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SummaryBackgroundThere are currently no effective treatments for outpatients with coronavirus disease 2019 (COVID-19). Interferon-lambda-1 is a Type III interferon involved in the innate antiviral response with activity against respiratory pathogens.MethodsIn this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomized to a single subcutaneous injection of peginterferon-lambda 180μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. The primary endpoint was proportion negative for SARS-CoV-2 RNA on Day 7 post-injection.FindingsThere were 30 patients per arm, with median baseline SARS-CoV-2 viral load of 6.71 (IQR 1.3-8.0) log copies/mL. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon-lambda than placebo (p=0.04). On Day 7, 24 participants (80%) in the peginterferon-lambda group had an undetectable viral load compared to 19 (63%) in the placebo arm (p=0.15). After controlling for baseline viral load, peginterferon lambda treatment resulted in a 4.12-fold (95CI 1.15-16.7, p=0.029) higher likelihood of viral clearance by Day 7. Of those with baseline viral load above 10E6 copies/mL, 15/19 (79%) in the peginterferon-lambda group were undetectable on Day 7 compared to 6/16 (38%) in the placebo group (p=0.012). Adverse events were similar between groups with only mild reversible transaminase elevations more frequently observed in the peginterferon-lambda group.InterpretationPeginterferon-lambda accelerated viral decline in outpatients with COVID-19 resulting in a greater proportion with viral clearance by Day 7, particularly in those with high baseline viral load. Peginterferon-lambda may have potential to prevent clinical deterioration and shorten duration of viral shedding.(NCT04354259)FundingThis study was supported by the Toronto COVID-19 Action Initiative, University of Toronto and the Ontario First COVID-19 Rapid Research Fund. Medication was supplied by Eiger BioPharma.Research in ContextTreatment trials for COVID-19 have largely focused on hospitalized patients and no treatments are approved for people with mild to moderate disease in the outpatient setting. A number of studies in ambulatory populations have been registered but no controlled studies in the outpatient setting have been reported to date (Pubmed Search October 20, 2020, COVID-19 treatment; controlled trials). Uncontrolled case series of hydroxychloroquine with or without azithromycin have been reported with mixed results but no clear signal of efficacy and some concerns raised about cardiac toxicity. Treamtent in the outpatient setting has potential to prevent infected individuals from deteriorating and perhaps more importantly, may shorten the duration of viral shedding, reducing the risk of transmission and the duration required for self-isolation, with significant public health and societal impact.Added value of this studyThis is the first study to show an antiviral effect in outpatients with COVID-19. After controlling for baseline viral load, those treated with peginterferon-lambda had a 4.12-fold (95%CI 1.15-16.7, p=0.029) higher odds of viral clearance by Day 7 compared to those who received placebo. The viral load decline was faster with pegterferon-lambda and the effect was most pronounced in those with high viral loads. In individuals with a baseline viral load of 10E6 copies/mL or higher, 15/19 (79%) in the peginterferon-lambda arm cleared by Day 7 compared to 6/16 (38%) (p=0.012) in the placebo arm (OR 6.25, 95%CI 1.49-31.1, p=0.012), translating to a median time to viral clearance of 7 days (95%CI 6.2-7.8 days) with peginterferon-lambda compared to 10 days (95%CI 7.8-12.2 days) with placebo (p=0.038). Those with low viral loads (Implications of all available evidenceThere is no currently approved therapy for outpatients with COVID-19. This study showed that peginterferon-lambda accelerated viral clearance, particularly in those with high baseline viral loads, highlighting the importance of quantitative viral load testing in the evaluation of antiviral agents for COVID-19. Treatment early in the course of disease may prevent clinical deterioration and shorenting of the duration of viral shedding may have important public health impact by limiting transmission and reducing the duration required for self-isolation. Additional trials of peginterferon-lambda and other antiviral strategies in the outpatient setting are required.

Introduction - Worldwide, nursing home residents have experienced disproportionately high COVID-19 mortality due to the intersection of congregate living, multimorbidity, and advanced age. Among 12 OECD countries, Canada has had the highest proportion of COVID-19 deaths in nursing home residents (78%), raising concerns about a skewed pandemic response that averted much transmission and mortality in community-dwelling residents, but did not adequately protect those in nursing homes. To investigate this, we measured temporal variations in hospitalizations among community and nursing home-dwelling decedents with COVID-19 during the first and second waves of the pandemic.Methods - We conducted a population-based cohort study of residents of Ontario, Canada with COVID-19 who died between March 11, 2020 (first COVID-19 death in Ontario) and October 28, 2020. We examined hospitalization prior to death as a function of 4 factors: community (defined as all non-nursing home residents) vs. nursing home residence, age in years (Results - A total of 3,114 people with confirmed COVID-19 died in Ontario from March to October, 2020 (Table 1), of whom 1,354 (43.5%) were hospitalized prior to death (median: 9 days before death, interquartile range: 4-19). Among nursing home decedents (N=2000), 22.4% were admitted to hospital prior to death, but this varied substantially from a low of 15.5% in March-April (peak of wave 1) to a high of 41.2% in June-July (nadir of wave 1). Among community-dwelling decedents (N=1,114), admission to acute care was higher (81.4%) and remained relatively stable throughout the first and second waves. Similar temporal trends for nursing home versus community decedents were apparent in age-stratified analyses (Figure 1). Women who died were less likely to have been hospitalized compared to men in both community (80% women vs 84% men) and nursing home (21% women vs 24% men) settings.Discussion - Only a minority of Ontario nursing home residents who died of COVID-19 were hospitalized prior to death, and that there were substantial temporal variations, with hospitalizations reaching their lowest point when overall COVID-19 incidence peaked in mid-April, 2020. While many nursing home residents had pre-pandemic advance directives precluding hospitalization, the low admission rate observed in March-April 2020 (15.5%) was inconsistent with both higher admission rates in subsequent months (>30%), and comparatively stable rates among community-dwelling adults. Our findings substantiate reports suggesting that hospitalizations for nursing home residents with COVID-19 were low during the peak of the pandemic’s first wave in Canada, which may have contributed to the particularly high concentration of COVID-19 mortality in Ontario’s nursing homes.

Summary Background To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. Methods In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. Findings Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15–16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49–31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. Interpretation Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. Funding The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.

BACKGROUND: Congregate settings have been disproportionately affected by coronavirus disease 2019 (COVID-19). Our objective was to compare testing for, diagnosis of and death after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across 3 settings (residents of long-term care homes, people living in shelters and the rest of the population). METHODS: We conducted a population-based prospective cohort study involving individuals tested for SARS-CoV-2 in the Greater Toronto Area between Jan. 23, 2020, and May 20, 2020. We sourced person-level data from COVID-19 surveillance and reporting systems in Ontario. We calculated cumulatively diagnosed cases per capita, proportion tested, proportion tested positive and case-fatality proportion for each setting. We estimated the age- and sex-adjusted rate ratios associated with setting for test positivity and case fatality using quasi-Poisson regression. RESULTS: Over the study period, a total of 173 092 individuals were tested for and 16 490 individuals were diagnosed with SARS-CoV-2 infection. We observed a shift in the proportion of cumulative cases from all cases being related to travel to cases in residents of long-term care homes (20.4% [3368/16 490]), shelters (2.3% [372/16 490]), other congregate settings (20.9% [3446/16 490]) and community settings (35.4% [5834/16 490]), with cumulative travel-related cases at 4.1% (674/16490). Cumulatively, compared with the rest of the population, the diagnosed cases per capita was 64-fold and 19-fold higher among long-term care home and shelter residents, respectively. By May 20, 2020, 76.3% (21 617/28 316) of long-term care home residents and 2.2% (150 077/6 808 890) of the rest of the population had been tested. After adjusting for age and sex, residents of long-term care homes were 2.4 (95% confidence interval [CI] 2.2-2.7) times more likely to test positive, and those who received a diagnosis of COVID-19 were 1.4-fold (95% CI 1.1-1.8) more likely to die than the rest of the population. INTERPRETATION: Long-term care homes and shelters had disproportionate diagnosed cases per capita, and residents of long-term care homes diagnosed with COVID-19 had higher case fatality than the rest of the population. Heterogeneity across micro-epidemics among specific populations and settings may reflect underlying heterogeneity in transmission risks, necessitating setting-specific COVID-19 prevention and mitigation strategies.

There is a pressing need for an in-depth understanding of immunity to SARS-CoV-2. Here we investigated T cell recall responses to fully glycosylated Spike trimer, recombinant N protein as well as to S, N, M and E peptide pools in the early convalescent phase. All subjects showed SARS-CoV-2-specific T cell responses to at least one antigen. SARS-CoV-2-specific CD4+ T cells were primarily of the central memory phenotype and exhibited a lower IFN-γ to TNF-α ratio compared to influenza-specific responses of the same donors, independent of disease severity. SARS-CoV-2-specific T cells were less multifunctional than influenza-specific T cells, particularly in severe cases, potentially suggesting exhaustion. High IL-10 production was noted in response to N protein, possibly contributing to immunosuppression, with potential implications for vaccine design. We observed granzyme B+/IFN-γg+ CD4+ and CD8+ proliferative responses to peptide pools in most individuals, with CD4+ responses predominating over CD8+ responses. Peripheral T follicular helper responses to S or N strongly correlated with serum neutralization assays as well as RBD-specific IgA. Overall, T cell responses to SARS-CoV-2 are robust, however, CD4+ Th1 responses predominate over CD8+ responses and are more inflammatory with a weaker Tfh response than influenza-specific CD4+ responses, potentially contributing to COVID-19 disease.

Objectives Primary Objective: To determine if pre-exposure prophylaxis (PrEP) with 400mg hydroxychloroquine (HCQ), taken orally once daily reduces microbiologically confirmed COVID-19 among front line health care workers at high risk for SARS-CoV-2 exposure. Secondary Objectives: To compare the following between study arms: adverse events; symptomatic COVID-19; duration of symptomatic COVID-19; days hospitalized attributed to COVID-19; respiratory failure attributable to COVID-19 requiring i) non-invasive ventilation or ii) intubation/mechanical ventilation; mortality attributed to COVID-19, number of days unable to work attributed to COVID-19, seroconversion (COVID-19 negative to COVID-19 positive over the study period); ability of participant plasma to neutralize SARS-CoV-2 virus in vitro; To describe short-term psychological distress associated with risk of COVID-19 exposure at 1, 60, 120 days of the study. To explore laboratory markers within participants with confirmed COVID-19: including circulating markers of host immune and endothelial activation in participant plasma and their correlation with disease severity and outcome Trial design The HEROS study is a two-arm, parallel-group, individually randomized (1:1 allocation ratio), placebo controlled, participant and investigator-blinded, multi-site superiority trial of oral HCQ 400 mg taken once daily for 90 days as PrEP to prevent COVID-19 in health care workers at high risk of SARS-CoV-2 exposure. At 90 days, there is an open label extension wherein all participants are offered a one-month course of HCQ 400mg once daily for PrEP of COVID-19. Participants Frontline HCWs aged 18 years of age or older, at high risk of SARS-CoV-2 exposure (including staff of emergency departments, intensive care units, intubation teams, COVID-wards, and staff deployed to Long Term Care facilities) of five academic hospitals in downtown Toronto, Canada. Exclusion criteria include: currently pregnant, planning to become pregnant during the study period, and/or breast feeding; known hypersensitivity/allergy to hydroxychloroquine or to 4-aminoquinoline compounds; current use of hydroxychloroquine; known prolonged QT syndrome and/or baseline resting ECG with QTc>450 ms and/or concomitant medications which simultaneously may prolong the QTc that cannot be temporarily suspended/replaced; known pre-existing retinopathy, G6PD deficiency, porphyria, liver disease including cirrhosis, encephalopathy, hepatitis or alcoholism, diabetes on oral hypoglycemics or insulin, or renal insufficiency/failure; disclosure of self-administered use of hydroxychloroquine or chloroquine within 12 weeks prior to study; confirmed symptomatic COVID-19 at time of enrollment. Intervention and comparator Intervention: hydroxychloroquine, 400mg (2 tablets) orally per day. Comparator: placebo, two tablets visually identical to the intervention, orally per day Main outcomes The primary outcome is microbiologically confirmed COVID-19 (i.e. SARS-CoV-2 infection). This is a composite endpoint which includes positive results from any validated SARS-CoV-2 diagnostic assay including detection of viral RNA, and/or seroconversion. Participants will be assessed at baseline, and then undergo monthly follow-up at day 30, 60, and 90, 120. At each visit, participants will provide an oropharyngeal sample, blood sample, and will undergo electrocardiogram monitoring of the QTc interval. Secondary outcome measures include: adverse events; symptom duration of COVID-19; days of hospitalization attributed to COVID-19; respiratory failure requiring ventilator support attributed to COVID-19; mortality attributed to COVID-19; total days off work attributed to COVID-19; seropositivity (reactive serology by day 120); and short term psychological impact of exposure to SARS-CoV-2 at day 1, 60, 120 days using the K10, a validated measure of non-specific psychological distress. Randomisation Within each site, participants will be individually randomized to either the intervention arm with HCQ or the placebo arm using a fixed 1:1 allocation ratio using an interactive web-based response system to ensure concealment of allocation. Randomization schedules will be computer-generated and blocked using variable block sizes. Blinding (masking) All participants, research coordinators, technicians, clinicians and investigators will be blinded to the participant allocation group. Numbers to be randomised (sample size) N=988, randomised into two groups of 494 patients. Trial Status This summary describes protocol version No. 1.6, May 15, 2020. Recruitment is ongoing - started April 20, 2020 and anticipated end date is July 30, 2021 Trial registration ISRCTN.com Identifier: ISRCTN14326006, registered April 14, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

BackgroundWe compared the risk of, testing for, and death following COVID-19 infection across three settings (long-term care homes (LTCH), shelters, the rest of the population) in the Greater Toronto Area (GTA), Canada.MethodsWe sourced person-level data from COVID-19 surveillance and reporting systems in Ontario, and examined settings with population-specific denominators (LTCH residents, shelters, and the rest of the population). We calculated cumulatively, the diagnosed cases per capita, proportion tested for COVID-19, daily and cumulative positivity, and case fatality proportion. We estimated the age- and sex-adjusted relative rate ratios for test positivity and case fatality using quasi-Poisson regression.ResultsBetween 01/23/2020-05/25/2020, we observed a shift in the proportion of cases: from travel-related and into LTCH and shelters. Cumulatively, compared to the rest of the population, the number of diagnosed cases per 100,000 was 59-fold and 18-fold higher among LTCH and shelter residents, respectively. By 05/25/2020, 77.2% of LTCH residents compared to 2.4% of the rest of the population had been tested. After adjusting for age and sex, LTCH residents were 2.5 times (95% confidence interval (CI): 2.3-2.8) more likely to test positive. Case fatality was 26.3% (915/3485), 0.7% (3/402), and 3.6% (506/14133) among LTCH residents, shelter population, and others in the GTA, respectively. After adjusting for age and sex, case fatality was 1.4-fold (95%CI: 1.1-1.9) higher among LTCH residents than the rest of the population.InterpretationHeterogeneity across micro-epidemics among specific populations in specific settings may reflect underlying heterogeneity in transmission risks, necessitating setting-specific COVID-19 prevention and mitigation strategies.

KEY POINTS Canada’s early response to coronavirus disease 2019 (COVID-19) largely comprised universal strategies of confinement alongside efforts to isolate people infected with or exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to increase testing. Underscoring early

BACKGROUND: In patients who are discharged home to self-isolate while coronavirus disease 2019 (COVID-19) test results are pending, there is no formal method for physician assessments or counselling to occur if the result returns positive. Our aim was to develop and test the feasibility of a virtual care program for self-isolating outpatients diagnosed with COVID-19. METHODS: In preparation for this gap in health care, the COVID-19 Expansion to Outpatients (COVIDEO) program was developed at the Sunnybrook Health Sciences Centre, Toronto, Ontario, to provide ongoing care for outpatients diagnosed with COVID-19. As part of a feasibility study, we describe our experiences with the first 50 patients managed using this program from its inception (Mar. 1, 2020) until Mar. 27, 2020. RESULTS: All 50 people who tested positive for COVID-19 at the Sunnybrook Health Sciences Centre and were discharged home to self-isolation during the study period were assessed through the COVIDEO program. Thirty-two patients (64%) were assessed via the Ontario Telemedicine Network virtual care platform, and the remainder by telephone. The median time from viral swab collection to first COVIDEO program assessment was 2 (interquartile range [IQR] 1–2) days. Among the 26 patients for whom further follow-up care through the COVIDEO program was discontinued by the end of March 2020, the median duration of virtual care was 12.5 (IQR 8.75–16) days. During the study period, 6 patients required transfer to hospital for assessment, of whom 4 required admission. INTERPRETATION: We have shown that a virtual care program can be used in the management of outpatients diagnosed with COVID-19. Further studies evaluating its sustainability and impact on health outcomes are underway.

BackgroundA hospital-level pandemic response involves anticipating local surge in healthcare needs.MethodsWe developed a mechanistic transmission model to simulate a range of scenarios of COVID-19 spread in the Greater Toronto Area. We estimated healthcare needs against 2019 daily admissions using healthcare administrative data, and applied outputs to hospital-specific data on catchment, capacity, and baseline non-COVID admissions to estimate potential surge by day 90 at two hospitals (St. Michael’s Hospital [SMH] and St. Joseph’s Health Centre [SJHC]). We examined fast/large, default, and slow/small epidemics, wherein the default scenario (R0 2.4) resembled the early trajectory in the GTA.ResultsWithout further interventions, even a slow/small epidemic exceeded the city’s daily ICU capacity for patients without COVID-19. In a pessimistic default scenario, for SMH and SJHC to remain below their non-ICU bed capacity, they would need to reduce non-COVID inpatient care by 70% and 58% respectively. SMH would need to create 86 new ICU beds, while SJHC would need to reduce its ICU beds for non-COVID care by 72%. Uncertainty in local epidemiological features was more influential than uncertainty in clinical severity. If physical distancing reduces contacts by 20%, maximizing the diagnostic capacity or syndromic diagnoses at the community-level could avoid a surge at each hospital.InterpretationAs distribution of the city’s surge varies across hospitals over time, efforts are needed to plan and redistribute ICU care to where demand is expected. Hospital-level surge is based on community-level transmission, with community-level strategies key to mitigating each hospital’s surge.

Background Ebola virus disease (EVD) survivors are at risk for uveitis during convalescence. Vision loss has been observed following uveitis due to cataracts. Since Ebola virus (EBOV) may persist in the ocular fluid of EVD survivors for an unknown duration, there are questions about the safety and feasibility of vision restorative cataract surgery in EVD survivors. Methods We conducted a cross-sectional study of EVD survivors anticipating cataract surgery and patients with active uveitis to evaluate EBOV RNA persistence in ocular fluid, as well as vision outcomes post cataract surgery. Patients with aqueous humor that tested negative for EBOV RNA were eligible to proceed with manual small incision cataract surgery (MSICS). Findings We screened 137 EVD survivors from June 2016 – August 2017 for enrolment. We enrolled 50 EVD survivors; 46 with visually significant cataract, 1 with a subluxated lens, 2 with active uveitis and 1 with a blind painful eye due to uveitis. The median age was 24.0 years (IQR 17–35) and 35 patients (70%) were female. The median logMAR visual acuity (VA) was 3.0 (Snellen VA Hand motions; Interquartile Range, IQR: 1.2-3.0, Snellen VA 20/320 – Hand motions). All patients tested negative for EBOV RNA by RT-PCR in aqueous humor/vitreous fluid and conjunctiva at a median of 19 months (IQR 18-20) from EVD diagnosis in Phase 1 of ocular fluid sampling and 34 months (IQR 32-36) from EVD diagnosis in Phase 2 of ocular fluid sampling. Thirty-four patients underwent MSICS, with a preoperative median VA improvement from hand motions to 20/30 at three-month postoperative follow-up (P, Highlights • Ebola virus disease (EVD) survivors are at-risk for severe vision impairment due to uveitis and subsequent cataract development. • Fifty EVD survivors underwent ocular fluid sampling and tested negative for Ebola virus by RT-PCR. • Thirty-four survivors underwent cataract surgery with excellent safety measures and vision restorative outcomes. Ebola virus disease (EVD) survivors are at high risk for uveitis, an inflammatory condition affecting the eye that may lead to severe vision impairment, often from cataract. Because persistent Ebola virus (EBOV) has been identified within the immune privileged eye, understanding the prevalence of intraocular EBOV persistence is significant for patients, providers, and public health policy. In this study, 50 EVD survivors tested negative for EBOV by RT-PCR of their intraocular fluid. Thirty-four underwent cataract surgery with vision restorative outcomes. These findings improve our ability to impact vision care and quality-of-life for thousands of EVD survivors at-risk for eye disease.

This case reports cryptococcal meningitis in an HIV positive woman on antiretroviral therapy, presenting with left middle cerebral artery stroke at 30 weeks gestation. The patient had well-controlled HIV (CD4 count over 200 cells/mL). The immunosuppressive effects of the pregnancy likely contributed to the development of cryptococcal disease. The patient was successfully treated with two weeks of amphotericin B followed by fluconazole, delivered a healthy baby, but remained with a permanent severe neurological deficit.

Objective To determine if inhaled and intranasal ciclesonide are superior to placebo at decreasing respiratory symptoms in adult outpatients with covid-19. Design Randomised, double blind, placebo controlled trial. Setting Three Canadian provinces (Quebec, Ontario, and British Columbia). Participants 203 adults aged 18 years and older with polymerase chain reaction confirmed covid-19, presenting with fever, cough, or dyspnoea. Intervention Participants were randomised to receive either inhaled ciclesonide (600 μg twice daily) and intranasal ciclesonide (200 μg daily) or metered dose inhaler and nasal saline placebos for 14 days. Main outcome measures The primary outcome was symptom resolution at day 7. Analyses were conducted on the modified intention-to-treat population (participants who took at least one dose of study drug and completed one follow-up survey) and adjusted for stratified randomisation by sex. Results The modified intention-to-treat population included 203 participants: 105 were randomly assigned to ciclesonide (excluding two dropouts and one loss to follow-up) and 98 to placebo (excluding three dropouts and six losses to follow-up). The median age was 35 years (interquartile range 27-47 years) and 54% were women. The proportion of participants with resolution of symptoms by day 7 did not differ significantly between the intervention group (42/105, 40%) and control group (34/98, 35%); absolute adjusted risk difference 5.5% (95% confidence interval −7.8% to 18.8%). Results might be limited to the population studied, which mainly included younger adults without comorbidities. The trial was stopped early, therefore could have been underpowered. Conclusion Compared with placebo, the combination of inhaled and intranasal ciclesonide did not show a statistically significant increase in resolution of symptoms among healthier young adults with covid-19 presenting with prominent respiratory symptoms. As evidence is insufficient to determine the benefit of inhaled and intranasal corticosteroids in the treatment of covid-19, further research is needed. Trial registration ClinicalTrials.gov NCT04435795 .

Setting: All community health workers (CHWs) in rural Kenema District, Sierra Leone. Objective: CHW programmes provide basic health services to fill gaps in human health resources. We compared trends in the reporting and management of childhood malaria, diarrhoea and pneumonia by CHWs before, during and after the Ebola outbreak (2014-2016). Design: Retrospective cross-sectional study using programme data. Results: CHW reporting increased from 59% pre-outbreak to 95% during the outbreak (P < 0.001), and was sustained at 98% post-outbreak. CHWs stopped using rapid diagnostic tests for malaria mid-outbreak, and their use had not resumed post-outbreak. The average monthly number of presumptive treatments for malaria increased from 2931 pre-outbreak to 5013 during and 5331 post-outbreak (P < 0.001). The average number of monthly treatments for diarrhoea and pneumonia decreased from respectively 1063 and 511 pre-outbreak to 547 and 352 during the outbreak (P = 0.01 and P = 0.04). Post-outbreak pneumonia treatments increased (mean 1126 compared to pre-outbreak, P = 0.003), and treatments for diarrhoea returned to pre-outbreak levels (P = 0.2). Conclusion: The CHW programme demonstrated vulnerability, but also resilience, during and in the early period after the Ebola outbreak. Investment in CHWs is required to strengthen the health care system, as they can cover pre-existing gaps in facility-based health care and those created by outbreaks.

Setting: All health facility and community malnutrition screening programmes in Tonkolili, a rural Ebola-affected district in Sierra Leone. Objectives: Before the Ebola disease outbreak, Sierra Leone had set a goal to reduce the prevalence of severe acute malnutrition (SAM) in children aged

Setting: All 100 health facilities providing maternal services in Moyamba, Sierra Leone, a rural district that experienced a smaller Ebola outbreak than other areas. Objective: To compare trends in antenatal care (the first and fourth visit [ANC1 and ANC4]), delivery, and postnatal care (PNC1) service utilisation before, during and after the Ebola outbreak (2014–2016). Design: Cross-sectional study using secondary programme data. Results: A total of 211 Ebola cases occurred in Moyamba District. The mean number of monthly ANC visits remained stable over time, except for the subset of care provided via outreach visits where, compared with before the outbreak (n = 390), ANC1 visits declined during (n = 331, P = 0.002) and after the outbreak (n = 342, P = 0.03). Most (>97%) deliveries occurred in health facilities, assisted by maternal and child health aides (>80%). During the outbreak, the mean number of community-based deliveries per month declined from 31 to 21 (P = 0.03), and the mean number of deliveries performed by midwives increased from 49 to 78 (P < 0.001) compared with before the outbreak. Before, during and after Ebola, there was no significant change in the mean number of live births (respectively n = 1134, n = 1110, n = 1162), maternal PNC1 (respectively n = 1110, n = 1105, n = 1165) or neonatal PNC1 (respectively n = 1028, n = 1050, n = 1085). Conclusion: In a rural district less affected by Ebola transmission than other areas, utilisation of maternal primary care remained robust, despite the outbreak.

Background HIV treatment models in Africa are labour intensive and require a high number of skilled staff. In this context, task-shifting is considered a feasible alternative for ART service delivery. In 2006, a lay health cadre of expert patients (EPs) at a tertiary referral HIV clinic in Zomba, Malawi was capacitated. There are few evaluations of EP program efficacy in this setting. Triage is the process of prioritizing patients in terms of the severity of their condition and ensures that no harmful delays occur to treatment and care. This study evaluates the safety of task-shifting triage, in an ambulatory low resource setting, to EPs. Methods As a quality improvement exercise in April 2010, formal triage training was conducted by adapting the World Health Organization Emergency Triage Assessment and Treatment Triage Module Guidelines. A cross sectional observation study was conducted 2 years after the intervention. Triage assessments performed by EPs were repeated by a clinical officer (gold standard) to assess sensitivities, specificities, positive and negative predictive values for EP triage scores. Proportions were calculated for categories of disposition by stratifying by EP and clinician triage scores. Results A total of 467 patients were triaged by 7 EPs and re-triaged by clinical officers. With combined triage scores for emergency and priority patients we report a sensitivity of 85% and specificity of 74% for the EP scoring, with a low positive predictive value (41%) and a high negative predictive value (96%). We calculate a serious miss rate of EP scoring (i.e. missed priority or emergency patients) as 2.2%. Admission rates to hospital were highest among those patients triaged as emergency cases either by the EP’s (21%) or the clinicians (83%). Fewer patients triaged as priority by either EPs (5%) or clinicians (15%) were admitted to hospital, however these patients had the highest prevalence of same day lab testing and/or specialty referral. Conclusions Our study provides reassurance that in the context of adequate training and ongoing supervision, task-shifting triage to lay health care workers does not necessarily lead to less accurate triaging. EPs have a tendency to be more conservative in over-triaging patients. Electronic supplementary material The online version of this article (doi:10.1186/s12913-017-2291-3) contains supplementary material, which is available to authorized users.

In Malawi, 236 participants from the Advancing Cryptococcal Meningitis Treatment for Africa trial were followed for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericin B plus flucytosine was associated with the lowest 1 year mortality (27.5% [95% confidence interval, 16.3 to 44.1]).

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.

Background: There are currently no effective treatments for outpatients with coronavirus disease. 2019 (COVID-19). Interferon-lambda-1 is a Type III interferon involved in the innate antiviral response with activity against respiratory pathogens. Methods: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomized to a single subcutaneous injection of peginterferon-lambda 180μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. The primary endpoint was proportion negative for SARS-CoV-2 RNA on Day 7 post-injection. Results: There were 30 patients per arm, with median baseline SARS-CoV-2 viral load of 6.71 (IQR 1.3-8.0) log copies/mL. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon-lambda than placebo (p=0.04). On Day 7, 24 participants (80%) in the peginterferon-lambda group had an undetectable viral load compared to 19 (63%) in the placebo arm (p=0.15). After controlling for baseline viral load, peginterferon-lambda treatment resulted in a 4.12-fold (95CI 1.15-16.7, p=0.029) higher likelihood of viral clearance by Day 7. Of those with baseline viral load above 10E6 copies/mL, 15/19 (79%) in the peginterferon-lambda group were undetectable on Day 7 compared to 6/16 (38%) in the placebo group (p=0.012). Adverse events were similar between groups with only mild reversible transaminase elevations more frequently observed in the peginterferon-lambda group. Conclusion: Peginterferon-lambda accelerated viral decline in outpatients with COVID-19 resulting in a greater proportion with viral clearance by Day 7, particularly in those with high baseline viral load. Peginterferon-lambda may have potential to prevent clinical deterioration and shorten duration of viral shedding. Trial Registration: NCT04354259 Funding Statement: This study was supported by the Toronto COVID-19 Action Initiative, University of Toronto and the Ontario First COVID-19 Rapid Research Fund. Medication was supplied by Eiger BioPharma. Declaration of Interests: JJF reports research support unrelated to this work from Eiger BioPharmaceuticals. BC has received research support unrelated to this work from Nubiyota LLC and Sanofi. IC and CH are employees of Eiger BioPharmaceuticals. JSG is a board member and founder of Eiger BioPharmaceuticals, Inc., in which he has an equity interest, and is an inventor on a patent application for the use of interferon lambda to treat coronavirus infections. All other authors have nothing to declare. Ethics Approval Statement: The Research Ethics Boards of all participating institutions approved the study, which was conducted under a Clinical Trial Application approved by Health Canada.

Background Management of Ebola virus disease (EVD) has historically focused on infection prevention, case detection and supportive care. Several specific anti-Ebola therapies have been investigated, including during the 2014–2016 West African outbreak. Our objective was to conduct a systematic review of the effect of anti-Ebola virus therapies on clinical outcomes to guide their potential use and future evaluation. Methods We searched PubMed, EMBASE, Global Health, Cochrane Library, African Index Medicus, WHOLIS (inception-9 April 2018), and trial registries for observational studies or clinical trials, in any language, that enrolled patients with confirmed EVD who received therapy targeting Ebola virus and reported on mortality, symptom duration, or adverse effects. Results From 11,257 citations and registered trials, we reviewed 55 full-text citations, of which 35 met eligibility criteria (1 randomized clinical trial (RCT), 8 non-randomized comparative studies, 9 case series and 17 case reports) and collectively examined 21 anti-Ebola virus agents. The 31 studies performed during the West African outbreak reported on 4.8% (1377/28616) of all patients with Ebola. The only RCT enrolled 72 patients (0.25% of all patients with Ebola) and compared the monoclonal antibody ZMapp vs. standard care (mortality, 22% vs. 37%; 95% confidence interval for risk difference, − 36 to 7%). Studies of convalescent plasma, interferon-β-1a, favipiravir, brincidofovir, artesunate-amodiaquine and TKM-130803 were associated with at least moderate risk of bias. Conclusions Research evaluating anti-Ebola virus agents has reached very few patients with EVD, and inferences are limited by non-randomized study designs. ZMapp has the most promising treatment signal. Electronic supplementary material The online version of this article (10.1186/s12879-019-3980-9) contains supplementary material, which is available to authorized users.

BackgroundEconomic evaluation studies often neglect the impact of disease and ill health on the social network of people living with HIV (PLHIV) and the wider community. An important concern relates to informal care requirements which, for some diseases such as HIV/AIDS, can be substantial.ObjectivesTo measure and value informal care provided to PLHIV in Malawi.MethodsA modified diary that divided a day into natural calendar changes was used to measure informal care time. The monetary valuation was undertaken by using four approaches: opportunity cost (official minimum wage used to value caregiving time), modified opportunity cost (caregiver’s reservation wage), willingness to pay (amount of money caregiver would pay for care), and willingness to accept (amount of money caregiver would accept for providing care to someone else) approaches. Data were collected from 130 caregivers of PLHIV who were accessing antiretroviral therapy from six facilities in Phalombe district in southeast Malawi.ResultsOf the 130 caregivers, 62 (48%) provided informal care in the survey week. On average, caregivers provided care of 8 h/wk. The estimated monetary values of informal care provided per week were US $1.40 (opportunity cost), US $2.41 (modified opportunity cost), US $0.40 (willingness to pay), and US $2.07 (willingness to accept).ConclusionsExclusion of informal care commitments may be a notable limitation of many applied economic evaluations. This work demonstrates that inclusion of informal care in economic evaluations in a low-income context is feasible.

Introduction Since June 2016, the national HIV programme in Malawi has adopted Universal Test and Treat (UTT) guidelines requiring that all persons who test HIV positive will be referred to start antiretroviral therapy (ART). Although there is strong evidence from clinical trials that early initiation of ART leads to reduced morbidity and mortality, the impact of UTT on retention on ART in real‐life programmatic settings in Africa is not yet known. Methods We conducted a retrospective cohort study in Zomba district, Malawi to compare ART outcomes of patients who initiated ART under 2016 UTT guidelines and those who started ART prior to rollout of UTT (pre‐UTT). We analysed data from 32 rural and urban health facilities of various sizes. Cox proportional hazards modelling was used to determine the independent risk factors of attrition from ART at 12 months. All analyses were adjusted for clustering by health facility using a robust standard errors approach. Results Among 1492 patients (mean age 34.4 years, 933 (63%) female) who initiated ART during the study period, 501 were enrolled in the pre‐UTT cohort and 911 during UTT. At 12 months, retention on ART in the UTT cohort was higher than in the pre‐UTT cohort 83.0% (95% confidence interval (CI): 81.0% to 85.0%) versus 76.2% (95% CI 73.9% to 78.5%). Adolescents, aged 10 to 19 years (adjusted hazard ratio (aHR) 1.53; 95% CI 1.01 to 2.32), and women who were pregnant or breastfeeding at ART initiation (aHR 1.87; 95% CI 1.30 to 2.38) were at higher risk of attrition in the combined pre‐UTT and UTT cohort. Conclusions Retention on ART was nearly 6% higher after UTT introduction. Young adults and women who were pregnant or breastfeeding at the start of ART were at increased risk of attrition, emphasizing the need for targeted interventions for these groups to achieve the 90‐90‐90 UNAIDS targets in the UTT era.

BackgroundCardiovascular disease (CVD) risk among people living with HIV is elevated due to persistent inflammation, hypertension and diabetes comorbidity, lifestyle factors and exposure to antiretroviral therapy (ART). Data from Africa on how CVD risk affects morbidity and mortality among ART patients are lacking. We explored the effect of CVD risk factors and the Framingham Risk Score (FRS) on medium-term ART outcomes.MethodsA prospective cohort study of standardized ART outcomes (Dead, Alive on ART, stopped ART, Defaulted and Transferred out) was conducted from July 2014-December 2016 among patients on ART at a rural and an urban HIV clinic in Zomba district, Malawi. The primary outcome was Dead. Active defaulter tracing was not done and patients who transferred out and defaulted were excluded from the analysis. At enrolment, hypertension, diabetes and dyslipidemia were diagnosed, lifestyle data collected and the FRS was determined. Cox-regression analysis was used to determine independent risk factors for the outcome Dead.ResultsOf 933 patients enrolled, median age was 42 years (IQR: 35-50), 72% were female, 24% had hypertension, 4% had diabetes and 15.8% had elevated total cholesterol. The median follow up time was 2.4 years. Twenty (2.1%) patients died, 50 (5.4%) defaulted, 63 (6.8%) transferred out and 800 (85.7%) were alive on ART care (81.7% urban vs. 89.9% rural). In multivariable survival analysis, male gender (aHR = 3.28; 95%CI: 1.33-8.07, p = 0.01) and total/HDL cholesterol ratio (aHR = 5.77, 95%CI: 1.21-27.32; p = 0.03) were significantly associated with mortality. There was no significant association between mortality and hypertension, body mass index, central obesity, diabetes, FRS, physical inactivity, smoking at enrolment, ART regimen and WHO disease stage.ConclusionsMedium-term all-cause mortality among ART patients was associated with male gender and elevated total/HDL cholesterol ratio.

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.

C. neoformansvar.grubii(C. neoformans) is an environmentally acquired pathogen causing 181 000 HIV-associated deaths each year. We used whole genome sequencing (WGS) to characterise 699 isolates, primarilyC. neoformansfrom HIV-infected patients, from 5 countries in Asia and Africa. We found that 91% of our clinical isolates belonged to one of three highly clonal sub-clades of VNIa, which we have termed VNIa-4, VNIa-5 and VNIa-93. Parsimony analysis revealed frequent, long distance transmissions ofC. neoformans; international transmissions took place on 13% of VNIa-4 branches, and intercontinental transmissions on 7% of VNIa-93 branches. The median length of within sub-clade internal branches was 3-6 SNPs, while terminal branches were 44.5-77.5 SNPs. The short median internal branches were partly driven by the large number (12-15% of internal branches) of polytomies in the within-sub-clade trees. To simultaneously explain our observation of no apparent molecular clock, short internal branches and frequent polytomies we hypothesise thatC. neoformansVNIa spends much of its time in the environment in a quiescent state, while, when it is sampled, it has almost always undergone an extended period of growth. Infections with VNIa-93 were associated with a significantly reduced risk of death by 10 weeks compared with infections with VNIa-4 (Hazard Ratio = 0.45, p = 0.003). We detected a recombination in the mitochondrial sequence of VNIa-5, suggesting that mitochondria could be involved in the propensity of this sub-clade to infect HIV-uninfected patients. These data highlight the insight into the biology and epidemiology of pathogenic fungi which can be gained from WGS data.

Background: The Lablite project captured information on access to antiretroviral therapy (ART) at larger health facilities ('hubs') and lower-level health facilities ('spokes') in Phalombe district, Malawi and in Kalungu district, Uganda. Methods: We conducted a cross-sectional survey among patients who had transferred to a spoke after treatment initiation (Malawi, n=54; Uganda, n=33), patients who initiated treatment at a spoke (Malawi, n=50; Uganda, n= 44) and patients receiving treatment at a hub (Malawi, n= 44; Uganda, n= 46). Results: In Malawi, 47% of patients mapped to the two lowest wealth quintiles (Q1-Q2); patients at spokes were poorer than at a hub (57% vs 23% in Q1-Q2; p

To determine whether C-reactive protein (CRP) is an inflammatory biomarker that may identify patients at risk of infections or death. Mortality among HIV-infected persons commencing antiretroviral therapy (ART) is often attributed to tuberculosis (TB) or bloodstream infections (BSI). In two district hospitals in southern Malawi we recruited HIV-infected adults with one or more unexplained symptoms present for at least one month (weight loss, fever, or diarrhea), and negative expectorated sputum microscopy for TB. CRP determination for 452/469 (96%) participants at study enrolment was analyzed for associations with TB, BSI or death to 120 days post-enrolment. Baseline CRP was significantly elevated among patients with confirmed and probable TB (52), BSI (50) or death (60) compared to those with no identified infection who survived at least 120 days (269). A CRP value of >10 mg/L was associated with confirmed and probable TB (adjusted odds ratio 5.7; 95% CI 2.6, 14.3; 87% sensitivity) or death by 30 days (adjusted odds ratio 9.2; 95% CI 2.2, 55.1; 88% sensitivity). CRP was independently associated with TB, BSI or Death but prediction of these endpoints was enhanced by including hemoglobin (all outcomes), CD4 count (BSI, death), and whether ART was started (death) in logistic regression models. High CRP at the time of ART initiation is associated with TB, BSI and early mortality, and so has potential utility for stratifying patients for intensified clinical and laboratory investigation and follow-up. They may also be considered for empirical treatment of opportunistic infections including TB. This article is protected by copyright. All rights reserved.

Background: We conducted unlinked cross-sectional population-based surveys in Northern Uganda before and after antiretroviral therapy (ART) provision (including Option B+ [lifelong ART for pregnant/breast-feeding women]) at a local primary care facility (Lira Kato Health Centre [HC]). Prior to decentralisation, people travelled 56-76 km round-trip for ART; we aimed to evaluate changes in uptake of HIV-testing, ART coverage and access to ART following decentralisation. Methods: A total of 2124 adults in 1351 households in two parishes closest to Lira Kato HC were interviewed using questionnaires between March and April 2013 and 2123 adults in 1229 households between January and March 2015. Results: Adults reporting HIV-testing in the last year increased from 1077/2124 (50.7%) to 1298/2123 (61.1%) between surveys (p

Background Lablite is an implementation project supporting and studying decentralized antiretroviral therapy (ART) rollout to rural communities in Malawi, Uganda and Zimbabwe. Task shifting is one of the strategies to deal with shortage of health care workers (HCWs) in ART provision. Evaluating Human Resources for Health (HRH) optimization is essential for ensuring access to ART. The Lablite project started with a baseline survey whose aim was to describe and compare national and intercountry delivery of ART services including training, use of laboratories and clinical care. Methods A cross-sectional survey was conducted between October 2011 and August 2012 in a sample of 81 health facilities representing different regions, facility levels and experience of ART provision in Malawi, Uganda and Zimbabwe. Using a questionnaire, data were collected on facility characteristics, human resources and service provision. Thirty three (33) focus group discussions were conducted with HCWs in a subset of facilities in Malawi and Zimbabwe. Results The survey results showed that in Malawi and Uganda, primary care facilities were run by non-physician clinical officers/medical assistants while in Zimbabwe, they were run by nurses/midwives. Across the three countries, turnover of staff was high especially among nurses. Between 10 and 20% of the facilities had at least one clinical officer/medical assistant leave in the 3 months prior to the study. Qualitative results show that HCWs in ART and non-ART facilities perceived a shortage of staff for all services, even prior to the introduction of ART provision. HCWs perceived the introduction of ART as having increased workload. In Malawi, the number of people on ART and hence the workload for HCWs has further increased following the introduction of Option B+ (ART initiation and life-long treatment for HIV positive pregnant and lactating women), resulting in extended working times and concerns that the quality of services have been affected. For some HCWs, perceived low salaries, extended working schedules, lack of training opportunities and inadequate infrastructure for service provision were linked to low job satisfaction and motivation. Conclusions ART has been decentralized to lower level facilities in the context of an ongoing HRH crisis and staff shortage, which may compromise the provision of high-quality ART services. Task shifting interventions need adequate resources, relevant training opportunities, and innovative strategies to optimize the operationalization of new WHO treatment guidelines which continue to expand the number of people eligible for ART.

Background: Lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women (Option B+) was rolled out in Zimbabwe from 2014, with simultaneous raising of the CD4 treatment threshold to 500 cells per cubic millimeter in nonpregnant/breastfeeding adults and children 5 years and over. Methods: Lablite is an implementation project in Zimbabwe, Malawi, and Uganda evaluating ART rollout. Routine patient-level data were collected for 6 months before and 12 months after Option B+ rollout at a district hospital and 3 primary care facilities in Zimbabwe (2 with outreach ART and 1 with no ART provision before Option B+). Results: Between September 2013 and February 2015, there were 1686 ART initiations in the 4 facilities: 91% adults and 9% children younger than 15 years. In the 3 facilities with established ART, initiations rose from 300 during 6 months before Option B+ to 869 (2.9-fold) and 463 (1.5-fold), respectively, 0–6 months and 6–12 months after Option B+. Post-Option B+, an estimated 43% of pregnant/breastfeeding women needed ART for their own health, based on World Health Organization stage 3/4 or CD4 ≤350 per cubic millimeter (64% for CD4 ≤500). Seventy-four men (22%) and 123 nonpregnant/breastfeeding women (34%) initiated ART with CD4 >350 after the CD4 threshold increase. Estimated 12-month retention on ART was 79% (69%–87%) in Option B+ women (significantly lower in younger women, P = 0.01) versus 93% (91%–95%) in other adults (difference P < 0.001). Conclusions: There were increased ART initiations in all patient groups after implementation of World Health Organization 2013 guidelines. Retention of Option B+ women was poorer than retention of other adults; younger women require attention because they are more likely to disengage from care.

Background Despite availability of effective treatment, tuberculosis (TB) remains an important cause of morbidity and mortality globally, with low- and middle-income countries most affected. In many such settings, including Malawi, the high burden of disease and severe shortage of skilled healthcare workers has led to task-shifting of outpatient TB care to lay health workers (LHWs). LHWs improve access to healthcare and some outcomes, including TB completion rates, but lack of training and supervision limit their impact. The goals of this study are to improve TB care provided by LHWs in Malawi by refining, implementing, and evaluating a knowledge translation strategy designed to address a recognized gap in LHWs’ TB and job-specific knowledge and, through this, to improve patient outcomes. Methods/design We are employing a mixed-methods design that includes a pragmatic cluster randomized controlled trial and a process evaluation using qualitative methods. Trial participants will include all health centers providing TB care in four districts in the South East Zone of Malawi. The intervention employs educational outreach, a point-of-care reminder tool, and a peer support network. The primary outcome is proportion of treatment successes, defined as the total of TB patients cured or completing treatment, with outcomes taken from Ministry of Health treatment records. With an alpha of 0.05, power of 0.80, a baseline treatment success of 0.80, intraclass correlation coefficient of 0.1 based on our pilot study, and an estimated 100 clusters (health centers providing TB care), a minimum of 6 patients per cluster is required to detect a clinically significant 0.10 increase in the proportion of treatment successes. Our process evaluation will include interviews with LHWs and patients, and a document analysis of LHW training logs, quarterly peer trainer meetings, and mentorship meeting notes. An estimated 10–15 LHWs and 10–15 patients will be required to reach saturation in each of 2 planned interview periods, for a total of 40–60 interview participants. Discussion This study will directly inform the efforts of knowledge users within TB care and, through extension of the approach, other areas of care provided by LHWs in Malawi and other low- and middle-income countries. Trial registration ClinicalTrials.gov NCT02533089. Registered 20 August 2015. Protocol Date/Version 29 May 2016/Version 2. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1563-2) contains supplementary material, which is available to authorized users.

Background Malawi adopted the PMTCT strategy ‘Option B+’ in 2011, providing life-long ART for all HIV-infected pregnant and breastfeeding women. We explored differences in characteristics and outcomes of women initiating ART during pregnancy versus breastfeeding. Methods We conducted a retrospective cohort analysis of women in Zomba District, southern Malawi, from January 2012- September 2013. Data were extracted from the Zomba District Observational Cohort Study, a surveillance project collecting data from standardized Ministry of Health ART monitoring tools. Results 1986 (67.2 %) women initiated ART during pregnancy and 969 (32.8 %) during breastfeeding. Women initiating ART in breastfeeding were more likely to be > 30 years (aOR = 1.33, 95 % CI1.11–1.59, p = 0.003) and have WHO Stage 3/4 (aOR = 2.74, 95 % CI1.94–3.87, p

As of 20 May 2016 there have been 28,646 cases and 11,323 deaths resulting from the West African Ebola virus disease (EVD) outbreak reported to the World Health Organization. There continue to be sporadic flare-ups of EVD cases in West Africa. EVD presentation is nonspecific and characterized initially by onset of fatigue, myalgias, arthralgias, headache, and fever; this is followed several days later by anorexia, nausea, vomiting, diarrhea, and abdominal pain. Anorexia and gastrointestinal losses lead to dehydration, electrolyte abnormalities, and metabolic acidosis, and, in some patients, acute kidney injury. Hypoxia and ventilation failure occurs most often with severe illness and may be exacerbated by substantial fluid requirements for intravascular volume repletion and some degree of systemic capillary leak. Although minor bleeding manifestations are common, hypovolemic and septic shock complicated by multisystem organ dysfunction appear the most frequent causes of death. Males and females have been equally affected, with children (0–14 years of age) accounting for 19 %, young adults (15–44 years) 58 %, and older adults (≥45 years) 23 % of reported cases. While the current case fatality proportion in West Africa is approximately 40 %, it has varied substantially over time (highest near the outbreak onset) according to available resources (40–90 % mortality in West Africa compared to under 20 % in Western Europe and the USA), by age (near universal among neonates and high among older adults), and by Ebola viral load at admission. While there is no Ebola virus-specific therapy proven to be effective in clinical trials, mortality has been dramatically lower among EVD patients managed with supportive intensive care in highly resourced settings, allowing for the avoidance of hypovolemia, correction of electrolyte and metabolic abnormalities, and the provision of oxygen, ventilation, vasopressors, and dialysis when indicated. This experience emphasizes that, in addition to evaluating specific medical treatments, improving the global capacity to provide supportive critical care to patients with EVD may be the greatest opportunity to improve patient outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s13054-016-1325-2) contains supplementary material, which is available to authorized users.

Uptake of antiretroviral therapy (ART) in patients co-infected with tuberculosis (TB) and the human immunodeficiency virus (HIV) has historically been low in Malawi. In response, the National TB Programme piloted the initiation of ART 2 weeks after initiation of TB treatment in 2008-2009, a change from the prior policy of 2 months.To determine at programme level if earlier initiation of ART in co-infected patients receiving TB treatment will increase the uptake and continuation of ART.A prospective observational pilot programme evaluation using routinely collected monitoring data from the first two sites with integrated TB-HIV services in Malawi.There was wide variability in the ART start time before and after the policy change. Before the policy change, 16% of patients initiated ART by 3 months compared to 24% after the policy change (P0.001). The proportion of all co-infected patients on ART increased from 32% before the policy change to 39% after (P0.001). Earlier initiation of ART did not increase the occurrence of side effects and did not reduce adherence to TB treatment.Earlier initiation of ART in co-infected patients receiving TB treatment improved the uptake and continuation of ART. Malawi ART guidelines in 2011 were changed from initiating ART after 2 months to as soon as possible after starting anti-tuberculosis treatment.Dans le passé, au Malawi, la mise en route du traitement antirétroviral (ART) chez les patients co-infectés par la tuberculose (TB) et le virus de l’immunodéficience humaine (VIH) a été peu courante. Comme réponse, le Programme National de la Tuberculose a réalisé en 2008–2009 une modification-pilote du moment de mise en route de l’ART passant à 3 semaines après le début du traitement TB contre la politique antérieure de 2 mois.Déterminer au niveau du programme si un début plus précoce de l’ART chez les patients co-infectés bénéficiant d’un traitement antituberculeux augmentera la mise en route et la poursuite de l’ART.Evaluation prospective observationnelle d’un programme pilote au moyen de données de suivi colligées en routine dans les deux premiers sites où les services TB-VIH avaient été intégrés au Malawi.On a noté d’importantes variabilités dans la période du début de l’ART à la fois avant et après la modification de politique. Avant la modification, 16% des patients commençaient l’ART dans les 3 mois, et 24% après celle-ci (Une initiation plus précoce de l’ART chez les patients co-infectés sous traitement antituberculeux a amélioré la mise en route et la poursuite de l’ART. Les directives ART ont changé en 2011 au Malawi, en passant d’un début de l’ART 2 mois après le commencement du traitement antituberculeux vers un début aussi précoce que possible.La aceptación del tratamiento antirretrovírico (ART) por parte de los pacientes que presentan coinfección por el virus de la inmunodeficiencia humana (VIH) y tuberculosis (TB) siempre ha sido baja en Malawi. Como respuesta a esta situación, del 2008 al 2009 en el Programa Nacional contra la Tuberculosis se ensayó una sincronización del comienzo del ART 2 semanas después de la iniciación del tratamiento antituberculoso, con lo cual se modificaba la anterior norma de 2 meses.Determinar si un comienzo más temprano del ART en los pacientes coinfectados que reciben tratamiento contra la TB mejoraría la aceptación y la continuidad del ART.Se trató de un programa experimental prospectivo de observación, en el cual se utilizaron los datos de supervisión recogidos de manera ordinaria en los dos primeros centros que integraron los servicios de atención de la TB y del VIH en Malawi.Hubo gran variabilidad en el momento del comienzo del ART antes y después de la modificación de las normas. Antes del cambio de políticas, 16% de los pacientes habían comenzado el ART a los 3 meses de tratamiento antituberculoso y después del cambio esta cifra aumentó a 24% (Comenzar de manera más temprana la administración de ART en los pacientes coinfectados que reciben tratamiento contra la TB mejoró la aceptación y la continuidad del ART. En el 2011, se modificaron las normas sobre el ART en Malawi y en lugar de comenzarlo 2 meses después, se comienza ahora tan pronto como sea posible después de iniciar el tratamiento antituberculoso.

During the Ebola outbreak, mortality reduction was attributed to multiple improvements in supportive care delivered in Ebola treatment units (ETUs). We aimed to identify high-priority supportive care measures, as well as perceived barriers and facilitators to their implementation, for patients with Ebola Virus Disease (EVD). We conducted a cross-sectional survey of key stakeholders involved in the response to the 2014&ndash, 2016 West African EVD outbreak. Out of 57 email invitations, 44 responses were received, and 29 respondents completed the survey. The respondents listed insufficient numbers of health workers (23/29, 79%), improper tools for the documentation of clinical data (n = 22/28, 79%), insufficient material resources (n = 22/29, 76%), and unadapted personal protective equipment (n = 20/28, 71%) as the main barriers to the provision of supportive care in ETUs. Facilitators to the provision of supportive care included team camaraderie (n in agreement = 25/28, 89%), ability to speak the local language (22/28, 79%), and having treatment protocols in place (22/28, 79%). This survey highlights a consensus across various stakeholders involved in the response to the 2014&ndash, 2016 EVD outbreak on a limited number of high-priority supportive care interventions for clinical practice guidelines. Identified barriers and facilitators further inform the application of guidelines.

A 41-year-old healthy woman from China presented to her local hospital with a 4-day history of fevers, malaise and epigastric pain. On examination, she had localised right upper quadrant abdominal pain on palpation. Laboratory investigations showed leukocytosis (13.8×109/L), thrombocytopaenia (82×109/L) and elevated alanine transaminase (184 U/L). An abdominal CT scan revealed a 10×8×9 cm multiloculated collection within the right liver lobe, with a second nodular septated collection under the left subcapsular region (figure 1). Her blood cultures returned positive for Klebsiella pneumoniae , resistant to ampicillin and susceptible to cefazolin, ciprofloxacin and meropenem. She was admitted to hospital and started on ceftriaxone. Figure 1 Abdominal CT showing large multiloculated liver abscesses in segments 2/3 of the left liver lobe (white arrow) and segments 6/7 of the right liver lobe (black arrow). Diagnostic and therapeutic ultrasound-guided 10F drains were inserted into both abscesses by interventional radiology, which drained purulent fluid positive for K. pneumoniae with identical susceptibility patterns as her blood cultures. However, she remained persistently …

Summary objective To assess the effect of decentralization (DC) of antiretroviral therapy (ART) provision in a rural district of Malawi using an integrated primary care model. methods Between October 2004 and December 2008, 8093 patients (63% women) were registered for ART. Of these, 3440 (43%) were decentralized to health centres for follow-up ART care. We applied multivariate regression analysis that adjusted for sex, age, clinical stage at initiation, type of regimen, presence of side effects because of ART, and duration of treatment and follow-up at site of analysis. results Patients managed at health centres had lower mortality [adjusted OR 0.19 (95% C.I. 0.15‐0.25)] and lower loss to follow-up (defaulted from treatment) [adjusted OR 0.48 (95% C.I. 0.40‐0.58)]. During the first 10 months of follow-up, those decentralized to health centres were approximately 60% less likely to default than those not decentralized; and after 10 months of follow-up, 40% less likely to default. DC was significantly associated with a reduced risk of death from 0 to 25 months of follow-up. The lower mortality may be explained by the selection of stable patients for DC, and the mentorship and supportive supervision of lower cadre health workers to identify and refer complicated cases. conclusion Decentralization of follow-up ART care to rural health facilities, using an integrated primary care model, appears a safe and effective way to rapidly scale-up ART and improves both geographical equity in access to HIV-related services and adherence to ART.

Introduction : Data from the Option B+ prevention of mother-to-child transmission (PMTCT) program in Malawi show considerable variation between health facilities in retention on antiretroviral therapy (ART). In a programmatic setting, we studied whether the “model of care,” based on the degree of integration of antenatal care (ANC), HIV testing and counselling (HTC) and ART service provision–influenced uptake of and retention on ART. Methods : We conducted a retrospective cohort study of pregnant women seeking ANC at rural primary health facilities in Zomba District, Malawi. Data were extracted from standardized national ANC registers, ART registers and ART master cards. The “model of care” of Option B+ service delivery was determined at each health facility, based on the degree of integration of ANC, HTC and ART. Full integration (Model 1) of HTC and ART initiation at ANC was compared with integration of HTC only into ANC services (Model 2) with subsequent referral to an existing ART clinic for treatment initiation. Results and discussion : A total of 10,528 women were newly registered at ANC between October 2011 and March 2012 in 23 rural health facilities (12 were Model 1 and 11 Model 2). HIV status was ascertained in 8,572 (81%) women. Among 914/8,572 (9%) HIV-positive women enrolling at ANC, 101/914 (11%) were already on ART; of those not on treatment, 456/813 (56%) were started on ART. There was significantly higher ART uptake in Model 1 compared with Model 2 sites (63% vs. 51%; p =0.001), but significantly lower ART retention in Model 1 compared with Model 2 sites (79% vs. 87%; p =0.02). Multivariable analysis showed that initiation of ART on the same day as HIV diagnosis, but not model of care, was independently associated with reduced retention in the first six months (adjusted odds ratio 2.27; 95% CI: 1.34–3.85; p =0.002). Conclusions : HIV diagnosis and treatment on the same day was associated with reduced retention on ART, independent of the level of PMTCT service integration at ANC. Keywords: PMTCT; Option B+; Malawi; service delivery model; ANC–ART integration; retention on ART. (Published: 11 March 2016) Citation: Chan AK et al. Journal of the International AIDS Society 2016, 19 :20672 http://www.jiasociety.org/index.php/jias/article/view/20672 | http://dx.doi.org/10.7448/IAS.19.1.20672

Background Pediatric uptake and outcomes in antiretroviral treatment (ART) programmes have lagged behind adult programmes. We describe outcomes from a population-based pediatric ART cohort in rural southern Malawi. Methods Data were analyzed on children who initiated ART from October/2003 –September/2011. Demographics and diagnoses were described and survival analyses conducted to assess the impact of age, presenting features at enrolment, and drug selection. Results The cohort consisted of 2203 children

BACKGROUND Option B+ is promoted as a key component to eliminating vertical transmission of HIV; however, little is known about the policy's impact on non-targeted populations, such as men and non-pregnant/non-breastfeeding women. We compare ART uptake among non-targeted populations during pre/post Option B+ periods in Zomba District, Malawi. METHODS Individual-level ART registry data from 27 health facilities were digitized and new ART initiates were disaggregated by sex and type of initiate (Option B+ or not). Data were analyzed over the pre- (January 2009-June 2011) and post- (July 2011- December 2013) Option B+ periods. RESULTS After the implementation of Option B+, the total number of new female initiates increased significantly (quarterly median: 547 vs. 816; P = 0.001) and their median age decreased from 34 to 31 years (P =

Summary Background Limited data are available on the prevalence and predictors of clinical sequelae in survivors of Ebola virus disease (EVD). The EVD Survivor Clinic in Port Loko, Sierra Leone, has provided clinical care for 603 of 661 survivors living in the district. We did a cross-sectional study to describe the prevalence, nature, and predictors of three key EVD sequelae (ocular, auditory, and articular) in this cohort of EVD survivors. Methods We reviewed available clinical and laboratory records of consecutive patients assessed in the clinic between March 7, 2015, and April 24, 2015. We used univariate and multiple logistic regression to examine clinical and laboratory features of acute EVD with the following outcomes in convalescence: new ocular symptoms, uveitis, auditory symptoms, and arthralgias. Findings Among 277 survivors (59% female), median age was 29 years (IQR 20–36) and median time from discharge from an EVD treatment facility to first survivor clinic visit was 121 days (82–151). Clinical sequelae were common, including arthralgias (n=210, 76%), new ocular symptoms (n=167, 60%), uveitis (n=50, 18%), and auditory symptoms (n=67, 24%). Higher Ebola viral load at acute EVD presentation (as shown by lower cycle thresholds on real-time RT-PCR testing) was independently associated with uveitis (adjusted odds ratio [aOR] 3·33, 95% CI 1·87–5·91, for every five-point decrease in cycle threshold) and with new ocular symptoms or ocular diagnoses (aOR 3·04, 95% CI 1·87–4·94). Interpretation Clinical sequelae during early EVD convalescence are common and sometimes sight threatening. These findings underscore the need for early clinical follow-up of survivors of EVD and urgent provision of ocular care as part of health systems strengthening in EVD-affected west African countries. Funding Canadian Institutes of Health Research.

Severe acute respiratory syndrome (SARS) is a threat to healthcare workers. After a brief, unexpected exposure to a patient with SARS, 69 intensive-care staff at risk for SARS were interviewed to evaluate risk factors. SARS developed in seven healthcare workers a median of 5 days (range 3–8) after last exposure. SARS developed in 6 of 31 persons who entered the patient’s room, including 3 who were present in the room >4 hours. SARS occurred in three of five persons present during the endotracheal intubation, including one who wore gloves, gown, and N-95 mask. The syndrome also occurred in one person with no apparent direct exposure to the index patient. In most, but not all cases, developing SARS was associated with factors typical of droplet transmission. Providing appropriate quarantine and preventing illness in healthcare providers substantially affects delivery of health care. Severe acute respiratory syndrome (SARS) is a disease that consists of fever and respiratory symptoms that can progress to respiratory failure and death (1). SARS is most likely to develop in healthcare workers and household or family contacts of infected persons (2–4) Unprotected exposure to SARS in hospitals has several potential consequences, which include the following: illness in persons and healthcare workers; transmission of SARS from ill healthcare workers and patients to visitors and household contacts; and reduced ability of the healthcare system to deliver care because of illness in or quarantine of healthcare workers. In addition, the psychological impact of isolation and quarantine can be substantial (5). As a result, understanding factors associated with SARS transmission after exposure to SARS patients is important and would assist with formulating appropriate quarantine procedures. We describe our experience with a large number of healthcare workers who were exposed to a patient in an intensive-care unit (ICU) with undiagnosed SARS.

background Severe acute respiratory syndrome (SARS) is a condition of unknown cause that has recently been recognized in patients in Asia, North America, and Europe. This report summarizes the initial epidemiologic findings, clinical description, and diagnostic findings that followed the identification of SARS in Canada. methods SARS was first identified in Canada in early March 2003. We collected epidemiologic, clinical, and diagnostic data from each of the first 10 cases prospectively as they were identified. Specimens from all cases were sent to local, provincial, national, and international laboratories for studies to identify an etiologic agent. results The patients ranged from 24 to 78 years old; 60 percent were men. Transmission occurred only after close contact. The most common presenting symptoms were fever (in 100 percent of cases) and malaise (in 70 percent), followed by nonproductive cough (in 100 percent) and dyspnea (in 80 percent) associated with infiltrates on chest radiography (in 100 percent). Lymphopenia (in 89 percent of those for whom data were available), elevated lactate dehydrogenase levels (in 80 percent), elevated aspartate aminotransferase levels (in 78 percent), and elevated creatinine kinase levels (in 56 percent) were common. Empirical therapy most commonly included antibiotics, oseltamivir, and intravenous ribavirin. Mechanical ventilation was required in five patients. Three patients died, and five have had clinical improvement. The results of laboratory investigations were negative or not clinically significant except for the amplification of human metapneumovirus from respiratory specimens from five of nine patients and the isolation and amplification of a novel coronavirus from five of nine patients. In four cases both pathogens were isolated. conclusions SARS is a condition associated with substantial morbidity and mortality. It appears to be of viral origin, with patterns suggesting droplet or contact transmission. The role of human metapneumovirus, a novel coronavirus, or both requires further investigation.

Background Decentralization of ART services scaled up significantly with the country wide roll out of option B plus in Uganda. Little work has been undertaken to examine population level access to HIV care particularly in hard to reach areas in rural Africa. Most work on ART scale up has been done at health facility level which omits people not accessing healthcare in the community. This study describes health service usage, particularly HIV testing and care in 2/6 parishes of Lapono sub-county of northern Uganda, prior to introduction of ART services in Lira Kato Health Centre (a local lower-level health centre III), as part of ART decentralization. Methods Household and individual questionnaires were administered to household members (aged 15–59 years). Logit random effects models were used to test for differences in proportions (allowing for clustering within villages). Results 2124 adults from 1351 households were interviewed (755 [36 %] males, 1369 [64 %] females). 2051 (97 %) participants reported seeking care locally for fever, most on foot and over half at Lira Kato Health Centre. 574 (76 %) men and 1156 (84 %) women reported ever-testing for HIV (P

Introduction Spontaneous atraumatic splenic rupture is a rare but dramatic occurrence that is most commonly attributed to infection or neoplasia. Deciphering the etiology can be challenging with many cases remaining unclear despite full investigation. Case presentation We report the case of a previously healthy and immunocompetent 52-year-old Caucasian woman with a remote history of clinically diagnosed infectious mononucleosis who experienced sudden atraumatic splenic rupture after an untreated stray cat bite. Conclusions The differential diagnosis for atraumatic splenic rupture, specifically its infectious causes, is reviewed. Key clinical and laboratory findings that differentiate Bartonella henselae infection and Epstein–Barr virus reinfection are reviewed.

Background In sub-Saharan Africa antiretroviral therapy (ART) is being decentralized from tertiary/secondary care facilities to primary care. The Lablite project supports effective decentralization in 3 countries. It began with a cross-sectional survey to describe HIV and ART services. Methods 81 purposively sampled health facilities in Malawi, Uganda and Zimbabwe were surveyed. Results The lowest level primary health centres comprised 16/20, 21/39 and 16/22 facilities included in Malawi, Uganda and Zimbabwe respectively. In Malawi and Uganda most primary health facilities had at least 1 medical assistant/clinical officer, with average 2.5 and 4 nurses/midwives for median catchment populations of 29,275 and 9,000 respectively. Primary health facilities in Zimbabwe were run by nurses/midwives, with average 6 for a median catchment population of 8,616. All primary health facilities provided HIV testing and counselling, 50/53 (94%) cotrimoxazole preventive therapy (CPT), 52/53 (98%) prevention of mother-to-child transmission of HIV (PMTCT) and 30/53 (57%) ART management (1/30 post ART-initiation follow-up only). All secondary and tertiary-level facilities provided HIV and ART services. In total, 58/81 had ART provision. Stock-outs during the 3 months prior to survey occurred across facility levels for HIV test-kits in 55%, 26% and 9% facilities in Malawi, Uganda and Zimbabwe respectively; for CPT in 58%, 32% and 9% and for PMTCT drugs in 26%, 10% and 0% of facilities (excluding facilities where patients were referred out for either drug). Across all countries, in facilities with ART stored on-site, adult ART stock-outs were reported in 3/44 (7%) facilities compared with 10/43 (23%) facility stock-outs of paediatric ART. Laboratory services at primary health facilities were limited: CD4 was used for ART initiation in 4/9, 5/6 and 13/14 in Malawi, Uganda and Zimbabwe respectively, but frequently only in selected patients. Routine viral load monitoring was not used; 6/58 (10%) facilities with ART provision accessed centralised viral loads for selected patients. Conclusions Although coverage of HIV testing, PMTCT and cotrimoxazole prophylaxis was high in all countries, decentralization of ART services was variable and incomplete. Challenges of staffing and stock management were evident. Laboratory testing for toxicity and treatment effectiveness monitoring was not available in most primary level facilities. Electronic supplementary material The online version of this article (doi:10.1186/1472-6963-14-352) contains supplementary material, which is available to authorized users.

Introduction : Malawi introduced a new strategy to improve the effectiveness of prevention of mother-to-child HIV transmission (PMTCT), the Option B+ strategy. We aimed to (i) describe how Option B+ is provided in health facilities in the South East Zone in Malawi, identifying the diverse approaches to service organization (the “model of care”) and (ii) explore associations between the “model of care” and health facility–level uptake and retention rates for pregnant women identified as HIV-positive at antenatal (ANC) clinics. Methods : A health facility survey was conducted in all facilities providing PMTCT/antiretroviral therapy (ART) services in six of Malawi’s 28 districts to describe and compare Option B+ service delivery models. Associations of identified models with program performance were explored using facility cohort reports. Results : Among 141 health facilities, four “models of care” were identified: A) facilities where newly identified HIV-positive women are initiated and followed on ART at the ANC clinic until delivery; B) facilities where newly identified HIV-positive women receive only the first dose of ART at the ANC clinic, and are referred to the ART clinic for follow-up; C) facilities where newly identified HIV-positive women are referred from ANC to the ART clinic for initiation and follow-up of ART; and D) facilities serving as ART referral sites (not providing ANC). The proportion of women tested for HIV during ANC was highest in facilities applying Model A and lowest in facilities applying Model B. The highest retention rates were reported in Model C and D facilities and lowest in Model B facilities. In multivariable analyses, health facility factors independently associated with uptake of HIV testing and counselling (HTC) in ANC were number of women per HTC counsellor, HIV test kit availability, and the “model of care” applied; factors independently associated with ART retention were district location, patient volume and the “model of care” applied. Conclusions : A large variety exists in the way health facilities have integrated PMTCT Option B+ care into routine service delivery. This study showed that the “model of care” chosen is associated with uptake of HIV testing in ANC and retention in care on ART. Further patient-level research is needed to guide policy recommendations. Keywords: PMTCT; Option B+; Malawi; service delivery model; model of care; retention. Published: 28 July 2014 Citation: van Lettow M et al. Journal of the International AIDS Society 2014, 17 :18994 http://www.jiasociety.org/index.php/jias/article/view/18994 | http://dx.doi.org/10.7448/IAS.17.1.18994