Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort

Cuzin, Lise; Puglièse, Pascal; Katlama, Christine; Bani‐Sadr, Firouzé; Ferry, Tristan; Rey, David; Lourenco, J; Brégigeon, Sylvie; Allavena, Clotilde; Reynes, Jacques; Cabie, André; Drobacheff-Thiébaut, C; Foltzer, A; Bouiller, Kévin; Hustache‐Mathieu, Laurent; Chirouze, Catherine; Lepiller, Quentin; Bozon, F.; Babre, O; Muret, Patrice; Laurichesse, H.; Lesens, Olivier; Vidal, María Amparo Gómez; Mrozek, Natacha; Auméran, C.; Baud, Olivier; Corbin, V.; Letertre, P; Casanova, S.; Jacomet, Christine; Hoën, Bruno; Lamaury, I.; Fabre, Isabelle; Curlier, Elodie; Ouissa, Rachida; Schepers, Kinda; Herrmann-Storck, Cécile; Dournon, Nathalie; Merrien, Dominique; Perre, Philippe Vande; Guimard, Thomas; Bollangier, O; Léautez, S; Morrier, Marine; Ader, Florence; Biron, F.; Boibieux, A.; Cotte, Laurent; Miailhes, Patrick; Perpoint, Thomas; Roux, Stanzi M le; Degroodt, S; Brochier, C; Valour, Florent; Chidiac, Christian; Dhiver, Catherine; Mokhtari, M.; Ménard, Amélie; Dupont, Hervé; Tomei, Christelle; Meddeb, Line; Belkhir, A Y; Ravaux, Isabelle; Zaegel-Faucher, Olivia; Obry-Roguet, Véronique; Orticoni, M; Soavi, M.J.; Luquet-Besson, I; Ressiot, E.; Carta-Padovani, M; Ducassou, M J; Bertone, H; Galie, Sébastien; Galinier, Anne; Monclar, M; Ritleng, A S; Ivanova, A; Blanco-Betancourt, Carla; Lions, C.; Poizot‐Martin, Isabelle; Abel, Sylvie; Césaire, Raymond; Santos, Georges Dos; Fagour, Laurence; Illiaquer, Marina; Najioullah, Fatiha; Nguyen, Duytrac Vu; Ouka, M.; Pierre-François, Sandrine; Pasquier, Jérémie; Pircher, Mathilde; Rozé, B.; Atoui, N.; Moing, Vincent Le; Makinson, Alain; Meftah, N; Boever, Corinne Merle De; Montès, Brigitte; Ferrer, Ana; André, Marie; Boyer, L.; Bouillon, M P; Delestan, M; May, Thierry; Bernaud, C; Billaud, Éric; Biron, Charlotte; Bonnet, B.; Bouchez, Sabelline; Boutoille, David; Brunet-Cartier, Cécile; Hall, Nolwenn; Jovelin, T; Morineau, P.; Reliquet, Véronique; Hüe, H.; Sécher, S.; Cavellec, M; Soria, A; Ferré, Virginie; André-Garnier, Élisabeth; Rodallec, Audrey; Guen, L. Le; Lefèbvre, M.; Grossi, Olivier; Point, P; Aubry, O; Khatchatourian, Lydie; Raffi, François; Bréaud, S; Ceppi, C; Courjon, Johan; Cua, Éric; Cottalorda, J.; Dellamonica, P.; Demonchy, Élisa; Monte, A. De; Durant, J.; Etienne, C; Ferrando, Stephen J.; Fuzibet, J. G.; Garraffo, R.; Joulié, A.; Risso, Karine; Mondain, V.; Naqvi, Alissa; Oran, Nazan Tuna; Perbost, I.; Pillet, Sylvie; Prouvost-Keller, B; Pradier, Christian; Wehrlen-Pugliese, S; Rio, V; Rosenthal, Eric S.; Sausse, S; Zouzou, G; Hocqueloux, Laurent; Chéret, Antoine; Goujard, Cécile; Quertainmont, Yann; Teicher, Elina; Lerolle, Nathalie; Vittecoq, D.; Deradji, O; Fourreau, Frédéric; Pallier, C.; Barrail-Tran, Aurélie; Landman, Roland; Joly, Véronique; Rioux, C.; Lariven, Sylvie; Gervais, Anne; Lescure, F.-X.; Matheron, Sophie; Louni, F; Godard, C.; Julia, Zélie; Chansombat, M.; Rahli, Djamila; Mackoumbou-Nkouka, C; Charpentier, Charlotte; Descamps, Diane; Peytavin, Gilles; Yazdanpanah, Yazdan; Consigny, Paul‐Henri; Cessot, G; Bossi, Philippe; Goesch, Julia; Gilquin, Jacques; Benabdelmoumen, G.; Lanternier, Fanny; Charlier, Caroline; Amazzough, Karima; Henry, Bonnie; Pilmis, Benoît; Rouzaud, Claire; Morgand, Marjolaine; Touam, F.; Louisin, C; Duvivier, Claudine; Lortholary, Olivier; Guéry, Romain; Danion, François; Parize, Perrine; Etienne, Nienguet Tsota; Launay, Manon; Rouzioux, Christine; Fenoel, Véronique Avettand; Valantin, M.A.; Flandre, Philippe; Caby, Fabienne; Tubiana, Roland; Agher, Rachid; Seang, Sophie; Schneider, Luminita; Palich, Romain; Blanc, Catherine; Berger, Jean-Luc; N’Guyen, Yohan; Lambert, D.; Lebrun, Delphine; Kmiec, I; Hentzien, Maxime; Brodard, Véronique; Botelho-Nevers, Élisabeth; Gagneux‐Brunon, Amandine; Frésard, A.; Lucht, F.; Fischer, Patricia; Partisani, M; Cheneau, Christine; Priester, M; Batard, Marie-Laure; Bernard-Henry, Claudine; Mautort, E de; Álvarez, Marta; Biezunski, N; Debard, Alexa; Delpierre, Cyrille; Lansalot, P; Lelièvre, L; Martin‐Blondel, Guillaume; Metsu, David; Piffaut, M; Porte, Lorena; Sauné, Karine; Delobel, Pierre; Ajana, F.; Alcaraz, I.; Baclet, V.; Boucher, Anne; Choisy, P.; Huleux, Thomas; Lafon‐Desmurs, B.; Melliez, H.; Meybeck, Agnès; Pasquet, Agnès; Pradier, M; Robineau, Olivier; Viget, N.; Valette, M.

doi:10.1093/jac/dky497

Cited by 43 publications

(20 citation statements)

References 23 publications

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“…However, to date, the rate of discontinuation of DTG-based therapies for NP-AEs has not been confirmed in a uniform way. Ours (3.9%) is concordant with those reported in some real-life studies, 17-25 which ranged between 1.7% and 5.6%. In contrast, this rate was significantly higher in 2 cohorts 7,8 (8.3% and 9.9%) and lower in the other 2, with only 0.6% and 0.7% of the patients having to stop DTG because of NP-AEs.…”

Section: Discussionsupporting

confidence: 92%

Effectiveness, Safety, and Costs of Dolutegravir/Abacavir/Lamivudine Single-Tablet Regimen in a Real-Life Cohort of HIV-1 Adult Infected Patients

et al. 2020

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Background: Real-life data on single-tablet regimen (STR) dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) is scarce, and concerns about DTG neuropsychiatric adverse events (NP-AEs) have recently arisen. Objective: To explore the effectiveness and safety, in particular NP-AEs, of DTG/ABC/3TC in a cohort of HIV-1 adult infected patients. Pill burden, adherence to this STR, and the impact of switching on costs were also evaluated. Methods: This was an observational, retrospective study. The study population included antiretroviral therapy (ART)-naive and treatment-experienced (TE) patients who started DTG/ABC/3TC between February 1, 2016, and October 31, 2016. Effectiveness and safety were analyzed at week 48 (W48) by intention-to-treat analysis. The Cox regression model was used to investigate predictors of DTG/ABC/3TC discontinuation. Results: A total of 253 patients were included (44 ART naïve, 209 TE). At W48, the proportion of patients with virological suppression was 72.7% (95% CI = 58.4-87.0) in ART-naive patients, 85.6% (95% CI = 80.3-90.9) in previously suppressed TE patients, and 86.4% (95% CI = 65.1-97.1) in previously not suppressed TE patients. The rate of protocol-defined virological failure was 4.3%. The incidence of AEs was higher in the subgroup of ART-naive patients (56.1% vs 39.0%), with a rate of interruptions for this reason of 13.6% and 7.6%, respectively. The incidence of NP-AEs was 20.6%, with 3.9% of patients requiring discontinuation. Patients who had switched from a raltegravir-containing regimen discontinued DTG/ABC/3TC because of AEs more frequently (relative risk = 2.83; 95% CI = 1.04-7.72; P = 0.041) in the multivariate analysis. After switching to DTG/ABC/3TC, the median pill burden was reduced from 3 to 1 and the proportion of patients with an adherence <90%, from 20.1% to 12.0%. The annual per-patient ART costs increased by €48 (0.6% increase). Conclusion and Relevance: DTG/ABC/3TC is an effective strategy as first-line and switching ART. Our data suggest a worse tolerance in ART-naive patients, although the rate of discontinuation resulting from NP-AEs was relatively low. In the short-term, the adherence was slightly improved without significant changes in costs.

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Section: Discussionsupporting

confidence: 92%

Effectiveness, Safety, and Costs of Dolutegravir/Abacavir/Lamivudine Single-Tablet Regimen in a Real-Life Cohort of HIV-1 Adult Infected Patients

et al. 2020

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“…. We did not identify this association in our cohort, in agreement with most cohort studies, all RCTs (in both men and women) and a meta‐analysis of five RCTs . Of note, some patients discontinuing dolutegravir/ABC/3TC because of NPAEs in our series actually included ABC/3TC in the subsequent ART regimen, with no NPAE recurrence.…”

Section: Discussionsupporting

confidence: 84%

Discontinuation of dolutegravir, elvitegravir/cobicistat and raltegravir because of toxicity in a prospective cohort

et al. 2019

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Objectives The aim of the study was to assess the rates of discontinuation of integrase inhibitor regimens because of any neuropsychiatric adverse event (NPAE) and the factors associated with discontinuation. Methods A population‐based, prospective, multicentre cohort study was carried out. Treatment‐naïve subjects starting therapy with a regimen containing integrase inhibitors, or those switching to such a regimen, with plasma HIV‐1 RNA < 50 HIV‐1 RNA copies/mL in 14 hospitals in Catalonia or the Balearic Islands (Spain) were included in the study. Every discontinuation because of adverse events (AEs) was double‐checked directly with treating physicians. Multivariable Cox models identified factors correlated with discontinuation. Results A total of 4165 subjects (37% treatment‐naïve) started regimens containing dolutegravir (n = 1650; 91% with abacavir), raltegravir (n = 930) or elvitegravir/cobicistat (n = 1585). There were no significant differences among regimens in the rate of discontinuation because of any AE. Rates of discontinuation because of NPAEs were low but higher for dolutegravir/abacavir/lamivudine [2.1%; 2.9 (95% confidence interval (CI) 2.0, 4.2) discontinuations/100 patients/year] versus elvitegravir/cobicistat (0.5%; 0.8 (95% CI 0.3, 1.5) discontinuations/100 patients/year], with significant differences among centres for dolutegravir/abacavir/lamivudine and NPAEs (P = 0.003). We identified an association of female gender and lower CD4 count with increased risk of discontinuation because of any AE [Incidence ratio (IR) 2.3 (95% CI 1.4, 4.0) and 1.8 (95% CI 1.1, 2.8), respectively]. Female gender, age > 60 years and abacavir use were not associated with NPAE discontinuations. NPAEs were commonly grade 1–2, and had been present before and improved after drug withdrawal. Conclusions In this large prospective cohort study, patients receiving dolutegravir, raltegravir or elvitegravir/cobicistat did not show significant differences in the rate of discontinuation because of any toxicity. The rate of discontinuations because of NPAEs was low, but was significantly higher for dolutegravir than for elvitegravir/cobicistat, with significant differences among centres, suggesting that greater predisposition to believe that a given adverse event is caused by a given drug of some treating physicians might play a role in the discordance seen between cohorts.

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“…In clinical trials, there were low and comparable rates of NP symptoms among patients receiving RAL, EVG-COBI, and DTG. However in real-life settings, findings about NP effects have been variable and at times contradictory, although several authors have reported higher rates of NP symptoms than in clinical trials (early or longer term symptoms, leading to discontinuations at times), especially among patients on DTG [21][22][23][24][25]. Reasons for these differences are likely two-tiered.…”

Section: Neuropsychiatric Symptomsmentioning

confidence: 99%

Update on Adverse Effects of HIV Integrase Inhibitors

Kołakowska

Maresca

Collins

et al. 2019

Curr Treat Options Infect Dis

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Keywords HIV integrase inhibitors I Drug-related side effects and adverse reactions I Raltegravir I Elvitegravir I Dolutegravir Abstract Purpose of review The goal of this paper is to provide an up-to-date review of adverse events related to the class of integrase strand transfer inhibitors (INSTIs), which became the class of choice in few years. We sought answers specifically to issues pertaining to neuropsychiatric adverse events, as well as weight gain, which were the two most important categories of adverse events raised in recent studies based on real-life experience. The primary focus of this paper is on adults with a brief summary on pregnant women and children/adolescents. Recent findings Dolutegravir (DTG) bears the heaviest burden of neuropsychiatric side effects. Weight gain was reported with all INSTIs, although there are methodological caveats in the analyses and the findings need to be interpreted with caution. Moreover, due to recent findings on neural tube defects in infants exposed to dolutegravir during their peri-conception period, its use is not recommended for women of childbearing age without proper birth control method, while raltegravir remains the only drug which may be prescribed without caution. Given the importance of cognitive and metabolic comorbidities in people living with HIV in regard to their quality of life, future research needs to focus on long-term effects of INSTIs in relation to these adverse events. Pharmacogenetics seems to be a promising tool. Safety during pregnancy is also another important issue to further clarify. Summary INSTIs are a generally well-tolerated class of antiretrovirals (ARV), and has a

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Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort

Cited by 43 publications

References 23 publications

Effectiveness, Safety, and Costs of Dolutegravir/Abacavir/Lamivudine Single-Tablet Regimen in a Real-Life Cohort of HIV-1 Adult Infected Patients

Effectiveness, Safety, and Costs of Dolutegravir/Abacavir/Lamivudine Single-Tablet Regimen in a Real-Life Cohort of HIV-1 Adult Infected Patients

Discontinuation of dolutegravir, elvitegravir/cobicistat and raltegravir because of toxicity in a prospective cohort

Update on Adverse Effects of HIV Integrase Inhibitors

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