Highly virulent strains of Clostridium difficile have emerged since 2003, causing large outbreaks of severe, often fatal, colitis in North America and Europe. In 2008-10, virulent strains spread between continents, with the first reported cases of fluoroquinolone-resistant C difficile PCR ribotype 027 in three Asia-Pacific countries and Central America. We present a risk assessment framework for assessing risks of further worldwide spread of this pathogen. This framework first requires identification of potential vehicles of introduction, including international transfers of hospital patients, international tourism and migration, and trade in livestock, associated commodities, and foodstuffs. It then calls for assessment of the risks of pathogen release, of exposure of individuals if release happens, and of resulting outbreaks. Health departments in countries unaffected by outbreaks should assess the risk of introduction or reintroduction of C difficile PCR ribotype 027 using a structured risk-assessment approach.
In developing countries, most people infected with HIV do not know their infection status. We aimed to assess whether HIV testing could be increased by combination of community mobilisation, mobile community-based voluntary counselling and testing (VCT), and support after testing.
Project Accept is underway in ten communities in Tanzania, eight in Zimbabwe, and 14 in Thailand. Communities at each site were paired according to similar demographic and environmental characteristics, and one community from each pair was randomly assigned to receive standard clinic-based VCT (SVCT), and the other community was assigned to receive community-based VCT (CBVCT) plus access to SVCT. Randomisation and assignment of communities to intervention groups was done by the statistics centre by computer; no one was masked to treatment assignment because the interventions were community based. Intervention was provided for about 3 years (2006-09). The primary endpoint of HIV incidence is pending completion of assessments after the intervention. In this interim analysis, we examined the secondary endpoint of uptake in HIV testing, differences in characteristics of clients receiving their first HIV test, and repeat testing. Analyses were limited to clients aged 16-32 years. This study is registered with ClinicalTrials.gov, number NCT00203749.
The proportion of clients receiving their first HIV test during the study was higher in CBVCT communities than in SVCT communities in Tanzania (2341 [37%] of 6250 vs 579 [9%] of 6733), Zimbabwe (5437 [51%] of 10,700 vs 602 [5%] of 12,150), and Thailand (7802 [69%] of 11,290 vs 2319 [23%] 10,033). The mean difference in the proportion of clients receiving HIV testing between CBVCT and SVCT communities was 40·2% (95% CI 15·8-64·7; p=0·019) across three community pairs (one per country). HIV prevalence was higher in SVCT communities than in CBVCT communities, but CBVCT detected almost four times more HIV cases than did SVCT across the three study sites (952 vs 264; p=0·003). Repeat HIV testing in CBVCT communities increased in all sites to reach 28% of all those testing for HIV by the end of the intervention period.
CBVCT should be considered as a viable intervention to increase detection of HIV infection, especially in regions with restricted access to clinic-based VCT and support services after testing.
US National Institute of Mental Health, HIV Prevention Trials Network (via US National Institute of Allergy and Infectious Diseases), and US National Institutes of Health.
Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes.
The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581.
1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group.
Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment.
US National Institute of Allergy and Infectious Diseases.
Routine national incidence testing with enzyme immunoassay for recent HIV-1 infections (EIA-RI) has been done in France since January, 2003. From the reported number of HIV infections diagnosed as recent, and accounting for testing patterns and under-reporting, we aimed to estimate the incidence of HIV infection in France in 2003-08.
We analysed reports from the French National Institute for Public Health Surveillance for patients who were newly diagnosed with HIV between January, 2003, and December, 2008. Missing data were imputed with multiple imputation. Patients were classified with non-recent or recent infection on the basis of an EIA-RI test, which was calibrated with serial measurements from HIV seroconverters from the French ANRS-PRIMO cohort. We used an adapted stratified extrapolation approach to calculate the number of new HIV infections in men who have sex with men (MSM), injecting drug users (IDUs), and heterosexual men and women by nationality. Population sizes were obtained from the national census and national behavioural studies.
After accounting for under-reporting, there were 6480 (95% CI 6190-6780) new diagnoses of HIV infection in France in 2008. We estimate that there were 6940 (6200-7690) new HIV infections in 2008, suggesting an HIV incidence of 17 per 100 000 person-years. In 2008, there were 3550 (3040-4050) new infections in heterosexuals (incidence of 9 per 100 000 person-years), 3320 (2830-3810) in MSM (incidence of 1006 per 100 000 person-years), and 70 (0-190) in IDUs (incidence of 86 per 100 000 person-years). Overall HIV incidence decreased between 2003 and 2008 (p<0·0001), but remained comparatively high and stable in MSM.
In France, HIV transmission disproportionately affects certain risk groups and seems to be out of control in the MSM population. Incidence should be tracked to monitor transmission dynamics in the various population risk groups and to help to target and assess prevention strategies.
French National Institute for Public Health Surveillance (InVS) and French National Agency for Research on AIDS and Viral Hepatitis (ANRS).
The normal microflora acts as a barrier against colonisation of potentially pathogenic microorganisms and against overgrowth of already present opportunistic microorganisms. Control of growth of opportunistic microorganisms is termed colonisation resistance. Administration of antimicrobial agents, therapeutically or as prophylaxis, causes disturbances in the ecological balance between the host and the normal microflora. Most studies on the impact of antimicrobial agents on normal microflora have been carried out on the intestinal flora. Less is known on the effects on oropharyngeal, skin, and vaginal microflora. Disturbances in the microflora depend on the properties of the agents as well as of the absorption, route of elimination, and possible enzymatic inactivation and/or binding to faecal material of the agents. The clinically most common disturbances in the intestinal microflora are diarrhoea and fungal infections that usually cease after the end of treatment. A well-balanced microflora prevents establishment of resistant microbial strains. By using antimicrobial agents that do not disturb colonisation resistance, the risk of emergence and spread of resistant strains between patients and dissemination of resistant determinants between microorganisms is reduced. In this article, the potential ecological effects of administration of antimicrobial agents on the intestinal, oropharyngeal, and vaginal microflora are summarised. The review is based on clinical studies published during the past 10 years.
Meningitis remains one of the most feared infectious diseases worldwide, yet there are few population-based studies on the epidemiology, causes, or trends over time in meningitis, especially in industrialised countries. Our aim was to do such a study using routinely reported data available in England and Wales.
In England and Wales, UK National Health Service hospitals routinely report laboratory-confirmed pathogens electronically to Public Health England. Records of all positive bacterial, mycobacterial, and fungal results from cerebrospinal fluid or from blood cultures in patients with clinical meningitis were extracted for analysis. The percentage change in annual incidence was estimated using linear regression analysis of the log of the annual incidence.
During 2004-11, 7061 cases of meningitis were reported (mean annual incidence 1·62 per 100 000 people, 95% CI 1·58-1·66), including 2594 cases in children (37%). The incidence of bacterial (1·44 per 100 000 people, 1·41-1·48), fungal (0·09, 0·08-0·10), and mycobacterial (0·09, 0·08-0·09) meningitis remained stable overall and across the age groups, apart from significant year-on-year increases in children younger than 3 months (978 cases; incidence 72·2 per 100 000 people; annual increase 7·4%, 5·1-9·8; p<0·0001) driven mainly by group B streptococci (GBS), and in adults aged 65 years or older (752 cases; incidence 1·2 per 100 000 people; annual increase 3·0%, 1·4-4·8; p<0·0001) primarily because of Escherichia coli. By contrast, meningococcal meningitis rates declined steadily, but remained the most common cause of meningitis in children. Overall, five groups of bacteria accounted for 60% (3790/6286) of bacterial meningitis cases: Neisseria meningitidis (1350 cases, 22%), Streptococcus pneumoniae (1143, 18%), Staphylococcus aureus (652, 10%), GBS (326, 5%), and E coli (319, 5%).
In England and Wales, laboratory-based surveillance shows a remarkably stable incidence of bacterial, fungal, and mycobacterial meningitis in recent years, although there were differences in individual trends among the main pathogens causing meningitis in different age groups.
During the past decade, several novel risk factors for atherosclerosis, including inflammation and infections, have been reported. Seroepidemiological studies suggest an association between several microbes and coronary heart disease. Microbes or their structural components are found in atherosclerotic plaques, but the only intact microbes commonly present are herpes viruses and Chlamydia pneumoniae. These agents are able to initiate and accelerate atherosclerosis in animal models. If they cause persistent infection in the vessel wall, they can directly promote a proinflammatory, procoagulant, and proatherogenic environment. Microbes could also have a remote effect--e.g., bacterial heat shock proteins with high sequence homology with human counterpart could, in the presence of a chronic infection, induce autoimmunity against vascular cells, and lead to an atherosclerotic process. Several intervention trials with antibiotics are underway, and will hopefully shed new light on the role of bacteria in atherosclerosis. The causal relationship can be proved by use of vaccination to prevent infections.
Pregnant women in malaria-endemic countries in sub-Saharan Africa are especially vulnerable to malaria. Recommended prevention strategies include intermittent preventive treatment with two doses of sulfadoxine-pyrimethamine and the use of insecticide-treated nets. However, progress with implementation has been slow and the Roll Back Malaria Partnership target of 80% coverage of both interventions by 2010 has not been met. We aimed to review the coverage of intermittent preventive treatment, insecticide-treated nets, and antenatal care for pregnant women in sub-Saharan Africa and to explore associations between coverage and individual and country-level factors, including the role of funding for malaria prevention.
METHODS We used data from nationally representative household surveys from 2009-11 to estimate coverage of intermittent preventive treatment, use of insecticide-treated nets, and attendance at antenatal clinics by pregnant women in sub-Saharan Africa. Using demographic data for births and published data for malaria exposure, we also estimated the number of malaria-exposed births (livebirths and stillbirths combined) for 2010 by country. We used meta-regression analysis to investigate the factors associated with coverage of intermittent preventive treatment and use of insecticide-treated nets.
RESULTS Of the 21·4 million estimated malaria-exposed births across 27 countries in 2010, an estimated 4·6 million (21·5%, 95% CI 19·3-23·7) were born to mothers who received intermittent preventive treatment. Insecticide-treated nets were used during pregnancy for 10·5 million of 26·9 million births across 37 countries (38·8%, 34·6-43·0). Antenatal care was attended at least once by 16·3 of 20·8 million women in 2010 (78·3%, 75·2-81·4; n=26 countries) and at least twice by 14·7 of 19·6 million women (75·1%, 72·9-77·3; n=22 countries). For the countries with previous estimates for 2007, coverage of intermittent preventive treatment increased from 13·1% (11·9-14·3) to 21·2% (18·9-23·5; n=14 countries) and use of insecticide-treated nets increased from 17·9% (15·1-20·7) to 41·6% (37·2-46·0; n=24 countries) in 2010. A fall in coverage by more than 10% was seen in two of 24 countries for intermittent preventive treatment and in three of 30 countries for insecticide-treated nets. High disbursement of funds for malaria control and a long time interval since adoption of the relevant policy were associated with the highest coverage of intermittent preventive treatment. High disbursement of funds for malaria control and high total fertility rate were associated with the greatest use of insecticide-treated nets, whereas a high per-head gross domestic product (GDP) was associated with less use of nets than was a lower GDP. Coverage of intermittent preventive treatment showed greater inequity overall than use of insecticide-treated nets, with richer, educated, and urban women more likely to receive preventive treatment than their poorer, uneducated, rural counterparts.
INTERPRETATION Although coverage of intermittent preventive treatment and use of insecticide-treated nets by pregnant women has increased in most countries, coverage remains far below international targets, despite fairly high rates of attendance at antenatal clinics. The effect of the implementation of WHO's 2012 policy update for intermittent preventive treatment, which aims to simplify the message and align preventive treatment with the focused antenatal care schedule, should be assessed to find out whether it leads to improvements in coverage.
FUNDING Bill & Melinda Gates Foundation.
We did a systematic review and meta-analysis of observational studies of the risk of HIV-1 transmission per heterosexual contact. 43 publications comprising 25 different study populations were identified. Pooled female-to-male (0.04% per act [95% CI 0.01-0.14]) and male-to-female (0.08% per act [95% CI 0.06-0.11]) transmission estimates in high-income countries indicated a low risk of infection in the absence of antiretrovirals. Low-income country female-to-male (0.38% per act [95% CI 0.13-1.10]) and male-to-female (0.30% per act [95% CI 0.14-0.63]) estimates in the absence of commercial sex exposure (CSE) were higher. In meta-regression analysis, the infectivity across estimates in the absence of CSE was significantly associated with sex, setting, the interaction between setting and sex, and antenatal HIV prevalence. The pooled receptive anal intercourse estimate was much higher (1.7% per act [95% CI 0.3-8.9]). Estimates for the early and late phases of HIV infection were 9.2 (95% CI 4.5-18.8) and 7.3 (95% CI 4.5-11.9) times larger, respectively, than for the asymptomatic phase. After adjusting for CSE, presence or history of genital ulcers in either couple member increased per-act infectivity 5.3 (95% CI 1.4-19.5) times versus no sexually transmitted infection. Study estimates among non-circumcised men were at least twice those among circumcised men. Low-income country estimates were more heterogeneous than high-income country estimates, which indicates poorer study quality, greater heterogeneity of risk factors, or under-reporting of high-risk behaviour. Efforts are needed to better understand these differences and to quantify infectivity in low-income countries.
Scaling up of antiretroviral therapy in low-resource countries is done on the basis of decentralised, integrated HIV care in rural facilities; however, laboratory monitoring is generally unavailable. We aimed to assess the effectiveness and safety of clinical monitoring alone (CLIN) in terms of non-inferiority to laboratory and clinical monitoring (LAB).
We did a randomised, open-label, non-inferiority trial in nine rural district hospitals in Cameroon. Eligible participants were adults (≥18 years) infected with HIV-1 group M (WHO disease stage 3-4) who had not previously received antiretroviral therapy, and were followed-up for 2 years by health-care workers in routine activities. We randomly assigned participants (1:1) to CLIN or LAB (counts of HIV viral load and CD4 cell every 6 months) groups with a computer-generated list. The primary outcome was non-inferiority of CLIN to LAB in terms of increase in CD4 cell count with a non-inferiority margin of 25%. We did all analyses in participants who attended at least one follow-up visit. This trial is registered with ClinicalTrials.gov, number NCT00301561.
238 (93%) of 256 participants assigned to CLIN and 221 (93%) of 237 assigned to LAB were eligible for analysis. CLIN was not non-inferior to LAB; the mean increase in CD4 cell count was 175 cells per μL (SD 190, 95% CI 151-200) with CLIN and 206 (190, 181-231) with LAB (difference -31 [-63 to 2] and non-inferiority margin -52 [-58 to -45]). Furthermore, in the predefined secondary outcome of treatment changes, 13 participants (6%) in the LAB group switched to second-line regimens whereas no participants in the CLIN group did so (p<0·0001). By contrast, other predefined secondary outcomes were much the same in both groups-viral suppression (<40 copies per mL; 465 [49%] of 952 measurements in CLIN vs 456 [52%] of 884 in LAB), HIV resistance (23 [10%] of 238 participants vs 22 [10%] of 219 participants), mortality (44 [18%] of 238 vs 32 [14%] of 221), disease progression (85 [36%] of 238 vs 64 [29%] of 221), adherence (672 [63%] of 1067 measurements vs 621 [61%] of 1011), loss to follow-up (21 [9%] of 238 vs 17 [8%] of 221), and toxic effects (46 [19%] of 238 vs 56 [25%] of 221).
Our findings support WHO's recommendation for laboratory monitoring of antiretroviral therapy. However, the small differences that we noted between the strategies suggest that clinical monitoring alone could be used, at least temporarily, to expand antiretroviral therapy in low-resource settings.
French National Agency for Research on AIDS (ANRS) and Ensemble pour une Solidarité Thérapeutique Hospitalière En Réseau (ESTHER).
Human papillomavirus vaccine prevents infection by two major oncogenic types of the virus. Continued screening is needed in vaccinated women to prevent cancers caused by high-risk types not included in the vaccine. An exaggerated sense of protection from the vaccine could lead to a decline in the rate of screening among vaccinated women, which in principle could lead to an increase in the incidence of cervical cancer. We present a simple mathematical model of vaccination, screening, and disease incidence, including an analysis of the effect of data uncertainties. For a population with opportunistic screening and 30% vaccine coverage, screening rates in vaccinated women would have to decline by at least 80% (median value of probabilistic uncertainty analysis) before the incidence of cervical cancer would increase in the era since the introduction of the vaccine. By comparison, the decline needed is at least 49% in a population with organised screening and 70% vaccine coverage. In populations that have highly effective cervical screening programmes, incidence of cervical cancer starts to increase after smaller, but still substantial, decreases in screening. Introduction of vaccine is unlikely to lead to an increased incidence of cervical cancer as a result of diminished screening.
One-third of the global population is believed to be infected with bacteria of the Mycobacterium tuberculosis complex, the causative agent of tuberculosis. More than 8 million new cases of tuberculosis occur annually leading to 2 million deaths. Mortality is particularly high in those coinfected with HIV and where the bacteria are multiple-drug-resistant strains--ie, strains resistant to at least isoniazid and rifampicin. Early diagnosis of tuberculosis and drug resistance improves survival and by identifying infectious cases promotes contact tracing, implementation of institutional cross-infection procedures, and other public-health actions. This review addresses significant advances made in the diagnosis of infection, clinical disease, and drug resistance over the past decade. It proposes operational criteria for a modern diagnostic service in the UK (as a model of a low-incidence country) and explores some of the economic issues surrounding the use of these techniques.
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.
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.
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.
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.
US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health.
Cationic antimicrobial peptides are produced by all organisms, from plants and insects to human beings, as a major part of their immediately effective, non-specific defences against infections. With the increasing development of antibiotic resistance among key bacterial pathogens, there is an urgent need to discover novel classes of antibiotics. Therefore, cationic peptides are being developed through clinical trials as anti-infective agents. In addition to their ability to kill microbes, these peptides seem to have effector functions in innate immunity and can upregulate the expression of multiple genes in eukaryotic cells. One such function might involve the dampening of signalling by bacterial molecules such as lipopolysaccharide and lipoteichoic acid.
Infection with either influenza A H5N1 virus in 1997 or avian influenza A H7N9 virus in 2013 caused severe pneumonia that did not respond to typical or atypical antimicrobial treatment, and resulted in high mortality. Both viruses are reassortants with internal genes derived from avian influenza A H9N2 viruses that circulate in Asian poultry. Both viruses have genetic markers of mammalian adaptation in their haemagglutinin and polymerase PB2 subunits, which enhanced binding to human-type receptors and improved replication in mammals, respectively. Hong Kong (affected by H5N1 in 1997) and Shanghai (affected by H7N9 in 2013) are two rapidly flourishing cosmopolitan megacities that were increasing in human population and poultry consumption before the outbreaks. Both cities are located along the avian migratory route at the Pearl River delta and Yangtze River delta. Whether the widespread use of the H5N1 vaccine in east Asia-with suboptimum biosecurity measures in live poultry markets and farms-predisposed to the emergence of H7N9 or other virus subtypes needs further investigation. Why H7N9 seems to be more readily transmitted from poultry to people than H5N1 is still unclear.
RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up.
Between March, 2007, and October, 2008, we enrolled healthy children aged 5-17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393.
894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5-54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1-61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12-18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria.
RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries.
PATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline.
Concurrent treatment of HIV and tuberculosis is complicated by drug interactions. We explored the safety and efficacy of raltegravir as an alternative to efavirenz for patients co-infected with HIV and tuberculosis.
We did a multicentre, phase 2, non-comparative, open-label, randomised trial at eight sites in Brazil and France. Using a computer-generated randomisation sequence, we randomly allocated antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≤18 years with a plasma HIV RNA concentration of >1000 copies per mL) to receive raltegravir 400 mg twice a day, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine (1:1:1; stratified by country). Patients began study treatment after the start of tuberculosis treatment. The primary endpoint was virological suppression at 24 weeks (HIV RNA <50 copies per mL) in all patients who received at least one dose of study drug (modified intention-to-treat analysis). We recorded death, study drug discontinuation, and loss to follow-up as failures to achieve the primary endpoint. We assessed safety in all patients who received study drugs. This study is registered in ClinicalTrials.gov, number NCT00822315.
Between July 3, 2009, and June 6, 2011, we enrolled and randomly assigned treatment to 155 individuals; 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65-88) in the raltegravir 400 mg group, 40 patients (78%, 67-90) in the raltegravir 800 mg group, and 32 patients (63%, 49-76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the raltegravir 400 mg group, four in the raltegravir 800 mg group, and two in the efavirenz group): none of the deaths was deemed related to study treatment.
Raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis.
French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Brazilian National STD/AIDS Program-Ministry of Health.
Immunomodulators include both immunostimulatory and immunosuppressive agents. Only recently have the basic mechanisms of topical immunotherapy been elucidated. Besides topical contact sensitisers (eg, diphencyprone or dinitrochlorobenzene), newer agents of the imidazoquinoline family such as imiquimod and resiquimod act by inducing cytokine secretion from monocytes or macrophages (interferon-alpha, interleukin-12, tumour-necrosis factor-alpha). The locally generated immune milieu leads to a Th1-dominance and cell-mediated immunity that have been used clinically to treat viral infections such as human papillomavirus (HPV), herpes simplex virus (HSV), mollusca, and cancerous lesions including initial squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. While these agents improve antigen-presentation by dendritic cells, they also act on B cells and lead to the synthesis of antibodies such as IgG2a much like the recently discovered immunostimulatory CpG-sequences that stimulate innate immunity. These sequences act as "danger signals" since they occur in bacterial and viral DNA, but are selectively methylated and inactivated in the mammalian genome. They share the induction of the same cytokines as imidazoquinolines but they show different magnitudes and kinetics of response. Topical immunotherapy with immunostimulatory agents shows potential for effective and patient-friendly treatment of inflammatory, infectious, and cancerous skin diseases. Immunoenhancers such as imdazoquinolines and CpG-sequences also have adjuvant properties that could improve conventional (protein) and DNA vaccination against cancer, atopy, and allergies.
Influenza A viruses are globally enzootic in swine populations. Swine influenza has been recognised only since 1918, but an anecdotal report suggests that a swine-influenza epizootic might have occurred in England in 1892, at the same time as an explosive epidemic (or pandemic recurrence) of human influenza. This outbreak suggests that the ecobiological association between human and swine influenza could extend to before 1918. By contrast with the recent documentation of swine influenza, influenza in horses has been well documented for hundreds of years, and was often linked temporally and geographically to epidemics of human influenza. Both decreased contact between people and horses, and the concomitant increase in swine production over the past century, might have altered the character and dynamics of influenza host-switch events between people and domestic mammals.
In 1918, two waves of epidemic influenza arose with very different clinical phenotypes. During the first wave, infection rates were high but mortality was low. During the second wave, high numbers of deaths occurred and mortality differed 30-100 times among seemingly similar groups of affected adults, but the reason for this variation is unclear. In 1918, the crews of most warships and some island populations were affected by influenza during both waves of infection and had no or very few deaths during the second wave. However, some warships and island populations were not affected during the first wave of infection and had high mortality during the second wave. These findings suggest that infection during the first wave protected against death, but not infection, during the second wave. If so, the two waves of infection were probably caused by antigenically distinct influenza viruses--not by one virus that suddenly increased in pathogenicity between the first and second waves. These findings are relevant to modern concerns that the 2009 influenza A H1N1 virus could suddenly increase in lethality.
Extensively drug-resistant (XDR) tuberculosis is defined as disease caused by Mycobacterium tuberculosis with resistance to at least isoniazid and rifampicin, any fluoroquinolone, and at least one of three injectable second-line drugs (amikacin, capreomycin, or kanamycin). The definition has applicable clinical value and has allowed for more uniform surveillance in varied international settings. Recent surveillance data have indicated that the prevalence of tuberculosis drug resistance has risen to the highest rate ever recorded. The gold standard for drug-susceptibility testing has been the agar proportion method; however, this technique requires several weeks for results to be determined. More sensitive and specific diagnostic tests are still unavailable in resource-limited settings. Clinical manifestations, although variable in different settings and among different strains, have in general shown that XDR tuberculosis is associated with greater morbidity and mortality than non-XDR tuberculosis. The treatment of XDR tuberculosis should include agents to which the organism is susceptible, and should continue for a minimum of 18-24 months. However, treatment continues to be limited in tuberculosis-endemic countries largely because of weaknesses in national tuberculosis health-care models. The ultimate strategy to control drug-resistant tuberculosis is one that implements a comprehensive approach incorporating innovation from the political, social, economic, and scientific realms.
The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results.
We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007.
511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0·0012) against first malaria episodes and 59% (36-74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6-77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4-78·0], p<0·001, according-to-protocol cohort).
Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment.
Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.
In this Historical Review we describe the 1950-59 UNICEF-supported campaign to eliminate tinea capitis, also known as ringworm, in Yugoslavia. Medical treatment for this infectious disease involved the use of ionising radiation. We discuss the possible health implications for the treated population. Data were collected from archive documents, newspapers from the 1950s, Yugoslavian scientific reports, interviews with patients who received treatment, and interviews with physicians who gave treatment during the campaign. The campaign screened 878 659 individuals and treated 49 389. On the basis of Israeli tinea capitis research, late health consequences (mainly cancer in the irradiated area) can be expected in the treated Serbian population. The discovery of treatment records for a substantial number of patients makes public-health action and further research possible. The findings are relevant to the Serbian medical community and populations in other countries that used a radiation-based technique for the treatment of tinea capitis.
The state of Bihar in India carries the largest share of the world's burden of antimony-resistant visceral leishmaniasis. We analysed clinical studies done in Bihar with different treatments between 1980 and 2004. Overall, 53 studies were included (all but one published), of which 15 were comparative (randomised, quasi-randomised, or non-randomised), 23 dose-finding, and 15 non-comparative. Data from comparative studies were pooled when appropriate for meta-analysis. Overall, these studies enrolled 7263 patients in 123 treatment arms. Adequacy of methods used to do the studies and report on them varied. Unresponsiveness to antimony has developed steadily in the past to such an extent that antimony must now be replaced, despite attempts to stop its progression by increasing dose and duration of therapy. The classic second-line treatments are unsuited: pentamidine is toxic and its efficacy has also declined, and amphotericin B deoxycholate is effective but requires hospitalisation for long periods and toxicity is common. Liposomal amphotericin B is very effective and safe but currently unaffordable because of its high price. Miltefosine-the first oral drug for visceral leishmaniasis-is now registered and marketed in India and is effective, but should be used under supervision to prevent misuse. Paromomycin (or aminosidine) is effective and safe, and although not yet available, a regulatory submission is due soon. To preserve the limited armamentarium of drugs to treat visceral leishmaniasis, drugs should not be deployed unprotected; combinations can make drugs last longer, improve treatment, and reduce costs to households and health systems. India, Bangladesh, and Nepal agreed recently to undertake measures towards the elimination of visceral leishmaniasis. The lessons learnt in Bihar could help inform policy decisions both regionally and elsewhere.
A better understanding of the effect of malaria control interventions on vector and parasite populations, acquired immunity, and burden of the disease is needed to guide strategies to eliminate malaria from highly endemic areas. We monitored and analysed the changes in malaria epidemiology in a village community in Senegal, west Africa, over 22 years.
Between 1990 and 2012, we did a prospective longitudinal study of the inhabitants of Dielmo, Senegal, to identify all episodes of fever and investigate the relation between malaria host, vector, and parasite. Our study included daily medical surveillance with systematic parasite detection in individuals with fever. We measured parasite prevalence four times a year with cross-sectional surveys. We monitored malaria transmission monthly with night collection of mosquitoes. Malaria treatment changed over the years, from quinine (1990-94), to chloroquine (1995-2003), amodiaquine plus sulfadoxine-pyrimethamine (2003-06), and finally artesunate plus amodiaquine (2006-12). Insecticide-treated nets (ITNs) were introduced in 2008.
We monitored 776 villagers aged 0-101 years for 2 378 150 person-days of follow-up. Entomological inoculation rate ranged from 142·5 infected bites per person per year in 1990 to 482·6 in 2000, and 7·6 in 2012. Parasite prevalence in children declined from 87% in 1990 to 0·3 % in 2012. In adults, it declined from 58% to 0·3%. We recorded 23 546 fever episodes during the study, including 8243 clinical attacks caused by Plasmodium falciparum, 290 by Plasmodium malariae, and 219 by Plasmodium ovale. Three deaths were directly attributable to malaria, and two to severe adverse events of antimalarial drugs. The incidence of malaria attacks ranged from 1·50 attacks per person-year in 1990 to 2·63 in 2000, and to only 0·046 in 2012. The greatest changes were associated with the replacement of chloroquine and the introduction of ITNs.
Malaria control policies combining prompt treatment of clinical attacks and deployment of ITNs can nearly eliminate parasite carriage and greatly reduce the burden of malaria in populations exposed to intense perennial malaria transmission. The choice of drugs seems crucial. Rapid decline of clinical immunity allows rapid detection and treatment of novel infections and thus has a key role in sustaining effectiveness of combining artemisinin-based combination therapy and ITNs despite increasing pyrethroid resistance.
Pasteur Institutes of Dakar and Paris, Institut de Recherche pour le Développement, and French Ministry of Cooperation.
The cascade of HIV care has become a focal point for implementation efforts to maximise the individual and public health benefits of antiretroviral therapy. We aimed to characterise longitudinal changes in engagement with the cascade of HIV care in British Columbia, Canada, from 1996 to 2011.
We used estimates of provincial HIV prevalence from the Public Health Agency of Canada and linked provincial population-level data to define, longitudinally, the numbers of individuals in each of the eight stages of the cascade of HIV care (HIV infected, diagnosed, linked to HIV care, retained in HIV care, highly active antiretroviral therapy (HAART) indicated, on HAART, adherent to HAART, and virologically suppressed) in British Columbia from 1996 to 2011. We used sensitivity analyses to determine the sensitivity of cascade-stage counts to variations in their definitions.
13 140 people were classified as diagnosed with HIV/AIDS in British Columbia during the study period. We noted substantial improvements over time in the proportions of individuals at each stage of the cascade of care. Based on prevalence estimates, the proportion of unidentified HIV-positive individuals decreased from 49·0% (estimated range 36·2-57·5%) in 1996 to 29·0% (11·6-40·7%) in 2011, and the proportion of HIV-positive people with viral suppression reached 34·6% (29·0-43·1%) in 2011.
Careful mapping of the cascade of care is crucial to understanding what further efforts are needed to maximise the beneficial effects of available interventions and so inform efforts to contain the spread of HIV/AIDS.
British Columbia Ministry of Health, US National Institute on Drug Abuse (National Institutes of Health).
Infectious diseases account for 15 million deaths per year worldwide, and disproportionately affect young people, elderly people, and the poorest sections of society. We aimed to describe the investments awarded to UK institutions for infectious disease research.
Methods: We systematically searched databases and websites for information on research studies from funding institutions and created a comprehensive database of infectious disease research projects for the period 1997–2010. We categorised studies and funding by disease, cross-cutting theme, and by a research and development value chain describing the type of science. Regression analyses were reported with Spearman's rank correlation coefficient to establish the relation between research investment, mortality, and disease burden as measured by disability-adjusted life years (DALYs).
Findings: We identified 6170 funded studies, with a total research investment of UK£2·6 billion. Studies with a clear global health component represented 35·6% of all funding (£927 million). By disease, HIV received £461 million (17·7%), malaria £346 million (13·3%), tuberculosis £149 million (5·7%), influenza £80 million (3·1%), and hepatitis C £60 million (2·3%). We compared funding with disease burden (DALYs and mortality) to show low levels of investment relative to burden for gastrointestinal infections (£254 million, 9·7%), some neglected tropical diseases (£184 million, 7·1%), and antimicrobial resistance (£96 million, 3·7%). Virology was the highest funded category (£1 billion, 38·4%). Leading funding sources were the Wellcome Trust (£688 million, 26·4%) and the Medical Research Council (£673 million, 25·8%).
Interpretation: Research funding has to be aligned with prevailing and projected global infectious disease burden. Funding agencies and industry need to openly document their research investments to redress any inequities in resource allocation.
Control of HIV transmission could be achievable through an expansion of HIV testing of at-risk populations together with ready access and adherence to antiretroviral therapy. To examine whether increases in testing rates and antiretroviral therapy coverage correspond to the control of HIV transmission, we estimated HIV incidence in men who have sex with men (MSM) in England and Wales since 2001.
A CD4-staged back-calculation model of HIV incidence was used to disentangle the competing contributions of time-varying rates of diagnosis and HIV incidence to observed HIV diagnoses. Estimated trends in time to diagnosis, incidence, and undiagnosed infection in MSM were interpreted against a backdrop of increased HIV testing rates and antiretroviral-therapy coverage over the period 2001-10.
The observed 3·7 fold expansion in HIV testing in MSM was mirrored by a decline in the estimated mean time-to-diagnosis interval from 4·0 years (95% credible interval [CrI] 3·8-4·2) in 2001 to 3·2 years (2·6-3·8) by the end of 2010. However, neither HIV incidence (2300-2500 annual infections) nor the number of undiagnosed HIV infections (7370, 95% CrI 6990-7800, in 2001, and 7690, 5460-10 580, in 2010) changed throughout the decade, despite an increase in antiretroviral uptake from 69% in 2001 to 80% in 2010.
CD4 cell counts at HIV diagnosis are fundamental to the production of robust estimates of incidence based on HIV diagnosis data. Improved frequency and targeting of HIV testing, as well as the introduction of ART at higher CD4 counts than is currently recommended, could begin a decline in HIV transmission among MSM in England and Wales.
UK Medical Research Council, UK Health Protection Agency.
National and international strategies for the control of antibiotic resistance recommend education for health-care professionals and the public to promote prudent antibiotic use. This paper, based on discussions at the 2002 colloquium of the International Forum on Antibiotic Resistance (IFAR), provides an international discourse between theoretical approaches to behaviour change and practical experience gained in large-scale antibiotic use educational campaigns. Interventions are more likely to be effective if their aim is to change behaviour, rather than provide information. They should target all relevant groups, especially parents, children, day-care staff, and health-care professionals. They should use clear and consistent messages concerning bacterial versus viral infection, prudent antibiotic use, symptomatic treatment, and infection-control measures (eg, handwashing). Campaigns should use a range of communications using pilot-testing, strong branding, and sociocultural adaptation. Prime-time television is likely to be the most effective public medium, while academic detailing is especially useful for health-care professionals. Multifaceted interventions can improve antibiotic prescribing to some degree. However, there are few data on their effects on resistance patterns and patient outcomes, and on their cost-effectiveness. Current research aims include the application of behaviour-change models, the development and validation of prudent antibiotic prescribing standards, and the refinement of tools to assess educational interventions.
Since it was first reported in December 2003, the outbreak of avian influenza A/H5N1 has spread to at least nine countries in Asia, affected multiple species of animals, and caused at least 42 human deaths. The magnitude and extent of this zoonotic outbreak are unprecedented, continue to grow, and threaten the start of a global human influenza pandemic. Control of the H5N1 outbreak has required the implementation of integrated human and veterinary health surveillance and response efforts. These efforts have also necessitated an unprecedented level of bilateral and multilateral international communication and cooperation. This report describes the contribution of one public-health veterinarian to the H5N1 outbreak response effort in Laos, and emphasises the value of multidisciplinary approaches to addressing this and future emerging infectious disease outbreaks.
Smallpox vaccine was the most important tool in the successful eradication of smallpox. In 1980, this achievement made it possible for all nations to cease smallpox vaccination. However, the threat of smallpox bioterrorism has made it necessary to reconsider the need for vaccination. Over the past 3 years, many nations have set up action plans for use in the event of such an attack. The setting up of these plans was not simple. Several factors needed to be considered, including the judgement of risk, vaccine complications, conventional vaccines versus new vaccines, optimal stockpile of smallpox vaccine, and its use for different target populations in different emergency situations. Here, I review measures taken by the USA, Japan, and other nations, and discuss likely national and global efforts in 2005 and subsequently, in view of the fact that half of the world's population is now apparently unvaccinated and that this proportion will increase with time.
We did a systematic search and synthesis of evidence on the incidence of invasive pneumococcal disease, symptomatic disease, and circulating Streptococcus pneumoniae serotypes in western Europe. Using data from studies published between 1992 and 2005 we calculated a weighted mean invasive pneumococcal disease and pneumococcal meningitis incidence rate per 100,000 children aged 2 years or younger within 95% confidence intervals, together with the prevalence of S. pneumoniae serotypes and resistance to penicillin. Invasive pneumococcal disease incidence was 27.03 cases per 100,000 children under 2 years (95% CI 21.85-33.43) [corrected] Heptavalent conjugate vaccine serotypes account for 43.18-75.32% of isolates among people aged under 18 years of age. 11% of isolates in individuals aged under 18 years were penicillin resistant. The incidence of invasive pneumococcal disease appeared consistently lower in western European countries compared with studies from the USA. Thus the use of studies of vaccine effectiveness based on the US population may lead to an overestimation of the benefits of its introduction in Europe.
Effective treatment of gonorrhoea is fundamental to public health control; however, the ability of Neisseria gonorrhoeae to successively develop resistance to different treatments has hampered control efforts. The extended-spectrum cephalosporins--cefixime and ceftriaxone--have been recommended in the UK for treatment of gonorrhoea since 2005. We looked at surveillance data from England and Wales to ascertain the current usefulness of these drugs and to inform changes to national treatment guidelines.
We obtained data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) for patients attending 26 genitourinary medicine clinics in England and Wales between 2007 and 2011. We did analyses with univariate and multivariable logistic regression methods to identify trends in susceptibility to cephalosporins and risk factors associated with infection with isolates with decreased susceptibility to cefixime, and we assessed changes in prescribing practices. We did molecular typing to investigate genetic relatedness of non-susceptible isolates.
The prevalence of decreased susceptibility to both cefixime and ceftriaxone rose between 2007 and 2010 but was more noticeable for cefixime (an increase from 1·5% in 2007 to 17·1% in 2010), with a bimodal distribution of minimum inhibitory concentration recorded between 2009 and 2010. By multivariable analysis, isolates with decreased susceptibility to cefixime were associated with infection in men who have sex with men (odds ratio 5·47, 95% CI 3·99-7·48; p<0·0001) and year of isolation (in 2010, 13·08, 7·49-22·8; p<0·0001). Such isolates had a largely clonal population, with most belonging to genogroup G1407 and harbouring the penA mosaic gene. Data from 2011 showed a significant decline in prevalence of isolates with decreased cefixime susceptibility, falling from 17·1% in 2010 to 10·8% in 2011 (p<0·0001), concomitant with the change in prescribing practice in 2010 from cefixime to ceftriaxone plus azithromycin.
Guidance for treatment of gonorrhoea in England and Wales was changed in 2010 to prolong the use of cephalosporins. The decline in prevalence of isolates with decreased cefixime susceptibility cannot be attributed unequivocally to this change in prescribing practice; however, the association is striking.
Department of Health (England), Public Health England.