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Globally, tuberculosis (TB) testing and treatment have declined dramatically during the COVID-19 pandemic. We quantified the change in TB visits, testing, and treatment compared with a 12-month pre-pandemic baseline at the national referral hospital’s TB Clinic in Lusaka, Zambia, in the first year of the pandemic. We stratified the results into early and later pandemic periods. In the first 2 months of the pandemic, the mean number of monthly TB clinic visits, prescriptions, and positive TB polymerase chain reaction (PCR) tests decreased as follow: −94.1% (95% CI: −119.4 to −68.8%), −71.4% (95% CI: −80.4 to −62.4%), and −73% (95% CI: −95.5 to −51.3%), respectively. TB testing and treatment counts rebounded in the subsequent 10 months, although the number of prescriptions and TB-PCR tests performed remained significantly lower than pre-pandemic. The COVID-19 pandemic significantly disrupted TB care in Zambia, which could have long-lasting impacts on TB transmission and mortality. Future pandemic preparedness planning should incorporate strategies developed over the course of this pandemic to safeguard consistent, comprehensive TB care.

Despite the escalating burden of antimicrobial resistance (AMR), the global response has not sufficiently matched the scale and scope of the issue, especially in low- and middle-income countries (LMICs). While many countries have adopted national action plans to combat AMR, their implementation has lagged due to resource constraints, dysfunctional multisectoral coordination mechanisms and, importantly, an under-recognized lack of technical capacity to adapt evidence-based AMR mitigation interventions to local contexts. AMR interventions should be tailored, context-specific, cost-effective and sustainable. The implementation and subsequent scale-up of these interventions require multidisciplinary intervention-implementation research (IIR). IIR involves both quantitative and qualitative approaches, occurs across a three-phase continuum (proof of concept, proof of implementation and informing scale-up), and across four context domains (inner setting, outer setting, stakeholders and the implementation process). We describe the theoretical underpinnings of implementation research (IR), its various components, and how to construct different IR strategies to facilitate sustainable uptake of AMR interventions. Additionally, we provide real-world examples of AMR strategies and interventions to demonstrate these principles in practice. IR provides a practical framework to implement evidence-based and sustainable AMR mitigation interventions. Despite the escalating burden of antimicrobial resistance (AMR), the global response has not sufficiently matched the scale and scope of the issue, especially in low- and middle-income countries (LMICs). While many countries have adopted national action plans to combat AMR, their implementation has lagged due to resource constraints, dysfunctional multisectoral coordination mechanisms and, importantly, an under-recognized lack of technical capacity to adapt evidence-based AMR mitigation interventions to local contexts. AMR interventions should be tailored, context-specific, cost-effective and sustainable. The implementation and subsequent scale-up of these interventions require multidisciplinary intervention-implementation research (IIR). IIR involves both quantitative and qualitative approaches, occurs across a three-phase continuum (proof of concept, proof of implementation and informing scale-up), and across four context domains (inner setting, outer setting, stakeholders and the implementation process). We describe the theoretical underpinnings of implementation research (IR), its various components, and how to construct different IR strategies to facilitate sustainable uptake of AMR interventions. Additionally, we provide real-world examples of AMR strategies and interventions to demonstrate these principles in practice. IR provides a practical framework to implement evidence-based and sustainable AMR mitigation interventions.

ImportanceFew epidemiologic studies related to COVID-19 have emerged from countries in Africa, where demographic characteristics, epidemiology, and health system capacity differ from other parts of the world.ObjectivesTo describe the characteristics and outcomes of patients admitted to COVID-19 treatment centers, assess risk factors for in-hospital death, and explore how treatment center admissions were affected by COVID-19 waves in Zambia.Design, Setting, and ParticipantsThis retrospective cohort study assessed patients admitted to COVID-19 treatment centers in 5 Zambian cities between March 1, 2020, and February 28, 2022.ExposuresRisk factors for in-hospital mortality, including patient age and severity of COVID-19, at treatment center admission.Main Outcomes and MeasuresPatient information was collected, including inpatient disposition (discharged or died). Differences across and within COVID-19 waves were assessed. Mixed-effects logistic regression models were used to assess associations between risk factors and in-hospital mortality as well as between characteristics of admitted patients and timing of admission.ResultsA total of 3876 patients were admitted during 4 COVID-19 waves (mean [SD] age, 50.6 [19.5] years; 2103 male [54.3%]). Compared with the first 3 waves (pooled), the proportion of patients who were 60 years or older admitted during wave 4, when the Omicron variant was circulating, was significantly lower (250 of 1009 [24.8%] vs 1116 of 2837 [39.3%]; P Conclusions and RelevanceThe characteristics of admitted patients during the Omicron wave and risk factors for in-hospital mortality in Zambia reflect data reported elsewhere. Within-wave analyses revealed a pattern in which it appeared that admission of higher-risk patients was prioritized during periods when there were surges in demand for health services during COVID-19 waves. These findings support the need to expand health system capacity and improve health system resiliency in Zambia and other countries with resource-limited health systems.

Background The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. Results The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Background: Since information on the pathology of COVID-19 from sub-Saharan Africa (SSA) remains scarce, the objective of our study was to define the gross pathology and histological features of COVID-19. We report data from 29 whole-body autopsies of COVID-19 deaths occurring in hospitals in Lusaka, Zambia - the first large autopsy case series from Africa. Methods: We performed a descriptive post-mortem examination study of inpatient COVID-19 related deaths at two hospitals in Lusaka, Zambia. Whole-body autopsies were conducted according to Standard Operating Procedures. Gross and histopathological examinations of all organs were performed. Patient demographics, history, co-morbidities, autopsy gross and microscopic findings, and cause(s) of death were recorded and analyzed using STATA version 14. Variables were grouped and presented as frequencies and percentages. Findings: Autopsies were performed on 29 decedents (mean age = 44 ± 15.8years; age range = 19-82; 17/29 [58.8%] males). 22/29 [75.9%] cases were

Background Coronavirus disease 2019 (COVID-19) vaccines are highly effective for reducing severe disease and mortality. However, vaccine effectiveness data are limited from Sub-Saharan Africa. We report COVID-19 vaccine effectiveness against progression to in-hospital mortality in Zambia. Methods We conducted a retrospective cohort study among admitted patients at 8 COVID-19 treatment centers across Zambia during April 2021 through March 2022, when the Delta and Omicron variants were circulating. Patient demographic and clinical information including vaccination status and hospitalization outcome (discharged or died) were collected. Multivariable logistic regression was used to assess the odds of in-hospital mortality by vaccination status, adjusted for age, sex, number of comorbid conditions, disease severity, hospitalization month, and COVID-19 treatment center. Vaccine effectiveness of ≥1 vaccine dose was calculated from the adjusted odds ratio. Results Among 1653 patients with data on their vaccination status and hospitalization outcome, 365 (22.1%) died. Overall, 236 (14.3%) patients had received ≥1 vaccine dose before hospital admission. Of the patients who had received ≥1 vaccine dose, 22 (9.3%) died compared with 343 (24.2%) among unvaccinated patients (P < .01). The median time since receipt of a first vaccine dose (interquartile range) was 52.5 (28–107) days. Vaccine effectiveness for progression to in-hospital mortality among hospitalized patients was 64.8% (95% CI, 42.3%–79.4%). Conclusions Among patients admitted to COVID-19 treatment centers in Zambia, COVID-19 vaccination was associated with lower progression to in-hospital mortality. These data are consistent with evidence from other countries demonstrating the benefit of COVID-19 vaccination against severe complications. Vaccination is a critical tool for reducing the consequences of COVID-19 in Zambia.

BackgroundCOVID-19 vaccines are highly effective for reducing severe disease and mortality. However, vaccine effectiveness data is limited from sub-Saharan Africa, where SARS-CoV-2 epidemiology has differed from other regions. We report COVID-19 vaccine effectiveness against progression to in-hospital mortality in Zambia.MethodsWe conducted a retrospective cohort study among admitted patients at eight COVID-19 treatment centers across Zambia during April 2021 through March 2022. Patient demographic and clinical information including vaccination status and hospitalization outcome (discharged or died) werecollected. Multivariable logistic regression was used to assess the odds of in-hospital mortality by vaccination status, adjusted for age, sex, number of comorbid conditions, disease severity, and COVID-19 treatment center. Vaccine effectiveness of ≥1 vaccine dose was calculated from the adjusted odds ratio.ResultsAmong 1,653 patients with data on their vaccination status and hospitalization outcome, 365 (22.1%) died. Overall, 236 (14.3%) patients had received ≥1 vaccine dose before hospital admission. For patients who had received ≥1 vaccine dose, 22 (9.3%) died compared with 343 (24.2%) among unvaccinated patients (p ConclusionsAmong patients admitted to COVID-19 treatment centers in Zambia, COVID-19 vaccination was associated with lower progression to in-hospital mortality. These data are consistent with evidence from other countries demonstrating benefit of COVID-19 vaccination against severe complications. Vaccination is a critical tool for reducing the consequences of COVID-19 in Zambia.Key points-Receipt of ≥1 COVID-19 vaccine dose reduced progression to in-hospital mortality in Zambia by 64.8%-Mortality benefit of COVID-19 vaccines was sustained during the period of omicron transmission in Zambia

Antiretroviral therapy (ART) uptake continues to increase across sub-Saharan Africa and emergence of drug-resistant HIV mutations poses significant challenges to management of treatment-experienced patients with virologic failure. In Zambia, new third-line ART (TLART) guidelines including use of dolutegravir (DTG) were introduced in 2018. We assessed virologic suppression, immunologic response, and HIV drug-resistant mutations (DRMs) among patients on TLART at the University Teaching Hospital (UTH) in Lusaka, Zambia. We conducted a retrospective review of patients enrolled at UTH on TLART for6 months between January 2010 and June 30, 2021. CD4 and HIV viral load (VL) at TLART initiation and post-initiation were assessed to determine virologic and immunologic outcomes. Regression analysis using bivariate and multivariate methods to describe baseline characteristics, virologic, and immunologic response to TLART was performed. A total of 345 patients met inclusion criteria; women comprised 57.6% (199/345) of the cohort. Median age at HIV diagnosis was 30 (interquartile range: 17.3-36.8). In 255 (73.8%) patients with at least two VLs, VL decreased from mean of 3.45 log

Highlights • Whilst African countries were relatively spared initially when COVID-19 was first reported from China, the frequent travel links between China, Europe and Africa, meant importation of SARS-CoV-2 into Africa was inescapable. • In preparation, Zambia had applied a multisectoral national epidemic disease surveillance and response system resulting in the identification of the first case within 48 hours of the individual entering the country by air travel from a trip to France. • Phylogenomic analysis showed that the detected SARS-CoV-2 belonged to lineage B.1.1., sharing the last common ancestor with SARS-CoV-2 strains recovered from South Africa. • At the African continental level, our analysis showed that lineage B.1 and B.1.1 lineages appear to be predominant in Africa. • Whole genome sequence analysis should be part of all surveillance activities to monitor the origin and evolution of SARS-CoV-2 lineages across Africa., Since its first discovery in December 2019 in Wuhan, China, COVID-19, caused by the novel coronavirus SARS-CoV-2, has spread rapidly worldwide. Whilst African countries were relatively spared initially, the initial low incidence of COVID-19 cases was not sustained for long due to continuing travel links between China, Europe and Africa.. In preparation, Zambia had applied a multisectoral national epidemic disease surveillance and response system resulting in the identification of the first case within 48 hours of the individual entering the country by air travel from a trip to France. Contact tracing showed that SARS-CoV-2 infection was contained within the patient’s household, with no further spread to attending health care workers or community members. Phylogenomic analysis of the patient’s SARS-CoV-2 strain showed it belonged to lineage B.1.1., sharing the last common ancestor with SARS-CoV-2 strains recovered from South Africa. At the African continental level, our analysis showed that lineage B.1 and B.1.1 lineages appear to be predominant in Africa. Whole genome sequence analysis should be part of all surveillance and case detection activities in order to monitor the origin and evolution of SARS-CoV-2 lineages across Africa.

background Screening of contacts of TB patients is not routinely done in resource-limited countries like Zambia despite WHO recommendations, leading to missed opportunities for prevention, early diagnosis and high mortality. OBJECTIVES Main objective was to establish the prevalence of latent and active tuberculosis in bedside contacts of smear-positive index patients and associated risk factors. METHODS We recruited bedside contacts of smear-positive TB patients in medical wards and contacts of surgical patients as a comparison group using a questionnaire to collect data on various variables. Active TB was diagnosed microbiologically and radiologically, while LTBI by TST. RESULTS We had 64 TB-unexposed and 70 TB-exposed, with a mean age of 41.2 [±13.5] years and 40.2 [±14.7] years respectively. Prevalence of active TB in the two groups was 10.0% and 0% respectively while that of LTBI was 83.1% and 38.3% respectively. TB exposure was significantly associated with active TB (p=0.014), LTBI (p

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. 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.

BackgroundThe unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear.Methods and FindingsWe develop a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care to explore the potential public-health impact of a range of different potential therapeutics, under a range of different scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) drug efficacy in the absence of supportive care. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. We find the impact of drugs like dexamethasone (which are delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics.ConclusionsThere is a global asymmetry in who is likely to benefit from advances in the treatment of COVID-19 to date, which have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

The effect of HIV infection on COVID-19 outcomes is unclear. Studies in South Africa (1) and the United Kingdom (2) found an independent association between HIV infection and COVID-19 mortality; however, other studies have not found an association between poor COVID-19 outcomes and either HIV status among hospitalized patients (3-5) or HIV-associated factors such as CD4 count, viral load, or type of antiretroviral therapy (ART) (6). The effect of HIV infection on COVID-19 outcomes remains an urgent question in sub-Saharan Africa, where many countries are experiencing dual HIV and COVID-19 epidemics, and capacity to treat severe COVID-19 is limited. Using data from patients with probable or confirmed COVID-19 admitted to specialized treatment centers during March-December 2020 in Zambia, the Zambian Ministry of Health and CDC assessed the relationship between HIV infection and severe COVID-19 and COVID-19-associated death. Among 443 patients included in the study, 122 (28%) were HIV-positive, and of these, 91 (89%) were receiving ART at the time of hospitalization. HIV status alone was not significantly associated with severe COVID-19 at admission or during hospitalization or with COVID-19-associated death. However, among HIV-positive persons, those with severe HIV disease were more likely to develop severe COVID-19 and were at increased risk for COVID-19-associated death. Ensuring that persons maintain HIV disease control, including maintaining ART continuity and adherence, achieving viral suppression, and addressing and managing underlying medical conditions, could help reduce COVID-19-associated morbidity and mortality in sub-Saharan Africa.

Background: Xpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF. Methods: We searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394. Findings: Our search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68–1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65–1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60–0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I2

This is the twelfth version (eleventh update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline.What is the role of drugs in the treatment of patients with covid-19?The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and under way. The emerging SARS-CoV-2 variants (such as omicron) and subvariants are also changing the role of therapeutics. This update provides updated recommendations for remdesivir, addresses the use of combination therapy with corticosteroids, interleukin-6 (IL-6) receptor blockers, and janus kinase (JAK) inhibitors in patients with severe or critical covid-19, and modifies previous recommendations for the neutralising monoclonal antibodies sotrovimab and casirivimab-imdevimab in patients with non-severe covid-19.• Remdesivir: a conditional recommendation for its use in patients with severe covid-19; and a conditional recommendation against its use in patients with critical covid-19. • Concomitant use of IL-6 receptor blockers (tocilizumab or sarilumab) and the JAK inhibitor baricitinib: these drugs may now be combined, in addition to corticosteroids, in patients with severe or critical covid-19. • Sotrovimab and casirivimab-imdevimab: strong recommendations against their use in patients with covid-19, replacing the previous conditional recommendations for their use.When moving from new evidence to updated recommendations, the Guideline Development Group (GDG) considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. For remdesivir, new trial data were added to a previous subgroup analysis and provided sufficiently trustworthy evidence to demonstrate benefits in patients with severe covid-19, but not critical covid-19. The GDG considered benefits of remdesivir to be modest and of moderate certainty for key outcomes such as mortality and mechanical ventilation, resulting in a conditional recommendation. For baricitinib, the GDG considered clinical trial evidence (RECOVERY) demonstrating reduced risk of death in patients already receiving corticosteroids and IL-6 receptor blockers. The GDG acknowledged that the clinical trials were not representative of the world population and that the risk-benefit balance may be less advantageous, particularly in patients who are immunosuppressed at higher risk of opportunistic infections (such as serious fungal, viral, or bacteria), those already deteriorating where less aggressive or stepwise addition of immunosuppressive medications may be preferred, and in areas where certain pathogens such as HIV or tuberculosis, are of concern. The panel anticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy or to combine medications in a stepwise fashion in patients who are deteriorating. The decision to combine the medications will depend on their availability, and the treating clinician's perception of the risk-benefit balance associated with combination immunosuppressive therapy, particularly in patient populations at risk of opportunistic infections who may have been under-represented in clinical trials. When making a strong recommendation against the use of monoclonal antibodies for patients with covid-19, the GDG considered in vitro neutralisation data demonstrating that sotrovimab and casirivimab-imdevimab evaluated in clinical trials have meaningfully reduced neutralisation activity of the currently circulating variants of SARS-CoV-2 and their subvariants. There was consensus among the panel that the absence of in vitro neutralisation activity strongly suggests absence of clinical effectiveness of these monoclonal antibodies. However, there was also consensus regarding the need for clinical trial evidence in order to confirm clinical efficacy of new monoclonal antibodies that reliably neutralise the circulating strains in vitro. Whether emerging new variants and subvariants might be susceptible to sotrovimab, casirivimab-imdevimab, or other anti-SARS-CoV-2 monoclonal antibodies cannot be predicted.• Recommended for patients with severe or critical covid-19—strong recommendations for systemic corticosteroids; IL-6 receptor blockers (tocilizumab or sarilumab) in combination with corticosteroids; and baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids. • Recommended for patients with non-severe covid-19 at highest risk of hospitalisation—a strong recommendation for nirmatrelvir/ritonavir; conditional recommendations for molnupiravir and remdesivir. • Not recommended for patients with non-severe covid-19—a conditional recommendation against systemic corticosteroids; a strong recommendation against convalescent plasma; a recommendation against fluvoxamine, except in the context of a clinical trial; and a strong recommendation against colchicine. • Not recommended for patients with non-severe covid-19 at low risk of hospitalisation—a conditional recommendation against nirmatrelvir/ritonavir. • Not recommended for patients with severe or critical covid-19—a recommendation against convalescent plasma except in the context of a clinical trial; and a conditional recommendation against the JAK inhibitors ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity—a strong recommendations against hydroxychloroquine and against lopinavir/ritonavir; and a recommendation against ivermectin except in the context of a clinical trial.This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact.Recommendations on anticoagulation are planned for the next update to this guideline.

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.

Background Healthcare workers (HCWs) in Zambia have become infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). However, SARS-CoV-2 prevalence among HCWs is not known in Zambia. Methods We conducted a cross-sectional SARS-CoV-2 prevalence survey among Zambian HCWs in 20 health facilities in 6 districts in July 2020. Participants were tested for SARS-CoV-2 infection using polymerase chain reaction (PCR) and for SARS-CoV-2 antibodies using enzyme-linked immunosorbent assay (ELISA). Prevalence estimates and 95% confidence intervals (CIs), adjusted for health facility clustering, were calculated for each test separately, and a combined measure for those who had PCR and ELISA was performed. Results In total, 660 HCWs participated in the study, with 450 (68.2%) providing a nasopharyngeal swab for PCR and 575 (87.1%) providing a blood specimen for ELISA. Sixty-six percent of participants were females, and median age was 31.5 years (interquartile range, 26.2–39.8). The overall prevalence of the combined measure was 9.3% (95% CI, 3.8%–14.7%). PCR-positive prevalence of SARS-CoV-2 was 6.6% (95% CI, 2.0%–11.1%), and ELISA-positive prevalence was 2.2% (95% CI, .5%–3.9%). Conclusions SARS-CoV-2 prevalence among HCWs was similar to a population-based estimate (10.6%) during a period of community transmission in Zambia. Public health measures such as establishing COVID-19 treatment centers before the first cases, screening for COVID-19 symptoms among patients who access health facilities, infection prevention and control trainings, and targeted distribution of personal protective equipment based on exposure risk might have prevented increased SARS-CoV-2 transmission among Zambian HCWs.

Clinical question What is the role of drugs in preventing covid-19? Why does this matter? There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. Recommendations The second version of this living guideline reiterates the previous strong recommendation against the use of hydroxychloroquine and includes a new conditional recommendation against the use of tixagevimab-cilgavimab in individuals who do not have covid-19. How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provides methodological support. A living systematic review with network analysis informs the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produces recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the recommendations The living network meta-analysis informing this guideline included 12 trials (8379 participants) comparing hydroxychloroquine to standard care/placebo, and one trial (5197 participants) comparing tixagevimab-cilgavimab to standard care/placebo. When moving from evidence to the continued strong recommendation against the use of hydroxychloroquine, the GDG emphasised additional evidence suggesting no or little effect on mortality and hospital admission, and an increased risk of adverse effects. For the new conditional recommendation against the use of tixagevimab-cilgavimab, the GDG emphasised in vitro evidence reducing the applicability of available trial data. While trial results demonstrated modest reduction in the occurrence of laboratory confirmed symptomatic covid-19, lack of in vitro neutralisation of new SARS-CoV-2 sub-lineages was considered to have rendered these results obsolete. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. Readers note This is the second version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19 and living guidance regarding covid-19 related clinical management. When citing this article, please consider adding the update number and date of access for clarity.

Summary Background Between March and December, 2020, more than 20 000 laboratory-confirmed cases of SARS-CoV-2 infection were reported in Zambia. However, the number of SARS-CoV-2 infections is likely to be higher than the confirmed case counts because many infected people have mild or no symptoms, and limitations exist with regard to testing capacity and surveillance systems in Zambia. We aimed to estimate SARS-CoV-2 prevalence in six districts of Zambia in July, 2020, using a population-based household survey. Methods Between July 4 and July 27, 2020, we did a cross-sectional cluster-sample survey of households in six districts of Zambia. Within each district, 16 standardised enumeration areas were randomly selected as primary sampling units using probability proportional to size. 20 households from each standardised enumeration area were selected using simple random sampling. All members of selected households were eligible to participate. Consenting participants completed a questionnaire and were tested for SARS-CoV-2 infection using real-time PCR (rtPCR) and anti-SARS-CoV-2 antibodies using ELISA. Prevalence estimates, adjusted for the survey design, were calculated for each diagnostic test separately, and combined. We applied the prevalence estimates to census population projections for each district to derive the estimated number of SARS-CoV-2 infections. Findings Overall, 4258 people from 1866 households participated in the study. The median age of participants was 18·2 years (IQR 7·7–31·4) and 50·6% of participants were female. SARS-CoV-2 prevalence for the combined measure was 10·6% (95% CI 7·3–13·9). The rtPCR-positive prevalence was 7·6% (4·7–10·6) and ELISA-positive prevalence was 2·1% (1·1–3·1). An estimated 454 708 SARS-CoV-2 infections (95% CI 312 705–596 713) occurred in the six districts between March and July, 2020, compared with 4917 laboratory-confirmed cases reported in official statistics from the Zambia National Public Health Institute. Interpretation The estimated number of SARS-CoV-2 infections was much higher than the number of reported cases in six districts in Zambia. The high rtPCR-positive SARS-CoV-2 prevalence was consistent with observed community transmission during the study period. The low ELISA-positive SARS-CoV-2 prevalence might be associated with mitigation measures instituted after initial cases were reported in March, 2020. Zambia should monitor patterns of SARS-CoV-2 prevalence and promote measures that can reduce transmission. Funding US Centers for Disease Control and Prevention.

Objective Dyslipidaemia and obesity have a synergistic effect on the development of cardiovascular diseases (CVDs). Anthropometric measurements have often been used as surrogate markers for obesity indices with diverse results. We evaluated the best obesity index for predicting dyslipidaemia among anthropometric measurements and body fat measurements with bio-electric impedance analysis (BIA). Results Among 116 adults, 62 (53.4%) were female. The median age was 39 years (quartile (Q)1, Q3: 20.8, 65.4). Waist circumference (odds ratio (OR) 4.54; 95% CI 1.56, 13.19; p=0.005) and total body fat percentage (OR 0.34; 95% CI 0.13, 0.91; p=0.031) measurements of obesity indices were significantly associated with dyslipidaemia.

Introduction: In 2018, there were appropriately 20.6 million [18.2 million–23.2 million] people living with HIV in Eastern and Southern Africa, and an estimated 67% of them were on antiretroviral therapy (ART). A major challenge in the scale-up of ART services in Sub-Saharan Africa is the severe shortage of clinical staff. Methods: We conducted a randomised trial in Tanzania and Zambia to test an innovative intervention that involved the use of lay health workers and screening for cryptococcal meningitis and tuberculosis. Here we describe the model of care with a particular focus on the trained lay worker component. Lay workers carried out home visits to patients in the intervention arm to deliver antiretroviral drugs, provide adherence counselling, and conduct simple monitoring for treatment side effects and other medical conditions. Lay workers were responsible for referring patients with conditions that might require further medical attention as well as discouraging self-referral. A total of 1999 participants were enrolled in the trial. Lay workers were recruited through public advertisements. Results: Six lay workers were recruited in each country and trained for two weeks. Each lay worker was paid a monthly salary of US$ 487.61 in Zambia and US$ 524.61in Tanzania. They were also paid communication and transport expenses for home visits. The median number of visits per patient was 3 for Tanzania and 4 for Zambia. On average a lay worker was responsible for 72.3 patients in Tanzania and 94.5 in Zambia for 1 year. Referrals were made in 9% of the home visits and self-referral was discouraged in 64% of visits. Conclusion: The use of paid lay workers to provide HIV/AIDS services in urban settings where there is a shortage of clinical staff may help to identify ART related side effects/adverse reactions and prevent unnecessary referrals.

Background A randomized trial demonstrated that among people living with late-stage human immunodeficiency virus (HIV) infection initiating antiretroviral therapy, screening serum for cryptococcal antigen (CrAg) combined with adherence support reduced all-cause mortality by 28%, compared with standard clinic-based care. Here, we present the cost-effectiveness. Methods HIV-infected adults with CD4 count, In a large phase 3 randomized controlled trial among persons presenting with late-stage HIV infection, we showed that cryptococcal meningitis screening and community-based early adherence support was a highly cost-effective strategy in reducing all-cause mortality.

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., The combination of flucytosine plus fluconazole (FLU) is cost-effective, compared with the commonly used regimen of FLU monotherapy, for cryptococcal meningitis treatment in Africa, with an incremental cost-effectiveness ratio of US $65 per life-year saved at the current price.

Cryptococcus gattii is an environmental pathogen that causes severe systemic infection in immunocompetent individuals more often than in immunocompromised humans. Over the past 2 decades, researchers have shown that C. gattii falls within four genetically distinct major lineages. By combining field work from an understudied ecological region (the Central Miombo Woodlands of Zambia, Africa), genome sequencing and assemblies, phylogenetic and population genetic analyses, and phenotypic characterization (morphology, histopathological, drug-sensitivity, survival experiments), we discovered a hitherto unknown lineage, which we name VGV (variety gattii five). The discovery of a new lineage from an understudied ecological region has far-reaching implications for the study and understanding of fungal pathogens and diseases they cause., We discovered a new lineage of the globally important fungal pathogen Cryptococcus gattii on the basis of analysis of six isolates collected from three locations spanning the Central Miombo Woodlands of Zambia, Africa. All isolates were from environments (middens and tree holes) that are associated with a small mammal, the African hyrax. Phylogenetic and population genetic analyses confirmed that these isolates form a distinct, deeply divergent lineage, which we name VGV. VGV comprises two subclades (A and B) that are capable of causing mild lung infection with negligible neurotropism in mice. Comparing the VGV genome to previously identified lineages of C. gattii revealed a unique suite of genes together with gene loss and inversion events. However, standard URA5 restriction fragment length polymorphism (RFLP) analysis could not distinguish between VGV and VGIV isolates. We therefore developed a new URA5 RFLP method that can reliably identify the newly described lineage. Our work highlights how sampling understudied ecological regions alongside genomic and functional characterization can broaden our understanding of the evolution and ecology of major global pathogens.

Background In Zambia, third-line regimens consist of a switch to darunavir/ritonavir (DRV/r) and/or raltegravir (RAL) and/or etravirine (ETV), and as of 2017, dolutegravir (DTG), from a failing second-line therapy.5 We assessed virologic suppression (HIV viral load (VL) ≤1000 copies/ml per Zambian national guidelines), immunological response, and patterns of HIV drug resistance mutation among patients on third-line ART at the University Teaching Hospital (UTH) in Lusaka, Zambia. Methods A retrospective evaluation of adults ≥18 years old on third-line ART regimens at UTH between January 2012 to June 30, 2020 was conducted. Patients were referred for second-line virologic failure defined as HIV RNA VL > 1000 copies/mL on two consecutive measurements after 6 months on second-line ART.5 We assessed virologic suppression VL ≤1000 copies/ml, CD4, mutations, and third-line regimens of this cohort. Patients were excluded if they were on third-line ART < 6 months or received RAL and/or ETV and/or DTG before starting third-line ART. Results A total of 539 patients were included; 231 males (42.9%) and 308 (57.1%) females. The mean age of third-line initiation was 29.8 years; mean time from ART initiation to third-line initiation was 9.9 years. Out of 25 combination 349 (64.7%) received DTG, 272 (50.5%) DRV/r, 85(15.8%) ETR, and 49 (9.1%) RAL. There were 215 (39.9%) genotypes; common mutations were to zidovudine (80%), non-nucleoside reverse transcriptase inhibitors (NNRTIs) (78%), and protease inhibitors (PIs) (41%). Patients with at least one viral load and CD4 upon third-line initiation was 296 (54.9%) and 350 (64.9%), respectively. Among patients with sufficient data (21%, n=115), VL suppression increased from 44 (38%) patients at baseline to 53 (46%) at next available follow-up; with mean baseline VL and follow-up VL of log10 3.60 and 3.33, respectively. The immunologic response revealed 49 (56.3%) had CD4 increase with mean increase of 61.1 cells/mm3. (See Table 1.) Conclusion We found moderate improvements in VL suppression and immunologic response. Nearly all third-line patients had genotypic resistance to first-line NNRTI and nearly half to second-line PI regimens. Quality improvement measures are needed to improve viral load timing following ART changes to better assess regimen efficacy. Disclosures All Authors: No reported disclosures

Zambia is a landlocked, lower-middle income country in southern Africa, with a population of 17 million (1). The first known cases of coronavirus disease 2019 (COVID-19) in Zambia occurred in a married couple who had traveled to France and were subject to port-of-entry surveillance and subsequent remote monitoring of travelers with a history of international travel for 14 days after arrival. They were identified as having suspected cases on March 18, 2020, and tested for COVID-19 after developing respiratory symptoms during the 14-day monitoring period. In March 2020, the Zambia National Public Health Institute (ZNPHI) defined a suspected case of COVID-19 as 1) an acute respiratory illness in a person with a history of international travel during the 14 days preceding symptom onset; or 2) acute respiratory illness in a person with a history of contact with a person with laboratory-confirmed COVID-19 in the 14 days preceding symptom onset; or 3) severe acute respiratory illness requiring hospitalization; or 4) being a household or close contact of a patient with laboratory-confirmed COVID-19. This definition was adapted from World Health Organization (WHO) interim guidance issued March 20, 2020, on global surveillance for COVID-19 (2) to also include asymptomatic contacts of persons with confirmed COVID-19. Persons with suspected COVID-19 were identified through various mechanisms, including port-of-entry surveillance, contact tracing, health care worker (HCW) testing, facility-based inpatient screening, community-based screening, and calls from the public into a national hotline administered by the Disaster Management and Mitigation Unit and ZNPHI. Port-of-entry surveillance included an arrival screen consisting of a temperature scan, report of symptoms during the preceding 14 days, and collection of a history of travel and contact with persons with confirmed COVID-19 in the 14 days before arrival in Zambia, followed by daily remote telephone monitoring for 14 days. Travelers were tested for SARS-CoV-2, the virus that causes COVID-19, if they were symptomatic upon arrival or developed symptoms during the 14-day monitoring period. Persons with suspected COVID-19 were tested as soon as possible after evaluation for respiratory symptoms or within 7 days of last known exposure (i.e., travel or contact with a confirmed case). All COVID-19 diagnoses were confirmed using real-time reverse transcription-polymerase chain reaction (RT-PCR) testing (SARS-CoV-2 Nucleic Acid Detection Kit, Maccura) of nasopharyngeal specimens; all patients with confirmed COVID-19 were admitted into institutional isolation at the time of laboratory confirmation, which was generally within 36 hours. COVID-19 patients were deemed recovered and released from isolation after two consecutive PCR-negative test results ≥24 hours apart. A Ministry of Health memorandum was released on April 13, 2020, mandating testing in public facilities of 1) all persons admitted to medical and pediatric wards regardless of symptoms; 2) all patients being admitted to surgical and obstetric wards, regardless of symptoms; 3) any outpatient with fever, cough, or shortness of breath; and 4) any facility or community death in a person with respiratory symptoms, and 5) biweekly screening of all HCWs in isolation centers and health facilities where persons with COVID-19 had been evaluated. This report describes the first 100 COVID-19 cases reported in Zambia, during March 18-April 28, 2020.

Background Patients with previous tuberculosis may have residual DNA in sputum that confounds nucleic acid amplification tests such as Xpert MTB/RIF. Little is known about the frequency of Xpert-positive, culture-negative ("false positive") results in retreatment patients, whether these are distinguishable from true positives, and whether Xpert's automated filter-based wash step reduces false positivity by removing residual DNA associated with nonintact cells. Methods Pretreatment patients (n = 2889) with symptoms of tuberculosis from Cape Town, South Africa, underwent a sputum-based liquid culture and Xpert. We also compared Xpert results from dilutions of intact or heat-lysed and mechanically lysed bacilli. Results Retreatment cases were more likely to be Xpert false-positive (45/321 Xpert-positive retreatment cases were false-positive) than new cases (40/461) (14% [95% confidence interval {CI}, 10%-18%] vs 8% [95% CI, 6%-12%];P= .018). Fewer years since treatment completion (adjusted odds ratio [aOR], 0.85 [95% CI, .73-.99]), less mycobacterial DNA (aOR, 1.14 [95% CI, 1.03-1.27] per cycle threshold [CT]), and a chest radiograph not suggestive of active tuberculosis (aOR, 0.22 [95% CI, .06-.82]) were associated with false positivity. CThad suboptimal accuracy for false positivity: 46% of Xpert-positives with CT> 30 would be false positive, although 70% of false positives would be missed. CT's predictive ability (area under the curve, 0.83 [95% CI, .76-.90]) was not improved by additional variables. Xpert detected nonviable, nonintact bacilli without a change in CTvs controls. Conclusions One in 7 Xpert-positive retreatment patients were culture negative and potentially false positive. False positivity was associated with recent previous tuberculosis, high CT, and a chest radiograph not suggestive of active tuberculosis. Clinicians may consider awaiting confirmatory testing in retreatment patients with CT> 30; however, most false positives fall below this cut-point. Xpert can detect DNA from nonviable, nonintact bacilli.

Antimicrobial resistance is a growing global health concern. Antimicrobial stewardship (AMS) curbs resistance rates by encouraging rational antimicrobial use. However, data on antimicrobial stewardship in developing countries is scarce. The objective of this study was to characterize antimicrobial use at the University Teaching Hospital (UTH) in Lusaka, Zambia as a guiding step in the development of an AMS program. This was a cross-sectional, observational study evaluating antimicrobial appropriateness and consumption in non-critically ill adult medicine patients admitted to UTH. Appropriateness was defined as a composite measure based upon daily chart review. Sixty percent (88/146) of all adult patients admitted to the general wards had at least one antimicrobial ordered and were included in this study. The most commonly treated infectious diseases were tuberculosis, pneumonia, and septicemia. Treatment of drug sensitive tuberculosis is standardized in a four-drug combination pill of rifampicin, isoniazid, pyrazinamide and ethambutol, therefore appropriateness of therapy was not further evaluated. The most common antimicrobials ordered were cefotaxime (n = 45), ceftriaxone (n = 28), and metronidazole (n = 14). Overall, 67% of antimicrobial orders were inappropriately prescribed to some extent, largely driven by incorrect dose or frequency in patients with renal dysfunction. Antimicrobial prescribing among hospitalized patients at UTH is common and there is room for optimization of a majority of antimicrobial orders. Availability of certain antimicrobials must be taken into consideration during AMS program development.

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.

We assessed the effect of fluconazole 1200 mg/day on the QT interval in cryptococcal meningitis patients. Mean corrected QT (QTc) change from baseline to day 7 was 10.1 ms (IQR: -28 to 46 ms) in the fluconazole treatment group and -12.6 ms (IQR: -39 to 13.5 ms) in those not taking fluconazole (P = 0.04). No significant increase in QTc measurements over 500 ms was observed with fluconazole. Nevertheless, it remains important to correct any electrolyte imbalance and avoid concomitant drugs that may increase QTc.

Summary WHO estimates that 9 million people developed active tuberculosis in 2013 and 1·5 million people died from it. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis continue to spread worldwide with an estimated 480 000 new cases in 2013. Treatment success rates of MDR and XDR tuberculosis are still low and development of new, more effective tuberculosis drugs and adjunct therapies to improve treatment outcomes are urgently needed. Although standard therapy for drug-sensitive tuberculosis is highly effective, shorter, more effective treatment regimens are needed to reduce the burden of infectious cases. We review the latest WHO guidelines and global recommendations for treatment and management of drug-sensitive and drug-resistant tuberculosis, and provide an update on new drug development, results of several phase 2 and phase 3 tuberculosis treatment trials, and other emerging adjunct therapeutic options for MDR and XDR tuberculosis. The use of fluoroquinolone-containing (moxifloxacin and gatifloxacin) regimens have failed to shorten duration of therapy, and the new tuberculosis drug pipeline is sparse. Scale-up of existing interventions with increased investments into tuberculosis health services, development of new antituberculosis drugs, adjunct therapies and vaccines, coupled with visionary political leadership, are still our best chance to change the unacceptable status quo of the tuberculosis situation worldwide and the growing problem of drug-resistant tuberculosis.

Summary Background WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per μL or more. Methods We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220–349 cells per μL vs ≥350 cells per μL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053). Findings We screened 13 588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8·5%) of 767 patients in the early ART group versus 71 (9·2%) of 771 in the delayed ART group (relative risk [RR] 0·91, 95% CI 0·64–1·30; p=0·9). Of patients with a CD4 cell count of 220–349 cells per μL, 26 (7·9%) of 331 patients versus 33 (9·6%) of 342 reached the primary endpoint (RR 0·80, 95% CI 0·46–1·39; p=0·6). For those with 350 cells per μL or more, 39 (8·9%) of 436 versus 38 (8·9%) of 429 reached the primary endpoint (RR 1·01, 95% CI 0·63–1·62; p=0·4). Mortality did not differ significantly between treatment groups (RR 1·4, 95% CI 0·8–2·3; p=0·23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0·37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0·56). Interpretation ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per μL. WHO guidelines should be updated accordingly. Funding USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR.

Summary Background The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa. Methods In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384. Findings Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0–3] in the smear microscopy group vs 2 [0·25–3] in the MTB/RIF group; p=0·85) or 6 months (1 [0–3] vs 1 [0–3]; p=0·35), nor did median KPS at 2 months (80 [70–90] vs 90 [80–90]; p=0·23) or 6 months (100 [90–100] vs 100 [90–100]; p=0·85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0·0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0·25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0·99) but higher specificity (952 [92%] of 1037; p=0·0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0·22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p vs 115 [15%] of 758; p=0·0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0·0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0·6408). Interpretation Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients. Funding European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.

Emerging infections caused by fungi have become a widely recognized global phenomenon and are causing an increasing burden of disease. Genomic techniques are providing new insights into the structure of fungal populations, revealing hitherto undescribed fine‐scale adaptations to environments and hosts that govern their emergence as infections. Cryptococcal meningitis is a neglected tropical disease that is responsible for a large proportion of AIDS‐related deaths across Africa; however, the ecological determinants that underlie a patient's risk of infection remain largely unexplored. Here, we use genome sequencing and ecological genomics to decipher the evolutionary ecology of the aetiological agents of cryptococcal meningitis, Cryptococcus neoformans and Cryptococcus gattii, across the central African country of Zambia. We show that the occurrence of these two pathogens is differentially associated with biotic (macroecological) and abiotic (physical) factors across two key African ecoregions, Central Miombo woodlands and Zambezi Mopane woodlands. We show that speciation of Cryptococcus has resulted in adaptation to occupy different ecological niches, with C. neoformans found to occupy Zambezi Mopane woodlands and C. gattii primarily recovered from Central Miombo woodlands. Genome sequencing shows that C. neoformans causes 95% of human infections in this region, of which over three‐quarters belonged to the globalized lineage VNI. We show that VNI infections are largely associated with urbanized populations in Zambia. Conversely, the majority of C. neoformans isolates recovered in the environment belong to the genetically diverse African‐endemic lineage VNB, and we show hitherto unmapped levels of genomic diversity within this lineage. Our results reveal the complex evolutionary ecology that underpins the reservoirs of infection for this, and likely other, deadly pathogenic fungi.

Summary Background HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality. Methods We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa—four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weightloss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730. Findings Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1–7). The risk ratio adjusted for country was 0·83 (95% CI 0·73–0·96), p=0·012, with a relative risk reduction of 17% (95% CI 4–28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0·82 [95% CI 0·70–0·96], p=0·015). No adverse events were associated with LAM testing. Interpretation Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital inpatients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum. Funding The European & Developing Countries Clinical Trials Partnership, the South African Medical Research Council, and the South African National Research Foundation.