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

Wijting, Ingeborg E A; Rokx, Casper; Boucher, Charles A.; Kampen, Jeroen J. A. van; Pas, Suzan D.; Vries-Sluijs, Theodora de; Schurink, Carolina A. M.; Bax, Hannelore I.; Derksen, Maarten; Andrinopoulou, Eleni‐Rosalina; Ende, Marchina van der; Gorp, Eric C. M. Van; Nouwen, Jan L.; Verbon, Annelies; Bierman, Wouter F W; Rijnders, Bart J. A.

doi:10.1016/s2352-3018(17)30152-2

Cited by 105 publications

(82 citation statements)

References 22 publications

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“…Moreover, recent in vitro studies indicated a protective role of M184V against the selection of dolutegravir resistance mutations, further explaining the lack of impact of this mutation on the efficacy of lamivudine plus dolutegravir [16]. Interestingly, in our cohort, 21 patients on lamivudine plus dolutegravir carried M184V, and none failed after a median follow-up of 10 months, whereas dolutegravir maintenance monotherapy studies have shown measurable failure rates during follow-up of similar duration [17, 18]. …”

Section: Discussionmentioning

confidence: 68%

Impact of the M184V Resistance Mutation on Virological Efficacy and Durability of Lamivudine-Based Dual Antiretroviral Regimens as Maintenance Therapy in Individuals With Suppressed HIV-1 RNA: A Cohort Study

Gagliardini

Ciccullo

Borghetti

et al. 2018

Open Forum Infectious Diseases

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BackgroundDual therapy (DT) with boosted protease inhibitors (bPIs) plus lamivudine has been shown to be superior to bPI monotherapy in virologically suppressed patients despite previous selection of the lamivudine resistance M184V mutation. We compared the virological efficacy of lamivudine-based DT in patients with and without a history of M184V detection.MethodsWe retrospectively analyzed patients with HIV-RNA ≤50 copies/mL switching to DT with at least 1 previous resistance genotype in the ARCA database. Time to virological failure (VF; HIV-RNA ≥200 copies/mL or 2 consecutive HIV-RNA >50 copies/mL) and to treatment discontinuation (TD) was analyzed by survival analysis.ResultsFour hundred thirty-six patients switching to lamivudine plus bPIs (70%) or integrase inhibitors (30%) were included. Patients with M184V (n = 87) were older, had lower nadir CD4+ cell count, longer duration of antiretroviral therapy and of virologic suppression, and higher rate of hepatitis C virus infection compared with patients without M184V. The 3-year probability of remaining free from VF was 91.9% (95% confidence interval [CI], 86.6–97.2) without M184V and 87.8% (95% CI, 78.4–97.2) with M184V (P = .323). The time to TD did not differ between groups. Multivariate analysis adjusting for baseline variables differing between groups also did not detect M184V as being associated with VF or TD; however, the 3-year probability of remaining free of viral blips (isolated HIV-RNA 51–199 copies/mL) was 79.8% (95% CI, 67.8%–91.8%) with M184V vs 90.1% (95% CI, 84.0%–96.2%) without M184V (P = .016).ConclusionsPrevious selection of M184V did not increase the risk of VF or TD with lamivudine-based DT but was associated with a higher probability of viral blips.

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Section: Discussionmentioning

confidence: 68%

Impact of the M184V Resistance Mutation on Virological Efficacy and Durability of Lamivudine-Based Dual Antiretroviral Regimens as Maintenance Therapy in Individuals With Suppressed HIV-1 RNA: A Cohort Study

Gagliardini

Ciccullo

Borghetti

et al. 2018

Open Forum Infectious Diseases

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“…Of these, 21 studies, including four RCTs, three single-arm clinical trials and 14 observational studies met our inclusion criteria 8, 11, 12, 18– 35 ( Figure 1). A description of the main study characteristics by type of maintenance strategy is given in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…In one study, patients with previous InSTI failure were also included 12 . Nineteen studies assessed virological outcomes at six months of maintenance therapy, whereas ten of them additionally showed outcomes at one year 8, 11, 12, 24, 27, 29– 33, 35 . Two studies assessed virological outcomes only at 48 weeks 25, 27 .…”

Section: Resultsmentioning

confidence: 99%

“…All RCTs were open-label non-inferiority trials 8, 18, 35 , of which one was a single center trial 18 and three were multicenter trials 8, 11, 35 . They reported adequate generation of random allocation sequences and allocation concealment.…”

Section: Resultsmentioning

confidence: 99%

“…While preliminary analyses of a Dutch DTG monotherapy simplification trial seemed encouraging at 24 weeks, rates of virological failures increased significantly by week 48, suggesting a sub-optimal potency of this regimen 8 . On the other hand, several studies evaluating DTG-based dual therapy with either 3TC or rilpivirine (RPV), showed a high virological efficacy 9– 12 .…”

Section: Introductionmentioning

confidence: 95%

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

Wandeler

Buzzi²,

Anderegg

et al. 2018

F1000Res

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Background: Dolutegravir-containing maintenance therapy is a promising simplification strategy for virologically suppressed HIV-infected individuals. However, most of the available data to inform this strategy come from small, uncontrolled studies. We estimated the proportion of HIV-infected patients experiencing virological failure (VF) and developing drug resistance on dolutegravir (DTG)-based maintenance therapy. Methods: We searched Medline, Embase, Cochrane Central, Web of Science, and conference abstracts for studies assessing VF on DTG-based maintenance therapy. Studies including ≥5 adults with an undetectable viral load on antiretroviral therapy (ART) who switched to a DTG-based mono- or dual therapy were included. Pooled proportions of VF were estimated using random-intercept logistic meta-regression and acquired drug resistance mutations described for each strategy. Results: Of 1719 studies considered, 21 met our selection criteria, including seven interventional and 14 observational studies. Eight studies including 251 patients assessed VF on DTG monotherapy and fourteen studies including 1670 participants VF on dual therapy. The participant’s median age ranged from 43 to 63 years, their median nadir CD4 count from 90 to 399 cells/µl, and 27.6% were female. The proportion of participants experiencing VF on DTG-monotherapy was 3.6% (95% confidence interval [CI] 1.9-6.7) at 24 weeks and 8.9% (95% CI 4.7-16.2) at 48 weeks. Resistance mutations developed in seven (3.6%) participants on DTG-monotherapy. Among patients on dual therapy, ten (0.7%, 95% CI 0.4-1.3) experienced VF by 48 weeks and none developed resistance to DTG. In adjusted analyses, VF at 24 weeks was less likely on dual therapy than on monotherapy (adjusted odds ratio: 0.10, 95% CI 0.03-0.30). Conclusions: Whereas VF is relatively common on DTG maintenance monotherapy, DTG-based dual therapy appears to be a promising simplification strategy for individuals with a suppressed HIV viral load on triple-ART.

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Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

Saag

Benson

Gandhi

et al. 2018

JAMA

498

280

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IMPORTANCE Antiretroviral therapy (ART) is the cornerstone of prevention and management of HIV infection. OBJECTIVE To evaluate new data and treatments and incorporate this information into updated recommendations for initiating therapy, monitoring individuals starting therapy, changing regimens, and preventing HIV infection for individuals at risk. EVIDENCE REVIEW New evidence collected since the International Antiviral Society–USA 2016 recommendations via monthly PubMed and EMBASE literature searches up to April 2018; data presented at peer-reviewed scientific conferences. A volunteer panel of experts in HIV research and patient care considered these data and updated previous recommendations. FINDINGS ART is recommended for virtually all HIV-infected individuals, as soon as possible after HIV diagnosis. Immediate initiation (eg, rapid start), if clinically appropriate, requires adequate staffing, specialized services, and careful selection of medical therapy. An integrase strand transfer inhibitor (InSTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is generally recommended for initial therapy, with unique patient circumstances (eg, concomitant diseases and conditions, potential for pregnancy, cost) guiding the treatment choice. CD4 cell count, HIV RNA level, genotype, and other laboratory tests for general health and co-infections are recommended at specified points before and during ART. If a regimen switch is indicated, treatment history, tolerability, adherence, and drug resistance history should first be assessed; 2 or 3 active drugs are recommended for a new regimen. HIV testing is recommended at least once for anyone who has ever been sexually active and more often for individuals at ongoing risk for infection. Preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and appropriate monitoring is recommended for individuals at risk for HIV. CONCLUSIONS AND RELEVANCE Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.

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

Cited by 105 publications

References 22 publications

Impact of the M184V Resistance Mutation on Virological Efficacy and Durability of Lamivudine-Based Dual Antiretroviral Regimens as Maintenance Therapy in Individuals With Suppressed HIV-1 RNA: A Cohort Study

Impact of the M184V Resistance Mutation on Virological Efficacy and Durability of Lamivudine-Based Dual Antiretroviral Regimens as Maintenance Therapy in Individuals With Suppressed HIV-1 RNA: A Cohort Study

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

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults

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