Dolutegravir Monotherapy as Maintenance Strategy: A Meta-Analysis of Individual Participant Data From Randomized Controlled Trials

Abstract

Background Dolutegravir monotherapy (DTG-m) results in virological failure (VF) in some people living with HIV (PWH). We sought to identify the independent factors associated with the risk of VF and to explore the effect size heterogeneity between subgroups of PWH enrolled in DTG-m trials. Methods We searched for randomized clinical trials (RCT) evaluating DTG-m versus cART amongst PWH virologically controlled for at least 6 months on combined antiretroviral therapy (cART). We performed an individual participant data meta-analysis (IPDMA) of VF risk factors and quantified their explained heterogeneity in random-effect models. Definition of VF was a confirmed plasma HIV-1 RNA >50 copies/ml by W48. Results Amongst 416 PWH from four RCTs, DTG-m significantly increased the risk of VF (16/227 (7%) versus 0/189 for cART; risk difference 7%, 95% confidence interval [1 to 12%], p=0·02, I 2=51%). Amongst 272 participants exposed to DTG-m, VF were more likely in participants with: first cART initiated ≥ 90 days from HIV acute infection (adjusted hazard ratio [aHR] 5·16; 95% confidence interval (95% CI) 1·60-16·65), CD4 T cells nadir <350/mm 3 (aHR 12·10; 95% CI 3·92-37·40), HIV RNA signal at baseline (aHR 4·84; 95% CI 3·68-6·38) and HIV-DNA copy number at baseline ≥2·7 log/10⁶ PBMCs (aHR 3·81; 95% CI 1·99-7·30). Amongst these independent risk factors, the largest effect size heterogeneity was found between HIV DNA subgroups (I²=80·2%;p for interaction=0·02). Conclusion Our study supports the importance of a large viral reservoir size for explaining DTG-m simplification strategy failure. Further studies are needed to link size and genetic diversity of the HIV-1 reservoir.

Cohort Profile: The Zurich Primary HIV Infection Study

“…Additionally, the ZPHI is unique in that it assigns an estimated date of infection to each participant, making it ideal for research into early events between the virus and host and investigations into the long-term effects of early treatment and to study ART simplification studies such as the Early Simplified Study [ 21 ]. The 10 most important of all 71 so-far-published papers are summarized in Table 4 [ 15 , 23 , 24 , 32 , 41 , 49 , 55 , 58 , 59 , 60 ]. Additionally, the collaboration with the SHCS gives the ZPHI access to an abundance of data for research purposes.…”

Sustained Viral Suppression With Dolutegravir Monotherapy Over 192 Weeks in Patients Starting Combination Antiretroviral Therapy During Primary Human Immunodeficiency Virus Infection (EARLY-SIMPLIFIED): A Randomized, Controlled, Multi-site, Noninferiority Trial

“…By contrast, DTG monotherapy has been associated with unacceptably high levels of virological failure and the development of integrase inhibitor resistance in patients who started cART during chronic HIV-1 infection in several randomized studies [ 8–10 ], with risk increasing over time and reaching up to 8.9% at 48 weeks [ 22 ]. Relevant risk factors for this viral failure were elucidated in a recent meta-analysis and include low CD4-nadir, longer timespan between HIV-1 diagnosis and ART initiation and larger HIV-1 reservoir [ 11 ]. Our study addressed these factors by restricting participation to those patients having commenced cART during primary HIV-1 infection and showed no cases of viral failure in either per protocol treatment group during a total of 192 weeks of follow-up.…”

“…Importantly, all these DTG simplification studies concerned patients initiating cART during chronic HIV-1 infection. A recent meta-analysis pooling data from 4 randomized controlled trials investigating the efficacy of DTG monotherapy examined the factors associated with viral failure and showed strong associations for initiation of ART ≥90 days after acute HIV infection, CD4 T-cell nadir <350 cells/mm 3 , HIV RNA signal at baseline and reservoir size at baseline [ 11 ].…”

Doravirine Plus Integrase Strand Transfer Inhibitors as a 2-Drug Treatment–Switch Strategy in People Living with HIV: The Real-Life DORINI Multicentric Cohort Study

“…It is known that previous attempts to use DTG as monotherapy have been unsuccessful and have led to the development of resistance mutation to the class of INIs. 19,20 In particular, the risk of DTG monotherapy simplification strategy appears higher in patients with higher baseline viral load, lower baseline CD4 + cell count, late start of ART, and documented large viral reservoir 21…”