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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
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
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
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
43.
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
46.
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
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