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