BackgroundCryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-course high-dose liposomal amphotericin B (AmBisome), given with high dose fluconazole, is non-inferior (in terms of microbiological and clinical endpoints) to standard-dose 14-day courses of AmBisome plus high dose fluconazole for treatment of HIV-associated CM.Methodology/designThis is an adaptive open-label phase II/III randomised non-inferiority trial comparing alternative short course AmBisome regimens. Step 1 (phase II) will compare four treatment arms in 160 adult patients (≥18 years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10 mg/kg day one (single dose); 2) AmBisome 10 mg/kg day one and AmBisome 5 mg/kg day three (two doses); 3) AmBisome 10 mg/kg day one, and AmBisome 5 mg/kg days three and seven (three doses); and 4) AmBisome 3 mg/kg/d for 14 days (control); all given with fluconazole 1200 mg daily for 14 days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70 days as the primary outcome: 1) the shortest course AmBisome regimen found to be non-inferior in terms of EFA to the 14-day control arm in STEP 1, and 2) AmBisome 3 mg/kg/d for 14 days (control), both given with fluconazole 1200 mg daily for 14 days. STEP 2 analysis will include all patients from STEP 1 and STEP 2 taking the STEP 2 regimens. All patients will be followed for ten weeks, and mortality and safety data recorded. All patients will receive consolidation therapy with fluconazole 400–800 mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat.Trial registrationISRCTN10248064. Date of Registration: 22 January 2014

The high human immunodeficiency virus (HIV) prevalence in sub-Saharan Africa has markedly changed the epidemiology and presentation of adult meningitis. We conducted a systematic review using PubMed, Embase, Ovid, CENTRAL, and African Index Medicus to identify studies in Africa with data on neurological outcomes in adults after meningitis. We found 22 articles meeting inclusion criteria. From 4 studies with predominately pneumococcal meningitis, a median of 19% of survivors experienced hearing loss up to 40 days. Two studies of cryptococcal meningitis evaluated 6- to 12-month outcomes; in one, 41% of survivors had global neurocognitive impairment and 20% severe impairment at 1 year, and in a second 30% of survivors had intermediate disability and 10% severe disability at 6 months. A single small study of patients with tuberculosis/HIV found marked disability in 20% (6 of 30) at 9 months. Despite the high burden of meningitis in sub-Saharan Africa, little is known about neurological outcomes of patients with HIV-associated meningitides.

Transplant eligibility for hepatocellular carcinoma (HCC) is determined by the imaging identification of tumor burden within the Milan criteria. Transjugular intrahepatic portosystemic shunt(s) (TIPS) reduce portal hypertension but may impact HCC visualization. It was hypothesized that the presence of pretransplant TIPS would correlate with occult HCC and reduced survival. A single-center, retrospective, case control study was performed among liver transplant recipients with HCC (2000-2017). The primary endpoint was occult disease on explant pathology. Backward stepwise logistic regression was performed. The secondary endpoints disease-free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and Cox regression analysis. Of 640 patients, 40 had TIPS and more frequently exhibited occult disease (80.0% versus 43.1%; P < 0.001; odds ratio [OR], 4.16; P < 0.001). Portal vein thrombosis (PVT) similarly correlated with occult disease (OR, 1.97; P = 0.02). Explant tumor burden was equivalent between TIPS subgroups; accordingly, TIPS status was not independently associated with reduced DFS or OS. However, exceeding the Milan criteria was associated with reduced DFS (hazard ratio, 3.21; P = 0.001), and TIPS status in patients with a single suspected lesion (n = 316) independently correlated with explant tumor burdens beyond these criteria (OR, 13.47; P = 0.001). TIPS on pretransplant imaging are associated with occult HCC on explant pathology. Comparable occult disease findings in patients with PVT suggest that the mechanism may involve altered hepatic perfusion, obscuring imaging diagnosis. TIPS are not independently associated with reduced DFS or OS but are associated with exceeding the Milan criteria for patients with a single suspected lesion. The presence of TIPS may necessitate a higher index of suspicion for occult HCC.

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