Embed Size (px)
Citation preview
David Cluck, PharmD, BCPS, AAHIVPAssociate Professor of Pharmacy Practice Office 326 Phone – 423-439-6245 Email – [email protected]
¡ Recall newly approved antiretrovirals and their respective place in therapy
¡ Discuss emerging data on new antiretroviralsthat are likely to be approved for clinical use
¡ Parallel, randomized, double-blind, active-controlled phase III studies§ Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 (FDA Snapshot)
Arribas JR, et al. CROI 2017. Abstract 453. Sax PE, et al. Lancet. 2015;385:2606-2615.
EVG/COBI/FTC/TAF*single-tablet regimen
(n = 866)
EVG/COBI/FTC/TDF†
single-tablet regimen(n = 867)
Treatment-naive HIV-infected pts with
HIV-1 RNA ≥ 1000 copies/mL,eGFR ≥ 50 mL/min
(N = 1733)
Stratified by HIV-1 RNA,CD4+ cell count, geographic region
Wk 48:Primary Endpoint Wk 144
*150/150/200/10 mg once daily.†150/150/200/300 mg once daily.
Arribas JR, et al. CROI 2017. Abstract 453.Sax PE, et al. Lancet. 2015;385:2606-2615.
¡ Efficacy similar across ptsubgroups, trending toward or significantly better with TAF in each group § By baseline HIV-1 RNA,
baseline CD4+ cell count, adherence, age, sex, race, region
¡ Virologic failure with resistance by Wk 144: 1.4% in each arm
Arribas JR, et al. CROI 2017. Abstract 453. Sax PE, et al. Lancet. 2015;385:2606-2615.
0
20
60
40
80
100
48 96 144 48 96 144 48 96 144Wk:VirologicSuccess
VirologicFailure
No Data
E/C/F/TAF (n = 866)E/C/F/TDF (n = 867)
92 90 87 85 8480
4 4 5 4 5 4 4 6 9 11 1116
Pts (
%)
Treatment DifferenceWk 48: 2.0% (95% CI: -0.7% to
4.7%)Wk 144: 4.2% (95% CI: 0.6% to
7.8%; P = .02)
¡ Rate of discontinuation for AEs higher with TDF vs TAF regimen
§ 3.3% vs 1.3% (P = .01)¡ Spine and hip BMD loss greater with
TDF vs TAF regimen
§ 6 discontinuations for bone AEs in TDF arm vs 0 in TAF arm
¡ TC, LDL, and HDL increases greater with TAF vs TDF regimen, but no difference in TC:HDL ratio
§ Rates of lipid-modifying therapy initiation similar: 5.5% vs 5.8%
Renal Events Leading to Discontinuation, n
E/C/F/TAF(n = 866)
E/C/F/TDF(n = 867)
Proximal renal tubulopathy 0 4
Cr elevation or eGFR decrease 0 3
Renal failure 0 2
Nephropathy 0 1
Proteinuria 0 1
Bladder spasm 0 1
Total 0 12
Arribas JR, et al. CROI 2017. Abstract 453.
§ Randomized, noninferiority phase III trial of RAL 800 mg QD (n = 382) vs RAL 400 mg BID (n = 389), both with TDF/FTC[1]
§ RAL QD inferior to RAL BID at Wk 48 in ITT (NC = F) analysis
§ Lower RAL trough levels associated with higher risk of failure in QD arm but not in BID arm
§ More resistance at failure in QD arm
§ PK studies of 2 new RAL formulations administered as 1200-mg once daily showed promise in healthy patients[2]
1. Eron J, et al. Lancet Infect Dis. 2011;11:907-915. 2. Krishna R, et al. EACS 2013, Abstract PE10/17.
HIV
-1 R
NA
< 5
0 c/
mL
(NC
= F
)
*Failure included both failure to suppress and rebounders. Most patients with VF and RAL resistance had ≥ 2 mutations associated with resistance to RAL.
Parameter, n RAL QD (n = 382)
RAL BID (n = 388)
Pts with VF* and HIV-1 RNA > 400 c/mL
30 16
Resistance data available 27 11
FTC resistance only 11 2
Integrase inhibitor and FTC resistance
9 2
No evidence of resistance 7 7
83 89
0
20
40
60
80
100
RAL 800 mgQD (n = 382)
RAL 400 mgBID (n = 389)
318/382
343/389
∆: -5.7 (95% CI: -10.7 to -0.83;
P for noninferiority = .044)
Wk 48
¡ Multicenter, double-blind, randomized phase III trial
¡ HIV-1 RNA < 40 c/mL at Wk 48 (primary endpoint; FDA snapshot)§ 89% with RAL QD vs 88% with RAL BID
▪ QD dose noninferior at Wk 48: treatment difference of 0.5% (95% CI: -4.2% to 5.2%)
§ Noninferiority maintained at Wk 96: 82% with RAL QD vs 80% with RAL BID (treatment difference of 1.4%; 95% CI: -4.4% to 7.3%)
Di Perri G, et al. EACS 2017. Abstract BPD1/3..
ART-naive adults with HIV-1 RNA ≥ 1000 c/mL, no BL
resistance to study agents(N = 802)
Follow-up for 14 days
RAL 1200 mg QD* + Placebo 400 mg BID + TDF/FTC(N = 533)
RAL 400 mg BID + Placebo 1200 mg QD + TDF/FTC(n = 269)
Wk 48 Wk 96Stratified by HIV-1 RNA (> vs ≤ 100,000
c/mL), HBV and/or HCV coinfection
*Administered as two 600-mg tablets.
Di Perri G, et al. EACS 2017. Abstract BPD1/3.
HIV-1 RNA < 40 c/mL at Wk 96,* %
RAL 1200 mg QD
(n = 533)
RAL 400 mg BID
(n = 269)
Age†
§≤ 34 yrs§> 34 yrs
88.791.1
88.992.1
Sex§Male§Female
90.088.9
90.790.0
Race§Asian§Black§White
93.878.291.9
97.378.692.2
Ethnicity§Hispanic/Latino§Non-Hispanic/Latino
95.787.4
88.690.7
Viral subtype§B§Non-B
90.089.5
88.994.4
HIV-1 RNA < 40 c/mL at Wk 96, %
RAL 1200 mg QD
(n = 533)
RAL 400 mg BID
(n = 269)
BL HIV-1 RNA, c/mL§≤ 100,000§> 100,000
91.984.7
93.982.9
BL CD4+ cell count, cells/mm3
§≤ 200§> 200
79.091.4
80.092.2
Hepatitis status§HBV and/or HCV positive§Both HBV/CV negative
100.0
89.6
71.4
91.2
Concomitant PPI/H2 blocker use§Yes§No
94.389.1
91.390.5
*No statistically significant differences between treatment arms across subgroups. †Median age of 34 yrs.
¡ Randomized, open-label, multicenter phase III trials§ Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (ITT-
E snapshot)
¡ 70% to 73% of pts receiving TDF at baseline
Llibre JM, et al. CROI 2017. Abstract 44LB.
Switch to DTG + RPV(n = 513)
Continue Baseline ART(n = 511)
HIV-infected pts withHIV-1 RNA < 50 c/mL for
≥ 12 mos while receiving first or second ART regimen with 2 NRTIs + INSTI, NNRTI, or
PI; no previous VF; HBV negative
(N = 1024)
Wk 52 Wk 148
Switch to DTG + RPV
Continue DTG + RPV
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 resistance
Llibre JM, et al. CROI 2017. Abstract 44LB.
Virologic Nonresponse
Wk 48
HIV-1 RNA< 50 c/mL
No Data
100
80
60
40
20
0
Pts (
%)
95 95
< 1 1 5 4
Treatment difference: -0.2% (95% CI: -3.0% to 2.5%)
DTG + RPV (n = 513)Baseline ART (n = 511)
¡ AE rates generally similar between treatment arms through Wk 52§ 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 serum lipid values from baseline to Wk 48 in either treatment arm
Llibre JM, et al. CROI 2017. Abstract 44LB.
Bone-specificalkaline
phosphatase
Osteocalcin Procollagen 1N-terminal propeptide
Bone Turnover Marker
DTG + RPV Baseline ART
0
20
60
40
80
Mea
n (µ
g/L)
BaselineWk 48
15.912.9
100 BaselineWk 48
16.2 17.123.8
19.024.0 23.1
53.045.6
55.3 54.7
P < .001P < .001
P < .001
¡ Comparison of VF rates among HIV-infected pts initiating ART from August 2013 to March 2017 at 8 CNICS sites (N = 5177)
Nance R, et al. IDWeek 2017. Abstract 1688.
Prop
ortio
n W
ithou
t VF
Kaplan-Meier Time to VF*
DTGOther INSTIDRV
*VF: HIV-1 RNA > 400 c/mL at ≥ 6 mos after initiating ART.†Cox models adjusted for age, CD4+ cell count, days from last HIV-1 RNA, CNICS site, sex, HBV, HCV, HIV risk factor, and race.
Pts Events, naHR† for VF of DTG vs Comparator (95% CI)
All pts
§ Other INSTI§ DTG
245143 0.82 (0.65-1.03)
§ DRV§ DTG
98143 0.41 (0.30-0.55)
Tx-naive pts
§ Other INSTI§ DTG
9328 0.93 (0.58-1.48)
§ DRV§ DTG
2328 0.32 (0.14-0.75)
Yrs0 1 2 3
0
0.25
0.50
0.75
1.00
§ Randomized comparison of switch to DTG 50 mg QD monotherapy (immediate switch) vs continued baseline ART for 24 wks followed by switch to DTG 50 mg QD monotherapy (delayed switch) in virologically suppressed pts with no previous VF
§ At Wk 24, DTG monotherapy noninferior to continued baseline ART for maintained HIV-1 RNA < 200 c/mL– After 24 wks, all pts allowed to switch to DTG QD monotherapy
§ Study d/c early because of high VF rate after 48 wks of DTG monotherapy– VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in
concurrent nonrandomized 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.
§ International, multicenter retrospective study evaluated virologically suppressed pts switched from combination ART to DTG 50 mg QD monotherapy– Pts with history of VF on INSTI and INSTI resistance
excluded
§ 11 of 122 pts switched to DTG monotherapy experienced VF– 9 of 11 had genotypic INSTI resistance at VF– INSTI resistance pathways varied: 92Q/155H (n = 1);
97A/155H (n = 1); 155H/148R (n = 1); 118R (n = 2); 148K (n = 1); 148H (n = 2); 148R (n = 1)
Blanco JL, et al. CROI 2017. Abstract 42.
¡ Treatment with EFV associated with increased risk of suicidality§ Absolute risk is small
¡ Risk of attempted or completed suicide also associated with EFV (HR: 2.58; 95% CI: 0.94 to 7.06; P = .06)
¡ EFV also associated with increased risk of death from injury, substance use, or unknown causes§ Careful attention should be paid to cause of
death in all clinical trials
HR: 2.28 (95% CI 1.27-4.10; P = .006)
47 events/5817 PY (8.08/1000 PY)
15 events/4099 PY (3.66/1000 PY)
Mollan K, et al. IDWeek 2013. Abstract 40032.
Multivariate Analysis of Factors Associated With Suicidality in ACTG Clinical Trials
Variable HR (95% CI) PValue
Randomly assigned EFV 2.15 (1.20-3.87) .01
Age category, yrs< 3030-44≥ 45
2.82 (1.25-6.34) 1.69 (0.81-3.55) 1.00 (reference)
.04
Hx IDU 2.18 (1.11 -4.30) .02
Psychiatric hx or psychoactive rx 3.90 (2.23 -6.82) < .001
EFVEFV-free
0.05
0.04
0.03
0.02
0.01
0
Prob
abili
ty
1920 24 48 72 96 120 144 168Wks to Suicidality
¡ Doravirine: next-gen NNRTI, unique resistance profile, low DDI potential, no food or PPI effects
¡ Multicenter, randomized, double-blind phase III trial§ Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
14-day follow-up
Molina JM, et al. CROI 2017. Abstract 45LB.
Wk 96
DOR 100 mg QD +FTC/TDF or ABC/3TC QD +
Placebo for DRV + RTV(n = 385)
DRV 800 mg + RTV 100 mg QD + FTC/TDF or ABC/3TC QD +
Placebo for DOR(n = 384)
HIV-infected ptswith HIV-1 RNA
≥ 1000 copies/mLwithin 45 days of Day 1;
no previous ART; no resistance to study drugs
(N = 769)
Stratified by HIV-1 RNA > 100,000 c/mL, baseline NRTI
Wk 48
¡ Efficacy similar in both arms regardless of baseline HIV-1 RNA or CD4+ cell count
¡ No drug 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 + RTV + 2 NRTIs (n = 383)
Molina JM, et al. CROI 2017. Abstract 45LB.
AE, %DOR
(n = 383)
DRV + RTV
(n = 383)
≥ 1 AE 80 78
Treatment-related AE31 32
Serious AE 5 6
Discontinuation for AE 2 3
AEs of clinical interest§Rash*§Neuropsychiatric† 7
11813
Fasting Lipid Δ From BL to Wk 48, mg/dL
DOR(n = 383)
DRV + RTV
(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 + RTV arm.†No discontinuation for neuropsychiatric conditions.
*P < .0001 for DOR vs DRV + RTV.
¡ Bictegravir: investigational QD INSTI, active against most INSTI RAVs, 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: HIV-1 RNA < 50 copies/mL 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
HIV-infected ptswith HIV-1 RNA
≥ 1000 copies/mL; CD4+ ≥ 200 cells/mm3;
no previous ART; HBV and HCV negative
(N = 98)
¡ 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 Failure
Wk 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)
¡ Difficult to conclude on safety from small study, but 4 fully enrolled phase III trials now evaluating efficacy, safety, tolerability of coformulatedBIC/FTC/TAF
Sax PE, et al. CROI 2017. Abstract 41.
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.
¡ Randomized, open-label, multicenter phase III trial¡ HIV-1 RNA ≥ 50 c/mL at Wk 48 (primary endpoint; FDA snapshot)
§ 1.7% in both arms; Wk 48 treatment difference showed noninferiority of switch: 0% (95% CI: -2.5% to 2.5%)
¡ HIV-1 RNA < 50 c/mL at Wk 48 (secondary endpoint): 92.1% BIC/FTC/TAF; 88.9% cont. baseline ART (difference: 3.2%; 95% CI: -1.6% to 8.2%)
Switch to BIC/FTC/TAF(n = 290)
Continue Boosted PI + 2 NRTI Regimen (n = 287)
Pts with HIV-1 RNA < 50 c/mL for ≥ 6 mos while receiving boosted DRV
or ATV + 2 NRTIs (ABC/3TC or FTC/TDF); eGFR ≥ 50 mL/min
(N = 577)
Wk 48
Daar ES, et al. IDWeek 2017. Abstract LB-4.
¡ No treatment-emergent resistance detected in BIC/FTC/TAF arm¡ Lipid parameters significantly improved with BIC/FTC/TAF vs continued baseline
ART § Change from baseline to Wk 48: TG, -6 vs +4 mg/dL (P = .002);
cholesterol:HDL ratio, -0.2 vs 0 (P = .033)
AE Associated With D/c, n
BIC/F/TAF(n = 290)
Continue Baseline
ART(n = 287)
Any AE 2 1
Acetabular fracture/acute kidney injury
0 1
Rash 1 0
Schizophrenia 1 0
Wk48
DRV/COBI/FTC/TAF(n = 362)
DRV/COBI + FTC/TDF (n = 363)
Treatment-naive pts with HIV-1 RNA ≥ 1000 c/mL; susceptible to DRV,
FTC, and TVF(N = 725)
AMBER: randomized, double-blind phase III trial[1]
1. Orkin C, et al. EACS 2017. Abstract PS8/2. 2. Orkin C, et al. IDWeek 2017. Abstract 1689b. 3. Orkin C, et al. Lancet HIV. 2017;[Epub ahead of print].
Wk48
Switch to DRV/COBI/FTC/TAF(n = 763)
Continue Boosted PI + FTC/TDF(n = 378)
Pts with HIV-1 RNA < 50 c/mL for ≥ 2 mos while receiving boosted PI + FTC/TDF for
≥ 6 mos; no previous VF on DRV; eGFR ≥ 50 mL/min
(N = 1141)
EMERALD: randomized, open-label phase III trial[2,3]
§ 1 treatment-emergent resistance mutation (M184I/V) observed in DRV/COBI/FTC/TAF arm
§ Similar low rates of grade 3/4 AEs between treatment groups
§ Lower rate of AE-related d/c for DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF (1.9% vs 4.4%)
§ Hip/spine BMD changes more favorable with DRV/COBI/FTC/TAF
§ Significantly higher eGFR by serum creatinine (P < .0001) and cystatin c (P = .001) with DRV/COBI/FTC/TAF
Orkin C, et al. EACS 2017. Abstract PS8/2.
*Primary endpoint: HIV-1 RNA < 50 c/mL by FDA snapshot.
Treatment difference: 2.7%(95% CI: -1.6% to 7.1%)
VirologicSuccess*
HIV-1 RNA ≥ 50 c/mL
91.4 88.4
3.3(n = 12)
4.4(n = 16)
Wk 48 Virologic Efficacy
DRV/COBI/FTC/TAF (n = 362)
DRV/COBI + FTC/TDF (n = 363)
Pts
(%)
100
80
60
40
20
0
Treatment difference: 0.4%(95% CI: -1.5% to 2.2%)
§ No PI or NRTI resistance mutations (viral rebound with resistance data: n = 1 DRV/ COBI/FTC/TAF; n = 3 control)
§ Similar low rates of grade 3/4 AEs, d/c for AEs between treatment groups
§ Significant improvements in hip/spine BMD for DRV/COBI/FTC/TAF vs control
§ Similar eGFR by serum creatinine between groups (P = .092); increased eGFR by cystatin c with DRV/COBI/ FTC/TAF (P = .034)
§ In post-hoc subanalysis, bone and renal parameters improved with switch regardless of sex, age, preexisting diabetes or HTNOrkin C, et al. IDWeek 2017. Abstract 1689b. Orkin C, et al. Lancet HIV.
2017;[Epub ahead of print]. Arribas JR, et al. EACS 2017. Abstract BPD2/8.
*HIV-1 RNA < 50 c/mL (FDA Snapshot). †Primary endpoint: confirmed HIV-1 RNA ≥ 50 c/mL or premature d/c with last HIV-1 RNA ≥ 50 c/mL.
Treatment difference: 1.2%(95% CI: -1.7% to 4.1%)
Virologic Rebound†
Pts (
%)
100
80
60
40
20
0Virologic Success*
94.9 93.7
2.5 2.1
DRV/COBI/FTC/TAF (n = 763)
Continue Boosted PI + FTC/TDF (n = 378)
Wk 48 Virologic Efficacy
§ Ibalizumab: humanized mAb to conformational epitope on CD4 receptor that blocks postattachment HIV entry into CD4+ T-cells without altering normal cell function
§ Single-arm, open-label phase III trial – Primary endpoint: ≥ 0.5 log10 HIV-1 RNA decrease at Day 14
§ 53% with resistance to all drugs from ≥ 3 classes; 68% with INSTI resistance
Lewis S, et al. CROI 2017. Abstract 449LB.
Pts with HIV-1 RNA > 1000 copies/mL;
on ART ≥ 6 mos, on stable ART ≥ 8 wks; resistant to
≥ 1 ARV from 3 classes, sensitive to ≥ 1 ARV for OBR
(N = 40)
Wk 25
Ibalizumab2000 mg IV Day 7
(loading dose)Continue Failing ART
Days 0-14
Ibalizumab800 mg IV Day 21, Q2W
(maintenance dose)Switch to OBR
Day 14
Primary Endpoint:
Day 14Control Period:Day 0-7
¡ Primary endpoint: 83% with ≥ 0.5 log10 HIV-1 RNA decrease at Day 14 vs 3% at end of control period (P < .0001)§ 60% with ≥ 1.0 log10 HIV-1 RNA
decrease§ Mean decrease by Day 14: 1.1 log10
¡ 9 pts reported 17 serious AEs§ 1 drug-related serious AE (IRIS)
resulted in discontinuation¡ 9 other pts discontinued
§ Death (n = 4; liver failure, Kaposi sarcoma; end-stage AIDS, lymphoma)
§ Consent withdrawal (n = 3)§ Lost to follow-up (n = 2)
¡ No cases of anti-ibalizumab antibodies
Lewis S, et al. CROI 2017. Abstract 449LB.
Wk 24 Virologic OutcomeIbalizumab +
OBR
≥ 1.0 log10 HIV-1 RNA decrease, % 55
≥ 2.0 log10 HIV-1 RNA decrease, % 48
HIV-1 RNA < 50 copies/mL, % 43
HIV-1 RNA < 200 copies/mL, % 50
Mean HIV-1 RNA decrease from baseline, log10
1.6
¡ Fostemsavir: prodrug of investigational attachment inhibitor temsavir¡ BRIGHTE: ongoing randomized, double-blind, placebo-controlled phase III trial with open-
label extension (N = 371 treated pts)§ Includes nonrandomized cohort with same eligibility criteria (except no remaining ARV
classes and no remaining fully active approved drugs) given FTR 600 mg BID + OBR during open-label extension (n = 99)
Kozal M, et al. EACS 2017. Abstract PS8/5.
HIV-infected pts experiencing failure of current ART, HIV-1
RNA ≥ 400 c/mL, with 1-2 remaining ARV classes
(≥ 1 fully active available agent/class), not able to
construct viable regimen with remaining agents
(n = 272)
Until rollover study, marketing approval, or
additional option available
FTR 600 mg BID + failing regimen
(n = 203)
PBO BID + failing regimen(n = 69)
Day 8Primary analysis Wk 96Randomized 3:1
FTR 600 mg BID + OBR
FTR 600 mg BID + OBR
Day 9Start OLE Wk 24
¡ Primary endpoint: adjusted* mean HIV-1 RNA log10 change at Day 8 in randomized ITT-E population§ FTR vs PBO: -0.79 vs -0.17
(difference: -0.625; 95% CI: -0.810 to -0.441; P < .0001†)
¡ Wk 24 viral suppression by snapshot§ Randomized cohort (N = 272):
▪ HIV-1 RNA < 40 c/mL: 54%▪ HIV-1 RNA < 200 c/mL: 71%
§ Nonrandomized cohort (N = 99): ▪ HIV-1 RNA < 40 c/mL: 36%
¡ Most common grade 2-4 tx-related AEs were nausea, diarrhea, headache, vomiting, fatigue, asthenia
Kozal M, et al. EACS 2017. Abstract PS8/5.
*Mean adjusted by HIV-1 RNA on Day 1. †Per Levene’s test of homogeneity of variance. ‡12 out 17 deaths from AIDS-related events; 1 death from recurrent atypical mycobacterial infection due to IRIS.
Wk 24 Safety Event, n (%)
Randomized Cohort
(n = 270)
Nonrandom. Cohort(n = 99)
All Treated Pts
(N = 371)
Any event 243 (90) 93 (94) 338 (91)
Grade 2-4 tx-related AE 49 (18) 19 (19) 68 (18)
AE leading to d/c 12 (4) 9 (9) 21 (6)
Serious AE 73 (27) 37 (37) 112 (30)
Tx-related serious AE 6 (2) 3 (3) 9 (2)
Death‡ 8 (3) 9 (9) 17 (5)
Margolis DA, et al. CROI 2015. Abstract 554LB. Margolis DA, et al. Lancet Infect Dis. 2015;15:1145-1155.
¡ Dose-ranging, randomized phase IIb study§ Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48§ At Wk 96: 76% of pts receiving CAB + RPV had HIV-1 RNA < 50 copies/mL
*Pts with HIV-1 RNA < 50 c/mL at Wk 24 continued to maintenance phase.�FTC/TDF or ABC/3TC.
CAB 10 mg QD +RPV 25 mg QD
CAB 30 mg QD +RPV 25 mg QD
ART-naive pts,HIV-1 RNA
≥ 1000 c/mL(N = 243)
CAB 60 mg QD +RPV 25 mg QD
EFV 600 mg QD + 2 NRTIs QD (n = 62)
CAB 10 mg QD + 2 NRTIs�(n = 60)
CAB 30 mg QD + 2 NRTIs�(n = 60)
CAB 60 mg QD + 2 NRTIs�
(n = 61)
Wk 48:Primary Endpoint
Wk 24Induction Phase* Maintenance Phase
Wk 96
CAB 30 mg QD +RPV 25 mg QD
Open-Label Phase
Wk 144:Ad Hoc
Margolis DA, et al. CROI 2017. Abstract 442. Margolis DA, et al. CROI 2015. Abstract 554LB. Margolis DA, et al. Lancet Infect Dis. 2015;15:1145-1155.
¡ Ad hoc analysis through Wk 144 of open-label phase
¡ Serious AEs: 9%; d/c for AEs: 3%¡ PDVF in 9 pts (ITT-E)
§ 6 during induction/maintenance
§ 3 during open-label (Wks 96-144)▪ 2 of 3 had emergent
mutations: n = 1 with V151V/I (IN); n = 1 with K101E + M230M/L (NNRTI)
¡ 1 pt without PDVF developed E138K + V108V/I (NNRTI)
Treatment Outcomes at Wk 144 (Snapshot), n (%)
CAB Subtotal*
(ITT-E)(n = 181)
CAB Subtotal*(ITT-ME)(n = 160)
HIV-1 RNA < 50 c/mL 122 (67) 122 (76)
HIV-1 RNA ≥ 50 c/mL§Previous change in ART
18 (10)3 (2)
13 (8)2 (1)
No virologic data in window§D/c for AE or death§D/c for other reasons§On study with missingdata in window
41 (23)8 (4)
27 (15)
6 (3)
25 (16)4 (3)
15 (9)
6 (4)
PDVF 9 (5) 6 (4)
*CAB 10 mg + CAB 30 mg + CAB 60 mg.
AgentMoA or
Formulation PhaseDosing/
Administration Implications
GS-CA1[1] HIV capsid inhibitorPre-
clinical
Extended release, suitable for SC of solid
depot formulation
§ 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-
clinicalPotential 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)
I10 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-
clinicalPotential for unboosted,
QD 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 I
nEFV: 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
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.
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.
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
IIbCombined 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
