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EPIDEMIOLOGY AND SOCIAL

HIV resistance testing and detected drug resistance in Europe

Schultze, Annaa; Phillips, Andrew N.a; Paredes, Rogerb; Battegay, Manuelc; Rockstroh, Jürgen K.d; Machala, Ladislave; Tomazic, Janezf; Girard, Pierre M.g; Januskevica, Ingah; Gronborg-Laut, Kamillai; Lundgren, Jens D.i; Cozzi-Lepri, Alessandroa on behalf of EuroSIDA in EuroCOORD

Author Information
doi: 10.1097/QAD.0000000000000708

Abstract

Introduction

Combination antiretroviral therapy (cART) has brought considerable clinical and public health benefits, by suppressing HIV-1 replication and consequently allowing CD4+ cell counts to increase [1–3]. However, in cases of incomplete viral suppression, resistance to antiviral drugs may develop [4]. Such acquired drug resistance limits the number of available treatment options, compromises the benefits of cART by impairing the response to therapy and could also contribute to the transmission of drug-resistant HIV strains [5–7]. Given these clinical consequences, monitoring trends in resistance prevalence is important.

Prevalence estimates from observational studies tend to rely on resistance tests done as part of routine clinical care in order to access genotypic data. Whether or not a resistance test is performed following virological failure is a matter of clinical judgment and cost, but there are several clinical guidelines available to guide decisions. Current European as well as US guidelines recommend testing for drug resistance at both initiation of therapy and following virological failure [8,9]; however, this has not always been the case. Since resistance testing first became widely available in the late 1990s, clinical guidelines have changed. This is in part to reflect the results from trials showing that knowledge of a patient's resistance profile results in treatment benefits [10–13], and partly due to the implementation of technologies that allow genotyping at lower viral loads [14,15]. This, coupled with the fact that resistance testing technologies have become more widely available and affordable, has resulted in a changing proportion of ART-experienced individuals receiving resistance tests in clinics over time [9]. Such changes complicate estimates of resistance prevalence and in particular the comparison of prevalence estimates between different studies, as the denominator varies with time and between different studies and countries. This makes trends in resistance testing important for interpreting prevalence estimates, particularly when these are derived from observational studies.

For this reason, the aims of the current analysis were first, to describe regional differences and trends in resistance testing among individuals experiencing virological failure, and second, to describe regional differences and trends in the prevalence of detected resistance among those individuals who had a genotypic resistance test.

Study population and methods

The EuroSIDA study

EuroSIDA is a large, ongoing prospective cohort study of more than 18 000 individuals living with HIV. At the time of analysis, the study collected data from 111 hospitals in 34 different countries across Europe, as well as Israel and Argentina [1]. For this analysis, these countries have been grouped into five different regions (Southern Europe, Central Western Europe, Northern Europe, Central Eastern Europe and Eastern Europe, as detailed in Supplementary Digital Content 2, https://links.lww.com/QAD/A700) as described previously [16]. Recruitment started in 1994, and data were collected 6-monthly on standardized case report forms (CRFs). Variables collected include demographic information, CD4+ cell counts, viral load measurements, as well as start and stop dates for all antiretroviral drugs used. All patients gave informed consent at enrolment, as described at http://www.cphiv.dk. An extensive programme of quality control is in place, details of which have been previously published [16,17].

Resistance data

Virological reports of resistance tests done by clinicians as part of routine clinical care are submitted to a centralized resistance database held at the IrsiCaixa Foundation, Badalona, Spain. The methods used to test for resistance differs depending on the centre, and our database contains very limited information on this. Clinicians can also indicate whether or not an individual's virus has been genotyped since the last clinic visit in the main CRF. These data give no genotypic information, and could therefore not be used to address the second aim of this particular study.

Resistance mutations were defined using the International Antiviral Society (IAS)-USA (2013) guidelines [18]. Throughout the article, ‘any resistance mutation’ will refer to at least one detected IAS-USA resistance mutation to nucleoside reverse-transcriptase inhibitor (NRTI), nonnucleoside reverse-transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drug classes, excluding minor PI mutations. As the analysis focused on detected drug resistance at a single time point, resistance mutations were not carried forward in a cumulative manner.

Inclusion criteria

All individuals aged above 16 years with evidence of virological failure (having a viral load measurement >500 copies/ml while on ART after at least 6 months of ART exposure [8]) after 1 January 1997 were considered eligible for a resistance test and were included in this analysis. We consciously used a broad definition of virological failure for our primary analysis in order to maximize the number of individuals that we could include. For any given year, a person was included if they experienced virological failure in that year, and considered as having a resistance test associated with the virological failure in that year if they had a resistance test no more than 1 month before or 12 months after the date of virological failure. If the same resistance test could be linked to more than one virological failure date in different calendar-years, it was attributed to the virological failure date occurring closest to the test. Individuals contributed one measurement for each year in which they experienced virological failure. This means that individuals could contribute data for more than 1 calendar-year, and were not excluded after they had their first virological failure or resistance test. The first included date of virological failure for each individual was considered as the baseline date for that person, and the characteristics of the study population at baseline were summarized.

Statistical methods

The proportion of individuals with a resistance test following virological failure (first aim of the study) and detected resistance after having a test (second aim of the study) was plotted against calendar-year with 95% confidence intervals (CIs). Logistic regression models with generalized estimating equations (GEEs) [19,20] were used to identify predictors and to test for changes in the prevalence of resistance testing and detected resistance. The rationale for which covariates to include in the multivariable models was based on clinical knowledge and previous publications [21,22], and included factors hypothesized to be associated with our exposures of interest and the relevant outcome. Adjustments are detailed in the relevant tables (Table 2, Supplementary Digital Content 3, https://links.lww.com/QAD/A700).

We also studied factors associated with virological failure in order to add to the context of the current analysis. This model was adjusted for age, sex, ethnicity, mode of HIV transmission, region, previous history of mono/dual therapy use, number of available previous resistance tests, CD4+ cell count, previous history of virological failure and calendar-year.

P values of less than 0.05 were taken to indicate statistical significance. All analyses were conducted using SAS 9.3 (Statistical Analysis Software, Cary, North Carolina, USA).

Sensitivity analyses

Several sensitivity analyses (Supplementary Digital Content 5, https://links.lww.com/QAD/A700) were done using varying definitions of virological failure.

Results

Characteristics of the individuals showing evidence of virological failure

In total, 8469 individuals – 57.3% of all ART-experienced individuals with at least one RNA measurement – met our main definition of virological failure on at least one occasion and were included in the analysis (Supplementary Digital Content 1, https://links.lww.com/QAD/A700). The odds of experiencing virological failure declined over calendar time [adjusted odds ratio (aOR) 0.79 per more recent calendar-year, 95% CI 0.78–0.79, P < .001]. Compared to 74.19% (95% CI 72.9–75.4) of individuals in 1997, only 5.11% (95% CI 3.22–8.00) showed evidence of virological failure in 2012. There was evidence that this decline differed significantly according to region (interaction P value < 0.001). The odds of experiencing virological failure declined most steeply in Central Eastern Europe (aOR 0.90, 95% CI 0.87–0.93, P < 0.001). In contrast, the decline in the odds of experiencing virological failure was less marked in Eastern Europe (aOR 0.95, 95% CI 0.91–0.99, P = 0.01; Supplementary Digital Content 3, https://links.lww.com/QAD/A700). The lowest levels of virological failure in 2012 were seen in Northern Europe (3%), and the highest levels in Eastern Europe (15.1%; Supplementary Digital Content 3, https://links.lww.com/QAD/A700). The median viral load at failure varied with calendar-year, and decreased somewhat from 5831 (1500–30000) copies/ml in 1997/1998 to 4378 (1230–21902) copies/ml in 2011/2012 (P < 0.001). Conversely, the number of viral load measurements per patient per year decreased over time, from a median of 4 (3–6)/year in 1997/1998 to 3 (2–4)/year in 2011/2012 (P < 0.001).

The characteristics of the individuals showing evidence of virological failure at date of the first virological failure are shown in Table 1; the majority of the individuals included were men (75%) and white (86%), and 40% had acquired their HIV infection through sex with another man.

T1-13
Table 1:
Baseline characteristics of the study population.

Resistance testing

Trends in proportion of individuals with a resistance test over time

Of the 8469 individuals experiencing virological failure, a total of 2676 (31.6%) were tested for resistance in at least one of the years in which they had evidence of virological failure. Among those who had a test, the median time between the date of virological failure and a resistance test was 0.7 months [inter-quartile range (IQR) 0–4 months; range 1–12 months]. Of those with at least one resistance test, 60.7% had one test, 23.5% had two tests, 8.5% had three tests and 7.3% had four or more resistance tests. The mean number of tests done per person was lower in Eastern Europe compared to other regions (P < 0.001; mean = 0.6 compared to mean = 1.2 in Northern Europe).

The proportion of individuals with a resistance test around the time of virological failure increased from just 2% in 1997 to 29% in 2004 [Unadjusted OR (uOR) 0.08 comparing 1997–1998 to 2003–2004, 95% CI 0.07–0.10, P < 0.001] and then declined back to 7.7% in 2012 (uOR 0.22 comparing 2011–2012 to 2003–2004, 95% CI 0.17–0.28, P < 0.001), as can be seen in Fig. 1a.

F1-13
Fig. 1:
Proportion of individuals with a resistance test following VF over time (a) and per region (b).

Multivariable models of factors associated with having a resistance test

The association between calendar-year of virological failure and the probability of having a resistance test was confirmed in multivariable analysis (global P < 0.001, Supplementary Digital Content 4, https://links.lww.com/QAD/A700), and adjustment for potential confounders had only a limited influence on the calendar-year effect estimates.

Compared to Southern Europe, individuals were more likely to be tested for resistance at or after virological failure in Northern Europe (aOR 2.15, 95% CI 1.96–2.36, P < 0.001) and Central Western Europe (aOR 1.66, 95% CI 1.51–1.82, P < 0.001). In contrast, individuals in Eastern Europe were less likely to be tested (aOR 0.72, 95% CI 0.55–0.94, P = 0.02) compared to individuals in Southern Europe. As expected, individuals with RNA levels of 1000–10 000 copies/ml at virological failure were more likely to have a resistance test compared to individuals with lower viral loads (aOR 2.10, 95% CI 1.86–2.37, P < .001 compared to 500–999 copies/ml, Supplementary Digital Content 2, https://links.lww.com/QAD/A700). Due to a small number of individuals being tested for resistance per region and per calendar-year, we did not perform a formal interaction test as this would be underpowered and restricted by empty cells in the regression model. However, plotting the time-trends by region showed that both the rise and decline in resistance testing following virological failure was somewhat more marked in Northern, Central Western and Southern Europe compared to Central Eastern and Eastern Europe (Fig. 1b), although the numbers were limited.

Detected drug resistance

Trends in proportion of individuals with detected drug resistance over time

In total, 2431 (77.9%) of the 3119 resistance tests with genotypic data detected drug resistance. The prevalence of mutations with more than 10% prevalence is shown in Fig. 2. Overall, NRTI resistance was most commonly detected in 70.3% of the tests, followed by NNRTI (51.6%) and PI (46.1%) resistance. The most commonly detected individual mutations were M184V (46.3%, NRTI), K103NS (23.4%, NNRTI) and L90M (26.8%, PI). Changes in the proportion of individuals with detected drug resistance each year can be seen in Fig. 3, both overall and after stratification by drug class. Univariable models indicated that calendar-year was associated with the detection of drug resistance (global P < 0.001). This trend was not linear, and the prevalence appeared to increase until 2003–2004 followed by somewhat of a decrease. In 1997, just less than two-thirds of the population had detected resistance, and this was somewhat higher (84%) in 2003. In 2012, an estimated 79% of the individuals had detected drug resistance. Looking at univariable specific contrasts, we found strong evidence (all P < 0.01) that the odds of detecting resistance were lower in 1997–1998, 1999–2000 and 2009–2010 as compared to 2003–2004 (Table 2).

F2-13
Fig. 2:
Prevalence of resistance mutations with > 10% prevalence, per resistance test.
F3-13
Fig. 3:
Prevalence of detected resistance over time, according to drug class.
T2-13
Table 2:
Factors associated with having detected resistance (any class).

Multivariable models of factors associated with detected drug resistance

The odds of detecting drug resistance varied by calendar time also after adjustment for confounding (global P < 0.001), with the odds of detecting any resistance being lower before and after 2003–2004 (Table 2). Individuals were less likely to have resistance detected in Northern (aOR 0.29, 95% CI 0.21–0.39, P < .001) and Central Eastern Europe (aOR 0.47, 95% CI 0.29–0.76, P = 0.002) compared to Southern Europe. A number of other factors were independently associated with the risk of resistance detection. Individuals with a history of mono/dual therapy were more likely to have detected drug resistance (aOR 1.54 vs. those who started cART from ART naive, 95% CI 1.14–2.08, P = 0.007), as were individuals who had experienced virological failure previously (aOR 1.85 vs. those who experienced virological failure for the first time, 95% CI 1.40–2.45, P < 0.001). Individuals with RNA levels between 1000 and 10 000 copies/ml were more likely to have detected resistance (aOR 1.63, compared to individuals with RNA levels less than 1000 95% CI 1.19–2.23, P = 0.002), but individuals with very high RNA levels (>50 000 copies/ml) were not significantly more likely to have detected resistance (aOR 1.20, 95% CI 0.84–1.72) compared to individuals with RNA levels less than 1000. Findings were broadly consistent when conducting the analysis for each drug class separately (data not shown).

Sensitivity analyses

The estimates of the prevalence of virological failure and resistance in a number of sensitivity analyses are shown in Supplementary Digital Content 5 (https://links.lww.com/QAD/A700). Briefly, the proportion of individuals with a resistance test was higher when using stricter criteria to define virological failure, including only considering virological failures that were followed by a switch in regimen, but remained below 50%. The proportion of resistance tests with detected drug resistance remained reasonably stable despite using stricter definitions of virological failure. Multivariable results from these sensitivity analyses were in broad agreement with the results described above (data not shown).

Discussion

In this analysis of a large cohort of HIV-positive individuals with virological failure from across Europe, around one-third of the individuals received a resistance test within 12 months of virological failure. This proportion decreased after 2004. The relatively low proportion of individuals in our study receiving a resistance test at or after virological failure extend and confirm previous EuroSIDA findings [21], and indicate that there is a potential discrepancy between clinical practice and current guidelines which recommend to always test for resistance after virological failure.

Several clinical trials have shown a direct clinical benefit of resistance testing [10–13], and it is important to encourage the use of genotyping by clinicians. However, clinical decisions are complicated by numerous factors and it is not uncommon that guidelines are not followed exactly in real life. The fact that the proportion tested for resistance is higher when considering virological failure followed by a switch in a sensitivity analysis is reassuring, as it indicates that clinicians may test selectively those individuals they are considering switching to a different drug class. Adjustment for a range of clinical variables did not affect the declining trend observed after 2004; however, we cannot rule out that this result might have been different if we could control for other unmeasured factors that could influence clinicians’ decisions to order a resistance, such as an increased availability of different drugs. In addition, the marked reduction in the proportion of individuals experiencing virological failure over time documented here indicates that virological failure is becoming less common. It could be that when seen in a clinical setting, the reason for the virological failure may be put down to poor adherence, a chaotic lifestyle or personal issues rather than drug resistance. This is in agreement with the higher proportion of adherent individuals having a resistance test observed in the sensitivity analyses. However, it should be noted that the adherence data available is of limited scope, and findings should therefore be interpreted with caution.

Other studies of trends in resistance testing have found conflicting results. A recent study of drug resistance prevalence in Sweden provided data on the number of tests done over time, and showed that these remained relatively stable [23]. This also appears to be the case in the United States, at least from 2003 onwards [24]. Nonetheless, our results are in broad agreement with a study conducted in British Columbia, Canada, from 2011, which found both under-utilization of resistance testing as well as a lower probability of testing after 2004 [25]. An analysis of data from the UK Collaborative HIV Cohort Study cohort has shown that 46% of individuals had a resistance test after viral rebound prior to a change in therapy, similar to the estimate of 47% we found when defining failure according to whether or not a high viral load was followed by a switch in the regimen [26].

Despite a declining trend in resistance testing, a relatively high proportion – almost 80% – of tests detected any drug resistance. This estimate is comparable to those obtained from other European cohorts [27], but somewhat higher than data obtained from the United Kingdom [28], potentially due to differences in the populations studied. The fact that a relatively high proportion of resistance tests did detect drug resistance could indicate that clinicians may be taking a selective approach to resistance testing, whereby those individuals judged most likely to have resistance are also the ones offered a test.

The proportion of tests detecting any resistance peaked in 2003–2004, and there was some evidence to suggest that this proportion had declined in the more recent calendar-years. A decline in the prevalence of resistance in recent years among individuals experiencing virological failure has been found in a number of European cohorts [22,23,28,29] and also in the USA [30]. Such a decrease could be explained by improvements in the potency of drugs used, minimized side effects and an increase in therapeutic options that have all lowered the risk of developing drug resistance [22,29]. Simplified drug regimens that are easier to take, combined with efforts to educate patients, and the development and use of drugs with a high genetic barrier may also play an important role. Taken together with the reduced proportion of individuals experiencing virological failure in more recent calendar-years, the current analysis documents a marked reduction in the number of individuals experiencing virological failure with acquired drug resistance.

Regional differences in the probability of both receiving a resistance test and detecting drug resistance were observed. Clinicians in Northern Europe were the most likely to test for resistance following virological failure, but also least likely to detect any drug resistance once the test was prescribed. In contrast, clinicians in Eastern Europe were comparatively less likely to test for resistance following virological failure compared to Central Western and Northern Europe, but also more likely to detect resistance when doing a test compared to Central Eastern and Northern Europe. As it is unlikely that the biological probability of developing drug resistance in a situation of virological failure differs according to region, it is possible that the lower testing rates in Eastern Europe are causing individuals to be maintained on failing therapies for longer, thus leading to the development of resistance. Clinicians in Eastern Europe may also be more selective about who they test for resistance, as indicated in a recent EuroSIDA survey [31].

Our findings should be interpreted with caution as the analysis was subject to several limitations. First of all, the definition of virological failure referred to by guidelines for resistance testing has changed over time. We attempted to address this possible bias in sensitivity analyses, and although the proportion receiving a test increased with more stringent definitions of virological failure, it still remained relatively low. Furthermore, we cannot rule out under-reporting of the numbers of tests ordered and performed from the clinical sites, although rigorous efforts are made to minimize such under-reporting by quality control visits. Resistance tests done in more recent years might also be subject to reporting delay, which similarly may have led to an underestimation of the number of tests done after a certain calendar period. We furthermore cannot exclude that some instances of virological failure have been misclassified. It is possible that some of the virological failures, particularly early on during follow-up, may be due to treatment interruptions. Finally, EuroSIDA clinics may not be representative of all HIV clinics in Europe, as some countries are represented by relatively few centres. It should also be noted that the prevalence of detected drug resistance in this study differs from the true population level prevalence of drug resistance, which requires genotypic data from all individuals on ART or some estimation of the prevalence of resistance in those who were not tested. We have taken this latter approach in one of our previous publications, which provided an estimate of the overall population level prevalence of resistance in 1 year (i.e. 2008) [32].

To conclude, our findings indicate that the clinical approach to resistance testing may diverge from that laid out in guidelines, and we observed calendar-year and regional differences both in resistance testing and the probability of detecting resistance. Public health policy aimed at minimizing the emergence of drug resistance might benefit from targeting specific regions of Europe, and efforts to minimize inter-regional differences in the availability and utilization of resistance testing in the European region may be warranted.

Acknowledgements

Author contributions: A.C.L., J.D.L. and A.S. designed the study and analysis plan. A.S. performed the statistical analyses with technical support from A.C.L. and support for data interpretation from J.D.L., A.N.P., R.P. and K.G.L. M.B., J.K.R., L.M., J.T., P.M.G. and B.R. collected data and all authors critically reviewed and commented on the manuscript. All authors have approved the final version of the manuscript for publication.

Source of funding: Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94–1637), BIOMED 2 (CT97–2713), the 5th Framework (QLK2–2000–00773), the 6th Framework (LSHP-CT-2006–018632) and the 7th Framework (FP7/2007–2013, EuroCoord n° 260694) programmes. Current support also includes unrestricted grants by Janssen R&D, Merck and Co. Inc., Pfizer Inc., GlaxoSmithKline LLC. The participation of centres from Switzerland was supported by The Swiss National Science Foundation (Grant 108787).

The EuroSIDA Study Group: The multicentre study group of EuroSIDA (national coordinators in parenthesis): Argentina: (M. Losso), M. Kundro, Hospital JM Ramos Mejia, Buenos Aires. Austria: (N. Vetter), Pulmologisches Zentrum der Stadt Wien, Vienna; R. Zangerle, Medical University Innsbruck, Innsbruck. Belarus: (I. Karpov), A. Vassilenko, Belarus State Medical University, Minsk, V.M. Mitsura, Gomel State Medical University, Gomel; D. Paduto, Regional AIDS Centre, Svetlogorsk. Belgium: (N. Clumeck), S. De Wit, M. Delforge, Saint-Pierre Hospital, Brussels; E. Florence, Institute of Tropical Medicine, Antwerp; L. Vandekerckhove, University Ziekenhuis Gent, Gent. Bosnia-Herzegovina: (V. Hadziosmanovic), Klinicki Centar Univerziteta Sarajevo, Sarajevo. Bulgaria: (K. Kostov), Infectious Diseases Hospital, Sofia. Croatia: (J. Begovac), University Hospital of Infectious Diseases, Zagreb. Czech Republic: (L. Machala), D. Jilich, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen. Denmark: (J. Nielsen), G. Kronborg, T. Benfield, M. Larsen, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, A.-B.E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, N.F. Møller, Odense University Hospital, Odense; L. Ostergaard, Skejby Hospital, Aarhus, U.B. Dragsted, Roskilde Hospital, Roskilde; L.N. Nielsen, Hillerod Hospital, Hillerod. Estonia: (K. Zilmer), West-Tallinn Central Hospital, Tallinn; Jelena Smidt, Nakkusosakond Siseklinik, Kohtla-Järve. Finland: (M. Ristola), Helsinki University Central Hospital, Helsinki. France: (C. Katlama), Hôpital de la Pitié-Salpétière, Paris; J.-P. Viard, Hôtel-Dieu, Paris; P.-M. Girard, Hospital Saint-Antoine, Paris; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l’Archet, Nice; F. Dabis, D. Neau, Unité INSERM, Bordeaux; C. Duvivier, Hôpital Necker-Enfants Malades, Paris. Germany: (J. Rockstroh), Universitäts Klinik Bonn; R. Schmidt, Medizinische Hochschule Hannover; J. van Lunzen, O. Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; H.J. Stellbrink, IPM Study Center, Hamburg; C. Stefan, J.W. Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Georgia: (N. Chkhartishvili) Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi, Greece: (J. Kosmidis), P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; H. Sambatakou, Ippokration General Hospital, Athens. Hungary: (D. Banhegyi), Szent Lásló Hospital, Budapest. Iceland: (M. Gottfredsson), Landspitali University Hospital, Reykjavik. Ireland: (F. Mulcahy), St James’ Hospital, Dublin. Israel: (I. Yust), D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; E. Shahar, G. Hassoun, Rambam Medical Center, Haifa; H. Elinav, M. Haouzi, Hadassah University Hospital, Jerusalem; Z.M. Sthoeger, AIDS Center (Neve Or), Jerusalem. Italy: (A. D’Arminio Monforte), Istituto Di Clinica Malattie Infettive e Tropicale, Milan; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; R. Pristera, Ospedale Generale Regionale, Bolzano; F. Mazzotta, A. Gabbuti, Ospedale S. Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; M. Zaccarelli, A. Antinori, R. Acinapura, G. D’Offizi, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, A. Castagna, N. Gianotti, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan. Latvia: (B. Rozentale), Infectology Centre of Latvia, Riga. Lithuania: V. Uzdaviniene, Lithuanian AIDS Centre, Vilnius. Luxembourg: (T. Staub), R. Hemmer, Centre Hospitalier, Luxembourg. Netherlands: (P. Reiss), Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway: (V. Ormaasen), A. Maeland, J. Bruun, Ullevål Hospital, Oslo. Poland: (B. Knysz), J. Gasiorowski, M. Inglot, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; A. Grzeszczuk, R. Flisiak, Medical University, Bialystok; M. Parczewski, M. Pynka, K. Maciejewska, Medical University, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; T. Smiatacz, Medical University, Gdansk; E. Jablonowska, E. Malolepsza, K. Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz; I. Mozer-Lisewska, Poznan University of Medical Sciences, Poznan. Portugal: (M. Doroana), L. Caldeira, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon. Romania: (R. Radoi), C. Oprea, Spitalul de Boli Infectioase si Tropicale: Dr Victor Babes, Bucharest. Russia: (A. Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; A. Rakhmanova, St Petersburg AIDS Centre, St Peterburg; T. Trofimora, Novgorod Centre for AIDS, Novgorod, I. Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E. Kuzovatova, Nizhny Novgorod Scientific and Research Institute, Nizhny Novogrod. Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: A. Shunnar, D. Staneková, Dérer Hospital, Bratislava. Slovenia: (J. Tomazic), University Clinical Centre Ljubljana, Ljubljana. Spain: S. Moreno, J.M. Rodriguez, Hospital Ramon y Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, Hospital Germans Trias i Pujol, Badalona; J.M. Gatell, J.M. Miró, Hospital Clinic Universitari de Barcelona, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona; J.M. Laporte, Hospital Universitario de Alava, Vitoria-Gasteiz. Sweden: (A. Blaxhult), Venhaelsan-Sodersjukhuset, Stockholm; L. Flamholc, Malmö University Hospital, Malmö, A. Thalme, A Sonnerborg, Karolinska University Hospital, Stockholm. Switzerland: (B. Ledergerber), R. Weber, University Hospital, Zürich; M. Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; A. Calmy, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel; P. Schmid, Kantonsspital, St Gallen. Ukraine: (E. Kravchenko), N. Chentsova, Kiev Centre for AIDS, Kiev; V. Frolov, G. Kutsyna, I. Baskakov, Luhansk State Medical University, Luhansk; A. Kuznetsova, Kharkov State Medical University, Kharkov; G. Kyselyova, Crimean Republican AIDS Centre, Simferopol. United Kingdom: (B. Gazzard), St Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, E. Simons, S. Edwards, Mortimer Market Centre, London; A. Phillips, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); C. Orkin, Royal London Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St Mary's, London; M. Fisher, Royal Sussex County Hospital, Brighton; C. Leen, Western General Hospital, Edinburgh.

The following centres have previously contributed data to EuroSIDA: Bernhard Nocht Institut für Tropenmedizin, Hamburg, Germany 1st; I.K.A Hospital of Athens, Athens, Greece; Ospedale Riuniti, Divisione Malattie Infettive, Bergamo, Italy; Ospedale Cotugno, III Divisione Malattie Infettive, Napoli, Italy; Hospital Carlos III, Departamento de Enfermedades Infecciosas, Madrid, Spain; Odessa Region AIDS Center, Odessa, Ukraine.

Steering Committee: J. Gatell, B. Gazzard, A. Horban, I. Karpov, B. Ledergerber, M. Losso, A. d’Arminio Monforte, C. Pedersen, A. Rakhmanova, M. Ristola, A. Phillips, P. Reiss, J. Lundgren, J. Rockstroh, S. De Wit Chair: J. Rockstroh.

Vice-Chair: S. De Wit; Study Co-leads: A. Mocroft, O. Kirk; EuroSIDA Representatives to EuroCoord: O. Kirk, A. Mocroft, J. Grarup, P. Reiss, A. Cozzi-Lepri, R. Thiebaut, J. Rockstroh, D. Burger, R. Paredes, L. Peters; EuroSIDA staff.

Coordinating Centre Staff: D. Podlekareva, L. Peters, J.E. Nielsen, C. Matthews, A.H. Fischer, A. Bojesen, D. Raben, D. Kristensen, K. Grønborg Laut, J.F. Larsen; Statistical Staff: A. Mocroft, A. Phillips, A. Cozzi-Lepri, D. Grint, L. Shepherd, A. Schultze.

Conflicts of interest

A.S. reports having been reimbursed for travel to meetings for the study through the project grant (specified as above); J.K.R. reports receiving consultancies from Abbvie, BMS, Bionor, Boehringer, Gilead, Merck, Janssen, Tobira and Viiv, grants pending from Gilead, payment for lectures from Abbvie, BMS, Boehringer, Gilead, Merck, Janssen and Viiv and payment for the development of educational presentations from Abbvie and BMS; M.B. reports board membership at Gilead, MSD and Pfizer and pending grants from AbbVie, BMS, Boehringer-Ingelheim, Gilead, Janssen, MSD, Pfizer and Viiv; P.M.G. reports board membership at MSD, Janssen, BMS and Gilead, pending grants from Roche and Gilead, payment for lectures from BMS, Janssen, Viiv as well as payment for the development of educational presentations and unrelated expenses. No other author has reported any conflict of interest.

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Keywords:

antiviral drug resistance; Europe; HIV; logistic models; prevalence

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