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Article ; Online: Cytomegalovirus viremia and advanced HIV disease: is there an argument for anti-CMV treatment?

Skipper, Caleb P / Schleiss, Mark R

2023 Volume 21, Issue 3, Page(s) 227–233

Abstract: Introduction: The role of cytomegalovirus (CMV) infection as a co-factor in HIV disease has been a topic of considerable interest since the beginning of the HIV pandemic. CMV is believed to function both as a co-factor in the progression of HIV ... ...

Abstract	Introduction: The role of cytomegalovirus (CMV) infection as a co-factor in HIV disease has been a topic of considerable interest since the beginning of the HIV pandemic. CMV is believed to function both as a co-factor in the progression of HIV infection, and as a contributor to enhanced disease for other opportunistic infections. Areas covered: In this special article, we review several recent studies that have enhanced our understanding of the role that CMV infection plays in the natural history of other HIV-related opportunistic infections. We review the clinical evidence that demonstrates how CMV viremia has emerged as an independent risk factor for the progression of infections such as those caused by Expert opinion: Evidence suggests that active CMV replication, manifest as CMV viremia (DNAemia), may play a key role in driving progression of HIV-associated opportunistic infections. We propose that control of CMV replication, independent of the known benefit of HAART therapy on reducing CMV end-organ disease, could reduce the risk of disease and mortality attributable to opportunistic infections such as cryptococcosis and tuberculosis. This could be achieved by the targeted use of CMV antivirals. The advent of newer (and safer) orally bioavailable CMV antivirals has renewed interest in, and opportunities for, randomized controlled trials to evaluate CMV viremia as a modifiable risk factor in high-risk persons with HIV disease.
MeSH term(s)	Humans ; HIV Infections/complications ; HIV Infections/drug therapy ; Cytomegalovirus ; Viremia/drug therapy ; Viremia/complications ; Cytomegalovirus Infections/drug therapy ; Cytomegalovirus Infections/epidemiology ; Cytomegalovirus Infections/complications ; Antiviral Agents/therapeutic use ; Opportunistic Infections/drug therapy
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2023-02-21
Publishing country	England
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2181279-2
ISSN	1744-8336 ; 1478-7210
ISSN (online)	1744-8336
ISSN	1478-7210
DOI	10.1080/14787210.2023.2172400
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Zs.A 6106: Show issues

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Article ; Online: Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19.

Skipper, Caleb P / Boulware, David R

Annals of internal medicine

2021 Volume 174, Issue 3, Page(s) 434–435

MeSH term(s)	Adult ; COVID-19/drug therapy ; Coronavirus Infections ; Humans ; Hydroxychloroquine/therapeutic use ; SARS-CoV-2
Chemical Substances	Hydroxychloroquine (4QWG6N8QKH)
Language	English
Publishing date	2021-03-15
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	336-0
ISSN	1539-3704 ; 0003-4819
ISSN (online)	1539-3704
ISSN	0003-4819
DOI	10.7326/L20-1426
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Article ; Online: Diagnosis and management of cryptococcal meningitis in HIV-infected adults.

McHale, Thomas C / Boulware, David R / Kasibante, John / Ssebambulidde, Kenneth / Skipper, Caleb P / Abassi, Mahsa

Clinical microbiology reviews

2023 Volume 36, Issue 4, Page(s) e0015622

Abstract: Cryptococcal meningitis is a leading cause of morbidity and mortality globally, especially in people with advanced HIV disease. Cryptococcal meningitis is responsible for nearly 20% of all deaths related to advanced HIV disease, with the burden of ... ...

Abstract	Cryptococcal meningitis is a leading cause of morbidity and mortality globally, especially in people with advanced HIV disease. Cryptococcal meningitis is responsible for nearly 20% of all deaths related to advanced HIV disease, with the burden of disease predominantly experienced by people in resource-limited countries. Major advancements in diagnostics have introduced low-cost, easy-to-use antigen tests with remarkably high sensitivity and specificity. These tests have led to improved diagnostic accuracy and are essential for screening campaigns to reduce the burden of cryptococcosis. In the last 5 years, several high-quality, multisite clinical trials have led to innovations in therapeutics that have allowed for simplified regimens, which are better tolerated and result in less intensive monitoring and management of medication adverse effects. One trial found that a shorter, 7-day course of deoxycholate amphotericin B is as effective as the longer 14-day course and that flucytosine is an essential partner drug for reducing mortality in the acute phase of disease. Single-dose liposomal amphotericin B has also been found to be as effective as a 7-day course of deoxycholate amphotericin B. These findings have allowed for simpler and safer treatment regimens that also reduce the burden on the healthcare system. This review provides a detailed discussion of the latest evidence guiding the clinical management and special circumstances that make cryptococcal meningitis uniquely difficult to treat.
MeSH term(s)	Adult ; Humans ; Amphotericin B/therapeutic use ; Deoxycholic Acid/therapeutic use ; Fluconazole/therapeutic use ; HIV Infections/complications ; HIV Infections/drug therapy ; Meningitis, Cryptococcal/diagnosis ; Meningitis, Cryptococcal/drug therapy ; Clinical Trials as Topic
Chemical Substances	Amphotericin B (7XU7A7DROE) ; Deoxycholic Acid (005990WHZZ) ; Fluconazole (8VZV102JFY)
Language	English
Publishing date	2023-11-28
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	645015-5
ISSN	1098-6618 ; 0893-8512
ISSN (online)	1098-6618
ISSN	0893-8512
DOI	10.1128/cmr.00156-22
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Zs.A 2409: Show issues

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Article: Hyponatremia as a Predictor of Cryptococcal Meningitis and Death Among Asymptomatic Persons With HIV and Cryptococcal Antigenemia.

Lehman, Alice / Nalintya, Elizabeth / Wele, Abduljewad / Kirumira, Paul / Naluyima, Rose / Namuli, Teopista / Turya Musa, Fred / Skipper, Caleb P / Meya, David B / Boulware, David R / Rajasingham, Radha

Open forum infectious diseases

2023 Volume 10, Issue 3, Page(s) ofad156

Abstract: Among persons with human immunodeficiency virus-associated cryptococcal meningitis serum hyponatremia is a risk factor for mortality; however, the role of hyponatremia in persons with asymptomatic cryptococcal antigenemia is unknown. We found that serum ... ...

Abstract	Among persons with human immunodeficiency virus-associated cryptococcal meningitis serum hyponatremia is a risk factor for mortality; however, the role of hyponatremia in persons with asymptomatic cryptococcal antigenemia is unknown. We found that serum hyponatremia ≤130 mmol/L is an independent risk factor for progression to meningitis and death in asymptomatic persons with cryptococcal antigenemia.
Language	English
Publishing date	2023-03-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofad156
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Article ; Online: Effect of Coronavirus Disease 2019 Lockdowns on Identification of Advanced Human Immunodeficiency Virus Disease in Outpatient Clinics in Uganda.

Nalintya, Elizabeth / Sekar, Preethiya / Kavuma, Paul / Kigozi, Joanita / Ssuna, Martin / Kirumira, Paul / Naluyima, Rose / Namuli, Teopista / Musa, Fred Turya / Skipper, Caleb P / Hullsiek, Kathy Huppler / Ellis, Jayne / Boulware, David R / Meya, David B / Rajasingham, Radha

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2023 Volume 76, Issue 11, Page(s) 2014–2017

Abstract: Using data from 67 Ugandan human immunodeficiency virus (HIV) clinics (July 2019-January 2022), we report a 40% (1005/1662) reduction in the number of people with HIV presenting to care after August 2021 compared to prepandemic levels, with a greater ... ...

Abstract	Using data from 67 Ugandan human immunodeficiency virus (HIV) clinics (July 2019-January 2022), we report a 40% (1005/1662) reduction in the number of people with HIV presenting to care after August 2021 compared to prepandemic levels, with a greater proportion presenting with advanced HIV disease (20% vs 16% in the pre-coronavirus disease 2019 period).
MeSH term(s)	Humans ; Uganda/epidemiology ; COVID-19 ; Communicable Disease Control ; HIV Infections/epidemiology ; HIV ; Ambulatory Care Facilities
Language	English
Publishing date	2023-02-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciad087
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Zs.A 1505: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Baseline Cytomegalovirus Viremia at Cryptococcal Meningitis Diagnosis Is Associated With Long-term Increased Incident TB Disease and Mortality in a Prospective Cohort of Ugandan Adults With HIV.

Ellis, Jayne / Bangdiwala, Ananta S / Skipper, Caleb P / Tugume, Lillian / Nsangi, Laura / Matovu, John / Pastick, Katelyn A / Ssebambulidde, Kenneth / Morawski, Bozena M / Musubire, Abdu K / Schleiss, Mark R / Moore, David A J / Jarvis, Joseph N / Boulware, David R / Meya, David B / Castelnuovo, Barbara

Open forum infectious diseases

2023 Volume 10, Issue 9, Page(s) ofad449

Abstract: Background: Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and ... ...

Abstract	Background: Adults with HIV-associated cryptococcal meningitis have overlapping burdens of cytomegalovirus (CMV) and tuberculosis (TB) coinfections. CMV infection/reactivation is strongly associated with CMV-specific memory T-cell activation and upregulation of type 1 interferons, which may lead to increased risk of TB disease and poor outcomes. Methods: We conducted a cohort study of 2-week survivors of cryptococcal meningitis during 2010-2021 to determine TB incidence and all-cause mortality over time stratified by baseline CMV status. Results: We followed 497 Ugandans with HIV-associated cryptococcal meningitis for a median (interquartile range) of 4.6 (2.6-53.9) months. Overall, 42% (210/497) developed incident TB disease or died. One-fifth (98/497, 19.7%) developed incident TB disease, and 29% (142/497) of participants died during follow-up. Of 259 participants with CMV viral load measured at baseline, 37% (96/259) had concurrent CMV viremia (defined as anyone with detectable CMV DNA in plasma/serum by qualitative polymerase chain reaction [PCR] detection). Of 59 with measured CMV immunoglobulin G (IgG), 100% had positive CMV IgG antibody serology (≥10 enzyme-linked immunosorbent assay units/mL). CMV viremia was positively associated with higher HIV viral load (196 667 vs 73 295 copies/mL; Conclusions: CMV viremia >1000 IU/mL at meningitis diagnosis was associated with increased incident TB disease and mortality during long-term follow-up. Future studies to determine the causal relationship and potential for therapeutic intervention are warranted.
Language	English
Publishing date	2023-09-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofad449
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Article ; Online: Determinants of cryptococcal antigen (CrAg) screening uptake in Kampala, Uganda: An assessment of health center characteristics.

Srishyla, Diksha / Saemisch, Gabriel / Turya, Fred / Nalintya, Elizabeth / Jjunju, Samuel / Kagimu, Enock / Rutakingirwa, Morris K / Skipper, Caleb P / Boulware, David R / Meya, David B / Rajasingham, Radha

Medical mycology

2022 Volume 60, Issue 4

Abstract: Cryptococcal antigen (CrAg) screening and pre-emptive antifungal therapy for people with CD4 cell counts <100 cells/μl are recommended by the World Health Organization and several national HIV guidelines. We sought to evaluate CrAg screening program ... ...

Abstract	Cryptococcal antigen (CrAg) screening and pre-emptive antifungal therapy for people with CD4 cell counts <100 cells/μl are recommended by the World Health Organization and several national HIV guidelines. We sought to evaluate CrAg screening program implementation across Uganda, in relation to health center level and distance from the capital. We conducted a cross-sectional study of 22 health centers across southern Uganda from April to June 2019. We reviewed laboratory records regarding number of CD4 cell count tests performed, proportion of outpatients with CD4 counts <200 cells/μl, and number of CrAg screening tests performed. We administered surveys to health center staff to understand barriers to advanced HIV care. We observed no significant difference in health center level and performance of CrAg screening; with each subsequent health center level, there was 1.17-fold (95% CI: 0.92-1.41) higher odds of CrAg screening performed per level. CrAg screening uptake was not associated with distance from the capital city (odds ratio = 0.96, 95% CI: 0.89-1.04). Qualitative data from surveys indicated that limitations to uptake of CrAg screening were secondary to dysfunctional CD4 machines, lack of provider awareness of CrAg screening guidelines, and inadequate/intermittent supply of CrAg tests. There were no significant associations between CrAg screening uptake and level of health center or distance of health center from the capital city. We identified systemic barriers to CrAg screening related to inadequate CD4 testing, insufficient knowledge regarding national screening guidelines, and irregular laboratory testing supplies. Lay summary: The objective of this study was to evaluate cryptococcal antigen (CrAg) screening program implementation in Uganda, by type of healthcare center and by distance from the capital city. CrAg screening uptake was not associated with distance from the capital city, or the type of healthcare center.
MeSH term(s)	Animals ; Antigens, Fungal ; Cross-Sectional Studies ; Cryptococcus ; Humans ; Meningitis, Cryptococcal/diagnosis ; Meningitis, Cryptococcal/veterinary ; Uganda
Chemical Substances	Antigens, Fungal
Language	English
Publishing date	2022-03-30
Publishing country	England
Document type	Journal Article
ZDB-ID	1421796-x
ISSN	1460-2709 ; 1369-3786
ISSN (online)	1460-2709
ISSN	1369-3786
DOI	10.1093/mmy/myac013
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Article: Clostridium Tetani Bacteremia From a Suspected Cutaneous Source.

Kazadi, David / Zychowski, Diana / Skipper, Caleb / Teravskis, Peter / Hansen, Glen T / Ordaya, Eloy E

Cureus

2022 Volume 14, Issue 3, Page(s) e22848

Abstract: Bacteremia is a rare complication ... ...

Abstract	Bacteremia is a rare complication of
Language	English
Publishing date	2022-03-04
Publishing country	United States
Document type	Case Reports
ZDB-ID	2747273-5
ISSN	2168-8184
ISSN	2168-8184
DOI	10.7759/cureus.22848
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Article ; Online: Evaluation of the effectiveness of a South African laboratory cryptococcal antigen screening programme using a retrospective cohort and a cluster-randomised trial design

David R Boulware / Radha Rajasingham / Rudzani Mashau / Nelesh P Govender / Daniel J DeSanto / Ananta S Bangdiwala / Erika Van Schalkwyk / Caleb P Skipper / Greg Greene / Juliet Paxton / Kathy Huppler Hullsiek

BMJ Open, Vol 12, Iss

2022 Volume 8

Abstract: Introduction Cryptococcal meningitis is a common fungal opportunistic infection and a leading cause of death among people with advanced HIV disease in sub-Saharan Africa. The WHO recommends cryptococcal antigen (CrAg) screening followed by pre-emptive ... ...

Abstract	Introduction Cryptococcal meningitis is a common fungal opportunistic infection and a leading cause of death among people with advanced HIV disease in sub-Saharan Africa. The WHO recommends cryptococcal antigen (CrAg) screening followed by pre-emptive therapy to prevent cryptococcal meningitis and death in this population. In 2016, South Africa was the first country to implement reflexive laboratory CrAg screening nationally. The Cryptococcal Antigen Screen-and-Treat National Evaluation Team (CAST-NET) aims to evaluate the effectiveness of this national screening programme to optimise health outcomes.Methods and analysis The CAST-NET study consists of two integrated parts: a retrospective cohort study and a cluster-randomised trial (CRT). The retrospective cohort study will determine 6-month cryptococcal meningitis-free survival among CrAg-positive patients. Secondary outcomes include the proportion of CrAg-positive results noted for action in the CrAg-positive patient chart, the proportion of CrAg-positive patients offered and accept/decline a lumbar puncture, the proportion of CrAg-positive patients prescribed antifungal therapy and the proportion of CrAg-positive patients who have antiretroviral therapy initiated or reinitiated at an appropriate time according to South African national guidelines. Cohort data will be analysed by the type of facility (ie, hospital vs primary health clinic) at which the patient was diagnosed with antigenaemia. The CRT will determine if the appointment and mentoring of a healthcare worker, or ‘crypto champion’, at intervention facilities is associated with a higher proportion of CrAg-positive persons initiating pre-emptive fluconazole therapy. Secondary outcomes will include 6-month cryptococcal meningitis-free survival and the proportion prescribed fluconazole maintenance treatment.Ethics and dissemination Ethics approvals were received from the University of the Witwatersrand Human Research Ethics Committee (Medical), the University of KwaZulu-Natal Biomedical Research Ethics ...
Keywords	Medicine ; R
Subject code	170
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
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Article ; Online: Evaluation of the Diagnostic Performance of a Semiquantitative Cryptococcal Antigen Point-of-Care Assay among HIV-Infected Persons with Cryptococcal Meningitis.

Tadeo, Kiiza Kandole / Nimwesiga, Audrey / Kwizera, Richard / Apeduno, Lucy / Martyn, Emily / Okirwoth, Michael / Nalintya, Elizabeth / Rajasingham, Radha / Williams, Darlisha A / Rhein, Joshua / Meya, David B / Kafufu, Bosco / Boulware, David R / Skipper, Caleb P

Journal of clinical microbiology

2021 Volume 59, Issue 8, Page(s) e0086021

Abstract: A newly developed cryptococcal antigen (CrAg) semiquantitative (SQ) lateral flow assay (LFA) provides a semiquantitative result in a rapid one-step test instead of performing serial dilutions to determine CrAg titer. We prospectively compared the ... ...

Abstract	A newly developed cryptococcal antigen (CrAg) semiquantitative (SQ) lateral flow assay (LFA) provides a semiquantitative result in a rapid one-step test instead of performing serial dilutions to determine CrAg titer. We prospectively compared the diagnostic performance of the CrAgSQ assay (IMMY) with the CrAg LFA (IMMY) on cerebrospinal fluid (CSF) samples collected from persons with HIV-associated meningitis. The CrAgSQ grades (1+ to 5+) were compared with CrAg LFA titers and quantitative CSF fungal cultures. Among 87 participants screened for HIV-associated meningitis, 60 had cryptococcal meningitis (59 CrAg positive [CrAg
MeSH term(s)	Antigens, Fungal ; Cryptococcus ; HIV Infections/complications ; Humans ; Meningitis, Cryptococcal/diagnosis ; Point-of-Care Systems
Chemical Substances	Antigens, Fungal
Language	English
Publishing date	2021-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	390499-4
ISSN	1098-660X ; 0095-1137
ISSN (online)	1098-660X
ISSN	0095-1137
DOI	10.1128/JCM.00860-21
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