EuResist Network HIV multidrug re sistanc e pathways in the E uRe - - PowerPoint PPT Presentation

EuResist Network

HIV multidrug re sistanc e pathways in the E uRe sist Inte grate d DataBase

Background on HIV MDR

• Small proportion of HIV patients

– Mostly but not exclusively generated during early ART era, e.g. suboptimal and sequential therapy – Poor adherence to ART often a key factor

• No consensus on MDR definition

– What level of resistance – How many inactive drug classes – How many inactive drugs within a class

• Challenging management

– Often receiving novel drugs as soon as available, sometimes using functional monotherapy – Treatment fatigue, comorbidities and drug-drug interactions may further complicate ART options – Not even considered in most guidelines

HIV MDR study aims

• Estimating the prevalence and trend over time
• f MDR as based on different definitions
• Identifying factors associated with

development of MDR

• Deriving successful treatment strategies in

MDR patients

HIV MDR virological ancillary study

• Investigating specific cases with unexpected

ART failure or unexpected ART success

– Unexpected with respect to what predicted by GSS – Subject to sample availability

• NGS testing for minority virus population
• Phenotypic testing of old and novel drugs
• Investigating the role of off-target regions, e.g. PPT for

IN resistance

HIV MDR study

Exploratory analysis

• 52,291 patients
• Stanford HIVdb v. 8.8 scoring

50 100 150 200 250 Number or patients At least high-level resistance for one drug in each of the four classes At least intermediate resistance for one drug in each of the four classes At least low-level resistance for one drug in each of the four classes

Indicators for definition of MDR

• Number of classes with at least one drug falling in intermediate

resistance

• Number of classes with at least one drug falling in full resistance
• A normalized score (0...1) indicating residual treatment options for

each of the 4 main classes

• A normalized global score (0...1) indicating global residual

treatment options derived from the scores of the individual classes

• Something more clinically relevant?

How to deal with missing sequences

• Integrase, gp41 or gp120 sequences not always

available for patients using INSTIs, T20, MVC

• T20 and MVC

– Full resistance if documented virological failure to the drug

• INSTI

– Full resistance to all INSTIs if documented virological failure to DTG/BIC – Full resistance to RAL/EVG and intermediate resistance to DTG/BIC if documented virological failure to RAL/EVG

How to compute MDR over time

• Analysis based on cumulative genotype
• MDR case assigned to the first year when

cumulative genotype (and failure data) meet the definition of MDR

• How to debias the denominator and derive

reliable estimates of prevalence and incidence

National registries

The PRESTIGIO registry in Italy

• Originally requested by the Italian drug agency (AIFA) to

monitor the safety of DTG 50mg BID

• Later expanded to include a large set of clinical and

virological data from patients with

– Documented resistance to NRTI, NNRTI, PI and – Documented resistance to INSTI or documented virological failure to INSTI in the absence of IN genotype information

• About 300 patients enrolled of the estimated 500-800 living

in Italy

• Very active group!
• Monthly TC
• Patient cases discussed on line
• Research studies already published and presented at CROI 2019 (BIC,

Fostemsavir)

• Ongoing studies on DOR and PRO-140



During a median follow-up of 17.5 (9.7-33.8) months in 191 patients, 62 treatment failures (TF) and 48 virological failure (VF) events occurred

• 27 (14%) pts discontinued DTG (10 VF, 9 clinical reasons,

4 deaths due to disease progression, 2 patient’s decision, 1 lost to follow-up, 1 adverse event)

Castagna, JAC 2017

TF – 47% at 48 months VF – 39% at 48 months

TMR RAMs (one S375N and two M426L) were detected in 3/23 samples and the polymorphic RAM M426L was associated with variable reduction of TMR susceptibility. Except for viruses harbouring M426L, the susceptibility to TMR was comparable to wild- type strains in all the samples, irrespective of coreceptor usage or exposure to other entry inhibitors.

24 patients enrolled in the PRESTIGIO cohort (4-class resistance, with INSTI resistance demonstrated by genotype

• r inferred from virological failure of INSTI regimen(s)

Saladini, CROI 2018

Santoro, CROI 2018



BIC retained activity against most isolates derived from patients harbouring a multi-drug resistant virus and who failed in their history INSTI regimens

• Reduced susceptibility to BIC and DTG was associated with presence of G140S + Q148H and often at least one another

substitution consisting of L74M, T97A, S119P/T, E138A/K, or Y143C/R/H and G163R in IN



These data support the study of BIC once daily in patients with INSTI-resistance