Genetic diversity and microevolution in clinical Cryptococcus isolates from Cameroon.

Cryptococcal meningitis is the second most common cause of death in people living with HIV/AIDS, yet we have a limited understanding of how cryptococcal isolates change over the course of infection. Cryptococcal infections are environmentally acquired, and the genetic diversity of these infecting isolates can also be geographically linked. Here, we employ whole genome sequences for 372 clinical Cryptococcus isolates from 341 patients with HIV-associated cryptococcal meningitis obtained via a large clinical trial, across both Malawi and Cameroon, to enable population genetic comparisons of isolates between countries. We see that isolates from Cameroon are highly clonal, when compared to those from Malawi, with differential rates of disruptive variants in genes with roles in DNA binding and energy use. For a subset of patients (22) from Cameroon, we leverage longitudinal sampling, with samples taken at days 7 and 14 post-enrollment, to interrogate the genetic changes that arise over the course of infection, and the genetic diversity of isolates within patients. We see disruptive variants arising over the course of infection in several genes, including the phagocytosis-regulating transcription factor GAT204. In addition, in 13% of patients sampled longitudinally, we see evidence for mixed infections. This approach identifies geographically linked genetic variation, signatures of microevolution, and evidence for mixed infections across a clinical cohort of patients affected by cryptococcal meningitis in Central Africa.

Cryptococcal meningitis, caused by Cryptococcus, results in approximately half a million deaths per year globally. We compare clinical Cryptococcus samples from Cameroon and Malawi to explore the genetic diversity of these isolates. We find instances of mixed-strain infections and identify genetic variants arising in Cryptococcus over disease.

Closing the gap in our understanding of infectious diseases.

Systematic reviews (SR) and meta-analyses (MA) have become important in addressing specific questions of clinical importance and presenting evidence from an in-depth analysis of literature and aiding clinical decision-making. The "Systematic Reviews on infectious diseases" collection will address several important questions by summarizing large bodies of evidence in a reproducible and concise approach to advance our knowledge and understanding of infectious diseases.

Cryptococcal Antigen in Serum and Cerebrospinal Fluid for Detecting Cryptococcal Meningitis in Adults Living With Human Immunodeficiency Virus: Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies.

Cryptococcal antigen (CrAg) detection could direct the timely initiation of antifungal therapy. We searched MEDLINE and Embase for studies where CrAg detection in serum/cerebrospinal fluid (CSF) and CSF fungal culture were done on adults living with human immunodeficiency virus (HIV) who had suspected cryptococcal meningitis (CM). With Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), we evaluated the risk of bias in 11 included studies with 3600 participants, and used a random-effects meta-analysis to obtain summary sensitivity and specificity of serum and CSF CrAg, as well as agreement between CSF CrAg and CSF culture. Summary sensitivity and specificity of serum CrAg were 99.7% (97.4-100) and 94.1% (88.3-98.1), respectively, and summary sensitivity and specificity of CSF CrAg were 98.8% (96.2-99.6) and 99.3% (96.7-99.9), respectively. Agreement between CSF CrAg and CSF culture was 98% (97-99). In adults living with HIV who have CM symptoms, serum CrAg negativity may rule out CM, while positivity should prompt induction antifungal therapy if lumbar puncture is not feasible. In a first episode of CM, CSF CrAg positivity is diagnostic.

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa.

BACKGROUND: Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODS: We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTS: A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. CONCLUSIONS: One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509 .).

Addition of Flucytosine to Fluconazole for the Treatment of Cryptococcal Meningitis in Africa: A Multicountry Cost-effectiveness Analysis.

BACKGROUND: Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. METHODS: The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. RESULTS: The mean costs per patient were US $847 (95% confidence interval [CI] $776-927) for FLU+5FC, and US $628 (95% CI $557-709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9-41.7%) with FLU+5FC and 53.8% (95% CI 43.1-64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28-208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. CONCLUSIONS: The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus-infected persons in Africa.

Burden of hepatitis E virus infection in pregnancy and maternofoetal outcomes: a systematic review and meta-analysis.

BACKGROUND: There is still a dearth of knowledge on the burden of HEV infection in the global population of pregnant women. Therefore, we conducted a systematic review and meta-analysis to estimate the global burden of HEV infection in pregnancy. METHODS: We searched PubMed, Embase, Web of Knowledge, and Global Index Medicus to identify articles published until January 26, 2020. We considered cross-sectional, case-control, and cohort studies reporting the immunoglobulins M HEV seroprevalence in asymptomatic and symptomatic (jaundice or elevated transaminases) pregnant women or investigating the association between HEV infection and maternofoetal outcomes. We used a random-effects model to pool studies. This review was registered with PROSPERO, CRD42018093820. RESULTS: For HEV prevalence estimates, we included 52 studies (11,663 pregnant women). The seroprevalence was 3.5% (95% confidence interval: 1.4-6.4) in asymptomatic women (most of whom from high endemic areas). The prevalence in symptomatic women was 49.6% (42.6-56.7) with data only from HEV high endemic countries. In the multivariable meta-regression model, the prevalence was higher in symptomatic women compared to asymptomatic (adjusted prevalence odds ratio [aPOR]: 1.76; 95%CI: 1.61-1.91) and decreased with increasing year of publication (by 10-year) (aPOR: 0.90; 95%CI: 0.84-0.96). The proportion of HEV vertical transmission was 36.9% (13.3-64.2). Risk of bias was low, moderate and high respectively in 12 (23%), 37 (70%), and 4 studies (7%) addressing HEV prevalence estimation. HEV infection was associated with maternal deaths (pooled OR 7.17; 3.32-15.47), low birth weight (OR: 3.23; 1.71-6.10), small for gestational age (OR: 3.63; 1.25-10.49), preterm < 32 weeks (OR: 4.18; 1.23-14.20), and preterm < 37 weeks (OR: 3.45; 2.32-5.13), stillbirth (OR: 2.61; 1.64-4.14), intrauterine deaths (OR: 3.07; 2.13-4.43), and not with miscarriage (OR: 1.74; 0.77-3.90). All studies which assessed the association between HEV infection and maternofoetal outcomes had a moderate risk of bias. CONCLUSIONS: Findings from this study are suggestive of a high burden of HEV infection in pregnancy in high endemic countries, its association with poor maternofoetal outcomes, and a high rate of vertical transmission. This study supports the need for specific strategies to prevent exposure of pregnant women to HEV infection, especially in high endemic areas.

Impact of Routine Cryptococcal Antigen Screening and Targeted Preemptive Fluconazole Therapy in Antiretroviral-naive Human Immunodeficiency Virus-infected Adults With CD4 Cell Counts <100/µL: A Systematic Review and Meta-analysis.

Cryptococcal antigen (CrAg) screening and targeted preemptive fluconazole in antiretroviral-naive human immunodeficiency virus-infected adults with CD4 cell counts <100/µL seems promising as a strategy to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg positivity (31 studies; 35644 participants) and asymptomatic CM in CrAg-positive participants and the incidence of CM and the all-cause mortality rate in screened participants. The pooled prevalence of blood CrAg-positivity was 6% (95% confidence interval [CI], 5%-7%), and the prevalence of asymptomatic CM in CrAg-positive participants was 33% (95% CI, 21%-45%). The incidence of CM was 21.4% (95% CI, 11.6%-34.4%) without preemptive fluconazole and 5.7% (95% CI, 3.0%-9.7%) with preemptive fluconazole therapy initiated at 800 mg/d. In CrAg-positive participants, postscreening lumbar puncture before initiating preemptive fluconazole at 800 mg/d further reduced the incidence of CM to null and showed some survival benefits. However, the all-cause mortality rate remained significantly higher in CrAg-positive than in CrAg-negative participants (risk ratio, 2.2; 95% CI, 1.7-2.9; P < .001).

Healthcare Costs and Life-years Gained From Treatments Within the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) Trial on Cryptococcal Meningitis: A Comparison of Antifungal Induction Strategies in Sub-Saharan Africa.

BACKGROUND: Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. METHODS: Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. RESULTS: Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91-1210) per life-year saved. CLINICAL TRIALS REGISTRATION: ISRCTN45035509. CONCLUSIONS: Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.

New Insights Into Cryptococcus Spp. Biology and Cryptococcal Meningitis.

PURPOSE OF REVIEW: Defective cell-mediated immunity is a major risk factor for cryptococcosis, a fatal disease if untreated. Cryptococcal meningitis (CM), the main presentation of disseminated disease, occurs through hematogenous spread to the brain from primary pulmonary foci, facilitated by yeast virulence factors. We revisit remarkable recent improvements in the prevention, diagnosis and management of CM. RECENT FINDINGS: Cryptococcal antigen (CrAg), main capsular polysaccharide of Cryptococcus spp. is detectable in blood and cerebrospinal fluid of infected patients with point of care lateral flow assays. Recent World Health Organization guidelines recommend 7-day amphotericin B plus flucytosine, then 7-day high dose (1200 mg/day) fluconazole for induction treatment of HIV-associated CM. Management of raised intracranial pressure, a consequence of CM, should rely mainly on daily therapeutic lumbar punctures until normalisation. In HIV-associated CM, following introduction of antifungal therapy, (re)initiation of antiretroviral therapy should be delayed by 4-6 weeks to prevent immune reconstitution inflammatory syndrome, common in CM. CM is a fatal disease whose diagnosis has recently been simplified. Treatment should always include antifungal combination therapy and management of raised intracranial pressure. Screening for immune deficiency should be mandatory in all patients with cryptococcosis.

Long-term Mortality and Disability in Cryptococcal Meningitis: A Systematic Literature Review.

Cryptococcal meningitis (CM) is the primary cause of meningitis in adults with human immunodeficiency virus (HIV) infection and an emerging disease in HIV-seronegative individuals. No literature review has studied the long-term outcome of CM. We performed a systematic review on the long-term (≥3-month) impact of CM (Cryptococcus neoformans and Cryptococcus gattii) on mortality and disability in HIV-infected and non-HIV-infected adults. Although the quality of current evidence is limited, the long-term impact of CM on survival and disability seems to be high. One-year mortality ranged from 13% in an Australian non-HIV-infected C. gattii-infected cohort to 78% in a Malawian HIV-infected cohort treated with fluconazole monotherapy. One-year impairment proportions among survivors ranged from 19% in an Australian C. gattii cohort to >70% in a Taiwanese non-HIV- and HIV-infected cohorts. Ongoing early therapeutic interventions, early detection of impairments and access to rehabilitation services may significantly improve patients' survival and quality of life.

Diagnostic and therapeutic strategies in cryptococcosis: impact on outcome.

Cryptococcosis diagnosis has been recently improved by the use of rapid cryptococcal antigen testing with lateral flow assays, which have proved sensitive and specific. Using "test and treat" screening strategies for cryptococcal disease with these tests has been showed effective in reducing cryptococcal meningitis (CM) in HIV-infected patients. Recommended induction, consolidation, and maintenance therapeutic strategy for CM is widely unavailable and/or expensive in low and middle-income settings. New therapeutic strategies, mostly using reduced duration, have recently shown acceptable outcome or are currently tested. Diagnostic and therapeutic guidelines for cryptococcal disease in limited resources countries are undergoing a paradigmatic shift.

Abstracts reporting of HIV/AIDS randomized controlled trials in general medicine and infectious diseases journals: completeness to date and improvement in the quality since CONSORT extension for abstracts.

BACKGROUND: Sufficiently detailed abstracts of randomized controlled trials (RCTs) are important, because readers often base their assessment of a trial solely on information in the abstract. We aimed at comparing reporting quality of RCTs in HIV/AIDS medicine before and after the publication of the 2008 CONSORT extension for abstracts and to investigate factors associated with better reporting quality. METHODS: We searched PubMed/Medline for HIV/AIDS RCTs published between 2006-07 (Pre-CONSORT) and 2014-15 (Post-CONSORT) in 40 leading general medicine and infectious diseases journals. Two investigators extracted data and scored abstracts. The primary outcome was the adjusted mean number of items reported among the 17 required. Proportions of abstracts reporting each of 17 items were considered as secondary outcome. The adjustment was done for journal field, CONSORT endorsement, abstract format, type of intervention, journal impact factor and authorship. This study received no funding. RESULTS: The adjusted mean number of reported items was 7.2 (95 % CI 6.6-7.7) in pre-CONSORT (n = 159) and 7.8 (95 % confidence interval [CI] 7.3-8.4) in post-CONSORT (n = 153) (mean difference 0.7; 95 % CI 0.1-1.2). Journal high impact factor (adjusted incidence rate ratio 2.16; 95 % CI 1.83-2.54), abstract with 13 authors or more (1.39; 95 % CI 1.07-1.79) and non-pharmacological intervention (1.19; 95 % CI 1.03-1.37) were independent factors for better reporting quality. There were significant improvements in reporting on participants, randomization, outcome results, registration and funding; regression for author contact; and no change for other items: title, design, interventions, objective, primary outcome, blinding, number randomized, recruitment, number analyzed, harms and conclusions. CONCLUSIONS: After the publication of the CONSORT extension for abstracts, the reporting quality of HIV/AIDS RCT abstracts in general medicine and infectious diseases journals has suboptimally improved. Thus, stricter adherence to the CONSORT for abstract are needed to improve the reporting quality of HIV/AIDS RCT abstracts.

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Tuberculous meningitis: presentation, diagnosis and outcome in hiv-infected patients at the douala general hospital, cameroon: a cross sectional study.

INTRODUCTION: Tuberculous meningitis (TBM) the most fatal presentation of tuberculosis (TB) especially in HIV-infected patients is a real diagnostic and therapeutic challenge worldwide. In Cameroon where HIV and TB are amongst the leading public health problems, the magnitude of TBM has not been defined. Therefore, the objective of this cross sectional study was to describe the presentation and in-hospital outcome of TBM among HIV patients in Douala as well as its diagnostic difficulties. METHODS: We did a clinical case note analysis of all HIV-1 infected patients treated for TBM in the Internal medicine unit of the Douala General Hospital, between January 1st 2004 and December 31st 2009. The diagnosis of TBM was made using clinical, laboratory [cerebrospinal fluid (CSF) analysis] and/or brain computerised tomographic (CT) scan features. RESULTS: During the study period, 8% (54/672) of HIV-infected patients had TBM. Their mean age was 40.3 ± 12.7 years. The main presenting complaint was headache in 74.1% (40/54) of patients. Their median CD4 cell count was 16 cells/mm3 (IQR: 10 - 34). CSF analysis showed median protein levels of 1.7 g/l (IQR: 1.3 - 2.2), median glucose level of 0.4 g/l (IQR: 0.3 - 0.5) and median white cell count (WCC) count of 21 cells/ml (IQR: 12 - 45) of which mononuclear cells were predominant in 74% of CSF. Acid fast bacilli were found in 1.9% (1/54) of CSF samples. On CT scan hydrocephalus was the main finding in 70.6% (24/34) of patients. In hospital case fatality was 79.6% (43/54). CONCLUSION: TBM is a common complication in HIV-infected patients in Douala with high case fatality. Its presumptive diagnosis reposes mostly on CSF analysis, so clinicians caring for HIV patients should not hesitate to do lumbar taps in the presence of symptoms of central nervous system disease.

Continental concerted efforts to control the seventh outbreak of Ebola Virus disease in Uganda: The first 90 days of the response.

On 20th September 2022, Uganda declared the 7th outbreak of Ebola virus disease (EVD) caused by the Sudan Ebola strain following the confirmation of a case admitted at Mubende Regional Referral Hospital. Upon confirmation, the Government of Uganda immediately activated the national incident management system to initiate response activities. Additionally, a multi-country emergency stakeholder meeting was held in Kampala; convening Ministers of Health from neighbouring Member States to undertake cross-border preparedness and response actions. The outbreak spanned 69 days and recorded 164 cases (142 confirmed, 22 probable), 87 recoveries and 77 deaths (case fatality ratio of 47%). Nine out of 136 districts were affected with transmission taking place in 5 districts but spilling over in 4 districts without secondary transmission. As part of the response, the Government galvanised robust community mobilisation and initiated assessment of medical counter measures including therapeutics, new diagnostics and vaccines. This paper highlights the response actions that contributed to the containment of this outbreak in addition to the challenges faced with a special focus on key recommendations for better control of future outbreaks.

HIV-associated sensory neuropathy in HIV-1 infected patients at the Douala General Hospital in Cameroon: a cross-sectional study.

BACKGROUND: Peripheral neuropathy (PN) which is the most common neurological complication of HIV infection is under recognised and undertreated especially in resource limited settings. This ailment which has a negative impact on the quality of life of HIV/AIDS patients exists in different clinical patterns of which HIV-associated Sensory neuropathy (HIV-SN) is the most common affecting up to two thirds of patients with advanced disease in some settings. In Cameroon where HIV is a major public health problem, the burden of HIV-SN has not yet been well defined. METHODS: Using the Brief Peripheral Neuropathy Screening (BPNS) tool validated by the AIDS Clinical Trial Group (ACTG) we carried out a cross sectional study to determine the prevalence of HIV-SN and its associated factors among HIV-1 patients at the Douala General Hospital between 1st July and 31st October 2011. HIV-SN was defined as the presence of neuropathic symptoms and at least an abnormal perception of vibrations of a 128Hz tuning fork on the great toe or abnormal ankle reflexes or both and expressed as a percentage of the study population. RESULTS: Out of 295 patients studied, 21% had HIV-SN. In HIV-SN patients the median duration of HIV infection was 79.8 months (IQR 46 - 107.5) and their median CD4 count 153cells/µL (IQR 80 - 280). Patient recall and clinical chart review showed that, 83.9% had neuropathic symptoms prior to HAART initiation and 16.1% after HAART initiation. Low CD4 count, history of alcohol intake and history of anti-tuberculosis treatment were strongly associated with HIV-SN (AOR 2.5, 2.8 and 2.9 respectively). CONCLUSIONS: HIV-SN is common among patients with advanced HIV infection in Cameroon. This simple diagnostic tool (BPNS) should therefore be routinely used to detect those with HIV-SN or at risk so as to minimise the negative impact it has on their quality of life.

Viral suppression and HIV-1 drug resistance 1 year after pragmatic transitioning to dolutegravir first-line therapy in Malawi: a prospective cohort study.

BACKGROUND: Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing. METHODS: In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (Cmin) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15). FINDINGS: Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1-98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0-94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5-99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5-93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir Cmin value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3-87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3-215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline. INTERPRETATION: High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen. FUNDING: Médecins Sans Frontières. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.

Short-term Mortality Outcomes of HIV-Associated Cryptococcal Meningitis in Antiretroviral Therapy-Naïve and -Experienced Patients in Sub-Saharan Africa.

BACKGROUND: An increasing proportion of patients with HIV-associated cryptococcal meningitis have received antiretroviral therapy (ART) before presentation. There is some evidence suggesting an increased 2-week mortality in those receiving ART for <14 days compared with those on ART for >14 days. However, presentation and outcomes for cryptococcal meningitis patients who have recently initiated ART, and those with virologic failure and/or nonadherence, are not well described. METHODS: Six hundred seventy-eight adults with a first episode of cryptococcal meningitis recruited into a randomized, noninferiority, multicenter phase 3 trial in 4 Sub-Saharan countries were analyzed to compare clinical presentation and 2- and 10-week mortality outcomes between ART-naïve and -experienced patients and between patients receiving ART for varying durations before presentation. RESULTS: Over half (56%; 381/678) the study participants diagnosed with a first episode of cryptococcal meningitis were ART-experienced. All-cause mortality was similar at 2 weeks (17% vs 20%; hazard ratio [HR], 0.85; 95% CI, 0.6-1.2; P = .35) and 10 weeks (38% vs 36%; HR, 1.03; 95% CI, 0.8-1.32; P = .82) for ART-experienced and ART-naïve patients. Among ART-experienced patients, using different cutoff points for ART duration, there were no significant differences in 2- and 10-week mortality based on duration of ART. CONCLUSIONS: In this study, there were no significant differences in mortality at 2 and 10 weeks between ART-naïve and -experienced patients and between ART-experienced patients according to duration on ART.

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.

Global guideline for the diagnosis and management of rare yeast infections: an initiative of the ECMM in cooperation with ISHAM and ASM.

Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Saccharomyces, and Sporobolomyces (ie, ascomycetes). A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimising patient outcomes; however, management guidelines are either region-specific or require updating. In alignment with the One World-One Guideline initiative to incorporate regional differences, experts from diverse geographical regions analysed publications describing the epidemiology and management of the previously mentioned rare yeasts. This guideline summarises the consensus recommendations with regards to the diagnostic and therapeutic options for patients with these rare yeast infections, with the intent of providing practical assistance in clinical decision making. Because there is less clinical experience of patients with rare yeast infections and studies on these patients were not randomised, nor were groups compared, most recommendations are not robust in their validation but represent insights by use of expert opinions and in-vitro susceptibility results. In this Review, we report the key features of the epidemiology, diagnosis, antifungal susceptibility, and treatment outcomes of patients with Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon spp infections.