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CROI 2014: ARV and other issues of
interest
Richard Haubrich, MD
Professor of Medicine
Division of Infectious Diseases
Director, California Collaborative Treatment Group
University of California, San Diego
OUTLINE
• Epidemiology
– TDR (CDC and Margott)
• ARV treatment naïve studies
– ACTG 5257: three EFV sparing regimens
– Neat 001: DRV with NRTI or RAL
– DTG 96 weeks
– Prelude to long acting therapy: LATTE 1
• ARV complications?
– DAD (again), Kaiser to block?
– ACTG 5280- save the bones?
• PrEP
– long acting 744, proof of concept
Is there a difference in efficacy between
ATVr and DRVr
1. Yes
2. No
Are all DHHS guidelines preferred
regimens equivalent?
1. Yes
2. No
3. I don’t read the guidelines, so
who cares!
Do you think there is adequate evidence
to suggest ABC has increased CV risk (all
other factors equal)
1. Yes
2. No
3. I am agnostic
Calcium and vitamin D can prevent ART
related bone loss
1. yes
2. no
3. stop the @$#^! questions and tell me the
answers
TDR EPIDEMIOLOGY
Sensitive Screening Reveals Widespread
Underestimation of Transmitted HIV Drug Resistance
• 2009-2011; 895 samples
• Allele specific PCR: RT mutations
– M41L, K103N, Y181C, M184V and K65R.
• Prevalence
– Bulk: 7.9%
– Sensitive: 13.6%
Jonson, et al. 21st CROI. Boston, 2014. Abstract 87.
Demographics
• Age: < 20 5%; 20-40 63%; > 40 32%
• Race/ Ethnicity
– Black- 54%
– White- 29%
– Hispanic- 14%
• Sex- 86% male
• Risk: MSM 71%
Jonson, et al. 21st CROI. Boston, 2014. Abstract 87.
Black: 15%, Hispanic 6%. White 16%
TDR: Naïve Gilead Studies (2000-2013)
• Retrospective analysis
– 4 studies: prior to treatment
• IN (n=1617, 100 from early studies)
• PR-RT (n=2531)
• Subtype B: 92%
– Enrollment years
• 2000 (study 903), 2003 (study 934), 2013 (studies 104 and 111)
• Transmitted resistance trends
– INST: 1 T66T/I mixture 2000, 0 in 2003, 1.4% T97A
– NNRTI and PI: increased presence
– NRTI: stable presence of NRTI
Margot NA, et al. 21st CROI. Boston, 2014. Abstract 578.
Resistance-Associated Mutation
0
1
2
3
4
5
6
7
8
9
10
NNRTI PIINSTI
Patients(%)
8.7%
2.4%
3.2%
1.0%
1.4%
0%
0.5%
4.2%
1.2%
NRTI
2.9%
2.6%
2000
2003
2013
HPTN 061: “TDR” Black MSMs
• Longitudinal cohort black MSM
in 6 US cities
– HIV uninfected (n=1167)
– HIV infected (n=348)
• Genotyped with resistance results
(n=169 with HIV RNA >200
copies/mL)
• ART drug resistance: 28%
– In 3 cities, >40% had drug-
resistance HIV
– Multiclass resistance: 11%
– 23% of newly infected had drug-
resistant
Chen I, et al. 21st CROI. Boston, 2014. Abstract 581.
ART Drug Resistance
in Black MSM (2009-2011)
0
10
20
30
40
50
60
70
Boston
(n=14)
LA
(n=41)
Atlanta
(n=30)
Patients(%)
50%
30%
17%17%
10%
20%
7%
41%
4%
Any resistance
Multi-class resistance
50%
8%
20%
SF
(n=10)
DC
(n=24)
NYC
(n=50)
‘some’ on arv based
on drug levels
ARV Treatment: Naïve
Efficacy and Tolerability of Atazanavir, Raltegravir,
or Darunavir with FTC/TDF: ACTG A5257
Landovitz RJ, Ribaudo HJ, Ofotokun I, Wang H, Baugh BP, Leavitt RY, Rooney
JF, Seekins D, Currier JS, and Lennox JL for the A5257 Study Team
Background
• DHHS Guidance for initial treatment of HIV-1
infection includes TDF/FTC with EFV, ATV/r,
DRV/r, INI’s*
• Globally, EFV most commonly prescribed, following
WHO guidelines
• Patients with transmitted drug resistance,
psychiatric disorders, and women who are
contemplating pregnancy** are not good EFV
candidates
• A5257 designed to provide a comprehensive
comparison of non-EFV based regimens
*ABC/3TC may be used with DTG; ** If other options are available
ACTG A5257 Study
• Open-label, naïve, n=1809
– HIV RNA >1000
– Any CD4 count
• Randomized to TDF/FTC plus:
– ATVr (n=605)
– RAL bid (n=603)
– DRVr QD (n=601)
• Primary endpoints
– Time to HIV RNA >1000 at weeks
16-24, or >200 at or after week 24
– Time to discontinuation for toxicity
Landovitz RJ, et al. 21st CROI. Boston, 2014. Abstract 85.
BASELINE Patients
(n=1809)
Age (years) 37
Male (%) 76
Race/ethnicity (%)
Black
Hispanic
42
42
CD4
Median
% <200
308
30
HIV RNA
Median
% >100K
% >500K
4.6
30
7
Cumulative Incidence of
Virologic Failure
Difference in 96 wk cumulative incidence (97.5% CI)
-20 0-10 10 20
3.4% (-0.7%, 7.4%)
5.6% (1.3%, 9.9%)
-2.2% (-6.7%, 2.3%)
ATV/r vs RAL
DRV/r vs RAL
ATV/r vs DRV/r
Cumulative Incidence of
Tolerability Failure
Difference in 96 wk cumulative incidence (97.5% CI)
-20 0-10 10 20
13% (9.4%, 16%)
3.6% (1.4%, 5.8%)
9.2% (5.5%, 13%)
ATV/r vs RAL
DRV/r vs RAL
ATV/r vs DRV/r
Favors RAL
Favors DRV/r
Cumulative Incidence of
Virologic or Tolerability Failure
Difference in 96 wk cumulative incidence (97.5% CI)
-20 0-10 10 20
15% (10%, 20%)
7.5% (3.2%, 12%)
7.5% (2.3%, 13%)
ATV/r vs RAL
DRV/r vs RAL
ATV/r vs DRV/r
Favors RAL
Favors RAL
Favors DRV/r
*Consistent results seen with TLOVR at a 200 copies/ml threshold
Tolerability Failure
Toxicity Associated Discontinuation of randomized ART *
ATV/r
(N=605)
RAL
(N=603)
DRV/r
(N=601)
Any toxicity discontinuation 95 (16%) 8 (1%) 32 (5%)
Gastrointestinal toxicity 25 2 14
Jaundice/Hyperbilirubinemia 47 0 0
Other hepatic toxicity 4 1 5
Skin toxicity 7 2 5
Metabolic toxicity 6 0 2
Renal toxicity (all nephrolithiasis) 4 0 0
Abnormal chem/heme (excl. LFTs) 0 0 2
Other toxicity 2 3 4
*Participants allowed to switch therapy for intolerable toxicity
Proportion VL ≤50 copies/mL
ITT, regardless of ART change ITT, off-ART=failure (SNAPSHOT)
96
ATV/r 88%
RAL 94%
DRV/r 89%
96
ATV/r 63%
RAL 80%
DRV/r 73%
Resistance to Study Agents*
75/94 VF
Available
RAL
99/115 VF
Available
9 Any Resistance
(1.5% of ATV/r)
18 Any Resistance
(3% of RAL)
4 Any Resistance
(<1% of DRV/r)
ATV/r DRV/r
295 Virologic Failures
1 Baseline Missing
56 VF Failed to Amplify
1809 Participants
65/85 VF
Available
*Stanford University Genotypic Resistance Interpretation Algorithm V 6.3.1
Resistance to Study Agents
75/94 VF
Available
RAL
99/115 VF
Available
9 Any Resistance
(1.5% of ATV/r)
18 Any Resistance
(3% of RAL)
4 Any Resistance
(<1% of DRV/r)
ATV/r DRV/r
295 Virologic Failures
1 Baseline Missing
56 VF Failed to Amplify
1809 Participants
65/85 VF
Available
5 isolated M184V
1 integrase mutation
2 T69D/T215A/T
1 K70N + M184V
7 isolated M184V
1 isolated integrase mutation
7 integrase + M184V
3 integrase + M184V + K65R
3 isolated M184V
1 integrase mutation
*Stanford University Genotypic Resistance Interpretation Algorithm V 6.3.1
Additional Clinical Outcomes
Mean change in CD4 count from
baseline
• CD4 increase at week 96
• ATV/r: 284
• RAL: 288
• DRV/r: 256
• Both PI/r arms had greater increases in
LDL and triglycerides than the RAL-arm
(p<0.001)
Conclusions
• ATV/r, RAL, and DRV/r were equivalent for virologic efficacy
• ATV/r was less well tolerated than DRV/r or RAL
– Largely due to cosmetic hyperbilirubinemia
• RAL was superior to both PI/r regimens for combined tolerability and virologic
efficacy
– DRV/r was superior to ATV/r
• VF with resistance was rare
– More frequently observed with RAL
• Analyses are ongoing to evaluate:
– Cardiovascular, metabolic, skeletal, fat, inflammatory biomarkers, behavior,
adherence, and key subgroup differences
either with DRVr QD
NEAT 001/ARNS 143: Raltegravir +
Darunavir/r in Treatment-Naïve Patients
Randomization
1:1
TDF + FTC (n=404)
RAL bid (n=401)Phase 3 study
(96 weeks)
Treatment-naïve
Open-label, non-inferiority
HIV RNA >1000 copies/mL
CD4 <500 cells/mm3
No major IAS-USA
resistance mutations
No HBV
Primary endpoint: time to virologic or clinical failure
(any of the following):
• Viral failure
• Death due to any cause.
• Any new or recurrent AIDS-defining event.
• Any new serious non-AIDS-defining event.
Raffi F, et al. 21st CROI. Boston, 2014. Abstract
NEAT 001/ARNS 143: Raltegravir +
Darunavir/r in Treatment-Naïve Patients
• DRVr + RAL
– Non-inferior at week 96 (adjusted
difference 3.7% [-1.1%, 8.6%];
P=0.12)
– Inferior to TDF/ FTC with CD4 <200
cells/mm3
• Similar safety between the 2 arms
• Treatment-emergent resistance
with available genotype at failure
– RAL: 18% (5/28)
• 4/5 with baseline HIV RNA >500K
copies/mL
– FTC/TDF: 0% (0/16)
Raffi F, et al. 21st CROI. Boston, 2014. Abstract 84LB.
Key Week 96 Outcomes
RAL
(n=401)
TDF/ FTC
(n=404)
Virologic/clinical failure (%)
Overall
Baseline CD4 <200
Baseline HIV RNA >100K
17
39
36
14
21
27
Secondary
HIV RNA <50 (%)
CD4 gain
Lipid changes (%)
Total cholesterol
LDL-C
HDL-C
Triglycerides
Change in eGFR (mL/min)
89
267
+0.9
+0.5
+0.2
+0.3
+0.9
93
266
+0.5*
+0.4*
+0.1*
+0.2
-3.8*
Raffi F, et al. 21st CROI. Boston, 2014. Abstract
Walmsley et al. CROI 2014: 543
DTG vs EFV (Single)- WEEK 96
• Randomized, PC, double blind
• Treatment naïve, HLA-B*5701 negative
• Randomized to:
– DTG + ABC/3TC
– EFV/TDF/FTC
Walmsley et al. CROI 2014: 543
CD4 increase: 325 DTG vs 281, p
= 0.004
Viral failure: 6% (25 subjects) in
each arm
HIV RNA < 50 (FDA snapshot)
HIV RNA < 50: snapshot by VL subgroup
Walmsley et al. CROI 2014: 543
Treatment related adverse events
Walmsley et al. CROI 2014: 543
• HIV-1 integrase inhibitor,
dolutegravir analogue
• Oral drug (t½ = 40 hours)
• Long-acting SC or IM injection
(apparent t½ ≈ 40 days)
• Good virologic response at 5
and 30 mg/day as oral 10-day
monotherapy
GSK1265744 (744)
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.Spreen et al. HIV Clin Trials. 2013;14:192-203.
LATTE Study: 744 + Rilpivirine as
2-Drug Oral Maintenance Therapy
Margolis D, et al. 21st CROI. Boston, 2014. Abstract 91LB.
Efavirenz + 2 NRTIs*
744 (10, 30, 60 mg) + 2
NRTIs*
Phase 2b study
(96 weeks)
Treatment-naïve
Open-label
HIV RNA >1000 copies/mL
CD4 >200 cells/mm3
Stratified by HIV RNA and NRTI
Week 0 24 48 96
Primary Endpoint
HIV RNA <50 copies/mL
(FDA “Snapshot”)
744 (10, 30, 60 mg) + Rilpivirine
Induction
(24 weeks)
Maintenance
(72 weeks)
Patients in the 744 arm with HIV RNA <50 copies/mL at week 20 were switched to maintenance regimen at week 24.
Baseline: CD4 ~ 400; HIV RNA ~ 4.2
Primary Endpoint
Virologic Success: HIV-1 RNA <50 c/mL by FDA Snapshot (ITT-E)
Week
744 overall response W48
82%
EFV response W48
71%
744 overall response W24
87%
EFV response W24
74%
Median (IQR) change from baseline
CD4+ cell count (cells/mm3)
Week 48
744 overall +219 (141,343)
EFV +227 (134,369)
Proportion,%
242 4 8 12 16 4032 48362628BL
0
20
40
60
80
100
744 10 mg (N=60) 744 30 mg (N=60) 744 60 mg (N=61) EFV 600 mg (N=62)
Induction Phase Maintenance Phase
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
Secondary Endpoint – Maintenance Population
Virologic Success: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)
24
Week
Proportion,%
2 4 8 12 16 4032 48362628BL
*EFV patients with a week 24 visit
0
20
40
60
80
100
744 10 mg (N=52) 744 30 mg (N=53) 744 60 mg (N=55) EFV 600 mg (N=47)
Induction Phase Maintenance Phase
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
Treatment Outcomes - Maintenance Population
HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)
Outcome at Week 48
744
total
n=160
EFV
600 mg
n=47*
Virologic success 149 (93%) 44 (94%)
Virologic failure 9 (6%) 2 (4%)
Data in window not <50 c/mL 7 (4%) 1 (2%)
Discontinued for lack of efficacy 0 1 (2%)
Change in ART 2 (1%) 0
No virologic data at Week 48 2 (1%) 1 (2%)
Discontinued due to AE‡ 2 (1%) 1 (2%)
*EFV patients with a W24 visit
†Carried forward from Induction Phase
‡Abnormal ECG (10 mg); anxiety (60 mg); colitis (EFV) Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
LATTE Study – Week 48 Analysis Conclusions
Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
• Following induction therapy, oral 744+RPV maintained virologic
suppression at a rate similar to EFV+NRTIs
• Primary Endpoint: 82% of 744+RPV and 71% of EFV+NRTIs
subjects had HIV-1 RNA <50 copies/mL
• Secondary Endpoint (ITT-ME): 93% of 744+RPV and 94% of
EFV+NRTIs subjects had HIV-1 RNA <50 copies/mL
• Similar response rate across 744 10mg, 30mg, and 60mg arms
• One subject, with persistently low 744 and RPV drug concentrations, developed
treatment emergent INI and NNRTI mutations
• 744+RPV was well tolerated, with few drug related AEs leading to
withdrawal
• Long-term data needed, however, these regimen POC results support
evaluation of long-acting injectable regimen of 744 LA + TMC278 LA as
maintenance therapy
Based on A5257 would you use ATVr:
1. More
2. Less
3. The same
4. I don’t use ATVr
When would you use a two drug regimen
(i.e. PIr + INSTI or NNRTI)?
1. Never
2. For maintenance in patients that develop NRTI
toxicity
3. For patients with high CD4 and low HIV RNA
ARV Complications?
D:A:D Study:
Update on MI Risk and Abacavir Exposure
• Prospective cohort (2000-2013)
– >49,000 HIV-positive patients from 11
cohorts in Europe, Australia, US
• Current abacavir use was associated with
a 98% increase in MI rate
– No difference between pre- and post-2008
– Results unchanged after stratifying by
Framingham risk group, as well as by
other factors (eg, renal function,
dyslipidemia, hypertension)
• Current findings argue against channeling
bias
Sabin CA, et al. 21st CROI. Boston, 2014. Abstract 747LB.
PY: person-years.
Adjusted Relative MI Rate
and Current Abacavir Use
1.98
Reference
No Abacavir
5
4
3
2
1
0.7
1.97 1.97
Overall
Pre
3/2008
Post
3/2008
No ABC
Events/PYs
Rate/PYs (95% CI)
600/2,95,642
0.20
(0.19, 0.22)
425/169,417
0.25
(0.23, 0.28)
175/126,225
0.14
(0.12, 0.16)
On ABC
Events/PYs
Rate/PYs (95% CI)
341/71,917
0.47
(0.42, 0.52)
247/40,833
0.61
(0.53, 0.68)
94/31,084
0.30
(0.24, 0.36)
Kaiser Permanente, Northern California:
MI Risk and HIV Infection Status
• Population-based cohort (1996-2011)
– Male: 91%
– HIV negative (n=257,600)
• MI events: 2483
• Follow-up: 1,506,676 person-years
– HIV positive (n=24,768)
• MI events: 320
• Follow-up: 119,587
• Higher risk of MI among HIV-positive adults
is no longer observed in more recent years
– Reduced risk likely due to cardiovascular
risk reduction, more lipid-friendly ART, and
reduced immunodeficiency
Klein DB, et al. 21st CROI. Boston, 2014. Abstract 737.
MI Rate Ratios for
HIV-infected vs negative
0 0.5 1.0 1.5 2.0 2.5 3.0
Adjusted Rate Ratio (95% CI)
1996-1999
2000-2003
2004-2007
2008-2009
2010-2011
1.8
1.7
1.3
Reference
HIV-
1.3
1.0
CROI Review: ARV and Other Issues of Interest
ACTG A5280: Impact of High-Dose
Vitamin D and Calcium on Bone Loss With ART
• Double-blind, prospective, 48-week trial in
treatment-naïve patients initiating efavirenz/
emtricitabine/tenofovir DF
– Vitamin D level <75 to >10 ng/mL
• Randomized arms
– Vitamin D3 4000 IU/ calcium 1000 mg
– Placebo
• Primary endpoint
– Percent change from baseline in total hip BMD at
week 96
Baseline Characteristics
Overton ET, et al. 21st CROI. Boston, 2014. Abstract 133.
Vitamin D
Calcium
(n=79)
Placebo
(n=86)
Age (years) 36 31
Male (%) 91 90
Race/ethnicity (%)
White
Black
Hispanic
35
30
29
38
35
21
BMI (kg/m2) 25.0 24.0
HIV RNA (log10 copies/mL) 4.5 4.5
CD4 (cells/mm3) 339 342
Estimated daily intake
Calcium (mg)
Vitamin D (IU)
813
120
811
137
ACTG A5280: Impact of High-Dose
Vitamin D and Calcium on Bone Loss With ART
• HIV outcomes
– HIV RNA <50 copies/mL: 90%
– Similar CD4 gains in both arms
• Change in 25(OH) vitamin D3 levels
– Vitamin D/calcium arm
• Increased from 26.7 ng/mL at baseline to 55.6 and 56.4
ng/mL at weeks 24 and 48, respectively
– Placebo arm: no change from baseline levels (25.1
ng/mL)
• Vitamin D3 and calcium
– Reduced hip and spine BMD loss by 50% with ART
– Attenuated bone turnover
• Adverse events
– Kidney stone (n=1, placebo)
– No hypercalcemia, hypophosphatemia
Overton ET, et al. 21st CROI. Boston, 2014. Abstract 133.
Week 96 Change in BMD
-4
-3
-2
-1
0
1
Lumbar
Spine
Total
Hip
Week48Change(%)
-1.4%
-2.9%
-1.4%
-3.2%
Vitamin D and calcium (n=79)
Placebo (n=86)
P<0.001 P<0.08
CROI Review: ARV and Other Issues of Interest
ACTG A5257 Substudy: Impact of
Raltegravir- and PI-Based Regimens on BMD
• Open-label, treatment-naïve patients (n=328)
– HIV RNA >1000 copies/mL
• Randomized groups
– Raltegravir + FTC/TDF (n=106)
– Atazanavir/r + FTC/TDF (n=109)
– Darunavir/r + FTC/TDF (n=113)
• Week 96 change in BMD
– Reduced BMD with all 3 arms
– Raltegravir arm had significantly less BMD loss at lumbar
spine and total hip versus PI-based arms (P<0.01)
– Less loss in total body BMD
• Raltegravir versus atazanavir/r (P=0.004)
• Darunavir/r versus atazanavir/r (P=0.001)
Brown TT, et al. 21st CROI. Boston, 2014. Abstract 779LB.
Week 96 Change in BMD
-5
-4
-3
-2
-1
0
1
Lumbar
Spine
Total
Body
Total
Hip
Week96Change(%)
-3.6%
-2.9%
-1.6%
-2.4%
-3.4%
-3.9%
-1.8%
-4.0%
-1.7%
Raltegravir (n=106)
Atazanavir/r (n=109)
Darunavir/r (n=113)
When would you use vitamin D and Ca++?
1. For post menopausal women
2. For all patients on EFV
3. For high-risk patients on EFV
4. After a fracture
5. Never- not enough data
Do you consider ABC-related CV effects in
selection of regimens for naïve patients?
1. Never
2. In a patient with moderate CV risk
3. In a patient with high CV risk
4. I don’t use ABC
PrEP
US PrEP Demonstration Project:
Implementation of PrEP (2012-2014)
• STD clinics in San Francisco, Miami, Washington,
DC (n=831)
– MSM, transgender women (1.4%)
– Clinic referrals (63%)
– Self-referrals (37%): more likely to be white, higher
education level, higher sexual risk behaviors and
risk perception versus clinic referrals
• Offered up to 48 weeks of open-label
emtricitabine/tenofovir DF
– Accepted PrEP: 60.4%
• 77% had TDF-DP levels consistent with taking >4
doses/week
• PrEP uptake associated with
– Self-referral, prior PrEP awareness, higher-risk
sexual behaviors
BLD: below limit of detection.
Cohen SE, et al. 21st CROI. Boston, 2014. Abstract 954.
Tenofovir-DP Levels (Week 4)
0
10
20
30
40
50
60
<250 250-550 >550-950BLD
Samples(%)
18%
43%
14%
5%
2%
>950
2%
11%
27%
4% 4%
52%
43%
40%
35%
Miami (n=157)
Washington, DC (n=100)
San Francisco (n=300)
Doses/Week: <2 <2 2 4 >4
Tenofovir-DP (fmol/punch)*
0%
*femtomole/punch: measure of flux density.
Partners PrEP Study: Low Frequency Resistance Testing
Among Seroconverters
• Double-blind, phase 3 study of serodiscordant,
heterosexual couples
– PrEP significantly reduced the risk of HIV infection by
67% to 75% (P<0.0001)
– Ultra-deep versus standard sequencing
• Detect drug resistance at frequencies >1% versus >20%,
respectively
• Ultra-deep sequencing on samples from 121
seroconverters
• Overall resistance: 7.4% (9/121)
– HIV positive at enrollment (n=3)
– Acquired HIV after enrollment (n=6)
• TDF (2/38): 1 M184V, 1 K65R/M184V
• TDF/FTC (5/25): 4 M184V, 1K65R/K70E
• Detection of PrEP drug in blood plasma was
associated with an increased risk of resistance
(P=0.0009)
Lehman DA, et al. 21st CROI. Boston, 2014. Abstract 590LB.
0
20
40
60
80
100
Resistance Detected Above Frequencies
of 1% in 121 Seroconverters
Seroconverters(%)
Overall
(n=25/38/58)
20%
3.5%5.3%
Before
(n=4/8/6)
After
(n=21/30/52)
Found to Be HIV Positive Before or
After Study Enrollment
Emtricitabine/tenofovir DF
Tenofovir DF
Placebo
50%
0%
12.5% 14.3%
3.8%3.3%
0
20
40
60
80
100
0
20
40
60
80
100
PrEP Proof-of-Concept: Long-Acting Integrase Inhibitor in
Nanosuspension for Injection
• Macaque model of SHIV transmission
• Study 1 (vaginal transmission)
– Low-dose SHIV (50 TCID50) twice a week
– GSK744 LA (50 mg/kg) 3 injections at week 0,
4, 8
– 6 of 6 pigtail macaques (lunar menstrual cycles)
protected against SHIV infection
• Study 2 (rectal transmission)
– Weekly SHIV (50 TCID50) until systemic infection
detected
– One GSK744 LA (50 mg/kg) injection at week 0
– After 1 to 2 challenges, placebo macaques
became infected
– With a single GSK744 injection, infection was
delayed by 5 to 10 challenges with SHIV
Radzlo J, et al. 21st CROI. Boston, 2014. Abstract 40LB.
Andrews CD, et al. 21st CROI. Boston, 2014. Abstract 39.
Andrews CD, et al. Science. 2014;343:1151-1154.
P=0.0005
Week
Aviremic(%)
GSK744 LA (n=6)
Placebo (n=6)
Week
0 2 4 6 8 10 12 14 16 30
Vaginal SHIV Exposure
Aviremic(%)
GSK744 LA (n=12)
Placebo (n=4)
Rectal SHIV Exposure
0 2 4 6 8 10 12 14 16 18 20 22 24
P<0.0001
Summary of Clinically Relevant Points
• TDR still alive and well
– Can find more using sensitive techniques
– Little evidence of transmitted INSTI
• ARV for naïve
– ATV has more tolerability issues than RAL or DRV
(mostly bilirubin)
– RAL best tolerated
– DTG with ABC/ 3TC superior to EFV/TDF/FTC (tolerability)
Summary of Clinically Relevant Points
• ARV for naïve
– Bone loss can be prevented with Ca and vitamin D
– ABC cv risk still controversial
• Long acting ART promising for
– Maintenance
– PrEP

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CROI Review: ARV and Other Issues of Interest

  • 1. CROI 2014: ARV and other issues of interest Richard Haubrich, MD Professor of Medicine Division of Infectious Diseases Director, California Collaborative Treatment Group University of California, San Diego
  • 2. OUTLINE • Epidemiology – TDR (CDC and Margott) • ARV treatment naïve studies – ACTG 5257: three EFV sparing regimens – Neat 001: DRV with NRTI or RAL – DTG 96 weeks – Prelude to long acting therapy: LATTE 1 • ARV complications? – DAD (again), Kaiser to block? – ACTG 5280- save the bones? • PrEP – long acting 744, proof of concept
  • 3. Is there a difference in efficacy between ATVr and DRVr 1. Yes 2. No
  • 4. Are all DHHS guidelines preferred regimens equivalent? 1. Yes 2. No 3. I don’t read the guidelines, so who cares!
  • 5. Do you think there is adequate evidence to suggest ABC has increased CV risk (all other factors equal) 1. Yes 2. No 3. I am agnostic
  • 6. Calcium and vitamin D can prevent ART related bone loss 1. yes 2. no 3. stop the @$#^! questions and tell me the answers
  • 8. Sensitive Screening Reveals Widespread Underestimation of Transmitted HIV Drug Resistance • 2009-2011; 895 samples • Allele specific PCR: RT mutations – M41L, K103N, Y181C, M184V and K65R. • Prevalence – Bulk: 7.9% – Sensitive: 13.6% Jonson, et al. 21st CROI. Boston, 2014. Abstract 87.
  • 9. Demographics • Age: < 20 5%; 20-40 63%; > 40 32% • Race/ Ethnicity – Black- 54% – White- 29% – Hispanic- 14% • Sex- 86% male • Risk: MSM 71% Jonson, et al. 21st CROI. Boston, 2014. Abstract 87.
  • 10. Black: 15%, Hispanic 6%. White 16%
  • 11. TDR: Naïve Gilead Studies (2000-2013) • Retrospective analysis – 4 studies: prior to treatment • IN (n=1617, 100 from early studies) • PR-RT (n=2531) • Subtype B: 92% – Enrollment years • 2000 (study 903), 2003 (study 934), 2013 (studies 104 and 111) • Transmitted resistance trends – INST: 1 T66T/I mixture 2000, 0 in 2003, 1.4% T97A – NNRTI and PI: increased presence – NRTI: stable presence of NRTI Margot NA, et al. 21st CROI. Boston, 2014. Abstract 578. Resistance-Associated Mutation 0 1 2 3 4 5 6 7 8 9 10 NNRTI PIINSTI Patients(%) 8.7% 2.4% 3.2% 1.0% 1.4% 0% 0.5% 4.2% 1.2% NRTI 2.9% 2.6% 2000 2003 2013
  • 12. HPTN 061: “TDR” Black MSMs • Longitudinal cohort black MSM in 6 US cities – HIV uninfected (n=1167) – HIV infected (n=348) • Genotyped with resistance results (n=169 with HIV RNA >200 copies/mL) • ART drug resistance: 28% – In 3 cities, >40% had drug- resistance HIV – Multiclass resistance: 11% – 23% of newly infected had drug- resistant Chen I, et al. 21st CROI. Boston, 2014. Abstract 581. ART Drug Resistance in Black MSM (2009-2011) 0 10 20 30 40 50 60 70 Boston (n=14) LA (n=41) Atlanta (n=30) Patients(%) 50% 30% 17%17% 10% 20% 7% 41% 4% Any resistance Multi-class resistance 50% 8% 20% SF (n=10) DC (n=24) NYC (n=50) ‘some’ on arv based on drug levels
  • 14. Efficacy and Tolerability of Atazanavir, Raltegravir, or Darunavir with FTC/TDF: ACTG A5257 Landovitz RJ, Ribaudo HJ, Ofotokun I, Wang H, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS, and Lennox JL for the A5257 Study Team
  • 15. Background • DHHS Guidance for initial treatment of HIV-1 infection includes TDF/FTC with EFV, ATV/r, DRV/r, INI’s* • Globally, EFV most commonly prescribed, following WHO guidelines • Patients with transmitted drug resistance, psychiatric disorders, and women who are contemplating pregnancy** are not good EFV candidates • A5257 designed to provide a comprehensive comparison of non-EFV based regimens *ABC/3TC may be used with DTG; ** If other options are available
  • 16. ACTG A5257 Study • Open-label, naïve, n=1809 – HIV RNA >1000 – Any CD4 count • Randomized to TDF/FTC plus: – ATVr (n=605) – RAL bid (n=603) – DRVr QD (n=601) • Primary endpoints – Time to HIV RNA >1000 at weeks 16-24, or >200 at or after week 24 – Time to discontinuation for toxicity Landovitz RJ, et al. 21st CROI. Boston, 2014. Abstract 85. BASELINE Patients (n=1809) Age (years) 37 Male (%) 76 Race/ethnicity (%) Black Hispanic 42 42 CD4 Median % <200 308 30 HIV RNA Median % >100K % >500K 4.6 30 7
  • 17. Cumulative Incidence of Virologic Failure Difference in 96 wk cumulative incidence (97.5% CI) -20 0-10 10 20 3.4% (-0.7%, 7.4%) 5.6% (1.3%, 9.9%) -2.2% (-6.7%, 2.3%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r
  • 18. Cumulative Incidence of Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) -20 0-10 10 20 13% (9.4%, 16%) 3.6% (1.4%, 5.8%) 9.2% (5.5%, 13%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r Favors RAL Favors DRV/r
  • 19. Cumulative Incidence of Virologic or Tolerability Failure Difference in 96 wk cumulative incidence (97.5% CI) -20 0-10 10 20 15% (10%, 20%) 7.5% (3.2%, 12%) 7.5% (2.3%, 13%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r Favors RAL Favors RAL Favors DRV/r *Consistent results seen with TLOVR at a 200 copies/ml threshold
  • 20. Tolerability Failure Toxicity Associated Discontinuation of randomized ART * ATV/r (N=605) RAL (N=603) DRV/r (N=601) Any toxicity discontinuation 95 (16%) 8 (1%) 32 (5%) Gastrointestinal toxicity 25 2 14 Jaundice/Hyperbilirubinemia 47 0 0 Other hepatic toxicity 4 1 5 Skin toxicity 7 2 5 Metabolic toxicity 6 0 2 Renal toxicity (all nephrolithiasis) 4 0 0 Abnormal chem/heme (excl. LFTs) 0 0 2 Other toxicity 2 3 4 *Participants allowed to switch therapy for intolerable toxicity
  • 21. Proportion VL ≤50 copies/mL ITT, regardless of ART change ITT, off-ART=failure (SNAPSHOT) 96 ATV/r 88% RAL 94% DRV/r 89% 96 ATV/r 63% RAL 80% DRV/r 73%
  • 22. Resistance to Study Agents* 75/94 VF Available RAL 99/115 VF Available 9 Any Resistance (1.5% of ATV/r) 18 Any Resistance (3% of RAL) 4 Any Resistance (<1% of DRV/r) ATV/r DRV/r 295 Virologic Failures 1 Baseline Missing 56 VF Failed to Amplify 1809 Participants 65/85 VF Available *Stanford University Genotypic Resistance Interpretation Algorithm V 6.3.1
  • 23. Resistance to Study Agents 75/94 VF Available RAL 99/115 VF Available 9 Any Resistance (1.5% of ATV/r) 18 Any Resistance (3% of RAL) 4 Any Resistance (<1% of DRV/r) ATV/r DRV/r 295 Virologic Failures 1 Baseline Missing 56 VF Failed to Amplify 1809 Participants 65/85 VF Available 5 isolated M184V 1 integrase mutation 2 T69D/T215A/T 1 K70N + M184V 7 isolated M184V 1 isolated integrase mutation 7 integrase + M184V 3 integrase + M184V + K65R 3 isolated M184V 1 integrase mutation *Stanford University Genotypic Resistance Interpretation Algorithm V 6.3.1
  • 24. Additional Clinical Outcomes Mean change in CD4 count from baseline • CD4 increase at week 96 • ATV/r: 284 • RAL: 288 • DRV/r: 256 • Both PI/r arms had greater increases in LDL and triglycerides than the RAL-arm (p<0.001)
  • 25. Conclusions • ATV/r, RAL, and DRV/r were equivalent for virologic efficacy • ATV/r was less well tolerated than DRV/r or RAL – Largely due to cosmetic hyperbilirubinemia • RAL was superior to both PI/r regimens for combined tolerability and virologic efficacy – DRV/r was superior to ATV/r • VF with resistance was rare – More frequently observed with RAL • Analyses are ongoing to evaluate: – Cardiovascular, metabolic, skeletal, fat, inflammatory biomarkers, behavior, adherence, and key subgroup differences
  • 26. either with DRVr QD NEAT 001/ARNS 143: Raltegravir + Darunavir/r in Treatment-Naïve Patients Randomization 1:1 TDF + FTC (n=404) RAL bid (n=401)Phase 3 study (96 weeks) Treatment-naïve Open-label, non-inferiority HIV RNA >1000 copies/mL CD4 <500 cells/mm3 No major IAS-USA resistance mutations No HBV Primary endpoint: time to virologic or clinical failure (any of the following): • Viral failure • Death due to any cause. • Any new or recurrent AIDS-defining event. • Any new serious non-AIDS-defining event. Raffi F, et al. 21st CROI. Boston, 2014. Abstract
  • 27. NEAT 001/ARNS 143: Raltegravir + Darunavir/r in Treatment-Naïve Patients • DRVr + RAL – Non-inferior at week 96 (adjusted difference 3.7% [-1.1%, 8.6%]; P=0.12) – Inferior to TDF/ FTC with CD4 <200 cells/mm3 • Similar safety between the 2 arms • Treatment-emergent resistance with available genotype at failure – RAL: 18% (5/28) • 4/5 with baseline HIV RNA >500K copies/mL – FTC/TDF: 0% (0/16) Raffi F, et al. 21st CROI. Boston, 2014. Abstract 84LB. Key Week 96 Outcomes RAL (n=401) TDF/ FTC (n=404) Virologic/clinical failure (%) Overall Baseline CD4 <200 Baseline HIV RNA >100K 17 39 36 14 21 27 Secondary HIV RNA <50 (%) CD4 gain Lipid changes (%) Total cholesterol LDL-C HDL-C Triglycerides Change in eGFR (mL/min) 89 267 +0.9 +0.5 +0.2 +0.3 +0.9 93 266 +0.5* +0.4* +0.1* +0.2 -3.8* Raffi F, et al. 21st CROI. Boston, 2014. Abstract
  • 28. Walmsley et al. CROI 2014: 543 DTG vs EFV (Single)- WEEK 96 • Randomized, PC, double blind • Treatment naïve, HLA-B*5701 negative • Randomized to: – DTG + ABC/3TC – EFV/TDF/FTC
  • 29. Walmsley et al. CROI 2014: 543 CD4 increase: 325 DTG vs 281, p = 0.004 Viral failure: 6% (25 subjects) in each arm HIV RNA < 50 (FDA snapshot)
  • 30. HIV RNA < 50: snapshot by VL subgroup Walmsley et al. CROI 2014: 543
  • 31. Treatment related adverse events Walmsley et al. CROI 2014: 543
  • 32. • HIV-1 integrase inhibitor, dolutegravir analogue • Oral drug (t½ = 40 hours) • Long-acting SC or IM injection (apparent t½ ≈ 40 days) • Good virologic response at 5 and 30 mg/day as oral 10-day monotherapy GSK1265744 (744) Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.Spreen et al. HIV Clin Trials. 2013;14:192-203.
  • 33. LATTE Study: 744 + Rilpivirine as 2-Drug Oral Maintenance Therapy Margolis D, et al. 21st CROI. Boston, 2014. Abstract 91LB. Efavirenz + 2 NRTIs* 744 (10, 30, 60 mg) + 2 NRTIs* Phase 2b study (96 weeks) Treatment-naïve Open-label HIV RNA >1000 copies/mL CD4 >200 cells/mm3 Stratified by HIV RNA and NRTI Week 0 24 48 96 Primary Endpoint HIV RNA <50 copies/mL (FDA “Snapshot”) 744 (10, 30, 60 mg) + Rilpivirine Induction (24 weeks) Maintenance (72 weeks) Patients in the 744 arm with HIV RNA <50 copies/mL at week 20 were switched to maintenance regimen at week 24. Baseline: CD4 ~ 400; HIV RNA ~ 4.2
  • 34. Primary Endpoint Virologic Success: HIV-1 RNA <50 c/mL by FDA Snapshot (ITT-E) Week 744 overall response W48 82% EFV response W48 71% 744 overall response W24 87% EFV response W24 74% Median (IQR) change from baseline CD4+ cell count (cells/mm3) Week 48 744 overall +219 (141,343) EFV +227 (134,369) Proportion,% 242 4 8 12 16 4032 48362628BL 0 20 40 60 80 100 744 10 mg (N=60) 744 30 mg (N=60) 744 60 mg (N=61) EFV 600 mg (N=62) Induction Phase Maintenance Phase Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
  • 35. Secondary Endpoint – Maintenance Population Virologic Success: HIV-1 RNA <50 c/mL by Snapshot (ITT-ME) 24 Week Proportion,% 2 4 8 12 16 4032 48362628BL *EFV patients with a week 24 visit 0 20 40 60 80 100 744 10 mg (N=52) 744 30 mg (N=53) 744 60 mg (N=55) EFV 600 mg (N=47) Induction Phase Maintenance Phase Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
  • 36. Treatment Outcomes - Maintenance Population HIV-1 RNA <50 c/mL by Snapshot (ITT-ME) Outcome at Week 48 744 total n=160 EFV 600 mg n=47* Virologic success 149 (93%) 44 (94%) Virologic failure 9 (6%) 2 (4%) Data in window not <50 c/mL 7 (4%) 1 (2%) Discontinued for lack of efficacy 0 1 (2%) Change in ART 2 (1%) 0 No virologic data at Week 48 2 (1%) 1 (2%) Discontinued due to AE‡ 2 (1%) 1 (2%) *EFV patients with a W24 visit †Carried forward from Induction Phase ‡Abnormal ECG (10 mg); anxiety (60 mg); colitis (EFV) Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.
  • 37. LATTE Study – Week 48 Analysis Conclusions Margolis et al. CROI 2014; Boston, MA. Abstract 91LB. • Following induction therapy, oral 744+RPV maintained virologic suppression at a rate similar to EFV+NRTIs • Primary Endpoint: 82% of 744+RPV and 71% of EFV+NRTIs subjects had HIV-1 RNA <50 copies/mL • Secondary Endpoint (ITT-ME): 93% of 744+RPV and 94% of EFV+NRTIs subjects had HIV-1 RNA <50 copies/mL • Similar response rate across 744 10mg, 30mg, and 60mg arms • One subject, with persistently low 744 and RPV drug concentrations, developed treatment emergent INI and NNRTI mutations • 744+RPV was well tolerated, with few drug related AEs leading to withdrawal • Long-term data needed, however, these regimen POC results support evaluation of long-acting injectable regimen of 744 LA + TMC278 LA as maintenance therapy
  • 38. Based on A5257 would you use ATVr: 1. More 2. Less 3. The same 4. I don’t use ATVr
  • 39. When would you use a two drug regimen (i.e. PIr + INSTI or NNRTI)? 1. Never 2. For maintenance in patients that develop NRTI toxicity 3. For patients with high CD4 and low HIV RNA
  • 41. D:A:D Study: Update on MI Risk and Abacavir Exposure • Prospective cohort (2000-2013) – >49,000 HIV-positive patients from 11 cohorts in Europe, Australia, US • Current abacavir use was associated with a 98% increase in MI rate – No difference between pre- and post-2008 – Results unchanged after stratifying by Framingham risk group, as well as by other factors (eg, renal function, dyslipidemia, hypertension) • Current findings argue against channeling bias Sabin CA, et al. 21st CROI. Boston, 2014. Abstract 747LB. PY: person-years. Adjusted Relative MI Rate and Current Abacavir Use 1.98 Reference No Abacavir 5 4 3 2 1 0.7 1.97 1.97 Overall Pre 3/2008 Post 3/2008 No ABC Events/PYs Rate/PYs (95% CI) 600/2,95,642 0.20 (0.19, 0.22) 425/169,417 0.25 (0.23, 0.28) 175/126,225 0.14 (0.12, 0.16) On ABC Events/PYs Rate/PYs (95% CI) 341/71,917 0.47 (0.42, 0.52) 247/40,833 0.61 (0.53, 0.68) 94/31,084 0.30 (0.24, 0.36)
  • 42. Kaiser Permanente, Northern California: MI Risk and HIV Infection Status • Population-based cohort (1996-2011) – Male: 91% – HIV negative (n=257,600) • MI events: 2483 • Follow-up: 1,506,676 person-years – HIV positive (n=24,768) • MI events: 320 • Follow-up: 119,587 • Higher risk of MI among HIV-positive adults is no longer observed in more recent years – Reduced risk likely due to cardiovascular risk reduction, more lipid-friendly ART, and reduced immunodeficiency Klein DB, et al. 21st CROI. Boston, 2014. Abstract 737. MI Rate Ratios for HIV-infected vs negative 0 0.5 1.0 1.5 2.0 2.5 3.0 Adjusted Rate Ratio (95% CI) 1996-1999 2000-2003 2004-2007 2008-2009 2010-2011 1.8 1.7 1.3 Reference HIV- 1.3 1.0
  • 44. ACTG A5280: Impact of High-Dose Vitamin D and Calcium on Bone Loss With ART • Double-blind, prospective, 48-week trial in treatment-naïve patients initiating efavirenz/ emtricitabine/tenofovir DF – Vitamin D level <75 to >10 ng/mL • Randomized arms – Vitamin D3 4000 IU/ calcium 1000 mg – Placebo • Primary endpoint – Percent change from baseline in total hip BMD at week 96 Baseline Characteristics Overton ET, et al. 21st CROI. Boston, 2014. Abstract 133. Vitamin D Calcium (n=79) Placebo (n=86) Age (years) 36 31 Male (%) 91 90 Race/ethnicity (%) White Black Hispanic 35 30 29 38 35 21 BMI (kg/m2) 25.0 24.0 HIV RNA (log10 copies/mL) 4.5 4.5 CD4 (cells/mm3) 339 342 Estimated daily intake Calcium (mg) Vitamin D (IU) 813 120 811 137
  • 45. ACTG A5280: Impact of High-Dose Vitamin D and Calcium on Bone Loss With ART • HIV outcomes – HIV RNA <50 copies/mL: 90% – Similar CD4 gains in both arms • Change in 25(OH) vitamin D3 levels – Vitamin D/calcium arm • Increased from 26.7 ng/mL at baseline to 55.6 and 56.4 ng/mL at weeks 24 and 48, respectively – Placebo arm: no change from baseline levels (25.1 ng/mL) • Vitamin D3 and calcium – Reduced hip and spine BMD loss by 50% with ART – Attenuated bone turnover • Adverse events – Kidney stone (n=1, placebo) – No hypercalcemia, hypophosphatemia Overton ET, et al. 21st CROI. Boston, 2014. Abstract 133. Week 96 Change in BMD -4 -3 -2 -1 0 1 Lumbar Spine Total Hip Week48Change(%) -1.4% -2.9% -1.4% -3.2% Vitamin D and calcium (n=79) Placebo (n=86) P<0.001 P<0.08
  • 47. ACTG A5257 Substudy: Impact of Raltegravir- and PI-Based Regimens on BMD • Open-label, treatment-naïve patients (n=328) – HIV RNA >1000 copies/mL • Randomized groups – Raltegravir + FTC/TDF (n=106) – Atazanavir/r + FTC/TDF (n=109) – Darunavir/r + FTC/TDF (n=113) • Week 96 change in BMD – Reduced BMD with all 3 arms – Raltegravir arm had significantly less BMD loss at lumbar spine and total hip versus PI-based arms (P<0.01) – Less loss in total body BMD • Raltegravir versus atazanavir/r (P=0.004) • Darunavir/r versus atazanavir/r (P=0.001) Brown TT, et al. 21st CROI. Boston, 2014. Abstract 779LB. Week 96 Change in BMD -5 -4 -3 -2 -1 0 1 Lumbar Spine Total Body Total Hip Week96Change(%) -3.6% -2.9% -1.6% -2.4% -3.4% -3.9% -1.8% -4.0% -1.7% Raltegravir (n=106) Atazanavir/r (n=109) Darunavir/r (n=113)
  • 48. When would you use vitamin D and Ca++? 1. For post menopausal women 2. For all patients on EFV 3. For high-risk patients on EFV 4. After a fracture 5. Never- not enough data
  • 49. Do you consider ABC-related CV effects in selection of regimens for naïve patients? 1. Never 2. In a patient with moderate CV risk 3. In a patient with high CV risk 4. I don’t use ABC
  • 50. PrEP
  • 51. US PrEP Demonstration Project: Implementation of PrEP (2012-2014) • STD clinics in San Francisco, Miami, Washington, DC (n=831) – MSM, transgender women (1.4%) – Clinic referrals (63%) – Self-referrals (37%): more likely to be white, higher education level, higher sexual risk behaviors and risk perception versus clinic referrals • Offered up to 48 weeks of open-label emtricitabine/tenofovir DF – Accepted PrEP: 60.4% • 77% had TDF-DP levels consistent with taking >4 doses/week • PrEP uptake associated with – Self-referral, prior PrEP awareness, higher-risk sexual behaviors BLD: below limit of detection. Cohen SE, et al. 21st CROI. Boston, 2014. Abstract 954. Tenofovir-DP Levels (Week 4) 0 10 20 30 40 50 60 <250 250-550 >550-950BLD Samples(%) 18% 43% 14% 5% 2% >950 2% 11% 27% 4% 4% 52% 43% 40% 35% Miami (n=157) Washington, DC (n=100) San Francisco (n=300) Doses/Week: <2 <2 2 4 >4 Tenofovir-DP (fmol/punch)* 0% *femtomole/punch: measure of flux density.
  • 52. Partners PrEP Study: Low Frequency Resistance Testing Among Seroconverters • Double-blind, phase 3 study of serodiscordant, heterosexual couples – PrEP significantly reduced the risk of HIV infection by 67% to 75% (P<0.0001) – Ultra-deep versus standard sequencing • Detect drug resistance at frequencies >1% versus >20%, respectively • Ultra-deep sequencing on samples from 121 seroconverters • Overall resistance: 7.4% (9/121) – HIV positive at enrollment (n=3) – Acquired HIV after enrollment (n=6) • TDF (2/38): 1 M184V, 1 K65R/M184V • TDF/FTC (5/25): 4 M184V, 1K65R/K70E • Detection of PrEP drug in blood plasma was associated with an increased risk of resistance (P=0.0009) Lehman DA, et al. 21st CROI. Boston, 2014. Abstract 590LB. 0 20 40 60 80 100 Resistance Detected Above Frequencies of 1% in 121 Seroconverters Seroconverters(%) Overall (n=25/38/58) 20% 3.5%5.3% Before (n=4/8/6) After (n=21/30/52) Found to Be HIV Positive Before or After Study Enrollment Emtricitabine/tenofovir DF Tenofovir DF Placebo 50% 0% 12.5% 14.3% 3.8%3.3%
  • 53. 0 20 40 60 80 100 0 20 40 60 80 100 PrEP Proof-of-Concept: Long-Acting Integrase Inhibitor in Nanosuspension for Injection • Macaque model of SHIV transmission • Study 1 (vaginal transmission) – Low-dose SHIV (50 TCID50) twice a week – GSK744 LA (50 mg/kg) 3 injections at week 0, 4, 8 – 6 of 6 pigtail macaques (lunar menstrual cycles) protected against SHIV infection • Study 2 (rectal transmission) – Weekly SHIV (50 TCID50) until systemic infection detected – One GSK744 LA (50 mg/kg) injection at week 0 – After 1 to 2 challenges, placebo macaques became infected – With a single GSK744 injection, infection was delayed by 5 to 10 challenges with SHIV Radzlo J, et al. 21st CROI. Boston, 2014. Abstract 40LB. Andrews CD, et al. 21st CROI. Boston, 2014. Abstract 39. Andrews CD, et al. Science. 2014;343:1151-1154. P=0.0005 Week Aviremic(%) GSK744 LA (n=6) Placebo (n=6) Week 0 2 4 6 8 10 12 14 16 30 Vaginal SHIV Exposure Aviremic(%) GSK744 LA (n=12) Placebo (n=4) Rectal SHIV Exposure 0 2 4 6 8 10 12 14 16 18 20 22 24 P<0.0001
  • 54. Summary of Clinically Relevant Points • TDR still alive and well – Can find more using sensitive techniques – Little evidence of transmitted INSTI • ARV for naïve – ATV has more tolerability issues than RAL or DRV (mostly bilirubin) – RAL best tolerated – DTG with ABC/ 3TC superior to EFV/TDF/FTC (tolerability)
  • 55. Summary of Clinically Relevant Points • ARV for naïve – Bone loss can be prevented with Ca and vitamin D – ABC cv risk still controversial • Long acting ART promising for – Maintenance – PrEP