Dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (cART) in patients who started cART during primary HIV infection and were virologically suppressed for >48 weeks, according to study results.
While some dolutegravir-based dual therapy has shown promising results, several randomised controlled trials have shown dolutegravir monotherapy to be inferior to cART. These dolutegravir monotherapy trials, however, have been conducted in patients initiating cART during chronic rather than primary HIV infection.
Since patients who start cART during the early phase of HIV infection show a reduced HIV reservoir and low viral diversity, the researchers evaluated whether these properties would allow for sustained virologic suppression after a switch to dolutegravir monotherapy. In this randomised open-label 10% non-inferiority margin trial, participants who started cART <180 days after a documented primary HIV infection and had a plasma HIV RNA <50 copies/mL for >48 weeks were randomly assigned on a 2:1 basis to either dolutegravir monotherapy (50 mg pill once daily; n=67) or cART (n=32) for 48 weeks.
The primary study end point was the percentage of patients with HIV RNA <50 copies/mL on or before week 48. Researchers led by DL Braun at the division of infectious diseases and hospital epidemiology, University Hospital Zurich and the Institute of Medical Virology, University of Zurich, also examined toxicity markers, HIV DNA levels in peripheral blood mononuclear blood cells, and potential central nervous system compartmentalisation.
In the per-protocol population, 100% of patients in the dolutegravir and cART groups had a virologic response on or before week 48 showing non-inferiority of dolutegravir monotherapy.
There was a significant decay of the total HIV DNA load in the dolutegravir group at week 48 compared with baseline (P =.0004), suggesting that the HIV latent reservoir was not replenished on dolutegravir monotherapy.
In all cerebrospinal fluid samples, HIV RNA was not detected above the limit of quantification of 40 HIV RNA copies/mL CSF at baseline (n=23 in the dolutegravir group; n=14 in the cART group) and at week 48 (n=10 in the dolutegravir group; n=2 in the cART group).
No significant changes from baseline were observed in renal function, proximal renal tubulopathy markers, or lipid profiles at week 48.
“Our results suggest that success of simplification strategies using dolutegravir monotherapy is likely governed by early start of treatment with subsequent low latent HIV-1 reservoir size, low viral diversity, and low immune activation,” noted the researchers.
Limitations of the study were the small number of patients and the short 48-week follow-up period.
In addition to longer follow-up trials, “more prospective controlled future simplification studies are needed that use stratification strategies according to the time of HIV infection and start of first cART guided by measurements of the latent reservoir,” concluded the researchers.
Background: Patients who start combination antiretroviral therapy (cART) during primary HIV-1 infection show a smaller HIV-1 latent reservoir, less immune activation and a smaller viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to test whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir monotherapy.
Methods: EARLY-SIMPLIFIED is a randomized, open label, non-inferiority trial. Patients who started cART <180 days after estimated date of a documented primary HIV-1 infection and had a 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; non-inferiority 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 versus 32/32 (100%) in the cART group (difference 0.00%, 95%-CI [-100%, 4.76%]). This showed non-inferiority of the dolutegravir monotherapy at the pre-specified level.
Conclusion: In this pilot study consisting of patients who initiated cART <180 days after the estimated day of a documented primary HIV-1 infection and had <50 HIV-1 RNA copies/mL for at least 48 weeks, monotherapy with once-daily dolutegravir was non-inferior to cART. Our results suggest that future simplification studies should use a stratification according to time of HIV infection and start of first cART.
Braun, DL; Turk, T; Tschumi, F; Grube, C; Hampel, B; Depmeier, C; Schreiber, PW; Brugger, SD; Greiner, M; Steffens, D; de Torrenté-Bayard, C; Courlet, P; Neumann, K; Kuster, H; Flepp, M; Bertisch, B; Decosterd, L; Böni, J; Metzner, KJ; Kouyos, RD; Günthard, HF