Elsevier

The Lancet HIV

Volume 4, Issue 12, December 2017, Pages e547-e554
The Lancet HIV

Articles
Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial

https://doi.org/10.1016/S2352-3018(17)30152-2Get rights and content

Summary

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.

Introduction

Combination antiretroviral therapy (ART) regimens containing the second-generation integrase inhibitor dolutegravir have similar or superior rates of virological suppression as combination ART regimens containing raltegravir, efavirenz, or darunavir in adults with an HIV-1 infection.1, 2, 3 The high virological efficacy, favourable safety profile, and high genetic resistance barrier of dolutegravir has led to the recommendation of dolutegravir-containing ART regimens as a first-line strategy in HIV treatment guidelines.4, 5 Although existing combination ART regimens are effective, maintenance therapy with one or two drugs might have advantages, including reduced side-effects, pill burden, and costs. Various factors make dolutegravir a suitable candidate for maintenance monotherapy: the development of resistance is rare in patients previously untreated with integrase inhibitors;1, 6, 7 the risk of drug interactions is low; and the drug has good tolerability, a once-daily dosing schedule, a small pill size, and a neutral effect on serum lipids.

Previous studies8, 9 have not shown monotherapy with protease inhibitors to be virologically non-inferior to ART, although virological failure during monotherapy has not been associated with an increased incidence of resistance to that drug class. However, in one study10 of virologically suppressed patients fulfilling strict criteria regarding HIV RNA zenith (<100 000 copies per mL) and CD4 nadir (>200 cells per μL), maintenance monotherapy with protease inhibitors was non-inferior to combination ART. We found dolutegravir maintenance monotherapy to be promising in a retrospective observational study11 of five patients, although no control group was used. Therefore, we did the DOMONO trial to investigate whether a switch to dolutegravir monotherapy would be non-inferior to continuation of combination ART in maintaining virological suppression in patients with an HIV-1 infection.

Research in context

Evidence before this study

There is an ongoing need for simplification of combination antiretroviral therapy (ART), preferably with nucleotide-sparing regimens. Dolutegravir has a high genetic barrier to resistance and, therefore, might be suitable as maintenance monotherapy, as suggested by findings from a small case series. We searched PubMed between Sept 1, and Dec 8, 2014, using the terms “dolutegravir” AND “monotherapy” AND “randomi*”, with inclusion of English-language articles only. We found no substantive evidence from published randomised trials of maintenance of virological suppression with dolutegravir monotherapy compared with combination ART.

Added value of this study

We aimed to show that dolutegravir monotherapy was non-inferior to combination ART for maintaining virological suppression in 104 patients with HIV-1 infection who had been successfully treated with combination ART, had HIV RNA zeniths of 100 000 copies per mL or less, and CD4 nadirs of 200 cells per μL or higher. We found that dolutegravir monotherapy was non-inferior to combination ART at 24 weeks: an HIV RNA viral load of 200 copies per mL or higher was observed in one of 50 patients who switched to dolutegravir monotherapy immediately and none of the 53 patients who switched after 24 weeks of continued combination ART (difference 2%, 95% CI −5 to 12). However, new mutations associated with resistance in the integrase gene were detected in three patients, and virological failure was eventually observed in eight of the 95 patients who started dolutegravir monotherapy.

Implications of the available evidence

Despite promising findings from an observational case series, our results clearly show that dolutegravir should not be used as maintenance monotherapy. Investigators in ongoing studies of dolutegravir monotherapy should strongly reconsider their study design and inform their institutional review boards and patients about these results.

Section snippets

Study design and participants

We did this open-label, phase 2, randomised non-inferiority trial in two university medical centres in the Netherlands: the Erasmus MC University Medical Center and University Medical Center Groningen. Eligible patients were 18 years or older, on combination ART, and had been virologically suppressed (HIV RNA <50 copies per mL) for at least 6 months at the time of screening, with an HIV RNA zenith of 100 000 copies per mL or less and a CD4 nadir of 200 cells per μL or higher. A previous HIV RNA

Results

Between March 10, 2015, and Feb 4, 2016, we randomly assigned 104 patients to receive immediate (n=51) or delayed (n=53) dolutegravir monotherapy (figure 1). Baseline characteristics were similar between the groups (table 1). For our concurrent control group, we recruited 152 consecutive patients who had chosen not to participate in the DOMONO study. Patients in this group had to have been available for follow-up for at least 1 year and have a viral load result available between 44 weeks and 56

Discussion

Dolutegravir monotherapy was non-inferior to combination ART in maintaining virological suppression for 24 weeks, with virological failure recorded in only one patient in the group that immediately switched to dolutegravir monotherapy and in no patient in the delayed switch group at this timepoint. No resistance-associated mutations in the integrase gene were detected in the virus from the one patient with virological failure at week 24, and viral replication in this patient was resuppressed

References (26)

  • JR Arribas et al.

    Efficacy of protease inhibitor monotherapy vs. triple therapy: meta-analysis of data from 2303 patients in 13 randomized trials

    HIV Med

    (2016)
  • PM Girard et al.

    Week 96 efficacy and safety of darunavir/ritonavir monotherapy vs. darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors in the PROTEA trial

    HIV Med

    (2017)
  • C Rokx et al.

    Dolutegravir as maintenance monotherapy: first experiences in HIV-1 patients

    J Antimicrob Chemother

    (2016)
  • Cited by (0)

    View full text