Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial

ASTRO-CM Team; Joshua Rhein; Kathy Huppler Hullsiek; Katelyn A. Pastick; Darlisha A. Williams; Ananta S. Bangdiwala; Mahsa Abassi; Melanie R. Nicol; David B. Meya; David R. Boulware; Anna Stadelman

doi:10.1016/S1473-3099(19)30127-6

Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial

ASTRO-CM Team, Joshua Rhein, Kathy Huppler Hullsiek, Katelyn A. Pastick, Darlisha A. Williams, Ananta S. Bangdiwala, Mahsa Abassi, Melanie R. Nicol, David B. Meya, David R. Boulware, Anna Stadelman

Research output: Contribution to journal › Article › peer-review

100 Scopus citations

Abstract

Background: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. Methods: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. Findings: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log₁₀ CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs 0·47 –log₁₀ CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. Interpretation: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. Funding: National Institutes of Health and Medical Research Council, Wellcome Trust.

Original language	English (US)
Pages (from-to)	843-851
Number of pages	9
Journal	The Lancet Infectious Diseases
Volume	19
Issue number	8
DOIs	https://doi.org/10.1016/S1473-3099(19)30127-6
State	Published - Aug 2019

Bibliographical note

Funding Information:
We thank the study participants, the trial scientific review board, members of independent review boards at each study site, members of the trial data safety and monitoring board including Joseph N Jarvis, Jason V Baker, Mohammed Lamorde, and Marcel Wolbers, as well as members of our trial steering committee, including John R Perfect, Graeme Meintjes, and Edward N Janoff. This research was supported by the National Institute of Neurologic Diseases and Stroke ( R01NS086312 ), the Fogarty International Center ( K01TW010268 , R25TW009345 ), the National Institute of Allergy and Infectious Diseases ( T32AI055433 ), UK Medical Research Council/Department for International Development/Wellcome Trust Global Clinical Trials ( M007413/1 ), and Grand Challenges Canada ( S4–0296–01 ). DBM was also supported by DELTAS Africa Initiative (grant number DEL-15–011 ) to THRiVE-2. The DELTAS Africa I nitiative i s an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science i n Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107742/Z/15/Z ) and the UK Government. The views expressed in this publication are our own and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK Government. This work was supported in part by the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota.

Funding Information:
JR and DRB report grants from the National Institutes of Health, and DBM reports grants from the National Institutes of Health and Medical Research Council/Wellcome Trust, outside of the submitted work. All other authors declare no competing interests.

Funding Information:
We thank the study participants, the trial scientific review board, members of independent review boards at each study site, members of the trial data safety and monitoring board including Joseph N Jarvis, Jason V Baker, Mohammed Lamorde, and Marcel Wolbers, as well as members of our trial steering committee, including John R Perfect, Graeme Meintjes, and Edward N Janoff. This research was supported by the National Institute of Neurologic Diseases and Stroke (R01NS086312), the Fogarty International Center (K01TW010268, R25TW009345), the National Institute of Allergy and Infectious Diseases (T32AI055433), UK Medical Research Council/Department for International Development/Wellcome Trust Global Clinical Trials (M007413/1), and Grand Challenges Canada (S4?0296?01). DBM was also supported by DELTAS Africa Initiative (grant number DEL-15?011) to THRiVE-2. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107742/Z/15/Z) and the UK Government. The views expressed in this publication are our own and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK Government. This work was supported in part by the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota.

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© 2019 Elsevier Ltd

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041360

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ASTRO-CM Team, Rhein, J., Huppler Hullsiek, K., Pastick, K. A., Williams, D. A., Bangdiwala, A. S., Abassi, M., Nicol, M. R., Meya, D. B., Boulware, D. R., & Stadelman, A. (2019). Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial. The Lancet Infectious Diseases, 19(8), 843-851. https://doi.org/10.1016/S1473-3099(19)30127-6

ASTRO-CM Team, Rhein, J, Huppler Hullsiek, K, Pastick, KA, Williams, DA, Bangdiwala, AS , Abassi, M , Nicol, MR, Meya, DB, Boulware, DR & Stadelman, A 2019, 'Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial', The Lancet Infectious Diseases, vol. 19, no. 8, pp. 843-851. https://doi.org/10.1016/S1473-3099(19)30127-6

@article{bd0e6f1a1c28472d9bcca89e207ce48d,

title = "Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial",

abstract = "Background: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. Methods: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. Findings: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log10 CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs 0·47 –log10 CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. Interpretation: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. Funding: National Institutes of Health and Medical Research Council, Wellcome Trust.",

author = "{ASTRO-CM Team} and Joshua Rhein and {Huppler Hullsiek}, Kathy and Lillian Tugume and Edwin Nuwagira and Edward Mpoza and Evans, {Emily E.} and Reuben Kiggundu and Pastick, {Katelyn A.} and Kenneth Ssebambulidde and Andrew Akampurira and Williams, {Darlisha A.} and Bangdiwala, {Ananta S.} and Mahsa Abassi and Musubire, {Abdu K.} and Nicol, {Melanie R.} and Conrad Muzoora and Meya, {David B.} and Boulware, {David R.} and Ndyetukira, {Jane Francis} and Cynthia Ahimbisibwe and Florence Kugonza and Carolyne Namuju and Alisat Sadiq and Alice Namudde and James Mwesigye and Tadeo, {Kiiza K.} and Paul Kirumira and Michael Okirwoth and Tonny Luggya and Julian Kaboggoza and Eva Laker and Leo Atwine and Davis Muganzi and Stewart Walukaga and Bilal Jawed and Matthew Merry and Anna Stadelman and Nicole Stephens and Flynn, {Andrew G.} and Fujita, {Ayako W.} and Richard Kwizera and Liliane Mukaremera and Lofgren, {Sarah M.} and Cresswell, {Fiona V.} and Morawski, {Bozena M.} and Bahr, {Nathan C.} and Kirsten Nielsen",

note = "Funding Information: We thank the study participants, the trial scientific review board, members of independent review boards at each study site, members of the trial data safety and monitoring board including Joseph N Jarvis, Jason V Baker, Mohammed Lamorde, and Marcel Wolbers, as well as members of our trial steering committee, including John R Perfect, Graeme Meintjes, and Edward N Janoff. This research was supported by the National Institute of Neurologic Diseases and Stroke ( R01NS086312 ), the Fogarty International Center ( K01TW010268 , R25TW009345 ), the National Institute of Allergy and Infectious Diseases ( T32AI055433 ), UK Medical Research Council/Department for International Development/Wellcome Trust Global Clinical Trials ( M007413/1 ), and Grand Challenges Canada ( S4–0296–01 ). DBM was also supported by DELTAS Africa Initiative (grant number DEL-15–011 ) to THRiVE-2. The DELTAS Africa I nitiative i s an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science i n Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107742/Z/15/Z ) and the UK Government. The views expressed in this publication are our own and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK Government. This work was supported in part by the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota. Funding Information: JR and DRB report grants from the National Institutes of Health, and DBM reports grants from the National Institutes of Health and Medical Research Council/Wellcome Trust, outside of the submitted work. All other authors declare no competing interests. Funding Information: We thank the study participants, the trial scientific review board, members of independent review boards at each study site, members of the trial data safety and monitoring board including Joseph N Jarvis, Jason V Baker, Mohammed Lamorde, and Marcel Wolbers, as well as members of our trial steering committee, including John R Perfect, Graeme Meintjes, and Edward N Janoff. This research was supported by the National Institute of Neurologic Diseases and Stroke (R01NS086312), the Fogarty International Center (K01TW010268, R25TW009345), the National Institute of Allergy and Infectious Diseases (T32AI055433), UK Medical Research Council/Department for International Development/Wellcome Trust Global Clinical Trials (M007413/1), and Grand Challenges Canada (S4?0296?01). DBM was also supported by DELTAS Africa Initiative (grant number DEL-15?011) to THRiVE-2. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107742/Z/15/Z) and the UK Government. The views expressed in this publication are our own and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK Government. This work was supported in part by the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = aug,

doi = "10.1016/S1473-3099(19)30127-6",

language = "English (US)",

volume = "19",

pages = "843--851",

journal = "The Lancet Infectious Diseases",

issn = "1473-3099",

publisher = "Elsevier Ltd",

number = "8",

}

TY - JOUR

T1 - Adjunctive sertraline for HIV-associated cryptococcal meningitis

T2 - a randomised, placebo-controlled, double-blind phase 3 trial

AU - ASTRO-CM Team

AU - Rhein, Joshua

AU - Huppler Hullsiek, Kathy

AU - Tugume, Lillian

AU - Nuwagira, Edwin

AU - Mpoza, Edward

AU - Evans, Emily E.

AU - Kiggundu, Reuben

AU - Pastick, Katelyn A.

AU - Ssebambulidde, Kenneth

AU - Akampurira, Andrew

AU - Williams, Darlisha A.

AU - Bangdiwala, Ananta S.

AU - Abassi, Mahsa

AU - Musubire, Abdu K.

AU - Nicol, Melanie R.

AU - Muzoora, Conrad

AU - Meya, David B.

AU - Boulware, David R.

AU - Ndyetukira, Jane Francis

AU - Ahimbisibwe, Cynthia

AU - Kugonza, Florence

AU - Namuju, Carolyne

AU - Sadiq, Alisat

AU - Namudde, Alice

AU - Mwesigye, James

AU - Tadeo, Kiiza K.

AU - Kirumira, Paul

AU - Okirwoth, Michael

AU - Luggya, Tonny

AU - Kaboggoza, Julian

AU - Laker, Eva

AU - Atwine, Leo

AU - Muganzi, Davis

AU - Walukaga, Stewart

AU - Jawed, Bilal

AU - Merry, Matthew

AU - Stadelman, Anna

AU - Stephens, Nicole

AU - Flynn, Andrew G.

AU - Fujita, Ayako W.

AU - Kwizera, Richard

AU - Mukaremera, Liliane

AU - Lofgren, Sarah M.

AU - Cresswell, Fiona V.

AU - Morawski, Bozena M.

AU - Bahr, Nathan C.

AU - Nielsen, Kirsten

N1 - Funding Information: We thank the study participants, the trial scientific review board, members of independent review boards at each study site, members of the trial data safety and monitoring board including Joseph N Jarvis, Jason V Baker, Mohammed Lamorde, and Marcel Wolbers, as well as members of our trial steering committee, including John R Perfect, Graeme Meintjes, and Edward N Janoff. This research was supported by the National Institute of Neurologic Diseases and Stroke ( R01NS086312 ), the Fogarty International Center ( K01TW010268 , R25TW009345 ), the National Institute of Allergy and Infectious Diseases ( T32AI055433 ), UK Medical Research Council/Department for International Development/Wellcome Trust Global Clinical Trials ( M007413/1 ), and Grand Challenges Canada ( S4–0296–01 ). DBM was also supported by DELTAS Africa Initiative (grant number DEL-15–011 ) to THRiVE-2. The DELTAS Africa I nitiative i s an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science i n Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107742/Z/15/Z ) and the UK Government. The views expressed in this publication are our own and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK Government. This work was supported in part by the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota. Funding Information: JR and DRB report grants from the National Institutes of Health, and DBM reports grants from the National Institutes of Health and Medical Research Council/Wellcome Trust, outside of the submitted work. All other authors declare no competing interests. Funding Information: We thank the study participants, the trial scientific review board, members of independent review boards at each study site, members of the trial data safety and monitoring board including Joseph N Jarvis, Jason V Baker, Mohammed Lamorde, and Marcel Wolbers, as well as members of our trial steering committee, including John R Perfect, Graeme Meintjes, and Edward N Janoff. This research was supported by the National Institute of Neurologic Diseases and Stroke (R01NS086312), the Fogarty International Center (K01TW010268, R25TW009345), the National Institute of Allergy and Infectious Diseases (T32AI055433), UK Medical Research Council/Department for International Development/Wellcome Trust Global Clinical Trials (M007413/1), and Grand Challenges Canada (S4?0296?01). DBM was also supported by DELTAS Africa Initiative (grant number DEL-15?011) to THRiVE-2. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107742/Z/15/Z) and the UK Government. The views expressed in this publication are our own and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK Government. This work was supported in part by the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota. Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/8

Y1 - 2019/8

N2 - Background: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. Methods: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. Findings: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log10 CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs 0·47 –log10 CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. Interpretation: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. Funding: National Institutes of Health and Medical Research Council, Wellcome Trust.

AB - Background: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. Methods: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. Findings: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log10 CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs 0·47 –log10 CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. Interpretation: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. Funding: National Institutes of Health and Medical Research Council, Wellcome Trust.

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UR - http://www.scopus.com/inward/citedby.url?scp=85069697857&partnerID=8YFLogxK

U2 - 10.1016/S1473-3099(19)30127-6

DO - 10.1016/S1473-3099(19)30127-6

M3 - Article

C2 - 31345462

AN - SCOPUS:85069697857

SN - 1473-3099

VL - 19

SP - 843

EP - 851

JO - The Lancet Infectious Diseases

JF - The Lancet Infectious Diseases

IS - 8

ER -

Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial

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The effect of sertraline on depression and associations with persistent depression in survivors of HIV-related cryptococcal meningitis

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Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial

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The effect of sertraline on depression and associations with persistent depression in survivors of HIV-related cryptococcal meningitis

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