Cytomegalovirus viremia as a risk factor for mortality in HIV-associated cryptococcal and tuberculous meningitis

ASTRO-CM and RifT Study Teams

doi:10.1016/j.ijid.2022.07.035

Cytomegalovirus viremia as a risk factor for mortality in HIV-associated cryptococcal and tuberculous meningitis

ASTRO-CM and RifT Study Teams

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

1 Scopus citations

Abstract

Objectives: CMV viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-naïve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of patients with HIV-associated meningitis at 18 weeks. Methods: We prospectively enrolled Ugandans with cryptococcal or TB meningitis into clinical trials in 2015-2019. We quantified CMV DNA concentrations from stored baseline plasma or serum samples from 340 participants. We compared 18-week survival between those with and without CMV viremia. Results: We included 308 persons with cryptococcal meningitis and 32 with TB meningitis, of whom 121 (36%) had detectable CMV DNA. Baseline CD4⁺ T-cell counts (14 vs. 24 cells/µl; P = 0.07) and antiretroviral exposure (47% vs. 45%; P = 0.68) did not differ between persons with and without CMV viremia. The 18-week mortality was 50% (61/121) in those with CMV viremia versus 34% (74/219) in those without (P = 0.003). Detectable CMV viremia (adjusted hazard ratio [aHR] 1.60; 95% confidence interval [CI] 1.13-2.25; P = 0.008) and greater viral load (aHR 1.22 per log₁₀ IU/ml increase; 95% CI 1.09-1.35; P <0.001) were positively associated with all-cause mortality through 18 weeks. Conclusion: CMV viremia at baseline was associated with a higher risk of death at 18 weeks among persons with HIV-associated cryptococcal or TB meningitis, and the risk increased as the CMV viral load increased. Further investigation is warranted to determine whether CMV is a modifiable risk contributing to deaths in HIV-associated meningitis or is a biomarker of immune dysfunction.

Original language	English (US)
Pages (from-to)	785-792
Number of pages	8
Journal	International Journal of Infectious Diseases
Volume	122
DOIs	https://doi.org/10.1016/j.ijid.2022.07.035
State	Published - Sep 2022

Bibliographical note

Funding Information:
The authors have no conflicts of interests to declare. This research was made possible by the National Institutes of Health's National Center for Advancing Translational Sciences (KL2TR002492 and UL1TR002494); National Institute of Allergy and Infectious Diseases (T32AI055433, U01AI089244); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD079918); National Institute of Neurologic Disorders and Stroke (R01NS086312); and the Fogarty International Center (K01TW010268, D43TW009345). FVC is supported by a Wellcome Ph.D. Fellowship (210772/Z/18/Z). DBM and DRB contributed equally to this work. We are appreciative of the study teams and hospital staff working continuously to provide compassionate care to the participants and patients at Mulago National Referral Hospital. ASTRO-CM Study team: Joshua Rhein, Kathy Huppler Hullsiek, Lillian Tugume, Edwin Nuwagira, Edward Mpoza, Emily E Evans, Reuben Kiggundu, Katelyn A Pastick, Kenneth Ssebambulidde, Andrew Akampurira, Darlisha A Williams, Ananta S Bangdiwala, Mahsa Abassi, Abdu K Musubire, Melanie R Nicol, Conrad Muzoora, David B Meya, David R Boulware, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Carolyne Namuju, Alisat Sadiq, Alice Namudde, James Mwesigye, Kiiza K Tadeo, Paul Kirumira, Michael Okirwoth, Tonny Luggya, Julian Kaboggoza, Eva Laker, Leo Atwine, Davis Muganzi, Stewart Walukaga, Bilal Jawed, Matthew Merry, Anna Stadelman, Nicole Stephens, Andrew G Flynn, Ayako W Fujita, Richard Kwizera, Liliane Mukaremera, Sarah M Lofgren, Fiona V Cresswell, Bozena M Morawski, Nathan C Bahr, Kirsten Nielsen. RIFT Study team: Jane Frances, Florence Kigundu, Cythia Ahimbisibwe, Carol Karuganda, Alice Namudde, Kiiza Tadeo Kandole, Alisat Sadiq, Mable Kabahubya, Edward Mpoza, Gavin Stead, Samuel Jjunju, Edwin Nuwagira, Nathan Bahr, Joshua Rhein, Darlisha Williams, Rhona Muyise, Eva Laker.

Funding Information:
This research was made possible by the National Institutes of Health's National Center for Advancing Translational Sciences (KL2TR002492 and UL1TR002494); National Institute of Allergy and Infectious Diseases (T32AI055433, U01AI089244); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD079918); National Institute of Neurologic Disorders and Stroke (R01NS086312); and the Fogarty International Center (K01TW010268, D43TW009345). FVC is supported by a Wellcome Ph.D. Fellowship (210772/Z/18/Z).

Publisher Copyright:
© 2022 The Author(s)

Keywords

CMV
Cryptococcal meningitis
Cytomegalovirus
HIV
Tuberculous meningitis

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ijid.2022.07.035

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@article{6ab89caf71d0416881bd01b4b9867c4e,

title = "Cytomegalovirus viremia as a risk factor for mortality in HIV-associated cryptococcal and tuberculous meningitis",

abstract = "Objectives: CMV viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-na{\"i}ve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of patients with HIV-associated meningitis at 18 weeks. Methods: We prospectively enrolled Ugandans with cryptococcal or TB meningitis into clinical trials in 2015-2019. We quantified CMV DNA concentrations from stored baseline plasma or serum samples from 340 participants. We compared 18-week survival between those with and without CMV viremia. Results: We included 308 persons with cryptococcal meningitis and 32 with TB meningitis, of whom 121 (36%) had detectable CMV DNA. Baseline CD4+ T-cell counts (14 vs. 24 cells/µl; P = 0.07) and antiretroviral exposure (47% vs. 45%; P = 0.68) did not differ between persons with and without CMV viremia. The 18-week mortality was 50% (61/121) in those with CMV viremia versus 34% (74/219) in those without (P = 0.003). Detectable CMV viremia (adjusted hazard ratio [aHR] 1.60; 95% confidence interval [CI] 1.13-2.25; P = 0.008) and greater viral load (aHR 1.22 per log10 IU/ml increase; 95% CI 1.09-1.35; P <0.001) were positively associated with all-cause mortality through 18 weeks. Conclusion: CMV viremia at baseline was associated with a higher risk of death at 18 weeks among persons with HIV-associated cryptococcal or TB meningitis, and the risk increased as the CMV viral load increased. Further investigation is warranted to determine whether CMV is a modifiable risk contributing to deaths in HIV-associated meningitis or is a biomarker of immune dysfunction.",

keywords = "CMV, Cryptococcal meningitis, Cytomegalovirus, HIV, Tuberculous meningitis",

author = "{ASTRO-CM and RifT Study Teams} and Skipper, {Caleb P.} and Hullsiek, {Katherine Huppler} and Cresswell, {Fiona V.} and Tadeo, {Kiiza K.} and Michael Okirwoth and Mark Blackstad and Nelmary Hernandez-Alvarado and Claudia Fern{\'a}ndez-Alarc{\'o}n and Stewart Walukaga and Emily Martyn and Jayne Ellis and Kenneth Ssebambulidde and Lillian Tugume and Edwin Nuwagira and Joshua Rhein and Meya, {David B.} and Boulware, {David R.} and Schleiss, {Mark R.}",

note = "Funding Information: The authors have no conflicts of interests to declare. This research was made possible by the National Institutes of Health's National Center for Advancing Translational Sciences (KL2TR002492 and UL1TR002494); National Institute of Allergy and Infectious Diseases (T32AI055433, U01AI089244); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD079918); National Institute of Neurologic Disorders and Stroke (R01NS086312); and the Fogarty International Center (K01TW010268, D43TW009345). FVC is supported by a Wellcome Ph.D. Fellowship (210772/Z/18/Z). DBM and DRB contributed equally to this work. We are appreciative of the study teams and hospital staff working continuously to provide compassionate care to the participants and patients at Mulago National Referral Hospital. ASTRO-CM Study team: Joshua Rhein, Kathy Huppler Hullsiek, Lillian Tugume, Edwin Nuwagira, Edward Mpoza, Emily E Evans, Reuben Kiggundu, Katelyn A Pastick, Kenneth Ssebambulidde, Andrew Akampurira, Darlisha A Williams, Ananta S Bangdiwala, Mahsa Abassi, Abdu K Musubire, Melanie R Nicol, Conrad Muzoora, David B Meya, David R Boulware, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Carolyne Namuju, Alisat Sadiq, Alice Namudde, James Mwesigye, Kiiza K Tadeo, Paul Kirumira, Michael Okirwoth, Tonny Luggya, Julian Kaboggoza, Eva Laker, Leo Atwine, Davis Muganzi, Stewart Walukaga, Bilal Jawed, Matthew Merry, Anna Stadelman, Nicole Stephens, Andrew G Flynn, Ayako W Fujita, Richard Kwizera, Liliane Mukaremera, Sarah M Lofgren, Fiona V Cresswell, Bozena M Morawski, Nathan C Bahr, Kirsten Nielsen. RIFT Study team: Jane Frances, Florence Kigundu, Cythia Ahimbisibwe, Carol Karuganda, Alice Namudde, Kiiza Tadeo Kandole, Alisat Sadiq, Mable Kabahubya, Edward Mpoza, Gavin Stead, Samuel Jjunju, Edwin Nuwagira, Nathan Bahr, Joshua Rhein, Darlisha Williams, Rhona Muyise, Eva Laker. Funding Information: This research was made possible by the National Institutes of Health's National Center for Advancing Translational Sciences (KL2TR002492 and UL1TR002494); National Institute of Allergy and Infectious Diseases (T32AI055433, U01AI089244); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD079918); National Institute of Neurologic Disorders and Stroke (R01NS086312); and the Fogarty International Center (K01TW010268, D43TW009345). FVC is supported by a Wellcome Ph.D. Fellowship (210772/Z/18/Z). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = sep,

doi = "10.1016/j.ijid.2022.07.035",

language = "English (US)",

volume = "122",

pages = "785--792",

journal = "International Journal of Infectious Diseases",

issn = "1201-9712",

publisher = "Elsevier",

}

TY - JOUR

T1 - Cytomegalovirus viremia as a risk factor for mortality in HIV-associated cryptococcal and tuberculous meningitis

AU - ASTRO-CM and RifT Study Teams

AU - Skipper, Caleb P.

AU - Hullsiek, Katherine Huppler

AU - Cresswell, Fiona V.

AU - Tadeo, Kiiza K.

AU - Okirwoth, Michael

AU - Blackstad, Mark

AU - Hernandez-Alvarado, Nelmary

AU - Fernández-Alarcón, Claudia

AU - Walukaga, Stewart

AU - Martyn, Emily

AU - Ellis, Jayne

AU - Ssebambulidde, Kenneth

AU - Tugume, Lillian

AU - Nuwagira, Edwin

AU - Rhein, Joshua

AU - Meya, David B.

AU - Boulware, David R.

AU - Schleiss, Mark R.

N1 - Funding Information: The authors have no conflicts of interests to declare. This research was made possible by the National Institutes of Health's National Center for Advancing Translational Sciences (KL2TR002492 and UL1TR002494); National Institute of Allergy and Infectious Diseases (T32AI055433, U01AI089244); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD079918); National Institute of Neurologic Disorders and Stroke (R01NS086312); and the Fogarty International Center (K01TW010268, D43TW009345). FVC is supported by a Wellcome Ph.D. Fellowship (210772/Z/18/Z). DBM and DRB contributed equally to this work. We are appreciative of the study teams and hospital staff working continuously to provide compassionate care to the participants and patients at Mulago National Referral Hospital. ASTRO-CM Study team: Joshua Rhein, Kathy Huppler Hullsiek, Lillian Tugume, Edwin Nuwagira, Edward Mpoza, Emily E Evans, Reuben Kiggundu, Katelyn A Pastick, Kenneth Ssebambulidde, Andrew Akampurira, Darlisha A Williams, Ananta S Bangdiwala, Mahsa Abassi, Abdu K Musubire, Melanie R Nicol, Conrad Muzoora, David B Meya, David R Boulware, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Carolyne Namuju, Alisat Sadiq, Alice Namudde, James Mwesigye, Kiiza K Tadeo, Paul Kirumira, Michael Okirwoth, Tonny Luggya, Julian Kaboggoza, Eva Laker, Leo Atwine, Davis Muganzi, Stewart Walukaga, Bilal Jawed, Matthew Merry, Anna Stadelman, Nicole Stephens, Andrew G Flynn, Ayako W Fujita, Richard Kwizera, Liliane Mukaremera, Sarah M Lofgren, Fiona V Cresswell, Bozena M Morawski, Nathan C Bahr, Kirsten Nielsen. RIFT Study team: Jane Frances, Florence Kigundu, Cythia Ahimbisibwe, Carol Karuganda, Alice Namudde, Kiiza Tadeo Kandole, Alisat Sadiq, Mable Kabahubya, Edward Mpoza, Gavin Stead, Samuel Jjunju, Edwin Nuwagira, Nathan Bahr, Joshua Rhein, Darlisha Williams, Rhona Muyise, Eva Laker. Funding Information: This research was made possible by the National Institutes of Health's National Center for Advancing Translational Sciences (KL2TR002492 and UL1TR002494); National Institute of Allergy and Infectious Diseases (T32AI055433, U01AI089244); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD079918); National Institute of Neurologic Disorders and Stroke (R01NS086312); and the Fogarty International Center (K01TW010268, D43TW009345). FVC is supported by a Wellcome Ph.D. Fellowship (210772/Z/18/Z). Publisher Copyright: © 2022 The Author(s)

PY - 2022/9

Y1 - 2022/9

N2 - Objectives: CMV viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-naïve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of patients with HIV-associated meningitis at 18 weeks. Methods: We prospectively enrolled Ugandans with cryptococcal or TB meningitis into clinical trials in 2015-2019. We quantified CMV DNA concentrations from stored baseline plasma or serum samples from 340 participants. We compared 18-week survival between those with and without CMV viremia. Results: We included 308 persons with cryptococcal meningitis and 32 with TB meningitis, of whom 121 (36%) had detectable CMV DNA. Baseline CD4+ T-cell counts (14 vs. 24 cells/µl; P = 0.07) and antiretroviral exposure (47% vs. 45%; P = 0.68) did not differ between persons with and without CMV viremia. The 18-week mortality was 50% (61/121) in those with CMV viremia versus 34% (74/219) in those without (P = 0.003). Detectable CMV viremia (adjusted hazard ratio [aHR] 1.60; 95% confidence interval [CI] 1.13-2.25; P = 0.008) and greater viral load (aHR 1.22 per log10 IU/ml increase; 95% CI 1.09-1.35; P <0.001) were positively associated with all-cause mortality through 18 weeks. Conclusion: CMV viremia at baseline was associated with a higher risk of death at 18 weeks among persons with HIV-associated cryptococcal or TB meningitis, and the risk increased as the CMV viral load increased. Further investigation is warranted to determine whether CMV is a modifiable risk contributing to deaths in HIV-associated meningitis or is a biomarker of immune dysfunction.

AB - Objectives: CMV viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-naïve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of patients with HIV-associated meningitis at 18 weeks. Methods: We prospectively enrolled Ugandans with cryptococcal or TB meningitis into clinical trials in 2015-2019. We quantified CMV DNA concentrations from stored baseline plasma or serum samples from 340 participants. We compared 18-week survival between those with and without CMV viremia. Results: We included 308 persons with cryptococcal meningitis and 32 with TB meningitis, of whom 121 (36%) had detectable CMV DNA. Baseline CD4+ T-cell counts (14 vs. 24 cells/µl; P = 0.07) and antiretroviral exposure (47% vs. 45%; P = 0.68) did not differ between persons with and without CMV viremia. The 18-week mortality was 50% (61/121) in those with CMV viremia versus 34% (74/219) in those without (P = 0.003). Detectable CMV viremia (adjusted hazard ratio [aHR] 1.60; 95% confidence interval [CI] 1.13-2.25; P = 0.008) and greater viral load (aHR 1.22 per log10 IU/ml increase; 95% CI 1.09-1.35; P <0.001) were positively associated with all-cause mortality through 18 weeks. Conclusion: CMV viremia at baseline was associated with a higher risk of death at 18 weeks among persons with HIV-associated cryptococcal or TB meningitis, and the risk increased as the CMV viral load increased. Further investigation is warranted to determine whether CMV is a modifiable risk contributing to deaths in HIV-associated meningitis or is a biomarker of immune dysfunction.

KW - CMV

KW - Cryptococcal meningitis

KW - Cytomegalovirus

KW - HIV

KW - Tuberculous meningitis

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UR - http://www.scopus.com/inward/citedby.url?scp=85137745422&partnerID=8YFLogxK

U2 - 10.1016/j.ijid.2022.07.035

DO - 10.1016/j.ijid.2022.07.035

M3 - Article

C2 - 35843498

AN - SCOPUS:85137745422

SN - 1201-9712

VL - 122

SP - 785

EP - 792

JO - International Journal of Infectious Diseases

JF - International Journal of Infectious Diseases

ER -

Cytomegalovirus viremia as a risk factor for mortality in HIV-associated cryptococcal and tuberculous meningitis

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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