang
e F
rom
BL
, m
g/dL +46
+29
+99
+59
+12+8
P = .008
P = .044
P = .015
LPV/RTV + RAL LPV/RTV + NRTIs
PROGRESS: Lipids and Adverse Events at Wk 48
Grade 3/4 laboratory events did not differ
between arms, except higher risk of CPK
> 4 x ULN in RAL arm– 12.9% vs 3.8% (P = .023)
00002-E-29 – 1 December 2003
A4001078: ATV/RTV + MVC vs ATV/RTV + TDF/FTC—Wk 24 Interim Analysis
CD4 + cell count increases similar– ATV/RTV + MVC: 195 cells/mm³
– ATV/RTV + TDF/FTC: 173 cells/mm³
Grade 3/4 hyperbilirubinemia – ATV/RTV + MVC: 59.3% – ATV/RTV + TDF/FTC: 49.2%
5 patients in MVC arm, 1 patient in TDF/FTC arm
switched to DRV/RTV per protocol for jaundice or
scleral icterus Mills A, et al. AIDS 2010. Abstract THLBB203.
40
0
100
20
80
HIV-1 RNA < 100K
95
80
60
7781
HIV-1 RNA 100K
HIV-1 RNA < 50 copies/mL Overall and by BL VL
22163944
Overall
8980
6160
Pat
ient
s (%
)
n =
ATV/RTV + MVC
ATV/RTV + TDF/FTC
00002-E-30 – 1 December 2003
SPARTAN: Pilot Study of ATV + RAL vs ATV/RTV + TDF/FTC in Naive Pts
Randomized, noncomparative, open-
label, multicenter pilot study in
treatment-naive patients with HIV-1
RNA ≥ 5000 copies/mL– ATV 300 mg BID +
RAL 400 mg BID (n = 63) vs
– ATV/RTV 3001/00 mg QD + TDF/FTC 300/200 mg QD (n = 31)
Mean BL HIV-1 RNA:
4.9 log10 copies/mL
Kozal MJ, et al. AIDS 2010. Abstract THLBB204. Graphic used with permission.
Wks
0
20
40
60
80
100
BL 4 8 12 16 20 24
Pat
ient
s (%
)
74.6%
63.3%
Primary Endpoint: HIV-1 RNA < 50 copies/mL Through Wk 24 (CVR*, NC = F)
ATV BID + RAL BID ATV/RTV QD + TDF/FTC
*CVR = modified ITT.
00002-E-31 – 1 December 2003
SPARTAN: Wk 24 Results
No significant changes in fasting
lipids observed in either arm
during study period
Trial terminated at Wk 24 due to
resistance data
and grade 4 bilirubin abnormalities
(21%) with experimental regimen
vs control arm (0%)
Resistance Through Wk 24, n
ATV + RAL(n = 63)
ATV/RTV + TDF/FTC(n = 30)
Virologic failure (HIV-1 RNA > 50 copies/mL) 11 8
BL HIV-1 RNA > 250,000 copies/mL 8 4
Evaluable for resistance testing * (HIV-1 RNA > 400 copies/mL) 6 1
Genotypic and phenotypic RAL resistance
N155H 2 NA
Q148R 1 NA
Q148R + N155H + T97A 1 NA
Phenotypic RAL resistance without genotypic evidence of resistance
1 NA
ATV resistance 0 0
TDF/FTC resistance NA 0
Kozal MJ, et al. AIDS 2010. Abstract THLBB204.
*Criteria for resistance testing: HIV-1 RNA ≥ 400 copies/mL at or after Wk 24 Rebound to HIV-1 RNA ≥ 400 any time during the study Discontinued before achieving HIV-1 RNA < 50 copies/mL after Wk
8 with last HIV RNA ≥ 400 copies/mL
00002-E-32 – 1 December 2003
SENSE: EFV vs ETR in Treatment-Naive Patients
Randomized, double-blind trial of treatment-
naive patients with
HIV-1 RNA > 5000 copies/mL– EFV 600 mg QD (n = 78) vs
– ETR 400 mg QD (n = 79)
– Each with investigator-selected NRTIs (TDF/FTC, ABC/3TC, or ZDV/3TC)
Primary endpoint: % of patients with grade 1-
4 drug-related treatment-emergent
neuropsychiatric AEs
at Wk 12
Mean change in HIV-1 RNA at Wk 12 similar
between arms (-2.9 log10 copies/mL)
More drug-related neuropsychiatric AEs
in EFV arm vs ETR arm
40
0
100
20
80
46
17
60
175
Grade 1-4 Grade 2-4
EFV ETR EFVETR
10 patients discontinued in ETR and 8 in EFV arm by Wk 12Gazzard B, et al. AIDS 2010. Abstract LBPE19.
Drug-Related Neuropsychiatric AEs
Pat
ient
s (%
)
P < .001 P = .02
00002-E-33 – 1 December 2003
Switch/simplification studies
00002-E-34 – 1 December 2003
BL HIV-1 RNA < 100,000 c/mL
BL HIV-1 RNA ≥ 100,000 c/mL
ATV (n = 210)
ATV/RTV (n = 209)
Squires K, et al. IAS 2009. Abstract WELBB103. Graphic used with permission.
HIV
-1 R
NA
< 5
0 c/
mL
at W
k 84
(%
)
Overall Results0
20
40
60
80
10086
80.885
7987
82
ARIES: Boosted vs Unboosted ATV Maintenance: Wk 84 Results
00002-E-35 – 1 December 2003
SPIRAL: Switch to RAL Noninferior to Maintaining PI/RTV Regimens
0
20
40
60
80
100
Switch to RAL
Continue PI/RTV
86.689.2
Free of Treatment Failure at Wk 48 (ITT, S = F)
Patients With VFRAL
(n = 4)PI/RTV(n = 6)
Prior VF 1 3
Prior suboptimal ART 2 3
Prior resistance mutations 1 5
Resistance test at VF 1 4
Mutations 0 3 (PR, RT)
Martinez E, et al. AIDS. 2010;24:1697-1707.
Mean Change From Baseline to Wk 48, %
Switch to RAL
Continue PI/RTV
P Value
Triglycerides -22.1 +4.7 < .0001
TC -11.2 +1.8 < .0001
LDL-C -6.5 +3.0 < .001
HDL-C -3.2 +5.8 < .0001
Total to HDL-C ratio
-4.9 -1.3 < .05
00002-E-36 – 1 December 2003
MONET Trial: 96-Wk Efficacy Results of Switch to DRV/RTV Monotherapy
Randomized, open-label trial of switch to
DRV/RTV monotherapy vs continuing
DRV/RTV HAART in virologically
suppressed pts
DRV/RTV monotherapy noninferior vs
DRV/RTV HAART at Wk 48[1]
Monotherapy NOT noninferior with switch =
failure analysis at Wk 96[2]
– Δ -5.8% (95% CI: -16.0% to +4.4%)
If resuppression with intensification included
as success, then monotherapy noninferior
at Wk 96– Δ +1.4% (95% CI: -5.5% to +8.3%)
1. Arribas JR, et al. IAS 2009. Abstract TUAB106LB. 2. Rieger A, et al. AIDS 2010. Abstract THLBB209.
HIV-1 RNA < 50 copies/mL, ITT, TLOVR (%)
40
0
100
20
80
Wk 48[1]
85.384.3
60
DRV/RTV monotherapy (n = 127)DRV/RTV + 2 NRTIs (n = 129)
80.674.8
Wk 96[2]
Switch = failure 92.1 90.7
Switch allowed
00002-E-37 – 1 December 2003
Treatment-experienced individuals
00002-E-38 – 1 December 2003
0 10 20 30 40 50 60 70 80 90 100
BENCHMRK PL
BENCHMRK
DUET PL
DUET
MOTIVATE PL
MOTIVATE
POWER PL
POWER
0 10 20 30 40 50 60 70 80 90 100
BENCHMRK PL
BENCHMRK
DUET PL
DUET
MOTIVATE PL
MOTIVATE
POWER PL
POWER
%
48w
96w
Evolving efficacy of antiretroviral regimens in multiexperienced patients (percent <50 copies/ml)
00002-E-39 – 1 December 2003
Pooled DUET 96-Wk Results: ETR + DRV/RTV-Containing OBR in Exp’d Pts
HIV
-1 R
NA
< 5
0 c/
mL
(%
)(I
TT
-TL
OV
R)
40
0
100
20
80P < .0001
Wk 48 Wk 96
39
60
36
5760
P < .0001
Randomized trial of ETR vs placebo, both with
DRV/RTV-containing OBR in multiclass-
resistant pts– Superior virologic suppression with ETR at Wks 24
(primary endpoint) and 48
Superior virologic suppression maintained at
Wk 96 in ETR vs placebo arm[1]
– Higher response with ETR irrespective of number of active agents, baseline ETR FC, weighted score, sex, race, and age
Greater mean change in CD4+ cell count with
ETR vs placebo – +123 vs +86 cells/mm³ (P < .0001) No new safety signals in Wks 48-96[2]
– New rash in < 1% of pts
– CNS adverse effects similar between arms in Wks 48-96
ETR (n = 599)
Placebo (n = 604)
1. Mills A, et al. IAS 2009. Abstract MOPEB036. 2. Nelson T, et al. IAS 2009. Abstract MOPEB038.
00002-E-40 – 1 December 2003
ODIN: QD vs BID Darunavir/Ritonavir + OBR in Treatment-Experienced Patients
Cahn P, et al. CROI 2010. Abstract 57.
QD DRV/RTV 800/100 mg + OBR*(n = 294)
Treatment-experienced adults with stable HAART for
≥ 12 wks, HIV-1 RNA> 1000 copies/mL, CD4+
> 50 cells/mm3, no DRV RAMs
(N = 590)
Wk 48
*OBR included ≥ 2 active NRTIs.
Stratified by baseline HIV-1 RNA ≤ and
> 50,000 copies/mL
BID DRV/RTV 600/100 mg + OBR* (n = 296)
Primary PI mutations in < 2% of patients in either arm
00002-E-41 – 1 December 2003
ODIN: HIV-1 RNA < 50 copies/mL at Wk 48 Overall and by Screening HIV-1 RNA
Similar CD4+ cell count increase between arms– QD DRV/RTV : +100 cells/mm3
– BID DRV/RTV : +94 cells/mm3
Cahn P, et al. CROI 2010. Abstract 57. Reproduced with permission.
100
Pts
Wit
h H
IV-1
RN
A
< 5
0 co
pies
/mL
(%
)
80
60
20
00 12 24 36 48
40
84Wks
Difference in response, QD vs BID:ITT = 1.2% (95% CI: -6.1%, 8.5%)
QD DRV/RTV 800/100 mgBID DRV/RTV 600/100 mg
72.170.9
100
Pts
Wit
h H
IV-1
RN
A
< 5
0 co
pies
/mL
(%
)
80
60
20
050,000
40
Screening HIV-1 RNA (copies/mL)
> 50,000
78.4 76.8
52.8 52.8
n = 222 224 72 72
00002-E-42 – 1 December 2003
ODIN: Virologic Failure Not Statistically Different Between Arms
Resistance Emergence in Pts With Virologic Failure and Paired Genotypes/Phenotypes
QD DRV/RTV + OBR BID DRV/RTV + OBR
Development of new RAMs,* n (%)
Primary PI 1 (1.7) 0
Any PI 7 (11.7) 4 (9.5)
Loss of susceptibility,† n (%)
Darunavir 1 (1.7) 0
Any PI 2 (3.4) 0
Cahn P, et al. CROI 2010. Abstract 57.
*Patients with paired baseline/endpoint genotypes evaluated (n = 60 in QD arm and n = 42 in BID arm).†Patients with paired baseline/endpoint phenotypes evaluated (n = 59 in QD arm and n = 41 in BID arm).
00002-E-43 – 1 December 2003
ODIN: Significantly Lower Rate of Lipid Abnormalities With DRV/RTV QD vs BID
Cahn P, et al. CROI 2010. Abstract 57.
AEs,* % QD DRV/RTV + OBR
(n = 294)
BID DRV/RTV + OBR
(n = 296)
P Value
Serious AEs 5.4 9.1 --
Grade 2-4 treatment-emergent laboratory abnormalities*
Total cholesterol† 10.1 20.6 < .0007
LDL-C† 9.8 16.7 < .019
Triglycerides 5.2 11.0 < .014*No significant differences in grade 3/4 AEs, AEs leading to treatment discontinuation, GI AEs, ALT levels, or AST levels.
00002-E-44 – 1 December 2003
VIKING: Second-Generation INSTI S/GSK1349572 in RAL-Resistant Patients
International, multicenter, single-arm, phase II
study in 27 patients with RAL resistance
– S/GSK572 50 mg QD to replace RAL in failing regimen (or added if RAL already d/c) for 10 days of functional monotherapy
– Day 11-Wk 24: S/GSK572 50 mg QD continued and regimen optimized
– Median fold-change in RAL susceptibility at BL: 161 (range: 0.6 - > 166)
– Median S/GSK572 FC at BL: 1.5 (range: 0.6-35)
Stratified by BL integrase genotype
– Group 1: Q148 + ≥ 1 secondary resistance mutations (n = 9)
– Group 2: All others (N155H and Y143H pathways) and single mutations at Q148 (n = 18)
HIV-1 RNA Response at Day 11
Group 1(n = 9)
Group 2(n = 18)
< 400 c/mL or ≥ 0.7 log10 c/mL decline, %
33 100
Change from baseline, log10 c/mL -0.72 -1.82
Day 1 FC to S/GSK572 highly predictive of Day 11 virologic response (r = 0.79; P < .001)
Among 18 paired isolates evaluated on Day 1 and Day 11, no evidence of emergent RAL mutations
– In 17 subjects, < 2 FC in susceptibility
– In 1 subject, ~ 6 FC in susceptibility
Eron J, et al. AIDS 2010. Abstract MOAB0105.
00002-E-45 – 1 December 2003
Resource-limited settings/special populations
ART in special populations: patients starting TB therapy for active disease
CD4 cell
count
recommendation Type of ART/comments
<350 Recommend ART as soon as TB
treatment tolerated
EFV-based > NVP
>350 Recommend ART as soon as TB
treatment tolerated (data
insufficient)
EFV-based >NVP
unavailable Recommend ART as soon as TB
treatment tolerated
EFV-based >NVP
00002-E-47 – 1 December 2003
SAPiT: Optimal Time to Initiate ART in HIV/TB-Coinfected Patients
Early ART ART initiated during intensive or
continuation phase of TB therapy (n = 429)
Sequential ART ART initiated after TB therapy
completed (n = 213)
HIV-infected patients diagnosed with TB and
CD4+ cell count < 500 cells/mm3
(N = 642)
Primary endpoint: all-cause mortality
00002-E-48 – 1 December 2003
Abdool Karim SS, et al. CROI 2009. Abstract 36a. Graphic reproduced with permission.
0.70
0.75
0.80
0.85
0.90
0.95
1.00
Sur
viva
l
Months Postrandomization
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Intensive phase of TB
treatment
Post-TB treatmentContinuationphase of TB
treatment
Early ARTSequential ART
SAPiT: Increased Survival With Concurrent HIV and TB Treatment
00002-E-49 – 1 December 2003
CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients (CD4<200)
Significantly higher incidence of IRIS with
early vs late HAART– 4.03 vs 1.44 per 100 person-mos, respectively (P
< .0001)
Blanc FX, et al. AIDS 2010. Abstract THLBB206. Graphic used with permission..
WkSurvival Probability, % (95% CI)
PEarly Arm Late Arm
50 86.1 (81.8-89.4)
80.7 (76.0-84.6) .07
100 82.6 (78.0-86.4)
73.0 (67.7-77.6) .006
150 82.0 (77.2-85.9)
70.2 (64.5-75.2) .002
Factor Multivariate Adjusted HR (95% CI)
P
Late therapy 1.52 (1.12-2.05) .007
BMI ≤ 16 1.68 (1.07-2.63) .01
Karnofsky score ≤ 40 4.96 (2.42-10.16) < .001`
Pulmonary + extrapulmonary TB
2.26 (1.62-3.16)< .001
NTM 2.84 (1.13-7.13) < .001
MDR-TB 8.02 (4.00-16.07) < .001
Factors Independently Associated With MortalitySurvival Probability, Early vs Late Therapy
Log rank P = .0042
Wks From TB Treatment Initiation
Pro
babi
lity
of
Sur
viva
l 1.00
0.90
0.80
0.70
0.60
Early arm wk 2Late arm wk 8
0 50 100 150 200 250
00002-E-50 – 1 December 2003
ART in special populations:pregnant women
Primarily consider mother’s need of ART and act accordingly (same as
guidelines for adults)
Used to prevent mother-to-infant transmission as well
Avoid EFV in first trimester (teratogenic)
Prevention of MTCT: conflicting data on pros and cons of single dose NVP to
mother and infant (negligible reduction in transmission in mothers who
breastfeed, selection of resistance to non-nucleosidic RT inhibitors); same
applies to other suboptimal therapies
00002-E-51 – 1 December 2003
BAN Study: Both Regimens Equally Effective at Preventing Transmission
Maternal HAART and infant
NVP regimens both significantly reduced
HIV-1 transmission by breastfeeding to
infants at Wk 28
Grade 3/4 adverse events generally
comparable across arms, except – Significantly higher rate of neutropenia in
women on maternal HAART vs control arm (6.7% vs 2.0%; P < .0001)
– Substantially higher number of hypersensitivity reactions in infants on NVP vs control arm (16 vs 0 events)
Age (Wks)E
stim
ated
Pro
babi
lity
of
Bei
ng H
IV P
osit
ive
1 4 8 12 16 20 24 280.00
0.02
0.04
0.06
0.08
Control vs maternal HAART: P = .0032
Control vs infant NVP: P < .0001Maternal HAART vs infant NVP: P =.1203
6.4%
3.0%
1.8%
Chasela C, et al. IAS 2009. Abstract WELBC103.Graphic used with permission..
Control
Maternal HAART
Infant NVP
00002-E-52 – 1 December 2003
WHO 2009 recommendations for PMTCT in mothers who do not need ART for their own health