Transcript Antiretroviral Therapy and Clinical Trials

HIV Treatment and Clinical Trials
Eric S. Daar, MD
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at UCLA
Overview
• Pathogenesis
• Testing
• Treatment
– When to start
– What to start
– When to switch
• Treatment as prevention
• Future
Viral Dynamics
Productively Infected
CD4+ Lymphocytes
Infected Resting Memory
CD4+ Lymphocytes
Activated Uninfected
CD4+ Lymphocytes
Activated Uninfected
CD4+ Lymphocytes
Perelson A, et al. 1995
Long-lived Cells
Viral Dynamics
Productively Infected
CD4+ Lymphocytes
Infected Resting Memory
CD4+ Lymphocytes
>95%
Log10 RNA
T1/2~1 day
Activated Uninfected
CD4+ Lymphocytes
Weeks
Activated Uninfected
CD4+ Lymphocytes
T1/2~20 min.
Long-lived
Cells
Viral Dynamics
Productively Infected
CD4+ Lymphocytes
Infected Resting Memory
CD4+ Lymphocytes
>95%
T1/2~1 day
T1/2~20 min.
Activated Uninfected
CD4+ Lymphocytes
<5%
Log10 RNA
T1/2~2-4 weeks
Activated Uninfected
CD4+ Lymphocytes
Long-lived Cells
Weeks
Viral Dynamics
Productively Infected
CD4+ Lymphocytes
Infected Resting Memory
CD4+ Lymphocytes
<1%
Log10 RNA
>95%
T1/2~6 monthsyears
T1/2~1 day
Weeks --- Year
T1/2~20 min.
Activated Uninfected
CD4+ Lymphocytes
<5%
T1/2~2-4 weeks
Activated Uninfected
CD4+ Lymphocytes
Long-lived Cells
Lessons From Pathogenesis
• High levels viral replication makes mutations
(resistance) inevitable if detectable viremia
• Persistent cellular reservoirs of infection
established early in course of infection
– Source of archived virus throughout course of disease
• Viral rebound likely regardless of duration of viral
suppression with current therapeutic options
Antiretroviral Activity:
An Historical Perspective
HIV RNA change (log10 c/mL)
1987: AZT
Monotherapy
1994:
Two-Drug Therapy
1997:
HAART
0
0
0
-0.5
-0.5
-0.5
-1
-1
-1
-1.5
-1.5
-1.5
-2
-2
-2
-2.5
-2.5
-2.5
-3
24-week response
-3
24-week response
Fischl, NEJM, 1987
Katzenstein, NEJM, 1996
Eron, NEJM, 1995;
Hammer, NEJM, 1996
-3
24-week response
Gulick, NEJM, 1997;
Cameron, Lancet, 1998
Life Expectancy of HIV-Infected
Patients
Years of Life Remaining
Age at time of death
Years lived
• Life expectancy of
Athena cohort to
general population
(n=4,174)
• Expected life years
remaining at age 25
– 53.1 (44.9-59.5) for general
population
– 52.7 for asymptomatic HIV+
patients
Remaining Life Years
Age at 24 weeks (years)
General Population
Asymptomatic HIV+ Patients
van Sighem A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 526.
Awareness of Serostatus Among
People with HIV and Estimates of
Transmission
~25%
Unaware
of
Infection
~54%
New
Infections
Accounting for:
~75%
Aware
of
Infection
People Living with HIV
Marks, et al, AIDS 2006;20:1447-50
~46%
New
Infections
New Sexual Infections
Revised CDC Recommendations for
HIV Testing in Healthcare Settings
• Routine voluntary testing
for patients ages 13 to 64
years in healthcare settings
– Not based on patient risk
• Opt-out testing
• No separate consent for
HIV
• Pretest counseling not
required
• Repeat HIV testing left to
discretion of provider
– Based on patient risk
Branson BM, et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.
Rapid HIV Testing
Rapid Home HIV Testing
(Approved July 2012)
Impact of Expanded HIV Testing in
Washington, DC
• 3.7-fold increase in number of
publicly funded HIV tests
performed in Washington, DC,
from 2004-2008
• 17% increase in number of new
HIV/AIDS name-based case
reports from 2004-2007
• Significant reduction in time to
progression to AIDS following
HIV diagnosis from 2004-2008
(P < .0001)
• Time interval between diagnosis
to entry into care significantly
improved from 2004-2008
Castel A, et al. CROI 2010. Abstract 34.
Median CD4+ cell count
– 2004: 19,766
– 2008: 72,866
Median CD4+ cell count at time of HIV
diagnosis between 2004-2008
P < .05 for trend
336
296
275
400
300
343
216
200
100
0
2004
2005 2006 2007
Year of Diagnosis
2008
HIV Cascade
When to Start?
Why not treat everyone?
•
•
•
•
Not ready to commit to treatment
Short-term and long-term toxicity
Need for life long therapy
Risk of virologic failure, resistance and crossresistance
• Limited evidence for earlier therapy being
associated with better outcomes than delayed
therapy
Physical Manifestations of Fat
Redistribution Syndromes
Case for Earlier Therapy
CIPRAHT001: Randomized Trial
of When to Start ART in Haiti
Randomized clinical endpoint study of when to start therapy
• Treatment-naive
• No hx AIDS-defining illness
• CD4 200-350
Early Treatment
(Immediate ZDV/3TC + EFV)
Primary
endpoint:
Survival
Standard Treatment
(Delay until CD4+ <200 or AIDS
Baseline Characteristics
Early (n=408)
Standard (n=408)
40
40
Male (%)
41%
44%
Median CD4+ (cells/mm3)
280
282
Body Mass Index (kg/m2)
21.4
21.0
Median age (years)
Severe P, et al. NEJM 2010 363:257-265.
CIPRAHT001: Clinical Endpoints
May 2009: DSMB review stopped study due to excess
deaths in Defer Treatment arm
Early
Standard
Hazards Ratio
(p value)
Death
6
23
4.0
(.0011 )
Incident
Tuberculosis
18
36
2.0
(.0125 )
Clinical Endpoints
• Infectious causes of death
– Early: 1 (gastroenteritis)
– Standard: 17 (7 gastroenteritis, 5 TB, 4 pneumonia, 1 cholangitis/sepsis)
• More toxicity from ART and intensive need for lab f/u for deferred grp
• WHO start guidelines now modified to <350 cells/uL
Severe P, et al. NEJM 2010 363:257-265.
NA-ACCORD: Risk of Death with ART
Deferral
351-500 CD4+
>500 CD4+
RR
95% CI
P
RR
95% CI
P
Deferral of ART
1.7
1.3, 2.3
<0.001
1.9
1.4, 2.8
<0.001
Female Sex
1.2
0.9, 1.6
0.24
1.9
1.3, 2.6
<0.001
Older Age (per 10
years)
1.7
1.5, 1.9
<0.001
1.8
1.6, 2.1
<0.001
Baseline CD4 count
(per 100 cells/mm3)
1.1
0.7, 1.8
0.59
0.9
0.9, 1.0
0.03
Kitahata M, et al. New Engl J Med 2009;360:1815-26.
Ultimate CD4 Cell Count Depends on
Where You Start
ATHENA National Cohort2
1000
800
600
400
≥500
350-500
200
200-350
50-200
<50
0
0
48
96
144
192
240
Weeks From Starting ART
Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.
288
336
Neurocognitive disorders associated
with CD4 nadir
Odds Ratio for Cognitive Impairment by CD4 Nadir
1.1
1
Odds Ratio
0.9
0.8
0.7
0.6
0.5
0.4
0.3
<50
50-199
200-349
CD4 Nadir
Odds Ratios for NP Impairment
Ellis R, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 429.
≥350
Consequences of stopping ARVs:
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.
SMART: Primary endpoint and
components
Endpoints
#Pts w/ Events
Relative Risk (95% CI)
2.5
Progression of Disease or
Death
164
Death
84
Serious HIV Events
21
1.9
6.1
>
1.5
Severe Complications*
114
*CVD, Renal, Hepatic Events (fatal/nonfatal)
►
0.1
El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.
1
Favors DC
Favors VS ►
10
SMART: Changes in D-Dimer and
IL-6 Levels
Change in Log IL-6 (pg/mL) and
HDL (μmol/L) BL to 1 Month2*
Change in D-Dimer*, BL to 1 Month
0.3
0.3
∆ IL-6 (pg/mL)
0.2
0.11
0.04
0
0
≤400
40110,000
10,00050,000
>50,000
Month 1 HIV RNA (c/mL)
• Suggests HIV viremia effect on endothelium,
leading to increased tissue factors and initiation of coagulation
cascade
P=.0003 for trend
0.3
0.2
0.2
0.1
0.1
0
0
-0.1
-0.1
-0.2
-0.2
P<.0001 for trend
-0.3
-0.4
≤400
401-10,000
10,000-50,000
>50,000
Month 1 HIV RNA Level (copies/mL)
*DC patients on ART at baseline with HIV RNA ≤400 copies/mL
1Kuller
0.4
L, et al. PLoS 2008;10:1496-1508. 2SMART/INSIGHT: Duprez et al, CROI, 2009.
-0.3
-0.4
∆ HDL (μmol/L)
μg/mL
P=.0005 for trend
0.1
∆ IL-6
∆ HDL
0.4
0.28
HPTN 052: Immediate vs Delayed
ART in Serodiscordant Couples
HIV-infected, sexually
active serodiscordant
couples; CD4+ cell count
of the infected partner:
350-550 cells/mm3
(N = 1763 couples)
Immediate ART
Initiate ART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed ART
Initiate ART at CD4+ cell count ≤ 250 cells/mm3*
(n = 877 couples)
*Based on 2 consecutive values ≤ 250 cells/mm3.
• Primary efficacy endpoint: virologically linked HIV transmission
• Primary clinical endpoints: WHO stage 4 events, pulmonary TB,
severe bacterial infection and/or death
• Couples received intensive counseling on risk reduction and use of
condoms
Cohen MS, et al. IAS 2011. Abstract MOAX0102.
Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]
Linked HIV Transmission Events
n=27; incidence rate
1.7 per 100 p-y (95% CI 1.1, 2.5)
n=1; incidence rate
0.1 per 100 p-y (95% CI 0.0, 0.4)
Cohen M, et al. NEJM July 18, 2011.
When to Start Treatment
3/27/12
DHHS
Guidelines
CD4 Count
HIV RNA
Clinical Category
(cells/mm3)
(copies/mL)
AIDS-defining illness
or severe symptoms
Any value
Any value
Treat
<500
Any value
Treat
>500
Any value
Treat
Pregnant women
Any value
Any value
Treat
HIV-associated
nephropathy
Any value
Any value
Treat
HIV/HBV coinfection
when HBV treatment
is indicated
Any value
Any value
Treat
Asymptomatic
2012
IAS-USA
Guidelines
*Unless elite controller (HIV RNA <50 copies/mL) or has stable CD4 cell count and low-level viremia in absence of therapy.
The IAS-USA guidelines also recommends initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus
infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection.
DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Revision March 27, 2012; Thompson MA, et al. JAMA. 2012;308:387-402.
Rationale for Recommending Therapy
for Those with >350 CD4 cells/uL
• Recent cohort studies (4 for 350-500 cells/uL
and 1 for >500 cells/uL)
• HIV replication associated with non-AIDSdefining diseases (e.g. cardiovascular, renal,
liver, malignancy)
• Evidence that ARVs may reduce risk of
transmission
• ARV more effective, convenient, better tolerated
than in the past
US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Guidelines.
What to Start
HIV replication cycle and sites of drug activity
NRTIs
AZT (Zidovudine-Retrovir)
ddI (Didanosine-Videx)
ddC (Zalcitabine-Hivid)
d4T (Stavudine-Zerit)
3TC (Lamivudine-Epivir)
ABC(Abacavir-Ziagen)
FTC (Emtricitabine, Emtriva)
nRTI
Tenofovir DF
(Viread)
NNRTIs
Efavirenz (Sustiva)
Delavirdine (Rescriptor)
Nevirapine (Viramune)
Etravirine (Intelense)
Rilpivirine (Edurant)
Cellular DNA
Nucleus
Protease Inhibitors
Indinavir (Crixivan)
Ritonavir (Norvir)
Saquinavir (Fortovase)
Nelfinavir (Viracept)
Lopinavir/ritonavir (Kaletra)
Atazanavir (Reyataz)
Fos Amprenavir (Lexiva)
Tipranavir (Aptivus)
Darunavir (Prezista)
HIV Virions
New HIV
particles
Reverse
Integrase
Transcriptase
Protease
Capsid
proteins
and viral
RNA
CD4
Receptor
Fusion Inhibitor
T-20
(Enfuvirtide,
Fuzeon)
Viral RNA
Integrase Inhibitor
Raltegravir (Isentress)
Elvitegravir (as QUAD)
CCR5 Antagonist
Maraviroc (Celsentri)
1
Attachment
Unintegrated
double stranded
Viral DNA
3
2
Uncoating
Integrated
viral DNA
Reverse
Transcription
Viral
mRNA
4
Integration Transcription
gag-pol
polyprotein
5
Translation
6
Assembly and
Release
Factors to consider in choosing firstline therapy
• Patients willingness to commit to therapy
• Baseline resistance
• Comorbid conditions
• Efficacy data
• Tolerability
• Convenience
• Consequences of failure (resistance)
• Since the introduction of potent ARV therapy
preferred regimens all include NRTIs + third drug
Nucleoside Reverse Transcriptase
Inhibitors
GS 934: Efficacy of ZDV/3TC vs. TDF/FTC
with Efavirenz (ITT)
HIV RNA <400 c/mL (n=456)
100
Responders (%)
80
71%
60
58%
p=0.004
(95% CI: 4.2%, 21.6%)
40
TDF/FTC*
20
ZDV/3TC
0
0 8 16
32
48
72
96
120
144
Weeks
*Fixed dose FTC/TDF used from Wks 96-144
Arribas JR, et al. 4th IAS, Sydney 2007, #WEPEB029
A5202: Study Design
HIV-1 RNA ≥1000 c/mL
Arm
A
Any CD4+ count
> 16 years of age
ART-naïve
1857
N=1858
enrolled
B
Randomized
Randomized 1:1:1:1
1:1:1:1
C
Stratified by screening HIV-1 RNA
TDF/FTC QD
ABC/3TC Placebo QD
ABC/3TC QD
TDF/FTC Placebo QD
TDF/FTC QD
ABC/3TC Placebo QD
EFV
QD
EFV
QD
ATV/r
QD
(< or ≥ 100,000 c/mL)
Enrolled 2005-2007
Followed through Sept 2009,
96 wks after last pt enrolled
D
ABC/3TC QD
TDF/FTC Placebo QD
ATV/r
QD
A5202: Time to Virologic Failure in
Patients with HIV RNA >100,000 c/mL
Probability of No Virologic Failure
100
Probability of No Virologic
Failure (%)
TDF-FTC (26 events)
80
ABC-3TC (57 events)
60
40
P<0.001, log-rank test
Hazard ratio, 2.33 (95% CI, 1.46-3.72)
20
0
0
12
24
36
48
60
72
84
96
108
Weeks since Randomization
No. at Risk
ABC-3TC
398
363
313
267
222
188
137
87
49
20
TDF-FTC
399
361
321
284
236
204
160
104
65
23
Sax PE, et al. NEJM 2009;361:2230-2240.
ABC/3TC vs. TDF/FTC
Time to Virologic Failure
(End of Study: Low Viral Load Stratum)
Sax P, et al.
JID 2011
Third Drug to Combine with NRTIs
Boosted-Protease Inhibitors
KLEAN1
(ITT-E, TLOVR)
48 weeks
100
100
66
80
CASTLE3
(ITT, NC=F)
96 weeks
ARTEMIS2
(ITT, TLOVR)
96 weeks
100
79
80
71
65
80
68
60
60
60
40
40
40
20
20
20
n=434
0
n=346
N=444
LPV/r FPV/r
400/100 700/100
BID
BID
0
74
n=343
LPV/r DRV/r
QD or 800/100
BID
QD
n=443
0
n=440
LPV/r ATV/r
400/100 300/100
BID
QD
Adapted from: 1. Eron J, et al. Lancet 2006; 368:476-482; 2. Mills A, et al. AIDS May 29, 2009
3. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d
ATV/r vs. EFV
Primary Endpoint
Daar ES, et al. Ann Intern Med 2011
A5202: Overall ITT
Percent of Failures with Emergence
of Major Resistance Mutations*
ABC/3TC
TDF/FTC
p=0.0003
p=0.046
Percent
p<0.0001
A
N
Y
M
A
J
O
R
Viral failures
No baseline resistance N=
p<0.0001
A
N
Y
N
N
R
T
I
N
R
T
I
P
I
p-values:
ATV/r vs. EFV
(amongst failures)
M
A
J
O
R
A
N
Y
A
N
Y
N
N
R
T
I
N
R
T
I
P
I
M
A
J
O
R
N
N
R
T
I
N
R
T
I
P
I
M
A
J
O
R
N
N
R
T
I
N
R
T
I
ATV/r
EFV
ATV/r
EFV
76
63
54
48
P
I
mutations defined by IAS-USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and Daar ES, et al.
AIM 2011
L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR
*Major
STARTMRK: RAL vs.
EFV
ITT, NC=F
Percentage of Patients with
HIV RNA Levels <50 Copies/mL
100
86
81
76
75
71
80
82
60
79
69
Twice per day vs. Once
per 67
day
BUT
Less side effects
40
20
61
CD4 Change: RAL +374 vs. EFV +312
0
Weeks
0
12 24
48
72
96
120
144
168
192
216
240
Number of Contributing Patients
Raltegravir 400 mg BID
281 278 279
280
281
281
277
280
281
281
277
279
Efavirenz 600 mg QHS
282 282 282
281
282
282
281
281
282
282
282
279
Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19.
Pooled ECHO and THRIVE: Virologic
Response (ITT-TLOVR)
84.3%
82.3%
Rimsky L, et al. 50th ICAAC 2010, Boston, MA. Abst. H-1810
Pooled ECHO and THRIVE: Virologic
Response (ITT-TLOVR)
Rimsky L, et al. 50th ICAAC 2010, Boston, MA. Abst. H-1810
ECHO and THRIVE: Rilpivirine
ECHO (TMC278-C209)1
RPV 25 mg QD + TDF/FTC (n=346)
N=690 patients
1:1
EFV 600 mg QD + TDF/FTC (n=344)
THRIVE (TMC278-C215) 2
N=678 patients
1:1
RPV 25 mg QD + 2 NRTIs* (n=340)
EFV 600 mg QD + 2 NRTIs* (n=338)
Baseline parameter
Median log10 VL, copies/mL (min–max)
Baseline VL >100,000 copies/mL
Median CD4 cells/mm3 (min–max)
Hepatitis B or C co-infection
RPV
N=686
EFV
N=682
5 (2–7)
5 (3–7)
46%
249 (1–888)
7%
52%
260 (1–1,137)
9%
* Investigator’s choice: TDF/FTC; AZT/3TC; ABC/3TC
Cohen C, et al. 18th IAC; Vienna, July 18-23, 2010. Abst. THLBB206. 1. Molina JM, et al. Lancet 2011; 378:238-46; 2.
Cohen CJ, et al. Lancet 2011; 378:229-37,
ECHO and THRIVE Studies:
HIV RNA <50 Copies/mL(ITT-TLOVR)
Rilpivirine
83%
86%
CD4
+196
cells/µL
CD4
+182
cells/µL
CD4
+189
cells/µL
82%
Efavirenz
78%
78%
CD4
+228
cells/µL
CD4
+219
cells/µL
Patients (%)
83%
ECHO
CD4
+171
cells/µL
THRIVE
(n=346/344)
(n=340/338)
Week 48
Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032.
Molina J-M, et al. Lancet. 2011;378:238-246.
Cohen CJ, et al. Lancet. 2011;378:229-237.
Pooled Data
(n=686/682)
Week 96
Pooled ECHO/THRIVE (Week 96):
Discontinuations and Virologic Failure
Rilpivirine
(n=686)
Efavirenz
(n=682)
HIV RNA <50 copies/mL (%)
78
78
Virologic failure (%)
Overall
Rebounder
Never suppressed
12
6
5
6
4
2
Discontinued due to (%)
Adverse events
Other reasons
4
7
8
8
0.1
1.0
Death (%)
Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032.
Pooled ECHO/THRIVE (Week 96):
Discontinuations and Virologic Failure
Baseline HIV RNA
<100K Copies/mL
81%
Rilpivirine
(n=368)
Responder
Discontinue due to:
80%
Efavirenz
(n=329)
Patients (%)
Patients (%)
Responder
Virologic failure
Discontinue due to:
AEs
Other
Baseline HIV RNA
>100K Copies/mL
Virologic failure
AEs
Other
70%
Rilpivirine
(n=368)
Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032.
75%
Efavirenz
(n=329)
Pooled ECHO and THRIVE:
Resistance
• Phenotypic analysis showed that in EFV arm none were resistant to RPV
or ETR whereas 50% of the RPV subjects had resistance to ETR
Rimsky L, et al. 50th CAAC; Boston, MA; September 12-15, 2010. Abst. H-1810.
Pooled ECHO/THRIVE (Week 96):
Safety
Rilpivirine
(n=686)
Efavirenz
(n=682)
Most common adverse events of interest (%)
Any neurologic
Dizziness
Any psychiatric
Abnormal dreams/nightmares
Rash (any type)
17
8
16
8
4
38*
27*
22*
13†
15*
Grade 2-4 laboratory abnormality (%)
Total cholesterol
LDL-C
AST
ALT
7
7
6
6
22*
18*
10
11
*P<0.0001 and †P=0.0039 versus rilpivirine.
Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032.
GS102 & GS103: EVG/COBI/TDF/FTC
vs. EFV/TDF/FTC or ATV/RTV +
TDF/FTC
Randomized, Phase III, Double-blind, Double Dummy,
Active-controlled, International Studies
GS 102
Quad QD
~89% men
33% >105 c/mL
CD4= ~385 c/uL
EFV/FTC/TDF Placebo QD
EFV/FTC/TDF QD
Treatment Naïve
Quad Placebo QD
HIV-1 RNA ≥5,000 c/mL
Any CD4 cell count
eGFR ≥70 mL/min
Quad QD
ATV/r +TDF/FTC Placebo QD
GS 103
~90% men
~41% >105 c/mL
CD4= ~370 c/uL
QUAD Placebo QD
ATV/r +TD/FTC QD
48 weeks
Sax P, et al, Lancet 2012: 379::2439-48; DeJesus E, et al, Lancet 2012; 379: 2429-38
192 weeks
Study 236-102: Primary Endpoint:
HIV-1 RNA < 50 copies/mL
+3.6%, 95% CI 3.6 (-1.6% to +8.8%)
CD4+ change: Quad +239 vs. EFV +206 c/mm3 (p=0.009)
No difference by baseline characteristics
Sax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101.
Study 236-102:
Common Adverse Events
Quad
EFV/FTC/TDF
(n=348)
(n=352)
Treatment Emergent Adverse Events in ≥ 10% of subjects (%)
Diarrhea
23%
19%
Nausea *
21%
14%
Abnormal Dreams ^
15%
27%
Upper Respiratory Infection
14%
11%
Headache
14%
9%
Fatigue
12%
13%
Insomnia *
9%
14%
Depression
9%
11%
Dizziness ^
7%
24%
Rash #
* p<0.05; ^ p<0.001; # p=0.009
Sax P, et al, Lancet 2012: 379::2439-48
6%
12%
DHHS Guidelines for
Adolescents/Adults:
What to Start (March 2013)
Preferred
Regimens
• EFV/TDF/FTC
• ATV/r + TDF/FTC
• DRV/r (once daily) + TDF/FTC
• RAL + TDF/FTC
[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]
Alternative
Regimens
• EFV + ABC/3TC
• RPV + (TDF or ABC)/(FTC or 3TC)
• ATV/r or DRV/r + ABC/3TC
• FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC
• RAL + ABC/3TC
• EVG/COBI/TDF/FTC
Acceptable
Regimens
• EFV or RPV + ZDV/3TC
• NVP + TDF/FTC or ZDV/3TC or ABC/3TC
• ATV + (ABC or ZDV)/3TC
• ATV/r, DRV/r, LPV/r, FPV/r , RAL + ZDV/3TC
• MVC + ZDV or ABC/3TC
• SQV/r + TDF/FTC or ABC/3TC or ZDV/3TC (with caution)
DHHS Guidelines. Available at:
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Revision March 27, 2012.
ART: What to Start
IAS–USA Recommendations, 2012
Component
Recommended Regimens
NNRTI plus nRTIs
• Efavirenz/tenofovir/emtricitabine (AIa)
• Efavirenz plus abacavir/lamivudine (AIa)
in HLA-B*5701-negative patients with baseline
plasma HIV-1 RNA <100,000 copies/mL
PI/r plus nRTIs
• Darunavir/r plus tenofovir/emtricitabine (AIa)
• Atazanavir/r plus tenofovir/emtricitabine (AIa)
• Atazanavir/r plus abacavir/lamivudine (AIa)
in patients with plasma HIV-1 RNA <100,000
copies/mL
InSTI plus nRTIs
• Raltegravir plus tenofovir/emtricitabine (AIa)
Thompson MA, et al. JAMA. 2012;308(4):387-402
When to Consider ARV Switch
• ARV intolerance
• Difficulty with adherence
• Treatment failure
• Incomplete virologic response
• Two consecutive HIV RNA>400 or >50
copies/mL after 24 and 48 weeks,
respectively
• Virologic rebound
• After virologic suppression HIV RNA
repeatedly above assay limit of detection
Adapted from US Department of Health and Human Services Guidelines; Revised January 10, 2011.
Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
Treatment-Experienced Patients: Full
Virologic Suppression is Often
Achievable?
Thorough assessment
of level of resistance
Assess ability
to adhere with
future treatment options
Treatment
history
Current
resistance testing
Available
active agents
Preferably at least
two fully active
agents needed
In general adding a
single drug should
be avoided
Genotypic Interpretation
SUSCEPTIBILITY
Slide 64
BENCHMRK-1 & -2: Raltegravir in
Treatment-Experienced Patients
Current Analysis:
Week 48
HIV-infected patients with
triple-class resistance and
HIV-1 RNA
> 1000 copies/mL
(BENCHMRK-1: N = 352;
BENCHMRK-2: N = 351)
Planned follow-up:
Week 156
Raltegravir 400 mg twice daily + OBR*
(BENCHMRK-1: n = 232;
BENCHMRK-2: n = 230)
Placebo + OBR*
(BENCHMRK-1: n = 118;
BENCHMRK-2: n = 119)
*Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir
permitted.
1. Cooper DA, et al. CROI 2008. Abstract 788.
2. Steigbigel R, et al. CROI 2008. Abstract 789.
BENCHMRK-1: Patients With
HIV-1 RNA < 50 c/mL at Week 48
RAL + OBR
BENCHMRK-1[1]
Placebo + OBR
100
62%*
65%*
33%
31%
Patients (%)
Patients (%)
80
60
40
20
0
n=
n=
0
2 4
8
12
16
24
Weeks
232
118
231
118
231
118
230
118
229
117
232
118
32
229
118
40
230
118
48
231
118
*P < .001 for RAL vs placebo, derived from a logistic regression model adjusted for baseline HIV-1 RNA level (log10), first
ENF use in OBR, first DRV use in OBR, active PI in OBR.
1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789.
Antiretrovirals for Prevention and
Future Developments
HPTN 052: Immediate vs Delayed
ART in Serodiscordant Couples
HIV-infected, sexually
active serodiscordant
couples; CD4+ cell count
of the infected partner:
350-550 cells/mm3
(N = 1763 couples)
Immediate ART
Initiate ART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed ART
Initiate ART at CD4+ cell count ≤ 250 cells/mm3*
(n = 877 couples)
*Based on 2 consecutive values ≤ 250 cells/mm3.
• Primary efficacy endpoint: virologically linked HIV transmission
• Primary clinical endpoints: WHO stage 4 events, pulmonary TB,
severe bacterial infection and/or death
• Couples received intensive counseling on risk reduction and use of
condoms
Cohen MS, et al. IAS 2011. Abstract MOAX0102.
Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]
Linked HIV Transmission Events
n=27; incidence rate
1.7 per 100 p-y (95% CI 1.1, 2.5)
n=1; incidence rate
0.1 per 100 p-y (95% CI 0.0, 0.4)
Cohen M, et al. NEJM July 18, 2011.
Scienceexpress, July 19th 2010.
18th IAC 2010, Vienna, Austria, Abst. TUS505
70
(N=444)
(N=445)
Scienceexpress, July 19th 2010.
18th IAC 2010, Vienna, Austria, Abst. TUS505
High adherers (>80%) effectiveness = 54%
71
Cumulative Probability of HIV Infection
iPrEx Study (n=2499)
Grant R. et al. NEJM 2010; 363:2587-2599.
N=64
N=36
Risk Reduction 44% (95% CI: 15, 63)
P=0.005
Weeks
iPrEx Protection and Adherence
Overall
Grant R. et al. NEJM 2010; 363:2587-2599.
>90%
Adherence
Detectable
Drug Levels
Efficacy Rates of Prevention Trials
Effect Size, Percent
(95% CI)
Study
ART for prevention; HPTN 052, Africa,
Asia, Americas
PrEP for discordant couples;
Partners PrEP, Uganda, Kenya
PrEP for heterosexual men and
women; TDF2, Botswana
Medical male circumcision;
Orange Farm, Rakai, Kisumu
PrEP for MSMs; iPrEX, Americas,
Thailand, South Africa
Sexually transmitted diseases
treatment; Mwanza, Tanzania
Microbicide;
CAPRISA 004, South Africa
HIV vaccine;
RV144, Thailand
PrEP for women; FEM-PrEP, Kenya,
SA, Tanzania
0
20
96 (73-99)
73 (49-85)
63 (21-84)
54 (38-66)
44 (15-63)
42 (21-58)
39 (6-60)
31 (1-51)
0 (-69-41)
40
60
Efficacy (Percent)
80
100
Adapted from: Abdool Karim SS and Karim QA. Lancet 2011; 378(9809):e23-5 and Celum
C and Baeten JM. Curr Opinion Infect Dis 2012; 25:51-57
Work Towards a Cure
Procedure and Events
•
•
•
•
Ablative chemotherapy
Total body XRT
Graft vs. host
Transplant with
CCR5∆32 homozygous
donor