Clinical case of transmitted resistance to HIV Integrase

Inhibitors

González-Domenech CM1, Viciana I1,2, Jarilla F3, Palacios R1,2,

Roldán J3, Santos J1,2

1Biomedical Research Institute of Malaga (IBIMA), Málaga, Spain; 2Infectious Diseases and Clinical

Microbiology Unit, Virgen de la Victoria Hospital, Málaga, Spain; 3Service of Internal Medicine,

Antequera Local Hospital, Málaga, Spain

2nd Global HIV Clinical Forum on Integrase Inhibitors. 22nd July, 2017. Paris (France)

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Background

Recommendations about resistance of HIV-1 to antiretroviral drugs

Assessment of baseline integrase resistance mutations is only recommended when there is a highsuspicion of transmission of resistance to integrase strand transfer inhibitors (INSTI).Multiple resistance in PR and/or RT or index patient treated with INSTI

Resistance should be studied by genotyping in all patients in whom virological failure has beenconfirmed. The study should include integrase resistance mutations if the patient's regimenincludes an INSTI

The Spanish Aids Research Network (RIS) study during period

2007-2012 Overall prevalence for protease and reverse

transcriptase resistances ~7.6%; rare integrase resistances

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Objective

To report a clinical case of INSTI resistance evident transmission from a long

treatment experienced HIV patient to his partner

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Patients and methods

Partner infection timeline

Initial

resistance

test

Genotypic tests & phylogenetic analysis

Phylogeny

of transmitted

HIV-1 strain

2004 2016 Present

Viral load evolution

Medical & treatment history of primary case

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

• Male (58 yrs)

• HIV-1 diagnosed in 2004

• HCV coinfected, genotype 1a

• Severe hypertension, associated

with cerebrovascular, kidney and

myocardial disease

Index case

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

Clinical follow-up

3TC + ddI + d4T Discontinuation

(CD4 count=123 cells/µL;

Viral Load=24,600 copies/mL)

AZT + ABC + EFV Viral suppression

HCV treatment beginning

3TC + ABC + EFV Virological failure

Index case

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

Clinical follow-up (cont.)

AZT + d4T + ATV/r

Virological failure

(HIV-1 VL=2,860 copies/mL)

GENOTYPE RESISTANCE TEST

74V, 184V, 100I, 103N

ABC, ddI, 3TC, NVP & EFV

Viral suppression

Index case

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

Clinical follow-up (cont.)

AZT + d4T + RAL

Occasional blips

Virological failure

Viral suppressionFrom 2008:

HCV treatment beginning

with Harvoni®

HCV cureGENOTYPE RESISTANCE

TEST

SVR

Index case

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

Clinical follow-up (cont.)

Virological failure

(HIV-1 VL=9,627 copies/mL)

GENOTYPE RESISTANCE TEST

98S (RT mutation)

G140S, Q148H (integrase mutations)

DRV/r + d4T + AZT

Rescue therapy

Index case

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

Partner of index case

• Female (52 yrs)

• HIV-1 diagnosis in May of 2016

• Baseline genotype resistance test

performed

- Initial CD4 count=476 cells/µL

- Initial Viral Load=48,412 copies/mL

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

98S (RT mutation)

G140S, Q148H (integrase mutations)

Baseline genotype resistance test

Partner of index case

Index case

Idem mutations pattern

Viral suppressionCD4=630 cells/µL

FTC + TDF+ RPV

Initial antiretroviral therapy

VL=142 copies/mLCD4=426 cells/µL

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

Phylogenetic relationship index case and partner

Identity

pol gene (PR+RT+IN) from index case in VF and his wife (naïve)

VF= Virological failure

pol gene 98.93%

IN region 98.95%

Aminoacids identity

96.83%

97.91%

Divergence

Integrase

PR+RT+IN

0.005%

0.011%

Protein divergence

Integrase

PR+RT+IN

pol gene 0.008%

IN region 0.004%

DNAstarsuite

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Results

VF= Virological failure

PR+RT+IN from the 2 patients(index case in VF and his wife)

pol gene from 150 patients epidemiologicallynon-related and randomly retrieved fromLANL database

Determination of nucleotidic sustitution model(in that case GTR+G+I, by Findmodel, MEGAv6.0)

Phylogenetic inference by ML (FastTreeprogram)

ML= Maximum Likelihood

Phylogenetic relationship index case and partner

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Phylogenetic relationship index case and partner FastTree

2004

B U

S.9

9.P

RB

959

03.A

Y33

1296

2004 B GB.x.MANC.U23487

90

0.01

99%

Phylogenetic relationship with HIV epidemic

Clinical case of transmitted resistance to HIV Integrase Inhibitors2nd Global HIV Clinical Forum

Conclusions

Both cases reported are epidemiological and phylogenetically related to eachother, also sharing the same integrase mutation pattern

Both strains are highly similar to each other and phylogenetic study confirms theirevolutive closeness

In summary, we can conclude the transmission of a HIV-1 strain showing InSTI

resistance mutations from the index case to his common partner.

Thanks for your attention!