Fungal Burden and Raised Intracranial Pressure Are Independently Associated With Visual Loss in Human Immunodeficiency Virus-Associated Cryptococcal Meningitis

Among 472 patients with human immunodeficiency virus-associated cryptococcal meningitis, 16% had severe visual loss at presentation, and 46% of these were 4-week survivors and remained severely impaired. Baseline cerebrospinal fluid opening pressure ≥40 cmH2O (adjusted odds ratio [aOR], 2.56; 95% confidence interval [CI], 1.36–4.83; P = .02) and fungal burden >6.0 log10 colonies/mL (aOR, 3.01; 95% CI, 1.58–5.7; P = .003) were independently associated with severe visual loss

Reduction in mortality from HIV-related CNS infections in routine care in Africa (DREAMM): a before-and-after, implementation study.

BACKGROUND: Four decades into the HIV epidemic, CNS infection remains a leading cause of preventable HIV-related deaths in routine care. The Driving Reduced AIDS-associated Meningo-encephalitis Mortality (DREAMM) project aimed to develop, implement, and evaluate pragmatic implementation interventions and strategies to reduce mortality from HIV-related CNS infection. METHODS: DREAMM took place in five public hospitals in Cameroon, Malawi, and Tanzania. The main intervention was a stepwise algorithm for HIV-related CNS infections including bedside rapid diagnostic testing and implementation of WHO cryptococcal meningitis guidelines. A health system strengthening approach for hospitals was adopted to deliver quality care through a co-designed education programme, optimised clinical and laboratory pathways, and communities of practice. DREAMM was led and driven by local leadership and divided into three phases: observation (including situational analyses of routine care), training, and implementation. Consecutive adults (aged ≥18 years) living with HIV presenting with a first episode of suspected CNS infection were eligible for recruitment. The primary endpoint was the comparison of 2-week all-cause mortality between observation and implementation phases. This study completed follow-up in September, 2021. The project was registered on ClinicalTrials.gov, NCT03226379. FINDINGS: From November, 2016 to April, 2019, 139 eligible participants were enrolled in the observation phase. From Jan 9, 2018, to March 25, 2021, 362 participants were enrolled into the implementation phase. 216 (76%) of 286 participants had advanced HIV disease (209 participants had missing CD4 cell count), and 340 (69%) of 494 participants had exposure to antiretroviral therapy (ART; one participant had missing ART data). In the implementation phase 269 (76%) of 356 participants had a probable CNS infection, 203 (76%) of whom received a confirmed microbiological or radiological diagnosis of CNS infection using existing diagnostic tests and medicines. 63 (49%) of 129 participants died at 2 weeks in the observation phase compared with 63 (24%) of 266 in the implementation phase; and all-cause mortality was lower in the implementation phase when adjusted for site, sex, age, ART exposure (adjusted risk difference -23%, 95% CI -33 to -13; p<0·001). At 10 weeks, 71 (55%) died in the observation phase compared with 103 (39%) in the implementation phase (-13%, -24 to -3; p=0·01). INTERPRETATION: DREAMM substantially reduced mortality from HIV-associated CNS infection in resource-limited settings in Africa. DREAMM scale-up is urgently required to reduce deaths in public hospitals and help meet Sustainable Development Goals. FUNDING: European and Developing Countries Clinical Trials Partnership, French Agency for Research on AIDS and Viral Hepatitis. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section

Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI −16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI −29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View

Cryptococcal meningitis: A neglected NTD?

Although HIV/AIDS has been anything but neglected over the last decade, opportunistic infections (OIs) are increasingly overlooked as large scale donors shift their focus from acute care to prevention and earlier antiretroviral treatment (ART) initiation. Of these OIs, cryptococcal meningitis, a deadly invasive fungal infection, continues to affect hundreds of thousands of HIV patients with advanced disease each year and is responsible for an estimated 15%-20% of all AIDS-related deaths [1,2]. Yet cryptococcal meningitis ranks amongst the most poorly funded “neglected” diseases in the world, receiving 0.2% of available relevant research and development (RandD) funding according to Policy Cures’ 2016 G-Finder Report [3,4]

Vitamin D status among HIV infected and HIV/TB co-infected patients attending Haydom Lutheran Hospital, rural Tanzania.

Human immune deficiency virus type 1 (HIV-1) infection remains the most common risk factor for the development of active and reactivation of latent tuberculosis (TB); on the other hand, TB is commonly known to accelerate the progression of HIV disease. Vitamin D has been shown to provide protection against tuberculosis, and its supplementation has also been shown to increase immunity. The currently available data from studies in humans regarding the potential value of vitamin D as adjunctive therapy in mycobacterial infection (TB) remain conflicting. There is also limited and contradictory evidence about the effect of vitamin D on the immune system. Furthermore, many of these studies were done in the developed world. Tanzania is faced with high burden of HIV and tuberculosis. Assessment data on vitamin D status in HIV and HIVTB were in short supply, especially the rural settings. When programmes are well planned, using locally relevant, up to date data, implementation is likely to be more effective than when international or national guidelines are followed without appropriate adaptation. We found reasonable and ethical to conduct this study investigating the interaction existed between vitamin D, calcium, parathyroid hormone, and CD4 cells count in HIV-1 monoinfected and HIV/TB co infected patients. Methods: A cross sectional study using quantitative methods was conducted from July 2010 to January 2011 at Haydom Lutheran Hospital in rural Tanzania. A purposive sampling technique was used to recruit 159 subjects aged 5 years and above. A standard data abstraction tool was used to obtain required information from the patients’ files/database. Serum vitamin D concentrations were measured by competitive Radioimmunoassay (RIA). Main findings The subjects mean (SD) age was 35.5 (11.3) years; 85 (53.5%) were female, and 71(44.7%), 41(25.8%), and 47(29.6%) were HIV, HIVTB and healthy controls respectively. Subjects enrolled during postharvest (Aug-Oct) season had significantly higher serum 25(OH)D compared to short rain season (Nov-Jan); (75.9 ± 20.8 vs. 64.6 ± 22.2, P = 0.034. Similarly subjects aged less than 25 yrs had higher level of serum 1, 25-(OH)2D than age groups 35 – 45 yrs and > 45 yrs; P = 0.043, 0.002 respectively. Overall hypovitaminosis D (serum 25-(OH)-D < 75nmol/l) was found in 60.4%. Subjects with HIV infection had higher serum 25-(OH)-D concentration than HIVTB-coinfected subjects (77.2 ± 20.8 vs 63.2 ± 23.8); P = 0.003. We observed hypovitaminosis D in 78.6% (11/14) of the HIVTB coinfected patients and in 52.1% (37/71) of the HIV monoinfected patients; the odd ratio (OR) of hypovitaminosis D for HIVTB coinfected patients was 3.4 (95% CI: 0.9, 13.1), P = 0.08. Advanced Clinical HIV stage (three and four) was significantly associated with lower serum 1,25-(OH)2D concentration, P = 0.021 and 0.0013 respectively. Subjects with CD4 cells count less 200 had lower level of serum 1,25(OH)2D than subjects with CD4 200 – 500 cells/mm3, 137.6 ± 63.9 vs 199.7 ± 58.1, P = 0.05. Both serum 25 (OH)D and 1,25 (OH)2D levels were higher in HIV positive patients not on ART compared with those on ART, but the difference did not reach statistical significance; 81.4 (20.5) vs 74.7 (20.7) nmol/l and 182.8 (67.1) vs 165.1 (75.5) pmol/l, P = 0.190, 0.323 respectively. However in both univariate and multivariate logistic regression analysis, hypovitaminosis D remained significantly higher among HIV patients on antiretroviral therapy (ART) compared to HIV patients not on ART, OR = 3.5 (95% CI; 1.1, 12.3). However this may be due to advanced disease. Conclusion; Advanced HIV stage was associated with lower serum 1,25(OH)2D concentrations, possibly due to reduced hydroxylation of 25(OH)D to 1,25(OH)2D in the macrophages. Serum 25-(OH)-D concentration was higher in HIV monoinfected than HIVTB coinfected patients, and hence hypovitaminosis D was more common among HIVTB coinfected than HIV monoinfected but the difference was not statistically significant due to small sample size. Hypovitaminosis D was higher in HIV patients on antiretroviral therapy compared with patients not on ART. In conclusion, hypovitaminosis D was more common in HIV and HIVTB patients. Both health professionals and policy makers should be aware of this common co-morbidity and act accordingly

Integrated care for human immunodeficiency virus, diabetes and hypertension in Africa.

The rising burden from non-communicable diseases (NCDs) poses a huge challenge for health care delivery in Africa, where health systems are already struggling with the long-term care requirements for the millions of people now on antiretroviral therapy requiring regular visits to health facilities for monitoring, adherence support and drugs. The HIV chronic disease management programme is comparatively well-funded, well-organised and well-informed and offers many insights and opportunities for the expansion of NCD prevention and treatment services. Some degree of human immunodeficiency virus (HIV) and NCD service integration is essential, but how to do this without risking the HIV treatment gains is unclear. Both HIV and NCD services must expand within a resource-constrained environment and policymakers are in urgent need of evidence to guide cost-effective and acceptable changes in these health services