Ingeborg Wijting1, Casper Rokx1, Charles Boucher2, Jeroen van Kampen2, Suzan Pas2, Theodora de Vries-Sluijs1, Carolina Schurink1, Hannelore Bax1, Maarten Derksen1, Eleni-Rosalina Andrinopoulou3, Marchina van der Ende1, Eric van Gorp4, Jan Nouwen1, Annelies Verbon1, Wouter Bierman5, Bart Rijnders6. 1. Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands. 2. Department of Viroscience, Erasmus MC University Medical Center, Rotterdam, Netherlands. 3. Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, Netherlands. 4. Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Viroscience, Erasmus MC University Medical Center, Rotterdam, Netherlands. 5. Department of Internal Medicine/Infectious Diseases, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. 6. Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands. Electronic address: b.rijnders@erasmusmc.nl.
Abstract
BACKGROUND: The high genetic barrier to resistance of dolutegravir might allow for its use as maintenance monotherapy in patients with HIV. We investigated whether dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (ART) for maintaining virological suppression in patients with HIV-1 infection successfully treated with combination ART. METHODS: We did this open-label, phase 2, randomised non-inferiority trial at two medical centres in the Netherlands. Eligible patients (aged ≥18 years) were on combination ART, had been virologically suppressed (HIV RNA <50 copies per mL) for at least 6 months, and had CD4 nadirs of 200 cells per μL or higher, HIV RNA zeniths of 100 000 copies per mL or less, and no history of virological failure. Patients were randomly assigned (1:1), via a web-based block randomisation method (variable block sizes of 4 and 6), to switch to dolutegravir monotherapy (50 mg once a day) either immediately or after a delay of 24 weeks of continued combination ART. Randomisation was stratified by HIV RNA zenith (<50 000 copies per mL vs 50 000-99 999 copies per mL). Investigators and patients were not masked to group allocation. The primary endpoint was the proportion of patients with plasma HIV RNA viral loads of less than 200 copies per mL at week 24, with a non-inferiority margin of 12%. We did analyses in the on-treatment and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, NCT02401828. FINDINGS: Between March 10, 2015, and Feb 4, 2016, we randomly assigned 51 patients to the immediate switch group and 53 patients to the delayed switch group. One patient who received immediate monotherapy discontinued treatment at week 12 because of disturbed sleep. At week 24, dolutegravir monotherapy was non-inferior to combination ART, with plasma HIV RNA loads of 200 copies per mL or higher observed in 2% (1/50) of patients in the immediate switch group and in no patients in the delayed switch group (difference 2%, 95% CI -5 to 12). Of patients assigned to the delayed switch group, 47 (89%) switched to dolutegravir monotherapy at week 24, two (4%) of whom subsequently discontinued monotherapy because of headache (n=1) and disturbed sleep (n=1). Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation. INTERPRETATION:Dolutegravir monotherapy was non-inferior to combination ART at 24 weeks. However, virological failure continued to occur thereafter and led to dolutegravir resistance. Dolutegravir should not be used as maintenance monotherapy. FUNDING: Erasmus Trustfonds.
RCT Entities:
BACKGROUND: The high genetic barrier to resistance of dolutegravir might allow for its use as maintenance monotherapy in patients with HIV. We investigated whether dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (ART) for maintaining virological suppression in patients with HIV-1 infection successfully treated with combination ART. METHODS: We did this open-label, phase 2, randomised non-inferiority trial at two medical centres in the Netherlands. Eligible patients (aged ≥18 years) were on combination ART, had been virologically suppressed (HIV RNA <50 copies per mL) for at least 6 months, and had CD4 nadirs of 200 cells per μL or higher, HIV RNA zeniths of 100 000 copies per mL or less, and no history of virological failure. Patients were randomly assigned (1:1), via a web-based block randomisation method (variable block sizes of 4 and 6), to switch to dolutegravir monotherapy (50 mg once a day) either immediately or after a delay of 24 weeks of continued combination ART. Randomisation was stratified by HIV RNA zenith (<50 000 copies per mL vs 50 000-99 999 copies per mL). Investigators and patients were not masked to group allocation. The primary endpoint was the proportion of patients with plasma HIV RNA viral loads of less than 200 copies per mL at week 24, with a non-inferiority margin of 12%. We did analyses in the on-treatment and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, NCT02401828. FINDINGS: Between March 10, 2015, and Feb 4, 2016, we randomly assigned 51 patients to the immediate switch group and 53 patients to the delayed switch group. One patient who received immediate monotherapy discontinued treatment at week 12 because of disturbed sleep. At week 24, dolutegravir monotherapy was non-inferior to combination ART, with plasma HIV RNA loads of 200 copies per mL or higher observed in 2% (1/50) of patients in the immediate switch group and in no patients in the delayed switch group (difference 2%, 95% CI -5 to 12). Of patients assigned to the delayed switch group, 47 (89%) switched to dolutegravir monotherapy at week 24, two (4%) of whom subsequently discontinued monotherapy because of headache (n=1) and disturbed sleep (n=1). Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation. INTERPRETATION:Dolutegravir monotherapy was non-inferior to combination ART at 24 weeks. However, virological failure continued to occur thereafter and led to dolutegravir resistance. Dolutegravir should not be used as maintenance monotherapy. FUNDING: Erasmus Trustfonds.
Authors: Ross S Milne; Rachel A Silverman; Ingrid A Beck; Jennifer Mckernan-Mullin; Wenjie Deng; Thomas R Sibley; Sandra Dross; James N Kiarie; Samah R Sakr; Robert W Coombs; Michael H Chung; Lisa M Frenkel Journal: AIDS Date: 2019-05-01 Impact factor: 4.177
Authors: Hanh T Pham; Lydia Labrie; Ingeborg E A Wijting; Said Hassounah; Ka Yee Lok; Inna Portna; Mark E Goring; Yingshan Han; Cynthia Lungu; Marchina E van der Ende; Bluma G Brenner; Charles A Boucher; Bart J A Rijnders; Jeroen J A van Kampen; Thibault Mesplède; Mark A Wainberg Journal: J Infect Dis Date: 2018-07-24 Impact factor: 5.226
Authors: Michael S Saag; Constance A Benson; Rajesh T Gandhi; Jennifer F Hoy; Raphael J Landovitz; Michael J Mugavero; Paul E Sax; Davey M Smith; Melanie A Thompson; Susan P Buchbinder; Carlos Del Rio; Joseph J Eron; Gerd Fätkenheuer; Huldrych F Günthard; Jean-Michel Molina; Donna M Jacobsen; Paul A Volberding Journal: JAMA Date: 2018-07-24 Impact factor: 56.272