Immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccination in exposed and potentially exposed persons in the Democratic Republic of the Congo.

Despite more than 300,000 rVSVΔG-ZEBOV-glycoprotein (GP) vaccine doses having been administered during Ebola virus disease (EVD) outbreaks in the Democratic Republic of the Congo (DRC) between 2018 and 2020, seroepidemiologic studies of vaccinated Congolese populations are lacking. This study examines the antibody response at 21 d and 6 mo postvaccination after single-dose rVSVΔG-ZEBOV-GP vaccination among EVD-exposed and potentially exposed populations in the DRC. We conducted a longitudinal cohort study of 608 rVSVΔG-ZEBOV-GP-vaccinated individuals during an EVD outbreak in North Kivu Province, DRC. Participants provided questionnaires and blood samples at three study visits (day 0, visit 1; day 21, visit 2; and month 6, visit 3). Anti-GP immunoglobulin G (IgG) antibody titers were measured in serum by the Filovirus Animal Nonclinical Group anti-Ebola virus GP IgG enzyme-linked immunosorbent assay. Antibody response was defined as an antibody titer that had increased fourfold from visit 1 to visit 2 and was above four times the lower limit of quantification at visit 2; antibody persistence was defined as a similar increase from visit 1 to visit 3. We then examined demographics for associations with follow-up antibody titers using generalized linear mixed models. A majority of the sample, 87.2%, had an antibody response at visit 2, and 95.6% demonstrated antibody persistence at visit 3. Being female and of young age was predictive of a higher antibody titer postvaccination. Antibody response and persistence after Ebola vaccination was robust in this cohort, confirming findings from outside of the DRC.

Infectious viral shedding of SARS-CoV-2 Delta following vaccination: A longitudinal cohort study.

The impact of vaccination on SARS-CoV-2 infectiousness is not well understood. We compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS-CoV-2-infected adults were enrolled within 5 days of symptom onset and nasal specimens were self-collected daily for two weeks and intermittently for an additional two weeks. SARS-CoV-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. We tested 1080 nasal specimens from 52 unvaccinated adults enrolled in the pre-Delta period and 32 fully vaccinated adults with predominantly Delta infections. While we observed no differences by vaccination status in maximum RNA levels, maximum infectious titers and the median duration of viral RNA shedding, the rate of decay from the maximum RNA load was faster among vaccinated; maximum infectious titers and maximum RNA levels were highly correlated. Furthermore, amongst participants with infectious virus, median duration of infectious virus detection was reduced from 7.5 days (IQR: 6.0-9.0) in unvaccinated participants to 6 days (IQR: 5.0-8.0) in those vaccinated (P = 0.02). Accordingly, the odds of shedding infectious virus from days 6 to 12 post-onset were lower among vaccinated participants than unvaccinated participants (OR 0.42 95% CI 0.19-0.89). These results indicate that vaccination had reduced the probability of shedding infectious virus after 5 days from symptom onset.

Adjusting Incidence Estimates with Laboratory Test Performances: A Pragmatic Maximum Likelihood Estimation-Based Approach.

Understanding the incidence of disease is often crucial for public policy decision-making, as observed during the COVID-19 pandemic. Estimating incidence is challenging, however, when the definition of incidence relies on tests that imperfectly measure disease, as in the case when assays with variable performance are used to detect the SARS-CoV-2 virus. To our knowledge, there are no pragmatic methods to address the bias introduced by the performance of labs in testing for the virus. In the setting of a longitudinal study, we developed a maximum likelihood estimation-based approach to estimate laboratory performance-adjusted incidence using the expectation-maximization algorithm. We constructed confidence intervals (CIs) using both bootstrapped-based and large-sample interval estimator approaches. We evaluated our methods through extensive simulation and applied them to a real-world study (TrackCOVID), where the primary goal was to determine the incidence of and risk factors for SARS-CoV-2 infection in the San Francisco Bay Area from July 2020 to March 2021. Our simulations demonstrated that our method converged rapidly with accurate estimates under a variety of scenarios. Bootstrapped-based CIs were comparable to the large-sample estimator CIs with a reasonable number of incident cases, shown via a simulation scenario based on the real TrackCOVID study. In more extreme simulated scenarios, the coverage of large-sample interval estimation outperformed the bootstrapped-based approach. Results from the application to the TrackCOVID study suggested that assuming perfect laboratory test performance can lead to an inaccurate inference of the incidence. Our flexible, pragmatic method can be extended to a variety of disease and study settings.

Programmatic Implications of National Recent HIV Infection Surveillance in Cambodia.

We compared characteristics of HIV diagnosis and recent HIV infection (ie, likely acquired within the last year) in Cambodia. We included individuals ≥ 15 years old accessing HIV testing. From August 2020 to August 2022, 53 031 people were tested for HIV, 6868 were newly diagnosed, and 192 were recently infected. We found differences in geographical burden and risk behaviors with diagnosis and recency (eg, men who have sex with men, transgender women, and entertainment workers had a nearly 2-fold increased odds of testing positive for recent infection compared to being diagnosed with HIV). Recent infection surveillance may provide unique insights into ongoing HIV acquisition to inform programs.

Identifying Paucisymptomatic or Asymptomatic and Unrecognized Ebola Virus Disease Among Close Contacts Based on Exposure Risk Assessments and Screening Algorithms.

BACKGROUND: There is limited evidence to evaluate screening algorithms with rapid antigen testing and exposure assessments as identification strategies for paucisymptomatic or asymptomatic Ebola virus (EBOV) infection and unrecognized EBOV disease (EVD). METHODS: We used serostatus and self-reported postexposure symptoms from a cohort study to classify contact-participants as having no infection, paucisymptomatic or asymptomatic infection, or unrecognized EVD. Exposure risk was categorized as low, intermediate, or high. We created hypothetical scenarios to evaluate the World Health Organization (WHO) case definition with or without rapid diagnostic testing (RDT) or exposure assessments. RESULTS: This analysis included 990 EVD survivors and 1909 contacts, of whom 115 (6%) had paucisymptomatic or asymptomatic EBOV infection, 107 (6%) had unrecognized EVD, and 1687 (88%) were uninfected. High-risk exposures were drivers of unrecognized EVD (adjusted odds ratio, 3.5 [95% confidence interval, 2.4-4.9]). To identify contacts with unrecognized EVD who test negative by the WHO case definition, the sensitivity was 96% with RDT (95% confidence interval, 91%-99%), 87% with high-risk exposure (82%-92%), and 97% with intermediate- to high-risk exposures (93%-99%). The proportion of false-positives was 2% with RDT and 53%-93% with intermediate- and/or high-risk exposures. CONCLUSION: We demonstrated the utility and trade-offs of sequential screening algorithms with RDT or exposure risk assessments as identification strategies for contacts with unrecognized EVD.

Incidence and Prevalence of Coronavirus Disease 2019 Within a Healthcare Worker Cohort During the First Year of the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic.

BACKGROUND: Preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2_ infections in healthcare workers (HCWs) is critical for healthcare delivery. We aimed to estimate and characterize the prevalence and incidence of coronavirus disease 2019 (COVID-19) in a US HCW cohort and to identify risk factors associated with infection. METHODS: We conducted a longitudinal cohort study of HCWs at 3 Bay Area medical centers using serial surveys and SARS-CoV-2 viral and orthogonal serological testing, including measurement of neutralizing antibodies. We estimated baseline prevalence and cumulative incidence of COVID-19. We performed multivariable Cox proportional hazards models to estimate associations of baseline factors with incident infections and evaluated the impact of time-varying exposures on time to COVID-19 using marginal structural models. RESULTS: A total of 2435 HCWs contributed 768 person-years of follow-up time. We identified 21 of 2435 individuals with prevalent infection, resulting in a baseline prevalence of 0.86% (95% confidence interval [CI], .53%-1.32%). We identified 70 of 2414 incident infections (2.9%), yielding a cumulative incidence rate of 9.11 cases per 100 person-years (95% CI, 7.11-11.52). Community contact with a known COVID-19 case was most strongly correlated with increased hazard for infection (hazard ratio, 8.1 [95% CI, 3.8-17.5]). High-risk work-related exposures (ie, breach in protective measures) drove an association between work exposure and infection (hazard ratio, 2.5 [95% CI, 1.3-4.8). More cases were identified in HCWs when community case rates were high. CONCLUSIONS: We observed modest COVID-19 incidence despite consistent exposure at work. Community contact was strongly associated with infections, but contact at work was not unless accompanied by high-risk exposure.

Magnitude and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Household Transmission: A Longitudinal Cohort Study.

BACKGROUND: Households have emerged as important venues for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Little is known, however, regarding the magnitude and determinants of household transmission in increasingly vaccinated populations. METHODS: From September 2020 to January 2022, symptomatic nonhospitalized individuals with SARS-CoV-2 infection by RNA detection were identified within 5 days of symptom onset; all individuals resided with at least 1 other SARS-CoV-2-uninfected household member. These infected persons (cases) and their household members (contacts) were subsequently followed with questionnaire-based measurement and serial nasal specimen collection. The primary outcome was SARS-CoV-2 infection among contacts. RESULTS: We evaluated 42 cases and their 74 household contacts. Among the contacts, 32 (43%) became infected, of whom 5 (16%) were asymptomatic; 81% of transmissions occurred by 5 days after the case's symptom onset. From 21 unvaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection among contacts was 18/40 (45% [95% confidence interval {CI}, 29%-62%]), most of whom were unvaccinated. From 21 vaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection was 14/34 (41% [95% CI, 25%-59%]) among all contacts and 12/29 (41% [95% CI, 24%-61%]) among vaccinated contacts. At least 1 comorbid condition among cases and 10 or more days of RNA detection in cases were associated with increased risk of infection among contacts. CONCLUSIONS: Among households including individuals with symptomatic SARS-CoV-2 infection, both vaccinated-to-vaccinated and unvaccinated-to-unvaccinated transmission of SARS-CoV-2 to household contacts was common. Because vaccination alone did not notably reduce risk of infection, household contacts will need to employ additional interventions to avoid infection.

All-cause and cause-specific mortality rates for Kisumu County: a comparison with Kenya, low-and middle-income countries.

BACKGROUND: Understanding the magnitude and causes of mortality at national and sub-national levels for countries is critical in facilitating evidence-based prioritization of public health response. We provide comparable cause of death data from Kisumu County, a high HIV and malaria-endemic county in Kenya, and compared them with Kenya and low-and-middle income countries (LMICs). METHODS: We analyzed data from a mortuary-based study at two of the largest hospital mortuaries in Kisumu. Mortality data through 2019 for Kenya and all LMICs were downloaded from the Global Health Data Exchange. We provided age-standardized rates for comparisons of all-cause and cause-specific mortality rates, and distribution of deaths by demographics and Global Burden of Disease (GBD) classifications. RESULTS: The all-cause age-standardized mortality rate (SMR) was significantly higher in Kisumu compared to Kenya and LMICs (1118 vs. 659 vs. 547 per 100,000 population, respectively). Among women, the all-cause SMR in Kisumu was almost twice that of Kenya and double the LMICs rate (1150 vs. 606 vs. 518 per 100,000 population respectively). Among men, the all-cause SMR in Kisumu was approximately one and a half times higher than in Kenya and nearly double that of LMICs (1089 vs. 713 vs. 574 per 100,000 population). In Kisumu and LMICs non-communicable diseases accounted for most (48.0 and 58.1% respectively) deaths, while in Kenya infectious diseases accounted for the majority (49.9%) of deaths. From age 10, mortality rates increased with age across all geographies. The age-specific mortality rate among those under 1 in Kisumu was nearly twice that of Kenya and LMICs (6058 vs. 3157 and 3485 per 100,000 population, respectively). Mortality from injuries among men was at least one and half times that of women in all geographies. CONCLUSION: There is a notable difference in the patterns of mortality rates across the three geographical areas. The double burden of mortality from GBD Group I and Group II diseases with high infant mortality in Kisumu can guide prioritization of public health interventions in the county. This study demonstrates the importance of establishing reliable vital registry systems at sub-national levels as the mortality dynamics and trends are not homogeneous.

Outdoor Transmission of SARS-CoV-2 and Other Respiratory Viruses: A Systematic Review.

BACKGROUND: While risk of outdoor transmission of respiratory viral infections is hypothesized to be low, there are limited data on SARS-CoV-2 transmission in outdoor compared to indoor settings. METHODS: We conducted a systematic review of peer-reviewed papers indexed in PubMed, EMBASE, and Web of Science and preprints in Europe PMC through 12 August 2020 that described cases of human transmission of SARS-CoV-2. Reports of other respiratory virus transmission were included for reference. RESULTS: Five identified studies found a low proportion of reported global SARS-CoV-2 infections occurred outdoors (<10%) and the odds of indoor transmission was very high compared to outdoors (18.7 times; 95% confidence interval, 6.0-57.9). Five studies described influenza transmission outdoors and 2 adenovirus transmission outdoors. There was high heterogeneity in study quality and individual definitions of outdoor settings, which limited our ability to draw conclusions about outdoor transmission risks. In general, factors such as duration and frequency of personal contact, lack of personal protective equipment, and occasional indoor gathering during a largely outdoor experience were associated with outdoor reports of infection. CONCLUSIONS: Existing evidence supports the wide-held belief that risk of SARS-CoV-2 transmission is lower outdoors but there are significant gaps in our understanding of specific pathways.

Will Coronavirus Disease 2019 Become Seasonal?

This manuscript explores the question of the seasonality of severe acute respiratory syndrome coronavirus 2 by reviewing 4 lines of evidence related to viral viability, transmission, ecological patterns, and observed epidemiology of coronavirus disease 2019 in the Southern Hemispheres' summer and early fall.

The Impact of Different Types of Violence on Ebola Virus Transmission During the 2018-2020 Outbreak in the Democratic Republic of the Congo.

BACKGROUND: Our understanding of the different effects of targeted versus nontargeted violence on Ebola virus (EBOV) transmission in Democratic Republic of the Congo (DRC) is limited. METHODS: We used time-series data of case counts to compare individuals in Ebola-affected health zones in DRC, April 2018-August 2019. Exposure was number of violent events per health zone, categorized into Ebola-targeted or Ebola-untargeted, and into civilian-induced, (para)military/political, or protests. Outcome was estimated daily reproduction number (Rt) by health zone. We fit linear time-series regression to model the relationship. RESULTS: Average Rt was 1.06 (95% confidence interval [CI], 1.02-1.11). A mean of 2.92 violent events resulted in cumulative absolute increase in Rt of 0.10 (95% CI, .05-.15). More violent events increased EBOV transmission (P = .03). Considering violent events in the 95th percentile over a 21-day interval and its relative impact on Rt, Ebola-targeted events corresponded to Rt of 1.52 (95% CI, 1.30-1.74), while civilian-induced events corresponded to Rt of 1.43 (95% CI, 1.21-1.35). Untargeted events corresponded to Rt of 1.18 (95% CI, 1.02-1.35); among these, militia/political or ville morte events increased transmission. CONCLUSIONS: Ebola-targeted violence, primarily driven by civilian-induced events, had the largest impact on EBOV transmission.

Association of neighborhood parks with child health in the United States.

While there is evidence that parks support pediatric health, there have been no national studies looking at both physical and mental health. We assessed whether the presence of a neighborhood park is associated with pediatric physical or mental health across the U.S. using a nationally representative cross-sectional random sample of American children ages 0-17. Caregivers reported on the park presence in their child's neighborhood and the child's physical activity, screen-time, sleep, weight, and diagnosis of anxiety, depression, or attention deficit hyperactivity disorder (ADHD). Covariates included child and family sociodemographics and, for 29 states, neighborhood urbanicity. Caregivers reported on 49,146 children (mean age 9.4 years; 49% female). There were 11,791 (24%) children living in neighborhoods lacking a park; children in non-urban locations (aOR 2.19, 95% CI 1.40-1.67) or below the federal poverty level (aOR = 1.48, 95%CI 1.38-1.58) had higher odds of lacking a park. Irrespective of sociodemographics, children lacking parks were more likely to be physically inactive (aOR1.36, 95% CI 1.24, 1.48), have excessive screen-time (aOR = 1.19, 95% CI 1.14, 1.25), or obtain inadequate sleep (aOR = 1.23, 95% CI 1.18, 1.29). Children without parks were more likely obese (aOR = 1.32, 95% CI 1.21, 1.43), overweight (aOR 1.25, 95%CI 1.17, 1.33), or diagnosed with ADHD (aOR 1.20, 95% CI 1.12, 1.29), but not more anxious or depressed (aOR = 1.04, 95%CI 0.97, 1.11). Associations between parks and pediatric physical and mental health suggests that the provision of neighborhood parks could represent a low-cost childhood health intervention.

Behind bars: the burden of being a woman in Brazilian prisons.

BACKGROUND: Brazil has the third largest prison population in the world. In 2016, the female prison population totaled 42,000, an increase of 656% over the population recorded in the early 2000s. The objective of this study was to describe the socialeconomic and reproductive health of women in Brazilian prisons, and the specific assistance received within the prison system. METHODS: This is a first of its kind national survey conducted in 15 female prisons in eight Brazilian states between 2014 and 2015. The sample consisted of 1327 women in closed or semi-open prison regimes. Data collection used Audio Computer-Assisted Self-Interviewing (ACASI). STATA v.15. Was use in analysis. The study was submitted to the Research Ethics Committee of the Federal University of Ceará, under CEP protocol No. 1,024,053. RESULTS: The population was overwhelmingly Black or Brown, poor and little educated. When women worked previously, they had worked as domestic servants and were the sole source of income for their families. Most were mothers, with 39% having children less than 10 years old, now in the care of others. Most were in jail for drug-related crimes. Prisons were crowded, with more than 2/3rds of the inmates sharing a cell with 6 or more inmates. Services were provide, but women had not had a cervical cancer screening within the past 3 years and breast cancer screening was not conducted. CONCLUSIONS: Overall, given their backround and prison conditions they are unlikely to change the circumstances that brought them to prison in the first place.

Neurological, Cognitive, and Psychological Findings Among Survivors of Ebola Virus Disease From the 1995 Ebola Outbreak in Kikwit, Democratic Republic of Congo: A Cross-sectional Study.

BACKGROUND: Clinical sequelae of Ebola virus disease (EVD) have not been described more than 3 years postoutbreak. We examined survivors and close contacts from the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo (DRC), and determined prevalence of abnormal neurological, cognitive, and psychological findings and their association with EVD survivorship. METHODS: From August to September 2017, we conducted a cross-sectional study in Kikwit, DRC. Over 2 decades after the EVD outbreak, we recruited EVD survivors and close contacts from the outbreak to undergo physical examination and culturally adapted versions of the Folstein mini-mental status exam (MMSE) and Goldberg anxiety and depression scale (GADS). We estimated the strength of relationships between EVD survivorship and health outcomes using linear regression models by comparing survivors versus close contacts, adjusting for age, sex, educational level, marital status, and healthcare worker status. RESULTS: We enrolled 20 EVD survivors and 187 close contacts. Among the 20 EVD survivors, 4 (20%) reported at least 1 abnormal neurological symptom, and 3 (15%) had an abnormal neurological examination. Among the 187 close contacts, 14 (11%) reported at least 1 abnormal neurologic symptom, and 9 (5%) had an abnormal neurological examination. EVD survivors had lower mean MMSE and higher mean GADS scores as compared to close contacts (MMSE: adjusted coefficient: -1.85; 95% confidence interval [CI]: -3.63, -0.07; GADS: adjusted coefficient: 3.91; 95% CI: 1.76, 6.04). CONCLUSIONS: EVD survivors can have lower cognitive scores and more symptoms of depression and anxiety than close contacts more than 2 decades after Ebola virus outbreaks.

Understanding why HIV-infected persons disengaged from pre-ART care in Freetown, Sierra Leone: a qualitative study.

In countries that have not implemented universal antiretroviral treatment (ART), loss to follow-up (LTFU) during pre-ART care remains a problem. We conducted semi-structured interviews with 41 HIV-infected persons who were LTFU during pre-ART care from a prospective cohort of persons newly diagnosed with HIV infection in Freetown, Sierra Leone, in 2012-2013. Interviews determined whether the participant disengaged or transferred care and explored the reasons for being LTFU. Of the 41 participants, 34 (83%) disengaged from care. For persons who disengaged from care, socioeconomic barriers emerged as a dominant theme in both ART-eligible and -ineligible groups while psychosocial barriers emerged as a dominant theme in the ART-ineligible group. Structural barriers emerged as a dominant theme for participants who transferred care. Interventions designed to address socioeconomic and psychosocial barriers may help reduce disengagement from pre-ART care.

Anatomy of a Hotspot: Chain and Seroepidemiology of Ebola Virus Transmission, Sukudu, Sierra Leone, 2015-16.

Studies have yet to include minimally symptomatic Ebola virus (EBOV) infections and unrecognized Ebola virus disease (EVD) in Ebola-related transmission chains and epidemiologic risk estimates. We conducted a cross-sectional, sero-epidemiological survey from October 2015 to January 2016 among 221 individuals living in quarantined households from November 2014 to February 2015 during the Ebola outbreak in the village of Sukudu, Sierra Leone. Of 48 EBOV-infected persons, 25% (95% confidence interval [CI], 14%-40%) had minimally symptomatic EBOV infections and 4% (95% CI, 1%-14%) were unrecognized EVD cases. The pattern of minimally symptomatic EBOV infections in the transmission chain was nonrandom (P < .001, permutation test). Not having lived in the same house as an EVD case was significantly associated with minimally symptomatic infection. This is the first study to investigate a chain of EBOV transmission inclusive of minimally symptomatic EBOV infections and unrecognized EVD. Our findings provide new insights into Ebola transmission dynamics and quarantine practices.

Mortality Rate and Predictors in Children Under 15 Years Old Who Acquired HIV from Mother to Child Transmission in Paraguay.

We estimated mortality rate and predictors of death in children and adolescents who acquired HIV through mother-to-child transmission in Paraguay. In 2000-2014, we conducted a cohort study among children and adolescents aged < 15 years. We abstracted data from medical records and death certificates. We used the Cox proportional hazards model for the multivariable analysis of mortality predictors. A total of 302 subjects were included in the survey; 216 (71.5%) were younger than 5 years, 148 (51.0%) were male, and 214 (70.9%) resided in the Asunción metropolitan area. There were 52 (17.2%) deaths, resulting in an overall mortality rate of 2.06 deaths per 100 person-years. The children and adolescents with hemoglobin levels ≤ 9 g/dL at baseline had a 2-times higher hazard of death compared with those who had levels > 9 g/dL (HR 2.27, 95% CI 1.01-5.10). The mortality of HIV-infected children and adolescents in Paraguay is high, and anemia is associated with mortality. Improving prenatal screening to find cases earlier and improving pediatric follow-up are needed.

Primary antifungal prophylaxis for cryptococcal disease in HIV-positive people.

BACKGROUND: Cryptococcal disease remains one of the main causes of death in HIV-positive people who have low cluster of differentiation 4 (CD4) cell counts. Currently, the World Health Organization (WHO) recommends screening HIV-positive people with low CD4 counts for cryptococcal antigenaemia (CrAg), and treating those who are CrAg-positive. This Cochrane Review examined the effects of an approach where those with low CD4 counts received regular prophylactic antifungals, such as fluconazole. OBJECTIVES: To assess the efficacy and safety of antifungal drugs for the primary prevention of cryptococcal disease in adults and children who are HIV-positive. SEARCH METHODS: We searched the CENTRAL, MEDLINE PubMed, Embase OVID, CINAHL EBSCOHost, WHO International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, conference proceedings for the International AIDS Society (IAS) and Conference on Retroviruses and Opportunistic Infections (CROI), and reference lists of relevant articles up to 31 August 2017. SELECTION CRITERIA: Randomized controlled trials of adults and children, who are HIV-positive with low CD4 counts, without a current or prior diagnosis of cryptococcal disease that compared any antifungal drug taken as primary prophylaxis to placebo or standard care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and risk of bias, and extracted and analysed data. The primary outcome was all-cause mortality. We summarized all outcomes using risk ratios (RR) with 95% confidence intervals (CI). Where appropriate, we pooled data in meta-analyses. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Nine trials, enrolling 5426 participants, met the inclusion criteria of this review. Six trials administered fluconazole, while three trials administered itraconazole.Antifungal prophylaxis may make little or no difference to all-cause mortality (RR 1.07, 95% CI 0.80 to 1.43; 6 trials, 3220 participants; low-certainty evidence). For cryptococcal specific outcomes, prophylaxis probably reduces the risk of developing cryptococcal disease (RR 0.29, 95% CI 0.17 to 0.49; 7 trials, 5000 participants; moderate-certainty evidence), and probably reduces deaths due to cryptococcal disease (RR 0.29, 95% CI 0.11 to 0.72; 5 trials, 3813 participants; moderate-certainty evidence). Fluconazole prophylaxis may make no clear difference to the risk of developing clinically resistant Candida disease (RR 0.93, 95% CI 0.56 to 1.56; 3 trials, 1198 participants; low-certainty evidence); however, there may be an increased detection of fluconazole-resistant Candida isolates from surveillance cultures (RR 1.25, 95% CI 1.00 to 1.55; 3 trials, 539 participants; low-certainty evidence). Antifungal prophylaxis was generally well-tolerated with probably no clear difference in the risk of discontinuation of antifungal prophylaxis compared with placebo (RR 1.01, 95% CI 0.91 to 1.13; 4 trials, 2317 participants; moderate-certainty evidence). Antifungal prophylaxis may also make no difference to the risk of having any adverse event (RR 1.07, 95% CI 0.88 to 1.30; 4 trials, 2317 participants; low-certainty evidence), or a serious adverse event (RR 1.08, 95% CI 0.83 to 1.41; 4 trials, 888 participants; low-certainty evidence) when compared to placebo or standard care. AUTHORS' CONCLUSIONS: Antifungal prophylaxis reduced the risk of developing and dying from cryptococcal disease. Therefore, where CrAG screening is not available, antifungal prophylaxis may be used in patients with low CD4 counts at diagnosis and who are at risk of developing cryptococcal disease.