COMPARATIVE NEUROPSYCHIATRIC TOXICITY PROFILE OF DOLUTEGRAVIR-BASED VERSUS EFAVIRENZ-BASED VERSUS OTHER RECOMMEND FIRST-LINE ANTIRETROVIRAL ...
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COMPARATIVE NEUROPSYCHIATRIC TOXICITY PROFILE OF
DOLUTEGRAVIR-BASED VERSUS EFAVIRENZ-BASED VERSUS OTHER
RECOMMEND FIRST-LINE ANTIRETROVIRAL THERAPIES (ART): DATA
FROM ICONA FOUNDATION STUDY COHORT.
A. Mondi1, A. Cozzi-Lepri2, A. Cingolani3, A. Tavelli4, M. Puoti5, V. Barocci6, A. Londero7, F. Bai8, C. Pinnetti1,
P. Cinque9, A. d’Arminio Monforte8, A. Antinori1 on behalf of the Icona Foundation Study Group
1.HIV/AIDS Department, National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy;
2. Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, UCL, London, UK;
3. Infectious Diseases Unit, Catholic University of Sacred Heart, Rome, Italy; 4. Icona Foundation, Milan, Italy;
5. Infectious Diseases Department, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy;
6. Clinic of Infectious Diseases, Dept. of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy;
7. Infectious Diseases Clinic, Department of Medicine University of Udine and Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy;
8.Clinic of Infectious and Tropical Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Milan, Italy;
9. Department of Infectious Diseases, San Raffaele Hospital, Vita-Salute University, Milan, Italy.
OC14 Milano, 5-7 giugno 2019
DISCLOSURES:
Dr. Mondi received honoraria from Gilead Sciences and Viiv Healthcare
FUNDING:
ICONA Foundation is supported by unrestricted grants from Gilead Science,
Janssen, MSD and ViiV Healthcare.
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019
BACKGROUND:
Recently, several concerns about an increased risk of neuropsychiatric adverse events (NPAEs) during exposure to
Dolutegravir (DTG) have been raised in observational, not randomized studies[1-5].
Historically, Efavirenz (EFV) was largely associated to a higher risk of neuropsychiatric toxicity with an increased
rate of discontinuations due to toxicity compared with other antiretrovirals[6].
Despite this common toxicity profile, comparison of NPAEs risk between DTG and EFV-based regimens are limited:
A large, a comparative, randomized clinical trial showed a lower rate of NPAEs with fewer discontinuations due to
adverse events in ART-naïve patients starting DTG compared to EFV[7,8].
On the contrary, direct comparisons in real-life setting are lacking.
1. De Boer M et al, AIDS 2016; 2. Hoffmann C et al. HIV Med 2017: 3. Menard A et al AIDS 2017; Peñ afiel J et al JAC 2017; 5. Elzi L et al AIDS 2017: 6. Ford N et al JAIDS 2015; 7. Walmsley S. et al NEJM 2013: 8. Moreno S et al, 6th international
Symposium of Neuropsychiatry and HIV.
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019
STUDY AIM:
The aims of the study were:
to estimate and compare the risk of neuropsychiatric toxicity among DTG-based, EFV-based
regimens as well as other currently recommended first-line antiretroviral regimens
to assess the predictive factors of treatment discontinuation due to NPAEs
in a large Italian cohort.
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019METHODS I:
STUDY DESIGN AND POPULATION:
Prospective, observational, multicentric study analysing data from Icona Foundation Study Cohort.
All consecutive HIV-infected ART-naïve patients, aged 18 years or more, enrolled in ICONA cohort, who started a
first-line recommended (as main or alternative) ART according to EACS guidelines 2018, from January 2006 to
December 2018, were included in the analysis.
Patients without at least one follow-up visit after ART start were excluded.
Included patients were divided into three treatment groups, according to the third drug-started:
DTG group: patients starting a DTG-based ART
EFV group: patients starting an EFV-based ART
Other group: patients starting a non-EFV non-DTG ART
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019METHODS II:
OUTCOME DEFINITIONS:
Treatment Discontinuation for NPAEs:
Discontinuation of the third drug, ignoring changes in the backbone, due to NPAEs, as reported by the treating
physician.
Neuropsychiatric toxicity:
Composite endpoint defined as
treatment discontinuation due to NPAEs (as defined above) or
an event classified as neuropsychiatric by the treating physician (including psicosis, depression, anxiety,
cognitive disorder or other) or
the new start of a psychoactive drug (including antidepressant, benzodiazepine, antiepileptic, neuroleptic or
other).
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019METHODS III:
STASTICAL ANALYSIS:
Characteristics at time of ART start (baseline) were compared among the treatment groups, using Chi square test
and non-parametric tests for the median, as appropriate.
The risk of experiencing neuropsychiatric toxicity either leading or not to treatment discontinuation
and discontinuing third drug due to NPAEs were estimated by Kaplan Meier analysis comparing the three treatment
groups.
Predictive factors of treatment discontinuation due to NPAEs were identified using multivariable Cox proportional
hazard model.
A sensitivity analysis restricted to patients starting ART from 2011* to identify predictors of treatment
discontinuation due to NPAEs was also performed.
*2011 was the first year in which DTG was available in Icona Foundation Study Electronic database (probably related to those patients included in DTG-
registration studies, until the EMA approval in 2014).
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019RESULTS: BASELINE CHARACTERISTICS
TOTAL POPULATION (N=7,854)
DTG group EFV group OTHER group
Characteristic p-value
(n=1,322, 16.8%) (n=1,542, 19.6%) (4,990, 63.5%)
Female gender, n (%) 223 (16.9) 230 (14.9) 1016 (20.4)RESULTS: ART REGIMENS ACCORDING TO TREATMENT GROUP
DTG group EFV group OTHER group
p-value
(n=1,322, 16.8%) (n=1,542, 19.6%) (4,990, 63.5%)
BACKBONERESULTS: PROBABILITY OF TD FOR NPAEs
AND NEUROPSYCHIATRIC TOXICITY
Median follow-up time: 16 months (IQR 6-33)
TREATMENT DISCONTINUATION FOR NPAES NEUROPSYCHIATRIC TOXICITY
Estimated probability of TD due to NPAEs (95% CI) Estimated probability of NPAEs (95% CI)
DTG-group EFV-group Other group DTG-group EFV-group Other group
1-year 1.6% 5.3 % 0.3 % 1-year 3.9% 6.9 % 2.7 %
(0.9-2.4) (4.0-6.6) (0.1-0.4) (2.8-5.1) (5.4-8.3) (2.2-3.2)
2-year 2.4 % 6.9 % 0.3 % 2-year 5.2% 8.5 % 3.2 %
(1.4-3.4) (5.4-8.5) (0.1-0.4) (3.7-6.6) (6.8-10.2) (2.7-3.7)
3-year 2.4 % 10.7 % 0.3 % 3-year 5.2% 12.4 % 4.1 %
(1.4-3.4) (8.5-12.9) (0.1-0.4) (3.7-6.6) (10.1-14.8) (3.5-4.7)RESULTS: PREDICTORS OF TREATMENT DISCONTINUATION DUE
TO NPAEs
OVERALL PERIOD (2006-2018) SENSITIVITY ANALYSIS 2011-2018
HR (95% CI) p aRH* (95% CI) p HR (95% CI) p aRH* (95% CI) p
Gender
Female versus Male 0.55 (0.31-0.99) 0.045 1.00 (0.36-2.78) 0.994
Calendar year of starting ART
per more recent 0.86 (0.81-0.91)RESULTS: NPAEs LEADING TO TREATMENT
DISCONTINUATION ACCORDING TO TREATMENT GROUP
More than one event per
person is possibile
# Other-group included the following ART: TDF/FTC/RPV (6); ATV/r-based ART (3): TAF/FTC/EVG/C (2); RAL-based ART (2).
* Abnormal dreams reported only in EFV-group
** Other NPAEs includes: paresthesia, anosmia, paranoid ideation, allucinations and headeache (DTG group); allucinations (EFV-group) and hands shacking
(other-group)
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019STRENGHTS AND LIMITATIONS:
STRENGHTS:
First study to compare in a large sample of individuals the risk of neuropsychiatric toxicity among DTG-based, EFV-based
regimens and other currently recommended first-line ART in a real life setting.
LIMITATIONS:
Observational study: residual or unmeasured confounding cannot be completely ruled out.
Due to discontinuation end point-based analysis, investigator’s bias cannot be ruled out
Little overlap in calendar periods of starting EFV-based and DTG-based regimens may have led to inefficient control of
potential confounding by regression analysis.
Lack of characterization of most NPAEs leading to EFV discontinuation.
Not standardized and measured analysis of sleep quality, mood disorders, neurocognitive impairment, suicidality risk.
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019CONCLUSIONS:
In this large observational study, the use of DTG-based first line regimens was associated to a 2.5%
risk of stopping DTG due to NPAEs by two years. Despite not negligible, this estimated risk was one
of the lowest reported for DTG in observational settings.
The risk of neuropsychiatric toxicity in patients on DTG-based first-line regimens is significantly
lower than that experienced by subjects taking EFV-based regimens but higher than seen for
people starting other recommended ART.
The neuropsychiatric toxicity profile of DTG and EFV seems to be only partially comparable.
However, these findings should be interpreted cautiously due to the lack of characterization of most
EFV-related NPAEs, and the lack of assessment of neurocognitive impairment and mood disorders.
11th ITALIAN CONFERENCE ON AIDS AND ANTIVIRAL REASERCH Milano, 5-7 giugno 2019ICONA Foundation Study Group BOARD OF DIRECTORS: A d’Arminio Monforte (President), A Antinori (Vice-President), M Andreoni, A Castagna, F Castelli, R Cauda, G Di Perri, M Galli, R Iardino, G Ippolito, A Lazzarin, GC Marchetti, G Rezza, F von Schloesser, P Viale. SCIENTIFIC SECRETARY: A d’Arminio Monforte, A Antinori, A Castagna, F Ceccherini-Silberstein, A Cozzi-Lepri, E Girardi, S Lo Caputo, C Mussini, M Puoti, CF Perno. STEERING COMMITTEE: A Antinori, F Bai, C Balotta, A Bandera, S Bonora, M Borderi, A Calcagno, A Capetti, MR Capobianchi, A Castagna, F Ceccherini- Silberstein, S Cicalini, A Cingolani, P Cinque, A Cozzi-Lepri, A d’Arminio Monforte, A De Luca, A Di Biagio, E Girardi, N Gianotti, A Gori, G Guaraldi, G Lapadula, M Lichtner, S Lo Caputo, G Madeddu, F Maggiolo, G Marchetti, L Monno, C Mussini, S Nozza, CF Perno, C Pinnetti, M Puoti, E Quiros Roldan, R Rossotti, S Rusconi, MM Santoro, A Saracino, L Sarmati. STATISTICAL AND MONITORING TEAM: A Cozzi-Lepri, I Fanti, L Galli, P Lorenzini, A Rodano’, M Macchia, A Tavelli. BIOLOGICAL BANK INMI: F Carletti, S Carrara, A Di Caro, S Graziano, F Petroni, G Prota, S Truffa. PARTICIPATING PHYSICIANS AND CENTERS: Italy A Giacometti, A Costantini, V Barocci (Ancona); G Angarano, L Monno, E Milano (Bari); F Maggiolo, C Suardi (Bergamo); P Viale, V Donati, G Verucchi (Bologna); F Castelnuovo, C Minardi, E Quiros Roldan (Brescia); B Menzaghi, C Abeli (Busto Arsizio); B Cacopardo, B Celesia (Catania); J Vecchiet, K Falasca (Chieti); A Pan, S Lorenzotti (Cremona); L Sighinolfi, D Segala (Ferrara); P Blanc, F Vichi (Firenze); G Cassola, C Viscoli, A Alessandrini, N Bobbio, G Mazzarello (Genova); M Lichtner, L Fondaco (Latina); P Bonfanti, C Molteni (Lecco); A Chiodera, P Milini (Macerata); G Nunnari, G Pellicanò (Messina); A d’Arminio Monforte, M Galli, A Lazzarin, G Rizzardini, M Puoti, A Castagna, ES Cannizzo, MC Moioli, R Piolini, D Bernacchia, S Salpietro, C Tincati, (Milano); C Mussini, C Puzzolante (Modena); C Migliorino, G Lapadula (Monza); V Sangiovanni, G Borgia, V Esposito, G Di Flumeri, I Gentile, V Rizzo (Napoli); AM Cattelan, S Marinello (Padova); A Cascio, M Trizzino (Palermo); F Baldelli, E Schiaroli (Perugia); G Parruti, F Sozio (Pescara); G Magnani, MA Ursitti (Reggio Emilia); M Andreoni, A Antinori, R Cauda, A Cristaudo, V Vullo, R Acinapura, D Moschese, M Capozzi, A Mondi, A Cingolani, M Rivano Capparuccia, G Iaiani, A Latini, R Gagliardini, MM Plazzi, G De Girolamo, A Vergori (Roma); M Cecchetto, F Viviani (Rovigo); G Madeddu, A De Vito(Sassari); B Rossetti, F Montagnani (Siena); A Franco, R Fontana Del Vecchio (Siracusa); D Francisci, C Di Giuli (Terni); P Caramello, G Di Perri, S Bonora, GC Orofino, M Sciandra (Torino); M Bassetti, A Londero (Udine); V Manfrin, G Battagin (Vicenza); G Starnini, A Ialungo (Viterbo).
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