Showing papers in "Lancet Infectious Diseases in 2012"
TL;DR: Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons.
Abstract: Summary Background No published meta-analyses have assessed efficacy and effectiveness of licensed influenza vaccines in the USA with sensitive and highly specific diagnostic tests to confirm influenza. Methods We searched Medline for randomised controlled trials assessing a relative reduction in influenza risk of all circulating influenza viruses during individual seasons after vaccination (efficacy) and observational studies meeting inclusion criteria (effectiveness). Eligible articles were published between Jan 1, 1967, and Feb 15, 2011, and used RT-PCR or culture for confirmation of influenza. We excluded some studies on the basis of study design and vaccine characteristics. We estimated random-effects pooled efficacy for trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) when data were available for statistical analysis (eg, at least three studies that assessed comparable age groups). Findings We screened 5707 articles and identified 31 eligible studies (17 randomised controlled trials and 14 observational studies). Efficacy of TIV was shown in eight (67%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 59% [95% CI 51–67] in adults aged 18–65 years). No such trials met inclusion criteria for children aged 2–17 years or adults aged 65 years or older. Efficacy of LAIV was shown in nine (75%) of the 12 seasons analysed in ten randomised controlled trials (pooled efficacy 83% [69–91]) in children aged 6 months to 7 years. No such trials met inclusion criteria for children aged 8–17 years. Vaccine effectiveness was variable for seasonal influenza: six (35%) of 17 analyses in nine studies showed significant protection against medically attended influenza in the outpatient or inpatient setting. Median monovalent pandemic H1N1 vaccine effectiveness in five observational studies was 69% (range 60–93). Interpretation Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality. Funding Alfred P Sloan Foundation.
1,579 citations
Centers for Disease Control and Prevention1, International Centre for Diarrhoeal Disease Research, Bangladesh2, Johns Hopkins University3, University of Alabama at Birmingham4, National Institutes of Health5, University of California, Berkeley6, University of Oxford7, All India Institute of Medical Sciences8, Medical Research Council9, Pasteur Institute10
TL;DR: The global number of deaths during the first 12 months of virus circulation in each country and the estimate of respiratory and cardiovascular mortality associated with the 2009 pandemic influenza A H1N1 was 15 times higher than reported laboratory-confirmed deaths.
Abstract: Summary Background 18 500 laboratory-confirmed deaths caused by the 2009 pandemic influenza A H1N1 were reported worldwide for the period April, 2009, to August, 2010. This number is likely to be only a fraction of the true number of the deaths associated with 2009 pandemic influenza A H1N1. We aimed to estimate the global number of deaths during the first 12 months of virus circulation in each country. Methods We calculated crude respiratory mortality rates associated with the 2009 pandemic influenza A H1N1 strain by age (0–17 years, 18–64 years, and >64 years) using the cumulative (12 months) virus-associated symptomatic attack rates from 12 countries and symptomatic case fatality ratios (sCFR) from five high-income countries. To adjust crude mortality rates for differences between countries in risk of death from influenza, we developed a respiratory mortality multiplier equal to the ratio of the median lower respiratory tract infection mortality rate in each WHO region mortality stratum to the median in countries with very low mortality. We calculated cardiovascular disease mortality rates associated with 2009 pandemic influenza A H1N1 infection with the ratio of excess deaths from cardiovascular and respiratory diseases during the pandemic in five countries and multiplied these values by the crude respiratory disease mortality rate associated with the virus. Respiratory and cardiovascular mortality rates associated with 2009 pandemic influenza A H1N1 were multiplied by age to calculate the number of associated deaths. Findings We estimate that globally there were 201 200 respiratory deaths (range 105 700–395 600) with an additional 83 300 cardiovascular deaths (46 000–179 900) associated with 2009 pandemic influenza A H1N1. 80% of the respiratory and cardiovascular deaths were in people younger than 65 years and 51% occurred in southeast Asia and Africa. Interpretation Our estimate of respiratory and cardiovascular mortality associated with the 2009 pandemic influenza A H1N1 was 15 times higher than reported laboratory-confirmed deaths. Although no estimates of sCFRs were available from Africa and southeast Asia, a disproportionate number of estimated pandemic deaths might have occurred in these regions. Therefore, efforts to prevent influenza need to effectively target these regions in future pandemics. Funding None.
1,170 citations
TL;DR: The estimated number of deaths worldwide in children younger than 5 years due to diarrhoea attributable to rotavirus infection is updated to help advocate for rotav virus vaccine introduction and to monitor the effect of vaccination on mortality once introduced.
Abstract: Summary Background WHO recommends routine use of rotavirus vaccines in all countries, particularly in those with high mortality attributable to diarrhoeal diseases. To establish the burden of life-threatening rotavirus disease before the introduction of a rotavirus vaccine, we aimed to update the estimated number of deaths worldwide in children younger than 5 years due to diarrhoea attributable to rotavirus infection. Methods We used PubMed to identify studies of at least 100 children younger than 5 years who had been admitted to hospital with diarrhoea. Additionally, we required the studies to have a data collection midpoint of the year 2000 or later, to be done in full-year increments, and to assesses diarrhoea attributable to rotavirus with EIAs or polyacrylamide gel electrophoresis. We also included data from countries that participated in the WHO-coordinated Global Rotavirus Surveillance Network (consisting of participating member states during 2009) and that met study criteria. For countries that have introduced a rotavirus vaccine into their national immunisation programmes, we excluded data subsequent to the introduction. We classified studies into one of five groups on the basis of region and the level of child mortality in the country in which the study was done. For each group, to obtain estimates of rotavirus-associated mortality, we multiplied the random-effect mean rotavirus detection rate by the 2008 diarrhoea-related mortality figures for countries in that group. We derived the worldwide mortality estimate by summing our regional estimates. Findings Worldwide in 2008, diarrhoea attributable to rotavirus infection resulted in 453 000 deaths (95% CI 420 000–494 000) in children younger than 5 years—37% of deaths attributable to diarrhoea and 5% of all deaths in children younger than 5 years. Five countries accounted for more than half of all deaths attributable to rotavirus infection: Democratic Republic of the Congo, Ethiopia, India, Nigeria, and Pakistan; India alone accounted for 22% of deaths (98 621 deaths). Interpretation Introduction of effective and available rotavirus vaccines could substantially affect worldwide deaths attributable to diarrhoea. Our new estimates can be used to advocate for rotavirus vaccine introduction and to monitor the effect of vaccination on mortality once introduced. Funding None.
1,117 citations
TL;DR: Although data characterising HIV risk among female sex workers is scarce, the burden of disease is disproportionately high and suggests an urgent need to scale up access to quality HIV prevention programmes.
Abstract: Summary Background Female sex workers are a population who are at heightened risk of HIV infection secondary to biological, behavioural, and structural risk factors. However, three decades into the HIV pandemic, understanding of the burden of HIV among these women remains limited. We aimed to assess the burden of HIV in this population compared with that of other women of reproductive age. Methods We searched PubMed, Embase, Global Health, SCOPUS, PsycINFO, Sociological Abstracts, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Web of Science, and POPLine for studies of female sex workers in low-income and middle-income countries published between Jan 1, 2007, and June 25, 2011. Studies of any design that measured the prevalence or incidence of HIV among female sex workers, even if sex workers were not the main focus of the study, were included. Meta-analyses were done with the Mantel-Haenszel method with a random-effects model characterising an odds ratio for the prevalence of HIV among female sex workers compared with that for all women of reproductive age. Findings Of 434 selected articles and surveillance reports, 102 were included in the analyses, representing 99 878 female sex workers in 50 countries. The overall HIV prevalence was 11·8% (95% CI 11·6–12·0) with a pooled odds ratio for HIV infection of 13·5 (95% CI 10·0–18·1) with wide intraregional ranges in the pooled HIV prevalence and odds ratios for HIV infection. In 26 countries with medium and high background HIV prevalence, 30·7% (95% CI 30·2–31·3; 8627 of 28 075) of sex workers were HIV-positive and the odds ratio for infection was 11·6 (95% CI 9·1–14·8). Interpretation Although data characterising HIV risk among female sex workers is scarce, the burden of disease is disproportionately high. These data suggest an urgent need to scale up access to quality HIV prevention programmes. Considerations of the legal and policy environments in which sex workers operate and actions to address the important role of stigma, discrimination, and violence targeting female sex workers is needed. Funding The World Bank, UN Population Fund.
1,040 citations
TL;DR: Fidaxomicin could be an alternative treatment for infection with C difficile, with similar efficacy and safety to vancomycin, and meet the criterion for non-inferiority in the mITT population.
Abstract: Summary Background Infection with Clostridium difficile is the primary infective cause of antibiotic-associated diarrhoea. We aimed to compare efficacy and safety of fidaxomicin and vancomycin to treat patients with C difficile infection in Europe, Canada, and the USA. Methods In this multicentre, double-blind, randomised, non-inferiority trial, we enrolled patients from 45 sites in Europe and 41 sites in the USA and Canada between April 19, 2007, and Dec 11, 2009. Eligible patients were aged 16 years or older with acute, toxin-positive C difficile infection. Patients were randomly allocated (1:1) to receive oral fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was clinical cure, defined as resolution of diarrhoea and no further need for treatment. An interactive voice-response system and computer-generated randomisation schedule gave a randomisation number and medication kit number for each patient. Participants and investigators were masked to treatment allocation. Non-inferiority was prespecified with a margin of 10%. Modified intention-to-treat and per-protocol populations were analysed. This study is registered with ClinicalTrials.gov, number NCT00468728. Findings Of 535 patients enrolled, 270 were assigned fidaxomicin and 265 vancomycin. After 26 patients were excluded, 509 were included in the modified intention-to-treat (mITT) population. 198 (91·7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90·6%) of 235 given vancomycin, meeting the criterion for non-inferiority (one-sided 97·5% CI −4·3%). Non-inferiority was also shown for clinical cure in the mITT population, with 221 (87·7%) of 252 patients given fidaxomicin and 223 (86·8%) of 257 given vancomycin cured (one-sided 97·5% CI −4·9%). In most subgroup analyses of the primary endpoint in the mITT population, outcomes in the two treatment groups did not differ significantly; although patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (46 [90·2%] of 51) than with vancomycin (33 [73·3%] of 45; p=0·031). Occurrence of treatment-emergent adverse events did not differ between groups. 20 (7·6%) of 264 patients given at least one dose of fidaxomicin and 17 (6·5%) of 260 given vancomycin died. Interpretation Fidaxomicin could be an alternative treatment for infection with C difficile , with similar efficacy and safety to vancomycin. Funding Optimer Pharmaceuticals.
638 citations
TL;DR: For patients with this invasive syndrome, appropriate antimicrobial treatment combined with percutaneous drainage of liver abscesses increases their chances of survival and Rapid detection of the hypervirulent strain that causes this syndrome allows earlier diagnosis and treatment, thus minimising the occurrence of sequelae and improving clinical outcomes.
Abstract: Klebsiella pneumoniae is a well known human nosocomial pathogen. Most community-acquired K pneumoniae infections cause pneumonia or urinary tract infections. During the past two decades, however, a distinct invasive syndrome that causes liver abscesses has been increasingly reported in Asia, and this syndrome is emerging as a global disease. In this Review, we summarise the clinical presentation and management as well the microbiological aspects of this invasive disease. Diabetes mellitus and two specific capsular types in the bacterium predispose a patient to the development of liver abscesses and the following metastatic complications: bacteraemia, meningitis, endophthalmitis, and necrotising fasciitis. For patients with this invasive syndrome, appropriate antimicrobial treatment combined with percutaneous drainage of liver abscesses increases their chances of survival. Rapid detection of the hypervirulent strain that causes this syndrome allows earlier diagnosis and treatment, thus minimising the occurrence of sequelae and improving clinical outcomes.
591 citations
TL;DR: In this article, the authors used Cox proportional hazards regression and marginal structural modeling to assess the effect of contraceptive use on HIV-1 risk and found that women who used hormonal contraception had higher risk of acquiring HIV than those who did not.
Abstract: Summary Background Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners. Methods In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk. Findings Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6–24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06–3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8–24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12–3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression. Interpretation Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1. Funding US National Institutes of Health and the Bill & Melinda Gates Foundation.
446 citations
TL;DR: Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients' preferences rather than on predictive ability alone.
Abstract: Summary Background We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than that of the tuberculin skin test (TST). Methods Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals. Findings 15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2–6), even in IGRA-positive individuals, was 4–48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42–3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 [95% CI 1·29–3·46] for IGRA vs 1·60 [0·94–2·72] for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals. Interpretation Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients' preferences rather than on predictive ability alone. Funding Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.
444 citations
TL;DR: The significant difference in unadjusted mortality and the fact that this difference disappears with severity adjustment raise important questions about the effect of the approach to critical care in Europe compared with that in the USA.
Abstract: Summary Background Mortality from severe sepsis and septic shock differs across continents, countries, and regions. We aimed to use data from the Surviving Sepsis Campaign (SSC) to compare models of care and outcomes for patients with severe sepsis and septic shock in the USA and Europe. Methods The SSC was introduced into more than 200 sites in Europe and the USA. All patients identified with severe sepsis and septic shock in emergency departments or hospital wards and admitted to intensive care units (ICUs), and those with sepsis in ICUs were entered into the SSC database. Patients entered into the database from its launch in January, 2005, through January, 2010, in units with at least 20 patients and 3 months of enrolment of patients were included in this analysis. Patients included in the cohort were limited to those entered in the first 4 years at every site. We used random-effects logistic regression to estimate the hospital mortality odds ratio (OR) for Europe relative to the USA. We used random-effects linear regression to find the relation between lengths of stay in hospital and ICU and geographic region. Findings 25 375 patients were included in the cohort. The USA included 107 sites with 18 766 (74%) patients, and Europe included 79 hospital sites with 6609 (26%) patients. In the USA, 12 218 (65·1%) were admitted to the ICU from the emergency department whereas in Europe, 3405 (51·5%) were admitted from the wards. The median stay on the hospital wards before ICU admission was longer in Europe than in the USA (1·0 vs 0·1 days, difference 0·9, 95% CI 0·8–0·9). Raw hospital mortality was higher in Europe than in the USA (41·1% vs 28·3%, difference 12·8, 95% CI 11·5–14·7). The median length of stay in ICU (7·8 vs 4·2 days, 3·6, 3·3–3·7) and hospital (22·8 vs 10·5 days, 12·3, 11·9–12·8) was longer in Europe than in the USA. Adjusted mortality in Europe was not significantly higher than that in the USA (32·3% vs 31·3%, 1·0, −1·7 to 3·7, p=0·468). Complete compliance with all applicable elements of the sepsis resuscitation bundle was higher in the USA than in Europe (21·6% vs 18·4%, 3·2, 2·2–4·4). Interpretation The significant difference in unadjusted mortality and the fact that this difference disappears with severity adjustment raise important questions about the effect of the approach to critical care in Europe compared with that in the USA. The effect of ICU bed availability on outcomes in patients with severe sepsis and septic shock requires further investigation. Funding Eli Lilly Co, Baxter Lifesciences, Philips Medical Systems, the Society of Critical Care Medicine, and the European Society of Intensive Care Medicine.
444 citations
TL;DR: Despite making conservative estimates, it is found that food-borne trematodiases are an important cluster of neglected diseases and knowledge gaps in crucial epidemiological disease parameters and methodological features for estimating the global burden of parasitic diseases are highlighted.
Abstract: Summary Background Food-borne trematodiases are a group of neglected tropical diseases caused by liver, lung, and intestinal parasitic fluke infections. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD 2010 study) and a WHO initiative, we assessed the global burden of human food-borne trematodiasis, as expressed in disability-adjusted life years (DALYs) for the year 2005. Methods We systematically searched electronic databases for reports about human food-borne trematodiasis without language restriction, between Jan 1, 1980, and Dec 31, 2008. We used a broad search strategy with a combination of search terms and parasite and disease names. The initial search results were then screened on the basis of title, abstract, and, finally, full text. Relevant quantitative and qualitative data on human prevalence, morbidity, and mortality of food-borne trematodiasis were extracted. On the basis of available information on pathological and clinical appearance, we developed simplified disease models and did meta-analyses on the proportions and odds ratios of specified sequelae and estimated the global burden of human food-borne trematodiasis. Findings We screened 33 921 articles and identified 181 eligible studies containing quantitative information for inclusion in the meta-analyses. About 56·2 million people were infected with food-borne trematodes in 2005: 7·9 million had severe sequelae and 7158 died, most from cholangiocarcinoma and cerebral infection. Taken together, we estimate that the global burden of food-borne trematodiasis was 665 352 DALYs (lower estimate 479 496 DALYs; upper estimate 859 051 DALYs). Furthermore, knowledge gaps in crucial epidemiological disease parameters and methodological features for estimating the global burden of parasitic diseases that are characterised by highly focal spatial occurrence and scarce and patchy information were highlighted. Interpretation Despite making conservative estimates, we found that food-borne trematodiases are an important cluster of neglected diseases. Funding Swiss National Science Foundation; Institute for Health Metrics and Evaluation.
415 citations
TL;DR: This initiative aims to strengthen and enhance academic-industrial partnerships, bring about revision of costly and laborious processes of licensing and regulation of new antibiotics, and address the economics of antimicrobial drugs (cost of use vs profit).
Abstract: Antibiotic use not only underpins modern medicine, but has brought huge changes to the world, especially in expectations of survival of children into adulthood. The theme of World Health Day, 2011, was "antimicrobial resistance: no action today and no cure tomorrow". The demise of antibacterial drug discovery brings the spectre of untreatable infections. To prevent this crisis immediate action is needed and a new initiative, Antibiotic Action, has been launched. By bringing together communities who need these drugs with academia, health-care professionals, and pharmaceutical companies, this initiative aims to strengthen and enhance academic-industrial partnerships, bring about revision of costly and laborious processes of licensing and regulation of new antibiotics, and address the economics of antimicrobial drugs (cost of use vs profit). A global alliance for antibiotic drug discovery and development would provide a platform for these initiatives.
TL;DR: The bivalent vaccine seems more efficacious against non-vaccine HPV types 31, 33, and 45 than the quadrivalent vaccine, but the differences were not all significant and might be attributable to differences in trial design.
Abstract: Summary Background The extent of cross-protection is a key element in the choice of human papillomavirus (HPV) vaccine to use in vaccination programmes. We compared the cross-protective efficacy of the bivalent vaccine (HPV 16 and 18; Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and quadrivalent vaccine (HPV 6, 11, 16, and 18; Gardasil, Merck, Whitehouse Station, NJ, USA) against non-vaccine type HPVs. Methods We searched Medline and Embase databases, conference abstracts, and manufacturers' websites for randomised clinical trials assessing the efficacy of bivalent and quadrivalent vaccines against persistent infections (lasting ≥6 months) and cervical intraepithelial neoplasia (CIN) associated with the non-vaccine type HPVs (types 31, 33, 45, 52, and 58). We included studies of participants who were HPV DNA negative before vaccination for all HPV types assessed. We assessed heterogeneity in vaccine efficacy estimates between trials with I 2 and χ 2 statistics. Findings We identified two clinical trials (Females United to Unilaterally Reduce Endo/Ectocervical Disease [FUTURE] I and II) of the quadrivalent vaccine and three (Papilloma Trial Against Cancer In Young Adults [PATRICIA], HPV007, and HPV-023) of the bivalent vaccine. Analysis of the most comparable populations (pooled FUTURE I/II data vs PATRICIA) suggested that cross-protective vaccine efficacy estimates against infections and lesions associated with HPV 31, 33, and 45 were usually higher for the bivalent vaccine than the quadrivalent vaccine. Vaccine efficacy in the bivalent trial was higher than it was in the quadrivalent trial against persistent infections with HPV 31 (77·1% [95% CI 67·2 to 84·4] for bivalent vaccine vs 46·2% [15·3 to 66·4] for quadrivalent vaccine; p=0·003) and HPV 45 (79·0% [61·3 to 89·4] vs 7·8% [–67·0 to 49·3]; p=0·0003), and against CIN grade 2 or worse associated with HPV 33 (82·3% [53·4 to 94·7] vs 24·0% [–71·2 to 67·2]; p=0·02) and HPV 45 (100% [41·7 to 100] vs −51·9% [–1717·8 to 82·6]; p=0·04). We noted substantial heterogeneity between vaccine efficacy in bivalent trials against persistent infections with HPV 31 ( I 2 =69%, p=0·04) and HPV 45 ( I 2 =70%, p=0·04), with apparent reductions in cross-protective efficacy with increased follow-up. Interpretation The bivalent vaccine seems more efficacious against non-vaccine HPV types 31, 33, and 45 than the quadrivalent vaccine, but the differences were not all significant and might be attributable to differences in trial design. Efficacy against persistent infections with types 31 and 45 seemed to decrease in bivalent trials with increased follow-up, suggesting a waning of cross-protection; more data are needed to establish duration of cross-protection. Funding Public Health Agency of Canada.
TL;DR: Conurrent interventions and a multifaceted approach are needed to define and eliminate criminal production, distribution, and poor manufacturing of antimalarial drugs.
Abstract: Poor-quality antimalarial drugs lead to drug resistance and inadequate treatment, which pose an urgent threat to vulnerable populations and jeopardise progress and investments in combating malaria. Emergence of artemisinin resistance or tolerance in Plasmodium falciparum on the Thailand-Cambodia border makes protection of the effectiveness of the drug supply imperative. We reviewed published and unpublished studies reporting chemical analyses and assessments of packaging of antimalarial drugs. Of 1437 samples of drugs in five classes from seven countries in southeast Asia, 497 (35%) failed chemical analysis, 423 (46%) of 919 failed packaging analysis, and 450 (36%) of 1260 were classified as falsified. In 21 surveys of drugs from six classes from 21 countries in sub-Saharan Africa, 796 (35%) of 2297 failed chemical analysis, 28 (36%) of 77 failed packaging analysis, and 79 (20%) of 389 were classified as falsified. Data were insufficient to identify the frequency of substandard (products resulting from poor manufacturing) antimalarial drugs, and packaging analysis data were scarce. Concurrent interventions and a multifaceted approach are needed to define and eliminate criminal production, distribution, and poor manufacturing of antimalarial drugs. Empowering of national medicine regulatory authorities to protect the global drug supply is more important than ever.
TL;DR: Heritable artemisinin resistance is established in a second Cambodian province and future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation.
Abstract: Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD , which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum : age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5·85 h (95% CI 5·54–6·18) in Pursat, similar to that reported in Pailin (p=0·109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0·55 h; p=0·078), those of male sex (0·96 h; p=0·064), and in 2010 (0·68 h; p=0·068); PG1 was associated with a significant increase (0·79 h; p=0·033). The mean parasite heritability of half-life was 0·40 (SD 0·17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
TL;DR: Determine TB-LAM is a simple, low-cost, alternative to existing diagnostic assays for tuberculosis screening in HIV-infected patients with very low CD4 cell counts and provides important incremental yield when combined with sputum smear microscopy.
Abstract: Summary Background The diagnostic accuracy of sputum smear microscopy and routine chest radiology for HIV-associated tuberculosis is poor, and culture-based diagnosis is slow, expensive, and is unavailable in most resource-limited settings We assessed the diagnostic accuracy of a urine antigen test Determine TB-LAM Ag (Determine TB-LAM; Alere, Waltham, MA, USA) for screening for HIV-associated pulmonary tuberculosis before antiretroviral therapy (ART) Methods In this descriptive study, consecutive adults referred to a community-based ART clinic in Gugulethu township, South Africa, were all screened for tuberculosis by obtaining sputum samples for fluorescence microscopy, automated liquid culture (gold-standard test), and Xpert MTB/RIF assays (Cepheid, Sunnyvale, CA, USA) and urine samples for the Clearview TB-ELISA (TB-ELISA; Alere, Waltham, MA, USA) and Determine TB-LAM test Patients with Mycobacterium tuberculosis cultured from one or more sputum samples were defined as cases of tuberculosis The diagnostic accuracy of Determine TB-LAM used alone or combined with sputum smear microscopy was compared with that of sputum culture and the Xpert MTB/RIF assay for all patients and subgroups of patients stratified by CD4 cell count Findings Patients were recruited between March 12, 2010, and April 20, 2011 Of 602 patients enrolled, 542 were able to provide one or more sputum samples, and 94 had culture-positive tuberculosis (prevalence 17·4%, 95% CI 14·2–20·8) Complete results from all tests were available for 516 patients (median CD4 count, 169·5 cells per μL; IQR 100–233), including 85 culture-positive tuberculosis, 24 of whom (28·2%, 95% CI 19·0–39·0) had sputum smear-positive disease Determine TB-LAM test strips provided results within 30 min Agreement was very high between two independent readers of the test strips (κ=0·97) and between the test strips and TB-ELISA (κ=0·84) Determine TB-LAM had highest sensitivity at low CD4 cell counts: 66·7% (95% CI 41·0–86·7) at Interpretation Determine TB-LAM is a simple, low-cost, alternative to existing diagnostic assays for tuberculosis screening in HIV-infected patients with very low CD4 cell counts and provides important incremental yield when combined with sputum smear microscopy Funding Wellcome Trust
TL;DR: Heterogeneity in prevalence estimates for tuberculosis, hepatitis C virus, and HIV suggests the need for local surveys to inform development of health services for homeless people, and guidelines for screening and treatment of infectious diseases in homeless people might need to be reviewed.
Abstract: Methods We searched PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature for studies of the prevalence of tuberculosis, hepatitis C virus, and HIV in homeless populations. We also searched bibliographic indices, scanned reference lists, and corresponded with authors. W e explored potential sources of heterogeneity in the estimates by metaregression analysis and calculated prevalence ratios to compare prevalence estimates for homeless people with those for the general population. Findings We identifi ed 43 eligible surveys with a total population of 63 812 (59 736 homeless individuals when duplication due to overlapping samples was accounted for). Prevalences ranged from 0·2% to 7·7% for tuberculosis, 3·9% to 36·2% for hepatitis C virus infection, and 0·3% to 21·1% for HIV infection. We noted substantial heterogeneity in prevalence estimates for tuberculosis, hepatitis C virus infection, and HIV infection (all Cochran’s χ² signifi cant at p<0·0001; I²=83%, 95% CI 76–89; 95%, 94–96; and 94%, 93–95; respectively). Prevalence ratios ranged from 34 to 452 for tuberculosis, 4 to 70 for hepatitis C virus infection, and 1 to 77 for HIV infection. Tuberculosis prevalence was higher in studies in which diagnosis was by chest radiography than in those which used other diagnostic methods and in countries with a higher general population prevalence than in those with a lower general prevalence. Prevalence of HIV infection was lower in newer studies than in older ones and was higher in the USA than in the rest of the world. Interpretation Heterogeneity in prevalence estimates for tuberculosis, hepatitis C virus, and HIV suggests the need for local surveys to inform development of health services for homeless people. The role of targeted and populationbased measures in the reduction of risks of infectious diseases, premature mortality, and other adverse outcomes needs further examination. G uidelines for screening and treatment of infectious diseases in homeless people might need to be reviewed.
TL;DR: Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses, and support the assessment of once daily 50 mg doluteg Gravir in phase 3 trials is supported.
Abstract: Summary Background Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses. Methods In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per μL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015. Findings 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group—we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir. Interpretation Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials. Funding Shionogi-GlaxoSmithKline Pharmaceuticals, LLC, now Shionogi-ViiV Healthcare, LLC.
TL;DR: Haemoglobin AS, CC, and AC genotypes and homozygous and heterozygous α-thalassaemia provide significant protection from severe malaria syndromes, but these haemoglobinopathies differ substantially in the degree of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia.
Abstract: Summary Background Haemoglobinopathies can reduce the risk of malaria syndromes. We aimed to quantify the relation between different haemoglobin mutations and malaria protection to strengthen the foundation for translational studies of malaria pathogenesis and immunity. Methods We systematically searched the Medline and Embase databases for studies that estimated the risk of malaria in patients with and without haemoglobinopathies up to Sept 9, 2011, and identified additional studies from reference lists. We included studies that enrolled mainly children or pregnant women and had the following outcomes: Plasmodium falciparum severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy-associated malaria, and Plasmodium vivax malaria. Two reviewers identified studies independently, assessed quality of the studies, and extracted data. We produced odds ratios (ORs; 95% CIs) for case-control studies and incidence rate ratios (IRRs; 95% CIs) for prospective studies. We did the meta-analysis with a random-effects model when equivalent outcomes were reported in more than one study. Findings Of 62 identified studies, 44 reported data for haemoglobin AS, 19 for haemoglobin AC and CC, and 18 for α-thalassaemia. Meta-analysis of case-control studies showed a decreased risk of severe P falciparum malaria in individuals with haemoglobin AS (OR 0·09, 95% CI 0·06–0·12), haemoglobin CC (0·27, 0·11–0·63), haemoglobin AC (0·83, 0·67–0·96), homozygous α-thalassaemia (0·63, 0·48–0·83), and heterozygous α-thalassaemia (0·83, 0·74–0·92). In meta-analysis of prospective trials only haemoglobin AS was consistently associated with protection from uncomplicated malaria (IRR 0·69, 95% CI 0·61–0·79); no haemoglobinopathies led to consistent protection from asymptomatic parasitaemia. Few clinical studies have investigated β-thalassaemia, haemoglobin E, P vivax malaria, or pregnancy-associated malaria. Interpretation Haemoglobin AS, CC, and AC genotypes and homozygous and heterozygous α-thalassaemia provide significant protection from severe malaria syndromes, but these haemoglobinopathies differ substantially in the degree of protection provided and confer mild or no protection against uncomplicated malaria and asymptomatic parasitaemia. Through attenuation of severity of malaria, haemoglobinopathies could serve as a model for investigation of the mechanisms of malaria pathogenesis and immunity. Funding US National Institute of Allergy and Infectious Diseases.
TL;DR: Risks of communicable diseases that are associated with mass gatherings (MGs) are assessed, approaches to risk assessment and mitigation are outlined, and some key challenges encountered by organisers and participants are drawn attention.
Abstract: We assess risks of communicable diseases that are associated with mass gatherings (MGs), outline approaches to risk assessment and mitigation, and draw attention to some key challenges encountered by organisers and participants. Crowding and lack of sanitation at MGs can lead to the emergence of infectious diseases, and rapid population movement can spread them across the world. Many infections pose huge challenges to planners of MGs; however, these events also provide an opportunity to engage in public health action that will benefit host communities and the countries from which participants originate.
TL;DR: The reported safety and efficacy outcomes support further development in a phase 3 trial, notwithstanding a lack of significant reduction in the use of cytomegalovirus-specific antiviral therapy compared with placebo in this phase 2 trial.
Abstract: Summary Background Cytomegalovirus reactivation occurs within 6 months in 60–70% of cytomegalovirus-seropositive patients after allogeneic haemopoietic stem-cell transplantation (HSCT), mainly due to immunosuppression associated with the procedure. Pre-emptive antiviral therapy reduces incidence of cytomegalovirus disease but can be toxic. To reduce the potential for disease and subsequent need for such antiviral drugs, we aimed to assess safety and efficacy of a cytomegalovirus therapeutic DNA vaccine compared with placebo. Methods In this exploratory double-blind, placebo-controlled, parallel group, phase 2 trial, up to 80 donor–recipient pairs and 80 unpaired recipients undergoing allogeneic HSCT were planned for enrolment at 16 transplant centres in the USA. Eligible recipients were cytomegalovirus-seropositive, 18–65 years old, without high-risk primary disease, T-cell depletion, previous vaccination for cytomegalovirus, or autoimmune diseases. We randomly allocated participants in both parallel groups in a 1:1 ratio to receive a cytomegalovirus therapeutic DNA vaccine (TransVax; Vical, San Diego, CA, USA) or placebo before conditioning and at 1, 3, and 6 months after transplantation. The vaccine contains plasmids encoding cytomegalovirus glycoprotein B and phosphoprotein 65 formulated with poloxamer CRL1005 and benzalkonium chloride. Randomisation was done by sequential allocation based on Pocock and Simon's method, and stratified by site, donor–recipient HLA matching status, and donor's cytomegalovirus serostatus. The primary outcome was the occurrence rate of clinically significant viraemia resulting in initiation of cytomegalovirus-specific antiviral therapy in the per-protocol assessable population. We assessed rates of adverse events in all participants who received at least one dose of vaccine or placebo. This study is registered with ClinicalTrials.gov, number NCT00285259. Findings We randomly allocated 108 participants (94 HSCT recipients and 14 paired donors) between June 29, 2006, and Dec 11, 2009. Enrolment of the paired arm was halted in February 2008 for logistical reasons. Safety was assessed in all participants; the efficacy population was restricted to 74 unpaired recipients. Groups were balanced for demographic and clinical variables. 19 (48%) of 40 vaccine recipients required cytomegalovirus-specific antiviral therapy, compared with 21 (62%) of 34 controls (p=0·145). However, during follow-up vaccine significantly reduced the occurrence and recurrence of cytomegalovirus viraemia and improved the time-to-event for viraemia episodes compared with placebo. The vaccine was well-tolerated; only one participant discontinued after an allergic reaction. Incidence of common adverse events after HSCT (eg, graft-versus-host disease or secondary infections) did not differ between groups. Interpretation We show proof of concept for an immunotherapeutic cytomegalovirus vaccine (TransVax) for clinically significant viraemia in the HSCT setting. The reported safety and efficacy outcomes support further development in a phase 3 trial, notwithstanding a lack of significant reduction in the use of cytomegalovirus-specific antiviral therapy compared with placebo in this phase 2 trial. Funding Vical and US National Institute of Allergy and Infectious Diseases.
TL;DR: In this article, the authors tried to limit confounding bias through exact matching on potential confounding factors associated with both exposure to malaria prevention (IPTp or ITNs) in pregnancy and birth outcomes, including local malaria transmission, neonatal tetanus vaccination, maternal age and education, and household wealth.
Abstract: Summary Background Low birthweight is a significant risk factor for neonatal and infant death. A prominent cause of low birthweight is infection with Plasmodium falciparum during pregnancy. Antimalarial intermittent preventive therapy in pregnancy (IPTp) and insecticide-treated mosquito nets (ITNs) significantly reduce the risk of low birthweight in regions of stable malaria transmission. We aimed to assess the effectiveness of malaria prevention in pregnancy (IPTp or ITNs) at preventing low birthweight and neonatal mortality under routine programme conditions in malaria endemic countries of Africa. Methods We used a retrospective birth cohort from national cross-sectional datasets in 25 African countries from 2000–10. We used all available datasets from multiple indicator cluster surveys, demographic and health surveys, malaria indicator surveys, and AIDS indicator surveys that were publically available as of 2011. We tried to limit confounding bias through exact matching on potential confounding factors associated with both exposure to malaria prevention (ITNs or IPTp with sulfadoxine–pyrimethamine) in pregnancy and birth outcomes, including local malaria transmission, neonatal tetanus vaccination, maternal age and education, and household wealth. We used a logistic regression model to test for associations between malaria prevention in pregnancy and low birthweight, and a Poisson model for the outcome of neonatal mortality. Both models incorporated the matched strata as a random effect, while accounting for additional potential confounding factors with fixed effect covariates. Findings We analysed 32 national cross-sectional datasets. Exposure of women in their first or second pregnancy to full malaria prevention with IPTp or ITNs was significantly associated with decreased risk of neonatal mortality (protective efficacy [PE] 18%, 95% CI 4–30; incidence rate ratio [IRR] 0·820, 95% CI 0·698–0·962), compared with newborn babies of mothers with no protection, after exact matching and controlling for potential confounding factors. Compared with women with no protection, exposure of pregnant women during their first two pregnancies to full malaria prevention in pregnancy through IPTp or ITNs was significantly associated with reduced odds of low birthweight (PE 21%, 14–27; IRR 0·792, 0·732–0·857), as measured by a combination of weight and birth size perceived by the mother, after exact matching and controlling for potential confounding factors. Interpretation Malaria prevention in pregnancy is associated with substantial reductions in neonatal mortality and low birthweight under routine malaria control programme conditions. Malaria control programmes should strive to achieve full protection in pregnant women by both IPTp and ITNs to maximise their benefits. Despite an attempt to mitigate bias and potential confounding by matching women on factors thought to be associated with access to malaria prevention in pregnancy and birth outcomes, some level of confounding bias possibly remains. Funding Malaria Control and Evaluation Partnership in Africa (MACEPA), Bill & Melinda Gates Foundation.
TL;DR: Data from studies of HCV reinfection after spontaneous clearance is assessed, flaws in the methods of previous human studies are discussed, and essential components for future investigations of control ofHCV infection are suggested.
Abstract: Hepatitis C virus (HCV) was discovered more than two decades ago, but progress towards a vaccine has been slow. HCV infection will spontaneously clear in about 25% of people. Studies of spontaneous HCV clearance in chimpanzees and human beings have identified host and viral factors that could be important in the control of HCV infection and the design of HCV vaccines. Although data from studies of chimpanzees suggest that protection against reinfection is possible after spontaneous clearance, HCV is a human disease. Results from studies of reinfection risk after spontaneous clearance in injecting drug users are conflicting, but some people seem to have protection against HCV persistence. To guide future vaccine development, we assess data from studies of HCV reinfection after spontaneous clearance, discuss flaws in the methods of previous human studies, and suggest essential components for future investigations of control of HCV infection.
TL;DR: A patient with Lemierre's syndrome caused by Fusobacterium necrophorum who developed a right frontal lobe brain abscess is presented and treatment should include a prolonged course of intravenous beta-lactam antibiotic plus metronidazole.
Abstract: We present a case of a patient with Lemierre's syndrome caused by Fusobacterium necrophorum who developed a right frontal lobe brain abscess. We summarise the epidemiology, microbiology, pathogenesis, clinical presentation, diagnosis, complications, therapy, and outcomes of Lemierre's syndrome. F necrophorum is most commonly associated with Lemierre's syndrome: a septic thrombophlebitis of the internal jugular vein. Patients usually present with an exudative tonsillitis, sore throat, dysphagia, and unilateral neck pain. Diagnosis of septic thrombophlebitis is best confirmed by obtaining a CT scan of the neck with contrast. Complications of the disease include bacteraemia with septic abscesses to the lungs, joints, liver, peritoneum, kidneys, and brain. Treatment should include a prolonged course of intravenous beta-lactam antibiotic plus metronidazole.
TL;DR: A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage and the risk of miscarriage was similar for women treated with chloroquine, quinine, or artesunate combination treatments in early pregnancy.
Abstract: Summary Background The effects of malaria and its treatment in the first trimester of pregnancy remain an area of concern. We aimed to assess the outcome of malaria-exposed and malaria-unexposed first-trimester pregnancies of women from the Thai–Burmese border and compare outcomes after chloroquine-based, quinine-based, or artemisinin-based treatments. Methods We analysed all antenatal records of women in the first trimester of pregnancy attending Shoklo Malaria Research Unit antenatal clinics from May 12, 1986, to Oct 31, 2010. Women without malaria in pregnancy were compared with those who had a single episode of malaria in the first trimester. The association between malaria and miscarriage was estimated using multivariable logistic regression. Findings Of 48 426 pregnant women, 17 613 (36%) met the inclusion criteria: 16 668 (95%) had no malaria during the pregnancy and 945 (5%) had a single episode in the first trimester. The odds of miscarriage increased in women with asymptomatic malaria (adjusted odds ratio 2·70, 95% CI 2·04–3·59) and symptomatic malaria (3·99, 3·10–5·13), and were similar for Plasmodium falciparum and Plasmodium vivax . Other risk factors for miscarriage included smoking, maternal age, previous miscarriage, and non-malaria febrile illness. In women with malaria, additional risk factors for miscarriage included severe or hyperparasitaemic malaria (adjusted odds ratio 3·63, 95% CI 1·15–11·46) and parasitaemia (1·49, 1·25–1·78 for each ten-fold increase in parasitaemia). Higher gestational age at the time of infection was protective (adjusted odds ratio 0·86, 95% CI 0·81–0·91). The risk of miscarriage was similar for women treated with chloroquine (92 [26%] of 354), quinine (95 [27%) of 355), or artesunate (20 [31%] of 64; p=0·71). Adverse effects related to antimalarial treatment were not observed. Interpretation A single episode of falciparum or vivax malaria in the first trimester of pregnancy can cause miscarriage. No additional toxic effects associated with artesunate treatment occurred in early pregnancy. Prospective studies should now be done to assess the safety and efficacy of artemisinin combination treatments in early pregnancy. Funding Wellcome Trust and Bill & Melinda Gates Foundation.
TL;DR: It is found that the combination of long-lasting insecticidal mosquito nets with indoor residual spraying or carbamate-treated plastic sheeting conferred enhanced protection against malaria and better management of pyrethroid-resistance in vectors than did LLINs alone.
Abstract: Summary Background Malaria control efforts and elimination in Africa are being challenged by the development of resistance of parasites to antimalarial drugs and vectors to insecticides. We investigated whether the combination of long-lasting insecticidal mosquito nets (LLINs) with indoor residual spraying (IRS) or carbamate-treated plastic sheeting (CTPS) conferred enhanced protection against malaria and better management of pyrethroid-resistance in vectors than did LLINs alone. Methods We did a cluster randomised controlled trial in 28 villages in southern Benin, west Africa. Inclusion criteria of the villages were moderate level of pyrethroid resistance in malaria vectors and minimum distance between villages of 2 km. We assessed four malaria vector control interventions: LLIN targeted coverage to pregnant women and children younger than 6 years (TLLIN, reference group), LLIN universal coverage of all sleeping units (ULLIN), TLLIN plus full coverage of carbamate-IRS applied every 8 months (TLLIN+IRS), and ULLIN plus full coverage of CTPS lined up to the upper part of the household walls (ULLIN+CTPS). The interventions were allocated to villages by a block randomisation on the basis of preliminary surveys and children of each village were randomly selected to participate with computer-generated numbers. The primary endpoint was the incidence density rate of Plasmodium falciparum clinical malaria in children younger than 6 years as was analysed by Poisson regression taking into account the effect of age and the sampling design with a generalised estimating equation approach. Clinical and parasitological information were obtained by active case detection of malaria episodes during 12 periods of 6 consecutive days scheduled at six weekly intervals and by cross-sectional surveys of asymptomatic plasmodial infections. Children or study investigators were not masked to study group. This study is registered with Current Controlled Trials, number ISRCTN07404145. Findings Of 58 villages assessed, 28 were randomly assigned to intervention groups. 413–429 children were followed up in each intervention group for 18 months. The clinical incidence density of malaria was not reduced in the children from the ULLIN group (incidence density rate 0·95, 95% CI 0·67–1·36, p=0·79), nor in those from the TLLIN+IRS group (1·32, 0·90–1·93, p=0·15) or from the ULLIN+CTPS group (1·05, 0·75–1·48, p=0·77) compared with the reference group (TLLIN). The same trend was observed with the prevalence and parasite density of asymptomatic infections (non significant regression coefficients). Interpretation No significant benefit for reducing malaria morbidity, infection, and transmission was reported when combining LLIN+IRS or LLIN+CTPS compared with a background of LLIN coverage. These findings are important for national malaria control programmes and should help the design of more cost-effective strategies for malaria control and elimination. Funding Ministere Francais des Affaires Etrangeres et Europeennes (FSP project 2006-22), Institut de Recherche pour le Developpement, President's Malaria Initiative (PMI) of US Governement.
TL;DR: In this article, the authors performed a post-hoc analysis of the trial's data to investigate behavioural risk and efficacy every 6 months after vaccination, and found that the vaccine efficacy seemed to peak early and declined quickly.
Abstract: Summary Background The Thai phase 3 HIV vaccine trial RV 144 showed modest efficacy of a vaccine against HIV acquisition. Baseline variables of age, sex, marital status, and risk did not modify vaccine efficacy. We did a post-hoc analysis of the trial's data to investigate behavioural risk and efficacy every 6 months after vaccination. Methods RV 144 was a randomised, multicentre, double-blind, placebo-controlled efficacy trial testing the combination of the HIV vaccines ALVAC-HIV (vCP1521) and AIDSVAX B/E to prevent HIV infection or reduce setpoint viral load. Male and female volunteers aged 18–30 years were recruited from the community. In this post-hoc analysis of the modified intention-to-treat population (16 395 participants), HIV risk behaviour was assessed with a self-administered questionnaire at the time of initial vaccination in the trial and every 6 months thereafter for 3 years. We classified participants' behaviour as low, medium, or high risk. Both the acquisition endpoint and the early viral-load endpoint were examined for interactions with risk status over time and temporal effects after vaccination. Multiple proportional hazards regression models with treatment and time-varying risk covariates were analysed. Findings Risk of acquisition of HIV was low in each risk group, but 9187 (58·2%) participants reported higher-risk behaviour at least once during the study. Participants classified as high or increasing risk at least once during follow-up were compared with those who maintained low-risk or medium-risk behaviour as a time-varying covariate, and the interaction of risk status and acquisition efficacy was significant (p=0·01), with greater benefit in low-risk individuals. Vaccine efficacy seemed to peak early—cumulative vaccine efficacy was estimated to be 60·5% (95% CI 22–80) through the 12 months after initial vaccination—and declined quickly. Vaccination did not seem to affect viral load in either early or late infections. Interpretation Future HIV vaccine trials should recognise potential interactions between challenge intensity and risk heterogeneity in both population and treatment effects. The regimen tested in the RV 144 phase 3 trial might benefit from extended immunisation schedules. Funding US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health.
TL;DR: Among all MGs, the public health issues, associated with the Hajj (an annual pilgrimage to Mecca, Saudi Arabia) is clearly the best reported—probably because of its international or even intercontinental implications in terms of the spread of infectious disease.
Abstract: Although definitions of mass gatherings (MG) vary greatly, they consist of large numbers of people attending an event at a specific site for a finite time. Examples of MGs include World Youth Day, the summer and winter Olympics, rock concerts, and political rallies. Some of the largest MGs are spiritual in nature. Among all MGs, the public health issues, associated with the Hajj (an annual pilgrimage to Mecca, Saudi Arabia) is clearly the best reported-probably because of its international or even intercontinental implications in terms of the spread of infectious disease. Hajj routinely attracts 2·5 million Muslims for worship. WHO's global health initiatives have converged with Saudi Arabia's efforts to ensure the wellbeing of pilgrims, contain infectious diseases, and reinforce global health security through the management of the Hajj. Both initiatives emphasise the importance of MG health policies guided by sound evidence and based on experience and the timeliness of calls for a new academic science-based specialty of MG medicine.
TL;DR: Improved access to alternative combinations of antiretroviral drugs in sub-Saharan Africa is warranted and improved access to alternatives to pretreatment drug resistance is warranted.
Abstract: Summary Background The effect of pretreatment HIV-1 drug resistance on the response to first-line combination antiretroviral therapy (ART) in sub-Saharan Africa has not been assessed. We studied pretreatment drug resistance and virological, immunological, and drug-resistance treatment outcomes in a large prospective cohort. Methods HIV-1 infected patients in the PharmAccess African Studies to Evaluate Resistance Monitoring (PASER-M) cohort started non-nucleoside reverse transcriptase inhibitor-based ART at 13 clinical sites in six countries, from 2007 to 2009. We used the International Antiviral Society-USA drug resistance mutation list and the Stanford algorithm to classify participants into three pretreatment drug resistance categories: no pretreatment drug resistance, pretreatment drug resistance with fully active ART prescribed, or pretreatment drug resistance with reduced susceptibility to at least one prescribed drug. We assessed risk factors of virological failure (≥400 copies per mL) and acquired drug resistance after 12 months of ART by use of multilevel logistic regression with multiple imputations for missing data. CD4 cell count increase was estimated with linear mixed models. Findings Pretreatment drug resistance results were available for 2579 (94%) of 2733 participants; 2404 (93%) had no pretreatment drug resistance, 123 (5%) had pretreatment drug resistance to at least one prescribed drug, and 52 (2%) had pretreatment drug resistance and received fully active ART. Compared with participants without pretreatment drug resistance, the odds ratio (OR) for virological failure (OR 2·13, 95% CI 1·44–3·14; p Interpretation At least three fully active antiretroviral drugs are needed to ensure an optimum response to first-line regimens and to prevent acquisition of drug resistance. Improved access to alternative combinations of antiretroviral drugs in sub-Saharan Africa is warranted. Funding The Netherlands Ministry of Foreign Affairs.
TL;DR: Recommendations for antiviral susceptibility testing, reporting results, and management of patients infected with 2009 pandemic influenza A H1N1 are proposed and optimisation of antiviral treatment, rapid sample testing, and timely reporting of susceptibility results are proposed.
Abstract: Influenza A H1N1 2009 virus caused the first pandemic in an era when neuraminidase inhibitor antiviral drugs were available in many countries. The experiences of detecting and responding to resistance during the pandemic provided important lessons for public health, laboratory testing, and clinical management. We propose recommendations for antiviral susceptibility testing, reporting results, and management of patients infected with 2009 pandemic influenza A H1N1. Sustained global monitoring for antiviral resistance among circulating influenza viruses is crucial to inform public health and clinical recommendations for antiviral use, especially since community spread of oseltamivir-resistant A H1N1 2009 virus remains a concern. Further studies are needed to better understand influenza management in specific patient groups, such as severely immunocompromised hosts, including optimisation of antiviral treatment, rapid sample testing, and timely reporting of susceptibility results.
TL;DR: Waiting for objective data to diagnose infection before treatment with antimicrobial drugs for suspected SICU-acquired infections does not worsen mortality and might be associated with better outcomes and use of antimicrobial Drugs.
Abstract: Summary Background Antimicrobial treatment in critically ill patients can either be started as soon as infection is suspected or after objective data confirm an infection. We postulated that delaying antimicrobial treatment of patients with suspected infections in the surgical intensive care unit (SICU) until objective evidence of infection had been obtained would not worsen patient mortality. Methods We did a 2-year, quasi-experimental, before and after observational cohort study of patients aged 18 years or older who were admitted to the SICU of the University of Virginia (Charlottesville, VA, USA). From Sept 1, 2008, to Aug 31, 2009, aggressive treatment was used: patients suspected of having an infection on the basis of clinical grounds had blood cultures sent and antimicrobial treatment started. From Sept 1, 2009, to Aug 31, 2010, a conservative strategy was used, with antimicrobial treatment started only after objective findings confirmed an infection. Our primary outcome was in-hospital mortality. Analyses were by intention to treat. Findings Admissions to the SICU for the first and second years were 762 and 721, respectively, with 101 patients with SICU-acquired infections during the aggressive year and 100 patients during the conservative year. Compared with the aggressive approach, the conservative approach was associated with lower all-cause mortality (13/100 [13%] vs 27/101 [27%]; p=0·015), more initially appropriate therapy (158/214 [74%] vs 144/231 [62%]; p=0·0095), and a shorter mean duration of therapy (12·5 days [SD 10·7] vs 17·7 [28·1]; p=0·0080). After adjusting for age, sex, trauma involvement, acute physiology and chronic health evaluation (APACHE) II score, and site of infection, the odds ratio for the risk of mortality in the aggressive therapy group compared with the conservative therapy group was 2·5 (95% CI 1·5–4·0). Interpretation Waiting for objective data to diagnose infection before treatment with antimicrobial drugs for suspected SICU-acquired infections does not worsen mortality and might be associated with better outcomes and use of antimicrobial drugs. Funding National Institutes of Health.