Dr. Luis Enrique Soto RamírezMEXICO

Transmitted and Acquired HIV Drug Resistance in

Latin America

Disclosure

Advisory boards and speaker for:

Abbvie

GSK/ViiV

MSD

Roche Diagnostics

OVERVIEW

The development and transmission of drug-resistant HIV variants continues to limit the efficacy of treatments for HIV infection.

Transmitted drug resistance may jeopardize the goals of early antiretroviral treatment among acute/recent HIV infected patients.

Secondary resistance after one or more treatment failures compromise the success of ART due to cross-resistance, decreasing treatment options and life expectancy

Factors related to high ARV resistance in Latin America

1.- Limited-access to monitoring tests- Viral load not available in all settings- No resistance assays before treatment and

sometimes not even after ART failure2.- Low frequency or absent follow-up after treatment

initiation or modification3.- Limited number of ARV drugs4.- Inadequate treatment combinations5.- Poor adherence6.- Many socioeconomic barriers7.- Elevated prevalence of coinfections (mainly Tuberculosis)

TRANSMITTED ARV DRUG RESISTANCE (TDR) IN

LATIN AMERICA

• Not representative of the complete population• Convenience sampling• Very limited sample size (more than half < 47)• Use of different survey populations

• Many in about to start treatment patients but not with recent infection• 90% No data on time of infection

• Limited repeated surveillance

Many local (in-country) and regional surveys

• IAS, Stanford DB and CPR, WHO, ANRS

Different interpretation algorithms

Limited effect on local or regional guidelines or policies

Overview TDR in Latin America

TDR prevalence in Latin America and the Caribbean

Ninety-eight studies published between January

2000 and June 2015

Brazil (50), Mesoamerica (17), Southern

Cone (16), Andean (8) and Caribbean (7).

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

TDR in Different regions of Latin America, 2000-2015

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

Change in prevalence of DRM in TDR in Brazil, 2000-2005 vs 2006-2015

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

Subtype distribution

in Brazil

This review and meta- analysis provides a moderate level, with a significant temporal increase in NNRTI TDR, consistent with the

dominant use of EFV-containing first-line ART regimens in the region based on current WHO

recommendations.

PLOS ONE | DOI:10.1371/journal.pone.0158560 June 29, 2016

TDR in MEXICO

Study type INCMNSZ1 INER2

Recent Dx Some Some

n 543 1655

Time frame 2004-2005 2007-2010

States n/31 9 12

Overall Prevalence 10.2% 6.8%

NRTIs 6.8% 4.2%

NNRTIs 3.1% 1.9%

PIs 2.2% 1.8%1.- Clin Infect Dis 2012:54(S4):328-33. 2.- PLoS One. 2011; 6(11): e27812

First studies of TDR in MEXICO

TDR in MEXICO 2015

Lancet HIV. 2016 Dec;3(12):e579-e591. doi: 10.1016/S2352-3018(16)30119-9. Epub 2016 Sep 14.

Lessons Learned from Survey Implementation

• Have Mexican National Guidelines changed due to

these findings?:

– EFV continue as preferred 1st line regimen

– DR testing is not performed in all starters

– Use of HIVDR is not widespread for continuing

routine surveillance

Only If costs change, integrase inhibitors might

become the preferred 1st line option

Patients with acute/recent HIV infection who

underwent resistance test before antiretroviral treatment initiation

Transmitted drug resistance was identified according to the Stanford

HIV Database

Comparison between patients with and without

transmitted drug resistance

Instituto Nacional de Infectologia Evandro Chagas, Fundac¸ Oswaldo Cruz, Rio de Janeiro, Brazil. 10 October 2016, Transmitted drug resistance in patients withacute/recent HIV infection in Brazil

POPULATION DISTRIBUTION

Instituto Nacional de Infectologia Evandro Chagas, Fundac¸ Oswaldo Cruz, Rio de Janeiro, Brazil. 10 October 2016, Transmitted drug resistance in patients withacute/recent HIV infection in Brazil

Instituto Nacional de Infectologia Evandro Chagas, Fundac¸ Oswaldo Cruz, Rio de Janeiro, Brazil. 10 October 2016, Transmitted drug resistance in patients withacute/recent HIV infection in Brazil

SECONDARY ARV DRUG RESISTANCE (SDR)

IN Latin America

• Not representative of the complete population• Convenience sampling• Use of different survey populations

• 1st failure (most), 2nd failure or more• No data on time on failure

• Not comparable data

Mostly local (in-center) surveys

• IAS, Stanford DB, ANRS

Different interpretation algorithms

Limited effect on local or regional guidelines or policies

Overview SDR in Latin America

Undetectable Viral Load According to Age

Resistance to different antiretroviral classes and number of class resistances

Use of resistancetesting in 3 class-

resistance salvagein Mexico

Multidrug failure with resistance to 3 classes.

• Use at least two, preferentially

three completely active ARV drugs.

Virological and Immunological response at w 24 and 48 according to basal viral load

Baseline viral loadCD4 cell count change from baseline count

3 FAA <3 FAA p

At week 24 (n=175) 63.8 (±212.6) 77.8 (±220.7) 0.67

At week 48(n=151) 218.5 (±209.5) 208.7 (±207.4) 0.87

At week 24 (n=65) 215.9 (±223.1) 190.5 (±235.4) 0.66

At week 48 (n=53) 131.0 (±227.7) 127.9 (±248.9) 0.94

Viral load < 100.000 copies per ml (n=228)

Viral load ≥ 100.000 copies per ml (n=85)

Difference between means (IC95%)-14.0 (-79.4-51.4)

9.9 (-105.6-125.3)

25.4 (-89.8-140.6)

3.1 (-75.3-81.5)

Baseline viral load Virological suppression 3 FAA <3 FAA p

At week 24 (n=181) 65/79 (82.3%) 86/102 (84.3%) 0.87

At week 48 (n=165) 64/70 (91.4%) 85/95 (89.5%) 0.88

At week 24 meses (n=65) 20/28 (71.4%) 27/37 (73.0%) 1

At week 48 (n=57) 20/25 (80.0%) 27/32 (84.4%) 0.94

RR (IC95%)

0.94 (0.65-1.35)

1.1 (0.73-1.64)

Viral load < 100.000 copies per ml (n=228)

0.97 (0.60-1.56)

0.87 (0.45-1.70)

Viral load ≥ 100.000 copies per ml (n=85)

International Workshop on Antiviral Drug Resistance, Berlin 2014. Abstract 62

International Workshop on Antiviral Drug Resistance, Berlin 2014. Abstract 62

Cumulative incidence of virologic failure according to GSS n=568

Relativerisk

pvalue

Cum

mul

ativ

epr

obab

ility

of v

irolo

gic

failu

re

Time since salvage ART startGSS and n patients 12 months 24 months 36 months 48 months

CORESAR OFID 2014

Secondary resistance to Integrase Inhibitors

in Mexico

VIKING-3: STUDY DESIGN (N=183)

VIKING 3: VIROLOGIC RESPONSE AT WEEK 24 ACCORDING TO INSTI-DRM

Day 8 response 1 Response week 241

INSTI DRM N HIV-1 ARN mean decrease

(log10 c/ml)

Complete response a

N(%)

N < 50 c/ml, N (%)

No Q148 122 -1.65 122 (92%) 72 57 (79%)

Q148+1b 35 -1.10 25 (71%) 20 9 (45%)

Q148+≥2b 20 -0.74 9 (45%) 9 1 (11%)

aRespuesta completa: disminución del ARN VIH-1 1 log10 c/ml o 50 c/ml al día 8. bL74I, E138A/K/T y G140A/C/S

Adaptado de Vavro C, et al. IDRW 2013. Abstract 29

Cross-resistance to integrase strand transfer inhibitors (INSTIs) in 23 multiexperienced

Mexican patients failing to raltegravir

Orta-Reséndiz A1, Rodríguez-Díaz RA1, Hernández-Flores M1, Angulo-Medina Luis2, Calva-Mercado JJ1, Ramirez JP1, Soto-Ramírez LE1.

July 16, 2016. Durban, South AfricaAbst#_O_05

1Laboratorio de Virología Molecular, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”,Mexico City, Mexico, 2Complejo Hemato Oncológico y Radiocirugía/Instituto Venezolano de los SegurosSociales IVSS, Caracas, Venezuela.

Methods

• Retrospective data and plasma samples from 23 multiexperienced patients failing to RAL from 2009 to 2016.

• Plasma viral load, COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, v2.0.

• Amplification and Sanger sequencing (PR-RT-IN):

– ViroSeq HIV-1 Integrase Genotyping Kit.

– Integrase home-made technique.

Molecular Virology LaboratoryInfectious Diseases Department

v7.0 v9.1.0

Study population

n=25(%)

Gender Male 80HIV-1 Subtype B 100

HIV-1 RNA VL Log10 c/mL (Mean, SD) 4.17 (1.11)CD4+ T-Cell count Cells/mm3 (Mean, SD) 328.5 (217.07)

Time on RAL prior failure Months (Mean, SD) 22.33 (20.38)

Optimized backbone regimen

NRTIs 29.41NRTI(s) + PI 29.41NNRTIs + PI 17.65

NRTIs + NNRTI 5.88Other* 17.65

Time on ART Years (Mean, SD) 10.65 (5.7)

Total prior ART regimens Combinations (Mean, SD) 5.31 (3.13)

ARV drugs used with RAL

OBR (n=15) n (%)NRTIs 5 (33.3)NRTIs+PIs 4 (26.7)NNRTIs+PIs 2 (13.3)NRTIs+NNRTIs 1 (6.7)Other 3 (20)

In all cases RAL containing regimens were third or more advanced line of

treatment.

TDF was the most common companion to RAL.

INSTIs DRMs in RAL failing patients(N=13)

n = 13

Major Accessory MutationsMajor Primary Mutations

30,4

21,7

13,0

8,7

17,4 17,4

13,0

8,7 8,7

4,3 4,3

0,0

5,0

10,0

15,0

20,0

25,0

30,0

35,0

Freq

uenc

y(%

)

Primary RAMSs distribution

DRM decreasing response to DolutegravirA Comparison with VIKING-3

RAMs combinations after RAL use

Prevalence (%)

VIKING-3 [20]

This study

No INSTIs mutations 33 40

No Q148* 36 48

Q148+1 secondary mutation 20 8

Q148+≥2 secondary mutations 11 4

Conclusions• Despite a decrease in developed countries, TDR is still

increasing in Latin America, specially to NNRTIs• Many of our countries have no access to genotype. This would increase

secondary resistance• The prevalence detected should favored the use of other ARV options• No action has been taken with these results

• Secondary resistance is widespread in Latin America due to poor adherence and repeated failure.• Information should be analyzed in specific situations• Salvage treatment with at least 2 active drugs seems to be enough to

rescue 3 class resistance failures• Resistance to RAL is still limited and guarantee sequencing with DTG