1. Monotherapy or Dual Therapy in Switch Studies: Which is the Best Regimen?
Dr. Jose R Arribas
@jrarribas

2. Conflict of Interest Speaker’s Bureau, Member/Advisory Panel
Only triple*
Triple and Dual
Triple, Dual and Mono
Gilead
ViiV
Janssen
MSD
*so far
Monotherapy or Dual Therapy

3. Monotherapy or Dual Therapy or Triple Therapy in Switch Studies: Which is the Best Regimen?
Dr. Jose R Arribas
@jrarribas

4. HOW TO EVALUATE AN ART REGIMEN? GUIDANCE FOR INDUSTRY
The goal of antiretroviral treatment is to indefinitely maintain suppression of plasma HIV- ribonucleic acid (RNA) levels (also called viral load) below the level of detection of sensitive HIV-RNA assays
ALL ABOUT VIRAL LOAD
Sourhttps://
Monotherapy or Dual Therapy

5. Monotherapy or Dual Therapy
REDUCED DRUG REGIMENS REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen)
DRV/r vs DRV/r + 2NRTis
(PROTEA)
-8.7%
PI MONOTHERAPY
bPI vs 2 NRTIs + 3rd drug
(PIVOT)
-1.4%* … … …
2015
2005
2008
2010
2014
2016
LPV/r vs
LPV/r + 2 NRTIs
(OK Pilot)
LPV/r vs
LPV/r + 2 NRTIs
(OK 04)
-5.7%
DRV/r vs
DRV/r + 2NRTis (MONET)
-1.6%
ATV/r vs
ATV/r + 2 NRTIs (MODAT)
-12%
bPI monotherapy
*(loss of future treatment options)
Source: Arribas JR et al. JAIDS 2009; 51:147–152. Pulido F et al. AIDS 2008; 22:F1–9. Arribas JR et al. AIDS 2010; 24:223–230. Castagna A et al. AIDS 2014; 28:2269–2279. Antinori A et al. AIDS 2015; 29:1811–1820. Paton NI et al. The Lancet HIV 2015; 2:e417–26
Monotherapy or Dual Therapy

6. Monotherapy or Dual Therapy
REDUCED DRUG REGIMENS REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen)
DUAL THERAPY
PI + MVC
PI + ISTI … … …
2015
2005
2008
2010
2014
2016
bPI+CCR5I
bPI + MVC vs
bPI + 2NRTIs
(MARCH)
-17.4% ↑R
ATV/r + RAL vs ATV/r + TDF/FTC
(HARNESS)
-17.1% ↑R
bPI+ISTI
Source: van Lunzen et al. J Acquir Immune Defic Syndr 2016; 71:538–543. Pett SL et al. Clin Infect Dis 2016; 63:122–132.
Monotherapy or Dual Therapy

7. Monotherapy or Dual Therapy
REDUCED DRUG REGIMENS REGIMENS IN SUPPRESSED Difference in % without primary endpoint (reduced regimen minus triple regimen)
ATV/r + 3TC vs
ATV/r + 2 NRTIs
(SALT, ATLAS)
+1%, +9.8%
DUAL THERAPY
PI + 3TC
LPV/r + 3TC vs
LPV/r + 2NRTIs
(OLE)
+1%
2015
2016
DRV/r + 3TC Vs
DRV/r + 2NRTIs (DUAL)
-4%
bPI+ 3TC (1051 patients in 4 RCT)
Source: Di Giambenedetto et al. J Antimicrob Chemother Jan 15. pii: dkw557. doi: /jac/dkw557. Arribas JR, et al. The Lancet Infectious Diseases 2015;15(7):785–92. Pérez-Molina JA et al. The Lancet Infectious Diseases 2015; 15:775–784.Pulido F et al. HIV13, 2016 Glasgow, abstract O331
Monotherapy or Dual Therapy

8. DUAL THERAPY IN SWITCH STUDIES: FINDINGS
MCV or RAL cannot substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI.
3TC, can substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI
Monotherapy or Dual Therapy

9. DUAL THERAPY IN SWITCH STUDIES: FINDINGS
MCV or RAL cannot substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI.
3TC, can substitute 2 N(t)RTIs in suppressed patients treated with a boosted PI
After 30 years of ART we still don’t know why only certain drug combinations control viral replication in the majority patients
Monotherapy or Dual Therapy

10. 1 BLIP IN 12 YEARS ON PI MONOTHERAPY (2005-2017)
Monotherapy or Dual Therapy

11. ANTIRETROVIRAL DRUG HALF-LIFES
Monotherapy or Dual Therapy

12. SWORD-1 AND SWORD-2 PHASE III STUDY DESIGN
Screening
Early switch phase
Late switch phase
Continuation phase
1:1
VL <50 c/mL on INI, NNRTI, or PI + 2 NRTIs
DTG + RPV (N=513)
DTG + RPV
DTG + RPV
CAR (N=511)
Day 1
Week 52
Week 148
Inclusion criteria
On stable CAR >6 months before screening
1st or 2nd ART with no change in prior regimen due to VF
Confirmed HIV-1 RNA <50 c/mL during the 12 months before screening
HBV negative
Primary endpoint at 48 weeks: subjects with VL <50 c/mL
(ITT-E snapshot)a
Countries Argentina Australia Belgium Canada France Germany Italy Netherlands Russia Spain Taiwan United Kingdom
United States
a-8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studies
Source: Llibre et al. CROI 2017; Seattle, WA. Abstract 2421.
Monotherapy or Dual Therapy

13. SWORD: SNAPSHOT OUTCOMES AT WEEK 48. ITT-E (POOLED)
One subject on DTG + RPV meeting virologic withdrawal criteria had identified an NNRTI resistance–associated mutation (K101K/E) No INI resistance–associated mutations were identified
Source: Llibre JM CROI 2017 #44LB
Monotherapy or Dual Therapy

14. LATTE-2 Week 96 HIV-1 RNA <50 c/mL - ITT-ME (Snapshot)
Virologic outcomes
Treatment differences (95% CI)
Oral IM
Q8W IM
TRIPLE
DUAL
− 0.6
20.5
−8.4
14.4
Q4W IM
Source: Eron et al. IAS 2017 Paris, France. Abstract MOAX0205LB.
Monotherapy or Dual Therapy

15. No INSTI resistance in 3 pts with virologic failure
LAMIDOL INTERIM ANALYSIS: SWITCH TO DTG + 3TC EFFECTIVE IN MAINTAINING VIRAL SUPPRESSION
100
100
100
100 99 99 99 98 97
97% (101/104) pts maintained therapeutic success through 40 wks of dual therapy (study Wk 48)
No INSTI resistance in 3 pts with virologic failure
7 pts with serious AEs; only 2 related to dual therapy 80 60
Pts With HIV-1 RNA < 50 copies/mL (%) 40 20
110/110
104/104
104/ 104
103/ 104
103/ 104
103/ 104
n/N =
102/ 104
101/ 104
Wk: 8 12 16 24 32 40 48
Wks 0-8: pts on baseline 3-drug ART switched to DTG + 2 NRTIs
Wks 8-56: pts with HIV-1 RNA < 50 copies/mL switched to DTG + 3TC
Source: Joly V, et al. CROI Abstract 458.
Monotherapy or Dual Therapy

16. Monotherapy or Dual Therapy
DOLUTEGRAVIR MONOTHERAPY. HIGHER RISK OF VIROLOGICAL FAILURE AND RESISTANCE
DOMONO: 8/77 (10%) VF, 3 with ISTI resistance
REDOMO: 11/122 (9%) VF, 9 with ISTI resistance
Monotherapy or Dual Therapy

17. Monotherapy or Dual Therapy
MONOTHERAPY OR DUAL THERAPY IN SWITCH STUDIES: WHICH IS THE BEST REGIMEN?
Only two types of reduced drug regimes have matched the efficacy of 2NRTIs + 3rd drug in switch studies
bPI + 3TC (vs bPI + 2 NRTIs)
DTG + RPV
These regimens contain a reverse transcriptase inhibitor with a long half life
Confirmation pending: CAB LA & RPV LA, DTG-3TC
Monotherapy or Dual Therapy

18. DO WE NEED TRIPLE THERAPY FOR EVERYONE FOR LIFE?
MONOTHERAPY OR DUAL THERAPY IN SWITCH STUDIES: WHICH IS THE BEST REGIMEN?
Dual
DO WE NEED TRIPLE THERAPY FOR EVERYONE FOR LIFE?
Do we Need a Reverse Transcriptase Inhibitor with a Long Half-life for Everyone for Life?
Monotherapy or Dual Therapy

19. HOW TO EVALUATE AN ART REGIMEN?
Residual viremia
Persistent inflammation
Immunoactivation
Penetration in reservoirs
Toxicity
COST
ONLY VIRAL LOAD?
Monotherapy or Dual Therapy

20. Monotherapy or Dual Therapy
AKNOWLEDGMENTS
Babafemi Taiwo, Pedro Cahn, Federico Pulido, L Ciaffi, B.J.A. Rijnders, I.E.A. Wijting, José Luis Blanco, V Joly, E Martinez, JM Gatell. Jules Levin Joe Eron. José Luis Narro
PARTICIPANTS IN CLINICAL TRIALS
HIV Unit at La Paz Hospital
Monotherapy or Dual Therapy