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

Abstract

Background Starting combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection results in a smaller HIV-1 latent reservoir, reduced immune activation, and less viral diversity compared to starting cART during chronic infection. We report results of a four-year study designed to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir (DTG) monotherapy. Methods EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. People with HIV (PWH) who started cART <180 days after a documented primary HIV-1 infection with suppressed viral load were randomized (2:1) to DTG monotherapy with 50mg daily or continuation of cART. The primary endpoints were the proportion of PWH with viral failure at 48, 96, 144 and 192 weeks; noninferiority margin 10%. After 96 weeks, randomization was lifted and patients were permitted to switch treatment groups as desired. Results Of 101 PWH randomized, 68 were assigned to DTG monotherapy and 33 to cART. At week 96 in the per-protocol population, 64/64 (100%) showed virological response in the DTG monotherapy group vs 30/30 (100%) in the cART group (difference, 0.00%; upper bound of 95% confidence interval 6.22%). This demonstrated noninferiority of DTG monotherapy at the prespecified level. At week 192, the study end, no virological failure occurred in either group during 13,308 and 4,897 person weeks of follow-up for the DTG monotherapy (n = 80) and cART groups, respectively. Conclusion This trial suggests that early cART initiation during primary HIV-infection allows sustained virological suppression after switching to DTG monotherapy. Clinical Trials Registration NCT02551523.

Population dynamics of HIV drug resistance during treatment scale-up in Uganda: a population-based longitudinal study

“…Encouragingly, DTG monotherapy has been shown to be robust to resistance evolution for at least 192 weeks. 52 However, treatment adherence was extremely high (>99%) in this cohort and these results may not hold in other settings.…”

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

“…DTG monotherapy (Scenario 6) : Table 4 also summarizes data from four clinical trials of DTG monotherapy that enrolled 276 PLWH with VS for six or more months [ 115 , 116 , 117 , 118 , 119 , 120 , 121 ]. The proportion with a history of receiving an INSTI ranged from 15% and 17% in DOMONO and DOLAM to 60% in EARLY SIMPLIFIED and 100% in MONCAY.…”

Cohort Profile: The Zurich Primary HIV Infection Study

“…Of note, there was an absence of viral evolution, reflecting the emergence of drug resistance in the viral reservoir, as assessed in the proviral DNA from peripheral blood mononuclear cells [ 22 ]. This trend continued for 96 weeks, with 64 out of 64 patients maintaining a virological response in the dolutegravir monotherapy group and 30 out of 30 patients in the cART group [ 24 ]. Remarkably, at the study’s endpoint on week 192, there were no instances of virological failure reported in either group, demonstrating the non-inferiority of dolutegravir monotherapy as a simplification strategy [ 24 ].…”

“…This trend continued for 96 weeks, with 64 out of 64 patients maintaining a virological response in the dolutegravir monotherapy group and 30 out of 30 patients in the cART group [ 24 ]. Remarkably, at the study’s endpoint on week 192, there were no instances of virological failure reported in either group, demonstrating the non-inferiority of dolutegravir monotherapy as a simplification strategy [ 24 ].…”

“…Notably, there were no instances of virological failure observed during the study; this is a novel discovery that diverges from the prior trials, where dolutegravir monotherapy had been found inferior to cART. It is crucial to emphasize that these earlier studies involved patients who initiated cART during the chronic phase of HIV-1 infection, in contrast to the EARLY-SIMPLIFIED study, which focused on individuals who commenced cART during PHI [ 24 ]. This distinction suggests that future simplification studies should consider stratifying the participants based on the timing of HIV infection and timing of the initiation of their initial cART regimen.…”