EECC DE DTG+3TC EN EL CROI 2020

Conference on Retroviruses and Opportunistic Infections; March 8-11, 2020; Boston, MA

EECC DE DTG+3TC EN EL CROI 2020

Celia MirallesUPI. Hospital Alvaro Cunqueiro de Vigo

1


• DTG + 3TC VS DTG + TDF/FTC (GEMINI-1 & -2): Confirmed virologic withdrawals through week 96. Mark Underwood. Abstract 483• Assessing the virologic impact of archived resistance in an HIV-1 switch study TANGO through

week 48. Ruolan Wang. Abstract 489• ART-PRO Trial:Long-Term DTG+3TC Switch Efficacy in Patients With Archived 3TC Resistance.

Rosa de Miguel. Abstract 485• HIV Suppression and Changes in Markers in CSF From Patients Randomly Switched to DTG +

3TC (Spanish HIV/AIDS ResearchNetwork, PreEC/RIS 62). Juan M. Tiraboschi. Abstract 435

2

INDICE


DTG + 3TC VS DTG + TDF/FTC (GEMINI-1 & -2): CONFIRMED VIROLOGIC WITHDRAWALS THROUGH WEEK 96

Mark Underwood,1 Ruolan Wang,1 Paul Benson,2 Norma Porteiro,3 Giuliano Rizzardini,4José R. Santos,5 Rickesh Patel,6 Justin Koteff,1 Rimgaile Urbaityte,7 Joe Horton,8 Jörg Sievers,6Choy Man,1 Allan R. Tenorio,1 Jean van Wyk6

1ViiV Healthcare, Research Triangle Park, NC, USA; 2Be Well Medical Center, Berkley, MI, USA; 3Hospital de Enfermedades Infecciosas Dr. Francisco J. Muñiz, Buenos Aires, Argentina; 4Department of Infectious Diseases, Sacco Hospital, Milan, Italy; 5Infectious Diseases Department, University Hospital Germans Trias i Pujol, Badalona, Spain; 6ViiV Healthcare, Brentford, UK; 7GlaxoSmithKline, Uxbridge, UK; 8PAREXEL International, Durham, NC, USA


• In the primary analysis of the GEMINI-1 & -2 studies at Week 48, the 2-drug regimen (2DR) of dolutegravir (DTG) + lamivudine (3TC) was non-inferior to the 3-drug regimen (3DR) of DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in HIV-1–infected, ART-naive adults, leading to the approval of the 2DR as a once-daily single-tablet regimen by the US FDA and the EMA1

• At the 96-week analysis, non-inferiority was maintained2

• Eleven participants on 2DR and seven on 3DR met protocol-defined confirmed virologic withdrawal (CVW) criteria through Week 96

• We present a detailed description of these CVWs

4

Introduction

1. Cahn et al. Lancet. 2019;393:143-155. 2. Cahn et al. J Acquir Immune Defic Syndr. 2020;83:310-318.

Underwood et al. CROI 2020; Boston, MA. Poster 483.


5

Methods


• Treatment-naive adults were eligible if screening HIV-1 RNA viral loads (VLs) were between 1000-500,000 c/mL, HIV-1 genotype showed no major RT/PR resistance mutations, and were HBV negative• CVW was defined as 2 consecutive VLs (suspected virologic withdrawal [SVW] result followed

by CVW result) meeting virologic non-response (VL ≥200 c/mL after Week 24 or <1.0 log decline in VL by Week 12 unless HIV-1 RNA is <200 c/mL) or virologic rebound criteria (≥200 c/mL after prior confirmed suppression to <200 c/mL)• Monogram Biosciences performed integrase and RT/PR genotypic and phenotypic resistance

testing on Day 1 and SVW samples• We evaluated CVW participant:

• Baseline (BL) VL and CD4+ cell count characteristics, • Resistance, • VL progression, • Potential adherence issues, • And study drug interruption (based on investigator reporting) through the study course


• In GEMINI-1 & -2, of 1974 participants screened:• 3 (0.15%) failed screening due to transmitted M184V resistance

• Overall, 11 participants on DTG + 3TC and 7 on DTG + TDF/FTC met CVW criteria through Week 96 • All CVWs experienced virologic rebound,

• 2 CVWs in each arm experienced at least one VL elevation ≥200 c/mL after suppression to <50 c/mL

• and none of the 18 CVWs had VL blips (defined as a single VL between ≥50 to <200 c/mL with adjacent values <50 c/mL) that preceded CVW

• One DTG + 3TC participant did not achieve suppression prior to withdrawal at Week 24

6

Results



7

Individual HIV-1 RNA Viral Load Progression by Visit for Participants Meeting CVW Criteria in the DTG + 3TC Arm

Arrows represent the week in which CVW occurred. The color of the arrow corresponds to the color assigned to each participant.



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Individual HIV-1 RNA Viral Load Progression by Visit for Participants Meeting CVW Criteria in the DTG + TDF/FTC Arm

Arrows represent the week in which CVW occurred. The color of the arrow corresponds to the color assigned to each participant.



• There were low and comparable CVWs across treatment arms by baseline VL or CD4+ cell count

Baseline subgroups DTG + 3TC DTG + TDF/FTC

BL CD4+ cell count, % (n/N)≤200 cells/mm3 4.8 (3/63) 3.6 (2/55)

>200 cells/mm3 1.2 (8/653) 0.8 (5/662)

BL HIV-1 RNA, % (n/N)≤100,000 c/mL 1.0 (6/576) 0.7 (4/564)

>100,000 c/mL 3.6 (5/140) 2.0 (3/153)

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CVWs by Baseline CD4+ Cell Count and Baseline HIV-1 RNA



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Resistance Analysis


• Resistance data to determine treatment emergence were available for all samples except 2 cases on DTG + TDF/FTC where testing failed with HIV-1 VL below the assay cut-off. • No treatment-emergent genotypic or phenotypic resistance in IN or RT was observed in

any CVWs on either treatment arm• All fold change (FC) at withdrawal visit were below the Monogram phenotypic clinical or

biological cut-offs. Maximum FC at withdrawal was 1.13 and 1.74 for DTG and 3TC, respectively, for CVWs in the DTG + 3TC arm, and 1.38, 1.07, and 1.28 for DTG, TDF, and FTC for CVWs, respectively, in the DTG + TDF/FTC arm • For participants with VLs at withdrawal:

• VL decreased ≥2 fold for 8 of 9 participants in the DTG + 3TC arm • and 3 of 5 in the DTG + TDF/FTC arm between the CVW and withdrawal time points• 6/11 CVWs in the DTG + 3TC arm and 1/7 in the DTG + TDF/FTC arm appeared to be associated with

adherence or treatment interruption issues


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*Participant K SVW visit occurred within the Week 96 window for the Snapshot analysis. WD, withdrawal.

Summary of CVWs in DTG + 3TC Arm


Participant SubtypeBL CD4+

(cells/mm3)CVW visit

(week)BL VL(c/mL)

SVW VL(c/mL)

CVW VL(c/mL)

WD VL(c/mL)

Adherence/treatment interruption

A BF 212 W16 124,492 6648 56,435 95 UnknownB B 284 W24 50,263 348 206 96 AdherentC B 529 W24 17,232 461 251 59 UnknownD B 213 W24 96,277 451 9602 67 Treatment interruptionE F 19 W24 368,439 212 376 362 AdherentF B 414 W48 37,701 43,908 38,457 ND Unknown; concurrent

SAE (psychosis)G B 567 W60 7654 3972 3131 1513 Non-adherentH B 347 W60 101,671 703 85,556 ND Treatment interruptionI B 50 W72 63,817 422 2154 115 Non-adherentJ B 74 W72 112,812 61,076 87,794 671 Non-adherentK* B 317 W96 341,818 396 726 280 Non-adherent


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*Participant L met CVW criteria at Week 12; not withdrawn from study due to central laboratory data reporting error and continued to remain suppressed to Week 108. WD, withdrawal.

Summary of CVWs in DTG + TDF/FTC Arm


Participant SubtypeBL CD4+

(cells/mm3)CVW visit

(week)BL VL(c/mL)

SVW VL(c/mL)

CVW VL(c/mL)

WD VL(c/mL)

Adherence/treatment interruption

L* B 22 W12 136,753 393 276 NA UnknownM B 226 W24 10,930 1136 809 647 UnknownN B 251 W24 76,325 569 362 46 UnknownO B 201 W24 156,701 213 1559 97 UnknownP B 602 W48 1568 8384 3653 3011 UnknownQ B 253 W72 66,881 254 232 121 UnknownR B 144 W96 28,905 30,316 7793 ND Non-adherent


• In GEMINI-1 & -2, there were:• Low and comparable numbers of participants meeting CVW

criteria through 96 weeks in the DTG + 3TC and DTG + TDF/FTC arms

• With low and comparable CVWs across treatment arms by baseline VL or CD4+ cell count

• There were no emergent genotypic or phenotypic resistance to INI or NRTIs observed through 96 weeks among CVWs

• VL progressions for CVWs generally show a steep increase in viral load followed by a decrease at withdrawal visit, consistent with non-adherence/treatment interruption and subsequent re-adherence

• These data further support the durability and high barrier to resistance of the 2DR DTG + 3TC

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Conclusions



ASSESSING THE VIROLOGIC IMPACT OF ARCHIVED RESISTANCE IN AN HIV-1 SWITCH STUDY TANGO THROUGH WEEK 48Ruolan Wang,1 Jonathan Wright,2 Mounir Ait-Khaled,3 Allan R. Tenorio,1 Maria Claudia Nascimento,3Thomas Lutz,4 Daniel Podzamczer,5 Richard Moore,6 Miguel Górgolas Hernández-Mora,7Clifford Kinder,8 Jean van Wyk,3 Mark Underwood1

1ViiV Healthcare, Research Triangle Park, NC, USA; 2GlaxoSmithKline, Stockley Park, UK; 3ViiV Healthcare, Brentford, UK; 4Infektio Research GmbH & Co. KG, Frankfurt, Germany; 5Hospital Universitari de Bellvitge, Barcelona, Spain; 6Northside Clinic, Fitzroy North, VIC, Australia; 7Jiménez Díaz Foundation University Hospital, Madrid, Spain; 8The Kinder Medical Group, Miami, FL, USA


• The TANGO study demonstrated that switching to a 2-drug regimen (2DR) of dolutegravir/lamivudine fixed-dose combination (DTG/3TC FDC) was non-inferior to continuing a tenofovir alafenamide–based 3-drug regimen (3DR) in maintaining virologic suppression in HIV-1–infected, ART-experienced adults through Week 481

• Next-generation sequencing (NGS)-based assay using HIV-1 proviral DNA can detect archived, pre-existing drug resistance in patients with suppressed viral load. The clinical utility of this testing has not been fully determined2 and testing results should be interpreted with caution3

• We performed resistance analyses and assessed the impact of pre-existing, HIV-1 drug resistance on virologic outcomes through Week 48

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Introduction

1. van Wyk et al. Clin Infect Dis. 2020 [Epub ahead of print]. 2. DHHS. 2018. 3. Günthard et al. Clin Infect Dis. 2019;68:177-187.

Wang et al. CROI 2020; Boston, MA. Poster 489.


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aStratified by baseline third agent class (PI, INSTI, or NNRTI). b2 participants excluded who were randomized but not exposed to study drug. c4% non-inferiority margin. dIncludes participants who changed a background therapy component or discontinued study treatment for lack of efficacy before Week 48, or who had HIV-1 RNA ≥50 c/mL in the 48-week window.

TANGO Study Design

DTG/3TC (N=369)b

Day 1

TAF-based regimen (N=372)

DTG/3TC

Week48

Early-switch phase Late-switch phase

Continuation phase

Week144

Week 24

Week96

• Adults, virologically suppressed (HIV-1 RNA <50 c/mL) for >6 months

• Stable TAF-based regimen

Randomizationa1:1

Week 148

Week196

DTG/3TC DTG/3TC

Primary endpointc: participants with virologic failure per FDA Snapshot (ITT-E)d

Screening



• Historic genotypic resistance report is not required for study entry; participants with identified historical IAS major NRTI or INSTI resistance-associated mutations (RAMs) prior to randomization were excluded from the study

• HIV-1 proviral DNA genotyping was conducted retrospectively on baseline whole blood samples from randomized participants per their consent by Monogram Biosciences using GenoSure Archive NGS platform assay that reports resistance mutations at frequencies of ≥15%

• Virologic outcomes based on IAS major NRTI, NNRTI, PI, and INSTI RAMs were determined by last available on-treatment HIV-1 RNA through Week 48 in order to assess pure virologic responses by censoring discontinuations due to non-efficacy reasons. Sensitivity analyses were performed using the FDA Snapshot algorithm at Week 48

• Proviral DNA resistance population (PRAP): based on the intention-to-treat–exposed (ITT-E) population for whom there were available proviral DNA baseline genotypic data; and at least one post-baseline on-treatment HIV-1 RNA viral load (VL) result available; and where reason for withdrawal is not protocol deviation

• The list of major RAMs used in these analyses was based on IAS 2019 update. Pre-specified INSTI substitutions are listed below (major IAS INSTI mutations are bolded):

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Methods


H51Y, T66I/A/K, L68I/V, L74M/I, E92Q/V/G, Q95K, T97A, G118R, F121Y, E138A/K/D/T, G140A/C/S, Y143C/H/R/K/S/G/A, P145S, Q146P, S147G, Q148H/K/R, V151I/L/A, S153F/Y, N155H/S/T, E157Q, G163R/K, G193E, S230R, R263K


• With a total of 919 participants screened for the study, 560 (61%) had historic genotypic reports, among those only 9 (1%) participants were excluded from the study due to exclusionary major NRTI resistance:• 1 of 9 participants had M41L and D67N, 2 had M41L, and the remaining 6 each had a single mutation identified as

M184I, K65R, K219E, K219Q, D67N, and L210W, respectively• Of treatment-exposed participants, 329/369 (89%) in the DTG/3TC group and 324/372 (87%) in the TAF-

based regimen group had proviral DNA genotypes available: 734 • For 734 participant samples tested, 80 (11%) had non-reportable results due to assay failure• The overall prevalence of any archived major RAM across 4 drug classes was 26% in the PRAP

• Archived NRTI RAMs were observed in 7% of participants and the frequency of M184V/I (1%) and K65N/R (<1%) was low, being detected as mutation mixtures with wild-type virus

• Major INSTI RAMs were infrequent, being detected in 1% of participants as mutation mixtures with wild-type virus • Other pre-specified INSTI substitutions were observed in 26% of participants and the most frequent substitutions were

polymorphic G193E, L74I, and V151I• Baseline characteristics (eg, age, sex, HIV-1 subtype, baseline 3rd agent class, median CD4+ count) were

similar between participants with or without any archived RAMs

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Results



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Prevalence of Archived Resistance and the Most Frequent Substitutions by Drug Class at Baseline in PRAP*,†

*PRAP: proviral resistance analysis population is described in the Methods section. †A participant can have more than one mutation. Numerator is the number of participants with a particular mutation or mutation mixture with wild-type detected. aTAMs: thymidine analogue mutations including M41L, D67N, K70R, L210W, T215F/Y, and K219E/Q. bParticipants with archived M184V or I all had mutation mixtures with wild-type virus. cParticipants with archived K65N or R all had mutation mixtures with wild-type virus. dOther NRTI RAMs detected <1% in total (n): V75I (6), L74V (3), F77L (1), and K70E (1). eOther NNRTI RAMs detected <1% in total: K101E (6), Y181C (4), G190A/S (4), V106A/M (4), Y188C/H/L (4), H221Y (3), E138G (2), M230I/L (2), P225H (2), F227C (1), and K103S (1).

Resistance class DTG/3TC TAF-based regimen Total (N=322) (N=321) (N=643)

No major RAMs 241 (75%) 235 (73%) 476 (74%)Any major RAMs 81 (25%) 86 (27%) 167 (26%)Major NRTI associated 25 (8%) 17 (5%) 42 (7%)

Any TAMa 9 (3%) 5 (2%) 14 (2%)A62V 5 (2%) 3 (<1%) 8 (1%)M184V/Ib 4 (1%) 3 (<1%) 7 (1%)K65N/Rc 0 2 (<1%) 2 (<1%)Othersd 7 (1%) 4 (1%) 11 (2%)

Major NNRTI associated 38 (12%) 52 (16%) 90 (14%)K103N 12 (4%) 17 (5%) 29 (5%)E138A/K 14 (4%) 13 (4%) 27 (4%)V108I 5 (2%) 7 (2%) 12 (2%)Otherse 8 (2%) 19 (6%) 27 (4%)



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*PRAP: proviral resistance analysis population is described in the Methods section. †A participant can have more than one mutation. Numerator is the number of participants with a particular mutation or mutation mixture with wild-type detected. aOther PI RAMs detected <1% in total (n): V82A (5), V82/F/L/S (4), Q58E (4), M46L (3), L90M (2), N88S (2), I47V (1), I50L (1), and N83D (1). bOther pre-specified INSTI substitutions detected <1% in total: T66A (5), G163K/R (5), E138K (2), L68V (2), N155S (2), Q95K (2), G140S (1), and H51Y (1).

Prevalence of Archived Resistance and the Most Frequent Substitutions by Drug Class at Baseline in PRAP*,† (cont)

Resistance class DTG/3TC TAF-based regimen Total (N=322) (N=321) (N=643)

Major PI associated 23 (7%) 20 (6%) 43 (7%)M46I 8 (2%) 7 (2%) 15 (2%)D30N 5 (2%) 2 (<1%) 7 (1%)Othersa 12 (4%) 12 (4%) 24 (4%)

Pre-specified INSTI substitutions 84 (26%) 85 (26%) 169 (26%)Major INSTI associated 3 (<1%) 5 (1%) 8 (1%)

Q148Q/R 2 (<1%) 1 (<1%) 3 (<1%)Y143Y/H 0 2 (<1%) 2 (<1%)Y143Y/C 1 (<1%) 0 1 (<1%)R263R/K 0 2 (<1%) 2 (<1%)

Other pre-specified INSTI substitutions 83 (25%) 82 (25%) 165 (26%)G193E 34 (11%) 30 (9%) 64 (10%)L74I 16 (5%) 24 (7%) 40 (6%)V151I 12 (4%) 13 (4%) 25 (4%)E157Q 9 (3%) 6 (2%) 15 (2%)E138D 4 (1%) 4 (1%) 8 (1%)T97A 5 (2%) 3 (<1%) 8 (1%)L74M 3 (<1%) 4 (1%) 7 (1%)Othersb 12 (4%) 7 (2%) 19 (3%)



• Through Week 48, 322/322 (100%) participants on DTG/3TC and 319/321 (>99%) on a TAF-based regimen were virologically suppressed• All participants with major NRTI, INSTI, NNRTI, or PI RAMs were suppressed

• Including 4 with archived M184V/I on DTG/3TC

• No participants in the DTG/3TC group met protocol-defined confirmed virologic withdrawal (CVW) criteria through Week 48 and one participant in the TAF-based regimen group without any archived major RAMs met CVW criteria with no emergent resistance • Frequency of viral rebound (VL ≥50 c/mL) at post-baseline visits was low among participants with

archived major NRTI or INSTI RAMs through Week 481

• No viral rebound was observed for participants with archived M184V/I or K65N/R

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Results (cont)

1. Wang et al. EACS 2019; Basel, Switzerland. Poster PE3/15.



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*PRAP is described in the Methods section. All P values based on Fisher’s exact test for the comparison of the proportions of participants with HIV-1 RNA <50 c/mL at Week 48 (within treatment group comparison for subgroup with class resistance vs subgroup without class resistance) were >0.99 for the TAF-based regimen group and non-calculable in the DTG/3TC group due to 100% response rates in both subgroups across all resistance classes.

Virologic Outcomes by Archived Resistance Category Through Week 48 Using Last On-Treatment HIV-1 RNA in PRAP*

Baseline resistance class

% of participants with last available on-treatment HIV-1 RNA <50 c/mL

DTG/3TC (N=322)

TAF-based regimen (N=321)

Overall participants 100% (322/322) >99% (319/321)Any major RAMs 100% (81/81) 100% (86/86)No major RAMs 100% (241/241) >99% (233/235)Any major NRTI RAMs 100% (25/25) 100% (17/17)No major NRTI RAMs 100% (297/297) >99% (302/304)Any major INSTI RAMs 100% (3/3) 100% (5/5)No major INSTI RAMs 100% (319/319) >99% (314/316)Any pre-specified INSTI substitutions 100% (84/84) 100% (85/85)No pre-specified INSTI substitutions 100% (238/238) >99% (234/236)Any major NNRTI RAMs 100% (38/38) 100% (52/52)No major NNRTI RAMs 100% (284/284) >99% (267/269)Any major PI RAMs 100% (23/23) 100% (20/20)No major PI RAMs 100% (299/299) >99% (299/301)



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*PRSAP: ITT-E population for all participants with available proviral baseline genotypic data.†One participant with pre-specified INSTI substitution L74I had an early withdrawal with the last on-study VL of 507 c/mL at Week 8 due to a protocol deviation of non-compliance.

Treatment Response at Week 48 by Archived Resistance Class –Snapshot Sensitivity Analysis in PRSAP*• Irrespective of presence of major RAMs, similar high suppression rates were observed

across both treatment groups using the FDA Snapshot endpoint



• In the TANGO study, archived resistance identified via proviral DNA testing on participants with no known resistance or a history of virologic failure was not associated with virologic outcomes at Week 48

• Due to high virologic efficacy rates observed in the TANGO study, the utility of proviral DNA testing in similar patients in a clinical setting may be of limited value

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Discussion



• In the TANGO study, the prevalence of archived, pre-existing resistance detected by proviral DNA genotyping to ARVs was consistent with recent findings by others1,2

• Archived major NRTI RAMs (eg, M184V/I, K65N/R, and TAMs) and INSTI RAMs (eg, Q148R, Y143C/H, R263K) were infrequent

• High rates of virologic suppression were maintained in participants in both treatment groups through Week 48

• The presence of archived major RAMs did not impact virologic outcomes through Week 48• For participants with any major RAMs across 4 drug classes, 100% of participants in both treatment groups had

HIV-1 RNA <50 c/mL at their last on-treatment study visit

25

Conclusions

1. McClung et al. CROI 2019; Seattle, WA. Abstract 3337. 2. Günthard et al. Clin Infect Dis. 2019;68:177-187.



ART-PRO TrialLong-Term DTG+3TC Switch

Efficacy in Patients With Archived 3TC Resistance

Rosa de Miguel,1 David Rial,2 Lourdes Domínguez-Domínguez,2 Rocio Montejano,1 Andrés Esteban-Cantos,1 Otilia Bisbal,2 Natalia Stella-Ascariz,1 Paula Aranguren,2 Mónica García-

Álvarez,2 Belen Alejos,3 Maria Lagarde,2 Jose I. Bernardino,1 Federico Pulido,2 Jose R. Arribas,1for the ART-PRO, PI16/00837-PI16/00678 study group

1Hospital La Paz Institute for Health Research, Madrid, Spain; 2Hospital Universitario 12 de Octubre, Madrid, Spain; 3Institute of Health Carlos III, Madrid, Spain


• At 48-weeks, DTG+3TC was effective in maintaining virologic control despite history of 3TC resistance and persistence of archived 3TC mutationsdetected by next-generation sequencing (NGS) (EACS2019 #PS7/5)

• Long term data to confirm durability of these results are needed

Background

de Miguel et al. CROI 2020; Boston, MA. Poster 485.


• Pilot, single-arm, phase IIa, open label clinical trial conducted at 2 sites

Study Design



Inclusion– CD4> 350 cells/μL and VL < 50 c/mL for 12 months (1 blip allowed)– Stable ART for 3 months– FTC or 3TC in past/present treatment– INSTI naïve

Exclusion– M184V/I or K65R in baseline proviral DNA Sanger genotype– HBAgS+– Pregnant/women wishing to conceive

Inclusion and Exclusion Criteria



Study Population



Study Population (cont)



Results


• In this pilot trial, DTG+3TC was effective at 96 weeks in maintaining long-term virologic control despite history of 3TC resistance and presence of archived 3TC mutations detected by NGS

• No case of virologic failure occurred after 2 years of follow-up


Adverse Events• There were 30 drug related AEs, only 1 led to discontinuation (insomnia, W8)• No related severe AEsHypermutation Analysis • 16/27 of samples with 3TC resistance-associated mutations (RAMs) detected

through NGS (>1% threshold) had retrotranscriptase defective viral genomes due to APOBEC-induced mutations

• After removal of reads identified as hypermutated (18.5%), 3TC RAMs remained present in 22/27 samples

Transient Viral Rebounds• 14 transient viral rebounds in 12 participants (6 in the group with historical

3TC-resistance)• No virologic failures

Results (cont)



HIV Suppression and Changes in Markers in CSF From Patients

Randomly Switched to DTG + 3TC(Spanish HIV/AIDS

ResearchNetwork, PreEC/RIS 62) Juan M. Tiraboschi,1 Jhon Rojas,2 Henrik Zetterberg,3 Jordi Niubo,1 Johanna Gostner,4

Antonio Navarro-Alcaraz,1 Camila Piatti,1 Dietmar Fuchs,4 Magnus Gisslén,3 Esteban Martinez,2, Daniel Podzamczer1

1Bellvitge University Hospital, Bellvitge Biomedical Research Institute, University of Barcelona, Barcelona, Spain; 2Hospital Clinic of Barcelona, Barcelona, Spain; 3University of Gothenburg, Gothenburg, Sweden;

4Innsbruck Medical University, Innsbrusk, Austria


• A major concern of dual therapy is the potential lower efficacy in viral reservoirs, especially in the central nervous system (CNS)

• The aim of this study was to evaluate the maintenance of HIV viral suppression as well as changes in neuronal injury and inflammatory markers in cerebrospinal fluid (CSF) in a group of patients receiving 3 drug regimen and after switching to Dolutegravir plus Lamivudine dual therapy

Background

Tiraboschi et al. CROI 2020; Boston, MA. Poster 435.


• To assess changes in HIV RNA in CSF after treatment switch from 3 drug-regimen to 2 drug therapy

• To assess changes in inflammatory and neuronal damage markers in CSF

• To assess Dolutegravir (total and unbound) concentrations in CSF

Objectives



• Prospective, single arm study• HIV+ virologically suppressed patients on triple therapy were randomly selected to switch to

Dolutegravir 50 mg + Lamivudine 300 mg once daily within the DOLAM Study (EUDRACT 2015-000274-35)

• A group of pts enrolled in two centers consented to participate in the Neuro-Substudy

Study Design



• CSF and blood samples were taken at BL and week 48– HIV-1 RNA in plasma and CSF were determined by real-time PCR– Neurofilament light chain (NFL) as well as inflammatory markers (sTREM-2, and YKL-40)

were measured in CSF by ELISA- NFL is a major structural component of myelinated axons is essential to maintain axonal caliber

and to facilitate effective nerve conduction◦ CSF concentrations of NFL provide a sensitive marker of CNS injury in a number of neurological diseases,

including HIV-related neuronal injury

- TREM2 is a receptor glycoprotein that belongs to the immunoglobulin superfamily◦ In the brain, TREM2 is expressed exclusively by myeloid cells, including microglia and macrophages. It is

more specific for activation of microglia and macrophages than neopterin, since the secreted form of the receptor is exclusively expressed on myeloid cells such as macrophages and microglia, but not on astrocytes

- YKL40, represents the activation of different cell types, especially astrocytes

Methods



Results


• 15 patients had baseline and week 48 plasma and CSF samples

• 80% male• Median age was 46 years

• Current CD4 count 746 (356) cells/μL, and nadir CD4 was 302 (165) cells/μL

• Baseline HIV viral load (Median IQR): 114000 (64248) copies/mL • Most patients switched from a NNRTI based regimen (60%) followed by

INSTI (26.7%)


Results (cont)



*Mann-Whitney U-test.

CSF Inflammation Markers



*Mann-Whitney U-test.

Neuronal Damage Marker



Patients 13, 14 and 15 had no available plasma samples for DTG concentrations. DTG concentration values are adapted to a logarithmic (Log10) scale.

Plasma and CSF DTG Concentrations



• Treatment simplification from triple therapy to Dolutegravir + Lamivudine resulted in no changes in viral suppression in plasma and CSF

• No evidence of neuronal damage or changes in inflammatory markers were found in CSF after 48 weeks of dual therapy

• Unbound CSF DTG concentrations were only 23% of total CSF concentrations, however unbound DTG CSF exceeded the EC50 (0.2 ng/mL) by 8-fold

• Our data suggests that dual therapy with Dolutegravir + Lamivudine maintains viral control within the CNS reservoir

Conclusions



• En los estudios GEMINI 1 y 2:– Muy pocos sujetos cumplieron los criterios de “retirada por fracaso virologico”

– Similar entre las ramas de biterapia con DTG+3TC y triple terapia con TAF

– Sin relación con las CV y CD4 en el basal

– Sin emergencia de mutaciones de Resistencia

• En el studio TANGO a la semana 48:– La prevalencia de mutaciones a ART pre-existentes detectada por genotipo en ADN- proviral fue

similar a otros estudios

– La presencia de M184V/I y K65N/R y mutaciones mayores asociadas a la INSTI fue muy baja.

– Se mantuvieron altas tasas de suppression virologica en ambos grupos

– La presencia de RAMs en las 4 familias no impacto en los resultados virologicos (100% éxito)

CONCLUSIONES (1)


• Estudio ART-PRO a 96 semanas– El cambio a biterapia con DTG+3TC (estudio piloto) fue eficaz a pesar de:

- Historia de resistencia a 3TC - Y persistencia de mutaciones al 3TC archivadas detectadas por NGS (next generation

sequencing)- Sin fracaso virológico despues de estos 2 años de seguimiento: durabilidad

– Plausibilidad para EC en FIII

• Cambio a DTG+3TC, datos en SNC:– Control virológico en plasma y LCR– Sin cambios en los marcadores inflamatorios en LCR– Las concentraciones de DTG- no ligado en LCR a pesar de ser un 23% de las

totales exceden la EC50 8 veces: control del reservorio

CONCLUSIONES ( y 2)


¡GRACIAS POR VUESTRA ATENCION¡

Documents

EECC DE DTG+3TC EN EL CROI 2020