Ten-year mortality trends among persons diagnosed with HIV infection in England and Wales in the era of antiretroviral therapy: AIDS remains a silent killer.

OBJECTIVES: We present national trends in death rates and the proportion of deaths attributable to AIDS in the era of effective antiretroviral therapy (ART), and examine risk factors associated with an AIDS-related death. METHODS: Analyses of the national HIV-infected cohort for England and Wales linked to death records from the Office of National Statistics were performed. Annual all-cause mortality rates were calculated by age group and sex for the years 1999-2008 and rates for 2008 were compared with death rates in the general population. Risk factors associated with an AIDS-related death were investigated using a case-control study design. RESULTS: The all-cause mortality rate among persons diagnosed with HIV infection aged 15-59 years fell over the decade: from 217 per 10 000 in 1999 to 82 per 10 000 in 2008, with declines in all age groups and exposure categories except women aged 50-59 years and persons who inject drugs (rate fluctuations in both of these groups were probably a result of small numbers). Compared with the general population (15 per 10 000 in 2008), death rates among persons diagnosed with HIV infection remained high, especially in younger persons (aged 15-29 years) and persons who inject drugs (13 and 20 times higher, respectively). AIDS-related deaths accounted for 43% of all deaths over the decade (24% in 2008). Late diagnosis (CD4 count < 350 cells/µL) was the most important predictor of dying of AIDS [odds ratio (OR) 10.55; 95% confidence interval (CI) 8.22-13.54]. Sixty per cent of all-cause mortality and 81% of all AIDS-related deaths were attributable to late diagnosis. CONCLUSIONS: Despite substantial declines, death rates among persons diagnosed with HIV infection continue to exceed those of the general population in the ART era. Earlier diagnosis could have prevented 1600 AIDS-related deaths over the decade. These findings highlight the need to intensify efforts to offer and recommend an HIV test in a wider range of clinical and community settings.

Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study.

Within the Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) project we conducted a multicentre case­control study in eight European Union (EU) Member States to estimate the 2011/12 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory-confirmed as influenza A(H3) among the vaccination target groups. Practitioners systematically selected ILI / acute respiratory infection patients to swab within seven days of symptom onset. We restricted the study population to those meeting the EU ILI case definition and compared influenza A(H3) positive to influenza laboratory-negative patients. We used logistic regression with study site as fixed effect and calculated adjusted influenza vaccine effectiveness (IVE), controlling for potential confounders (age group, sex, month of symptom onset, chronic diseases and related hospitalisations, number of practitioner visits in the previous year). Adjusted IVE was 25% (95% confidence intervals (CI): -6 to 47) among all ages (n=1,014), 63% (95% CI: 26 to 82) in adults aged between 15 and 59 years and 15% (95% CI: -33 to 46) among those aged 60 years and above. Adjusted IVE was 38% (95%CI: -8 to 65) in the early influenza season (up to week 6 of 2012) and -1% (95% CI: -60 to 37) in the late phase. The results suggested a low adjusted IVE in 2011/12. The lower IVE in the late season could be due to virus changes through the season or waning immunity. Virological surveillance should be enhanced to quantify change over time and understand its relation with duration of immunological protection. Seasonal influenza vaccines should be improved to achieve acceptable levels of protection.

Influenza-related deaths--available methods for estimating numbers and detecting patterns for seasonal and pandemic influenza in Europe.

Two methodologies are used for describing and estimating influenza-related mortality: Individual-based methods, which use death certification and laboratory diagnosis and predominately determine patterns and risk factors for mortality, and population-based methods, which use statistical and modelling techniques to estimate numbers of premature deaths. The total numbers of deaths generated from the two methods cannot be compared. The former are prone to underestimation, especially when identifying influenza-related deaths in older people. The latter are cruder and have to allow for confounding factors, notably other seasonal infections and climate effects. There is no routine system estimating overall European influenza-related premature mortality, apart from a pilot system EuroMOMO. It is not possible at present to estimate the overall influenza mortality due to the 2009 influenza pandemic in Europe, and the totals based on individual deaths are a minimum estimate. However, the pattern of mortality differed considerably between the 2009 pandemic in Europe and the interpandemic period 1970 to 2008, with pandemic deaths in 2009 occurring in younger and healthier persons. Common methods should be agreed to estimate influenza-related mortality at national level in Europe, and individual surveillance should be instituted for influenza-related deaths in key groups such as pregnant women and children.

Experience and lessons from surveillance and studies of the 2009 pandemic in Europe.

Surveillance and studies in a pandemic is a complex topic including four distinct components: (1) early detection and investigation; (2) comprehensive early assessment; (3) monitoring; and (4) rapid investigation of the effectiveness and impact of countermeasures, including monitoring the safety of pharmaceutical countermeasures. In the 2009 pandemic, the prime early detection and investigation took place in the Americas, but Europe needed to undertake the other three components while remaining vigilant to new phenomenon such as the emergence of antiviral resistance and important viral mutation. Laboratory-based surveillance was essential and also integral to epidemiological and clinical surveillance. Early assessment was especially vital because of the many important strategic parameters of the pandemic that could not be anticipated (the 'known unknowns'). Such assessment did not need to be undertaken in every country, and was done by the earliest affected European countries, particularly those with stronger surveillance. This was more successful than requiring countries to forward primary data for central analysis. However, it sometimes proved difficult to get even those analyses from European counties, and information from Southern hemisphere countries and North America proved equally valuable. These analyses informed which public health and clinical measures were most likely to be successful, and were summarized in a European risk assessment that was updated repeatedly. The estimate of the severity of the pandemic by the World Health Organization (WHO), and more detailed description by the European Centre for Disease Prevention and Control in the risk assessment along with revised planning assumptions were essential, as most national European plans envisaged triggering more disruptive interventions in the event of a severe pandemic. Setting up new surveillance systems in the midst of the pandemic and getting information from them was generally less successful. All European countries needed to perform monitoring (Component 3) for the proper management of their own healthcare systems and other services. The information that central authorities might like to have for monitoring was legion, and some countries found it difficult to limit this to what was essential for decisions and key communications. Monitoring should have been tested for feasibility in influenza seasons, but also needed to consider what surveillance systems will change or cease to deliver during a pandemic. International monitoring (reporting upwards to WHO and European authorities) had to be kept simple as many countries found it difficult to provide routine information to international bodies as well as undertaking internal processes. Investigation of the effectiveness of countermeasures (and the safety of pharmaceutical countermeasures) (Component 4) is another process that only needs to be undertaken in some countries. Safety monitoring proved especially important because of concerns over the safety of vaccines and antivirals. It is unlikely that it will become clear whether and which public health measures have been successful during the pandemic itself. Piloting of methods of estimating influenza vaccine effectiveness (part of Component 4) in Europe was underway in 2008. It was concluded that for future pandemics, authorities should plan how they will undertake Components 2-4, resourcing them realistically and devising new ways of sharing analyses.

"I-MOVE" towards monitoring seasonal and pandemic influenza vaccine effectiveness: lessons learnt from a pilot multi-centric case-control study in Europe, 2008-9.

Within I-MOVE (European programme to monitor seasonal and pandemic influenza vaccine effectiveness (IVE)) five countries conducted IVE pilot case-control studies in 2008-9. One hundred and sixty sentinel general practitioners (GP) swabbed all elderly consulting for influenza-like illness (ILI). Influenza confirmed cases were compared to influenza negative controls. We conducted a pooled analysis to obtain a summary IVE in the age group of >or=65 years. We measured IVE in each study and assessed heterogeneity between studies qualitatively and using the I2 index. We used a one-stage pooled model with study as a fixed effect. We adjusted estimates for age-group, sex, chronic diseases, smoking, functional status, previous influenza vaccinations and previous hospitalisations. The pooled analysis included 138 cases and 189 test-negative controls. There was no statistical heterogeneity (I2=0) between studies but ILI case definition, previous hospitalisations and functional status were slightly different. The adjusted IVE was 59.1% (95% CI: 15.3-80.3%). IVE was 65.4% (95% CI: 15.6-85.8%) in the 65-74, 59.6% (95% CI: -72.6 -90.6%) in the age group of >or=75 and 56.4% (95% CI: -0.2-81.3%) for A(H3). Pooled analysis is feasible among European studies. The variables definitions need further standardisation. Larger sample sizes are needed to achieve greater precision for subgroup analysis. For 2009-10, I-MOVE will extend the study to obtain early IVE estimates in groups targeted for pandemic H1N1 influenza vaccination.

Oseltamivir-resistant influenza A(H1N1) viruses detected in Europe during season 2007-8 had epidemiologic and clinical characteristics similar to co-circulating susceptible A(H1N1) viruses.

During the 2007-08 influenza season, high levels of oseltamivir resistance were detected among influenza A(H1N1) viruses ina number of European countries. We used surveillance data to describe influenza A(H1N1) cases for whom antiviral resistance testing was performed. We pooled data from national studies to identify possible risk factors for infection with a resistant virus and to ascertain whether such infections led to influenza illness of different severity. Information on demographic and clinical variables was obtained from patients or their physicians. Odds ratios for infection with an oseltamivir resistant virus and relative risks for developing certain clinical outcomes were computed and adjusted through multivariable analysis. Overall, 727 (24.3%) of 2,992 tested influenza A(H1N1) viruses from 22 of 30 European countries were oseltamivir-resistant. Levels of resistance ranged from 1% in Italy to 67% in Norway. Five countries provided detailed case-based data on 373 oseltamivir resistant and 796 susceptible cases. By multivariable analysis, none of the analysed factors was significantly associated with an increased risk of infection with anoseltamivir-resistant virus. Similarly, infection with an oseltamivir-resistant virus was not significantly associated with a different risk of pneumonia, hospitalisation or any clinical complication. The large-scale emergence of oseltamivir-resistant viruses in Europe calls for a review of guidelines for influenza treatment.

Pandemic influenza A(H1N1) 2009 vaccines in the European Union.

Pandemic vaccines from four manufacturers are now available for use within the European Union (EU). Use of these vaccines will protect individuals and reduce the impact on health services to more manageable levels. The majority of the severely ill will be from known risk groups and the best strategy will be to start vaccinating in line with the recommendation from the European Union Health Security Committee prioritizing adults and children with chronic conditions, pregnant women and healthcare workers. The composition of authorized vaccines is reviewed in this article. The vaccine strain in all authorized pandemic vaccines worldwide is based on the same initial isolate of influenza A/California/7/2009 (H1N1)v but the vaccines differ in conditions for virus propagation, antigen preparation, antigen content and whether they are adjuvanted or not. The vaccines are likely to be effective since no significant genetic or antigenic drift has occurred and there are already mechanisms for estimating clinical effectiveness. Influenza vaccines have good safety records and no safety concerns have so far been encountered with any of the vaccines developed. However, special mechanisms have been devised for the early detection and rigorous investigation of possible significant side effects in Europe through post-marketing surveillance and analysis. Delivery of the vaccines to the risk groups will pose difficulties where those with chronic illnesses are not readily identifiable to the healthcare services. There is considerable scope for European added value through Member States with excess vaccines making them available to other states.

Use of oseltamivir in 12 European countries between 2002 and 2007--lack of association with the appearance of oseltamivir-resistant influenza A(H1N1) viruses.

Variable levels of oseltamivir resistance among seasonal influenza A(H1N1) isolates have been reported in Europe during the 2007-8 northern Hemisphere influenza season. It has been questioned whether oseltamivir use could have driven the emergence and predominance of resistant viruses. This study aimed at describing the levels of use of oseltamivir in 12 European Union (EU) Member States and European Economic Area (EEA)/European Free Trade Area (EFTA) countries. The data were converted into prescription rates and compared with the national proportions of resistant influenza A(H1N1) viruses through regression analysis. Overall use of oseltamivir in European countries between 2002 and 2007 was low compared to e.g. the use in Japan. High variability between the countries and over time was observed. In eight of the 12 countries, there was a peak of prescriptions in 2005, coinciding with concerns about a perceived threat from an influenza pandemic which might have lead to personal stockpiling. Ecological comparison between national levels of use of oseltamivir in 2007 and the proportions of A(H1N1) viruses that were resistant to oseltamivir showed no statistical association. In conclusion, our results do not support the hypothesis that the emergence and persistence of these viruses in 2007-8 was related to the levels of use of oseltamivir in Europe. Further investigation is needed to elucidate the reasons for different level of use between the countries.

Start of the influenza season 2008-9 in Europe - increasing influenza activity moving from West to East dominated by A(H3N2).

The influenza season 2008-9 started in week 49 of 2008 and is so far characterised by influenza virus type A subtype H3N2. Isolates of this subtype that were tested proved susceptible to neuraminidase inhibitors, but resistant to M2 inhibitors. The circulating A(H3N2) viruses are antigenically similar to the component in the current northern hemisphere influenza vaccine.

Observed oseltamivir resistance in seasonal influenza viruses in Europe interpretation and potential implications.

In this weeks issue of Eurosurveillance, Zambon and colleagues describe the first findings of the European Union-funded European Surveillance Network for Vigilance Against Viral Resistance (VIRGIL) of some seasonal influenza viral isolates resistant to the antiviral drug oseltamivir in Europe.

[Kidney transplantation in Italy: an evolving scenario]. / Il trapianto di rene in Italia: una realtà in evoluzione.

BACKGROUND: Italian transplantation systems have dramatically improved in the last decade. Kidney transplantations are now strictly monitored and excellent results has been achieved in terms of quality and the ability to reduce waiting times for receiving transplantation. METHODS: The Italian organizational retrieval and transplant system is articulated on four levels: local, regional, inter-regional and national. The Italian Transplant Information System (SIT) was set up in 2000 in accordance with Law 91/99. Patient data on the waiting lists and follow-up of transplanted patients are routinely collected. RESULTS: A total of 4406 kidney transplants have been carried out in the 40 Italian kidney transplant centers in 2001-2003. The survival analysis was conducted for the 2000-2002 in 4222 cases. Overall 1-yr survival was 92.4% for the graft and 97% for the patients. After adjusting for variables independently associated with the outcome at multivariate analysis (for example, the case-mix), patient and graft survival at 1 yr was 98.1% and 93.8%, respectively. No remarkable differences in 1-yr graft survival were observed between the 40 Italian kidney transplant centers. At multivariate analysis, variables independently associated with graft failure were donor age, degree of HLA mismatch and recipient case-mix. Analysis of the waiting list showed approximately 6500 patients waiting for kidney transplantation. The mean waiting time was 3.04 yrs, with a mortality rate of 1.18% per year. CONCLUSIONS: Kidney transplantation activity in Italy has produced excellent results in terms of quality and number of transplants per year. However, the number of patients on the waiting list and the waiting time call for further action to increase the number of available organs.

Optimizing the organ procurement process: organizational prerequisites and monitoring strategies in a national network.

The current project sought to collect detailed information on the Italian donation system and in particular on the organization and functioning of the local coordinating centers. The final objective was to provide local and regional institutions with the information required to improve the system. While improving the knowledge of current Italian donation system, the project had constructive purposes. Our intention was to analyze how the national system is working, what the coordinating centers are actually doing, how they are organized, to what extent existing rules are obeyed, and what are the main limits of the system. This analysis sought to lead to the development of a set of proposals that can be summarized in two categories: (1) "intrinsic" actions, that is, those established and implemented at the hospital level; and (2) supporting "extrinsic" actions, that is, those identified by the National Transplant Centre and addressed to the regional and interregional coordinating networks. Finally, the analysis of the application of the existing rules should lead to the development of practice guidelines such that each center conforms to the existing regulations established by European directives.

Correlates of independent HIV-1 replication in the CNS and of its control by antiretrovirals.

OBJECTIVE: To investigate in detail factors associated with independent replication of HIV-1 in CNS, and to predict its therapeutic control. METHODS: HIV RNA concentration was measured by PCR in 134 cross-sectional paired plasma and CSF samples from 95 patients infected with HIV-1 with various conditions, and in longitudinal CSF samples from 50 patients on antiretroviral treatment. Monocyte chemotactic protein (MCP)-1 was quantified in CSF by ELISA. RESULTS: High HIV RNA levels either in plasma or in CSF did not correlate with HIV RNA concentration in the paired biologic sample. A high CSF-to-plasma HIV RNA ratio, suggesting independent viral replication in the CNS, was associated with higher CSF viral load and higher CSF MCP-1 levels. Higher MCP-1 levels in the CSF were also associated with neurologic disorders and were not influenced by the use of highly active antiretroviral therapy (HAART). A higher number of antiretroviral drugs with CSF penetration correlated with a more profound CSF HIV-1 load reduction, independently from the use of HAART alone. Virologic suppression in CSF was predicted by a higher number of CSF-penetrating antiretrovirals and by the baseline CSF viral load, whereas lower baseline CD4 counts and higher MCP-1 levels were associated with increased risk of virologic failure. CONCLUSIONS: Quantification of HIV RNA in CSF is clinically useful, particularly in patients with neurologic disorders. CSF penetration of antiretrovirals must be considered when choosing treatments, mainly in patients with higher CSF viral loads, advanced disease, and CNS disorders associated with significant macrophage activation.

Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy.

OBJECTIVES: To evaluate the impact of response to highly active antiretroviral therapy (HAART) on the natural history of AIDS non-Hodgkin's lymphoma (NHL) and to analyse the feasibility, efficacy and toxicity of HAART in combination with chemotherapy. DESIGN: Prospective observational study in two AIDS clinical centres in Italy. METHODS: All consecutive HIV-infected patients with NHL were included (n = 44; 48% high-risk group) and prospectively followed for 27 months. HAART was administered concomitantly with chemotherapy. The association between response to HAART and clinical presentation, response to chemotherapy and toxicity was analysed by univariate and multivariate models. Survival analysis was performed by Kaplan-Meier estimates and the Cox proportional hazards regression model. RESULTS: A complete response (CR) to chemotherapy was achieved in 71% of HAART responders and 30% of non-responders. Virological response to HAART was the only variable associated with tumour response on multivariate analysis. A higher relative dose intensity (RDI) of chemotherapy was administered in patients with virological response compared with those without. The probability of 1 year survival was higher in patients with virological or immunological response. At Cox regression analysis, immunological response, a higher RDI and a CR to chemotherapy were all associated with a reduced risk of death. CONCLUSION: In HIV-infected patients with NHL, response to HAART was strongly associated with a better response to chemotherapy and prolonged survival. Concurrent treatments were well tolerated, and HAART-responder patients could receive a higher RDI of chemotherapy. In patients with AIDS lymphomas, combining HAART with chemotherapy could be a feasible and effective approach.

Epidemiology and prognosis of AIDS-associated progressive multifocal leukoencephalopathy in the HAART era.

Whereas most AIDS-related neurologic disorders have reduced incidence since HAART therapy was introduced, we find that the incidence of progressive multifocal leukoencephalopathy (PML) did not significantly differ between the pre-HAART and the HAART period (OR 0.78; 95% CI 0.41-1.50). These findings were confirmed by the preliminary results of the Italian Register Investigative Neuro AIDS (IRINA) Study, a prospective multicenter study started in January 2000, which showed that PML was the second most frequently diagnosed neurologic disorder after TE. A similar proportion of cases were found in HAART-naïve and HAART-experienced patients in our experience. PML was more common in the presence of HIV RNA > 500 copies/ml. Most of the cases occurring in HAART-exposed patients developed within the first 6 months of therapy. As others have reported, we find a prolonged survival in PML subjects prescribed HAART (245 days in the group treated with HAART versus 66 days in the group not treated with HAART; P at log rank = 0.001). However despite the survival benefit, AIDS-associated PML still has a serious prognosis. In fact, PML had the lowest 1-year survival probability of any cerebral disorder in our study (P = 0.0005). Our findings also confirm that CSF JCV DNA burden at baseline is a useful prognostic indicator with a threshold of 4.7 log(10) JCV copies/ml (P at log rank = 0.01) in our experience. CSF JCV DNA load at 4 weeks of follow-up and clearance of JCV-DNA from CSF are associated with a better neurologic outcome and a longer survival.