terapie dual: stato dell’arte, criticità e vantaggi
TRANSCRIPT
Diego Ripamonti
Malattie Infettive – ASST Papa Giovanni XXIII - Bergamo
.
Terapie dual: stato dell’arte, criticità e
vantaggi
24 SETTEMBRE 2018 - Milano
NOVITA’ NELLA PREVENZIONE E NELLA TERAPIA
DELL’INFEZIONE DA HIV
Ospedale L. Sacco-Polo Universitario - ASST FBF Sacco
EVOLVING TREATMENT PARADIGM
HAART
1996
PI-based
NNRTI-based
II-based
2NRTI
backbone
MODERN
study
NEAT
study
NRTI-sparing in naive
GEMINI
studies
Changing paradigm
Naive Switch strategies
Intensification (5 drugs) Intensification (4 drugs)
NRTI sparing monotherapy
Dual regimen Dual regimens
Rasmussen TA et al. Lancet HIV 2018;5:e221-e230.
DIORR study
The effect of antiretroviral intensification with DTG on residual virus replication in HIV-
infected individuals: a randomised, placebo-controlled, double-blind trial.
56 days
HAART* > 3 ys
VL: < 20 c/ml
HAART + DTG
HAART + placebo
2-LTR circles
Unspliced HIV RNA
HIV DNA (single copy)
T-cell activation markers
sCD14, d-Dimer, IL-6, hs-CRP
«not supporting ongoing residual viral
replication in blood»
No difference! Hatano et al. JID 2011(+RAL)
19 pts
21 pts* on PI=12%
Intensification: 4-drug regimens
Intensive five-drug antiretroviral therapy regimen versus
standard triple-drug therapy during primary HIV-1 infection
(OPTIPRIM-ANRS 147):
The primary endpoint was the median number of HIV-DNA copies per 10⁶ peripheral blood
mononuclear cells (PBMC) at month 24 (ITT analysis)
5-drug regimen in acute infection
Cheret A et al. Lancet Infect Dis. 2015;15:387-96
ACUTE INFECTIONDRV/r TDF/FTC RAL MRV
DRV/r TDF/FTC
24 weeks
45 pts
45 pts
No difference in HIV DNA load at month 24 between intensified
and standard HAART
Dual vs triple
TDF, TAF or nothing?
Dual or triple: that is the question
Dual versus TAF
Dual versus Triple
Why a dual regimen?
When a dual or triple option?
What is a «standard regimen»?
What is needed to change a treatment paradigm?
Randomized trials
• How many studies?
• How large?
• Duration?
• Surrogate markers?
• Clinical end points?
Metanalysis of boosted PI + 3TC
4 trials: 1051 pts
new FDA cut-off = 4% margin of non-
inferiority
JA Perez-Molina et al. 16th EACS 2017. Abstract PS1/1
SWORD 1 and 2 studies
- Food & antacids for RPV-based regimens
- Defined history before switching to RPVLlibre JM et al. Lancet 2018;391:839-849
SWORD 1 and 2: snapshot analysis at week 48 (Pooled data)
Llibre JM et al. Lancet 2018;391:839-849
Llibre JM et al. Lancet 2018;391:839-849
Response rate at week 48 by subgroupsITT analysis
SWORD 1-2: 96-week data
Aboud M et al. AIDS 2018. Abs THPEB047. Llibre JM et al. Lancet. 2018;391:839-849.
10/990 (1%) confirmed virologic withdrawals through week 100
(NNRTI resistance in 3/10, all from early switch arm).
8993
0
20
40
60
80
100
HIV RNA < 50 c/ml (Snapshot), week 100
Early Late
No changes in lipid levels (total cholesterol, LDL-C, HDL-C, triglycerides, tot cholesterol:HDL-C ratio) or atherogenesis and inflammation biomarkers at week 100 vs baseline in either group.
Early switch group maintained improvements in markers of renal tubular
function (urine RBP/creatinine ratio, urine β2-M/creatinine ratio)
from baseline to wk 48 and wk 100.
CD4 count increase in DUAL vs TRIPLE regimens
-40
-20
0
20
40
60
80
OLE SALT ATLAS-M DUAL SWORD 1-2
Dual
Triple
Arribas JR et al. Lancet ID 2015; Perez-Molina JA et al. Lancet ID 2015; Di Giambenedetto S et al. JAC 2017
Pulido F. et al. CID 2017;65:2112-2118; Llibre JM et al. Lancet 2018;391:839-849
week 48 data
Switch studies
ns
ns
nsns
ns
Which benefit from switching to a dual regimen?
ATLAS M study (96 weeks, dual versus triple)
- eGFR (+5 vs. –3 mL/min/1.73 m2, p<0.001)
- total cholesterol (+15 vs. 0 mg/dL, p=0.005 )
- grade 3/4 hyperTG (7.6% vs 1.6%, p=0.027) but HDL (+5 vs 0 mg/dL, p=0.002).
- hyperbilirubinemia: (59.6% vs 35.8%, p=0.001)
- Better BMD (week-48 data)
DUAL study (48 weeks, dual versus triple)
- no significant improvement in kidney function
- no improvement in Col tot/HDL ratio
- no difference in drug discontinuation for AEs
SALT study (96 weeks, dual versus triple)
- eGFR, bone density, fat distribution: same
- TG: +12.1 vs -6.2 %, cholest: +5.1 vs -1.9, Chol/HDL ratio: -2.6 vs -3.7 (for all p < .001)
- grade 3/4 toxicity: 70.7 vs 70.2 %, same
- neurocognitive study: same
- treatment discontinuation: 5.0% vs 7.1 % same
1. Arribas JR et al. Lancet ID 2015 2. Perez-Molina JA et al. Lancet ID 2015 3. Di Giambenedetto S et al. JAC 2017
SWORD studies: Changes in Serum Lipids and Bone Markers at Week 48
• *Adjusted for baseline third agent, age, sex, body mass index, smoking status, and baseline biomarker level. Statistical model uses log-transformed data.
DTG/RPV CARBaseline Week 48 Baseline Week 48
Serum Lipids Bone Markers
Switching to DTG + RPV had a neutral effect on lipids while significantly improving bone turnover
biomarkers
Llibre et al. CROI 2017; Seattle #O44LB
From PI/r: 26% (most common: DRV)
From INSTI: 20% (most common: RAL)
From NNRTI: 54% (most common: EFV)
On TDF at baseline: 70-73%
DUAL vs TRIPLE regimens in naive patients?
a−10% noninferiority margin for individual studies.
GEMINI-1 and -2 Phase III Study Design
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
Baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL) CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).
DTG + 3TC (N=716)
Day
1
Screening
(28 d)
Identically designed, randomized, double-blind, parallel-group,
multicenter, noninferiority studies
DTG + TDF/FTC (N=717)
DTG + 3TC
Week
48
Primary endpoint
at Week 48:
participants with
HIV-1 RNA <50 c/mL
(ITT-E snapshot)a
Double-blind
phase
Open-label
phase
Continuation
phase
CountriesArgentina Australia Belgium
Canada France Germany
Italy Republic of Korea Mexico
Netherlands Peru Poland
Portugal Romania Russian Federation
South Africa Spain Switzerland
Taiwan United Kingdom United States
Week
144
Week
24
Week
96
• ART-naive adults
• VL 1000-500,000 c/mL
1:1
Eligibility criteria• ≤10 days of prior ART
• No evidence of pre-existing viral
resistance based on presence of any
major resistance-associated mutation
• No HBV infection or need for HCV
therapy
DTG + 3TC (n = 716)
DTG + TDF/FTC (n = 717)
Virologic
Success
Virologic
Nonresponse
No Virologic Data
HIV
-1 R
NA
< 5
0 c
op
ies
/mL
(%
)
ITT-E
100
80
60
40
20
0
91 93
3 26 5
Treatment Difference
ITT-E: -1.7% (95% CI: -4.4% to 1.1%)
PP : -1.3% (95% CI: -3.9% to 1.2%)
Gemini 1- 2: naive pts, week 48
No treatment-emergent mutations
Bone and kidney safety markers
better for DTG+3TC
Similar CD4 count increase
Metabolic????????
Cahn P et al. AIDS 2018. Abstract TUAB0106LB.
HIV RNA < 500.000 c/ml: all
HIV RNA > 105 c/ml: 20 %
No HBV coinfection
CD4 < 200 cells: 10%
Baseline characteristics
48 week-data
Switch if no resistance to study drugs!
Not all the dual combinations are effective (see DRV/r + MRV or ATV/r + RAL)
Boosted PI + 3TC: 4 trials, 1051 pts (mostly from PI-based rx)
DTG+ RPV: 2 trials, 1024 pts (from cARV, all switch to a new regimen)
Is the «RT inhibition» mandatory for a dual rx ?
The right time of switching ?
Are «48-week data» a too short follow-up?
Are there any other risk in dual options??
Critical reading of dual regimen studies
Future dual options in switch strategy?
DRV/c + RPV25mg
DRV/r + DTG50 mg
DTG50 mg + 3TC300 mg Studio TANGO (440 pts on TAF)
Studio DUALIS (320 pts)
Studio PROBE2 (160 pts)
Braccio sperimentale Studi di switch
Cabotegravir plus RPV (long acting formulation)
Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial
Margolis DA et al. Lancet HIV 2017; sept
What for whom: where evidence is
Maintenance strategies
Naive patients
Highly viremic
Acute infection
Advanced patients
HBV coinfection
Non adherent
HIV encephalopathy
Pregnancy
Triple HAART Dual Regimen
Maintenance strategies
No HBV coinfection
Naive patients
(< 500.000 c/ml, CD4 > 200 cells)?
The new standard?
Why the third drug may be necessary?
Proven benefits Theoretical advantages
over time
1. 22 years of HAART efficacy
2. Success driven by the 3-drug
regimens
3 agents are better than 2:
• in controlling the replication
• in all compartments
• in blocking escapesModern regimens:
a. More potent
b. Low risk of resistance
c. Better tolerability (PI)
d. Lower toxicity (TAF)
e. Coformulation (1 pill)
Grazie
Efficacy and tolerability of DTG+3TC as a switch strategy in a
multicentre cohort of patients with suppressed HIV‐1 replication
Borghetti A et al HIV Medicine 2018
Significant improvement in immunological function: CD4 e CD4/CD8
Number: 206 patients
Switch strategy
- simplification: (32.5%)
- toxicity: (54.5%)
98 95
0
20
40
60
80
100
48 wks 96 wks
HIV RNA < 50 copie
McManus WR al. CROI 2018. Oral Abs 70
Time for a paradigm shift
No evidence of ongoing HIV replication in lymph nodes during suppressive HAART