ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)–infected Participants With HIV-1 RNA &lt;500000 Copies/mL

Taiwo, Babafemi; Li, Zheng; Ștefănescu, Andrei; Nyaku, Amesika; Bezins, Baiba; Wallis, Carole L.; Godfrey, Catherine; Sax, Paul E.; Acosta, Edward P.; Haas, David W.; Smith, Kimberly Y.; Sha, Beverly E.; Dam, Cornelius Van; Gulick, Roy M.

doi:10.1093/cid/cix1083

Cited by 92 publications

(75 citation statements)

References 21 publications

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“…A number of large prospective studies evaluating the efficacy of DTG-based dual therapy are under way and will inform its potential implementation at a large scale. In addition to the studies on maintenance therapy 39, 40 , clinical trials are also assessing the efficacy of DTG/XTC in treatment-naïve patients 41 . Furthermore, it will be critical to evaluate the efficacy of DTG-XTC dual therapy in specific sub-groups such as pregnant and breast-feeding women, adolescents, patients with previous failure to standard triple regimens and harboring the M184V resistance mutation, as well as in patients with HIV associated neurocognitive disorder and tuberculosis coinfection.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…The study concluded that the two‐drug regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV‐therapy‐naive PLWH . The results of the PADDLE study were later confirmed in the ACTG 5353 study and, more recently, in two large phase III clinical trials (GEMINI studies). In these latter studies, a combination of 3TC+dolutegravir proved to be as efficacious as a triple‐drug combination consisting of TDF/FTC + dolutegravir as initial therapy in PLWH with a viral load of < 500 000 HIV‐RNA copies/mL (90% vs .…”

Section: The Use Of Two‐drug Combinations: Information From Clinical mentioning

confidence: 93%

“…Additionally, there was lower resistance protection when bPIs or dolutegravir (DTG) when used as two‐drug combination therapy. Although resistance to DTG has not developed in patients failing a triple‐drug regimen containing the drugs, neither in clinical trials nor in clinical practice, resistance to DTG was selected only in one of three patients who failed a combination of 3TC+dolutegravir in a controlled clinical trial . However, no resistant mutants were selected in patients who failed 3TC+dolutegravir in the Gemini Studies .…”

Section: The Use Of Two‐drug Combinations: Information From Clinical mentioning

confidence: 99%

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

et al. 2019

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Three‐drug combination antiretroviral therapy (ART) became available in 1996, dramatically improving the prognosis of people living with HIV. The clinical benefits of ART are due to the sustained viral load suppression and CD4 T cell gains. Major drawbacks of the first ART regimens were adverse events, and high pill burden, which led to the reduction of drug adherence resulting in frequent treatment discontinuations and the development of drug resistance. Due to increased viral potency of new antiretroviral drugs consideration of a two‐drug combination therapy repositioning occurred in an effort to reduce adverse events, drug‐drug interactions and cost, while maintaining a sustained antiviral effect. Various combinations of two‐drug regimens have been studied, and non‐inferiority compared to a three‐drug regimen has been shown only for some of them. In addition, a two‐drug combination regimen may not be suitable for every patient, especially those who are pregnant, those with tuberculosis or coexisting HBV infection. Furthermore no information has been generated concerning the secondary transmission of HIV from patients who have undetectable plasma viral load on two‐drug regimens. Additional studies of two‐drug combinations are also necessary to evaluate the debated existence of low viral replication in tissues and on immune activation. While there is no urgent need to routinely switch patients to two‐drug combination therapy, due to the availability of drug combinations without significant toxicities, dual regimens represent a suitable option that deserve long‐term evaluation before being introduced to clinical practice.

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“…Any virologic failure with resistance development to DTG as part of a three-drug regimen has been rare in treatment-naive patients but has occurred when DTG was not used with two fully active antiretroviral drugs. In the ACTG A5353 study investigating the use of DTG plus 3TC in treatment-naive participants, one participant developed M184V in RT plus the DTG-selected mutation R263R/K in IN (22). The mutation R263K has additionally been reported in four patients who were ART experienced but INSTI naive and received a DTG-containing regimen (23,24).…”

mentioning

confidence: 99%

Resistance Analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 Weeks

Acosta

Willkom

Martin

et al. 2019

Antimicrob Agents Chemother

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In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravirabacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTGϩF-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.Of the 1,421 participants with screening genotypes, only 3 had protocol-defined exclusion mutations (1 with M184V, 1 with M184M/V, and 1 with M184V, M41L, L210W, T215F/Y, and K219Q in RT) and were excluded for drug resistance reasons. The studies enrolled and dosed 1,274 participants who showed full sensitivity to FTC and TAF based on the proprietary genotypic algorithm from Monogram Biosciences. No participant had HIV-1 with the tenofovir or FTC-3TC resistance-associated substitutions K65R/E/N or M184V/I, respectively, according to the population genotype at screening. Retrospective deep-sequencing analyses of PR, RT, and integrase (IN) were performed on baseline samples of enrolled participants using the deepType HIV assay (Seq-IT GmbH & Co. KG, Kaiserslautern, Germany), and resistance mutations seen at frequencies of Ն15% were tabulated and combined with population sequencing results (Table 1). The 15% cutoff was chosen to mirror population sequencing thresholds and to ensure that mutations were above the background error of the assay. Primary NRTI resistance (NRTI-R) substitutions were observed in 2.7% (35 of 1,274) of participants, and the most frequent substitutions were M41L and K219E/N/Q/R in RT. These are thymidine analog resistance mutations (TAMs) and remain sensitive to FTC and tenofovir when fewer than three TAMs are present (7). Although not detected by population sequencing at screening, K65R/E was observed by deep sequencing above the 15% threshold in three participants (two with K65E in the B-F-TAF group; frequencies of 15% to 23%). Primary NNRTI resistance (NNRTI-R) substitutions were observed in 14.1% (179 of 1,274) of participants, and the most frequent substitutions were K103N/S and E138A/G/K/Q in RT. Primary protease inhibitor (PI) resistance substitutions were observed in 3.5% (44 of 1,274) of participants, and the most frequent substitutions were M46I/L, Q58E, and L90M in PR. The frequencies of baseline-transmitted resistance to antiretrovirals (ARVs) were consistent with findings of other reports (8-10).No genotyping of HIV integrase (IN) was conducted at screening in studies 1489 and 1490. However, retrospective baseline IN genotypic data...

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ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)–infected Participants With HIV-1 RNA <500000 Copies/mL

Abstract: NCT02582684.

Cited by 92 publications

References 21 publications

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

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

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

Resistance Analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 Weeks

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