Encore Presentations
Tuesday, November 14, 2023
08:30 AM–10:00 AM
Abstract
Background: Antiretroviral regimens are typically not recommended if resistance to components is known or suspected, but historical resistance results are not always available when considering treatment options. In phase 3 trials evaluating switch to dolutegravir/lamivudine (DTG/3TC), absence of historical resistance results (n=294; pooled TANGO/SALSA) or presence of archived M184V/I mutations (TANGO, n=4; SALSA, n=5) did not impact virologic efficacy. This meta-analysis describes virologic failure (VF) at Weeks 24, 48, and 96 using real-world data from people with HIV-1 (PWH) receiving DTG+3TC in a suppressed switch setting, with historical RNA- or archived proviral DNA-detected M184V/I mutation.
Materials and Methods: A systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Embase®, Ovid MEDLINE®, MEDLINE® In-Process, and Cochrane library (January 2013-March 2022) and relevant conference archives (2016-2021) were searched for real-world studies reporting virologic outcomes for PWH receiving DTG+3TC. A targeted literature review was performed to identify randomized controlled trials (RCTs) assessing M184V/I impact on DTG+3TC efficacy. Studies were screened for populations reporting historical M184V/I mutations before DTG+3TC initiation. Fixed- and random-effects model analyses were conducted from real-world studies (primary objective). Sensitivity analyses were performed using RCT data (secondary objective).
Results: Of 3492 publications and 198 conference abstracts identified via systematic literature review, 5 real-world studies met all search criteria and were analyzed; the targeted literature review also identified 5 relevant RCTs. Few VFs and no treatment-emergent resistance mutations were reported at each time point (Table). Random-effects model–estimated proportions (95% confidence interval) of PWH with historical M184V/I with VF at Weeks 24, 48, and 96 were low in real-world studies (0.01 [0.00-0.14], 0.03 [0.01-0.08], and 0.04 [0.01-0.17], respectively) and RCTs (0.00 [0.00-0.02], 0.00 [0.00-0.01], and 0.00 [0.00-0.03], respectively). Including all studies increased sample sizes without significantly impacting estimates.
Conclusions: Although overall M184V/I incidence was low, real-world studies of PWH with historical M184V/I receiving DTG+3TC identified low incidence of VF through 96 weeks, as did sensitivity analyses from RCTs. Though not indicated in PWH with known resistance mutations, this meta-analysis provides reassuring data on outcomes with DTG+3TC in PWH with incomplete history or in cases where archived M184V/I was inadvertently missed.
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Table. Summary of VF Definitions and Outcomes for PWH With M184V/I RAMs Receiving DTG+3TC in Real-world Studies and RCTs
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Study (cohort)
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PWH with pre-switch M184V/I,
n/N (%)
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M184V/I identification method
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VF time point, week
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VF outcomes, n/N (%)
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VF definition
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Real-world studies
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Hocqueloux 2021 (Dat’AIDS)
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105/695 (15.11)
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RNA and proviral DNA genotypes (pooling both)
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24
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1/105 (0.95)
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2 consecutive confirmed VL >50 c/mL or
1 VL >200 c/mL
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48
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2/105 (1.90)
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96
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2/105 (1.90)
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Santoro 2021 (LAMRES)
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36/533 (6.75)
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RNA and proviral DNA genotypes
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24
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2/36 (5.56)
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2 consecutive confirmed VL >50 c/mL or
1 VL =200 c/mL
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48
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2/36 (5.56)
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96
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3/36 (8.33)
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Borghetti 2021 (ODOACRE)
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48/669 (7.17)a
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Historical genotypes; does not specify RNA or proviral DNA
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24
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0/45
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2 consecutive VL =50 c/mL or 1 VL =200 c/mL
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48
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1/45 (2.22)
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96
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2/45 (4.44)
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Galizzi 2020 (NR)
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47/174 (27.01)b
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Either RNA or proviral
DNA genotypes at baseline (before switch)
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24
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—
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2 consecutive confirmed VL >50 c/mL or
1 VL >50 c/mL followed by ART modification or 1 VL >1000 c/mL
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48
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1/47 (2.13)
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96
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—
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Hidalgo-Tenorio 2019 (DOLAMA)
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4/178 (2.25)
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Baseline RNA genotype
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24
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—
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2 consecutive VL >50 c/mL
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48
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1/4 (25.00)
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96
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—
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RCTs
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ART PRO
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21/41 (51.22)c
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Historical DNA genotype
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24
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0/21d
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VL =50 c/mL
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48
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0/21
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96
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0/21
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SOLAR 3D
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50/100 (50.00)
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Historical genotypes; does not specify RNA or proviral DNA
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24
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—
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VL =50 c/mL followed by consecutive VL >200 c/mL
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48
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0/50
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96
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—
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TANGO
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4/322 (1.24)
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Proviral DNA genotype
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24
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0/4e
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VL =50 c/mL followed by consecutive VL =200 c/mL
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48
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0/4e
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96
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—
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DOLULAM
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17/27 (62.96)
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RNA and proviral DNA genotypes
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24
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0/17
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VL >50 c/mL
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48
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0/17
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96
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0/17
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SALSA
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5/192 (2.60)
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Proviral DNA genotype
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24
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—
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VL =40 c/mL
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48
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0/5
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96
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—
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ART, antiretroviral therapy; DTG, dolutegravir; VL, viral load; NR, not reported; PWH, people with HIV-1; RAM, resistance-associated mutation; RCT, randomized controlled trial; 3TC, lamivudine; VF, virologic failure. aCohort reference reporting the proportion with VF for individuals with M184V/I was used for analysis (n=45 individuals with M184V/I). bAssumption: n=60 PWH with M184V/I were reported out of N=220 total PWH with available pre-switch genotype resistance data across 2 groups but not reported for DTG+3TC specifically. Table n with M184V/I was calculated according to the proportion of PWH in the DTG+3TC (n=174) vs other group (n=46). cOf the 20 PWH without known M184V/I at baseline, next-generation sequencing identified n=7, n=3, and n=1 with M184I at 1%, 5%, and 20% thresholds, respectively. dRefers to the number of PWH with historical 3TC resistance (M184V/I and/or K65R/E/N); 3 PWH with historical 3TC resistance discontinued before Week 24 but had VL <50 c/mL at time of discontinuation (2 protocol violations and 1 adverse event–related discontinuation). eAssumption: Week 24 was not reported, but reports described no VF to Week 48.
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Presenting Author
Cale Williams PharmDViiV Healthcare
Authors
Clotilde Allavena MD
Tristan Barber MD
Bryn Jones MBChB, MRCP
Madhusudan Kabra BPharm, MSc
ViiV Healthcare
Emilio Letang MD, MPH, PhD
Anne-Geneviève Marcelin MD
Nicola Gianotti MD
Cale Harrison MS
Chinyere Okoli PharmD, MSc, DIP
Chris Parry PhD
Juan Pasquau MD
Julie Priest MSHP
ViiV Healthcare
Simona Di Giambenedetto MD
Matthew Turner PhD
Gustavo Verdier BSc
Tammy Wynne BSc