Dr. Luis Enrique Soto Ramírez MEXICO Transmitted and Acquired HIV Drug Resistance in Latin America
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