Neurotoxicity with high-dose disulfiram and vorinostat used for HIV latency reversal
The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal. Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents ma...
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| Veröffentlicht in: | AIDS (London) Jg. 36; H. 1; S. 75 |
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01.01.2022
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| Abstract | The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal.
Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal.
Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram.
The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1.
The combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal. |
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| AbstractList | The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal.
Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal.
Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram.
The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1.
The combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal. The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal.OBJECTIVEThe aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal.Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal.DESIGNVorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal.Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram.METHODSVirologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram.The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1.RESULTSThe first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1.The combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal.CONCLUSIONThe combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal. |
| Author | Lee, Sulggi Zetterberg, Henrik H Bumpus, Namandje Solomon, Ajantha Evans, Vanessa A Zerbato, Jennifer M Fisher, Katie Tennakoon, Surekha Wu, Guoxin Hagenauer, Michelle Lewin, Sharon R Palmer, Sarah Dantanarayana, Ashanti Burger, David Chang, Judy Symons, Jori Blennow, Kaj McMahon, James H Zuck, Paul Rasmussen, Thomas A Lau, Jillian S Y Heck, Carley J S Howell, Bonnie J Gisslen, Magnus |
| Author_xml | – sequence: 1 givenname: James H surname: McMahon fullname: McMahon, James H organization: Department of Infectious Diseases, Alfred Hospital and Monash University – sequence: 2 givenname: Vanessa A surname: Evans fullname: Evans, Vanessa A organization: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia – sequence: 3 givenname: Jillian S Y surname: Lau fullname: Lau, Jillian S Y organization: Department of Infectious Diseases, Alfred Hospital and Monash University – sequence: 4 givenname: Jori surname: Symons fullname: Symons, Jori organization: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia – sequence: 5 givenname: Jennifer M surname: Zerbato fullname: Zerbato, Jennifer M organization: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia – sequence: 6 givenname: Judy surname: Chang fullname: Chang, Judy organization: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia – sequence: 7 givenname: Ajantha surname: Solomon fullname: Solomon, Ajantha organization: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia – sequence: 8 givenname: Surekha surname: Tennakoon fullname: Tennakoon, Surekha organization: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia – sequence: 9 givenname: Ashanti surname: Dantanarayana fullname: Dantanarayana, Ashanti organization: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia – sequence: 10 givenname: Michelle surname: Hagenauer fullname: Hagenauer, Michelle organization: Department of Infectious Diseases, Alfred Hospital and Monash University – sequence: 11 givenname: Sulggi surname: Lee fullname: Lee, Sulggi organization: University of California San Francisco, San Francisco, California, USA – sequence: 12 givenname: Sarah surname: Palmer fullname: Palmer, Sarah organization: The Westmead Institute for Medical Research, University of Sydney, Sydney, Westmead, Australia – sequence: 13 givenname: Katie surname: Fisher fullname: Fisher, Katie organization: The Westmead Institute for Medical Research, University of Sydney, Sydney, Westmead, Australia – sequence: 14 givenname: Namandje surname: Bumpus fullname: Bumpus, Namandje organization: Johns Hopkins University, Baltimore, Maryland, USA – sequence: 15 givenname: Carley J S surname: Heck fullname: Heck, Carley J S organization: Johns Hopkins University, Baltimore, Maryland, USA – sequence: 16 givenname: David surname: Burger fullname: Burger, David organization: Department of Pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands – sequence: 17 givenname: Guoxin surname: Wu fullname: Wu, Guoxin organization: Department of Infectious Disease & Vaccine Research, Merck & Co., Inc., Kenilworth, New Jersey, USA – sequence: 18 givenname: Paul surname: Zuck fullname: Zuck, Paul organization: Department of Infectious Disease & Vaccine Research, Merck & Co., Inc., Kenilworth, New Jersey, USA – sequence: 19 givenname: Bonnie J surname: Howell fullname: Howell, Bonnie J organization: Department of Infectious Disease & Vaccine Research, Merck & Co., Inc., Kenilworth, New Jersey, USA – sequence: 20 givenname: Henrik H surname: Zetterberg fullname: Zetterberg, Henrik H organization: UK Dementia Research Institute at UCL, London, UK – sequence: 21 givenname: Kaj surname: Blennow fullname: Blennow, Kaj organization: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden – sequence: 22 givenname: Magnus surname: Gisslen fullname: Gisslen, Magnus organization: Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden – sequence: 23 givenname: Thomas A surname: Rasmussen fullname: Rasmussen, Thomas A organization: The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia – sequence: 24 givenname: Sharon R surname: Lewin fullname: Lewin, Sharon R organization: Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria |
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| Title | Neurotoxicity with high-dose disulfiram and vorinostat used for HIV latency reversal |
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