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Background: Cryptococcal meningitis (CM) is a leading cause of HIV-related mortality. Based on phase-II study data showing that a single high-dose of 10 mg/kg liposomal amphotericin-B (AmBisome, Gilead Sciences Inc) [...]

INTRODUCTION: An adverse event following immunisation is any untoward medical occurrence which follows vaccination. Frequency of adverse events ranges from 13% to 34% and they should be reported regardless of severity. From the beginning of 2016 to mid-2017, Guruve district in Zimbabwe did not report any AEFIs. This suggests the surveillance system may be failing to detect adverse events. We therefore evaluated the AEFI surveillance system in Guruve district. METHODS: we conducted a surveillance system evaluation using the updated Centers for Disease Control guidelines for evaluating public health surveillance systems. We interviewed health workers and caregivers of babies under 2 years in Guruve district. We also reviewed all records on AEFI surveillance for the period of January 2016 to November 2017. RESULTS: We recruited 31 health workers and 33 caregivers into the study. Between January 2016 and mid-2017, 39% of the caregivers had children who had suffered AEFIs and 45% of the health workers had encountered AEFIs but none had been notified. The main reasons for failure to report AEFIs included health workers' fear of personal consequences and caregivers thinking that an adverse event was not serious enough to report. Knowledge of the surveillance system was good amongst the majority of health workers. All the resources needed by the surveillance system were available. CONCLUSION: We concluded that health workers in Guruve district were afraid to report adverse events following immunization and caregivers were reluctant to report mild adverse events hence the surveillance system was performing poorly and was not useful. However, the stability of the system and the good knowledge gives a good foundation for improving the surveillance system.

Background: We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin., Methods: Infants with HIV aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported., Results: Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively., Conclusions: Dolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection., Competing Interests: Potential conflicts of interest. A. C. reports research grants from ViiV Healthcare, Gilead Sciences, and Merck, all paid to institution; consulting fees for serving on a Gilead advisory board and Merck advisory board, all paid to institution; participation in the Pharmacokinetics and Safety of DolutegravIr in Neonate (PETITE) study on a data and safety monitoring board (DSMB) and in the Doravirine Dose Optimisation in Pregnancy (DORADO) study on a DSMB; and a role as member of Paediatric Antiretroviral Working Group (PAWG) and as co-chair of the HIV, Hepatitis and STIs Pregnancy and Breastfeeding Therapeutics Working Group. P. R. reports grants from ViiV Healthcare and Merck. D. B. reports being cofounder of Global DDI solutions and that his employer, RadboudUMC, has received grants from ViiV Healthcare, Gilead Sciences, Merck, and Pfizer. W. C. B. reports support for attending the Pediatrics & HIV 2023 Conference in Brisbane, Australia, to present an EMPIRICAL abstract with study funding. V. M. reports support for attending international conference from Viatris and participation on a DSMB and advisory board for ViiV Healthcare. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

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 log 10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log 10 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.)., (Copyright © 2022 Massachusetts Medical Society.)