Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

BACKGROUND: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known. METHODS: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin. RESULTS: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%). CONCLUSIONS: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

Recognition and management of community-acquired acute kidney injury in low-resource settings in the ISN 0by25 trial: A multi-country feasibility study.

BACKGROUND: Acute kidney injury (AKI) is increasingly encountered in community settings and contributes to morbidity, mortality, and increased resource utilization worldwide. In low-resource settings, lack of awareness of and limited access to diagnostic and therapeutic interventions likely influence patient management. We evaluated the feasibility of the use of point-of-care (POC) serum creatinine and urine dipstick testing with an education and training program to optimize the identification and management of AKI in the community in 3 low-resource countries. METHODS AND FINDINGS: Patients presenting to healthcare centers (HCCs) from 1 October 2016 to 29 September 2017 in the cities Cochabamba, Bolivia; Dharan, Nepal; and Blantyre, Malawi, were assessed utilizing a symptom-based risk score to identify patients at moderate to high AKI risk. POC testing for serum creatinine and urine dipstick at enrollment were utilized to classify these patients as having chronic kidney disease (CKD), acute kidney disease (AKD), or no kidney disease (NKD). Patients were followed for a maximum of 6 months with repeat POC testing. AKI development was assessed at 7 days, kidney recovery at 1 month, and progression to CKD and mortality at 3 and 6 months. Following an observation phase to establish baseline data, care providers and physicians in the HCCs were trained with a standardized protocol utilizing POC tests to evaluate and manage patients, guided by physicians in referral hospitals connected via mobile digital technology. We evaluated 3,577 patients, and 2,101 were enrolled: 978 in the observation phase and 1,123 in the intervention phase. Due to the high number of patients attending the centers daily, it was not feasible to screen all patients to assess the actual incidence of AKI. Of enrolled patients, 1,825/2,101 (87%) were adults, 1,117/2,101 (53%) were females, 399/2,101 (19%) were from Bolivia, 813/2,101 (39%) were from Malawi, and 889/2,101 (42%) were from Nepal. The age of enrolled patients ranged from 1 month to 96 years, with a mean of 43 years (SD 21) and a median of 43 years (IQR 27-62). Hypertension was the most common comorbidity (418/2,101; 20%). At enrollment, 197/2,101 (9.4%) had CKD, and 1,199/2,101 (57%) had AKD. AKI developed in 30% within 7 days. By 1 month, 268/978 (27%) patients in the observation phase and 203/1,123 (18%) in the intervention phase were lost to follow-up. In the intervention phase, more patients received fluids (observation 714/978 [73%] versus intervention 874/1,123 [78%]; 95% CI 0.63, 0.94; p = 0.012), hospitalization was reduced (observation 578/978 [59%] versus intervention 548/1,123 [49%]; 95% CI 0.55, 0.79; p < 0.001), and admitted patients with severe AKI did not show a significantly lower mortality during follow-up (observation 27/135 [20%] versus intervention 21/178 [11.8%]; 95% CI 0.98, 3.52; p = 0.057). Of 504 patients with kidney function assessed during the 6-month follow-up, de novo CKD arose in 79/484 (16.3%), with no difference between the observation and intervention phase (95% CI 0.91, 2.47; p = 0.101). Overall mortality was 273/2,101 (13%) and was highest in those who had CKD (24/106; 23%), followed by those with AKD (128/760; 17%), AKI (85/628; 14%), and NKD (36/607; 6%). The main limitation of our study was the inability to determine the actual incidence of kidney dysfunction in the health centers as it was not feasible to screen all the patients due to the high numbers seen daily. CONCLUSIONS: This multicenter, non-randomized feasibility study in low-resource settings demonstrates that it is feasible to implement a comprehensive program utilizing POC testing and protocol-based management to improve the recognition and management of AKI and AKD in high-risk patients in primary care.

The Role of Human Immunodeficiency Virus-Associated Vasculopathy in the Etiology of Stroke.

Background: Human immunodeficiency virus (HIV) infection is a recognized risk factor for stroke among young populations, but the exact mechanisms are poorly understood. We studied the clinical, radiologic, and histologic features of HIV-related ischemic stroke to gain insight into the disease mechanisms. Methods: We conducted a prospective, in-depth analysis of adult ischemic stroke patients presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, in 2011. Results: We recruited 64 HIV-infected and 107 HIV-uninfected patients. Those with HIV were significantly younger (P < .001) and less likely to have established vascular risk factors. Patients with HIV were more likely to have large artery disease (21% vs 10%; P < .001). The commonest etiology was HIV-associated vasculopathy (24 [38%]), followed by opportunistic infections (16 [25%]). Sixteen of 64 (25%) had a stroke soon after starting antiretroviral therapy (ART), suggesting an immune reconstitution-like syndrome. In this group, CD4+ T-lymphocyte count was low, despite a significantly lower HIV viral load in those recently started on treatment (P < .001). Conclusions: HIV-associated vasculopathy and opportunistic infections are common causes of HIV-related ischemic stroke. Furthermore, subtypes of HIV-associated vasculopathy may manifest as a result of an immune reconstitution-like syndrome after starting ART. A better understanding of this mechanism may point toward new treatments.

"An increase in COVID-19 patients would be overwhelming": A qualitative description of healthcare workers' experiences during the first wave of COVID-19 (March 2020 to October 2020) at Malawi's largest referral hospital.

Background  COVID-19 is currently a global health threat. Healthcare workers are on the front-line of the COVID-19 outbreak response and therefore at heightened risk of infection. There is a dearth of evidence from Sub-Saharan Africa about healthcare worker experiences in managing COVID-19.  We have reported on healthcare worker responses, experiences, and perspectives on epidemic response strategies at Queen Elizabeth Central Hospital, Malawi's largest referral hospital.   Methods  We conducted 39 face-to-face in-depth interviews with a purposively selected sample of healthcare workers during the first wave of COVID-19 in Malawi (March 2020 to October 2020). The study included healthcare workers who provided direct and indirect patient care.   Results  During the early phase of the first wave (March to May 2020), healthcare workers expressed concerns with inadequate working space, unconducive infrastructure, delayed and rushed training on the management of COVID-19, and lack of incentives. Additionally, the hospital had staff shortages and limited essential resources such as piped oxygen and personal protective equipment. This increased healthcare worker fears of contracting COVID-19 and they were less willing to volunteer at COVID-19 isolation units. Resource constraints and limited preparedness compromised the care pathway particularly with increased numbers of COVID-19 patients. By the peak of the first wave (June to August 2020) many of these issues had been resolved. The hospital provided refresher training courses, personal protective equipment became available, incentives were offered to healthcare workers working in COVID-19 units and piped oxygen was installed. Staff morale was boosted, and more staff were willing to work at the COVID-19 isolation centres.   Conclusion  Experiences of healthcare workers during the first wave of COVID-19 are critical for improving care in future COVID-19 waves. Response strategies in resource-constrained areas should prioritise timely training of staff, creation of adequate isolation areas, provision of adequate medical supplies and strengthening leadership.

Diagnostic performance of a point-of-care saliva urea nitrogen dipstick to screen for kidney disease in low-resource settings where serum creatinine is unavailable.

BACKGROUND: Kidney disease is prevalent in low-resource settings worldwide, but tests for its diagnosis are often unavailable. The saliva urea nitrogen (SUN) dipstick is a laboratory and electricity independent tool, which may be used for the detection of kidney disease. We investigated the feasibility and performance of its use in diagnosing kidney disease in community settings in Africa. METHODS: Adult patients at increased risk of kidney disease presenting to three community health centres, a rural district hospital and a central hospital in Malawi were recruited between October 2016 and September 2017. Patients underwent concurrent SUN and creatinine testing at enrolment, and at 1 week, 1 month, 3 months and 6 months thereafter. RESULTS: Of 710 patients who presented at increased risk of kidney disease, 655 (92.3%) underwent SUN testing at enrolment, and were included (aged 38 (29-52) years, 367 (56%) female and 333 (50.8%) with HIV). Kidney disease was present in 482 (73.6%) patients and 1479 SUN measurements were made overall. Estimated glomerular filtration rate (eGFR) correlated with SUN (r=-0.39; p<0.0001). The area under the receiver operating characteristics curve was 0.61 for presenting SUN to detect acute or chronic kidney disease, and 0.87 to detect severe (eGFR <15 mL/min/1.73 m2) kidney disease (p<0.0001; sensitivity 82.3%, specificity 81.8%, test accuracy 81.8%). In-hospital mortality was greater if enrolment SUN was elevated (>test pad #1) compared with patients with non-elevated SUN (p<0.0001; HR 3.3 (95% CI 1.7 to 6.1). CONCLUSIONS: SUN, measured by dipstick, is feasible and may be used to screen for kidney disease in low resource settings where creatinine tests are unavailable.

HIV, antiretroviral treatment, hypertension, and stroke in Malawian adults: A case-control study.

OBJECTIVE: To investigate HIV, its treatment, and hypertension as stroke risk factors in Malawian adults. METHODS: We performed a case-control study of 222 adults with acute stroke, confirmed by MRI in 86%, and 503 population controls, frequency-matched for age, sex, and place of residence, using Global Positioning System for random selection. Multivariate logistic regression models were used for case-control comparisons. RESULTS: HIV infection (population attributable fraction [PAF] 15%) and hypertension (PAF 46%) were strongly linked to stroke. HIV was the predominant risk factor for young stroke (≤45 years), with a prevalence of 67% and an adjusted odds ratio (aOR) (95% confidence interval) of 5.57 (2.43-12.8) (PAF 42%). There was an increased risk of a stroke in patients with untreated HIV infection (aOR 4.48 [2.44-8.24], p < 0.001), but the highest risk was in the first 6 months after starting antiretroviral therapy (ART) (aOR 15.6 [4.21-46.6], p < 0.001); this group had a lower median CD4(+) T-lymphocyte count (92 vs 375 cells/mm(3), p = 0.004). In older participants (HIV prevalence 17%), HIV was associated with stroke, but with a lower PAF than hypertension (5% vs 68%). There was no interaction between HIV and hypertension on stroke risk. CONCLUSIONS: In a population with high HIV prevalence, where stroke incidence is increasing, we have shown that HIV is an important risk factor. Early ART use in immunosuppressed patients poses an additional and potentially treatable stroke risk. Immune reconstitution inflammatory syndrome may be contributing to the disease mechanisms.