Joshua Rhein1, Kathy Huppler Hullsiek2, Lillian Tugume3, Edwin Nuwagira4, Edward Mpoza3, Emily E Evans4, Reuben Kiggundu3, Katelyn A Pastick5, Kenneth Ssebambulidde3, Andrew Akampurira3, Darlisha A Williams5, Ananta S Bangdiwala2, Mahsa Abassi5, Abdu K Musubire3, Melanie R Nicol6, Conrad Muzoora4, David B Meya7, David R Boulware8. 1. Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN, USA; Infectious Diseases Institute, Makerere University, Kampala, Uganda. Electronic address: joshua.rhein@gmail.com. 2. School of Public Health, Division of Biostatistics, University of Minnesota, Minneapolis, MN, USA. 3. Infectious Diseases Institute, Makerere University, Kampala, Uganda. 4. Mbarara University of Science and Technology, Mbarara, Uganda. 5. Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN, USA; Infectious Diseases Institute, Makerere University, Kampala, Uganda. 6. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA. 7. Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN, USA; Infectious Diseases Institute, Makerere University, Kampala, Uganda; School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda. 8. Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN, USA.
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.
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.
Authors: David R Boulware; David B Meya; Conrad Muzoora; Melissa A Rolfes; Katherine Huppler Hullsiek; Abdu Musubire; Kabanda Taseera; Henry W Nabeta; Charlotte Schutz; Darlisha A Williams; Radha Rajasingham; Joshua Rhein; Friedrich Thienemann; Melanie W Lo; Kirsten Nielsen; Tracy L Bergemann; Andrew Kambugu; Yukari C Manabe; Edward N Janoff; Paul R Bohjanen; Graeme Meintjes Journal: N Engl J Med Date: 2014-06-26 Impact factor: 91.245
Authors: Rogelio de J Treviño-Rangel; Hiram Villanueva-Lozano; Pedro Hernández-Rodríguez; Michel F Martínez-Reséndez; Jaime García-Juárez; Humberto Rodríguez-Rocha; Gloria M González Journal: Med Mycol Date: 2015-12-24 Impact factor: 4.076
Authors: Justin Beardsley; Marcel Wolbers; Freddie M Kibengo; Abu-Baker M Ggayi; Anatoli Kamali; Ngo Thi Kim Cuc; Tran Quang Binh; Nguyen Van Vinh Chau; Jeremy Farrar; Laura Merson; Lan Phuong; Guy Thwaites; Nguyen Van Kinh; Pham Thanh Thuy; Wirongrong Chierakul; Suwatthiya Siriboon; Ekkachai Thiansukhon; Satrirat Onsanit; Watthanapong Supphamongkholchaikul; Adrienne K Chan; Robert Heyderman; Edson Mwinjiwa; Joep J van Oosterhout; Darma Imran; Hasan Basri; Mayfong Mayxay; David Dance; Prasith Phimmasone; Sayaphet Rattanavong; David G Lalloo; Jeremy N Day Journal: N Engl J Med Date: 2016-02-11 Impact factor: 91.245
Authors: Martha P Montgomery; Noeline Nakasujja; Bozena M Morawski; Radha Rajasingham; Joshua Rhein; Elizabeth Nalintya; Darlisha A Williams; Kathy Huppler Hullsiek; Agnes Kiragga; Melissa A Rolfes; Renee Donahue Carlson; Nathan C Bahr; Kate E Birkenkamp; Yukari C Manabe; Paul R Bohjanen; Jonathan E Kaplan; Andrew Kambugu; David B Meya; David R Boulware Journal: BMC Neurol Date: 2017-06-12 Impact factor: 2.474
Authors: Joshua Rhein; Kathy H Hullsiek; Emily E Evans; Lillian Tugume; Edwin Nuwagira; Kenneth Ssebambulidde; Reuben Kiggundu; Edward Mpoza; Abdu K Musubire; Ananta S Bangdiwala; Nathan C Bahr; Darlisha A Williams; Mahsa Abassi; Conrad Muzoora; David B Meya; David R Boulware Journal: Open Forum Infect Dis Date: 2018-05-24 Impact factor: 3.835
Authors: Jonathan Dyal; Andrew Akampurira; Joshua Rhein; Bozena M Morawski; Reuben Kiggundu; Henry W Nabeta; Abdu K Musubire; Nathan C Bahr; Darlisha A Williams; Tihana Bicanic; Robert A Larsen; David B Meya; David R Boulware Journal: Med Mycol Date: 2016-01-14 Impact factor: 4.076
Authors: Mark W Tenforde; Adrienne E Shapiro; Benjamin Rouse; Joseph N Jarvis; Tianjing Li; Ingrid Eshun-Wilson; Nathan Ford Journal: Cochrane Database Syst Rev Date: 2018-07-25
Authors: David R Boulware; Elizabeth Nalintya; Radha Rajasingham; Paul Kirumira; Rose Naluyima; Fred Turya; Sylvia Namanda; Morris K Rutakingirwa; Caleb P Skipper; Yofesi Nikweri; Kathy Huppler Hullsiek; Ananta S Bangdiwala; David B Meya Journal: Med Mycol Date: 2020-11-10 Impact factor: 4.076
Authors: William J Hurt; Mark W Tenforde; Mooketsi Molefi; Hannah K Mitchell; Thandi Milton; Martin S Azama; Irene Goercke; Fredah Mulenga; Nametso Tlhako; Katlego Tsholo; Tuhina Srivastava; Tshepo B Leeme; Godfrey Simoonga; Charles Muthoga; Kwana Lechiile; Madisa Mine; Joseph N Jarvis Journal: Clin Infect Dis Date: 2021-05-18 Impact factor: 9.079
Authors: Matthew F Pullen; Katherine Huppler Hullsiek; Joshua Rhein; Abdu K Musubire; Lillian Tugume; Edwin Nuwagira; Mahsa Abassi; Kenneth Ssebambulidde; Edward Mpoza; Ruben Kiggundu; Andrew Akampurira; Henry W Nabeta; Charlotte Schutz; Emily E Evans; Radha Rajasingham; Caleb P Skipper; Katelyn A Pastick; Darlisha A Williams; Bozena M Morawski; Ananta S Bangdiwala; Graeme Meintjes; Conrad Muzoora; David B Meya; David R Boulware Journal: Clin Infect Dis Date: 2020-10-23 Impact factor: 9.079
Authors: Anna M Stadelman; Kenneth Ssebambulidde; Lillian Tugume; Katelyn A Pastick; Kathy Huppler Hullsiek; Sarah Lofgren; Edwin Nuwagira; Emily E Evans; Darlisha A Williams; Conrad Muzoora; David B Meya; Radha Rajasingham; Joshua Rhein; David R Boulware Journal: Med Mycol Date: 2021-07-06 Impact factor: 4.076