11/1/2016 1 Joel Gallant, MD, MPH Southwest CARE Center Santa Fe, NM Johns Hopkins University School of Medicine University of New Mexico School of Medicine HIV Treatment Update When and What to Start When and How to Switch Disclosures Consulting, Advisory Boards, and DSMBs Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Theratechnologies ViiV Healthcare/GSK Research Support AbbVie Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. Sangamo BioSciences ViiV Healthcare/GSK When to Start
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11/1/2016
1
Joel Gallant, MD, MPH
Southwest CARE CenterSanta Fe, NM
Johns Hopkins University School of Medicine
University of New Mexico School of Medicine
HIV Treatment UpdateWhen and What to Start
When and How to Switch
Disclosures
Consulting, Advisory Boards, and DSMBs
Bristol-Myers Squibb
Gilead Sciences
Janssen Therapeutics
Theratechnologies
ViiV Healthcare/GSK
Research Support
AbbVie
Bristol-Myers Squibb
Gilead Sciences
Janssen Therapeutics
Merck & Co.
Sangamo BioSciences
ViiV Healthcare/GSK
When to Start
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START: 57% Reduced Risk of Serious Events or Death With Immediate ART
1.8% vs 4.1% in deferred vs immediate arms experienced serious AIDS or non-AIDS related event or death: HR = 0.43 (95% CI: 0.30 to 0.62); P < .001
10
8
6
4
2
0
Cum
ulat
ive
Per
cent
With
Eve
nt
0 6 12 18 24 30 36 42 48 54 60
Month
Deferred ART
Immediate ART
Lundgren J, et al. N Engl J Med. 2015
When to Start?: GuidelinesSymptoms CD4
<200CD4
200-350CD4
350-500CD4 >500
US DHHS YES YES YES YES YES
IAS-USA YES YES YES YES YES
EACS YES YES YES YES YES
BHIVA (UK) YES YES YES YES YES
WHO YES YES YES YES YES
T.F.
• 28-year-old gay man presents with 3 days of fever, night sweats, lymphadenopathy, and sore throat. A rapid 4th
generation HIV test is positive
• Tested negative 6 months ago. Has been having condomless sex with multiple partners. He asked his primary care provider about PrEP and was told he would have to see “a specialist.”
• Otherwise in good health. Has well controlled depression on citalopram. He has been vaccinated against hepatitis B.
• Sees a nurse and case manager the day after diagnosis, and baseline lab tests are drawn. Has appointment with HIV provider in 10 days. Wants to start ART as soon as possible
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T.F.
When would you start ART?
1. After he keeps several clinic appointments (~3 months)
2. After baseline genotype results are available (~2-3 weeks)
3. At the HIV provider visit (10 days)
4. If creatinine is normal and HBsAg is negative (1-2 days)
5. Today
Same-Day ART vs Standard of Care in Haiti
HIV Dx
CD4, CXR, physician evaluation
ART readiness questionnaire
If no TB on CXR, and wants to start ART
Koenig S, et al. AIDS 2016; Durban, July 18-22, 2016; Abst. WEAE0202.
SOC• Days 7, 14, 21: physician &
social work visits• Day 21: ART initiation• Week 5: physician and social
work visit
Immediate ART• Days 1: counseling and ART
initiation• Days 3, 10, 17: physician &
social work visits• Day 24: physician visit
• 1255 patients evaluated
• 821 patients referred to study team
• 762 enrolled/randomized
Monthly visits
Standard Group (n=285)
Same-Day ART Group (n=279)
P-value
262 (92%) 279 (100%) p<0.001
Died 19 (7%) 8 (3%) p=0.035
Alive and in care 201 (71%) 224 (80%) p=0.007
In care, VL <50 120 (42%) 151 (54%) p=0.004
In care, VL <1000 143 (50%) 171 (61%) p=0.008
Koenig S, et al. AIDS 2016; Durban, South Africa; July 18-22, 2016; Abst. WEAE0202.
IMMEDIATE ART Study: 12 Month Outcomes
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561
Referral 1st Clinic Visit
1st PCPVisit
ART Prescribed
Viral load suppressed
RAPID Start of ART: UCSF experience
CD4-guided(2006-9)
Universal(2010-3)
RAPID
13237
Pilcher CD, et al. J Acquir Immune Defic Syndr 2016
Rapid Start:Potential regimens
Regimens to consider
DTG + FTC/TAF
EVG/c/FTC/TAF
DRV/c + FTC/TAF
Drugs to avoid
ABC (need HLA B*5701)
TDF (need eGFR)
RPV (need VL, CD4)
EFV, NVP (need genotype)
What to Start
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DHHS Guidelines, July 2016: What to Start
Recommended regimens
PI based DRV/r + (TDF/FTC or TAF/FTC)
INSTI based RAL + (TDF/FTC or TAF/FTC) EVG/c/TDF/FTC or EVG/c/TAF/FTC DTG + (TDF/FTC or TAF/FTC) DTG/ABC/3TC
Alternative regimens
NNRTI based EFV/TDF/FTC or EFV + TAF/FTC RPV/TDF/FTC or RPV/TAF/FTC (VL <100,000; CD4 >200)
PI based (ATV/c or ATV/r) + (TDF/FTC or TAF/FTC) (DRV/c or DRV/r) + ABC/3TC DRV/c + (TDF/FTC or TAF/FTC)
DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, July 2016.
Drug interactions (including HCV) DTG or RAL-based regimen
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Switching Therapy in Virologically Suppressed Patients
D.F.
48-year-old man with HIV since 2008. His nadir CD4 count was 362 and peak VL was 89,000.
Has been on EFV/TDF/FTC since diagnosis, with undetectable VL and a CD4 >500
2 years ago he declined switch to a newer regimen because he had no side effects other than vivid dreams, which he usually enjoyed, and he wanted a single-tablet regimen
eGFR consistently >60
Other medications: losartan 50 mg/d and atorvastatin 10 mg/d
HLA B*5701-negative
D.F.
What do you recommend now?1. Make no changes
2. Suggest switch to EFV + FTC/TAF
3. Suggest switch to DTG/ABC/3TC
4. Suggest switch to EVG/c/FTC/TAF
5. Suggest switch to DTG + FTC/TAF
6. Order bone density scan before deciding
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Switching therapy in suppressed patients: When and why?
• To manage side effects
• To manage or prevent drug toxicity
• To simplify regimen (number of doses or pills)
• To address food restrictions
• To address drug interactions
• To plan for pregnancy
Reasons to consider switching therapy in patients on older regimens
Nevirapine: Maybe– Reduce pill burden– Not toxicity (most toxicity
occurs with initiation)
Efavirenz: Maybe– CNS side effects– No TAF-based
coformulation
Older PIs: Maybe– Reduce pill burden– Decrease metabolic effects– Decrease GI side effects
GS 1089: Switch from F/TDF to F/TAFWeeks 48 and 96 Efficacy
FTC/TAF noninferior to FTC/TDF at Weeks 48 and 96
Raffi F, et al. HIV Glasgow, October 2016, Glasgow, UK, Presentation O125
FTC/TDF FTC/TAF
Pa
tien
ts, %
94
05
93
26
89
29
89
1
10
0
20
40
60
80
100
Treatment Difference (95% CI)Virologic Outcome
48 48 4896 96 96Week
Wk 48
Wk 96
Success(< 50 copies/mL)
Failure No Virologic Data
FTC/TAF (n=333) FTC/TDF (n=330)
-4.2 3.7
-0.3
-8 0 8
GS 1216: RPV/FTC/TDF to RPV/FTC/TAFVirologic Suppression at Week 48 (FDA snapshot)
Efficacy comparable across age, sex, geographic region
No emergent resistance mutations detected in either group
94
<16
94
06
0
20
40
60
80
100
Success Failure No Data
RPV/FTC/TAF n=316RPV/FTC/TDF n=313
Treatment Difference, % (95% CI)Virologic Outcome
Pat
ient
s, %
296 294n= 2 0 18 19
Orkin C, et al. HIV Glasgow 2016, Glasgow, UK
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-5.9 1.8
-2.0
-8 0 8
GS-1160: EFV/FTC/TDF to RPV/FTC/TAFVirologic Suppression at Week 48 (FDA snapshot)
Efficacy comparable across age, sex, geographic region No emergent resistance mutations detected in RPV/FTC/TAF group 1 pt in EFV/FTC/TDF group developed mutations (M184V, V106I/L, Y188L)
GS-1249: Switch to E/c/F/TAF in HIV/HBV co-infected patients
94
1 4
92
3 6
0
20
40
60
80
100
VirologicSuccess
Virologic Failure No Data
35
Pat
ient
s (%
)
FDA Snapshot HIV-1 RNA <50 c/mL
HBV DNA <29 IU/mL (Missing=Failure)
Outcomes of 3 patients on non-TDF based regimens• LPV/r+ ABC/3TC: HIV RNA <50 c/mL; HBV DNA declined from 143 to <20 IU/mL• RAL+ATV/r : HIV RNA remained <50 c/mL; HBV DNA declined from 259,000,000 to 51 IU/mL• ATV/r monotherapy: HIV RNA remained <50 c/mL; HBV DNA remained <20 IU/mL
Week 24
Week 48
Gallant J, et al. JAIDS 2016
TAF: Renal safety
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-26
3
-4
-30
3
27
43 47
-50
-25
0
25
50
GS 1089: Switch from F/TDF to F/TAF Change in Renal Biomarkers at Weeks 48 and 96
All differences between treatments statistically significant (p <0.001)
Med
ian
% C
hang
e
UrineAlbumin:Cr
Urine Protein:Cr
Urineβ2M:Cr
UrineRBP:Cr
10 4
-20
-10
0
10
20
Me
dian
Cha
nge,
mL/
min
eGFR
FTC/TAF FTC/TDF
Raffi F, et al. HIV Glasgow, October 2016, Glasgow, UK, Presentation O125
4.5
p=0.002
Med
ian
(Q1,
Q3)
Cha
nge
eGF
R (
mL/
min
)*
Week Week
-0.6-4.1
p <0.001
GS 1216 and 1160:Change in eGFR at Week 48
0.7
Study 1216 Study 1160
RPV/FTC/TAFEFV/FTC/TDF
RPV/FTC/TAFRPV/FTC/TDF
Orkin C, et al. HIV Glasgow 2016, Glasgow, UK
TAF: Bone safety
3
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GS 1089: Switch from F/TDF to F/TAF: Bone density changes through Week 96
321 310 300
320 310 306
294
297
287
292
321 309 300
317 305 303
293
296
288
289
FTC/TAF
FTC/TDF
n
Mea
n %
Cha
nge
(95%
CI)
Spine
WeekWeek
2.2
-0.2
p <0.001
Hip
1.9
-0.3
p <0.001
1.7
-0.1
1.2
-0.1
FTC/TAF FTC/TDF p value FTC/TAF FTC/TDF p value
≥ 3% increase 40% 18% < 0.001 29% 11% < 0.001
≥ 3% decrease 8% 19% < 0.001 6% 15% < 0.001
Raffi F, et al. HIV Glasgow, October 2016, Glasgow, UK, Presentation O125
-2
-1
0
1
2
BL Wk 24 Wk 48
GS 1216 and 1160Change in Spine BMD Through Week 48
Mea
n %
Cha
nge
(95%
CI)
1.61
0.08
1.65
-0.05
p <0.001 p <0.001
-2
-1
0
1
2
BL Wk 24 Wk 48
Study 1216 Study 1160
187 178 172
(n=) 176 174 168
394 373 351
400 382 369
(n=)
(n=)
(n=)
RPV/FTC/TAFEFV/FTC/TDF
RPV/FTC/TAFRPV/FTC/TDF
RPV/FTC/TAF RPV/FTC/TDF RPV/FTC/TAF EFV/FTC/TDF
≥3% increase 27% 11% p<0.001 29% 13% p<0.001
≥3% decrease 6% 13% p=0.044 7% 14% p=0.001
Orkin C, et al. HIV Glasgow 2016, Glasgow, UK
TDF to TAF switch
Advantages:
Greater renal safety
Improved bone density
Smaller pill size
Disadvantages:
Loss of TDF lipid effect
TAF will be more expensive than generic TDF
Günthard HF, et al. JAMA 2016;316:191-210.
IAS-USA recommendations: “If there is no increase in the price of TAF vs. that of TDF, switching from TDF to
TAF is reasonable even if patients are not experiencing TDF-related toxic effects.”
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Slide 43 of 39
D.F.
Outcome: D.F. decided to make a switch based on the greater safety of TAF. He considered switching to FTC/TAF + EFV but decided that the dreams weren’t always enjoyable, and ended up switch to EVG/c/FTC/TAF
LATTE-2: IM Cabotegravir + Rilpivirine For Long-Acting Maintenance ART
Phase IIb, multicenter, open-label study
– Primary endpoints: VL < 50 by FDA snapshot, PDVF, and safety at maintenance Wk 32
Margolis DA, et al. CROI 2016. Abstract 31LB.
CAB 400 mg IM + RPV 600 mg IM Q4W(n = 115)
CAB 600 mg IM + RPV 900 mg IM Q8W(n = 115)
*Pts with VL < 50 from Wk 16 to Wk 20 continued to maintenance phase.
Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure
SWITCHMRK: Prior failure predicts failure
Eron JJ, et al. Lancet. 2010;375:396-407.
Outcome
SWITCHMRK1 SWITCHMRK 2
RAL(n = 174)
LPV/r (n = 174)
RAL(n = 176)
LPV/r (n = 178)
Patients without previous virologic failure
VL < 50 at Wk 24, % 85.1 85.8 92.5 93.5
Treatment difference, % (95% CI) -0.7 (-9.9 to 8.6) -1.0 (-8.5 to 6.3)
Patients with previous virologic failure
VL < 50 at Wk 24, % 72.3 89.7 79.7 93.8
Treatment difference, % (95% CI) -17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6)
Switching: Caveats
Know the treatment and resistance history
Avoid switching from high barrier to lower barrier agents when you don’t
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Switching and simplifying therapy
“Vertical Switches”: switch to drug with lower resistance barrier
Most drug discontinuations
Boosted PI → NNRTI
Boosted PI → INSTI
Boosted PI → any STR
DRV/r twice daily → once daily
“Horizontal Switches”: switch to drug with equal or higher resistance barrier
RTV → COBI (boosters)
Switches within INSTI class
EFV or NVP → RPV or ETR
LPV/r or ATV/r → DRV/r
ABC or AZT → TDF/TAF
TDF → TAF
Toma J, et al. ICAAC 2015, September 17-21, 2015, San Diego.
• Concordance with historical resistance (individual ARVs): 85%
• NNRTIs: 93%• PIs: 84%• NRTIs: 76%
• Identified major wild-type (nonmutant) variants at 97% • False omission rate 3%.
The rationale for 2-drug regimens
• (To avoid NRTI toxicity)
• Reduce cost (e.g. 3TC + X)
• Allow for long acting therapy (e.g. CAB + RPV)
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“Nuke-sparing” and “nuke-lite” regimens
Regimen Results
DRV/r + RAL (ACTG 52621) Poor performance at high VL
DRV/r + RAL (NEAT2) Less effective at high VL, low CD4
DRV/r + MVC (MODERN3) Less effective than standard ART
ATV/r + RAL (HARNESS4 – switch) Less effective than standard ART
LPV/r + RAL (PROGRESS5) Small study; few pts with high VL
LPV/r + EFV (ACTG 51426) Poorly tolerated but effective
LPV/r + 3TC (GARDEL7) As effective as standard ART
LPV/r + 3TC or FTC (OLE8 – switch) As effective as standard ART
ATV/r + 3TC (SALT9 – switch) As effective as standard ART
DTG + 3TC (PADDLE10) Promising but preliminary1. Taiwo B, et al. AIDS. 2011;25:2113-222. Raffi et al. CROI 2014, Abstract 84LB3. Stellbrink H-J, et al. IAD 2014. Abstract MOAB01014. Van Lunzen J et al. IAC 2014. Abstract A-641-0126-113075. Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-65
6. Daar ES et al. Ann Intern Med 2011 7. Cahn P, et al. Lancet Infect Dis 2014;14:572-808. Gatell J, et al. AIDS 2014. Abstract LBPE17. 9. Perez-Molina, JA, et al. IAC 2014. Abstract LBPE18.10 Figueroa MI, et al. EACS 2015. Abstract 1066.
The pipeline
Integrase Inhibitors• Raltegravir: Once daily formulation (two 600 mg tabs)• Bictegravir: Once-daily unboosted INSTI coformluated with FTC/TAF• Cabotegravir: Long-acting injectable for treatment or PrEP
NNRTIs• Doravirine: Active against resistant virus, better tolerated than EFV• Rilpivirine: Long-acting injectable version for treatment or PrEP
Entry Inhibitors• Ibalizumab: Monoclonal antibody that binds to CD4, given by IV infusion
every 2 weeks • Fostemsavir: Binds to gp120
Conclusions
ART should be started as soon as possible after diagnosis in patients who are ready
Immediate initiation (e.g. day of diagnosis) is now feasible with some regimens and shortens time to suppression
TAF- and integrase inhibitor-based regimens now dominate the list of recommended regimens
Switching therapy can be considered in suppressed patients to improve convenience, tolerability, or safety
Resistance and resistance barriers must be considered when switching therapy in experienced patients