1. Institute of Clinical Infectious Diseases. Catholic University, Rome
Anti-HIV drugs
Andrea De Luca, M.D.
Institute of Clinical Infectious Diseases. Catholic University, Rome
2nd Division of Infectious Diseases, University Hospital of Siena, Italy

2. Goals of antiretroviral therapy
HAART
Goals of antiretroviral therapy
CD4 +
Mortality
Opportunistic
infections
HIV RNA
time

3. 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

4. New AIDS cases per year of diagnosis
in Italy

5. 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
Adherence
Tolerability

6. Antiviral potency and development of drug-resistance
Risk of development
of drug-resistance
poor
suboptimal
high
Poor pharmacokinetics
Suboptimal adherence
Drug pressure selects
resistant virus
Inadequate drug pressure to select
Complete viral suppression
Increasing adherence
In generale, il rischio di selezione di mutanti resistenti aumenta fino a un picco massimo con l’aumentare della pressione selettiva. Una pressione minore (potenza antivirale scarsa) può infatti consentire un sufficiente livello di replicazione virale senza che un’eventuale mutante, per definizione meno efficiente del virus wild-type, prevalga. D’altra parte, una pressione maggiore (attività antivirale elevata) può comportare un’inibizione pressoché totale dell’attività replicativa virale, facendo venire meno il presupposto essenziale per la generazione delle varianti resistenti. Alla condizione di potenza antivirale di livello intermedio, associata a una consistente probabilità di selezione di mutanti resistenti, concorrono vari fattori, fra cui un’imperfetta aderenza e condizioni farmacocinetiche non ottimali. 6

7. Attachment, fusion and entry Viral zinc-finger nucleocapsid proteins
Viral protease
RNA
RNA
Proteins
Reverse transcriptase RT
RNA
RNA
DNA
DNA RT
Viral regulatory
proteins
DNA
DNA
DNA
DNA
Provirus
Viral integrase

8. 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

9. 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)

10. 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)

11. 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)

12. 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

13. 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

14. New treatments and strategies for naive patients

15. 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 60 56
DRV/RTV 50
LPV/RTV 40 35
Median Increase at Wk 96 (mg/dL) 30 26 20 17 15 18 8 10 5 TC
LDL-C
HDL-C TG
Statistically greater % increases in TC, TG in LPV/RTV arm than DRV/RTV arm (P < .001)
Baraldi E, et al. IAS Abstract MOPEB034.

16. STARTMRK: Metabolic, Body Composition Changes at Wk 96 With RAL vs EFV50
EFV 40
P < .001 30 40
P < .001
18.1
18.2 20
Appendicular Fat Mean Percent (SE) Change
17.7
17.0 30 10
P < .001
Mean Change (mg/dL) 20
P < .001 10
P = .025 48 96
Wks
Contributing Patients, n
RAL 55 40 37 TC
HDL-C
LDL-C TG
Glucose
-10
EFV 56 46 38
DeJesus E, et al. CROI 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.

17. 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: % 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
MERIT-ES
100
ITT, NC = F
Modified
ITT
TLOVR 80
69.3
65.3
68.3
68.5
62.4 60
58.5
60.7
60.5
HIV-1 RNA < 50 c/mL (%) 40 20 n
Wk 48
Wk 96
3TC, lamivudine; D/M; dual/mixed; ES, enhanced sensitivity; MERIT, Maraviroc vs Efavirenz Regimens as Initial Therapy; R5, CCR5-utilizing virus; ZDV, zidovudine
For more information about this study, go online to: clinicaloptions.com/HIV/Conference%20Coverage/Cape%20Town%202009/Tracks/Developed/Capsules/TUAB103.aspx
Higher levels of dyslipidemia on EFV
5/15 pts who discontinued EFV for tolerability developed NNRTI mutations in follow-up[3]
1. Saag M, et al. ICAAC/IDSA Abstract 1232a. 2. Heera J, et al. IAS Abstract TUAB Nelson M, et al. IAS Abstract MOPEB040.

18. ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
Randomized, double-blind phase III trials
Stratification by BL HIV-1 RNA < 100,000 vs ≥ 100,000 copies/mL, NRTI use*
Wk 48
primary analysis
Wk 96
final analysis
Rilpivirine 25 mg QD
+ TDF/FTC 300/200 mg QD
(n = 346)
ECHO
(N = 690)
EFV 600 mg QD + TDF/FTC 300/200 mg QD (n = 344)
Treatment-naive,
HIV-1 RNA ≥ 5000 copies/mL
no NNRTI RAMs,
susceptible to NRTIs
THRIVE
(N = 678)
Rilpivirine 25 mg QD + 2 NRTIs† (n = 340)
EFV 600 mg QD + 2 NRTIs† (n = 338)
*THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC.
Cohen C, et al. AIDS Abstract THLBB206.

19. ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL
6.6 ( )
HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48
100 90 90 91 84 83 84 80
100 60
85.6
84.3
82.3
Patients (%)
82.9
82.8
81.7 40 80 20
332/ 368
276/ 330
162/ 181
136/ 163
170/ 187
140/ 167 60
Patients (%)
Pooled
ECHO
THRIVE 40
≤100,000 copies/mL
-3.6 (-9.8 to +2.5) 20
100 81 82 79 80
n =
686
682
346
344
340
338 80 77 76
Pooled
ECHO
THRIVE 60
Patients (%) 40 20
*P < for noninferiority at -12% margin.
246/ 318
285/ 352
125/ 165
149/ 181
121/ 153
136/ 171
Cohen C, et al. AIDS Abstract THLBB206. Graphics used with permission.
Pooled
ECHO
THRIVE
> 100,000 copies/mL

20. ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events
Treatment Failure in ECHO and THRIVE 15
Rilpivirine
Adverse Events and Discontinuation 12
EFV
9.0
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 14 9
6.7
Patients (%) 6
4.8
2.0 3
n =
346
686
682
686
682 VF AE
Resistance at Virologic Failure
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 Abstract THLBB206. Table used with permission.

21. GS-9350–Boosted Elvitegravir + FTC/TDF Noninferior to EFV/FTC/TDF in Naive Pts
Cobicistat (GS-9350): investigational CYP3A inhibitor (boosting agent)
Elvitegravir: investigational integrase inhibitor
GS-9350/EVG/FTC/TDF
EFV/FTC/TDF
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
100 90 80 83
ITT, M = F 60
HIV-1 RNA < 50 c/mL (%) 40
Wk 24 stratum-weighted difference: +5% (95% CI: -11.0% to 21.1%) 20 4 8 12 16 20 24 Wk
Cohen C, et al. CROI Abstract 58LB. Reproduced with permission.

22. GS-9350–Boosted ATV Virologic Efficacy Similar to ATV/RTV in Naive Pts
Phase II study comparing cobicistat (GS-9350) vs ritonavir as boosting agent for atazanavir
Wk 24 primary endpoint
GS-9350
Wk 48
100
RTV 86 80 84
Treatment-naive pts with CD4+ ≥ 50 cells/mm3, HIV-1 RNA ≥ 5000 c/mL, no NRTI, NNRTI, or PI resistance
(N = 79)
GS-9350–Boosted ATV + FTC/TDF (n = 50)
ITT, M = F 60
HIV-1 RNA < 50 c/mL (%)
RTV-Boosted ATV + FTC/TDF (n = 29) 40
Wk 24 stratum-weighted difference: -1.9% (95% CI: -18.4% to 14.7%) 20 4 8 12 16 20 24 Wk
Cohen C, et al. CROI Abstract 58LB. Reproduced with permission.

23. SPRING-1: S/GSK1349572 vs EFV in Treatment-Naive Patients
Wk 16
Wk 48
Dose-ranging, partially blinded phase IIb trial
S/GSK mg QD
+ 2 NRTIs QD*
(n = 53)
S/GSK mg QD
(n = 51)
S/GSK mg QD
EFV 600 mg QD
(n = 50)
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.
Arribas J, et al. AIDS Abstract THLBB205.

24. SPRING-1: Virologic Response to S/GSK1349572 vs EFV at Wk 16
100
96%
92%
90% 80
50-mg dose chosen for phase III trial 60
60%
HIV-1 RNA < 50 copies/mL (TLOVR), % 40
Time to < 50 copies/mL shorter for S/GSK dose than EFV (P < .001 for each comparison) 20 mg mg mg
EFV 600 mg BL 1 2 4 8 12 16
Wks
CD4+ cell count increases cells/mm³ on S/GSK vs 116 cells/mm3 on EFV
No serious adverse events related to S/GSK
Arribas J, et al. AIDS Abstract THLBB205. Graphic used with permission.

25. 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%)
ITT, NC = F
100
P = .63 80
66.8
67.0
65.3
66.5 60
HIV-1 RNA < 50 c/mL at Wk 48 (%)
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
1.6
No confirmed response at Wk 48
5.3
12.4 40 20
n =
376
193
188
188
Any NVP
ATV/ RTV
NVP QD
NVP
BID
Soriano V, et al. IAS Abstract LBPEB07.

26. HIV-1 RNA < 50 copies/mL (TLOVR)
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
HIV-1 RNA < 50 copies/mL (TLOVR)
Adjusted difference 4.92% (95% CI: to 9.96)
100
Patients (%)
81.0 80
75.9 60 40 20
NVP IR
NVP XR
Similar safety and tolerability for both arms
AEs included
Stevens-Johnson (n = 5)
Hepatitis (n = 14)
Rash (n = 21)
Gathe J, et al. AIDS Abstract THLBB202.

27. 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 20 40 60 80
100
Wks
HIV-1 RNA < 40 copies/mL (ITT-TLOVR) 8 16 24 32 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 < .002 Wk 16 P = .038 *
Patients (%)
LPV/RTV + RAL
Similar CD4+ cell count gain at Wk 48
LPV/RTV + RAL: 215 cells/mm³
LPV/RTV + NRTIs: 245 cells/mm³
Reynes J, et al. AIDS Abstract MOAB0101. Graphic used with permission.

28. PROGRESS: Lipids and Adverse Events at Wk 48
Mean increases in TC, TG, and HDL-C from BL to Wk 48 significantly greater in RAL arm vs NRTI arm
Resistance Development at VF
LPV/RTV + RAL
LPV/RTV + NRTIs
Met criteria for resistance testing 4 3
INSTI mutation (N155H) 1
NRTI mutations (M184V)
LPV/RTV + RAL
LPV/RTV + NRTIs
P = .044
+99
100
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) 80
P = .008
+59 60
Mean Change From BL, mg/dL
+46 40
+29
P = .015
+12 20 +8 TC TG
HDL-C
Reynes J, et al. AIDS Abstract MOAB0101.

29. A4001078: ATV/RTV + MVC vs ATV/RTV + TDF/FTC—Wk 24 Interim Analysis
HIV-1 RNA < 50 copies/mL Overall and by BL VL
ATV/RTV + MVC
100 95 89
ATV/RTV + TDF/FTC 80 80 81 80 77 60
Patients (%) 40 20
n = 60 61 44 39 16 22
Overall
HIV-1 RNA < 100K
HIV-1 RNA  100K
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 Abstract THLBB203.

30. 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
Primary Endpoint: HIV-1 RNA < 50 copies/mL Through Wk 24 (CVR*, NC = F)
ATV BID + RAL BID
ATV/RTV QD + TDF/FTC
100
74.6% 80 60
Patients (%) 40
63.3% 20 BL 4 8 12 16 20 24
Wks
*CVR = modified ITT.
Kozal MJ, et al. AIDS Abstract THLBB204. Graphic used with permission.

31. 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 4
Evaluable for resistance testing * (HIV-1 RNA > 400 copies/mL) 6 1
Genotypic and phenotypic RAL resistance
N155H 2 NA
Q148R
Q148R + N155H + T97A
Phenotypic RAL resistance without genotypic evidence of resistance
ATV resistance
TDF/FTC resistance
*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
Kozal MJ, et al. AIDS Abstract THLBB204.

32. 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
Drug-Related Neuropsychiatric AEs
100
Grade 1-4
Grade 2-4 80
P < .001
P = .02 60
Patients (%) 46 40 20 17 17 5
ETR
EFV
ETR
EFV
10 patients discontinued in ETR and 8 in EFV arm by Wk 12
Gazzard B, et al. AIDS Abstract LBPE19.

33. Switch/simplification studies

34. ARIES: Boosted vs Unboosted ATV Maintenance: Wk 84 Results
ATV (n = 210)
100
ATV/RTV (n = 209) 86 85 87
80.8 82 79 80 60
HIV-1 RNA < 50 c/mL at Wk 84 (%) 40 20
Overall Results
BL HIV-1 RNA < 100,000 c/mL
BL HIV-1 RNA ≥ 100,000 c/mL
Squires K, et al. IAS Abstract WELBB103. Graphic used with permission.

35. SPIRAL: Switch to RAL Noninferior to Maintaining PI/RTV Regimens
Patients With VF
RAL (n = 4)
PI/RTV (n = 6)
Prior VF 1 3
Prior suboptimal ART 2
Prior resistance mutations 5
Resistance test at VF 4
Mutations
3 (PR, RT)
Free of Treatment Failure at Wk 48 (ITT, S = F)
Patients (%)
100
89.2
86.6 80 60 40
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
LDL-C
-6.5
+3.0
< .001
HDL-C
-3.2
+5.8
Total to HDL-C ratio
-4.9
-1.3
< .05 20
Switch to RAL
Continue PI/RTV
Martinez E, et al. AIDS. 2010;24:

36. 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%)
HIV-1 RNA < 50 copies/mL, ITT, TLOVR (%)
DRV/RTV monotherapy (n = 127)
DRV/RTV + 2 NRTIs (n = 129)
Switch allowed
100
Switch = failure
92.1
90.7
84.3
85.3
80.6 80
74.8 60 40 20
Wk 48[1]
Wk 96[2]
1. Arribas JR, et al. IAS Abstract TUAB106LB. 2. Rieger A, et al. AIDS Abstract THLBB209.

37. Treatment-experienced individuals

38. Evolving efficacy of antiretroviral regimens in multiexperienced patients (percent <50 copies/ml)
48w
96w %

39. Pooled DUET 96-Wk Results: ETR + DRV/RTV-Containing OBR in Exp’d Pts
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)
ETR (n = 599)
100
Placebo (n = 604) 80
P < .0001
P < .0001 60 57 60
HIV-1 RNA < 50 c/mL (%)
(ITT-TLOVR) 39 40 36 20
Wk 48
Wk 96
No new safety signals in Wks 48-96[2]
New rash in < 1% of pts
CNS adverse effects similar between arms in Wks
1. Mills A, et al. IAS Abstract MOPEB Nelson T, et al. IAS Abstract MOPEB038.

40. ODIN: QD vs BID Darunavir/Ritonavir + OBR in Treatment-Experienced Patients
Stratified by baseline HIV-1 RNA ≤ and > 50,000 copies/mL
Wk 48
Treatment-experienced adults with stable HAART for ≥ 12 wks, HIV-1 RNA > 1000 copies/mL, CD4+ > 50 cells/mm3, no DRV RAMs
(N = 590)
QD DRV/RTV 800/100 mg + OBR* (n = 294)
BID DRV/RTV 600/100 mg + OBR* (n = 296)
*OBR included ≥ 2 active NRTIs.
Primary PI mutations in < 2% of patients in either arm
Cahn P, et al. CROI Abstract 57.

41. ODIN: HIV-1 RNA < 50 copies/mL at Wk 48 Overall and by Screening HIV-1 RNA
QD DRV/RTV 800/100 mg
BID DRV/RTV 600/100 mg
100
100
78.4
76.8 80 80
72.1
52.8
52.8
70.9 60 60
Pts With HIV-1 RNA < 50 copies/mL (%)
Pts With HIV-1 RNA < 50 copies/mL (%) 40 40 20
Difference in response, QD vs BID: ITT = 1.2% (95% CI: -6.1%, 8.5%) 20
n =
222
224 72 72 4 8 12 24 36 48
£ 50,000
> 50,000
Wks
Screening HIV-1 RNA (copies/mL)
Similar CD4+ cell count increase between arms
QD DRV/RTV : +100 cells/mm3
BID DRV/RTV : +94 cells/mm3
Cahn P, et al. CROI Abstract 57. Reproduced with permission.

42. 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)
Any PI
7 (11.7)
4 (9.5)
Loss of susceptibility,† n (%)
Darunavir
2 (3.4)
*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).
Cahn P, et al. CROI Abstract 57.

43. ODIN: Significantly Lower Rate of Lipid Abnormalities With DRV/RTV QD vs BID
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.
Cahn P, et al. CROI Abstract 57.

44. VIKING: Second-Generation INSTI S/GSK1349572 in RAL-Resistant Patients
International, multicenter, single-arm, phase II study in 27 patients with RAL resistance
S/GSK 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/GSK mg QD continued and regimen optimized
Median fold-change in RAL susceptibility at BL: (range: > 166)
Median S/GSK572 FC at BL: 1.5 (range: )
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 Abstract MOAB0105.

45. Resource-limited settings/special populations

46. 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

47. 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)
HIV-infected patients diagnosed with TB and CD4+ cell count < 500 cells/mm3
(N = 642)
Sequential ART
ART initiated after TB therapy completed
(n = 213)
ART, antiretroviral therapy; SAPiT, Starting Antiretrovirals at Three Points in Tuberculosis; TB, tuberculosis.
One unanswered question in the context of patients who present with acute opportunistic infections has concerned the potential benefits associated with starting antiretroviral therapy promptly vs deferring antiretroviral therapy until after treatment of the opportunistic infection. The trial shown on this slide examined this question in the context of tuberculosis (TB). A previous study conducted by the ACTG demonstrated clinical benefits associated with starting antiretroviral therapy within the first few weeks of diagnosis for a variety of different opportunistic infections, particularly Pneumocystis carinii pneumonia, but patients with TB were excluded from that analysis.
The South African SAPiT trial included 642 patients with CD4+ cell counts < 500 cells/mm3 who were recently diagnosed with TB. Patients were randomly assigned 2:1 to initiate antiretroviral therapy at some point during TB therapy, either during the initial intensive 2 months or the subsequent 4-month continuation phase, or to receive sequential therapy by initiating antiretrovirals after completing TB treatment. This analysis compared the pooled group of patients who received antiretroviral therapy during either the intensive or continuous phase of TB therapy vs those receiving sequential therapy.
Primary endpoint: all-cause mortality

48. SAPiT: Increased Survival With Concurrent HIV and TB Treatment
1.00
Early ART
Sequential ART
0.95
0.90
Survival
0.85
0.80
ART, antiretroviral therapy; SAPiT, Starting Antiretrovirals at Three Points in Tuberculosis; TB, tuberculosis.
The curves shown on this slide describe survival during the course of intensive, continuous, and post‑TB treatment. The orange line represents patients who started antiretrovirals after completing TB therapy. It is clear that the survival curves of patients who received early vs sequential antiretroviral therapy diverged, but the divergence was greatest following completion of TB therapy. It is interesting that most of the survival difference between the 2 treatment groups seemed to occur somewhat late. As mentioned earlier, data assessing whether there is a survival difference between patients treated with antiretrovirals during the intensive phase vs the continuous phase of TB therapy are awaited.
Intensive phase of TB treatment
0.75
Continuation phase of TB treatment
Post-TB treatment
0.70 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Months Postrandomization
Abdool Karim SS, et al. CROI Abstract 36a. Graphic reproduced with permission.

49. Multivariate Adjusted HR (95% CI) Survival Probability, % (95% CI)
CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients (CD4<200)
Survival Probability, Early vs Late Therapy
Log rank P = .0042
Wks From TB Treatment Initiation
Probability of Survival
1.00
0.90
0.80
0.70
0.60
Early arm wk 2
Late arm wk 8 50
100
150
200
250
Factors Independently Associated With Mortality
Factor
Multivariate Adjusted HR (95% CI) P
Late therapy
1.52 ( )
.007
BMI ≤ 16
1.68 ( )
.01
Karnofsky score ≤ 40
4.96 ( )
< .001`
Pulmonary + extrapulmonary TB
2.26 ( )
< .001
NTM
2.84 ( )
MDR-TB
8.02 ( ) Wk
Survival Probability, % (95% CI) P
Early Arm
Late Arm 50
( )
( )
.07
100
( )
( )
.006
150
( )
( )
.002
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 Abstract THLBB206. Graphic used with permission..

50. 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

51. 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)
Control
0.08
Maternal HAART
Infant NVP
6.4%
0.06
Estimated Probability of Being HIV Positive
0.04
3.0%
0.02
1.8%
0.00 1 4 8 12 16 20 24 28
Age (Wks)
Control vs maternal HAART: P = .0032
Control vs infant NVP: P < .0001
Maternal HAART vs infant NVP: P =.1203
Chasela C, et al. IAS Abstract WELBC103.Graphic used with permission..

52. WHO 2009 recommendations for PMTCT in mothers who do not need ART for their own health