Efficacy and safety of three antiretroviral therapy regimens started in pregnancy up to 50 weeks post partum: a multicentre, open-label, randomised, controlled, phase 3 trial

Chinula, Lameck; Ziemba, Lauren; Brummel, Sean; McCarthy, Katie; Coletti, Anne; Krotje, Chelsea; Johnston, Benjamin; Knowles, Kevin R.; Moyo, Sikhulile; Stranix‐Chibanda, Lynda; Hoffman, Risa M.; Sax, Paul E.; Stringer, Jeffrey S. A.; Chakhtoura, Nahida; Jean‐Philippe, Patrick; Korutaro, Violet; Cassim, Haseena; Fairlie, Lee; Masheto, Gaerolwe; Boyce, Ceejay L; Frenkel, Lisa M.; Amico, K Rivet; Purdue, Lynette; Shapiro, Roger; Mmbaga, Blandina T.; Patel, Faeezah; Wyk, Jean van; Rooney, James F.; Currier, Judith S.; Lockman, Shahin; Best, Brookie M.; Blanchette, Cheryl; Browning, Renee; Jaliaah, Nagawa; Mirochnick, Mark; Murtaugh, William; Patras, Emmanuel; Momper, Jeremiah D.; Ponatshego, Ponego; Tirelo, Lesedi; Seme, Boitshepo; Modise, Georginah O.; Raesi, Mpho S.; Budu, Marian E.; Ramogodiri, Moakanyi; Oliveira, Ricardo Hugo de; Hofe, Cristina B; Abreu, Thalita; Pestanha, Lorena M.; João, Esaú; Sidi, Leon Claude; Fuller, Trevon; Cruz, Maria Letícia Santos; Pinto, Jorge; Ferreira, Flavia F; Corrêa, Mário Dias; Romeiro, Juliana Ribeiro; Pilotto, José Henrique; Fernandes, Luis Eduardo; Moreira, L.F.P.; Gomes, Ivete Martins; Naik, Shilpa; Nevrekar, Neetal; Mave, Vidya; Kinikar, Aarti; Horne, Elizea; Soma-Kasiram, Hamisha; Violari, Avy; Mathiba, Sisinyana Ruth; Nyati, Mandisa; Theron, Gerhard; Jager, Jack; Rossouw, Magdel; Rossouw, Lindie; Hanley, Sherika; Desmond, Alicia C; Gazu, Rosemary; Govender, Vani; Chalermchockcharoenkit, Amphan; Thamkhantho, Manopchai; Werarak, Peerawong; Rungmaitree, Supattra; Achalapong, Jullapong; Sitiritkawin, Lukkana; Cressey, Tim R.; Sukrakanchana, Pra-ornsuda; Aurpibul, Linda; Tongprasert, Fuanglada; Khamrong, Chintana; Kiattivej, Sopida; Wabwire, Deo; Kabugo, Enid; Maena, Joel; Nakayiwa, Frances; Ndyanabangi, Victoria; Nagaddya, Beatrice; Sekabira, Rogers; Ashaba, Justus; Mitchell, Charles D.; Drada, Adriana; Alvarez, Grace; Scott, Gwendolyn B.; Rathore, Mobeen H.; Mahmoudi, Saniyyah; Shabbir, Adnan; Maraqa, Nizar; Mandima, Patricia; Mutambanengwe, Mercy; Maonera, Suzen; Chareka, Gift; Nematadzira, Teacler; Chanaiwa, Vongai; Matubu, Taguma Allen; Tamirepi, Kevin; Maturure, Sukunena; Mhembere, Tsungai; Vhembo, Tichaona; Chidemo, Tinashe; Whalen, Frances

doi:10.1016/s2352-3018(23)00061-9

Cited by 17 publications

(5 citation statements)

References 15 publications

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“…DTG plus two NRTIs: Table 2 summarizes the population characteristics, prevalence of VF, and GRT results in 16 clinical trials of 4636 ART-naïve PLWH treated with DTG plus two NRTIs [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. The trials included seven multicenter registration trials in which participants were evaluated at week 96 (and week 144 in one trial), two trials from Sub-Saharan Africa in which participants were evaluated at week 96, two trials in which participants were evaluated at week 48, and five trials of special populations.…”

Section: Resultsmentioning

confidence: 99%

“…At the time of VF, GRT was performed on 147 individuals (3.2% of all participants) receiving DTG and only one (0.02% of all participants and 0.7% of those with VF) developed an INSTI DRM. This individual was 1 of 405 women treated during the second trimester of pregnancy and evaluated 50 weeks post-partum [ 30 ]. The emergent INSTI DRMs included S147G, N155H, and S230R.…”

Section: Resultsmentioning

confidence: 99%

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Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Chu,

Tao,

Kouamou

et al. 2024

Viruses

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Background: Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART. Methods: We performed a PubMed search using the term “Dolutegravir”, last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART. Results: Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details. Conclusions: In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Chu,

Tao,

Kouamou

et al. 2024

Viruses

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“…Following the review of their titles and abstracts, 232 publications were submitted for full-text review. Following full-text review, 36 publications were found to have reports of INSTI-naïve PLWH who developed one or more INSTI-associated DRMs while receiving DTG [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], and 21 publications contained in vitro susceptibility results performed using the PhenoSense assay [ 32 , 33 , 35 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , ...…”

Section: Resultsmentioning

confidence: 99%

Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review

Tao,

Rhee,

Chu

et al. 2023

Viruses

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Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) rarely leads to virological failure (VF) and drug resistance in integrase strand transfer inhibitor (INSTI)-naïve persons living with HIV (PLWH). As a result, limited data are available on INSTI-associated drug resistance mutations (DRMs) selected by DTG-containing ART regimens. Methods: We reviewed studies published through July 2023 to identify those reporting emergent major INSTI-associated DRMs in INSTI-naïve PLWH receiving DTG and those containing in vitro DTG susceptibility results using a standardized assay. Results: We identified 36 publications reporting 99 PLWH in whom major nonpolymorphic INSTI-associated DRMs developed on a DTG-containing regimen and 21 publications containing 269 in vitro DTG susceptibility results. DTG-selected DRMs clustered into four largely non-overlapping mutational pathways characterized by mutations at four signature positions: R263K, G118R, N155H, and Q148H/R/K. Eighty-two (82.8%) viruses contained just one signature DRM, including R263K (n = 40), G118R (n = 24), N155H (n = 9), and Q148H/R/K (n = 9). Nine (9.1%) contained ≥1 signature DRM, and eight (8.1%) contained just other DRMs. R263K and G118R were negatively associated with one another and with N155H and Q148H/K/R. R263K alone conferred a median 2.0-fold (IQR: 1.8–2.2) reduction in DTG susceptibility. G118R alone conferred a median 18.8-fold (IQR:14.2–23.4) reduction in DTG susceptibility. N155H alone conferred a median 1.4-fold (IQR: 1.2–1.6) reduction in DTG susceptibility. Q148H/R/K alone conferred a median 0.8-fold (IQR: 0.7–1.1) reduction in DTG susceptibility. Considerably higher levels of reduced susceptibility often occurred when signature DRMs occurred with additional INSTI-associated DRMs. Conclusions: Among INSTI-naïve PLWH with VF and treatment emergent INSTI-associated DRMs, most developed one of four signature DRMs, most commonly R263K or G118R. G118R was associated with a much greater reduction in DTG susceptibility than R263K.

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“…Only three treatment options are recommended as first‐line regimens for ART‐naïve pregnant women, including triple‐drug regimens consisting of tenofovir (either TDF or TAF) with either XTC plus DTG 50 mg daily, RAL 400 mg twice daily (bid), or boosted darunavir/ritonavir (DRV/r) 600/100 mg bid. All restrictions to the use of TAF or DTG in pregnant women have been now removed because of a favourable risk/benefit ratio in recent studies [5].…”

Section: Methodsmentioning

confidence: 99%

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023

Ambrosioni,

Levi,

Alagaratnam

et al. 2023

HIV Medicine

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BackgroundThe European AIDS Clinical Society (EACS) guidelines were revised in 2023 for the 19th time, and all aspects of HIV care were updated.Key Points of the Guidelines UpdateVersion 12.0 of the guidelines recommend the same six first‐line treatment options for antiretroviral treatment (ART)‐naïve adults as versions 11.0 and 11.1: tenofovir‐based backbone plus an unboosted integrase inhibitor or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. The long‐acting section has been expanded in the ART and drug–drug interaction (DDI) panels. Tables for preferred and alternative ART in children and adolescents have been updated, as has the section on prevention of vertical transmission, particularly with new guidance for breastfeeding. A new DDI table has been included for the ART and anti‐infective drugs used for opportunistic infections, sexually transmitted infections, and other infectious conditions; lenacapavir has been included in all DDI tables. New sections on alcohol use and patient‐reported outcome measures (PROMs) have been included in the comorbidity panel, in addition to updates on many relevant topics, such as new resource guidance for deprescribing in people with HIV. Other sections, including travel, cognitive impairment, cancer screening, sexual health, and diabetes have also been revised extensively. The algorithm for the management of acute hepatitis C virus infection has been removed, as current guidelines recommend immediate treatment of all people with recently acquired hepatitis C virus. Updates on vaccination for hepatitis B virus and recommendations for simplification to tenofovir‐free two‐drug regimens in people with isolated anti‐hepatitis B core antibodies are provided. In the opportunistic infections and COVID‐19 panel, guidance on the management of COVID‐19 in people with HIV has been updated according to the most up‐to‐date evidence, and a new section on monkeypox has been added.ConclusionsIn 2023, the EACS guidelines were updated extensively and now include several new sections. The recommendations are available as a free app, in interactive web format, and as a pdf online.

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Efficacy and safety of three antiretroviral therapy regimens started in pregnancy up to 50 weeks post partum: a multicentre, open-label, randomised, controlled, phase 3 trial

Cited by 17 publications

References 15 publications

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023

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