Transcript HIV Update Ardis Moe, M.D. [email protected] UCLA CARE clinic/NEVHC Van Nuys 21 June 2014 24th Annual CCO HIV and Hepatitis C Symposium clinicaloptions.com  I do not.

HIV Update
Ardis Moe, M.D.
[email protected]
UCLA CARE clinic/NEVHC Van
Nuys
21 June 2014
24th Annual CCO HIV and Hepatitis C Symposium
clinicaloptions.com
 I do not have any financial arrangements or affiliations
with commercial sponsors which have direct interest in the
subject matter
24th Annual CCO HIV and Hepatitis C Symposium
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Goals:
 Discuss PREP and PEP options
 DHHS treatment options
 New HIV meds
PREP and PEP update
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Audience Response Questions
8%
92%
 1)I have prescribed PREP for at least one
patient
 2)I have never prescribed PREP
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PREP
 Truvada (tenofovir/emtricitabine) 1 pill a day
 FDA approved to prevent HIV infections in
MSM/transgender women
 Needs baseline HIV, hep B testing and testing every 3
months while on truvada
 $8 a pill. Risk of kidney, bone damage.
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ART Prophylaxis for HIV Infection in
Injection Drug Users in Bangkok, Thailand
 Randomized, double-blind, placebo-controlled, phase 3
clinical trial of tenofovir vs placebo to prevent HIV
 DOT option based on investigator discretion
 N = 2413
– Median age, 31 yrs
– 80% men
– < 10% injected daily; 18% shared needles
Choopanya K, et al. 2013;381:2083-2090.
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PrEP for IDUs: Results
Kaplan-Meier Estimates of Time to HIV Infection
in Modified ITT Population
Cumulative Probability
of HIV Infection (%)
10
8
6
4
2
0
Pts at Risk, n
Tenofovir
Placebo
Incident infections:
TDF: 17
Placebo: 33
48.9% reduction (95% CI: 9.6-72.2; P = .01)
Tenofovir
Placebo
0
12
24
1204
1207
1007
1029
933
948
48
36
60
Mos Since Randomization
Choopanya K, et al. Lancet. 2013;381:2083-2090.
857
844
736
722
521
500
72
241
234
84
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Update to Interim Guidance for PrEP for
Prevention of HIV Infection: PrEP for IDUs
 Recommendations
– Consider for those at “very high risk”:
– Sharing of equipment
– Injecting daily
– Using cocaine or crystal meth
– Critical to exclude HIV first
– Use TDF/FTC (truvada --not tenofovir)
MMWR. 2013;62:463-465.
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US PrEP Demonstration Project:
Implementation of PrEP (2012-2014)


STD clinics in San Francisco,
Miami, Washington, DC (N = 831)
Tenofovir-DP Levels (Wk 4)
60
Offered up to 48 wks of open-label
TDF/FTC
Miami (n = 157)
Washington, DC (n = 100)
San Francisco (n = 300)
50
52
43 43
– Accepted PrEP: 60.4%

Adherence rate higher than in
previously reported studies
̶
77% had TDF-DP levels consistent
with taking > 4 doses/wk
Samples (%)
40
40
35
30
27
18
20
14
11
10
5
2
0
BLD
Doses/Wk:
<2
0
2
4
4
< 250
250-550
<2
2
> 550-950
4
Tenofovir-DP (fmol/punch)*
*Measure of flux density.
Cohen SE, et al. CROI 2014. Abstract 954.
> 950
>4
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 PREP.
 Any alternatives to taking pills?
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PrEP Proof-of-Concept: Long-Acting Integrase
Inhibitor in Nanosuspension for Injection
Macaque model of SHIV transmission

Study 1 (vaginal transmission)[1]
–
Low-dose SHIV (50 TCID50) twice a wk
–
GSK744 LA (50 mg/kg) 3 injections at Wks 0,
4, 8
–
100
80
40
20
Study 2 (rectal transmission)[2,3]
–
–
GSK744 LA (n = 6)
Placebo (n = 6)
0 2 4 6 8 10 12 14 16
Wk
30
Rectal SHIV Exposure
Wkly SHIV (50 TCID50) until systemic
infection detected
One GSK744 LA (50 mg/kg) injection at Wk 0
P = .0005
60
0
100
Aviremic (%)

6 of 6 pigtail macaques (lunar menstrual
cycles) protected against SHIV infection
Vaginal SHIV Exposure
Aviremic (%)

80
GSK744 LA (n = 12)
Placebo (n = 4)
60
40
20
0
P < .0001
0 2 4 6 8 10 12 14 16 18 20 22 24
1. Radzlo J, et al. CROI 2014. Abstract 40LB. 2. Andrews CD,
Wk
et al. CROI 2014. Abstract 39. 3. Andrews CD, et al. Science. 2014;343:1151-1154.
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Treatment as Prevention
 PARTNER study
 1st study to show that treatment of MSM also prevents
transmission to HIV neg partner
 40% MSM couples in this study
 Average 2 years of observation
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PARTNER: Risk of HIV Transmission With
Condomless Sex on Suppressive ART

Observational study of rate of HIV
transmission in heterosexual and
MSM serodiscordant couples
(N = 767 couples)
0
HT♀ Vaginal sex with ejaculation
HT♂
Vaginal sex
Receptive anal sex
– HIV+ partner on suppressive ART
– Condoms not used
Risk Behaviors, %
20 40 60 80 100
MSM
Receptive anal sex with
ejaculation
Only insertive anal sex



Analyses: Risk-behavior
questionnaire every 6 mos, HIV-1
RNA (HIV+), HIV test (HIV)
Endpoint: Phylogenetically linked
transmissions
No linked transmissions recorded in
any couple during study period
Rodger A, et al. CROI 2014. Abstract 153LB.
Reproduced with permission.
Rate of Within-Couple Transmission Events
Per 100 CYFU, % (95% CI)
4
0
1
2
3
HT♀
HT♂
Vaginal sex with ejaculation
(CYFU = 192)
Vaginal sex (CYFU = 272)
Receptive anal sex with
ejaculation (CYFU = 93)
MSM Receptive anal sex without
ejaculation (CYFU = 157)
Insertive anal sex (CYFU = 262)
Estimated rate
95% CI
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Study will continue for 3 more years
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Management of Occupational Exposure to
HIV and Recommendations for PEP
 First choice: TDF/FTC + raltegravir (isentress and
truvada)x 28 days[1]
 ID consult recommended for complex cases (eg, source
patient on isentress and truvada)
 Follow-up shortened to 4 mos if 4th-generation Ag/Ab
combination test used
 Baseline HIV testing, 6 weeks, 3 months, 6 months.
1. Kuhar DT, et al. Inf Cont Hosp Epi. 2013. 2. NYS Dept Health. HIV prophylaxis following occupational
exposure. October 2012.
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 For pregnant HCW: Lopinavir/ritonavir +
zidovudine/lamivudine (Kaletra+Combivir)
still first choice for PEP
Initial Therapy –
Established Drugs
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Proportion of Patients (%)
Dolutegravir Plus Abacavir-Lamivudine
(Tivicay+Epzicom) vs Atripla
DTG + ABC/3TC
100
EFV/TDF/FTC
DTG: 80%
80
60
EFV: 72%
Wk 96 adjusted difference in response (95% CI):
+8.0% (+2.3% to +13.8%); P = .006
40
CD4 ∆
from BL
20
0
0
4 8 1216
Wk 96 ∆ From BL
Adjusted Mean
SE
DTG + ABC/3TC QD (n = 414)
325.3
10.5
EFV/TDF/FTC QD (n = 419)
281.4
10.9
Treatment
24
32
40
48
Wk
60
72
Difference in
Response (95% CI)
44.0 (14.3, 73.6)
P = .004
84
96

DTG superior to EFV at Wk 48[1] and Wk 96[2]

Treatment-related study d/c: 3% in DTG vs 11% in EFV arm at Wk 96; comparable rates of virologic
failure (6% in each arm at Wk 96)

No resistance in DTG arm through Wk 9
1. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 2. Walmsley S, et al. CROI 2014. Abstract 543.
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DHHS May 2014: What to Start
For All Pts, Regardless of
BL VL or CD4+ Count
Only for Pts With Pre-ART
VL < 100,000 c/mL
NNRTI
 EFV/TDF/FTC (Atripla)
 EFV + ABC/3TC*
 Sustiva/epzicom
 RPV/TDF/FTC (complera)
Boosted PI
 ATV/RTV + TDF/FTC
(reyataz/norvir/truvada)
 DRV/RTV + TDF/FTC
(prezista/norvir/truvada)
 ATV/RTV + ABC/3TC*
 (Reyataz/norvir/epzicom)
 RAL + TDF/FTC
*Only for pts who are (isentress/truvada)
HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm3.
 EVG/COBI/TDF/FTC(stribild)
INSTI
 DTG +
ABC/3TC*(tivicay/epzicom)
 DTG +
DHHS guidelines. May TDF/FTC(tivicay/truvada)
2014.
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 Ok, so what cocktail works best for what sort of patient?
 Plan A, B,C, D system—Dr. Moe’s quick and dirty plan of
action
Plan A: A pill a day for Type A
Personalities
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Plan A drugs
 Complera (only for those with <100,000 viral load and no
GERD)
 Atripla (risk of depression,vivid dreams, panic attacks)
 Stribild (risk of diarrhea)
 Tivcay/epzicom (risk of diarrhea; needs HLAB5701 blood
test to be negative before starting)
 All with low barriers to resistance; need for near perfect
adherence
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Increased Risk of Suicidality
Associated With EFV
5%
.05
Efavirenz
Efavirenz-free
Probability
.04
HR (95% CI)
2.28 (1.27-4.10), P = .006
.03
47 events/5817 PY*
(8.08/1000 PY)
.02
.01
15 events/4099 PY*
(3.66/1000 PY)
0
As-treated HR
2.16 (1.16-4.00)
0
24
48
72
96
120 144
Wks to Suicidality
*Person-years, sum of at-risk follow-up.
Mollan K, et al. IDWeek 2013. Abstract 40032.
168 192
Plan B: Boosted protease
inhibitors for batty buddies on the
brink:
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Plan B: poor adherence risk factors
 Mentally ill
 Meth/cocaine/alcoholic
 In and out of jail
 Homeless
 Chaotic home life
 Or: on the brink: CD4 count <200, AIDS OI or cancer
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Plan B drugs
 Reytataz/norvir/truvada
 Prezista/norvir/truvada
Plan C: Curses I forgot the
contraception
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Plan C
 Combivir and Kaletra
 Still has the most extensive and best data on safety in
pregnancy.
– Reyataz, norvir, truvada
– Complera
– Truvada and isentress are also options
– AVOID Sustiva (efavirenz, atripla) : neural tube defects on
one study in France
Plan D: Darn I stuck myself or
Drug-Drug interactions
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Plan D
 Isentress and truvada
– Fewest drug interactions (warfarin, dilantin)
– Need to double dose of isentress when taken with rifampin
– Preferred PEP med for needlestick injuries
Novel Strategies for Treatment
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HIV Cure: The Score So Far
 Still without HIV relapse
– 1 patient (“Berlin”) post–stem cell transplant from CCR5 delta 32 negative
donor
– 1 baby (“Mississippi”) treated at birth[1]
 No consistently detectable virus in reservoir (important: still on ART)
– Another baby treated at birth (“Long Beach”)[1]
1. Persaud D, et al. CROI 2014. Abstract 75LB. 2. Hatano H, et al. CROI 2014. Abstract 397LB.
3. Heinrich TH, et al. CROI 2014. Abstract 144LB.
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 What if my Plan B patient (or patient on
Atripla) wants to switch to Stribild?
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STRATEGY Trials: Switch to
EVG/COBI/TDF/FTC in Suppressed Pts

Randomized, open-label switch studies in pts virologically suppressed on an
NNRTI- or boosted PI–based regimen (both with TDF/FTC) for ≥ 6 mos

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
STRATEGY-NNRTI[1]
(N = 434)
HIV-1 RNA < 50 c/mL,
 2 previous regimens, no
resistance to FTC or TDF
and CrCl ≥ 70 mL/min
STRATEGY-PI[2]*
(N = 433)
*Pts with previous VF ineligible.
Switch to EVG/COBI/TDF/FTC QD
(n = 291)
Remain on NNRTI + TDF/FTC
(n = 143)
Switch to EVG/COBI/TDF/FTC QD
(n = 293)
Remain on Boosted PI + TDF/FTC
(n = 140)
1. Pozniak A, et al. CROI 2014. Abstract 553LB. 2. Arribas J, et al. CROI 2014. Abstract 551LB.
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STRATEGY-NNRTI: Change to EVG/COBI
Noninferior to Stable NNRTIs at Wk 48
Δ +5.3%
(95% CI: -0.5 to +12)
100
93
88
Regimens: EFV, 78%; NVP, 17%;
RPV, 4%; ETR, < 1%; 74% on
EFV/TDF/FTC; 91% on first
regimen

Results similar across all baseline
virologic and demographic
subgroups

3 pts with VF in EVG/COBI arm
and 1 in NNRTI arm
EVG/COBI/TDF/FTC
(n = 290)
80
Patients (%)

Stable NNRTIs
(n = 143)
60
40
20
n=
0
271
126
1
<1
6
3
1
16
Virologic
Virologic
Success* Nonresponse
– No pts with resistance in either arm
11
16
No Data

5 in the switch arm and 1 in the
NNRTI arm discontinued due to AE
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.
Discontinued for AE, death, or missing data.
Pozniak A, et al. CROI 2014. Abstract 553LB. Reproduced with permission.
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STRATEGY-PI: Change to EVG/COBI
Better Than Maintaining bPIs at Wk 48
Δ +6.7%
(95% CI: 0.4-13.7)
100
94
Regimens: ATV, 40%; DRV, 40%;
LPV, 17%; FPV, 3%; SQV, < 1%;
79% on first regimen

Results similar across all baseline
virologic and demographic
subgroups

2 pts with VF in each arm but no
pts with resistance in either arm

5 in the switch arm and 2 in the bPI
arm discontinued due to AE

Lipids in switch pts
–
 TGs vs all bPIs
–
 TC, TG, HDL-C vs LPV/RTV
–
 HDL-C vs DRV/RTV
EVG/COBI/TDF/FTC
(n = 290)
87
80
Patients (%)

Stable bPIs
(n = 139)
60
40
20
n=
0
272
121
<1
1
6
2
2
16
Virologic
Virologic
Success* Nonresponse
12
16
No Data
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.
Discontinued for AE, death, or missing data.
Arribas J, et al. CROI 2014. Abstract 551LB.
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Audience Response: Which is TRUE
0%
9%
9%
83%
 1)there have been 10 cases of cure of HI
so far
 2)the best drug cocktail for pregnant
women is atripla
 3)the best drug cocktail for a homeless,
mentally ill man is atripla
 4)if my patient has an undetectable viral
load and is on reyataz/norvir/truvada and
wants to switch to stribild, this is safe to
do.
Investigational Drugs
TAF:Son of viread
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48-Wk Results of TAF vs Tenofovir DF in
ART-Naive Pts
 TAF (GS-7340), investigational
prodrug of tenofovir with lower
TFV plasma concentrations,
increased delivery to
hepatocytes, lymphoid cells
Gut
Plasma
TFV
TDF
TDF/TFV
TAF
TAF
 Randomized, placebocontrolled, phase II trial of TAF
vs TDF, each coformulated with
FTC/EVG/COBI, in ART-naive
patients
Wk 24
Wk 48
Lymphoid
Cells
TAF
TFV
Cathepsin A
TFV-MP
ART-naive patients,
CD4+ cell count
> 50 cells/mm3,
eGFR ≥ 70 mL/min
(N = 170)
TAF/FTC/EVG/COBI
(n = 112)
TDF/FTC/EVG/COBI
(n = 58)
TFV-DP
Zolopa A, et al. CROI 2013. Abstract 99LB. Sax P, et al. ICAAC 2013. Abstract H-1464d.
Reproduced with permission.
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TAF/FTC/EVG/COBI Noninferior to
TDF/FTC/EVG/COBI Through Wk 48
100
Δ 1.0%
(95% CI: -12.1 to +10.0;
P = .84)
88.4 87.9
TAF/FTC/EVG/COBI
TDF/FTC/EVG/COBI
80
Patients (%)
 Noninferiority at Wk 24
primary endpoint analysis[1]
 6 pts (3 per arm) eligible for
resistance analysis at Wk
48[2]
60
40
20
6.3
0
– 89.7% vs 87.5 % with HIV-1
RNA < 50 c/mL, respectively
10.3
51
6
7
n = 99
Virologic
Virologic
Success* Nonresponse
5.4 1.7
6
1
No Data
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.
Discontinued for AE, death, or missing data.
– No pts with resistance in
TAF arm
– 1 pt with NRTI and INSTI
resistance in TDF arm
(M184V, E92Q)
1. Zolopa A, et al. CROI 2013. Abstract 99LB. 2. Sax P, et al. ICAAC 2013. Abstract H-1464d.
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Median (Q1, Q3) Change From Baseline
eGFR Cockroft-Gault (mL/min)
TAF vs TDF Phase II Study: Change in
Estimated GFR Over Time
20
TAF/FTC/EVG/COBI
TDF/FTC/EVG/COBI
10
0
-5.5
-10
P = .041
-10.0
-20
0
12
24
Time (Wks)
36
48
TAF/FTC/EVG/COBI also had significantly less effect on markers of renal tubular toxicity
(retinol binding protein, B2 microglobulin) than TDF/FTC/EVG/COBI
Sax P, et al. ICAAC 2013. Abstract H-1464d.
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Median (Q1, Q3) Change in BMD
TAF vs TDF Phase II cont’d: Percent
Change in Spine and Hip BMD (DEXA)
HIP
SPINE
TDF/FTC/EVG/COBI
TAF/FTC/EVG/COBI
2
2
-1.00
0
0
-2
-2
-0.62
P < .001
P < .001
-4
-3.37
-2.39
-4
-6
-6
0
12
24
Time (Wks)
36
48
0
12
24
36
Time (Wks)
48
No decrease in hip BMD in 32% TAF/FTC/EVG/COBI pts vs 7% TDF/FTC/EVG/COBI pts (P < .001)
Wk 48 Median Value of Bone Biomarkers as % of Baseline: TAF/FTC/EVG/COBI vs TDF/FTC/EVG/COBI
Procollagen Type 1 N-terminal propeptide (P1NP):
109% vs 169% (P < .001)
C-terminal telopeptide (CTx):
119% vs 178% (P < .001)
Sax P, et al. ICAAC 2013. Abstract H-1464d.
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Drugs With Novel Mechanisms for
Pan-Resistant HIV in Phase II or Later
 BMS-663068
(attachment inhibitor)
 … that’s it!
It is therefore critical that
patients with highly
resistant virus preserve
virologic suppression
through excellent
adherence!
Lalezari J, et al. CROI 2014. Abstract 86.
Discontinuation notice for vircoTYPE,
November 2013
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Mean Change in HIV-1 RNA
From Baseline (Log10 C/mL)
AI438011: BMS-663068 Monotherapy:
Mean Change in HIV-1 RNA From BL*
0.5
0
-0.5
-0.69
-1
-1.22
-1.37
-1.47
-1.5
-2
0
2
4
Day
*Error bars represented standard error of the mean.
Lalezari J, et al. CROI 2014. Abstract 86.
6
8
400 mg BID
(n = 7)
800 mg BID
(n = 5)
600 mg QD
(n = 10)
1200 mg
QD (n = 10)
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In next few months expect…
 Coformulated cobisistat with prezista, reyataz.
 New one pill regimen: tivicay/epzicom
 Son of viread: TAF
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Summary
 Truvada works for IDU as well as MSM and transgender
women.
 Injectable once monthly PREP meds in future
 Ok to switch to stribild if HIV viral load undetectable on
boosted PI or atripla
 Plan A,B,C,D cocktails
 Truvada and isentress first choice for PEP
 Son of viread coming