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Dolutegavir Monotherapy in a Unique Unusual Patient Population
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Sustained viral suppression with dolutegravir monotherapy over 192 weeks in patients starting combination antiretroviral therapy during primary HIV infection (EARLY-SIMPLIFIED): a randomized, controlled, multi-site, non-inferiority trial
Clinical Infectious Diseases
Published:
20 June 2023
Download the PDF here
Download the PDF here
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.
In conclusion, this proof-of-concept study underscores the differing ART requirements between PWH and the need for patient stratification according to predictors of viral failure with the goal of minimizing ART toxicity. In light of robust evidence for the efficacy and low side-effect profile of dual ART with DTG and lamivudine, we see no widespread indication for DTG monotherapy. However, we believe our study contributes to existing evidence that triple-ART represents over-treatment of HIV-infection in a significant proportion of patients. We hope to pave the way for additional work to reduce ART-burden by patient stratification according to latent reservoir size or duration of active infection before starting therapy.
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Noninferiority of Simplified Dolutegravir Monotherapy Compared to Continued Combination Antiretroviral Therapy That Was Initiated During Primary Human Immunodeficiency Virus Infection: A Randomized, Controlled, Multisite, Open-label, Noninferiority Trial
02 January 2019
In this randomized, open-label, noninferiority trial, we recruited patients aged ≥18 years with a primary HIV-1 infection and no previous antiretroviral treatment failure, no prior treatment interruption, no major resistance mutations to INSTIs according to the Stanford algorithm [17], an HIV-1 RNA of less than 50 copies/mL plasma for 48 weeks or longer, and a negative hepatitis B virus surface antigen. Patients with documented resistance to any NRTI, non-NRTI, or protease inhibitors were allowed to be included. Exclusion criteria were pregnancy or breastfeeding, use of contraindicated drugs to dolutegravir, and previous intolerance to dolutegravir.
We obtained ethics committee approval at all participating centers in accordance with the principles of the 2008 Declaration of Helsinki. All participants gave their written informed consent before undergoing any study procedure.
Abstract
Background
Patients who start combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection show a smaller HIV-1 latent reservoir, less immune activation, and less viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir monotherapy.
Methods
EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. Patients who started cART <180 days after a documented primary HIV-1 infection and had an HIV-1 RNA <50 copies/mL plasma for at least 48 weeks were randomized (2:1) to monotherapy with dolutegravir 50 mg once daily or to continuation of cART. The primary efficacy endpoint was the proportion of patients with <50 HIV-1 RNA copies/mL on or before week 48; noninferiority margin 10%.
Results
Of the 101 patients randomized, 68 were assigned to simplification to dolutegravir monotherapy and 33 to continuation of cART. At week 48 in the per-protocol population, 67/67 (100%) had virological response in the dolutegravir monotherapy group vs 32/32 (100%) in the cART group (difference, 0.00%; 95% confidence interval, –100%, 4.76%). This showed noninferiority of the dolutegravir monotherapy at the prespecified level.
Conclusion
In this pilot study consisting of patients who initiated cART during primary HIV-1 infection and had <50 HIV-1 RNA copies/mL for at least 48 weeks, monotherapy with once-daily dolutegravir was noninferior to cART. Our results suggest that future simplification studies should use a stratification according to time of HIV infection and start of first cART.
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