Dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA &lt;500 000 copies/mL: week 48 outcomes from ACTG 5353

Nyaku, Amesika; Li, Zheng; Gulick, Roy M.; Olefsky, Maxine; Berzins, Baiba; Wallis, Carole L.; Godfrey, Catherine; Sax, Paul E.; Acosta, Edward P.; Haas, David W.; Smith, Kimberly Y.; Sha, Beverly E.; Dam, Cornelius N. Van; Taiwo, Babafemi; Hawkins, Elizabeth; Kumwenda, Johnstone; Hernández, Ángel Goyenechea; Ha, Belinda; Jarocki, Bernadette; Tegha, Gerald; Sullivan, Tanisha

doi:10.1093/jac/dky564

Cited by 20 publications

(10 citation statements)

References 11 publications

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“…The largest trial was a randomized controlled trial (GEMINI) that reported a non-inferior 91% virological response rate at week 48 for 716 persons receiving dolutegravir/lamivudine compared with a similar number of persons receiving dolutegravir plus tenofovir/emtricitabine 75 . The remaining two trials were pilot trials that enrolled 120 persons for 48 weeks (A5353) 20 , 77 or 20 persons for 48 weeks 76 . The VF rate was 10% in these two trials.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of the genetic mechanisms of dolutegravir resistance

Rhee

Grant

Tzou

et al. 2019

Journal of Antimicrobial Chemotherapy

119

105

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Background Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy. Methods We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in vitro dolutegravir susceptibility, and the virological efficacy of dolutegravir in antiretroviral-experienced persons. Results and conclusions We analysed 14 studies describing 84 in vitro passage experiments, 26 studies describing 63 persons developing VF plus INSTI resistance mutations on a dolutegravir-containing regimen, 41 studies describing dolutegravir susceptibility results, and 22 clinical trials and 16 cohort studies of dolutegravir-containing regimens. The most common INSTI resistance mutations in persons with VF on a dolutegravir-containing regimen were R263K, G118R, N155H and Q148H/R, with R263K and G118R predominating in previously INSTI-naive persons. R263K reduced dolutegravir susceptibility ∼2-fold. G118R generally reduced dolutegravir susceptibility >5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations. Dolutegravir two-drug regimens were highly effective for first-line therapy and for virologically suppressed persons provided dolutegravir’s companion drug was fully active. Dolutegravir three-drug regimens were highly effective for salvage therapy in INSTI-naive persons provided one or more of dolutegravir’s companion drugs was fully active. However, dolutegravir monotherapy in virologically suppressed persons and functional dolutegravir monotherapy in persons with active viral replication were associated with a non-trivial risk of VF plus INSTI resistance mutations.

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Section: Resultsmentioning

confidence: 99%

A systematic review of the genetic mechanisms of dolutegravir resistance

Rhee

Grant

Tzou

et al. 2019

Journal of Antimicrobial Chemotherapy

119

105

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“…Whilst many studies have shown 2DRs are non-inferior to 3DRs for short-term virologic and immunologic endpoints, data comparing clinical endpoints remains scarce (11)(12)(13)(14)(15)(16)(17)(18)(19)37,38).…”

Section: Discussionmentioning

confidence: 99%

Clinical Outcomes of 2-Drug Regimens vs 3-Drug Regimens in Antiretroviral Treatment–Experienced People Living With Human Immunodeficiency Virus

Greenberg

Ryom

Neesgaard

et al. 2020

Clinical Infectious Diseases

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Background Limited data exist comparing clinical outcomes of two-drug regimens (2DRs) and three-drug regimens (3DRs) in people living with HIV. Methods Antiretroviral treatment-experienced individuals in RESPOND switching to a new 2DR or 3DR from 1/1/12-1/10/18 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median 52.6 years [interquartile range 46.7-59.0] vs 47.7 [39.7-54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27,159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU [95% CI 20.7-24.5]) on 3DRs, 79 (30.9/1000 PYFU [24.8-38.5]) on 2DRs. The most common events were death (7.5/1000 PYFU [95% CI 6.5-8.6]) and non-AIDS cancer (5.8/1000 PYFU [4.9-6.8]). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio: 0.92 [0.72-1.19]; p=0.53). Conclusions This is the first large, international cohort assessing clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes; further research on resistance barriers and long-term durability of 2DRs is needed.

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“…DTG/3TC: a switch to the two-drug combination DTG/3TC, a regimen shown to be effective as initial therapy, 81 was also recently shown to be non-inferior to continuing a TAF-based three-drug regimen in maintaining virologic suppression in HIV-1-infected ART-experienced adults. 82 This regimen may be considered for patients with significant metabolic comorbidities, such as cardiovascular, renal, or bone disease.…”

Section: Optimizing Antiretroviral Therapy In Setting Of Virologic Sumentioning

confidence: 99%

The management of treatment-experienced HIV patients (including virologic failure and switches)

Cutrell

Jodlowski

Bedimo

2020

Therapeutic Advances in Infection

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Significant advances in the potency and tolerability of antiretroviral therapy (ART) have led to very high rates of virologic success for most who remain adherent to therapy. As a result, the life expectancy of people living with HIV (PLWH) has increased significantly. PLWH do, however, continue to experience a significantly higher risk of noninfectious comorbidities and chronic age-related complications, including cardiovascular disease and malignancies, which are now the biggest drivers of this excess morbidity and mortality. Therefore, in addition to virologic failure, the management of the treatment-experienced patient increasingly requires optimization of ART to enhance tolerability, avoid drug–drug interactions, and mitigate non-AIDS complications and comorbid conditions. This article will present principles of the management of virologic failure, poor immunologic recovery, and strategies for optimizing ART in the setting of virologic suppression.

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Dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA <500 000 copies/mL: week 48 outcomes from ACTG 5353

Cited by 20 publications

References 11 publications

A systematic review of the genetic mechanisms of dolutegravir resistance

A systematic review of the genetic mechanisms of dolutegravir resistance

Clinical Outcomes of 2-Drug Regimens vs 3-Drug Regimens in Antiretroviral Treatment–Experienced People Living With Human Immunodeficiency Virus

The management of treatment-experienced HIV patients (including virologic failure and switches)

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