Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa...
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Verso terapie long-
acting: cosa cambia
nella gestione
clinica del paziente Andrea Calcagno
Università di Torino
Nano-formulations?
Solid lipid nanoparticles Liposomes
Dendrimers
TARGETING
PASSIVE ACTIVE
NANOEMULSIONNANOSUSPENSION
TISSUE
PENETRATION
BIOAVAILABILITY
SOLUBILITY
BIO-POLYMERS
TOPICAL
ADMINISTRATION
LIPOSOME
NANO
MATERIA
L
BIOAVAILABILITY
PATHOGEN
TARGETINGTISSUE
TARGETING
SMALL LIGANDS
ANTIBODIES NUCLEIC ACIDS
PEPTIDES
PROTEINS
LA-Cabotegravir (GSK-744)
Trezza C, et al. Current Opinion HIV AIDS 2015
Spreen W, et al. JAIDS 2014
Time (Weeks)
0 2 4 6 8 10 12 14 16
Me
an (
SD
) R
PV
(ng/m
L)
0
20
40
60
80
100
120
140
160
RPV 1200mg IM/900mg IM (+GSK1265744 200mg IM )
RPV 1200mg IM/600mg IM (+GSK1265744 400mg IM )
RPV Mean C0 observed in Phase III Studies of 25mg QD (80ng/mL )
Mean RPV plasma concentration-time profilesM
= q 28 day injection
Rilpivirine Plasma Concentrations Following TMC278 LA Injections are Comparable to Oral 25mg/day in HIV-infected Subjects
7
I Long-acting in
altri ambiti di
terapia
• Schizophrenia -- adherence
• Osteoporosis -- convenience
• Contraception -- choice
• The majority of patients with schizophrenia relapse after 5 years and poor adherence is the most common cause.
• The discontinuation rate for oral antipsychotics is 26%-44%.
• Up to a third of patients are at least partially non-adherent.
• Non-adherence is associated with increased relapse, hospitalization and suicide.
• Long-acting injectable treatment is associated with lower rates of relapse, discontinuation and hospitalization versus oral anti-psychotics, and increased cost-effectiveness, functionality, quality of life and patient satisfaction.
• Improved quality of life reported with less frequent injections.
Use of LA in Chronic
Schizophrenia
• Adherence to oral bisphosphonates for the treatment of osteoporosis is low.
• At least one-third of patients do not consistently take oral bisphosphonates as
prescribed.
• Rates of adherence to oral tablets decrease over time.
• Patients overwhelmingly prefer a once-yearly injectable product (IV zoledronic
acid).
• Once-yearly injectable treatment improves adherence and drug persistence and may be
especially suitable for people who do not
tolerate or adhere to oral drugs (e.g.,
people with cognitive dysfunction,
polypharmacy, physical limitations).
Use of LA in Osteoporosis
Uptake of contraceptive implants
in SSA
- Rattan J et al., Global Health: Sci Prac 2016; 4: Suppl 2
Uptake of contraceptive implants in
SSA
- Rattan J et al., Global Health: Sci Prac 2016; 4: Suppl 2
• Over 40 million women worldwide use injectable contraception, and nearly half (47%) of modern
contraception users in sub-Saharan Africa rely on
injectable or implantable contraceptives to
prevent pregnancy.
• Returning to a health care provider for an injection every 2-3 months is considered a
disadvantage of DMPA. Discontinuation rates of
injectable contraceptives in sub-Saharan Africa
are high, contributing to the growing popularity
of longer-acting implants.
• Norplant-2 (levonorgestrel; JadelleTM, Levoplant, Sinoplant – 2 rods, 5-year duration) is now used
by millions of women in SSA. Cost per generic
implant is less than $15 USD (~$3 pppy for
effective hormonal contraception).
Use of LA in Hormonal Contraception
LA Antiretrovirals
ApprovedIbalizumab (in U.S.)
Albuvirtide (in China)
Phase 3Cabotegravir-LA
Rilpivirine-LA
Phase 2+PRO-140 (Leronlimab)
Broadly-neutralizing monoclonal
antibodies
VRC01 and -LS; 3BNC117 and -LS;
10-1074 and -LS, etc.
EFdA; MK8591
Phase 1+GS-6207
LA-CAB future companion drugs?
Mechanism Half-lifeRoute of
administration
Ibalizumab CD4 binding 3-4 days i.v. every 2 weeks
Albuvirtide Entry inhibition 10-13 days i.v. weekly
PRO-140CCR5 binding 3 days
i.v. or s.c. every
week*
BnMAb Gp120/gp41 binding Variable, days i.v.
MK8591 NRT translocation Months? implant
GS-6207 Capsid 40 days s.c.
LA-TAF NtRTI Months? implant
LA-FTC NRTI 10 days? i.m., s.c.?
Caskey et al., New Engl J Med 2016; 375: 2019
PK profile of
VRC01-LS
Gaudinski MR et al., PLoS Med 2018; January 24
PK profile of PGT 121Anti V3 Env broad (60-70%)
-1.7 Log in HIV RNA at 10 days (rebound at
28)
Half-life 13-19 days in PLWH
Stephenson KE, et al. CROI 2019 #145
Efficacy profile of PGT 1215/9 participants responded
2 had a sustained viral suppression (after
one single infusion) for more than 6 months
Stephenson KE, et al. CROI 2019 #145
Albuvirtide + LPV/r
20 naïve patients randomized to ABT by intravenous infusion at dose
levels of 160 or 320 mg on Day 5–7 daily and then weekly plus LPV/r
(400/100 mg) twice daily
Zhang H, et al AIDS Res and Ther 2016
+52
CD4
-5
CD4
MK-8591(4’-Ethynyl-2-Fluoro-2’-Deoxyadenosine, EFdA)
• Potent and long acting nucleoside reverse transcriptase translocationinhibitor (NRTTI)
• Multiple mechanisms of action• Immediate chain termination by inhibition of primer translocation
• Delayed chain termination which prevents nucleotide excision (a significant mechanism of NRTI drug resistance) from occurring
• MK-8591-TP concentrates in both rectal and cervical tissue
Michailidis et al 2009, 2014 J Biol Chem; Grobler et al 2017 CROI, Seattle, WA
Ruane PJ, et al. JAIDS 2013; Friedman CROI 2016
EFdA PK and Antiviral
Effect
Cosa non cambia?
1. Efficacia
Phase IIb, multicenter, parallel-
group, open-label study in
ART-naive HIV-infected adults
LATTE-2 – 160
weeks
Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.
ART, antiretroviral therapy; CAB, cabotegravir; EP, extension period; IM,
intramuscular; LA, long acting; MP, maintenance period; PO, oral; QD, once daily;
Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine.
309 patients were enrolled (ITT-exposed): 91% male,
20% non-white, and 19% >100,000 c/mL HIV-1 RNA. 286
patients were randomized into the MP; 258 completed
MP with 252 entering EP
Snapshot Outcomes at Week
160
Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.
aData presented for the randomized Q8W/Q4W IM arms are inclusive of MP and EP. Data
presented for the optimized Q8W/Q4W IM arms are inclusive of on-treatment events
occurring from the first date of first injection in the EP, W100. b77 c/mL. c>50 c/mL at W96 and did not qualify for EP. dAdded in EP: CAD; MI (death);
motor neuron disease. eRelocation; entered LTFU; burden of travel; lost to FU. fAdded
in EP: PD; lost to FU; WD by patient.
Outcome at W160a
Q8W IMn (%)
Q4W IMn (%)
OptimizedQ8W IM
n (%)
OptimizedQ4W IM
n (%)
Snapshot (ITT-ME) N=115 N=115 N=34 N=10
HIV-1 RNA <50 c/mL 104 (90) 95 (83) 33 (97) 10 (100)
HIV-1 RNA ≥50 c/mL 5 (4) 0 1 (3) 0
Data in window not <50 c/mL 1 (<1)b 0 0 0
DC for lack of efficacy 1 (<1) 0 1 (3) 0
DC for other reason while not<50 c/mL
3 (3)c 0 0 0
No virologic data in window 6 (5) 20 (17) 0 0
W/D due to AE or death 1 (<1) 12 (10)d 0 0
W/D due to other reasons 5 (4)e 8 (7)f 0 0
• Through 160 weeks, there were 2 PDVFs,
both Q8W
• No additional PDVFs occurred after Week 48 in any arm
• Resistance data were previously reported1
Protocol-Defined Virologic
Failure
Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.
PDVF, protocol-defined virologic failure; Q8W, every 8 wk.
1. Margolis et al. Lancet. 2017;390:1499-1510.
1University of Nebraska Medical Center, Omaha, NE, United States; 2University of Guadalajara, Guadalajara, Mexico; 3Broward Health Medical Center, Fort Lauderdale, FL, United States; 4Fatebenefratelli Sacco Hospital, Milan, Italy; 5Center for Infectious Diseases, ZIBP, Berlin, Germany; 6Hospital General Universitario de Elche, Alicante, Spain; 7Maxwell Centre, Durban, South Africa; 8Central Research Institute of Epidemiology, Moscow, Russian Federation; 9ViiV Healthcare, Research Triangle Park, NC, United States; 10GlaxoSmithKline, Mississauga, ON, Canada; 11Janssen Research and Development, Beerse, Belgium
LONG-ACTING CABOTEGRAVIR + RILPIVIRINE FOR MAINTENANCE THERAPY: ATLAS WEEK 48 RESULTS
S Swindells,1 JF Andrade-Villanueva,2 GJ Richmond,3 G Rizzardini,4 A Baumgarten,5
M Masiá,6 G Latiff,7 V Pokrovsky,8 JM Mrus,9 J Huang,10 KJ Hudson,9
DA Margolis,9 KY Smith,9 P Williams,11 WR Spreen9
ATLAS Study Design: Randomized, Multicenter, International, Open-Label, Noninferiority Study in Adults with Virologic Suppression (Ongoing)
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
ART, antiretroviral therapy; CAB, cabotegravir; CAR, current ART; IM, intramuscular; INSTI, integrase strand transfer inhibitor;LA, long-acting; NNRTI, non-nucleoside RTI; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RPV, rilpivirine; VL, viral load.
*Uninterrupted ART 6 months and VL <50 c/mL at Screening, 2× VL <50 c/mL ≤12 months; †INSTI-based regimen capped at 40% of enrolment; Triumeq excluded from study; ‡Optional switch to CAB LA + RPV LA at Week 52 for those on CAR; §Participants who withdraw/complete IM CAB LA + RPV LA must complete 52 weeks of follow-up;
‖Participants received an initial loading dose of CAB LA (600 mg) and RPV LA (900 mg) at Week 4b. From Week 8 onwards, participants received CAB LA (400 mg) + RPV LA (600 mg) injections every 4 weeks.
CAB LA (400 mg) + RPV LA (600 mg)§
IM monthly n=303
Screening Phase Maintenance Phase Extension Phase‡
PI, NNRTI or INSTI†
Current daily oral ART n=308N=705
PI-, NNRTI-, or
INSTI-based
regimen with
2 NRTI
backbone* Ra
nd
om
iza
tio
n
1:1
Extension Phase or
transition to the
ATLAS-2M studyOral CAB +
RPV n=308
Primary endpoint
Day 1
Baseline
Week
96
Week
48Week 4‖ Week
52
ATLAS – Baseline Characteristics: ITT-E Population
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; CAB, cabotegravir; CAR, current ART; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; ITT-E, intention-to-treat exposed; LA, long-acting; NNRTI, non-nucleoside RTI; PI, protease inhibitor; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
*Common backbone regimens included: FTC/TDF (LA 60% vs CAR 56%), FTC/TAF (LA 16% vs CAR 17%), ABC/3TC (LA 13% vs CAR 13%).
Parameter
CAB LA + RPV LA
N=308
CAR
N=308
Total
N=616
Median age (range) – year 40.0 (21–74) 43 (18–82) 42 (18–82)
Age ≥50 years – n (%) 66 (21) 96 (31) 162 (26)
Female gender – n (%) 99 (32) 104 (34) 203 (33)
Race – n (%)
White 214 (70) 207 (67) 421 (68)
Black or African American 62 (20) 77 (25) 139 (23)
Other 32 (10) 24 (8) 56 (9)
Median body mass index (range) – kg/m2 26 (15–51) 26 (18–58) 26 (15–58)
Median CD4+ cell count (range) – cells/mm3 654 (185–1903) 653 (150–2543) 653 (150–2543)
Median duration of prior ART (range) – year 4 (1–19) 4 (1–21) 4 (1–21)
Baseline third ART agent class – n (%)*
NNRTI 155 (50) 155 (50) 310 (50)
INSTI 102 (33) 99 (32) 201 (33)
PI 51 (17) 54 (18) 105 (17)
ATLAS Virologic Snapshot Outcomes at Week 48 for ITT-E: Noninferiority Achieved for Primary and Secondary Endpoints
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
CAB, cabotegravir; CAR, current ART; CI, confidence interval; ITT-E, intention-to-treat exposed; LA, long-acting; NI, noninferiority; RPV, rilpivirine.
*Adjusted for sex and baseline third agent class.
Key secondary endpoint:
LA noninferior to CAR (HIV-1 RNA <50 c/mL) at Week 48
Difference (%)
-10 -8 -6 -4 -2 0 2 4 6 8 10
-6.7 0.7
-3.0
CAR LA
−10% NImargin
Primary endpoint:
LA noninferior to CAR (HIV-1 RNA ≥50 c/mL) at Week 48
Difference (%)
-10 -8 -6 -4 -2 0 2 4 6 8 10
-1.2 2.5
0.6
CARLA
6% NImargin
Virologic outcomes Adjusted treatment difference (95% CI)*
1,6
92,5
5,81,0
95,5
3,6
0
20
40
60
80
100
Pro
po
rtio
n o
f P
art
icip
an
ts % CAB LA + RPV LA
(n=308)
CAR (n=308)
Virologic
nonresponse
(≥50 c/mL)
Virologic
success
(<50 c/mL)
No virologic
data
ATLAS Snapshot Outcomes at Week 48 for ITT-E
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
AE, adverse event; CAB, cabotegravir; CAR, current ART; ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine.
*Discontinued due to AEs: LA arm (n) – ISR (3); Hepatitis A (2); acute Hepatitis B (1); acute Hepatitis C (1); headache (1); depression suicidal (1); memory impairment (1); diarrhea/nausea/headache (1); CAR arm (n) – colitis (1); blood creatinine increased (1); methamphetamine overdose (1); renal impairment (1); Anxiety disorder/depression/suicidal ideation (1);
†Other reasons for discontinuation included: LA arm (n): pregnancy (4), lost to follow up (1), non-compliance with treatment (1) and relocation (1); CAR arm: pregnancy (1), lost to follow up (1), and withdrawal by participant due to frequency of visits (4).
n (%)
CAB LA + RPV LA
N=308
CAR
N=308
HIV-1 RNA <50 copies/mL 285 (92.5) 294 (95.5)
HIV-1 RNA ≥50 copies/mL 5 (1.6) 3 (1.0)
Data in window not below threshold 1 (0.3) 1 (0.3)
Discontinued for lack of efficacy 3 (1.0) 2 (0.6)
Discontinued for other reason while not
below threshold1 (0.3) 0
No virologic data 18 (5.8) 11 (3.6)
Discontinued due to AE or death* 11 (3.6) 5 (1.6)
Discontinued for other reasons† 7 (2.3) 6 (1.9)
FLAIR Study Design: Randomized, Multicenter, International, Open-label, Noninferiority Study in ART-Naïve Adults (Ongoing)
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; CAB, cabotegravir; DTG, dolutegravir; IM, intramuscular; HBsAg, hepatitis B surface antigen; LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; RPV, rilpivirine.
*NNRTI RAMS but not K103N were exclusionary. †DTG plus 2 alternative non-ABC NRTIs was permitted if participant was intolerant or HLA-B*5701-positive (n=30 as last regimen during induction: n=2 discontinued during induction, n=14 randomized to CAB LA + RPV LA, n=14 randomized to DTG/ABC/3TC arm and continued on DTG plus 2 alternative non-ABC NRTIs in maintenance phase). ‡Participants who withdraw/complete CAB LA + RPV LA enter 52-week long-term follow-up. §Participants received initial loading doses of CAB LA 600 mg and RPV LA 900 mg at Week 4. Beginning Week 8, participants received CAB LA 400 mg + RPV LA 600 mg injections every 4 wks.
Day 1 100484§ 96
Induction Phase Maintenance Phase Extension Phase
Extension
DTG/ABC/3TC Oral daily n=283
N=629
DTG/ABC/3TC
single-tablet
regimen for
20 weeks†
Randomization (1:1)
Oral CAB+ RPV n=283
Primary endpoint
Screening Phase
N=809ART-naïveHIV-1 RNA ≥1000Any CD4 countHBsAg negativeNNRTI RAMs excluded*
−4
Confirm HIV-1 RNA<50 copies/mL
−20
CAB LA (400 mg) + RPV LA (600 mg)‡
IM monthly n=278
Study Week
FLAIR Baseline* Characteristics: ITT-E Population
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; DTG, dolutegravir; HCV, hepatitis C virus; ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine.
*Baseline was Week −20 .
Parameter
CAB LA + RPV LA
N=283
DTG/ABC/3TC
N=283
Total
N=566
Median age (range) – year 34 (19–68) 34 (18–68) 34 (18–68)
Age ≥50 years – n (%) 33 (12) 29 (10) 62 (11)
Female gender – n (%) 63 (22) 64 (23) 127 (22)
Race – n (%)
White 216 (76) 201 (71) 417 (74)
Black or African American 47 (17) 56 (20) 103 (18)
Other or missing 20 (7) 26 (9) 46 (8)
Median body mass index (range) – kg/m2 24 (17–45) 24 (13–47) 24 (13–47)
HIV-1 RNA, copies/mL – n (%)
<100,000 227 (80) 227 (80) 454 (80)
≥100,000 56 (20) 56 (20) 112 (20)
Median Baseline CD4+ cell count (IQR) – cells/mm3 437 (314, 609) 452 (321, 604) 444 (320, 604)
<200 cells/mm3 – n (%) 16 (6) 23 (8) 39 (7)
Median Day 1 CD4+ cell count (IQR) – cells/mm3 624 (473, 839) 625 (472, 799) 625 (473, 818)
HIV-1 – HCV co-infection – n (%) 19 (7) 9 (3) 28 (5)
FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E:
Noninferiority Achieved for Primary and Secondary Endpoints
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-acting; NI, noninferiority; RPV, rilpivirine.
*Adjusted for sex and baseline HIV-1 RNA (< vs ≥100,000 c/mL).
Virologic outcomes
2,1
93,6
4,22,5
93,3
4,2
0
20
40
60
80
100
Pro
po
rtio
n o
f P
art
icip
an
ts (
%)
CAB LA + RPV LA
(n=283)
ABC/DTG/3TC
(n=283)
Primary endpoint:
LA noninferior to DTG/ABC/3TC (≥50 c/mL) at Week 48
Difference (%)
-10 -8 -6 -4 -2 0 2 4 6 8 10
−2.8 2.1
−0.4
DTG/ABC/3TCCAB LA + RPV LA
Adjusted treatment difference (95% CI)*
6% NImargin
Key secondary endpoint:
LA noninferior to DTG/ABC/3TC (<50 c/mL) at Week 48
Difference (%)
CAB LA + RPV LA
-10 -8 -6 -4 -2 0 2 4 6 8 10
−3.7 4.5
0.4
DTG/ABC/3TC
−10% NImargin
Virologic nonresponse
(≥50 c/mL)
Virologic success
(<50 c/mL)
No virologic data
FLAIR Snapshot Outcomes at Week 48 for ITT-E
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
3TC, lamivudine; ABC, abacavir; AE, adverse event; CAB, cabotegravir; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine.
*Relocation (1), lost to follow-up (1); †LA arm: Hepatitis A (1); acute hepatitis B (1); acute hepatitis C (1); transaminases increase (1) hepatitis A/secondary syphilis (1), injection site pain (1); injection site pain/discomfort/diarrhoea/vomiting (1); adenocarcinoma of colon (1). ** DTG/ABC/3TC arm: Renal failure (1); suicide attempt (1); ‡Tolerability of injections (1), incarceration (1), lost to follow-up (2); §Frequency of visits (participant decision [4]), noncompliance with study treatment and protocol procedures (2), relocation (1), participant decision to stop treatment (1), late to attend visits (1), lost to follow-up (1).
n (%)
CAB LA + RPV LA
N=283
DTG/ABC/3TC
N=283
HIV-1 RNA <50 copies/mL 265 (93.6) 264 (93.3)
HIV-1 RNA ≥50 copies/mL 6 (2.1) 7 (2.5)
Data in window not below threshold 2 (0.7) 2 (0.7)
Discontinued for lack of efficacy 4 (1.4) 3 (1.1)
Discontinued for other reason while
not below threshold0 2 (0.7)*
No virologic data 12 (4.2) 12 (4.2)
Discontinued due to AE† 8 (2.8) † 2 (0.7) **
Discontinued for other reasons 4 (1.4)‡ 10 (3.5)§
Cosa non cambia?
1. Efficacia
2. Selezione di
Resistenze
• NNRTI—K103N, E138G, and K238T (FC RPV=3.3; etravirine=1.9); INI—Q148R (FC CAB=5.1; dolutegravir=1.38)c
• No additional PDVFs beyond W48 on any arm (all subjects through W160)d
LATTE-2 - RAMs
Margolis D, et al. AIDS 2016; Abstract THAB0206LB.
PDVF: <1.0 log10 c/mL decrease in plasma HIV-1 RNA by W4, OR confirmed HIV-1 RNA ≥200 c/mL after prior suppression to <200 c/mL, OR >0.5 log10 c/mL increase from nadir HIV-1 RNA value ≥200 c/mL. aOne additional PDVF without treatment-emergent resistance occurred during the oral induction period due to oral medication non-adherence. bOnePDVF at W4: no detectable RPV at W4 and W8, suggesting maladministration. cOne PDVF at W48 at HIV-1 RNA 463 c/mL (confirmed at 205 c/mL). dContains data beyond W48.
Maintenance perioda
Q8W IM
(n=115)
Q4W IM
(n=115)
Oral CAB
(n=56)
Subjects with PDVF, n (%) 2 (1)b 0 1 (2)
INI-r mutations 1c 0 0
NRTI-r mutations 0 0 0
NNRTI-r mutations 1c 0 0
Only two subjects met PDVF criteria across the CAB IM arms through W48
ATLAS Confirmed Virologic Failure: CAB LA + RPV LA Arm
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
3TC, lamivudine; ABC, abacavir; AZT, azidothymidine; CAB, cabotegravir; CAR, current ART; CVF, confirmed virologic failure; DTG, dolutegravir; EFV, efavirenz;
FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; LA, long-acting; LPV, lopinavir; NVP, nevirapine; PBMC, peripheral blood mononuclear cell; r, ritonavir; RAL, raltegravir; RAM, resistance-associated mutation; RPV, rilpivirine; RT, reverse transcriptase; SVF, suspected virologic failure; TDF, tenofovir disoproxil fumarate.
*L74I is not considered an INSTI RAM by IAS-US guidelines and has no impact on CAB activity.
Gender,
Country,
HIV-1
Subtype
Previous CAR
Baseline RAMs
(PBMC/HIV-1 DNA;
Day 1)SVF
Timepoint
Viral Load at
SVF/CVF
(c/mL)
SVF Timepoint RAMs
(HIV-1 RNA)Drug Sensitivity at
SVF
(Fold Change) RT INSTI* RT INSTI
F, Russia
A3TC, AZT, LPV/r E138E/A L74I Week 8 79,166 / 25,745 E138A L74I
RPV (2.4)
CAB (0.8)
DTG (0.9)
F, France
AG
3TC, AZT, NVP
to 3TC, ABC,
NVP
V108V/I
E138KNone Week 12 695 / 258
V108I
E138KNone
RPV (3.7)
CAB (1.2)
DTG (1.0)
M, Russia
A1
FTC, RAL, TDF
to ABC, EFV,
3TC
None L74I Week 24 544 / 1841 E138E/KN155H
L74I
RPV (6.5)
CAB (2.7)
DTG (1.2)
• Plasma CAB and RPV concentrations at the time of failure were below the population means but within the range for the large majority of individuals who maintained virologic suppression
ATLAS Confirmed Virologic Failure: CAR Arm
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
3TC, lamivudine; AZT, azidothymidine; c, cobicistat; CAR, current ART; CVF, confirmed virologic failure; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; PBMC, peripheral blood mononuclear cell; RAM, resistance-associated mutation; RT, reverse transcriptase; SVF, suspected virologic failure; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
Gender,
Country,
HIV-1
Subtype
Study CAR
Baseline RAMs
(PBMC/HIV-1 DNA; Day 1) SVF
Timepoint
Viral Load at
SVF/CVF
(c/mL)
SVF timepoint RAMs
(HIV-1 RNA)
RT INSTI RT INSTI
M, Russia
A1 EFV, 3TC, AZT M184M/I L74I Week 20 1295 / 9727
M184V
G190SL74I
M, USA
BEVG/c, FTC, TAF None None Week 20 339 / 264 None None
F, USA
BEVG/c, FTC, TDF None None Week 32 524 / 815 M184I None
M, USA
BEVG/c, FTC, TDF None None Week 40 392 / 512 M230M/I None
RPV resistance under LA-RPV
Penrose KJ, et al. JID 2016
Cosa non cambia?
1. Efficacia
2. Selezione di
Resistenze
3. Tollerabilità
• Through Week 160, the most commonly reported
non-ISR AEs for the randomized Q8W/Q4W IM arms
included nasopharyngitis (38%; 87/230), diarrhea
(22%; 50/230), and headache (22%; 50/230)
• The most commonly reported non-ISR, drug-related (per investigator) AEs for the
randomized Q8W/Q4W IM arms included pyrexia
(5%; 12/230), headache (3%; 7/230), and
fatigue (3%; 6/230)
• The most commonly reported non-ISR AEs for the
optimized Q8W/Q4W IM arms included
nasopharyngitis (14%; 6/44), back pain (11%;
5/44), and influenza (11%; 5/44)
• The most commonly reported non-ISR, drug-
related (per investigator) AEs for the
optimized Q8W/Q4W IM arms were asthenia,
fatigue and palpitations, each at 2% (1/44)
LATTE-2 Adverse Events
Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.
AE, adverse event; IM, intramuscular; ISR, injection-site reaction; Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine.
LATTE-2 Adverse Events
Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.
aData presented for the randomized Q8W/Q4W IM arms are inclusive of MP and EP. Data presented for the
optimized Q8W/Q4W IM arms are inclusive of on-treatment events occurring from the first date of first
injection in the EP, W100. bMI (possibly drug-related, fatal), epilepsy (fatal). cAdded in EP: Q8W: Hep
C; Q4W: CAD, MI, motor neuron disease, hypoesthesia/muscular weakness/fatigue; Optimized Q4W: injection
site pain.
Week 160 Safetya
Q8W IM
N=115
n (%)
Q4W IM
N=115
n (%)
Optimized
Q8W IM
N=34
n (%)
Optimized
Q4W IM
N=10
n (%)
Grade 3/4 AEs, excluding ISRs 24 (21) 29 (25) 0 1 (10)
Drug-related grade 3/4 AEs,
excluding ISRs
2 (2) 6 (5) 0 0
Serious AEs 17 (15) 21 (18) 2 (6) 0
Drug-related SAEs 0 1 (<1)b 0 0
Fatal SAEs 0 2 (2)b 0 0
AEs leading to withdrawalc 3 (3) 12 (10) 0 1 (10)
Grade 3/4 hematology labs 4 (3) 2 (2) 0 0
Grade 3/4 chemistry labs 28 (24) 38 (33) 3 (9) 1 (10)
Select grade 3-4 laboratory abnormalities
Creatine kinase (CK) 11 (10) 13 (11) 1 (3) 0
Alanine aminotransferase (ALT) 6 (5) 5 (4) 0 0
Lipase 8 (7) 7 (6) 1 (3) 1 (10)
Total neutrophils 3 (3) 2 (2) 0 0
• In the randomized Q8W/Q4W IM arms, 99% of ISR
events were mild (85%) or moderate (14%), and 87%
resolved within 7 days
• 2/230 (<1%) had an ISR that led to discontinuation (both Q8W subjects) through
Week 160
• No randomized IM patient had an ISR that led to discontinuation after Week 48
• In the optimized Q8W/Q4W IM arms, 98% of ISR
events were mild (81%) or moderate (17%), and 91%
resolved within 7 days
• 1/44 (2%) had an ISR that led to discontinuation (Q4W)
LATTE-2 Adverse Events
Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.
IM, intramuscular; ISR, injection-site reaction; LA, long acting; Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine.
• 83/88 (94%) of CAB + RPV subjects with drug related AEs had max Grade 1 or 2*
• No cases of drug related SAEs, drug hypersensitivity (HSR) or drug induced liver injury observed on CAB + RPV arm
• AE’s leading to withdrawal: 10 (3%) on CAB + RPV vs. 5 (1%) on CAR1
ATLAS Adverse Events (excluding ISRs)
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
*Grade 3 DR-AE LA arm(n): pyrexia (1), nausea (1), diarrhea (1), and headache (2), and grade 4 lipase increased (1); 1AEs leading to withdrawal: LA arm (n) – Hepatitis A (2); acute Hepatitis B (1); acute Hepatitis C (1); headache (1); depression suicidal (1); memory impairment (1); diarrhea/nausea/headache (1); asthenia & myalgia (1); anxiety (1); CAR arm (n) – colitis (1); blood creatinine increased (1); fatal methamphetamine overdose (1); renal impairment (1); anxiety disorder/depression/suicidal ideation (1);, lamivudine; ABC, abacavir; AE, adverse event; CAB, cabotegravir; DTG, dolutegravir; ISR, injection site reaction; RPV, rilpivirine.
Drug Related AEs (≥3%), n (%)Any event (per subject) 88 (29) 8 (3)
Fatigue 11 (4) 0
Pyrexia 11 (4) 0
Headache 11 (4) 0
Any AE (≥10%), n (%)
CAB + RPV
(N=308)
CAR
(N=308)
Any event (per subject) 264 (86) 220 (71)
Nasopharyngitis 52 (17) 42 (14)
Upper respiratory tract infection 32 (10) 25 (8)
Headache 34 (11) 17 (6)
• The majority (99% [1439/1460]) of ISRs were grade 1–2 and most (88%) resolved within ≤7 days
ATLAS Injection Site Reactions (ISRs)
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
CAB, cabotegravir; ISR, injection site reaction; LA, long-acting; RPV, rilpivirine.
Bars represent incidence of onset ISRs relative to the most recent IM injection visit.
Event
CAB LA + RPV LA
N=308
Participants receiving injections 303
Injections given, n 6978
ISR events, n (%) 1460 (20.9)
Pain 1208 (82.7)
Nodule 54 (3.7)
Induration 54 (3.7)
Swelling 48 (3.3)
Grade 3 ISR pain, no. of events (%) 20 (1.7)
Median duration of ISRs, days 3
Participants with ISR leading to
withdrawal, n (%)4 (1.3)
0
20
40
60
80
100
4B 8 12 16 20 24 28 32 36 40 44 48
Pa
rtic
ipa
nts
wit
h I
SR
s (%
)
Study Week
ISR Incidence by Week
• 75/79 (95%) of CAB + RPV subjects with drug related AEs had max Grade 1 or 2
• 1 drug-related SAE on CAB + RPV – Right knee monoarthritis (0 - DTG/ABC/3TC)
• No cases of drug hypersensitivity (HSR) or drug induced liver injury observed
• AE’s leading to withdrawal: 9 (3%) on CAB + RPV vs. 4 (1%) on DTG/ABC/3TC1
FLAIR Adverse Events (excluding ISRs)
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
1Events leading to withdrawal included: CAB LA + RPV LA arm: Acute hepatitis A (n=1), B (n=2), C (n=1), Acute hepatitis A/secondary syphilis (n=1), injection site pain (n=1), injection site pain/general discomfort/diarrhea/vomiting (n=1), increased transaminases (n=1), and adenocarcinoma of colon (n=1); DTG/ABC/3TC arm: fatigue/nausea/dizziness (n=1), amnesia/disturbance in attention/dysarthria(n=1), suicide attempt (n=1) and renal failure (n=1)
3TC, lamivudine; ABC, abacavir; AE, adverse event; CAB, cabotegravir; DTG, dolutegravir; ISR, injection site reaction; RPV, rilpivirine.
Any AE (≥10%), n (%)
CAB + RPV
(N=283)
DTG/ABC/3TC
(N=283)Any event (per subject) 246 (87) 225 (80)
Nasopharyngitis 56 (20) 48 (17)
Headache 39 (14) 21 (7)
Upper respiratory tract infection 38 (13) 28 (10)
Diarrhea 32 (11) 25 (9)
Drug Related AEs (≥3%), n (%)Any event (per subject) 79 (28) 28 (10)
Headache 14 (5) 1 (4)
Pyrexia 13 (5) 0Body Temperature Increase 8 (3) 0
• The majority (99% [2189/2203]) of ISRs were grade 1–2 and most (88%) resolved within ≤7 days
FLAIR Injection Site Reactions
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
CAB, cabotegravir; ISR, injection site reaction; LA, long-acting; RPV, rilpivirine.
Bars represent incidence of onset ISRs relative to the most recent IM injection visit.*No events worse than grade 3 were reported; †ISR leading to withdrawal: 2 due to ISR pain. Two additional participants withdrew due to injection intolerability.
Event
CAB LA + RPV LA
N=283
Participants receiving injections, n 278
Injections given, n 7704
ISR events, n (%) 2203 (28.6)
Pain 1879 (85.3)
Nodule 86 (3.9)
Induration 82 (3.7)
Swelling 38 (1.7)
Warmth 38 (1.7)
Grade 3 ISR pain events, n (%) 12 (<1)*
Median duration of ISRs, days 3
Participants with ISR leading to
withdrawal, n (%)2 (<1)†
0
20
40
60
80
100
4B 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Pa
rtic
ipa
nts
wit
h I
SR
s (%
)
Study Week
ISR Incidence by Week
HPTN 077
Cosa non cambia?
1. Efficacia
2. Selezione di
Resistenze
3. Tollerabilità
4. Penetrazione nei
santuari
1UCSD Antiviral Research Center, San Diego, CA, USA; 2Mills Clinical Research, Los Angeles, CA, USA; 3Chatham County Health Department,
Savannah, GA, USA; 4University of Nebraska Medical Center, Omaha, NE, USA; 5Office of Franco Felizarta, MD, Bakersfield, CA, USA; 6Long
Beach Education and Research Consultants, Long Beach, CA, USA; 7North Texas Infectious Diseases Consultants, P.A., Dallas, TX, USA; 8PAREXEL International, Durham, NC, USA; 9GlaxoSmithKline, Research Triangle Park, NC, USA; 10ViiV Healthcare, Research Triangle Park, NC,
USA; 11GlaxoSmithKline, Collegeville, PA, USA; 12Janssen Research and Development, Beerse, Belgium
Distribution in Cerebrospinal Fluid (CSF) of Cabotegravir (CAB) and Rilpivirine (RPV) After Intramuscular Administration of Long-Acting (LA) Injectable Suspensions in HIV-1-Infected Patients
Scott Letendre,1 Anthony Mills,2 Debbie Hagins,3 Susan Swindells,4
Franco Felizarta,5 Jerome DeVente,6 Christopher Bettacchi,7 Yu Lou,8
Susan Ford,9 Annie Cameron,9 Kenneth Sutton,10 Jafar Sadik Shaik,11
Herta Crauwels,12 Ronald D’Amico,10 Parul Patel10
• CAB and RPV are LA injectables in phase III development for the maintenance of HIV virologic suppression
• CAB LA + RPV LA administered IM Q4W or Q8W may offer a better tolerability profile, improved adherence, and greater treatment satisfaction relative to daily oral ART
• The CNS typically has lower concentrations of ARV agents compared with blood
• This study assessed CAB and RPV distribution into the CSF and HIV-1 RNA levels within this “sanctuary” site
Background
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
ART, antiretroviral therapy; ARV, antiretroviral; CAB, cabotegravir; CNS, central nervous system; CSF, cerebrospinal fluid; IM, intramuscularly; LA, long-acting; Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine.
CAB RPV
RPV CAB
• To determine plasma and CSF CAB and RPV concentrations and to determine the CSF-to-plasma concentration ratio of CAB and RPV following LA administration
• To assess HIV-1 RNA suppression in plasma and CSF and the relationship between CAB and RPV concentrations in the CSF and CSF HIV-1 RNA levels
• To assess the safety and related AEs reported during the sub-study
Objectives
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
AE, adverse event; CAB, cabotegravir; CSF, cerebrospinal fluid; LA, long-acting; RPV, rilpivirine.
• LATTE-2 parent studya
• HIV-1 infected adults receiving monthly (Q4W) or bimonthly (Q8W) injections during the LATTE-2 Extension period were eligible for the CNS sub-study following Week 152
Study Design
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
ABC, abacavir; CAB, cabotegravir; CNS, central nervous system; IM, intramuscularly; LA, long-acting; PO, oral; QD, once a day; Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine; 3TC, lamivudine. aLATTE-2 Week 160 data are being presented as a poster (P118) and a thistle presentation (Wednesday, 31 October at 12:15–13:05). bParticipants who withdrew after ≥1 IM dose in the Maintenance or Extension periods entered the long-term follow-up period. cParticipants who successfully completed 96 weeks of oral CAB in the maintenance period had the option of continuing study participation in the extension period by switching to an optimized IM regimen of their choice (either Q4W and Q8W LA dosing).
CAB loading doses at Day 1 (800 mg) and Week 4 (600 mg)
Induction
Week 32
Primary analysis Dosing regimen
selection
Day 1
Randomization2:2:1
Week 48
Analysis Dosing regimen
confirmation
CAB 400 mg IM + RPV 600 mg IM Q4W (n=115)
Week 96b
CAB loading dose at Day 1 (800 mg) CAB 30 mg + ABC/3TC for
20 wk
CAB 30 mg + ABC/3TC PO QD (n=56)
Maintenance periodb
Add RPV
4 wk
Extension periodc
CAB 400 mg IM + RPV 600 mg IM Q4W (n=101)
CAB 600 mg IM + RPV 900 mg IM Q8W (n=107)
Week 160
CAB 400 mg IM + RPV 600 mg IM Q4W (n=10)
CAB 600 mg IM + RPV 900 mg IM Q8W (n=34)
• Paired plasma and CSF samples were collected 7 days (±3) after an injection visit
• CAB concentrations: total and unbound in plasma; total in CSF
• RPV concentrations: total in plasma and CSF
• Paired plasma and CSF samples for HIV-1 RNA were assessed using Abbott (<50 c/mL; plasma) and SuperLow (<2 c/mL; plasma and CSF) assays
Methods
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
CAB, cabotegravir; CSF, cerebrospinal fluid; LP, lumbar puncture; PK, pharmacokinetics; RPV, rilpivirine.
• A follow-up visit by phone occurred 2 weeks following LP for safety assessment
• 6 US sites participated in the CSF PK sub-study
• A sample size of 10 participants with evaluable PK per dosing arm was targeted for this sampling of CAB and RPV PK concentrations
Screening LP visit
1 wk post (±3 d)
Day 1 injection
Follow-up
2 wk
Baseline Characteristics of CSF Sub-Study Population
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
BMI, body mass index; IM, intramuscularly; Q4W, every 4 wk; Q8W, every 8 wk; SD, standard deviation.
Demographics
Q8W IM
(N=15)
Q4W IM
(N=3)
Total
(N=18)
Age, mean (SD), y 37.2 (11.12) 44.0 (13.08) 38.3 (11.35)
Male gender, n (%) 12 (80) 3 (100) 15 (83)
BMI, mean (SD), kg/m2 26.7 (5.28) 26.0 (1.51) 26.5 (4.83)
Weight, mean (SD), kg 82.2 (15.27) 87.0 (18.81) 83.0 (15.40)
Race/Ethnicity, n (%)
Not Hispanic/Latino 11 (73) 3 (100) 14 (78)
White 9 (60) 2 (67) 11 (61)
Black/African American 5 (33) 0 5 (28)
Asian 1 (7) 1 (33) 2 (11)
Plasma HIV-1 RNA <50 c/mL, n (%) 15 (100) 3 (100) 18 (100)
CD4 cell count, mean (SD), cells/mm3 827 (280) 685 (164) 803 (266)
• CSF concentrations exceeded the upper limit of the in vitro IC50 for wild-type HIV (CAB, 0.0003 µg/mL; RPV, 0.081 ng/mL), except for 1 patient with CSF RPV concentration <1 ng/mL (NQ)
• CAB CSF concentrations were significantly positively correlated with total plasma CAB concentrations (r=0.899; P<0.001)
Plasma and CSF CAB and RPV Pharmacokinetics
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
CAB, cabotegravir; CSF, cerebrospinal fluid; IC50, half maximal inhibitory concentration; Q4W, every 4 wk; Q8W, every 8 wk; NP, not performed; NQ, not quantifiable; RPV, rilpivirine. aCSF collection was successful in 13/15 Q8W participants.b1 participant had NQ RPV CSF concentrations (HIV-1 RNA <2 c/mL in CSF and 5 c/mL in plasma).
Pharmacokinetics
CAB (µg/mL) median (min, max) RPV (ng/mL) median (min, max)
Q8W (N=15) Q4W (N=3) Q8W (N=15) Q4W (N=3)
Total plasma 3.92(1.30, 6.41)
3.02 (2.37, 5.10)
192 (91.7, 378)
134 (83.0, 187)
Plasma unbound 0.0047 (0.0007, 0.0220)
0.0019 (0.0014, 0.0698)
NP NP
Unbound fraction in plasma, %
0.103 (0.056, 0.912)
0.075 (0.062, 1.45)
NP NP
Total CSF 0.0106 (0.0053, 0.0245)a
0.0127 (0.0082, 0.0159)
1.84 (NQ, 2.90)a,b
1.67 (1.40, 2.47)
CSF/Total plasma, %
0.304 (0.218, 0.449)a
0.344 (0.312, 0.421)
1.07 (NQ, 1.52)a,b
1.32 (1.25, 1.69)
Plasma and CSF HIV-1 RNA
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
CSF, cerebrospinal fluid; Q4W, every 4 wk; Q8W, every 8 wk.
aActual HIV-1 RNA levels in plasma on Day 8 for the 6 participants who were not <2 c/mL: 3, 5, 5, 10, 15, and 42 c/mL. bN=13, failed to collect CSF for 2 participants. cAll except 1 participant in the Q8W arm had CSF viral load <2 c/mL. This participant had CSF HIV-1 RNA of 2 c/mL and plasma HIV-1 RNA of <2 c/mL.
All patients maintained high rates of virologic suppression in plasma and CSF
Antiviral activity
Abbott real-time assayHIV-1 RNA <50 c/mL
n/N (%)
SuperLow assayHIV-1 RNA <2 c/mL
n/N (%)
Q8W(N=15)
Q4W(N=3)
Q8W(N=15)
Q4W(N=3)
Plasma HIV-1 RNA on Day 8 15/15(100)
3/3(100)
9/15a
(60)3/3
(100)
CSF HIV-1 RNA on Day 8 13/13b
(100)3/3
(100)12/13b,c
(92)3/3
(100)
Relationship Between CAB and RPV Concentration in Plasma and CSF
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
Individual unbound plasma cabotegravir concentrations are represented as mean of the 4 replicates.CSF, cerebrospinal fluid; IM, intramuscularly; LLQ, lower limit of quantification; Q4W, every 4 wk; Q8W, every 8 wk.
LLQ of total plasma and CSF
LLQ of total plasma
LLQ of free plasma and CSF
Q4W IM Q8W IM Q4W IM Q8W IMQ4W IM Q8W IM
• CAB median CSF/total plasma ratios of 0.30% to 0.34% were similar for Q4W and Q8W
• CAB total concentrations in CSF exceeded unbound CAB concentrations in plasma
• RPV median CSF-to-plasma ratios of 1.07% to 1.32% were consistent with observations following oral RPV 25 mg once daily
• CAB and RPV concentrations exceeded their respective in vitro IC50 values for wild-type HIV-1, suggesting CAB and RPV achieve therapeutic concentrations in the CSF at steady-state following LA administration
• High rates of virologic suppression in plasma and CSF were observed in this sub-study with 92% to 100% of participants achieving CSF HIV-1 RNA levels <2 c/mL following CAB LA + RPV LA IM administration either Q4W or Q8W
Conclusions
Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.
Cosa cambia?
1. Comodità dei
pazienti
LATTE-2 Patient-Reported Outcomes at Week 96 Maintenance Treatment
Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.
CAB, cabotegravir; IM, intramuscular; LA, long acting; Q4W, every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine. aBased on observed case data set of subjects who completed HIV Treatment Satisfaction Questionnaire status version at Week 96.
How satisfied are you with your current treatment?
How satisfied would you be to continue with your present form of treatment?
Very satisfied Very dissatisfied
6 5 4 3 2 1 0
0,44
6,12
1,05
6,43CAB LA + RPV LA (Wk
24, n=300; Wk 44,
n=300)
CAR (Wk
24, n=288; Wk 44,
n=294)
Week 24*
Week 44*
Single-item question on participants’ preference at Week 48
• ITT-E population: 86% (266/308) preferred LA; 2% (7/308) preferred daily oral therapy
• Responding participants: 97% (266/273) preferred the LA regimen over previous oral therapy
ATLAS: High Participant Satisfaction (HIVTSQs) and Preference For Injectable Therapy
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
CAB, cabotegravir; CAR, current ART; HIVTSQs, HIV Treatment Satisfaction Questionnaire Status; ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine.
*Adjusted mean change from baseline; adjusted for baseline score, sex, age, race, and baseline third agent class. Error bars show 95% confidence interval.
55 66ImprovementHIVTSQs total score 50
***p<0.001
***p<0.001
Patient Preference Survey (LA arm)
• Change in satisfaction with current treatment vs induction phase treatment was significantly higher for LA vs DTG/ABC/3TC
FLAIR: High Participant Satisfaction (HIVTSQc) and Preference For Injectable Therapy
Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.
3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; HIVTSQc, HIV Treatment Satisfaction Questionnaire (change version); ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine; SE, standard error.
*Adjusted for baseline HIV-1 RNA (< vs ≥100,000 c/mL), sex, age, and race, ± SE. Based on observed dataset of participants who completed the questionnaire at Week 48 or early withdrawal. Maintenance (Day 1) HIVTSQs baseline mean score comparable between both arms with the same mean value of 59 out of 66 points.
Patient Preference Survey
0 ImprovementHIVTSQc total score*
25,5
29,6
0 10 20 30
Week 48CAB LA + RPV LA (n=263)
ABC/DTG/3TC (n=266)
Single-item question on participants’ preference at Week 48:
• ITT-E population: 91% (257/283) preferred LA; 1% (2/283) preferred daily oral therapy
– Responding participants: 99% (257/259) preferred the LA regimen over previous oral therapy
33-33
95% CI for difference: 2.8, 5.5p<0.001
Cosa cambia?
1. Comodità dei
pazienti
2. Aderenza
100%
CAB PK profile tail
Trezza C Curr Opin HIV AIDS. 2015 Jul; 10(4):
239 245
Spreen et al. JAIDS 2014;
After last dose CAB oral monotherapy
still> PA-IC90 over 14-15 days.
By Day 3, all regimens achieved mean plasma concentrations in excess of 0.67 μg/ml
(4X the PA – IC 90%). Cabotegravir concentrations remained above this threshold
throughout the monthly or quarterly dosing interval for each of the tested regimens
HPTN 077 – LA CAB PK
tail
• 135/177 participants (33 placebo) who had follow up 76-weeks after
the final injection13%
31%
11%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
(n=40) (n=82) (n=30) (n=64)
Men Women Men Women
Week 60 Week 76
<LLOQ LLOQ to <1xPA-IC90 1x to 4 x PA-IC90
In multivariate
analysis, factors
associated with
longer PK tail
were female sex
at birth [1.45
(95%CI: 1.17 to
1.81) p=0.001]
and higher BMI
per unit increase
[1.02 (95%CI 1.01
to 1.04)
p<0.003].
Landovitz R, et al. HIVR4P 2018 OA15.06LB.
Cosa cambia?
1. Comodità dei
pazienti
2. Aderenza
3. Organizzazione
ambulatoriale
Cosa cambia?
1. Comodità dei
pazienti
2. Aderenza
3. Organizzazione
ambulatoriale
4. Farmacocinetica e
interazioni
Cabotegravir Clinical Pharmacology Attributes
AttributeCabotegravir
Oral IM
Dose (Phase 3) 30mg600mg loading dose (3 ml)
400mg maintenance dose (2 ml)
Dosing frequency (Phase 3) Once daily Once monthly or Q2 months
Absorption Rapidly absorbed; Tmax 1-3 hrs Slowly absorbed, Tmax 1 week
Impact of Food None Not Applicable
Inter-subject PK variability Low (%) Moderate to High (%) consistent with IM dosing
Impact of covariates on PK No age, race, or gender impactSlower absorption rate in females and subjects with
high BMI; not clinically significant
Elimination half-life ~40 hours ~40 days (18-50 days) (absorption-limited t1/2)
Metabolism/protein bindingPrimarily metabolized by UGT1A1, with minor UGT1A9 component
Protein binding 99% protein bound
Drug Interaction Liability Low potential to cause or be a victim of drug-drug interactions
• Plasma concentrations of IM CAB and RPV were comparable with those using oral dosing
ATLAS Plasma CAB and RPV Trough Concentrations
Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.
CAB, cabotegravir; IM, intramuscular; LA, long-acting; RPV, rilpivirine.
Median (5th, 95th percentile) concentration–time data for CAB (left) and RPV (right) following monthly LA administration.
4 488 12 16 20 24 28 32 36 40 44
Visit (week)
0.1
1
10
Pla
sm
a C
AB
(μ
g/m
L)
ATLAS (n=308)
PA-IC90 (0.166 µg/mL)
4 488 12 16 20 24 28 32 36 40 44
Visit (week)
10
100
Pla
sm
a R
PV
(n
g/m
L)
ATLAS (n=308)
PA-IC90 (12 ng/mL)
FIRST PASS METABOLISM
SYSTEMIC CLEARANCE
ORAL
IM
Pharmacokinetic IM cabotegravir (800 mg IM) with and without rifampicin (600 mg OD oral)
AUC = -25%
Rifampin decreased the cabotegravir area under the concentration-time curve from 0 h to infinity and the half-life by 59% and 57%
Long-acting cabotegravir
Oral cabotegravir
DDIs and transporters
Trezza C, et al. Current Opinion HIV AIDS 2015
OAT1 and OAT3
• In vitro studies indicated that CAB inhibits renal transporters OAT1 and OAT3 with half maximal inhibitory concentrations of 0.81 and 0.41 µM
• A mechanistic PBPK model of CAB in the adult population was built using the Simcyp® v17.1 simulator
• the exposure of OAT1/OAT3 substrates(methotrexate, tenofovir, ciprofloxacin, cidofovir, cefuroxime, oseltamivir carboxylate, baricitinib, and S44121).
• <25%Taskar Ks, et al. CROI 2019. #470
Exp(β)
Any Contraceptive Use
Not of Reproductive Potential
Oral Contraceptive
Injectable Contraceptive
Vaginal Ring
Contraceptive
Implantable
Contraceptive
Other Contraceptive
0.97; 0.80-1.17; p=0.74
1.02; 0.88-1.18; p=0.80
1.01; 0.83-1.23; p=0.91
0.72; 0.42-1.26; p=0.26
0.92; 0.81-1.05; p=0.22
0.94; 0.84-1.04; p=0.20
0.91; 0.80-1.04; p=0.16
1.13; 0.77-1.67; p=0.54
0.94; 0.84-1.05; p=0.28
1.01; 0.93-1.10; p=0.82
0.97; 0.87-1.08; p=0.58
1.05; 0.76-1.45; p=0.75
1.04; 0.94-1.15; p=0.45
1.01; 0.93-1.09; p=0.89
1.05; 0.95-1.16; p=0.34
0.89; 0.66-1.20; p=0.44
0.79; 0.57-1.09; p=0.16
0.83; 0.64-1.07; p=0.15
0.83; 0.62-1.11; p=0.22
1.27; 0.53-3.03; p=0.59
1.07; 0.93-1.24; p=0.33
1.06; 0.94-1.18; p=0.35
1.08; 0.94-1.25; p=0.27
0.81; 0.53-1.24; p=0.34
1.08; 0.94-1.25; p=0.26
1.04; 0.94-1.16; p=0.45
1.03; 0.90-1.19; p=0.63
0.97; 0.65-1.45; p=0.87
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Hormonal Contraceptives Do Not Alter Cabotegravir PK in HIV Uninfected Women: HPTN 077 Cheríe S Blair1, Sue Li2, Gordon Chau2, Leslie Cottle2, Paul Richardson3, Mark A Marzinke3, Susan H Eshleman3, Adeola Adeyeye4, David Burns4, Alex R Rinehart5, David Margolis5, Marybeth McCauley6, Craig W Hendrix3, and Raphael J Landovitz1 on behalf of the HPTN 077 Study Team
1UCLA Center for Clinical AIDS Research & Education, 2Statistical Center for HIV/AIDS Research and Prevention, 3Johns Hopkins University School of Medicine, 4NIH/DAIDS, 5ViiV Healthcare, 6FHI360
Presented at the 2019 CROI Conference
Seattle, WA, USA, March 6, 2019
The HIV Prevention Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068619, UM1AI068613, UM1AI1068617), with co-funding from the National Institute of Mental Health, and the National Institute on Drug Abuse, all components of the U.S. National Institutes of Health. The work presented here was funded by NIH grants
UM1AI068619 (and UM1AI068613 or UM1AI1068617), and study products were provided by ViiV Healthcare. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
For more information, visit hptn.org and follow us:
Facebook: HIVptn | Twitter: @HIVptn | Youtube: HIVptn
Univariate Regression Analysis of Contraceptive Use, Contraceptive Type and Select PK Parameters [log (Cτ) and log (T1/2)]
• Long-acting injectable cabotegravir (CAB LA) is a strand-transfer integrase inhibitor, currently in development for HIV prevention and treatment
• Hormonal contraception is crucial for women of reproductive potential who are at-risk or infected with HIV to prevent the vertical transmission of HIV1
• Unexpected drug-drug interactions between ARVs and hormones for contraception or cross-sex therapy have been noted in several previous studies:
– Oral contraceptives containing ethinyl estradiol/desogestrel reduced efavirenz serum concentrations by 18% (p=0.03)2
– Ethinyl estradiol/norelgestromin transdermal patch with lopinavir/ritonavir resulted in lower ritonavir maximum concentration and AUC (8% and 24%, respectively, p=0.03)3
– Medroxyprogesterone acetate has been noted to decrease intracellular levels of tenofovir-diphosphate concentrations in blood CD4+ T cells, resulting in reduced anti-HIV activity of tenofovir4
– Estrogen with or without anti-androgen use has been noted to result in 13-38% reduction in tenofovir exposure (AUC)5-6
– In a fixed sequence crossover study, oral CAB was shown to have no impact on oral ethinyl estradiol or levonorgestrel7
• Given the widespread use of hormones for both contraception and cross-sex hormone therapy, understanding potential DDIs between sex hormones and ART is critical to the complete understanding of safety, efficacy, and acceptability of novel treatment and prevention paradigms
N PK Parameter Exp(β) 95% CI p Value
Contraceptive Use 79 log (Cτ) 0.99 0.84-1.17 0.94
log (T1/2) 0.83 0.50-1.38 0.47
Not of Reproductive Potential
12 log (Cτ) 0.95 0.84-1.06 0.33
log (T1/2) 1.15 0.78-1.70 0.48
Oral Contraceptive 18 log (Cτ) 1.00 0.90-1.10 0.92
log (T1/2) 1.08 0.78-1.49 0.64
Injectable Contraceptive
26 log (Cτ) 1.00 0.92-1.09 0.98
log (T1/2) 0.95 0.71-1.27 0.74
Vaginal Ring Contraceptive
2 log (Cτ) 0.81 0.62-1.05 0.12
log (T1/2) 1.19 0.50-2.83 0.69
Implantable Contraceptive
10 log (Cτ) 1.07 0.94-1.21 0.30
log (T1/2) 0.79 0.52-1.21 0.28
Other Contraceptive 11 log (Cτ) 1.04 0.93-1.17 0.46
log (T1/2) 0.89 0.60-1.32 0.57
BACKGROUND
CONTACT: Cherίe Blair 10833 Le Conte Ave (Room 37-121 CHS) Los Angeles, CA 90095 [email protected]
METHODS
STUDY POPULATION AND DESIGN
• We performed a secondary analysis of 85 cisgender women who were enrolled and randomized to CAB in HPTN 077, a Phase 2a multicenter study that enrolled HIV-uninfected, low-risk individuals in Malawi, Brazil, South Africa, and the United States from February 2015 – May 20168
• Participants received CAB 30mg orally daily x 4 weeks, followed by
– CAB LA 800mg IM every 12 weeks for 3 injections (Cohort 1), or
– CAB LA 600mg for 5 injections (Cohort 2)
• First two injections separated by 4 weeks, the remainder by 8 weeks
– Primary endpoint was at week 41 for both cohorts
• CAB plasma concentration measurements were obtained at weeks:
– 6, 9, 13, 18, 23, 30, 35, and 41 (Cohort 1)
– 6, 10, 13, 18, 21, 26, 29, 34, 37, 41 (Cohort 2)
• Participants were followed 52-76 weeks subsequent to their final injection
STATISTICAL ANALYSIS
• Linear regression was used to evaluate pharmacokinetic (PK) parameters between hormonal contraception (use vs not based on self-report) and contraception type (oral, injectable, vaginal ring, implants, other)
• As all women not of reproductive potential were on a hormonal contraceptive, they were included as a separate group in the analysis
• Peak concentration [Cmax], trough [Cτ], exposure after the last injection [AUC0-τ] were
estimated for each injection, and apparent terminal half-life after the last injection [T1/2app] was included in the analysis.
• A linear mixed model was used to assess associations of hormonal contraception between Cmax, Cτ, and AUC0-τ in order to account for correlations of these PK parameters across injections
• Linear regression analysis was utilized for T1/2app
• Cohorts 1 and 2 were combined in univariate and multivariate analysis
• Multivariate analysis assessed baseline covariates associated with PK parameters, adjusting for BMI and CAB dose cohort
• P-values ≤ 0.05 were considered statistically significant
Multivariate Regression Analysis of Contraceptive Use (yes vs no), Contraceptive Type and PK Parameters [log(Cmax), log(Cτ), log(AUC), and log(T1/2)], Controlling for BMI and Cohort
• Among HIV-uninfected females in HPTN 077, use of hormonal contraception (regardless of type used) did not alter the CAB LA concentration profile during injections or during the pharmacokinetic tail in either univariate or multivariate analysis
• In the multivariate analysis, the sample size of this study can rule out an effect size of a 2-fold change for log(Cmax), 2-fold change for log(Cτ), 1.8-fold change for log(AUC), and 2.1-fold change for log(T1/2) with 80% power using a 5% type 1 error rate for any hormonal contraceptive use vs not.
• No significant associations were found between hormonal contraception use and PK parameters among the women who received CAB injections in HPTN 077
• The findings in this study are consistent with the expectation that there would not be an interaction of hormonal contraception on CAB PK, since CAB is metabolized by UGT1A1 and A99.
• While we did not measure the effect of CAB on hormone concentration profiles in this study, it is expected that there would be no interaction, as oral CAB had no significant effect on PK profiles of levonorgestrel/ethinyl estradiol oral contraceptives in a prior fixed-sequence crossover study 7
• Future research regarding the effect of CAB on sex hormone levels gender-affirming therapy is warranted
CONCLUSIONS
1. Robinson et al, “Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy” J InfectiDis Obgyn 2012
2. Landolt et al, “Efavirenz, in contrast to nevirapine, is associated with unfavorable progesterone and antiretroviral levels when co-administered with combined oral contraceptives” JAIDS 2013
3. Vogler et al, “Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1–infected women: pharmacokinetic results of ACTG trial A5188” JAIDS 2010
4. Shen et al, “Hormonal contraceptives differentially suppress TFV and TAF inhibition of HIV infection and TFV-DP in blood and genital tract CD4+ t-cells” Scientific Reports 2017
5. Hendrix et al, “Transgender women on estrogen have significantly lower tenofovir/emtricitabine concentrations during directly observed dosing when compared to cis men” HIV R4P 2018
6. Hiransuthikul et al, “Drug-drug interactions between the use of feminizing hormone therapy and pre-exposure prophylaxis among transgender women: the iFACT study” 22nd International AIDS Conference 2018
7. Trezza et al. “Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in
8. healthy adult women” Br J Clin Pharmacol 2017
9. Landovitz et al, “Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial” PLOS Medicine
2018
10. Bowers et al, “Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans” Xenobiotica 2016
REFERENCES
Women Enrolled in Study (n=132)
Cohort 1
(n=72)
Randomized to CAB (n=54)
Received at least 1 injection (n=49)
Included in Analysis (n=46)
Not of Reproductive
Potential (n=5)
Oral Contraceptive (n=11)
Injectable Contraceptive
(n=12)
Vaginal Ring Contraceptive
(n=2)
Implantable Contraceptive
(n=6)
Other Contraceptive
(n=8)
No Contraceptive (n=2)
Transgender Men Excluded from Analysis (n=3)
Randomized to Placebo (n=18)
Cohort 2
(n=60)
Randomized to CAB (n=46)
Received at least 1 injection (n=39)
Included in Analysis (n=39)
Not of Reproductive
Potential (n=7)
Oral Contraceptive (n=7)
Injectable Contraceptive
(n=14)
Vaginal Ring Contraceptive
(n=0)
Implantable Contraceptive
(n=4)
Other Contraceptive
(n=3)
No Contraceptive (n=4)
Randomized to Placebo (n=14)
Study Consort Diagram of Women Included in Analysis and Contraceptive Use
Exp β-estimate; 95% CI; p-value
0 0.5 1 1.5 2 2.5 3 3.5
Poster Number: 1791
RESULTS
Exp(β)
Any Contraceptive Use
Not of Reproductive Potential
Oral Contraceptive
Injectable Contraceptive
Vaginal Ring Contraceptive
Implantable Contraceptive
Other Contraceptive
0.97; 0.80-1.17; p=0.74
1.02; 0.88-1.18; p=0.80
1.01; 0.83-1.23; p=0.91
0.72; 0.42-1.26; p=0.26
0.92; 0.81-1.05; p=0.22
0.94; 0.84-1.04; p=0.20
0.91; 0.80-1.04; p=0.16
1.13; 0.77-1.67; p=0.54
0.94; 0.84-1.05; p=0.28
1.01; 0.93-1.10; p=0.82
0.97; 0.87-1.08; p=0.58
1.05; 0.76-1.45; p=0.75
1.04; 0.94-1.15; p=0.45
1.01; 0.93-1.09; p=0.89
1.05; 0.95-1.16; p=0.34
0.89; 0.66-1.20; p=0.44
0.79; 0.57-1.09; p=0.16
0.83; 0.64-1.07; p=0.15
0.83; 0.62-1.11; p=0.22
1.27; 0.53-3.03; p=0.59
1.07; 0.93-1.24; p=0.33
1.06; 0.94-1.18; p=0.35
1.08; 0.94-1.25; p=0.27
0.81; 0.53-1.24; p=0.34
1.08; 0.94-1.25; p=0.26
1.04; 0.94-1.16; p=0.45
1.03; 0.90-1.19; p=0.63
0.97; 0.65-1.45; p=0.87
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Log (Cmax)
Log (Cτ)
Log (T1/2)
Log (AUC)
Multivariate Regression Analysis of Contraceptive Use (yes vs no), Contraceptive Type and PK Parameters [log(Cmax), log(Cτ), log(AUC), and log(T1/2)], Controlling for BMI and Cohort
Exp β-estimate; 95% CI; p-value
0 0.5 1 1.5 2 2.5 3 3.5
Nuove tecnologie per
LA ARVs?
• Potential advantages over injectables• Removable• More consistent and predictable drug release• PK not dependent on injection site• May remain in place for years (inert, non-
degradable subcutaneous versions)
• Potential disadvantages over injectables• Specialized device required for insertion• Minor surgical procedure to remove• Regulated as both a drug and a device• Difficulty moving to a generic marketplace
Long Acting ARV Implants
- Flexner C. Current Opin HIV/AIDS 2018; 13: 289
LA ARV Implants – Tenofovir Alafenamide
M Gunawardana et al., Antimicrob Agents Chemother 2015; 59: 3913
LA ARV Implants – Tenofovir Alafenamide
M Gunawardana et al., Antimicrob Agents Chemother 2015; 59: 3913
MK-8591 (EFdA) Implant Formulations Release Effective Drug Levels for >180 days
- Barrett SE et al. Antimicrob Agents Chemother 2018; DOI: 10.1128/AAC.01058-18
>180-day extended release from solid state formulations after a single injection in rats.
Data suggest the potential to provide coverage for durations up to 1 year.
- Vora et al. J Contr Release 2017
- Vora LK et al. J Contr Release 2017
- Vora et al. J Contr Release 2017
What is it like to wear a microneedle patch?
Estimated
cabotegravir
concentrations after
applying a 30-60 cm2
microneedle patch
(adults)
- Rajoli et al. CROI 2018
LA @ CROI 2019
MK-8591 Potency and PK Provide High Inhibitory Quotients at Low Doses QD and QW
AbstractBackground: MK-8591, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), has demonstrated HIV-1 suppression for ≥7 days with single doses as low as 0.5 mg. It is currently in a Phase 2 clinical trial (NCT03272347) for the treatment of HIV-1 infection with once-daily (QD) administration of 0.25 mg, 0.75 mg, or 2.25 mg in combination with doravirine. Inhibitory quotients (IQ) for nucleoside inhibitors, based on the ratio of intracellular phosphorylated drug concentrations at trough (Ctrough,IC) and the intracellular concentrations required for efficacy (IC50,IC), predict virologic response. We evaluated the IQ of MK-8591-triphosphate (MK-8591-TP) in relation to other NRTIs for W T and NRTI-resistant HIV-1 to assess the likelihood of virologic response and barrier to resistance at clinically relevant doses.
Methods: MK-8591-TP, TFV-DP, 3TC-TP, and FTC-TP IC50,IC levels were determined in activated, uninfected human peripheral blood mononuclear cells (hPBMC) after 24 hr incubation with varying concentrations of MK-8591, TDF, 3TC, or FTC, followed by lysis and analysis by LC-MS/MS. MK-8591 IQs for wild-type (W T) HIV-1 were calculated as the ratio of steady-state Ctrough,IC, as observed with QD or weekly (QW) dosing in Phase 1 clinical studies, to the IC50,IC in hPBMCs. TDF, TAF, 3TC, and FTC IQs were calculated using their corresponding Ctrough,ICs, as determined after dosing in humans at clinical dose levels, and hPBMC IC50,ICs. IQs for NRTI-resistant HIV-1 were calculated using fold-shifts for NRTI-resistant clinical isolates.
Results: The MK-8591-TP IC50,IC for W T HIV-1 is >4-fold lower than any marketed NRTI. MK-8591 IQs at steady state with 0.25 mg QD and 10 mg QW dosing are 85.3 and 101, respectively, and proportionately greater for higher dose levels. Common NRTI mutations, including M184I/V, thymidine analog mutations, K65R, and K70E, confer low fold-shifts in antiviral potency, and MK-8591 retains greater IQs against these NRTI-resistant viruses than those of TDF, TAF, and 3TC with W T virus.
Conclusion: The IQs of MK-8591 for both W T and NRTI-resistant HIV-1 at low QD and QW doses are substantially higher than those of any NRTIs approved for HIV treatment. Coupled with the long intracellular half-life of MK-8591-TP, these IQs suggest the opportunity for multiple low dosing options with the potential for a high barrier to the development of resistance.
BACKGROUND
MK-8591: A Novel Nucleoside With a Unique Mechanism of Action
• MK-8591 (4’-ethynyl-2-fluoro-2’-deoxyadenosine; EFdA), licensed from Yamasa
• First-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI)
– Inhibits HIV replication through multiple mechanisms
• Potency, pharmacokinetics, and physical properties amenable to once-daily, once-weekly, and long-acting parenteral administration
• Currently being investigated in a Phase 2 clinical trial (NCT03272347) for the treatment of HIV-1 infection with once-daily (QD) administration of 0.25 mg, 0.75 mg, or 2.25 mg in combination with doravirine
N N
N
N
F
NH2
O
OH
OH
EFdA
Jay A. Grobler1; Kerry L. Fillgrove2; Daria J. Hazuda1; Qian Huang1; Ming-Tain Lai1; Randolph P. Matthews3; Deanne J. Rudd2; Ryan C. Vargo2
Departments of 1Infectious Disease and Vaccines; 2PPDM; 3Translational Pharmacology;
Merck & Co., Inc., Kenilworth, NJ, USA
SUMMARY AND CONCLUSIONS
• The MK-8591-TP IC50,IC for WT HIV-1 is >4-fold lower than any marketed NRTI
• MK-8591 IQs at steady state with 0.25 mg QD and 10 mg QW dosing are 85.3 and 101, respectively, and proportionately greater for higher dose levels
• Common NRTI mutations, including M184I/V, thymidine analog mutations, K65R, and K70E, confer low fold-shifts in antiviral potency, and MK-8591 retains greater IQs against these NRTI-
resistant viruses than those of TDF, TAF, and 3TC with WT virus
• Coupled with the long intracellular half-life of MK-8591-TP, these IQs suggest the opportunity for multiple low dosing options with the potential for a high barrier to the development of resistance
MK-8591 Exhibits Potent Antiviral Activity Against Wild-Type and NRTI-Resistant HIV-1
150
Log [Compound] (M)
MK-8591 (WT virus)
MK-8591 (M184I virus)
MK-8591 (M184V virus)
TAF (WT virus)
AZT (WT virus)
3TC (WT virus)
100
% I
nh
ibitio
n
50
0
-50
Compound Virus
IC50 (nM)
HIVNL4-3-GFPa HIVIIIB
b
MK-8591
WT 0.2 ± 0.1 (n=68) 0.2 ± 0.1 (n=6)
M184I 1.0 ± 0.4 (n=9) ND
M184V 1.6 ± 0.3 (n=10) ND
TAF WT 2.8 ± 0.8 (n=22) ND
AZT WT 2.6 ± 0.3 (n=5) 10.1 ± 3.9 (n=4)
TDF WT 73.3 ± 37.1 (n=20) 48.0 ± 29.5 (n=4)
3TC WT 112.3 ± 19.9 (n=10) 144 ± 68 (n=4)
Results are geometric means ± standard deviations, with number of replicates displayed in parentheses.aIC50s were determined by quantification of GFP-positive PBMCs infected with an HIV reporter virus in the presence of increasing compound concentrations and 10% normal human serum.bIC50s were determined by monitoring p24 production from infected PBMCs in the presence of increasing compound concentration and 10% fetal bovine serum.
MK-8591 Is More Potent Against Most Resistant Mutants Than Approved NRTIs
4 T
AM
s +
M1
84
I
K7
0E
+ M
184
I/V
WT
M1
84
IM
18
4V
L7
4V
L7
4V
+ M
18
4V
Q15
1M
Q1
51
M +
M1
84
I/V
69in
s6
9in
s +
M1
84
I/V
K65
RK
65
R +
M1
84
I/V
K65
R +
L74
I +
M18
4V
K6
5R
+ L
74
V +
Y1
15
F +
M18
4V
K65
R +
T6
9I
+ Q
15
1M
K6
5R
+ T
69I
+ Q
15
1M
+ M
18
4V
2 T
AM
s +
L74
I2
TA
Ms
+ M
184
I2 T
AM
s +
L74
I +
M18
4V
3 T
AM
s3
TA
Ms
+ L
74V
3 T
AM
s +
M1
84
I/V
4 T
AM
s
4 T
AM
s +
M18
4V
5 T
AM
s +
L7
4V
6 T
AM
s6
TA
Ms
+ M
184
I/V
0.01
0.1
1
10
100
1000
Ca
lcu
late
d h
PB
MC
IC
50 (
nM
)
MK-8591 3TC TAF AZT
Antiviral Activity of MK-8591 and NRTIs Requires Intracellular Phosphorylation to Their Active Anabolites
MK-8591-TP Accumulates to High Levels at Low Doses in Humans and Exhibits a Long Intracellular t1/2
Time (days) Time (days)
Week 1
0 1 2 3 4 5 6 7
[MK
-85
91
-TP
] PB
MC
(pm
ol/1
06 c
ells
)
[MK
-85
91
-TP
] PB
MC
(pm
ol/1
06 c
ells
)
0.1
1
10
100
0 10 20
Time (days)
30 40
0.1
1
10
0
0.1
1
10
100
Week 3
1 2 3 4 5 6 7 8 9 10 11 12 13 14
MK-8591-TP Concentration-Time Profile with QW Dosing
MK-8591-TP Concentration-Time Profile with QD Dosing
10 mg QW 30 mg QW 100 mg QW
0.25 mg MK-8591
0.75 mg MK-8591
5 mg MK-8591
Matthews, CROI 2018
Grobler et al., CROI 2016
RESULTS
Intracellular MK-8591-TP and NRTI-TP Concentrations at IC50
0.002
0.02
0.2
2
MK-8591 3TC FTC TDF
pm
ol/m
illio
n c
ells
at
IC50
MP
DP
TP
Drug Dose Levels Active Form
IC50
(fmol/106
hPBMCs)Mean ± SD
Steady-State
Ctrough
(fmol/106
hPBMCs)Mean (CV%) N IQ (90% CI)
MK-8591
0.25 mg QD
MK-8591-TP 9.74 ± 4.063
831 (28.5) 9 85.3 (44.8-126)
0.75 mg QD 3320 (23.6) 9 341 (221-460)
10 mg QW 983 (26) 6 101 (53.1-149)
3TC150 mg BID/
300 mg QD3TC-TP 635 ± 3312 2620 (112)4,5,6 68 4.13 (1.47-6.79)
FTC 200 mg QD FTC-TP 1131 4160 (63.7)7,8,9 64 36.9 (32.1-41.7)
TAF 25 mg QD TFV-DP 41.5 ± 19.72 311 (19.8)11,12 160 7.48 (3.37-11.6)
TDF 300 mg QD TFV-DP 41.5 ± 19.72 95.0 (59.7)7,8,10 63 2.29 (1.00-3.58)
1N=1, 2N=2, 3N=44Moore KH, et al. AIDS. 1999;13(16):2239-2250.5Rodriguez JF, et al. Antimicrob Agents Chemother. 2000;44(11):3097-3100.6Yuen G J, et al. Antimicrob Agents Chemother. 2004;48(1):176-182.7Jackson A, et al. J Acquir Immune Defic Syndr. 2013;62(3):275-281.8Seifert SM, et al. AIDS Res Hum Retroviruses. 2016;32(10-11):981-991.9Wang LH, et al. AIDS Res Hum Retroviruses. 2004;20(11):1173-1182.10Pruvost A, et al. Antimicrob Agents Chemother. 2009;53(5):1937-1943.11Clinical Pharmacology Review. NDA208215 FTC/TAF.12Ruane PJ, et al. J Acquir Immune Defic Syndr. 2013;63(4):449-455.
MK-8591 Administered at Low Doses Exhibits Substantially Higher Inhibitory Quotients Than Marketed NRTIs
MK-8591
0.25 mg Q
DMK-8591
0.75 mg Q
DMK-8591
10 mg Q
W FTC
200 mg Q
D
3TC 150 mg B
ID/
300 mg Q
D
TAF 25 mg Q
D
TDF 300 mg Q
D
100
Ctr
ough I
nh
ibito
ry Q
uo
tie
nt
10
1
Inhibitory Quotients of MK-8591 and NRTIs Against Wild-Type and NRTI-Resistant HIV-1
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Copyright © 2019 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.Presented at CROI: Conference on Retroviruses and Opportunistic Infections; Seattle, W A, USA; March 4-7, 2019.
3530
GS-6207 (Capsid Inhibitor) –
Sager JE
PRO 140 (leronlimab) SC: Long-Acting Single-Agent Maintenance Therapy (SAMT) for HIV-1 Infection
Kush Dhody1, Kazem Kazempour1, Nader Pourhassan2 and Paul J. Maddon3
1Amarex Clinical Research, LLC, Germantown, MD 2CytoDyn Inc., Vancouver, WA, 3Maddon Advisors LLC, Scarsdale, NY
PRO 140 (leronlimab) is a humanized IgG4 monoclonal
antibody that blocks HIV-1 from entering and infecting
immune cells by binding to CCR5 with high affinity
Potently inhibits CCR5-mediated HIV-1 entry without
blocking the natural activity of CCR5 in vitro
q High genetic barrier to virus resistance
PRO 140 (leronlimab) broadly inhibits genotypically
diverse viruses in vitro
q Wild-type and multidrug-resistant HIV-1
q Viruses resistant to maraviroc (SELZENTRY®)
q Both laboratory and low-passage clinical strains
PRO 140 has been administered intravenously or
subcutaneously to more than 650 healthy and HIV-1
infected individuals in Phase I/II/III studies showing
potent, long-term antiviral activity in clinical studies.
No dose-limiting toxicity in animals and generally well
tolerated following intravenous administration of single
doses of 0.5 to 10 mg/kg or up to 700 mg weekly doses
as subcutaneous (SC) injection in clinical studies. The
longest duration of exposure lasting more than 4 years at
350 mg SC weekly dose.
Designated FDA Fast Track drug candidate
Contact: Nader Pourhassan, President & CEO, CytoDyn Inc. Email: [email protected], Phone: 503-348-4173 Kush Dhody, Vice President, Clinical Operations, Amarex Clinical Research, LLC, Email: [email protected], Phone:301-956-2536
Introduction
Conclusions and Path Forward
Results Safety Summary
Figure 1. PRO 140 (leronlimab) IC50
Fold Changes For HIV Subtypes
Figure 2. PRO 140 (leronlimab)
Concentration - Viral Inhibition Curve
Figure 3. Antiviral Activity of Short-Term Monotherapy with PRO 140
The CD03 study was designed to assess the clinical safety
and treatment strategy of PRO 140 (leronlimab) SC as a
long-acting, single-agent, maintenance therapy in virally
suppressed HIV-1 patients with CCR5-tropic HIV-1
receiving combination antiretroviral therapy.
Objectives
Key Inclusion Criteria
q Age 18 years
q Receiving combination antiretroviral therapy for last 24
weeks
q Exclusive R5-tropic virus (Trofile™ DNA Assay)
q Plasma HIV-1 RNA <50 c/mL at Screening and no
documented detectable viral loads (>50 c/mL) within the
last 24 weeks prior to Screening
q Nadir CD4 count >200 cells/mm3
q CD4 count >350 cells/mm3 at in preceding 24 weeks and
at Screening
Key Exclusion Criteria
q Hepatitis B
q A history of an AIDS-defining illness
q ≥ Grade 4 DAIDS lab abnormality
Patients were shifted from combination antiretroviral
regimen to weekly PRO 140 (leronlimab) monotherapy
for 48 weeks during the Treatment Phase with the one
week overlap of existing retroviral regimen and PRO 140
(leronlimab) at the beginning of the study treatment.
Patients who experienced virologic failure were given the
option of receiving a higher dose of PRO 140 under
rescue arm or returning to their prior ART regimen .
The first ~150 eligible subjects were enrolled to receive
PRO 140 (leronlimab) 350mg SC weekly injection in a
single-arm study. Subsequently, next ~150 subjects were
randomized 1:1 to PRO 140 (leronlimab) 350mg (Group
A) or PRO 140 (leronlimab) 525mg (Group B). An
additional ~200 subjects will be randomized 1:1 to PRO
140 (leronlimab) 525mg (Group B) or PRO 140
(leronlimab) 700mg (Group C).
Methods and Materials
Baseline Characteristics
Group A (350 mg)
Efficacy
Note: 20 subjects were early terminated from the study.
3 subjects were randomized, not treated
Note: 7 subjects were early terminated from the study.
Note: 1 subject was early terminated from the study.
Based on preliminary results, the majority of patients receiving higher doses of PRO 140 (leronlimab) (525 or 700 mg) as single-
agent maintenance therapy (SAMT) were able to maintain virologic suppression.
Pharmacokinetic parameters demonstrated dose-proportionality over the range of three doses tested in this study.
Additionally, there were no significant anti-drug antibodies to PRO 140 (leronlimab) detected in subjects.
Now that response rates for higher doses are more aligned with standard of care and the drug has been generally well-tolerated,
PRO 140 (leronlimab) could be a paradigm shift in the treatment of HIV as a single-agent maintenance therapy.
In 2019, CytoDyn is targeting a BLA submission for PRO 140 (leronlimab) in treatment of HIV-1 in treatment-experienced patients
with CCR5-tropic virus and demonstrated evidence of HIV-1 replication despite ongoing antiretroviral therapy with documented
genotypic or phenotypic multi-drug resistance. As the results from the recently completed CD02 study demonstrated that the
proportion of subjects in the PRO 140 (leronlimab) group with reductions ≥ 0.5 log10 copies/mL was significantly higher than
subjects in the placebo group (p=0.0032).
Prior clinical experience of PRO 140 (leronlimab) in over 650 subjects has provided a strong foundation for upcoming clinical trials
for cancer and graft vs. host disease (GvHD) indications.
Group B (525 mg)
Group C (700 mg)
Note: No enrolled subjects at 700mg dose have reached the 24 week time point as of 1 Jan 2019.
Parameter Statistic
PRO 140 (leronlimab)
350 mg 525 mg 700 mg
N=227 N=115 N=43
Age Mean (SD) 49.9 ( 12.5) 49.3 ( 12.0) 49.4 ( 11.7)
Gender Male, n(%) 183 ( 81.0%) 87 ( 75.7%) 34 ( 79.1%)
Race Caucasian, n(%) 149 ( 65.9%) 59 ( 51.3%) 31 ( 72.1%)
Time since HIV
Diagnosis (yrs) Mean (SD) 17.1 (9.57) 15.1 (10.3) 14.6 (10.0)
Years of HAART Mean (SD) 15.1 (8.93) 12.7 (8.26) 12.3 (9.10)
PRO 140 (leronlimab)
350 mg 525 mg 700 mg
Parameter N=226 N=115 N=43 Total # of subjects with ≥1 AE 170 (75.2%) 65 (56.5%) 21 (48.8%)
Total Number of AEs 983 314 69
Mild 62 (27.4%) 33 (28.7%) 16 (37.2%)
Moderate 90 (39.8%) 28 (24.3%) 4 (9.3%)
Severe 18 (8.0%) 3 (2.6%) 1 (2.3%)
Missing 0 (0.0%) 1 ( 0.9%) 0 (0.0%) All percentages are based on the number of subjects in the treatment group (N).
A subject is counted only once within each category.
PRO 140 (leronlimab)
350 mg 525 mg 700 mg
Parameter N=226 N=115 N=43 Total Number of Subjects with ≥1 AE 170 (75.2%) 65 (56.5%) 21 (48.8%)
Total Number of AEs 983 314 69
Definitely Related 42 ( 18.6%) 21 ( 18.3%) 5 ( 11.6%)
Probably Related 14 ( 6.2%) 0 ( 0.0%) 1 ( 2.3%)
Possibly Related 35 ( 15.5%) 2 ( 1.7%) 1 ( 2.3%)
Unlikely 22 ( 9.7%) 12 ( 10.4%) 7 ( 16.3%)
Unrelated 57 ( 25.2%) 30 ( 26.1%) 7 ( 16.3%) All percentages are based on the number of subjects in the treatment group (N).
A subject is counted only once within each category.
PRO 140 (leronlimab)
350 mg 525 mg 700 mg
Parameter N=226 N=115 N=43
Number of subjects with any reported SAE, n(%) 19 (8.4%) 4(3.5%) 2 (4.7%)
Incidence of all SAEs 23 5 2
All percentages are based on the number of subjects in the treatment group (N).
A subject is counted only once within each category.
PRO 140 (leronlimab)
350 mg 525 mg 700 mg
Parameter N=226 N=115 N=43 Total Number of Subjects with ≥ Injection Site Reaction
59 ( 26.1%) 19 ( 16.5%) 1 ( 2.3%)
Total Number of Injection Site
Reactions 164 78 1
All percentages are based on the number of subjects in the treatment group (N).
A subject is counted only once within each category.
Summary of AEs by Relationship Summary of Adverse Events (AEs) by Severity
Summary of Serious Adverse Events (SAEs) Injection Site Reactions (ISR)
Virologic failure is defined as two consecutive plasma HIV-1 RNA levels of ≥200 c/mL.
None of the reported SAEs were definitely or probably related to PRO 140 (leronlimab).
Overall, the majority of AEs were considered mild in nature and there were no patterns of drug-related toxicities observed.
Approximately 95% of injection site reactions were mild in intensity and considered to be self-resolving.
No dose-proportional increase in incidence and severity of AEs were reported with higher doses of PRO 140 (leronlimab).
Subjects who experienced virologic failure were able to achieve viral suppression upon re-initiation of baseline HAART regimens
without the loss of any treatment options.
No evidence of emergence of viral isolates with reduced susceptibility to PRO 140 (leronlimab) or altered viral tropism in subjects
experiencing virologic failure.
47.3%
65.4%
81.4%
73.0%
86.8% 88.6% 83.7%
100.0%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
12 Weeks 24 Weeks 48 Weeks
% S
ub
ject
s
Timepoint
Summary of Virologic Suppression (VL <50 c/mL)
350 mg
525 mg
700 mg
47.3%
22.6%
14.0%
30.8%
13.2%
0.0%
12.9%
6.8%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
350 mg 525 mg 700 mg
% S
ub
ject
s
Dose Group
Summary of Virologic Failure (Two consecutive VL>200 c/mL)
0-12 Weeks
12-24 Weeks
24-48 Weeks
Note: The PRO 140_CD03 study is currently ongoing. The baseline characteristics and results presented in
this poster are based on interim data as of 01 Jan 2019.
Group A (350 mg)
Note: 20 subjects were early terminated from the study.
3 subjects were randomized, not treated
Note: 7 subjects were early terminated from the study.
Note: 1 subject was early terminated from the study.
Group B (525 mg)
Group C (700 mg)
Virologic failure is defined as two consecutive plasma HIV-1 RNA levels of ≥200 c/mL.
Efficacy
Note: No enrolled subjects at 700mg dose have reached the 24 week time point as of 1 Jan 2019
47.3%
65.4%
81.4%
73.0%
86.8% 88.6% 83.7%
100.0%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
12 Weeks 24 Weeks 48 Weeks
% S
ub
ject
s
Timepoint
Summary of Virologic Suppression (VL <50 c/mL)
350 mg
525 mg
700 mg
47.3%
22.6%
14.0%
30.8%
13.2%
0.0%
12.9%
6.8%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
350 mg 525 mg 700 mg %
Su
bje
cts
Dose Group
Summary of Virologic Failure (Two consecutive VL>200 c/mL)
0-12 Weeks
12-24 Weeks
24-48 Weeks
Long-Acting Emtricitabine Prodrugs Provide Protection From HIV Infection In VivoPaul Curley1, James J Hobson2, Neill J Liptrott1, Amer Al-khouja3, David Meyers3, Caren L. Freel Meyers3, Charles Flexner4, Marco Siccardi1, Steve Rannard2
Larisa Poluektova5 and Andrew Owen1
1 Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool,, UK, 2 Department of Chemistry, University of Liverpool, Crown Street,, UK , 3 Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine,
Baltimore, MD, USA , 4 Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, MD, USA , 5 Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Centre, Omaha, NE, USA
Poster Number: 2262 Contact: [email protected]
Funded by National Institutes of Health - 1R01AI114405-01
• Antiretroviral drugs are predominantly administered orally for both
therapy and pre-exposure prophylaxis (PrEP).
• Despite ease of administration, oral delivery is prone to patient non-
adherence exacerbated for some drugs by pill fatigue and
gastrointestinal intolerance (1).• By decreasing frequency of administration, long-acting injectables
(LAIs) may offer an effective strategy to circumvent these issues (2).• We report here a preclinical assessment of LAI semi-solid prodrug
nanoparticle (SSPN) formulations of novel emtricitabine (FTC)
prodrugs to prevent HIV infection.
Background• SSPNs of FTC carbamate/carbonate prodrugs were generated using a proprietary
emulsion-templated freeze-drying technology.
• 2 lead formulations were tested for their ability to prevent HIV infection in NSG-
cmah-/- mice humanised by CD34+ cell transplantation.
• Animals received 140 mg/kg FTC equivalent (SSPN 9 or 10) via 2 intramuscular
injections vs an untreated control (n= 7-6 per group).
• At days 7 and 14 mice were challenged intraperitoneally with a 103 TCID50 dose of
HIVADA.
• Animals were sacrificed at 28 days post infection.
• Plasma samples were taken for determination of viral load (VL). Tissue samples were
collected for viral RNA and proteins detection via RT-PCR and immunohistology.
Methods
Conclusions
Results • Mice treated with SSPN 9 and 10 demonstrated undetectable VL
(700 copies/mL detection limit), and HIV RNA remained
undetectable 28 days post infection in plasma, spleen, lung and
liver in all animals for the 7 day challenge.
• Following 14-day challenge, mice treated with SSPN 9
demonstrated undetectable HIV in plasma and all tissues.
• Mice treated with SSPN 10 demonstrated 2 mice had detectable
plasma VL (4.77 x 103 copies/mL) and 3 mice showed presence
of HIV RNA in plasma and proteins in spleen, lung and liver in
day 28.
• HIV was detectable in all untreated animals.
• The data presented here demonstrate both
formulations were 100% effective at
preventing HIV infection 7 days post LAI
administration.
• Following 14 days, SSPN 9 prevented HIV
infection in 100% of mice while SSPN 10
prevented infection in 50% of mice.
• These data indicate great potential for
delivering FTC via LAI and the approach
may support LAI development for PrEP.
• Further studies will aim to optimise
formulations to produce exposure beyond 14
days and to assess applications in therapy as
part of a combination.
References(1) Curley et al, Advances in nanomedicine drug delivery applications for HIV therapy, Future Science OA, 2017(2) Owen A & Rannard S, Strengths, weaknesses, opportunitiesand challenges for long acting injectable therapies: Insights forapplications in HIV therapy, Advanced Drug Delivery Reviews,2016
Figure 1 shows the experimental design used to investigate the potential for LAI SSPN formulations to prevent HIV infection
Co
nt r
ol
SS
PN
9
SS
PN
10
0
1 0
2 0
3 0
4 0
S p l e e n
C o n d i t i o n
Av
er
ag
e C
t v
alu
e
Co
nt r
ol
SS
PN
9
SS
PN
10
0
1 0
2 0
3 0
4 0
L u n g
C o n d i t io n
Av
er
ag
e C
t v
alu
e
Co
nt r
ol
SS
PN
9
SS
PN
10
0
1 0
2 0
3 0
4 0
L i v e r
C o n d i t i o n
Av
er
ag
e C
t v
alu
e
14 Day Challenge
Co
nt r
ol
SS
PN
9
SS
PN
10
0
1 0
2 0
3 0
4 0
S p l e e n
C o n d i t i o n
Av
er
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t v
alu
e
Co
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ol
SS
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9
SS
PN
10
0
1 0
2 0
3 0
4 0
L u n g
C o n d i t i o n
Av
er
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e C
t v
alu
e
Co
nt r
ol
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PN
9
SS
PN
10
0
1 0
2 0
3 0
4 0
L i v e r
C o n d i t i o n
Av
er
ag
e C
t v
alu
e
7 Day Challenge
Control SSPN 9
Figure 3 plasma viral load at 7 and 14 days post IM injection.Plasma samples were taken 14 days and 28 days post HIVinfection.
Figure 4 Characterisation of human PBMCs by flow cytometry. Blood samples were collectedat point of termination and stained for expression of CD45 mononuclear cells and CD3 T Cells.T cells were also stained for CD4 and CD8 expression assessed.
Figure 5 shows detection of HIV-1 Gag-p24 rna via PCR in humanised mice following HIV infection 7 and 14days post IM injection. Tissue samples from spleen, lung and liver were taken 28 days post HIV infection.
Figure 6 Representativehistopathology samplestaken from spleen, liverand lung tissues 7 dayspost IM injection from theA) control group and B)SSPN 9 treated group.Tissue samples werecollected 28 days postHIV infection. Sampleswere stained for HLA- DRand Gag-p24 6A highlightGag-p24 positive stainingin the control group(brown). No Gag-p24 wasdetected in the SSPN 9treated group.
A B
0 2 0 0 4 0 0 6 0 0 8 0 0
1
1 0
1 0 0
1 0 0 0
T i m e ( h o u r s )
FT
C P
las
ma
co
nc
en
tr
atio
n (
ng
/mL
)
Figure 2 PK profile of the SSPN 9 over 28 days following2 intra-muscular injections (1 injection in each leg, 70mg/kg mg/kg based on FTC content). PK was examinedin BALB/c mice in order to inform PD studies.
SSPN 9 Plasma Concentrations
HLA-DR HIV-1 p24 HLA-DR HIV-1 p24
U n t r e a t e d S D N 9 S D N 1 0
0
5 1 05
1 1 06
1 . 5 1 06
C o n d i t i o n
Pla
sm
a V
ira
l L
oa
d (
co
pie
s/m
L)
U n t r e a t e d S S P N 9 S S P N 1 0
0
2 1 05
4 1 05
6 1 05
8 1 05
C o n d i t i o n
Pa
sm
a V
ira
l L
oa
d (
co
pie
s/m
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7 Day Challenge
14 days post infection 28 days post infection
U n t r e a t e d S D N 9 S D N 1 0
0
2 1 05
4 1 05
6 1 05
C o n d i t i o n
Pla
sm
a V
ir
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d (
co
pie
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U n t r e a t e d S D N 9 S D N 1 0
0
1 1 06
2 1 06
3 1 06
4 1 06
5 1 06
C o n d i t i o n
Pa
sm
a V
ira
l L
oa
d (
co
pie
s/m
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7 Day Challenge
Co
nt r
ol
SS
PN
9
SS
PN
10
0
2 0
4 0
6 0
8 0
1 0 0
C D 4 5 +
C o n d i t i o n
Fr
eq
ue
nc
y (
%)
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nt r
ol
SS
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9
SS
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10
0
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Fr
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y (
%)
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%)
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y (%
)
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SS
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9
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10
0
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C o n d i t i o n
Fr
eq
ue
nc
y (
%)
14 Day Challenge
1.5x106
1x106
5x105
0
6x105
4x105
2x105
0
8x105
6x105
4x105
2x105
0
5x106
4x106
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0 Pla
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d (
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pie
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Pla
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Cost-effectiveness of Long-Acting ART for Adolescents and Young Adults in Kenya
Jessica Culhane1, Monisha Sharma1, Kate Wilson1, D. Allen Roberts1, Cyrus Mugo2, Dalton Wamalwa2, Irene Inwani2, Ruanne Barnabas1, Pamela Kohler1 1University of Washington, 2University of Nairobi/Kenyatta National Hospital
RESULTS
• We project an LA-ART intervention for Kenyan AYA would prevent 9,800-40,500 new HIV infections in the overall population over ten years, along with 4,500-20,500 deaths averted
• The maximum incremental cost of LA-ART administration to remain cost-effective is between $18-$231 USD depending on uptake/adherence scenario and cost-effectiveness threshold ($500/DALY averted or Kenya’s GDP ($1,508) / DALY averted)
CONCLUSIONS
• Providing LA-ART to AYA in Kenya has the potential to avert thousands of HIV infections and save thousands of lives through increased treatment adherence.
• For LA-ART to be cost-effective in this population, it needs to be low-cost.
• Results were sensitive to the rate of viral suppression under LA-ART
#1076
Figure 1. Model transition diagram: Schematic of HIV natural history progression by CD4 count, viral load, and ART use.
Table 1: Modeled scenarios
2017 2029
Proportion of HIV-positive Kenyans on ART 75% 81%a
Adherence Scenario
Base High Medium Low Variable
Proportion of AYA on ART
who switch to LA-ARTb0% 85% 85% 85%
Varies by
agec
Viral suppression of AYA
on LA-ARTd n/a 94% 85% 75%e 94%
Overall (oral and long-
acting) viral suppression of
AYA ART users
75% 91% 83% 79% 90%
a Assumes UNAIDS target of 90% aware of status, 90% on ART is reached by 2029.
b 85% of AYA on ART switching to LA-ART based on LA-ART interest surveys in U.S.6,7
c 95% of AYA who are not virally suppressed under oral ART and 75% who are suppressed under oral ART
d 94% viral suppression based on LATTE-2 phase 2 trial3e Assumes non-adherent LA-ART users receive one injection per year
OBJECTIVES
BACKGROUND
• Adolescents and young adults (AYA) ages 10–24 years in sub-Saharan Africa (SSA) are disproportionately affected by HIV1
• Despite high efficacy of oral ART, viral suppression among AYA living with HIV in SSA remains low2
• Long-acting ART (LA-ART) may simplify adherence and consequently decrease transmission, morbidity, and mortality in this priority population
• In a phase II trial, injectable LA-ART with 8-week duration resulted in 94% viral suppression at 96 weeks; HIV patients have shown high interest in LA-ART3
• LA-ART will likely cost more to administer than oral ART ($147/person on ART in Kenya4,5), and the cost needs to be balanced with the health benefits
• Adapted a compartmental mathematical model from a previously published HIV model, with new AYA age-specific parameters
• Simulated HIV acquisition, transmission, natural history, and viral suppression, calibrated to HIV prevalence in Kenya
• Model stratified by age, sex, sexual activity (low, medium, high), circumcision status, and ART use
• Modeled four LA-ART adherence scenarios (Table 1).
• Assessed population-level effects of LA-ART over a 10-year time horizon and calculated the maximum incremental cost of LA-ART at which it would be considered cost-effective compared to oral ART
• Project health benefits of providing LA-ART to AYA currently on oral ART in Kenya
• Determine the maximum cost at which LA-ART will remain cost-effective in Kenya
METHODS
Figure 2. Model Calibration: Comparison of modeled age-specific HIV prevalence to the observed 2012 Kenya AIDS Indicator Survey prevalence
$82
$229
$42
$121
$18 $50
$83
$231
$500 ICER KENYA GDP ($1,508) ICER
High Medium Low Variable
40,540
20,480 17,804 11,061 9,836
4,488
38,251
19,504
HIV INFECTIONS AVERTED DEATHS AVERTED
High Medium Low Variable
Funding: National Institutes of Health R01HD08507 (PI: Kohler)
Figure 3. Proportion of HIV-positive AYA who are on ART and virally suppressed under each model scenario
Figure 4. Cumulative HIV infections and deaths averted over 10-year projection by model scenario
Figure 5. Maximum incremental cost of LA-ART in order to be cost-effective by model scenario and ICER threshold ($500 and 1,508/DALY averted)
References: 1 UNAIDS 2018, 2Adejumo 2015, 3Margolis 2017, 4Eaton 2014, 5CHAI 2018, 6Williams 2013, 7Weld 2018
LIMITATIONS
• Model results are specific to Kenya, but we expect our qualitative findings to apply to other settings in SSA with generalized HIV epidemics
• Increases in drug resistance due to non-adherence to LA-ART would decrease health benefits and should be evaluated in future analyses
CONCLUSIONI
• LA CABO + RPV associati a una
elevata efficacia (rarissima
selezione di RAMs), ottima
tollerabilità e una netta
preferenza da parte dei
pazienti arruolati
• Cambierà l’approccio alla
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