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Objectives Diagnostic tests for SARS-CoV-2 are important for epidemiology, clinical management, and infection control. Limitations of oro-nasopharyngeal real-time PCR sensitivity have been described based on comparisons of single tests with repeated sampling. We assessed SARS-CoV-2 PCR clinical sensitivity using a clinical and radiological reference standard. Methods Between March-May 2020, 2060 patients underwent thoracic imaging and SARS-CoV-2 PCR testing. Imaging was independently double- or triple-reported (if discordance) by blinded radiologists according to radiological criteria for COVID-19. We excluded asymptomatic patients and those with alternative diagnoses that could explain imaging findings. Associations with PCR-positivity were assessed with binomial logistic regression. Results 901 patients had possible/probable imaging features and clinical symptoms of COVID-19 and 429 patients met the clinical and radiological reference case definition. SARS-CoV-2 PCR sensitivity was 68% (95% confidence interval 64–73), was highest 7-8 days after symptom onset (78% (68–88)) and was lower among current smokers (adjusted odds ratio 0.23 (0.12–0.42) p Conclusions In patients with clinical and imaging features of COVID-19, PCR test sensitivity was 68%, and was lower among smokers; a finding that could explain observations of lower disease incidence and that warrants further validation. PCR tests should be interpreted considering imaging, symptom duration and smoking status.

ObjectiveIn sub-Saharan Africa, hepatitis B is the principal cause of liver disease. Non-invasive biomarkers of liver fibrosis are needed to identify patients requiring antiviral treatment. We assessed aspartate aminotransferase-to-platelet ratio index (APRI), gamma-glutamyl transferase-to-platelet ratio (GPR) and FIB-4 to diagnose significant fibrosis and cirrhosis in an individual patient data (IPD) meta-analysis.DesignIn total, 3,549 patients from 12 cohorts of HBsAg positive individuals in 8 sub-Saharan African countries were included. Transient elastography was used as a reference test for cirrhosis (>12.2 kPa), excluding patients who were pregnant, had hepatitis C, D, or HIV co-infection, were on hepatitis B therapy, or had acute hepatitis. A bivariate Bayesian IPD model was fitted with patient-level covariates and study-level random effects.ResultsAPRI and GPR had the best discriminant performance (area under receiver operating curve 0.81 and 0.82) relative to FIB-4 (0.77) for cirrhosis. The World Health Organization (WHO) recommended APRI threshold of ≥2.0 was associated with a sensitivity and specificity (95% credible interval) of 16.5% (12.5-20.5) and 99.5% (99.2-99.7) for cirrhosis. For APRI, we identified an optimised rule-in threshold for cirrhosis (cut-off 0.65) with a sensitivity and specificity of 56.2% (50.5-62.2) and 90.0% (89.0-91.0), and an optimised rule-out threshold (cut-off 0.36) with a sensitivity and specificity of 80.6% (76.1-85.1) and 64.3% (62.8-65.8).ConclusionsThe WHO recommended APRI threshold of 2.0 is too high to diagnose cirrhosis in sub-Saharan Africa. We identified new and optimised rule-in and rule-out thresholds for cirrhosis, with direct consequences for treatment guidelines in this setting.

PURPOSE OF REVIEW We reviewed evidence concerning the novel nonnucleoside reverse transcriptase inhibitor doravirine, aiming to identify situations where it may be selected in preference to integrase inhibitors. RECENT FINDINGS Doravirine is licenced for the treatment of HIV-1 in North America and Europe. In two multicentre randomized controlled trials, noninferiority with comparator drugs efavirenz and darunavir/ritonavir was observed at 96 weeks. Doravirine is associated with a lower incidence of neuropsychiatric side effects relative to efavirenz, and favourable lipid changes relative to darunavir over 96 weeks. A lower incidence of weight gain, relative to indirect comparisons with integrase inhibitors, was observed. Doravirine has a high genetic barrier to resistance with retained activity in the presence of single NNRTI mutations K103N, Y181C and G190A. Primary drug resistance is infrequent and may be higher in South Africa relative to European populations. Doravirine may be used in renal or hepatic impairment and has a low potential for drug-drug interactions. SUMMARY Doravirine is a well tolerated and effective agent in ART-naive patients. Direct comparison with integrase inhibitors, and evidence on the outcomes of treatment with doravirine in the presence of prior NNRTI experience are required to better elucidate which patients will benefit most from doravirine therapy.

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. There are no previous representative community HCV prevalence studies from Southern Africa, and limited genotypic data. Epidemiological data are required to inform an effective public health response. We conducted a household census-based random sampling serological survey, and a prospective hospital-based study of patients with cirrhosis and hepatocellular carcinoma (HCC) in Blantyre, Malawi. We tested participants with an HCV antigen/antibody ELISA (Monolisa, Bio-Rad), confirmed with PCR (GeneXpert, Cepheid) and used line immunoassay (Inno-LIA, Fujiribio) for RNA-negative participants. We did target-enrichment whole-genome HCV sequencing (NextSeq, Illumina). Among 96,386 censused individuals, we randomly selected 1661 people aged ≥16 years. Population-standardized HCV RNA prevalence was 0.2% (95% CI 0.1-0.5). Among 236 patients with cirrhosis and HCC, HCV RNA prevalence was 1.9% and 5.0%, respectively. Mapping showed that HCV RNA+ patients were from peri-urban areas surrounding Blantyre. Community and hospital HCV RNA+ participants were older than comparator HCV RNA-negative populations (median 53 vs 30 years for community, p = 0.01 and 68 vs 40 years for cirrhosis/HCC, p 0.001). Endemic HCV genotypes (n = 10) were 4v (50%), 4r (30%) and 4w (10%). In this first census-based community serological study in Southern Africa, HCV was uncommon in the general population, was centred on peri-urban regions and was attributable for5% of liver disease. HCV infection was observed only among older people, suggesting a historic mechanism of transmission. Genotype 4r, which has been associated with treatment failure with ledipasvir and daclatasvir, is endemic.

Background Hepatitis B is the leading cause of cirrhosis and liver cancer in sub-Saharan Africa. To reduce mortality, antiviral treatment programs are needed. We estimated prevalence, vaccine impact, and need for antiviral treatment in Blantyre, Malawi. Methods We conducted a household study in 2016–2018. We selected individuals from a census using random sampling and estimated age-sex-standardized hepatitis B surface antigen (HBsAg) seroprevalence. Impact of infant hepatitis B vaccination was estimated by binomial log-linear regression comparing individuals born before and after vaccine implementation. In HBsAg-positive adults, eligibility for antiviral therapy was assessed. Results Of 97386 censused individuals, 6073 (median age 18 years; 56.7% female) were sampled. HBsAg seroprevalence was 5.1% (95% confidence interval [CI], 4.3%–6.1%) among adults and 0.3% (95% CI, .1%–.6%) among children born after vaccine introduction. Estimated vaccine impact was 95.8% (95% CI, 70.3%–99.4%). Of HBsAg-positive adults, 26% were HIV-positive. Among HIV-negative individuals, 3%, 6%, and 9% were eligible for hepatitis B treatment by WHO, European, and American hepatology association criteria, respectively. Conclusions Infant HBV vaccination has been highly effective in reducing HBsAg prevalence in urban Malawi. Up to 9% of HBsAg-positive HIV-negative adults are eligible, but have an unmet need, for antiviral therapy.

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Background The World Health Organization (WHO) has targeted a reduction in viral hepatitis-related mortality by 65% and incidence by 90% by 2030, necessitating enhanced hepatitis B treatment and prevention programmes in low- and middle-income countries. Hepatitis B e antigen (HBeAg) status is used in the assessment of eligibility for antiviral treatment and for prevention of mother-to-child transmission (PMTCT). Accordingly, the WHO has classified HBeAg rapid diagnostic tests (RDTs) as essential medical devices. Methods We assessed the performance characteristics of three commercially available HBeAg RDTs (SD Bioline, Alere, South Africa; Creative Diagnostics, USA; and Biopanda Reagents, UK) in two hepatitis B surface antigen-positive cohorts in Blantyre, Malawi: participants of a community study (n = 100) and hospitalised patients with cirrhosis or hepatocellular carcinoma (n = 94). Two investigators, blinded to the reference test result, independently assessed each assay. We used an enzyme-linked immunoassay (Monolisa HBeAg, Bio-Rad, France) as a reference test and quantified HBeAg concentration using dilutions of the WHO HBeAg standard. We related the findings to HBV DNA levels, and evaluated treatment eligibility using the TREAT-B score. Results Among 194 HBsAg positive patients, median age was 37 years, 42% were femaleand 26% were HIV co-infected. HBeAg prevalence was 47/194 (24%). The three RDTs showed diagnostic sensitivity of 28% (95% CI 16–43), 53% (38–68) and 72% (57–84) and specificity of 96–100% for detection of HBeAg. Overall inter-rater agreement κ statistic was high at 0.9–1.0. Sensitivity for identifying patients at the threshold where antiviral treatment is recommended for PMTCT, with HBV DNA > 200,000 IU/ml (39/194; 20%), was 22, 49 and 54% respectively. Using the RDTs in place of the reference HBeAg assay resulted in 3/43 (9%), 5/43 (12%) and 8/43 (19%) of patients meeting the TREAT-B treatment criteria being misclassified as ineligible for treatment. A relationship between HBeAg concentration and HBeAg detection by RDT was observed. A minimum HBeAg concentration of 2.2–3.1 log10IU/ml was required to yield a reactive RDT. Conclusions Commercially available HBeAg RDTs lack sufficient sensitivity to accurately classify hepatitis B patients in Malawi. This has implications for hepatitis B public health programs in sub-Saharan Africa. Alternative diagnostic assays are recommended.

Background Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. Patients and methods Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann–Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. Results In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. Conclusion Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity., Highlights • Pre-infection haematological/biochemical characteristics are not associated with COVID-19 severity. • Significant haematological/biochemical changes occur upon infection with heterogeneity in response observed. • High not low neutrophils were associated with oxygen requirement and COVID-19 mortality – GCSF should be used with caution. Age, haematological cancer, high neutrophil:lymphocyte ratio, CRP and low albumin were significant predictors of death in multivariable analysis. No significant complications requiring readmission were seen upon restart of cancer therapy following diagnosis of COVID-19.

The COVID-19 pandemic has been a disruptive event for cancer patients, especially those with haematological malignancies (HM). They may experience a more severe clinical course due to impaired immune responses. This multi-center retrospective UK audit identified cancer patients who had SARS-CoV-2 infection between 1 March and 10 June 2020 and collected data pertaining to cancer history, COVID-19 presentation and outcomes. In total, 179 patients were identified with a median age of 72 (IQR 61, 81) and follow-up of 44 days (IQR 42, 45). Forty-one percent were female and the overall mortality was 37%. Twenty-nine percent had HM and of these, those treated with chemotherapy in the preceding 28 days to COVID-19 diagnosis had worse outcome compared with solid malignancy (SM): 62% versus 19% died [HR 8.33 (95% CI, 2.56-25), p p = 0.001). Patients with haematological malignancies and those who acquire nosocomial transmission are at increased risk of death. Therefore, there is an urgent need to reassess shielding advice, reinforce stringent infection control, and ensure regular patient and staff testing to prevent nosocomial transmission.

Background: Patients with cancer are at increased risk of severe COVID-19, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 in cancer patients predicting severe disease and build a decision-support online tool; COVID-19 Risk in Oncology Evaluation Tool (CORONET). Methods: Patients with active cancer (stage I-IV) and laboratory confirmed COVID-19 presenting to hospitals worldwide were included. Discharge (within 24hrs), admission (≥24hrs inpatient), oxygen requirement (O2) and death were combined in a 0-3 point severity scale. Association of features with outcome were investigated using Lasso regression and Random Forest (RF) combined with SHapley Additive exPlanations (SHAP). RF was further validated in 4 cohorts, split by geography. The CORONET model was then examined in the entire cohort to build an online CORONET decision-support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Findings: The dataset comprised 920 patients; median age 70 (range 5-99), 56% males, 44% females, 81% solid vs. 19% haematological cancers. In derivation, RF demonstrated superior performance over Lasso with lower mean squared error (0.801 vs. 0.807) and was selected for development. During validation, RF achieved mean AUROC 0.77, 0.80 and 0.75 for prediction of admission, O 2 and death, respectively. Using the entire cohort, CORONET cut-offs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died. SHAP explanations revealed National-Early-Warning-Score-2, C-reactive protein and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation. Interpretation: CORONET, a decision-support tool validated in healthcare systems worldwide can aid admission decisions and predict COVID-19 severity in patients with cancer. Funding Information: R. Lee and T. Robinson and J. Weaver are supported by the National Institute for Health Research as Clinical Lecturers. T. Bhogal is supported by the National Institute for Health Research as an academic clinical fellow. U. Khan is an MRC Clinical Training Fellow based at the University of Liverpool supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Award Ref. MR/N025989/1). The Liverpool Experimental Cancer Medicine Centre for providing infrastructure support (Grant Reference: C18616/A25153) and The Clatterbridge Cancer charity (North West Cancer Research). C. Dive is funded by CRUK Core funding to Manchester Institute (C5757/A27412) and is supported by the CRUK Manchester Centre Award (C5759/A25254), and by the NIHR Manchester Biomedical Research Centre. C. Zhou is funded by the CRUK Manchester Centre Award (C5759/A25254), J. Stevenson and P. Fitzpatrick are funded by the CRUK Accelerator Award (29374). This research was funded in part, by the Wellcome Trust [205228/Z/16/Z]. LT is also supported by the National Institute for Health Research Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. LT is based at University of Liverpool. MS is supported by a grant from the Ministry of Science and Higher Education of the Russian Federation for the state support for the creation and development of World Class Research Centers "Digital biodesign and personalized healthcare” N.075-15-2020-926. Declaration of Interests: R Lee research funding (institution) BMS and speaker fees Astrazeneca. A. Croitoru Consulting or Advisory Role: Lilly, Merck, Roche, Bayer, Novartis, Ipsen, Research Funding me and my hospital: Gilead Sciences, Pfizer, Canfite, NanoCarrier, Bristol-Myers Squibb, Merck, Amgen, Servier, Five Prime Therapeutics, Travel Accommodations: Pfizer, Genekor, and oz, Merck, Pfizer, Servier, Roche. O. Michielin reports personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Roche, personal fees from Amgen, personal fees from NeraCare GmbH, outside the submitted work. E. Romano institutional research grants from Amgen, Astra Zeneca, Bristol-Myers Squibb. G. Pentheroudakis advisory board for Amgen, Astra Zeneca, Bristol-Myers Squibb, Lilly, Merck, MSD, Roche, Abbvie, institutional research grants from Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Debbio, Enorasis, Genekor, Ipsen, Janssen, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, Servier. Solange Peters reports consultation/advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody, talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda, receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. M Rowe honoraria from Astellas Pharma, speaker fees MSD and Servier. C. Wilson consultancy and speaker fees Pfizer, Amgen, Novartis, A Armstrong conference fee Merck, spouse shares in Astrazeneca. T Robinson financial support to attend educational workshops from Amgen and Daiichi-Sankyo. C Dive, outside of this scope of work, has received research funding from AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck AG, Taiho Oncology, Clearbridge Biomedics, Angle PLC, Menarini Diagnostics, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Thermofisher. C Dive is on advisory boards for, and has received consultancy fees/honoraria from, AstraZeneca, Biocartis and Merck KGaA. No other authors have nothing to declare. Ethics Approval Statement: Approval (reference 20/WA/0269) was granted from the UK Research Ethics Committee for the study. Information regarding governance/regulatory approvals for each international cohort are available in the Supp. Methods.

Background Evidence is conflicting about how human immunodeficiency virus (HIV) modulates coronavirus disease 2019 (COVID-19). We compared the presentation characteristics and outcomes of adults with and without HIV who were hospitalized with COVID-19 at 207 centers across the United Kingdom and whose data were prospectively captured by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) World Health Organization (WHO) Clinical Characterization Protocol (CCP) study. Methods We used Kaplan-Meier methods and Cox regression to describe the association between HIV status and day-28 mortality, after separate adjustment for sex, ethnicity, age, hospital acquisition of COVID-19 (definite hospital acquisition excluded), presentation date, 10 individual comorbidities, and disease severity at presentation (as defined by hypoxia or oxygen therapy). Results Among 47 592 patients, 122 (0.26%) had confirmed HIV infection, and 112/122 (91.8%) had a record of antiretroviral therapy. At presentation, HIV-positive people were younger (median 56 vs 74 years; P Conclusions HIV-positive status was associated with an increased risk of day-28 mortality among patients hospitalized for COVID-19.

BackgroundCancer patients are at increased risk of severe COVID-19. As COVID-19 presentation and outcomes are heterogeneous in cancer patients, decision-making tools for hospital admission, severity prediction and increased monitoring for early intervention are critical.ObjectiveTo identify features of COVID-19 in cancer patients predicting severe disease and build a decision-support online tool; COVID-19 Risk in Oncology Evaluation Tool (CORONET)MethodData was obtained for consecutive patients with active cancer with laboratory confirmed COVID-19 presenting in 12 hospitals throughout the United Kingdom (UK). Univariable logistic regression was performed on pre-specified features to assess their association with admission (≥24 hours inpatient), oxygen requirement and death. Multivariable logistic regression and random forest models (RFM) were compared with patients randomly split into training and validation sets. Cost function determined cut-offs were defined for admission/death using RFM. Performance was assessed by sensitivity, specificity and Brier scores (BS). The CORONET model was then assessed in the entire cohort to build the online CORONET tool.ResultsTraining and validation sets comprised 234 and 66 patients respectively with median age 69 (range 19-93), 54% males, 46% females, 71% vs 29% had solid and haematological cancers. The RFM, selected for further development, demonstrated superior performance over logistic regression with AUROC predicting admission (0.85 vs. 0.78) and death (0.76 vs. 0.72). C-reactive protein was the most important feature predicting COVID-19 severity. CORONET cut-offs for admission and mortality of 1.05 and 1.8 were established. In the training set, admission prediction sensitivity and specificity were 94.5% and 44.3% with BS 0.118; mortality sensitivity and specificity were 78.5% and 57.2% with BS 0.364. In the validation set, admission sensitivity and specificity were 90.7% and 42.9% with BS 0.148; mortality sensitivity and specificity were 92.3% and 45.8% with BS 0.442. In the entire cohort, the CORONET decision support tool recommended admission of 99% of patients requiring oxygen and of 99% of patients who died.Conclusions and RelevanceCORONET, a decision support tool validated in hospitals throughout the UK showed promise in aiding decisions regarding admission and predicting COVID-19 severity in patients with cancer presenting to hospital. Future work will validate and refine the tool in further datasets.

BACKGROUND AND AIMS\ud There are uncertainties about the epidemic patterns of hepatitis delta virus (HDV) infection and its contribution to the burden of liver disease. We estimated the global prevalence of HDV infection and explored its contribution to the development of cirrhosis and hepatocellular carcinoma (HCC) among hepatitis B surface antigen (HBsAg)-positive people.\ud METHODS\ud We searched Pubmed, EMBASE and Scopus for studies reporting on total or IgG anti-HDV among HBsAg-positive people. Anti-HDV prevalence was estimated using a binomial mixed model, weighting for study quality and population size. The population attributable fraction (PAF) of HDV to cirrhosis and HCC among HBsAg-positive people was estimated using random-effects models.\ud RESULTS\ud We included 282 studies, comprising 376 population samples from 95 countries, which together tested 120,293 HBsAg-positive people for anti-HDV. The estimated anti-HDV prevalence was 4.5% (95% CI 3.6, 5.7) among all HBsAg-positive people and 16.4% (14.6, 18.6) among those attending hepatology clinics. Worldwide, 0.16% (0.11, 0.25) of the general population, totalling 12.0 (8.7, 18.7) million people, were estimated to be anti-HDV positive. Prevalence among HBsAg-positive people was highest in Mongolia, the Republic of Moldova and countries in Western and Middle Africa, and was higher in injecting drug users, haemodialysis recipients, men who have sex with men, commercial sex workers, and those with hepatitis C virus or HIV. Among HBsAg-positive people, preliminary PAF estimates of HDV were 18% (10, 26) for cirrhosis and 20% (8, 33) for HCC.\ud \ud CONCLUSIONS\ud \ud An estimated 12 million people worldwide have experienced HDV infection, with higher prevalence in certain geographic areas and populations. HDV is a significant contributor to HBV-associated liver disease. More quality data are needed to improve the precisions of burden estimates.

Background.There is conflicting evidence about how HIV infection influences COVID-19. We compared the presentation characteristics and outcomes of people with and without HIV hospitalised with COVID-19 at 207 centres across the United Kingdom.Methods.We analysed data from people with laboratory confirmed or highly likely COVID-19 enrolled into the ISARIC CCP-UK study. The primary endpoint was day-28 mortality after presentation. We used Kaplan-Meier methods and Cox regression to describe the association with HIV status after adjustment for sex, ethnicity, age, indeterminate/probable hospital acquisition of COVID-19 (definite hospital acquisition excluded), presentation date, and presence/absence of ten comorbidities. We additionally adjusted for disease severity at presentation as defined by hypoxia/oxygen therapy.Findings.Among 47,539 patients, 115 (0·24%) had confirmed HIV-positive status and 103/115 (89·6%) had a record of antiretroviral therapy. At presentation, relative to the HIV-negative group, HIV-positive people were younger (median 55 versus 74 years; pInterpretation.HIV-positive status may be associated with an increased risk of day-28 mortality following a COVID-19 related hospitalisation.Funding.NIHR, MRC, Wellcome Trust, Department for International Development, Bill and Melinda Gates Foundation.Study registrationISRCTN66726260RESEARCH IN CONTEXTEvidence before this studyWe searched PubMed for articles in all languages containing the words “COVID*”, “coronavirus”, “SARS CoV-2” AND “HIV”. After screening on 23rd July 2020, we found 51 articles reporting outcomes of COVID-19 in HIV-positive people. Of these, 2 were systematic reviews, 24 were single case reports or case series of under 10 participants, and 12 were larger case series or retrospective cohorts without matched controls. There were two cohort studies that matched HIV-positive people diagnosed with COVID-19 to the general population attending for HIV care in the same area, and three studies that matched HIV-positive people diagnosed with COVID-19 to HIV-negative controls. Some of the evidence from the United States and Europe to date suggests that people with HIV experience a similar disease course and outcomes of COVID-19 compared to the general population. However, many of the studies are limited by small sample size, lack of comparator group and lack of adjustment for potential confounding. In contrast, preliminary results from a cohort study of over 20,000 participants in South Africa indicate that HIV-positive status more than doubles the risk of COVID-19 related mortality. Currently, the evidence from the United Kingdom is limited to two case series comprising a total of 21 patients.Added value of this studyThis study analysed data collected from 207 sites across the United Kingdom as part of ISARIC CCP, the largest prospective cohort of patients hospitalised with COVID-19, to evaluate the association between HIV-positive status and day-28 mortality. The study has the benefit of a relatively large number of participants with HIV (n=115, almost all receiving antiretroviral therapy) and importantly, the ability to direct compare their presenting characteristics and outcomes to those of 47,424 HIV-negative controls within the same dataset. This includes the ability to assess the influence of gender, ethnicity and age, as well as the effect of key comorbidities including chronic cardiac, pulmonary, renal and haematological disease, diabetes, obesity, chronic neurological disorder, dementia, liver disease, and malignancy. Unlike some of the other evidence to date, but in line with the data from South Africa, this study indicates that HIV-positive status may increase the risk of mortality with COVID-19 compared to the general population, with an effect that was especially evident among people with HIV aged below 60 years and was independent of gender or ethnicity. Although we detected an association between mortality among people with HIV and occurrence of obesity and diabetes with complication, the effect of HIV-positive status persisted after adjusting for comorbidities.Implications of all the available evidencePeople with HIV may be at increased risk of severe outcomes from COVID-19 compared to the general population. Ongoing data collection is needed to confirm this association. Linkage of hospital outcome data to the HIV history will be paramount to establishing the determinants of the increased risk. COVID-19 related hospitalisation should pursue systematic recording of HIV status to ensure optimal management and gathering of evidence.

Objectives The study assessed markers of renal health in HIV/HBV co-infected patients receiving TDF-containing antiretroviral therapy in Ghana. Methods Urinary protein-to-creatinine ratio (uPCR) and albumin-to-protein ratio (uAPR) were measured cross-sectionally after a median of four years of TDF. At this time, alongside extensive laboratory testing, patients underwent evaluation of liver stiffness and blood pressure. The estimated glomerular filtration rate (eGFR) was measured longitudinally before and during TDF therapy. Results Among 101 participants (66% women, median age 44 years, median CD4 count 572 cells/mm3) 21% and 17% had detectable HIV-1 RNA and HBV DNA, respectively. Overall 35% showed hypertension, 6% diabetes, 7% liver stiffness indicative of cirrhosis, and 18% urinary excretion of Schistosoma antigen. Tubular proteinuria occurred in 16% of patients and was independently predicted by female gender and hypertension. The eGFR declined by median 1.8 ml/min/year during TDF exposure (IQR -4.4, -0.0); more pronounced declines (≥5ml/min/year) occurred in 22% of patients and were associated with receiving ritonavir-boosted lopinavir rather than efavirenz. HBV DNA, HBeAg, transaminases, and liver stiffness were not predictive of renal function abnormalities. Conclusions The findings mandate improved diagnosis and management of hypertension and suggest targeted laboratory monitoring of patients receiving TDF alongside a booster in sub-Saharan Africa.

We read the meta-analysis of global hepatitis D prevalence by Chen et al and have some serious concerns relating to the proposed epidemiological estimates.1 Seroprevalence of hepatitis delta virus (HDV) was not adequately defined. In the methods, hepatitis delta antibody (anti-HDV), HDV RNA and HDV antigen (HDAg) were described as markers of HDV infection. In Supplementary Table S8, it is evident that total, IgG and IgM anti-HDV and HDAg were variably used to define HDV infection. HDAg is a transient marker of HDV infection, whereas IgM expression is inconsistently associated with both acute and chronic infection; neither are suitable epidemiological markers of chronic HDV infection.2 A total of 50 cohorts were used to inform the primary outcome, global HDV seroprevalence in the general population; of these, 30 were conducted in the last 20 years. The authors estimated …

Antiretroviral treatment (ART) programs in sub-Saharan Africa have for many years included lamivudine as the sole hepatitis B virus (HBV) inhibitor. Long-term outcomes and the effects of introducing tenofovir as part of ART in these populations have not been characterized.The study comprised a cross-sectional analysis of 106 human immunodeficiency virus (HIV)/HBV-coinfected subjects maintained on lamivudine, as well as a prospective analysis of 76 lamivudine-experienced subjects who introduced tenofovir. Patients underwent assessment of liver fibrosis by transient elastography (TE) and testing to characterize HIV type 1 (HIV-1) and HBV replication.After a median of 45 months of lamivudine treatment, HIV-1 RNA and HBV DNA were detectable in 35 of 106 (33.0%) and 54 of 106 (50.9%) subjects, respectively, with corresponding drug resistance rates of 17 of 106 (16.0%) and 31 of 106 (29.2%), respectively. Median TE values were 5.7 kPa (interquartile range, 4.7-7.2 kPa) and independently associated with HBV DNA load, aspartate aminotransferase levels, and platelet counts; 13 of 106 (12.3%) subjects had TE measurements9.4 kPa. Twelve months after the first assessment, and a median of 7.8 months after introducing tenofovir, HBV DNA levels declined by a mean of 1.5 log10 IU/mL (P.001). TE values changed by a mean of -0.2 kPa (P = .097), and declined significantly in subjects who had pretenofovir HBV DNA levels2000 IU/mL (mean, -0.8 kPa; P = .048) or TE values7.6 kPa (mean, -1.2 kPa; P = .021). HIV-1 RNA detection rates remained unchanged.A proportion of HIV/HBV-coinfected patients on long-term lamivudine-containing ART had poor HIV and HBV suppression, drug resistance, and TE values indicative of advanced liver fibrosis. Tenofovir improved HBV control and reduced liver stiffness in subjects with high HBV DNA load and TE values.

Objective To provide information on the effect of timing of antiretroviral therapy (ART) initiation on outcomes of TB infection in real-life, non-clinical trial, rural settings in sub-Saharan Africa. Methods We conducted an observational cohort study of all HIV-infected TB patients presenting to a rural hospital in Kenya between 2005 and 2009. We analysed the association between timing of initiation of ART and mortality, using a Cox regression survival analysis, adjusted for measured confounders. Results A total of 404 antiretroviral-naive HIV/TB coinfected patients were included in the study. Initiation of ART during the first 8 weeks of TB treatment (early group) was not associated with changes in mortality at 1 year compared with initiation of ART after 8 weeks (late group) [Hazard Ratio (HR) = 0.74 (Confidence Interval (CI), 0.33–1.64, P = 0.46]. In patients with baseline CD4 counts ≤50 cells/μl, there was a significant reduction in mortality in the early group compared with the late group (HR = 0.20; 95% CI, 0.042–0.99; P = 0.049). In patients with a CD4 count >50 cells/μl, there was no significant difference between early and late groups (HR 1.79; 95% CI, 0.64–5.03; P = 0.27). Conclusions We found that in HIV/TB coinfected patients in rural Kenya, early ART initiation (within 8 weeks) was associated with reduced mortality in those with CD4 counts ≤50 cells/μl. In patients with CD4 counts >50 cells/μl, there was no association seen between timing of ART and mortality.

Hepatitis D virus (also known as hepatitis delta virus) can establish a persistent infection in people with chronic hepatitis B, leading to accelerated progression of liver disease. In sub-Saharan Africa, where HBsAg prevalence is higher than 8%, hepatitis D virus might represent an important additive cause of chronic liver disease. We aimed to establish the prevalence of hepatitis D virus among HBsAg-positive populations in sub-Saharan Africa.We systematically reviewed studies of hepatitis D virus prevalence among HBsAg-positive populations in sub-Saharan Africa. We searched PubMed, Embase, and Scopus for papers published between Jan 1, 1995, and Aug 30, 2016, in which patient selection criteria and geographical setting were described. Search strings included sub-Saharan Africa, the countries therein, and permutations of hepatitis D virus. Cohort data were also added from HIV-positive populations in Malawi and Ghana. Populations undergoing assessment in liver disease clinics and those sampled from other populations (defined as general populations) were analysed. We did a meta-analysis with a DerSimonian-Laird random-effects model to calculate a pooled estimate of hepatitis D virus seroprevalence.Of 374 studies identified by our search, 30 were included in our study, only eight of which included detection of hepatitis D virus RNA among anti-hepatitis D virus seropositive participants. In west Africa, the pooled seroprevalence of hepatitis D virus was 7·33% (95% CI 3·55-12·20) in general populations and 9·57% (2·31-20·43) in liver-disease populations. In central Africa, seroprevalence was 25·64% (12·09-42·00) in general populations and 37·77% (12·13-67·54) in liver-disease populations. In east and southern Africa, seroprevalence was 0·05% (0·00-1·78) in general populations. The odds ratio for anti-hepatitis D virus detection among HBsAg-positive patients with liver fibrosis or hepatocellular carcinoma was 5·24 (95% CI 2·74-10·01; p0·0001) relative to asymptomatic controls.Findings suggest localised clusters of hepatitis D virus endemicity across sub-Saharan Africa. Epidemiological data are needed from southern and east Africa, and from patients with established liver disease. Further studies should aim to define the reliability of hepatitis D virus testing methods, identify risk factors for transmission, and characterise the natural history of the infection in the region.Wellcome Trust, Royal Society.

In sub-Saharan Africa, chronic infection with the hepatitis B virus (HBV) is a profoundly important public health issue characterised by high prevalence, frequent co-infection with HIV, and suboptimally applied ascertainment and management strategies. Prevalence of hepatitis B surface antigen (HBsAg) in the general population varies geographically, with the highest rates (.8%)

We report a severe case of typhus group rickettsiosis in a returning traveler from Indonesia. This typically mild illness was characterized by progressive pulmonary edema and prolonged fever, with defervescence 4 days after the commencement of doxycycline.

We report a severe case of typhus group rickettsiosis in a returning traveler from Indonesia. This typically mild illness was characterized by progressive pulmonary edema and prolonged fever, with defervescence 4 days after the commencement of doxycycline.

Background: Acute bacterial meningitis (ABM) is a rare disease associated with severe neurological sequelae and death. Clinical features on admission may be subtle and thus delay recognition. Previous studies have shown association between early administration of antibiotics and favourable outcomes. Aim: To examine the presenting clinical features of patients aged >15 years with ABM admitted to a University teaching hospital. To audit investigations and treatment including lumbar puncture (LP), computed tomography (CT) and antibiotics against British Infection Association guidelines. Design: Retrospective observational audit. Methods: Hospital records were reviewed for presenting clinical features and timing of CT scan, LP and antibiotics. Results: Records of 39 patients with ABM were reviewed. The classical triad of fever, neck stiffness and altered mental state was present on admission in only 21% of cases. LP was contraindicated in 69% of cases. Immediate LP was carried out in only 17% of those who had no contraindication. Antibiotics were administered after a median of 79 min (interquartile range 24–213 min); 65% were given within 3 h after arrival. Eighty-five percent of patients had antibiotics in accordance with local guidelines. Conclusions: In patients with ABM, the classical clinical features are uncommon on arrival to hospital and frequently evolve following admission. The majority of patients have contraindications to immediate LP. Efforts should be made to facilitate immediate LP performed in the Emergency Department when there are no contraindications. Earlier administration of antibiotics in cases of suspected ABM and close review following admission is recommended.