Dolutegravir monotherapy was noninferior 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 published in Clinical Infectious Diseases.1

While some dolutegravir-based dual therapy has shown promising results,2,3 several randomized controlled trials have shown dolutegravir monotherapy to be inferior to cART.4-6 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 reservoir7,8 and low viral diversity,9,10  the researchers evaluated whether these properties would allow for sustained virologic suppression after a switch to dolutegravir monotherapy. In this randomized open-label 10% noninferiority margin trial (ClinicalTrials.gov identifier: NCT02551523), 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.1

The primary study end point was the percentage of patients with HIV RNA <50 copies/mL on or before week 48. Researchers also examined toxicity markers, HIV DNA levels in peripheral blood mononuclear blood cells, and potential central nervous system compartmentalization.

In the per-protocol population, 100% of patients in the dolutegravir and cART groups had a virologic response on or before week 48 showing noninferiority 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.

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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.

Disclosure: Multiple authors disclosed affiliations with pharmaceutical companies. See the reference for complete disclosure information.


References

1. Braun DL, Turk T, Tschumi F, et al. Non-inferiority of simplified dolutegravir monotherapy compared to continued combination antiretroviral therapy that was initiated during primary HIV infection: a randomized, controlled, multi-site, open-label, non-inferiority trial [published online January 2, 2019]. Clin Infect Dis. doi:10.1093/cid/ciy1131

2. Llibre JM, Hung C-C, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-849.

3. Cahn P, Madero JS, Arribas JR, et al; GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2019;393(10167):143-155.

4. Wijting I, Rokx C, Boucher C, et al. Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial. Lancet HIV. 2017;4(12): e547-e554.

5. Blanco JL, Rojas J, Paredes R, et al; DOLAM Study Team. Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial. J Antimicrob Chemother. 2018;73(7):1965-1971.

6. Hocqueloux L, Raffi F, Prazuck T, et al; MONCAY Study Group. Dolutegravir monotherapy versus dolutegravir/abacavir/lamivudine for virologically suppressed people living with chronic HIV infection: the randomized non-inferiority MONCAY trial [published online January 2, 2019]. Clin Infect Dis. doi:10.1093/cid/ciy1132

7. Schmid A, Gianella S, von Wyl V, et al. Profound depletion of HIV-1 transcription in patients initiating antiretroviral therapy during acute infection. PLoS One. 2010;5(10):e13310.

8. Strain MC, Little SJ, Daar ES, et al. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. J Infect Dis. 2005;191(9):1410-1418.

9. Oliveira MF, Chaillon A, Nakazawa M, et al. Early antiretroviral therapy is associated with lower HIV DNA molecular diversity and lower inflammation in cerebrospinal fluid but does not prevent the establishment of compartmentalized HIV DNA populations. PLoS Pathog. 2017;13(1):e1006112.

10. Rieder P, Joos B, Scherrer AU, et al. Characterization of human immunodeficiency virus type 1 (HIV-1) diversity and tropism in 145 patients with primary HIV-1 infection. Clin Infect Dis. 2011;53(12):1271-1279.