The Situation of Hiv/m. Tuberculosis Co-infection in Europe

This article provides an overview of the situation of HIV/AIDS, tuberculosis (TB), and HIV/MTB co-infection in the 27 member states of the European Union (EU27), prepared in the context of the FP7 project EUCO-Net (European Network for global cooperation in the field of AIDS & TB). Information contained herein, together with similar reports compiled for the four other EUCO-Net partner regions Africa, India, Russia, and South America provided the basis for the development of the EUCO-Net AIDS/TB Roadmap, a document which was compiled to support and facilitate the development of national, regional, and global research priorities and health policies, and to help boost international cooperation aimed at combating the scourge of HIV/AIDS, TB, and their deadly combination. A comprehensive overview of the national situation in all 27 EU member states is a prerequisite for effective disease management and adequate priority setting in research and development (R&D) activities in Europe. Therefore, results presented here include demographic and epidemiological data on HIV and MTB infection, both separately and combined, as well as information concerning disease management such as diagnostics, resistance testing, treatment, and associated economic costs. Results of the primary data collection were presented at the " AIDS/TB workshop on research challenges and opportunities for future collaboration " at the University of Stellenbosch, South Africa, in July 2009, which brought together more than 60 scientists from Europe and all EUCO-Net target regions to discuss future joint AIDS/TB research. In this context, intercultural aspects that may hamper cross-national cooperation and research in these fields such as language barriers, different ethical regulations, or operational challenges were also taken into account. The article concludes by summarizing the jointly identified key areas to improve disease management within the EU and by recommending priority areas for future AIDS/TB research in Europe.


BACKGROUND
Tuberculosis and HIV/AIDS represent a global public health problem with considerable mutual interaction: HIV suppresses parts of the immune system rendering patients more vulnerable to acquiring TB infection or reactivation, and TB is a leading cause of mortality for people living with HIV/AIDS.In addition, the diagnosis of TB in HIV-infected patients is particularly challenging.
The burden of morbidity and mortality without doubt lies heaviest upon areas of the world such as sub-Saharan Africa, Russia, and the Indian subcontinent.Nevertheless, the EU cannot afford to be complacent as it faces its own crisis from HIV/MTB infection.The greatest threat is conferred by the high rate of multidrug-resistant (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB).These forms of TB that are resistant to first-line (MDR-TB) and second-line (XDR-TB) medications require early diagnosis to prevent further spread, prolonged hospital stays, and protracted courses of expensive treatment with no guarantee of cure.Groups particularly at risk for MDR-TB and XDR-TB include those from countries of the former USSR, central Asia, and institutionalized populations such as prisoners [1].
*Address correspondence to this author at the European Research and Project Office GmbH, Saarbrücken, Germany; Tel: +49 681 95923378; Fax: +49 681 95923370; E-mail: c.giehl@eurice.eu The predominant transmission mode of HIV infection varies by area, illustrating the wide diversity in the epidemiology of HIV in Europe.In the East, injecting drug use is still the main mode of transmission and incidence is increasing, while in central Europe HIV transmission predominantly occurs between men who have sex with men (MSM) followed by heterosexual contact.This also holds true for Western Europe, when cases originating from countries with generalized epidemics are excluded [2].In all EU countries, sex workers and migrant populations from high prevalence areas are particularly at risk.Although mother-to-child transmission (MTCT) may represent a further concern, effective antenatal, delivery, and postnatal interventions can decrease its risk to <1% [3].
Co-infection with both HIV and MTB is a serious and, in some areas, growing health issue within Europe [4].In 2008, 5.6% (23,800) of all reported new TB cases in the WHO European Region § were estimated to be associated with HIV co-infection [5].

DEMOGRAPHIC DATA
Demographic data for each European country were collected from the WHO Annual Report or National Statistics Institutes, with the year of reference of available data varying from 2004 to 2010.
The combined population of the EU member states is provisionally estimated at 501 million people for 2010 [6].In comparison to some of the EUCO-Net partner regions, the age distribution within the EU is weighted towards older members of society, with those aged greater than 64 years constituting 12.7% of the total population, and children under 14 years constituting 15.8% [6].In 2008, the predicted life expectancy at birth in the EU for males was 76.3 years and 82.4 for females, again in striking contrast to some of our partner regions [7].Overall, population growth remains relatively static for the EU with estimated growth of 0.098% for 2010.
Within the EU, there is significant variation between the member states on key demographic variables (Table 1).All but one of the 11 countries whose life expectancy for males falls below the average for the EU are former Eastern European countries who joined the EU in 2004 or 2007 (Lithuania, Latvia, Estonia, Romania, Bulgaria, Hungary, Slovakia, Poland, Czech Republic, and Slovenia).Nine of these countries also have the lowest gross national product (GNP) of the EU countries (Fig. 1) and show the largest net decrease in population (Fig. 2).

HIV/AIDS AND TB IN EUROPE
The HIV epidemiological data collection was mainly based on the UNAIDS 2008 Report on the global AIDS epidemic, the HIV/AIDS surveillance in Europe 2008 report by the European Centre for Disease Prevention and Control (ECDC) and the WHO Regional Office for Europe, and the UN General Assembly Special Session (UNGASS) country progress reports.
The TB epidemiological data collection was mainly based on data from the ECDC or the WHO report "Global tuberculosis control: a short update to the 2009".Data which could not be obtained from these sources were retrieved by accessing national statistical data or data from national TB programmes.

HIV/AIDS Epidemiological Data
The EU has an estimated HIV incidence of 5.4 cases per 100,000, with an AIDS incidence of 1.4 cases per 100,000 [7].The highest prevalence (Fig. 3) and incidence (Fig. 4) is found in Estonia and Latvia, as is the calculated associated mortality (Table 2).Of note, in contrast to the TB epidemiological data below, several Western European countries such as Spain, Portugal, Italy, and France are amongst those with the highest HIV prevalence.The highest incidence of AIDS is found in Estonia, followed by Latvia, Spain, Portugal and Italy.A similarly diverse picture is seen with the proportions of HIV positive patients on treatment with Latvia, Lithuania, Cyprus and Ireland all reporting less than 30% of patients being on antiretroviral treatment.Availability of data on transmitted drug resistant HIV was limited (Table 3).

TB Epidemiological Data
Overall, the EU has an estimated prevalence of TB of 18.3 per 100,000, an estimated incidence of 19.5 per 100,000, and an estimated mortality of 2.4 per 100,000 [7].The burden of TB infection and disease is distributed unevenly within the EU27 (Table 3).Former Eastern European countries bear the brunt of its impact.Five countries share the highest TB prevalence (Fig. 5), TB incidence (Fig. 6), and calculated mortality attributable to TB.These countries are Romania, Lithuania, Bulgaria, Latvia, and Estonia (in descending order for incidence and attributable mortality).The same five countries have the highest prevalence (Fig. 7) and incidence (Fig. 8) of MDR-TB, with the three Baltic states being most severely affected.Latvia, Lithuania and Estonia also have the highest XDR-TB prevalence and incidence of those countries for which estimates were available.

HIV/MTB Co-Infection Epidemiological Data
Data on HIV/MTB co-infection were limited, with no data available for 14 out of the 27 EU member states.Of those countries for whom information was accessible, Spain and Portugal had the largest numbers of TB/HIV co-infected patients in absolute terms.In these countries, the percentage of TB patients for whom the HIV status was known ranged from 0% (Poland) to 93% (Estonia).At present, the data suggest that TB and HIV co-infection is still a relatively low cause of mortality within the EU.All member states have a mortality of one or less than one per 100,000 population attributable to HIV/MTB co-infection (Table 4).
A recent study summarizing prevalence data for 23 European countries over several years also reports findings on the development of co-infection, showing that in England, for example, the prevalence of HIV co-infection among TB patients rose from 5% in 2000 to 8% in 2005, with a peak at 9% in 2003-2004.France, Iceland and Portugal (11-15%) had higher coinfection levels, while similar levels were found for Estonia and Malta (9%), and very low levels were reported from central European countries (0-1%).
A rise in co-infection levels was seen in Estonia, Latvia, Lithuania, the UK and Belgium, while decreases were seen in Spain and Portugal [4].

HIV -Country Standards and Availability of Standard Diagnostic Tests
There were limited data from countries on the availability, cost, and frequency of use of different diagnostic tests for HIV infection.
Available data show that HIV screening is performed in 17 countries, 16 of which use enzyme-linked immunosorbent assay tests (ELISA), whilst one country uses a "fourth generation" combined ELISA with p24 antigen assay.Confirmatory tests were reported for 19 countries, of which 16 countries reported commonly using a Western blot to confirm diagnosis, whilst one reported ELISA, one a "fourth generation" combined ELISA with p24 antigen assay, and one country PCR for children less than 18 months old.For viral load measurements, 18 countries report using polymerase chain reactions (PCR) to confirm viral load at diagnosis and follow-up.The level of CD4 cells is quantified by flow cytometry in eighteen countries once diagnosis is confirmed and at follow-up.Phenotypic resistance testing was reported by 17 countries which use cell culture-based viral replication assays to assess for phenotypic resistance.For 18 countries, the use of gene sequencing of HIV to detect mutations for genotypic resistance was reported.

MTB/TB -Country Standards and Availability of best Possible Diagnostic Tests
As with HIV testing, only limited data could be retrieved on the availability, cost, and frequency of use of different diagnostic tests for MTB infection/TB disease across countries.In all 27 EU member states chest x ray is used to diagnose TB and the tuberculin skin test (TST) is employed to support the diagnosis.All countries have access to microscopy with appropriate staining for Mycobacterium tuberculosis and culture.16 countries reported use of polymerase chain reactions (PCR) either to distinguish between Mycobacterium tuberculosis and other mycobacteria, to detect clonal relatedness, or to detect resistance mutations (see below).However, nine of these 15 countries only rarely use PCR.When testing contacts of patients with TB, all 27 EU member states report using TST followed by chest X-ray where indicated.17 countries have access to interferon-release assays (IGRA) to detect latent Mycobacterium tuberculosis infection.However, for ten countries its use was categorized as 'rare'.Of those who specified which IGRA was utilized, three had access to the T-SPOT.TB test (Oxford Immunotec, Abingdon, UK), and six utilized the Quantiferon TB Gold assay (Cellestis, Carnegie, Australia).18 countries test for phenotypic resistance through drug susceptibility testing.Genotypic resistance testing is commonly performed in five countries, whilst 12 use such methods only rarely.The methods of genotypic resistance testing used in the EU include techniques such as DNA sequencing, and line-probe assays.19 of the EU states for whom data were available provide TB diagnostic tests free of charge for all suspected cases through national TB treatment programmes.Three also provide free diagnostic testing based on other criteria.20 of the 27 EU member states routinely perform first-line drug susceptibility testing on all new cases.19 countries have access to second line drug susceptibility testing within the country, and another four have access to such tests through another country (Table 5).

Medical Treatment Standards for HIV
There were very limited data available from the survey of EU countries on the use of antiretroviral therapy for treatment of HIV/AIDS.The annual progress report "Towards universal access: scaling up priority HIV/AIDS    6).Of note, where data were available, HIV testing in pregnancy had an estimated coverage of as low as 8% of pregnant women, and antiretroviral therapy for infants of mothers living with HIV to prevent MTCT was as low as 44%.

Medical Treatment Standards for TB
Treatment success for TB across the EU member states remains a target for improvement with 18 of the 22 countries for whom data were available failing to attain the WHO target of >85%.Of note, poor treatment success rates do not necessarily mirror MDR-TB rates.Many low TB and MDR-TB prevalence countries also fail to reach the WHO target.These findings reflect those of previous publications [8,9].12 of the 21 countries for whom data were available did not have formulations for anti-TB drugs procured specifically for children (WHO Global Tuberculosis Control Report Short Update, 2009).Of the 22 countries for whom data were available, seven did not have a national surveillance system to measure the prevalence of drug resistance among TB cases.There is also variability in the policies on screening immigrants for TB, with nine of the 21 countries for whom data were available routinely screening all immigrants (Tables 7 and 8).

SCIENTIFIC CHALLENGES FOR THE FUTURE
Based on the description of the situation of HIV/AIDS, TB, and HIV/MTB co-infection in Europe and subsequent discussions among all EUCO-Net experts at the "AIDS/TB Workshop on Research Challenges and Opportunities for Future Collaboration" in Stellenbosch [10], the group agreed that European research would largely benefit from joint open-access facilities for data collection and statistical analysis, and emphasized the need for centralized facilities for biobanking and immunomonitoring.The experts furthermore identified a number of scientific challenges as of particular importance for their region and of special interest to researchers in Europe.Specifically, they agreed that more basic research is needed.An improved understanding of HIV/MTB pathogenesis is a pre-requisite for the urgently needed development of better treatments and treatment strategies for both adults and children, as well as for the prediction of TB latency/progression.The experts stated that further research should lead to improved diagnostics (in adults and in children) of active and latent TB, improved smear-negative TB diagnostics (especially in HIV+ patients), and the development and dissemination of rapid, simple and cheap diagnostic tools including rapid drug-resistance testing.Despite recent advances such as the GeneXpert MTB/RIF assay (Cepheid, Sunnyvale, CA), an automated real-time PCR test that simultaneously identifies M. tuberculosis and detects rifampicin resistance directly from clinical sputum specimens within hours [11], offering great potential in TB diagnostics and endorsed by the World Health Organization [12], critical factors such as expense, the need for a power supply, and limitations for paediatric populations remain a concern.Biological approaches aiming at the improvement of TB diagnostics from blood, urine, and saliva still need to be further investigated.
In addition, a joint European strategy on when and how to start therapy for co-infected patients needs to be developed.Varied and low rates of TB treatment success highlight the need for increased efforts to develop new short-course TB treatments and to further investigate HIV/MTB drug interactions in order to avoid toxicity.Particular attention should be paid to the improved diagnosis and management of immune reconstitution inflammatory syndrome (IRIS).
With regards to disease management, the experts stated that increased and improved capacity building, training, and education programs for the management of HIV/MTB coinfection are needed, specifically addressing health care workers, communities, schools, policymakers, and patient organizations.

LIMITATIONS Methodogical Issues
Attributable mortality (Tables 3 and 4): The rates are expressed differently from one country to another (absolute rate with or without confidence interval vs approximative rate).The classical way of recording mortality rate is absolute rate with confidence interval.We were unable to calculate the confidence interval because global mortality data were not always available.3 and 4): The results presented in Tables 3 and 4 should be interpreted very carefully.As far as prevalence was concerned, the annual prevalence was only taken into account in the analysis and not the cumulative prevalence on a period of time as usually given in WHO reports.When only cumulative cases on a period of time were available, we tried to calculate an annual prevalence rate considering the same year from all countries.

Prevalence and Incidence rates (Tables
When the annual reference year for demographic data was different from the prevalence and incidence year of reference, we took as a reference the data published by OECD [13].
Where data were unavailable in our survey on issues of relevance to this report, existing data from the European Union and World Health Organization were utilized.

Comments on Results
The variation of HIV prevalence rates between countries may be due to the difficulty to assess HIV/AIDS prevalence.It is not clear if the prevalence data are collected from HIV registry (mandatory declaration of HIV+) or registry of AIDS disease.The very high prevalence of TB in Romania is questionable, as well as the number of treated patients (higher than the number of HIV patients).
An estimation of treatment success for HIV patients is poorly documented and raises the question how treatment success is best evaluated with regard to existing national and international guidelines).

INTERCULTURAL CHALLENGES AND SENSITIVITIES
Given the fact that the EU combines 27 countries with different languages and cultures, EU wide, harmonized HIV/AIDS and TB treatment and care and related research naturally face a number of particular challenges that were also discussed at the "AIDS/TB Workshop on Research Challenges and Opportunities for Future Collaboration".
Even though a high risk group, migrants to and within the EU from high prevalence TB and HIV regions struggle with limited understanding of the language of the country they now live in, which may negatively impact their access to healthcare and/or health awareness.For instance, in Belgium, of those people living with HIV whose nationality is known (70% of all cases), 63% are not Belgian nationals.Fear of contact with the authorities by immigrants with uncertain legal status was raised as an issue by experts from several Western European countries, with corresponding concerns of infectious patients presenting advanced disease to health services, with risks both to their own health, and that of the population through ongoing spread of disease.Also, prevention strategies are influenced on a countryby-country basis by cultural and religious customs, and on national level are usually tailored to the demographic groups at highest risk.
While the demographics of different marginalized groups vary within the EU as described in Section 4, intravenous drug users, migrants, sex workers, institutionalized citizens, and MSM are all at greater risk for HIV and/or MTB infection than the general population.For several of these groups and again varying among different cultural environments there is again a fear of involvement with authorities, with corresponding public health consequences.
Despite greater awareness and public visibility of HIV/AIDS, many patients still fear the stigma associated with such a diagnosis, with a concomitant impact upon presenting to health services when at risk or symptomatic, and engaging with care thereafter.
Disease registration and epidemiological data collection, as highlighted throughout this report, are fundamental for assessing the extent, impact, and trends of these diseases.There is a clear and urgent need for improved data collection systems to record factors relevant to clinical, epidemiological, and resistance variables for HIV and TB.
Lastly, both within and between EU countries, there is a perceived lack of integration and co-ordination between governmental agencies involved in dealing with AIDS and TB disease management and research funding.

CONCLUSIONS AND RECOMMENDATIONS
The data presented underline that HIV/AIDS and TB are major and urgent health problems within the EU.However, reliable and consistent epidemiological, demographic, treatment, and resistance data for HIV-, MTB-, and especially for co-infection are not easily accessible across the EU member states.There is an urgent need for appropriate resources to co-ordinate harmonized and comprehensive data collection relevant to public health and clinical management at national and EU levels.
With regards to HIV/AIDS, a high awareness and a low threshold for testing for HIV are key to prevent late presentation with attendant immune deterioration.Much remains to be done to prevent spread of HIV infection through transmission between MSM, heterosexual intercourse, intravenous drug use, and mother-to-child transmission.
To prevent the spread of TB infection, early and appropriate initiation of treatment and infection control procedures is a key prerequisite.Until recently, diagnosis of TB however has relied primarily on clinical assessment, microscopy, and culture and confirmation of active TB by culture, which can take several weeks.The GeneXpert MTB/RIF assay (Cepheid, Sunnyvale, CA) marks a major advance in this area, and can provide a diagnosis within hours, including of MDR-TB [11].Investigation of host biomarkers and urinary tests for mycobacterial-specific substances remain key areas for research.
The reasons behind the suboptimal and varied treatment success rates for TB within the EU require exploration.Resistance and failures in reporting are likely to play a role, although these and other factors need further elucidation.
MDR-and XDR-TB are a serious threat to public health within the EU.There are significant morbidity, mortality, and health care costs associated with these conditions due to lengthy lag times before drug susceptibility results are available, limited therapeutic options, and the need for inpatient treatment and isolation.The failure to meet WHO treatment success targets for TB across many of the EU member states contributes to development of further resistance.

Management of patients with HIV/MTB co-infection
should take into account the increasing movement of people between EU member states, and from high prevalence areas outside of the EU.
There is a need to implement prevention strategies for TB infection and intensify TB case-finding among people living with HIV.Appropriate implementation of international recommendations on treatment should be monitored and evaluated.
Collaboration between agencies, researchers, and governments involved in management of HIV and MTB infection is key to a coordinated approach to these fundamentally interwoven diseases [14] and joint research into HIV/MTB co-infection needs to be better represented in international funding programs.

Table 2 . HIV Epidemiological Data in Order of Decreasing HIV Prevalence
interventions in the health sector" by WHO, UNAIDS, and UNICEF which provides information on antiretroviral therapy primarily focuses on low-and middle-income countries and does not contain individual data on most European countries (Table

Table 4 . TB/HIV Co-Infection Epidemiological Data in Order of Decreasing Absolute Number of Co-Infected Patients
data from 2008 from WHO Global tuberculosis control: a short update to the 2009 report, unless otherwise specified.* Data from 2007, † 2007 Data from WHO REPORT 2009, Global Tuberculosis Control -Epidemiology, strategy, financing.‡ The WHO European Region includes the EU together with 26 other countries, including the Russian Federation, Turkey, and some Central Asian states. All