5/10/2017 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 Disclosures Consulting, Advisory Boards, and DSMBs Bristol-Myers Squibb Gilead Sciences Merck & Co. Theratechnologies ViiV Healthcare/GSK Research Support AbbVie Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. Sangamo BioSciences ViiV Healthcare/GSK
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HIV Treatment Update · Switch to E/C/F/TAF in Women at Wk48 Open-label extension study Hodder S, ... *Adjusted for: BMI, CKD, DM, CD4, dyslipidemia. Limitations: potential for unmeasured
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5/10/2017
1
Joel Gallant, MD, MPH
Southwest CARE CenterSanta Fe, NM
Johns Hopkins University School of MedicineUniversity of New Mexico School of Medicine
HIV Treatment Update
Disclosures
Consulting, Advisory Boards, and DSMBs
Bristol-Myers Squibb
Gilead Sciences
Merck & Co.
Theratechnologies
ViiV Healthcare/GSK
Research Support
AbbVie
Bristol-Myers Squibb
Gilead Sciences
Janssen Therapeutics
Merck & Co.
Sangamo BioSciences
ViiV Healthcare/GSK
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2
DHHS Guidelines, July 2016: What to Start
Recommended regimens
PI based DRV/r + (TDF/FTC or TAF/FTC)
INSTI based DTG + (TDF/FTC or TAF/FTC) DTG/ABC/3TC EVG/c/TDF/FTC or EVG/c/TAF/FTC RAL + (TDF/FTC or TAF/FTC)
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.
– Prevalence of INSTI resistance through 2014: 65/14,468 (0.4%)
– Pre-ART prevalence of INSTI resistance (ie, transmitted): 2/4631 (0.04%)
UNC CFAR HIV Clinical Cohort[2]:
– 2015 INSTI resistance prevalence in 685 pts who began ART in 2007 or later: 1%
Modeling: assuming 0.1% rate of transmitted INSTI resistance and $250 cost per test: pre-ART INSTI resistance testing correlated with worse outcomes, higher costs vs no test[3]
1. Hernandez AL, et al. CROI 2017. Abstract 478. 2. Davy T, et al. CROI 2017. Abstract 483. 3. Koullias Y, et al. CROI 2017. Abstract 493.
Emergence of INSTI Resistance in Acute Infection Treated With DTG + FTC/TDF
45-yo man with PCP and ARS
Started DTG + FTC/TDF and discharged; readmitted to ICU several days later for hypoxia
VL increased after readmission despite adherence (including DOT in hospital); no divalent cation use
– DRV/r added, VL decreased
– Pneumonia improved; pt discharged
Rapid INSTI emergence by deep seq: eg, Q148K population increased from 0.0015% at Timepoint 1 to 20.9% at Timepoint 3
Cumulative expos. to DRV/r, but not ATV/r, assoc. with increased CVD risk in multivariate analysis: 59% risk increase per 5-yrs’ DRV/r– Not mediated by dyslipidemia,
in contrast with 1st-generation PIs
Ryom L, et al. CROI 2017. Abstract 128LB.
CVD Risk per 5 Yrs of ARV Exposure, IRR (95% CI)
Model ATV/r DRV/r
Univariate1.25 (1.10-
1.43)1.93 (1.63-
2.28)
Multivariate
Baseline adjusted*
1.03 (0.90-1.18)
1.59 (1.33-1.91)
Time-updated adjusted*
1.01 (0.88-1.16)
1.53 (1.28-1.84)
*Adjusted for: BMI, CKD, DM, CD4, dyslipidemia.
Limitations: potential for unmeasured confounding; observational study; unable to distinguish between DRV/r800/100 mg QD vs DRV/r 600/100 mg BID
Initial Therapy:My choices for specific clinical scenarios
Tuberculosis EFV/FTC/TDF RAL 800 mg bid + (FTC/TDF or ABC/3TC)
Drug interactions (including HCV) DTG or RAL-based regimen
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When to Start?: Guidelines
Symptoms CD4 <200
CD4 200-350
CD4 350-500
CD4 >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
RAPID Start: Time to VL suppression by ART initiation strategy: SFGH 2006-2014
RAPID
RAPID vs. universal ART p<0.001
Universal ART
CD4-guided ART
Pro
po
rtio
n
<20
0 c/
mL N = 39
Pilcher CD, et al. J Acquir Immune Defic Syndr 2016
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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)
Switching Therapy
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Summary of TAF Switch Studies in Virologically Suppressed Patients
Trials:
GS-109: TDF-containing regimens to EVG/COBI/FTC/TAF
GS -112: Switch to EVG/COBI/FTC/TAF in patients with impaired renal function
GS-119: ART + DRV/r to EVG/COBI/FTC/TAF + DRV in ART-experienced patients
GS-1089: FTC/TDF to FTC/TAF
GS-1160: EFV/FTC/TDF to RPV/FTC/TAF
GS-1216: RPV/FTC/TDF to RPV/FTC/TAF
Results:
Noninferiority, with superiority in GS-109 (switch from EFV/FTC/TDF or ATV/r + FTC/TDF) and superiority in GS-119
Increase in bone density
Stability of eGFR (increase in GS-1089 and GS-112) with no tubular toxicity and decrease in overall and tubular proteinuria
.
-2.5 5.1
1.3
-5.3
-0.5
4.4
-10 0 10
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
Pat
ient
s, %
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)
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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
Med
ian
Cha
nge,
mL/
min
eGFR
FTC/TAF FTC/TDF
Raffi F, et al. HIV Glasgow, October 2016, Glasgow, UK, Presentation O125
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
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TDF to TAF switch
Advantages:
Increased eGFR
Decreased proteinuria
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.”
Alternative StrategiesUsing Approved Drugs
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SWORD 1 & 2: Switch From Suppressive ART to DTG + RPV
Open-label, multicenter phase III trials of pts with virologic suppression (N=1024) randomized to continue baseline ART vs switch to DTG + RPV
1 pt with confirmed criteria for virologic withdrawal at Wk 36 in DTG + RPV arm had K101K/E
– Documented nonadherence at VF
– Resuppressed with continued DTG + RPV
– No INSTI resistanceLlibre JM, et al. CROI 2017. Abstract 44LB.
Virologic Nonresponse
HIV-1 RNA< 50 c/mL
No Data
100
80
60
40
20
0
Pts
(%
)
95 95
< 1 15 4
Treatment difference: -0.2% (95% CI: -3.0% to 2.5%)
DTG + RPV (n=513)Baseline ART (n=511)
SWORD 1 & 2: Switch From Suppressive ART to DTG + RPV: Safety Outcomes
AE rates generally similar between arms through Wk52– Numerically higher rate of
drug-related grade 1/2 AEs with switch: 17% vs 2%
– Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1%
No notable change in lipids through Wk 48 in either treatment arm
Llibre JM, et al. CROI 2017. Abstract 44LB.
Bone-specificalkaline
phosphatase
Osteocalcin Procollagen 1N-terminal propeptide
Bone Turnover Markers
DTG + RPV Baseline ART
0
20
60
40
80
Me
an
(µ
g/L
)
BaselineWk 48
15.912.9
100 BaselineWk 48
16.2 17.123.8
19.024.0 23.1
53.0
45.6
55.3 54.7
P < .001P < .001
P < .001
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PADDLE: Dolutegravir + Lamivudine for Treatment-Naive Pts
Cahn P, et al. AIDS 2016. Abstract FRAB0104LB.
Pt #
HIV-1 RNA (copies/mL)Screen BL Day 2 Day 4 Day 7 Day 10 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 24 Wk 36 Wk 48
Wk 8 (end of phase I, start of phase II) 104/104 (100)
Wk 12 104/104 (100)
Wk 16 103/104 (99)
Wk 24 103/104 (99)
Wk 32 103/104 (99)
Wk 40 102/104 (98)
Wk 48 101/104 (97)
*Pts enrolled in phase I, N = 110; pts enrolled in phase II, N = 104.
DOMOMO: Switch to DTG Monotherapy in Virologically Suppressed Pts
Randomized comparison: switch to DTG monotherapy vs continued baseline ART for 24 wks in suppressed pts without previous VF[2]
At Wk 24, DTG monotherapy noninferior to continued baseline ART (VL <200)
– After 24 wks, all pts allowed to switch to monotherapy
Study stopped early because of high VF rate after 48 wks of monotherapy
– VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in concurrent control group (P = .03)
– Among 6 VF cases with resistance data in DTG monotherapy group, 3 developed INSTI resistance
Wijting I, et al. CROI 2017. Abstract 451LB.
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Emergent INSTI Resistance After Switch to DTG Monotherapy
International, multicenter retrospective study – Evaluated virologically
suppressed pts switched to DTG monotherapy
– Pts with history of VF on INSTI and INSTI resistance excluded
11 of 122 pts (9%) switched to DTG monotherapy experienced VF– 9 of 11 had genotypic INSTI
resistance at VF
INSTI resistance pathways varied
Blanco JL, et al. CROI 2017. Abstract 42.
INSTI Resistance at VF
92Q/155H (n = 1)
97A/155H (n = 1)
155H/148R (n = 1)
118R (n = 2)
148K (n = 1)
148H (n = 2)
148R (n = 1)
Investigational Drugs
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Doravirine vs. DRV/r at Wk 48FDA Snapshot
Efficacy similar in both arms regardless of baseline VL or CD4 count
No resistance detected in pts with PDVF through Wk 48 in either arm
– n = 1 pt with noncompliance discontinued at Wk 24, developed DOR and FTC resistance
Molina JM, et al. CROI 2017. Abstract 45LB.
Virologic Nonresponse
Wk 48
HIV-1 RNA< 50 c/mL
No Data
100
80
60
40
20
0
Pts
(%
)
84 80
11 135 7
Treatment difference: 3.9% (95% CI: -1.6% to 9.4%)
DOR + 2 NRTIs (n = 383)DRV/r + 2 NRTIs (n = 383)
Doravirine vs DRV/r in Combination With FTC/TDF or ABC/3TC: Safety
Molina JM, et al. CROI 2017. Abstract 45LB.
AE, %DOR
(n = 383)DRV/r
(n = 383)
≥ 1 AE 80 78
Treatment-related AE 31 32
Serious AE 5 6
Discontinuation for AE 2 3
AEs of clinical interest Rash* Neuropsychiatric†
711
813
Fasting Lipid Δ From BL to Wk 48, mg/dL
DOR(n = 383)
DRV/r(n = 383)
LDL-c* -4.51 9.92
Non-HDL-c* -5.3 13.75
Cholesterol -1.37 17.9
Triglyceride -3.14 21.97
HDL-c 3.94 4.15
*Discontinued due to rash: n = 2 in DOR arm; n = 1 in DRV/r arm.†No discontinuation for neuropsychiatric conditions.
*P < .0001 for DOR vs DRV + RTV.
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Bictegravir + FTC/TAF vs DTG + FTC/TAF in Treatment-Naive Pts
Bictegravir: novel QD INSTI, active against most INSTI mutations, low DDI potential, half-life ~ 18 hrs, no food requirement with dosing, primarily metabolized by CYP3A4 and UGT1A1
Randomized, double-blind, active-controlled phase II trial
– Primary endpoint: VL < 50 at Wk 24
Open-label extension
Sax PE, et al. CROI 2017. Abstract 41. Sax PE, et al. Lancet HIV. 2017;[Epubahead of print]. Zhang H, et al. CROI 2017. Abstract 40.
Wk 48
BIC + FTC/TAF QD +Placebo for DTG QD
(n = 65)
DTG + FTC/TAF QD +Placebo for BIC QD
(n = 33)
Wk 24
ART-naive ptswith VL ≥ 1000;
CD4 ≥ 200;HBV and HCV negative
(N = 98)
Bictegravir + FTC/TAF vs DTG + FTC/TAF: Wk 24 and Wk 48 Efficacy (FDA Snapshot)
No drug resistance detected in either arm through Wk 48
Sax PE, et al. CROI 2017. Abstract 41.
Virologic Failure
Wk 48
Virologic Success
No Data
100
80
60
40
20
0
9791
2 6 2 3
Treatment difference: 6.4% (95% CI: -6% to 18.8%)
Virologic FailureWk 24
Virologic Success
No Data
100
80
60
40
20
0
Pts
(%
)
97 94
3 6 0 0
Treatment difference: 2.9% (95% CI: -8.5% to 14.2%)
BIC + FTC/TAF (n = 65) DTG + FTC/TAF (n = 33)
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Difficult to drawn conclusions on safety from small study, but 4 fully enrolled phase III trials in progress now evaluating efficacy, safety, tolerability of coformulated BIC/FTC/TAF
Bictegravir + FTC/TAF vs DTG + FTC/TAF: AEs and Lab Abnormalities
Sax PE, et al. CROI 2017. Abstract 41. Reproduced with permission.
Any Grade AE Occurring in ≥ 5% in Either Arm, %
BIC + FTC/TAF(n = 65)
DTG + FTC/TAF(n = 33)
Diarrhea 12 12
Nausea 8 12
Headache 8 3
URTI 8 0
Fatigue 6 6
Arthralgia 6 6
Chlamydial infection 6 3
Back pain 6 0
Furuncle 5 6
Flatulence 2 6
Gastroenteritis 2 6
Costochondritis 0 6
Hemorrhoids 0 6
Pruritus 0 6
Grade 2-4 Lab Abnormality ≥ 5% in Either Arm, %
BIC + FTC/TAF(n = 64*)
DTG + FTC/TAF(n = 32*)
Creatine kinase 13 9
AST 9 3
Hyperglycemia 8 13
ALT 6 0
LDL 6 9
Amylase 5 6
Hematuria 3 6
Glycosuria 2 6
*Pts with ≥ 1 post-BL laboratory assessment, excluding those not specified for all pts.
Potent ART with orthoganol resistance profile to existing ART; potential for long-acting formulation due to low aqueous solubility, high stability
GS-9131[2] NRTIPre-
clinical
Potential for once daily dosing
Potent ART active against NRTI RAMs K65R, L74V, M184V alone or in combination; minimal loss of susceptibility with 4 or more TAMs
MK-8591[3]
Nucleoside Reverse Transcriptase Translocation
Inhibitor (NRTTI)
Pre-clinica
l
10 mg QW PO; potential for extended duration
Comparable MK-8591 levels in animal rectal, vaginal tissue to TDF levels in tissues of human subjects highlights potential prophylaxis utility
GS-PI1[4] PIPre-
clinical
Potential for unboosted, once daily dosing
Potent ART with high barrier to resistance, including < 2-fold loss in potency against major PI RAMs, and 10-fold to 40-fold longer in vivo half life vs ATV or DRV
NANO-EFV, NANO-LPV[5]
Oral, lower dose SDN
InEFV: 50 mg QD, 21 dnLPV/RTV: 200/100 mg
BID, 7 d
Enhanced oral bioavailability suggests can reduce EFV, LPV dose by ~ 50% while maintaining PK
Additional Investigational Agents Reported at CROI 2017: Preclinical and Phase I
1. Tse WC, et al. CROI 2017. Abstract 38. 2. White KL, et al. CROI 2017. Abstract 436. 3. Grobler J, et al. CROI 2017. Abstract 435. 4. Link JO, et al. CROI 2017. Abstract 433. 5. Owen A, et al. CROI 2017. Abstract 39.
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Additional Investigational Agents Reported at CROI 2017: Phase II
1. Bekker L-G, et al. CROI 2017. Abstract 421LB. 2. Murphy R, et al. CROI 2017. Abstract 452LB. 3. Wang C-Y, et al. CROI 2017. Abstract 450LB. 4. Lalezari J, et al. CROI 2017. Abstract 437.
AgentMoA or
FormulationPhase
Dosing/ Administration
Implications
TMC278 LA[1] LA injectable RPV (IM)
II 1200 mg IM Q8W Potential as injectable, long-acting PrEP
Elsulfavirine[2]Prodrug of new NNRTI VM1500A
IIb
Combined therapy: 20 mg
elsulfavirine + FTC/TDF PO QD
Less toxic alternative to EFV for initial ART
UB-421[3] Anti-CD4 receptor mAb
II10 mg/kg QW IV
or 25 mg/kg Q2W IV
Possible ART alternative for maintenance therapy in virologically suppressed pts
PRO-140[4]Anti-CCR5
mAbIIb 350 mg SC/wk
Being studied for both monotherapy and combination therapy
Conclusions
Integrase inhibitor-based regimens are now the standard of care for initial therapy
TAF/FTC is the preferred NRTI backbone for all regimens except DTG/ABC/3TC
Some regimens allow for immediate ART initiation while awaiting baseline labs results
Switching from TDF to TAF increases bone density and eGFR and decreases proteinuria
Stay tuned for The Great Debate: 3 drugs vs. 2
DTG resistance can happen but is rare…
…except with DTG monotherapy. Don’t do it!
New drugs keep coming, including long-acting agents