Dolutegravir Monotherapy Versus Dolutegravir/Abacavir/Lamivudine for Virologically Suppressed People Living With Chronic Human Immunodeficiency Virus Infection: The Randomized Noninferiority MONotherapy of TiviCAY Trial

Abstract

Background We investigated whether dolutegravir (DTG) monotherapy could be used to maintain virological suppression in people living with human immunodeficiency virus (HIV) on a successful dolutegravir-based triple therapy. Methods MONCAY (MONotherapy of TiviCAY) was a 48-week, multicentric, randomized, open-label, 12% noninferiority margin trial. Patients with CD4 nadir >100/μL, plasma HIV-1 RNA <50 copies/mL for ≥12 months, and stable regimen with DTG/abacavir (ABC)/lamivudine (3TC) were 1:1 randomized to continue their regimen or to DTG monotherapy. The primary endpoint was the proportion of patients with HIV RNA <50 copies/mL at week 24 in intention-to-treat snapshot analysis. Virologic failure (VF) was defined as 2 consecutive HIV RNA >50 copies/mL within 2 weeks apart. Results Seventy-eight patients were assigned to DTG monotherapy and 80 to continue DTG/ABC/3TC. By week 24, 2 patients in the DTG group experienced VF without resistance to the integrase strand transfer inhibitor (INSTI) class; 1 patient discontinued DTG/ABC/3TC due to an adverse event. The success rate at week 24 was 73/78 (93.6%) in the DTG arm and 77/80 (96.3%) in the DTG/ABC/3TC arm (difference, 2.7%; 95% confidence interval [CI], –5.0 to 10.8). During subsequent follow-up, 5 additional VFs occurred in the DTG arm (2 of which harbored emerging resistance mutation to INSTI). The cumulative incidence of VF at week 48 was 9.7% (95% CI, 2.8 to 16.6) in the DTG arm compared with 0% in the DTG/ABC/3TC arm (P = .005 by the log-rank test). The Data Safety Monitoring Board recommended to reintensify the DTG arm with standardized triple therapy. Conclusions Because the risk of VF with resistance increases over time, we recommend avoiding DTG monotherapy as a maintenance strategy among people living with chronic HIV infection. Clinical Trials Registration NCT02596334 and EudraCT 2015-002853-36.

Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis

“…When including this variable, the tau-squared were reduced from 1.17 (95% CI 0.33-2.19) to 0.00 (95% CI 0.00-1.11) in the 24 week analysis and from 1.37 (95% CI 0.54-2.15) to 0.00 (95% CI 0.00-1.00) in the 48 week analysis. The inclusion of other variables did not impact the estimates of tau-squared.” Discussion: (page 9) Please provide some references (at least one) for the impact of M184V on viral fitness (this one is of interest for DTG-based regimen: doi: 10.1097/QAD.0000000000001191)(page 9) I think authors should provide some data on VF (%, emerging mutations) during switch from a triple therapy to another one (in order to have an “historical comparator” for dual therapy)(page 10, “In addition, more data on the activity of DTG-based simplified regimens in compartments other than blood are needed.”) There are some references for mono- or dual-therapy in the genital tract (Hocqueloux et al 1 and Gianella et al 2 )and CNS (Doco Lecompte et al 3 )(page 10) Authors should cite recent reports (all communicated at the IAS 2018 in Amsterdam) confirming their conclusions, even though they cannot include them in the analyses: two randomized-controlled clinical trials on DTG monotherapy (Braun et al 4  and Hocqueloux et al 5 ), the extended follow-up of the SWORD trials at week 100 (Aboud et al 6 ) and results of the GEMINI trials (Cahn et al 7  ). References: (references 25 and 28) I think two references (Gantner and Bonijoly) are duplicates (as they are based on the analyze of the same database; Bonijoly et al have included more patients / with longer duration of follow-up than Gantner). …”

“…(page 10) Authors should cite recent reports (all communicated at the IAS 2018 in Amsterdam) confirming their conclusions, even though they cannot include them in the analyses: two randomized-controlled clinical trials on DTG monotherapy (Braun et al 4  and Hocqueloux et al 5 ), the extended follow-up of the SWORD trials at week 100 (Aboud et al 6 ) and results of the GEMINI trials (Cahn et al 7  ).…”

Antiretroviral treatment for HIV infection: Swedish recommendations 2019

“…Dolutegravir þ 3TC demonstrated non-inferiority in the GEMINI-1 and GEMINI-2 trials compared to three drugs (dolutegravir þ TDF/FTC) after 48 weeks of treatment of previously untreated patients without detectable drug resistance [41]. Previous studies have shown a high risk of development of resistance to INSTI in dolutegravir monotherapy [42,43], which is why it is of great importance that dolutegravir þ 3TC is given to patients with no known prior virological failure or history of 3TC resistance. The working group's assessment is that dolutegravir þ 3TC is a conceivable new strategy, especially when switching in patients with already suppressed virus, but that this combination should be given with great caution until results from longer follow-up studies are available.…”

Two’s a Company, Three’s a Crowd: A Review of Initiating or Switching to a Two-Drug Antiretroviral Regimen in Treatment-Naïve and Treatment-Experienced Patients Living with HIV-1

“…In an openlabel, phase 2, randomized non-inferiority trial, DTG monotherapy was non-inferior to combination ART at 24 weeks; however, viriologic failure was seen after 24 weeks with continued monotherapy, which led to DTG resistance [6]. The switch to certain monotherapy treatments occurred in patients already virologically suppressed; these regimens have largely failed to maintain viral suppression for an extended duration, with frequent cases of virologic rebound and emerging resistance [6][7][8].…”