To evaluate the potential impact of baseline resistance on the efficacy of future therapy, we analysed the RT and protease genotypes using three resistance interpretation algorithms The great majority [967/1050 (92.1%)] of the 1050 HIV-1 strains identified from the newly diagnosed individuals was fully susceptible to all drugs in the three classes. Within the group of viruses with TDRMs, 79.2% of the strains displayed full susceptibility to all NNRTIs, 82.3% to all PIs and 44.8% to all NRTIs (Fig. 1). Moreover, 25% (24/96) of the TDRM-HIV strains were predicted to be fully susceptible to all drugs. These 25 strains contained only single amino acid substitutions, with limited impact on resistance, and therefore were predicted not to have an impact on therapy outcome.
Reduced susceptibility in the remaining TDRM-containing strains was frequently limited to one or only a few drugs within a class (Tables 2 and 3). Some exceptions, however, existed where resistance was quite extensive and affected all drugs of a class (Table 2 NNRTI section, and Table 3). Twenty strains [20/96 (20.8%)] had reduced NNRTI class susceptibility, 14 of these strains were predicted to display high level of resistance to both currently approved NNRTIs. Four strains (4.2%) had reduced susceptibility to all drugs of the NRTI class, one of them was predicted to have high-level resistance to each NRTI. Three (3.1%) strains had reduced susceptibility to all PIs but none was predicted to be highly resistant to all PIs.
Remarkably, in one individual, the resistance pattern was so extensive that none of the currently available antiretroviral drugs was predicted to be fully active. Loss of susceptibility was most extensive for the NRTI zidovudine, with only 50% (48/96) of the strains with TDRMs predicted to be fully susceptible, 27.1% displaying intermediate resistance and 22.9% high-level resistance. In contrast, the least affected drug was the PI tipranavir, for which 96.9% of all strains harbouring TDRMs were predicted to be fully susceptible.
The SPREAD programme is the first large, prospective and sufficiently powered multinational European study performing a well-controlled assessment of the prevalence of transmitted drug resistance. This study prospectively studied transmission of resistant virus in a representative population of over 1000 newly diagnosed HIV-1-infected individuals, consisting of 235 individuals in whom a recent seroconversion was documented.
Our study shows that the prevalence of viruses with transmitted drug resistance mutations in newly diagnosed individuals is around 9% and that in the majority of individuals only single drug resistance-related mutations are detected.
For two reasons, it cannot be excluded that we underestimate the transmission of drug-resistant mutations. First, we used population sequencing for detection of resistance-related mutations and it is possible that mutant populations comprising a minority of the viral population remained undetected [15,16]. Second, we assessed prevalence of TDRMs among newly HIV-1-diagnosed individuals. The population of newly diagnosed individuals in our study represents a range from acutely infected individuals to those with a chronic HIV-1 infection. Although persistence of drug-resistant mutant viruses in the absence of selection pressure of therapy frequently has been reported [17–20], it is possible that in the period between infection and diagnosis, reversion to wild-type and/or outgrowth of minority wild-type species may result in disappearance of resistant viruses from plasma. Indeed, we observed a trend towards a higher prevalence of resistance-related mutants but a lower prevalence of mixture and revertants in individuals with documented recent infection. These results indicate that transmitted mutations can revert over time in the absence of therapy.
In the retrospective Child and Adolescent Trial for Cardiovascular Health (CATCH) study, which collected samples from 1996 to 2002 before the start of the prospective SPREAD programme, we reported earlier a higher prevalence of TDRMs in subtype B viruses than in non-B viruses . Also, in this prospective study, we identified more frequently TDRMs in subtype B viruses compared with non-B viruses (10.4 vs. 6.3%). Using the epidemiological data collected in the SPREAD programme, we established that a vast majority of patients from or known to be infected in countries with a high prevalence of HIV-1 carried predominantly non-B virus, the wild-type HIV-1. In contrast, the prevalence of TDRM-HIV was equally distributed among B and non-B strains carried by patients who had been infected in Europe. This indicates that the overall difference observed is not attributed to specific viral characteristics of non-B strains but rather to the lack of exposure to drugs in the high-prevalence countries .
With the current lack of prospective data collected over a prolonged period, making definite statements regarding the patterns and prevalence of TDRM changes over time is still difficult. In the retrospective CATCH study, however, a prevalence of TDRMs of 10% was reported from surveillance data from several European countries between 1996 and 2002 . In Fig. 2, the incidence of TDRMs in recently infected patients (<1 year) from the retrospective CATCH study (data taken from 1996 to 2001) and the prospective SPREAD study (data from 2002 to 2003) is shown. Despite the limitations of comparing two datasets with different sampling strategies, it is still of interest to see that the proportion of recently infected individuals diagnosed with strains harbouring TDRMs does not continue to rise but seems to decrease over time in Europe  (Fig. 2).
The results of SPREAD are generally consistent with the results of several other studies that recruited various risk groups from individual high-income countries, with prevalences ranging from 0 to 17% in Europe . Some observational and retrospective studies in the US and UK observed an increased prevalence of TDRMs in recently infected individuals over time to more than 20% in recent years [24–27]. These studies, however, had a different design with an inclusion of predominantly MSM in urban areas exposed to highly antiretroviral drugs. In contrast, a sentinel study describing data from 1083 individuals collected during 1998–2000 in several cities in the US using a consecutive sampling approach observed a prevalence of TDRMs of 7.4% among chronically infected patients and 12% among recently infected patients . The prevalence of TDRMs in this study was significantly higher in MSM (11% in chronically and 15% in recently infected) than in heterosexual infected individuals. In our study, the prevalence of TDRMs was comparable and not significantly higher in MSM as compared with heterosexual individuals infected in Europe (11 vs. 10%). The prevalence of TDRMs in MSM, however, was significantly higher compared with patients coming from outside Europe (5.5%). These results indicate the importance of collection of epidemiological data from all transmission groups for surveillance of TDRMs.
Insights into the dynamics of transmission of drug-resistant viruses can be obtained by analysing the patterns of transmitted mutations in more detail. The predominance of single thymidine-associated mutations (TAMSs) and 215 revertants can be explained by a combination of factors. TAMSs are selected by the thymidine analogues (zidovudine and stavudine); therefore, transmission of viruses with solitary TAMS most likely reflects a predominant circulation of these viruses at points in time (e.g. late 1980s and early 1990s), when there was extensive use of non-suppressive mono and dual therapies with thymidine analogues. Introduction of highly active antiretroviral therapy in the mid-1990s caused a more equal distribution of resistance among the three classes in patients with treatment failure. As a result, more recent transmissions patterns show a relative decrease in the proportion of NRTI resistance (Fig. 2).
Given the fact that the majority of the HIV-1 strains harboured only a single mutation, the effect on the response to future therapy may be limited. Indeed, a quarter of the isolated viruses harbouring TDRMs were predicted to be fully susceptible to all currently approved antiretroviral drugs. Nevertheless, identification of these resistance-related mutations is essential as they give insight into the transmission patterns of viruses that have been exposed to therapy in previous hosts.
The predicted effect of other single TDRMs on therapy outcome depends on the specific class of antiretroviral drugs. The presence of most single TAMS is not predicted to affect initial therapy response dramatically, especially given that NRTIs are in general combined with a NNRTI or PI. Then again, the presence of baseline resistance mutations can decrease the genetic barrier, reducing the number of mutations necessary for loss of susceptibility. For instance, the presence of baseline 215 revertants has been reported to be associated with a higher risk of virological failure on regimens containing a thymidine analogue .
The effect of single PI mutations on first-line therapy is expected to be limited in the era of boosted PIs because multiple mutations have to be generated before therapy fails .
In contrast, most solitary NNRTI mutations are sufficient for a complete loss of activity of the first-generation NNRTIs (efavirenz and nevirapine) . Treatment guidelines advise to initiate first-line therapy with a boosted PI or a NNRTI accompanied by a NRTI backbone. As solitary mutations may dramatically effect the susceptibility of NNRTIs, we support the recommendations for baseline resistance testing for newly diagnosed individuals and, if necessary, subsequent customizing of initial therapy. Furthermore, minority strains with transmitted drug resistance related mutations might not always be detected by conventional resistance testing [15,16]. A single mutation or a revertant might be an indication that more extensive resistance has been transmitted. Therefore, in cases of infection with HIV-1 carrying a single transmitted drug resistance mutation, the initiation of antiretroviral combination regimens with a high genetic barrier should be considered. In addition, treatment response should be closely monitored and resistance testing should be urgently considered if treatment failure is suspected.
In conclusion, we have shown that the prevalence of viruses with transmitted drug resistance mutations in newly diagnosed individuals in Western Europe and Israel is approximately 9% and that in the majority of cases detection is limited to single drug resistance-related mutations.
Continuous monitoring remains indicated to determine the patterns, rates and factors contributing to the transmission of TDRMs, as well as the potential clinical consequences.
This study was funded by grants from European Commission: QLK2-CT-2001-01344, 5th Framework. Belgium: The Belgian AIDS Reference Laboratory fund, the Belgian Fonds voor Wetenschappelijk Onderzoek (F.W.O. G.0266.04). Denmark: The Danish AIDS foundation. Germany: Federal Ministry of Health (grant 325-4476-02/3) and the Federal Ministry of Education and Research (grant 01 KI 0211). Italy: 5th National Programme on HIV/AIDS, Istituto Superiore di Sanità (grants N 40F.56 and 20D.1.6). Luxembourg: The Fondation Recherche sur le SiDA and the Ministry of Health. Serbia Montenegro: Ministry of Science and Environmental of the Republic of Serbia Montenegro (grant 145047). Sweden: Swedish Research Council. Spain: Maraton TV3 Foundation (MARATÓN-TV3/02-1730).
Writing committee: Annemarie M.J. Wensing, University Medical Center, Utrecht, the Netherlands, Jurgen Vercauteren, Katholieke Universiteit Leuven, Leuven, Belgium; David A. van de Vijver, University Medical Center, Utrecht, the Netherlands; Jan Albert, Swedish Institute for Infectious Disease Control, Solna, Sweden; Birgitta Åsjö, University of Bergen, Bergen, Norway; Claudia Balotta, University of Milan, Milan, Italy; Ricardo Camacho, Hospital Egas Moniz, Lisbon, Portugal; Suzie Coughlan, National Virus Reference Laboratory, University College Dublin, Dublin, Ireland; Zehava Grossman, Sheba Medical Center, Tel-Hashomer, Israel; Andrzej Horban, Hospital for Infectious Diseases & AIDS Diagnosis and Therapy Center, Warsaw, Poland; Claudia Kücherer, Robert Koch Institute, Berlin, Germany; Claus Nielsen, Statens Serum Institute, Copenhagen, Denmark; Dimitris Paraskevis, Athens University Medical School, Athens, Greece; Wei C. Loke, Guys and St Thomas' Hospital, London, UK; Gabrielle Poggensee, Robert Koch Institute, Berlin, Germany; Elisabeth Puchhammer-Stöckl, University of Vienna, Vienna, Austria; Chiara Riva, University of Milan, Milan, Italy; Lidia Ruiz, Retrovirology Laboratory IRSICAIXA Foundation, Badalona, Spain; Jean-Claude Schmit, Centre Hospitalier de Luxembourg, Luxembourg; Rob Schuurman, University Medical Center, Utrecht, the Netherlands; Mika Salminen, National Public Health Institute, Helsinki, Finland; Anders Sonnerborg, Karolinska University Hospital, Stockholm, Sweden; Maja Stanojevic, University of Belgrade School of Medicine and Ministry of Health, Serbia Montenegro; Daniel Struck, Centre Hospitalier de Luxembourg, Luxembourg; Anne-Mieke Vandamme, Katholieke Universiteit Leuven, Leuven, Belgium; Charles A.B. Boucher, University Medical Center, Utrecht, the Netherlands, on behalf of the SPREAD programme.
SPREAD national coordinators: E. Puchhammer-Stockl, Austria; A.-M. Vandamme, Belgium; C. Nielsen, Denmark; M. Salminen, Finland; K. Korn, Germany; A. Hatzakis, Greece; W. Hall, Ireland; Z. Grossman, Israel; C. Balotta, Italy; J. Albert, Sweden; J.C. Schmit, Luxembourg; C.A.B. Boucher and A.M.J. Wensing, the Netherlands; B. Åsjö, Norway; A. Horban, Poland; R. Camacho, Portugal; M. Stanejovic, Serbia Montenegro; B. Clotet, Spain; D. Pillay, UK.
Programme coordination team: C.A.B. Boucher, A.M.J. Wensing, R. Schuurman, D.A.M.C. van de Vijver, A.I. Stolwijk, M. Toet.
Data analysis team: J. Albert, C. Balotta, G. Poggensee, C. Kucherer, J.-C. Schmit, D. Struck, A.-M. Vandamme, J. Vercauteren, D.A. van de Vijver, A.M.J. Wensing.
Austria: M. Sarcletti, B. Schmied, M. Geit, G. Balluch.
Rega Institute for Medical Research and University Hospitals, Leuven, Belgium: J. Vercauteren, K. Van Laethem, A. Abecasis, I. Derdelinckx, K. Deforche; Universitair Ziekenhuis Gent, Gent, Belgium: M. Bogaert; Rega Institute for Medical Research and University Hospitals, Leuven, Belgium: H. Ceunen; St Pierre University Hospital, Brussels, Belgium: S. De Wit; Academisch Ziekenhuis, Vrije Universiteit Brussel, Brussel, Belgium: F. Echahidi; Cliniques Universitaires de Bruxelles, Hôpital Erasme, Brussels, Belgium: C.M. Farber; Prince Leopold Institute of Tropical Medicine, Antwerpen, Belgium: K. Fransen; Cliniques Universitaires de Bruxelles, Hôpital Erasme, Brussels, Belgium: J.C. Goffard; St Pierre University Hospital, Brussels, Belgium: E. Goudeseune; Cliniques Universitaires St-Luc, Brussels, Belgium: A. Henry; Academisch Ziekenhuis, Vrije Universiteit Brussel, Brussel: P. Lacor; Cliniques Universitaires de Bruxelles, Hôpital Erasme, Brussels, Belgium: C. Liesnard; University of Liège, Liège, Belgium: M. Moutschen; Academisch Ziekenhuis, Vrije Universiteit Brussel, Brussel: D. Pierard; Rega Institute for Medical Research and University Hospitals, Leuven, Belgium: R. Rens, Y. Schrooten; University of Liège, Liège, Belgium: D. Vaira; Cliniques Universitaires St-Luc, Brussels, Belgium: B. Vandercam; Prince Leopold Institute of Tropical Medicine, Antwerpen, Belgium: A. Van den Heuvel; Universitair Ziekenhuis Gent, Gent, Belgium: B. Van Der Gucht; Rega Institute for Medical Research and University Hospitals, Leuven, Belgium: M. Van Ranst, E. Van Wijngaerden; Universitair Ziekenhuis Gent, Gent, Belgium: C. Verhofstede; St Pierre University Hospital, Brussels, Belgium: N. Clumeck; Scientific Institute of Public Health, Brussels, Belgium: A. Sasse; Rega Institute for Medical Research and University Hospitals, Leuven, Belgium: A.-M. Vandamme.
Denmark: L.B. Jørgensen, J. Gerstoft, L. Mathiesen, C. Pedersen, H. Nielsen, A. Laursen, B. Kvinesdal.
Finland: M. Ristola, K. Liitsola, J. Suni, J. Sutinen.
Labor Berg, Berlin, Germany: T. Berg; PZB, Aachen, Germany: P. Braun; Robert Koch Institute, Berlin, Germany: G. Breugelmans; University of Cologne, Cologne, Germany: M. Däumer; Max von Pettenkofer Institut, München, Germany: J. Eberle; Robert Koch Institute, Berlin, Germany: O. Hamouda; Hannover Medical School, Hannover, Germany: H. Heiken; University of Cologne, Cologne, Germany: R. Kaiser; PZB, Aachen, Germany: H. Knechten; Fenner and Partner, Hamburg, Germany: H. Müller; Labor Berg, Berlin, Germany: S. Neifer; University of Erlangen-Nuremberg, Germany: B. Schmidt, H. Walter.
Athens University Medical School, Athens, Greece: A. Hatzakis, D. Paraskevis, E. Magiorkinis, E. Hatzitheodorou.
National Virus Reference Laboratory, University College Dublin, Ireland: C. Byrne, M. Duffy; St. James's Hospital, Dublin, Ireland: C. Bergin, G. Farrell, A. Rochford, J. Low, P. Coakely; National Virus Reference Laboratory, University College Dublin, Ireland: W. Hall.
Israel: I. Levi, D. Chemtob.
University of Milan, Milan, Italy: C. Riva; University of Modena, Modena, Italy: C. Mussini; University of Milan, Milan, Italy: I. Caramma, J. Cibella, A. Cappelletti; L. Sacco Hospital, Milan, Italy: A. Capetti; Sant'Anna Hospital of Como, Como, Italy: M.C. Colombo; San Camillo Hospital of Treviso, Treviso, Italy: C. Rossi; University of Modena, Modena, Italy: F. Prati; University of Palermo, Palermo, Italy: F. Tramuto, F. Vitale; Istituto Superiore di Sanità, Rome, Italy: M. Ciccozzi; University of Foggia, Foggia, Italy: G. Angarano; Istituto Superiore di Sanità, Rome, Italy: G. Rezza; University of Milan, Milan, Italy: C. Balotta.
Luxembourg: R. Hemmer, V. Arendt, T. Staub, F. Schneider, F. Roman.
Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands: A.M.J. Wensing, D.A.M.C. van de Vijver; Ziekenhuis Rijnstate, Arnhem, the Netherlands: P.H.M. van Bentum; Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands: K. Brinkman; Rijksinstituut voor Volksgezondheid & Milieu, Bilthoven, the Netherlands: E.L. op de Coul; Erasmus Medisch Centrum, Rotterdam, the Netherlands: M.E. van der Ende; Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands: I.M. Hoepelman; St. Elisabeth Ziekenhuis, Tilburg, the Netherlands: M. van Kasteren, J. Juttmann, M. Kuipers; Ziekenhuis Rijnstate, Arnhem, the Netherlands: N. Langebeek; St. Elisabeth Ziekenhuis, Tilburg, the Netherlands: C. Richter, R.M.W.J. Santegoets, L. Schrijnders-Gudde; Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands: R. Schuurman; St. Elisabeth Ziekenhuis, Tilburg, the Netherlands: B.J.M. van de Ven; Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands: Charles A.B. Boucher.
Department of Infectious Disease, Ullevaal University Hospital, Oslo, Norway: V. Ormaasen; The Norwegian Institute of Public Health, Oslo, Norway: P. Aavitsland, C. Holm-Hansen.
Hospital for Infectious Diseases & AIDS Diagnosis and Therapy Center, Warsaw, Poland: J.J. Stanczak, G.P. Stanczak, E. Firlag-Burkacka; Medical University, Bialystok, Poland: A. Wiercinska-Drapalo; Medical University, Lodz, Poland: E. Jablonowska, E. Małolepsza; Pomeranian Medical University, Szczecin, Poland: M. Leszczyszyn-Pynka; National Institute of Hygiene, Warsaw, Poland: W. Szata.
Portugal: C. Palma, F. Borges, T. Paixão, V. Duque, F. Araújo, on behalf of the Portuguese SPREAD Network.
Serbia Montenegro: Dj. Jevtovic, D. Salemovic.
IrsiCaixa Foundation, Badalona, Spain: J. Martinez-Picado; Hospital Ramon y Cajal, Madrid, Spain: C. Gutiérrez; C. de Mendoza; IrsiCaixa Foundation, Badalona, Spain: I. Erkicia; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain: P. Domingo; Hospital Nuestra Donostia, San Sebastián, Spain: X. Camino; Hospital Clínico Universitario, Valencia, Spain: M.J. Galindo; Hospital Clínico, Barcelona, Spain: J.L. Blanco; Hospital Virgen del Rocío, Sevilla, Spain: M. Leal; Hospital de Palamós, Barcelona, Spain: A. Masabeu; Hospital del Mar, Barcelona, Spain: A. Guelar; Hospital Sant Jaume, Barcelona, Spain: J.M. Llibre; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain: N. Margall; Hospital Nuestra Donostia, San Sebastián, Spain: J.A. Iribarren; Hospital Virgen del Rocío, Sevilla, Spain: S. Gutierrez; Hospital Clínico Universitario, Valencia, Spain: J.F. Baldoví; Hospital Juan Canalejo, A. Coruña, Spain: J.D. Pedreira; Hospital Clínico, Barcelona, Spain: J.M. Gatell; Hospital Ramon y Cajal, Madrid, Spain: S. Moreno; Hospital Carlos III, Madrid, Spain: B. Clotet; Hospital Ramon y Cajal, Madrid, Spain: V. Soriano; IrsiCaixa Foundation, Badalona, Spain: L. Ruiz on behalf of the Maraton TV3 Study Group.
Sweden: M. Arneborn, M. Gisslén, P. Björkman, G. Bratt, Annette Alaeus.
UK: D. Pillay, V. Delpech, D. Dunn.
J. Albert has given presentations for Abbott, Roche, BMS. B. Åsjö has given presentations for Abbott, Glaxo Smith Kline and Roche and received travel grants from Glaxo Smith Klein. C.A.B. Boucher has received travel and study grants and or participated in advisory boards for the following companies: Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Bayer diagnostics, Glaxo Smith Kline, Roche, UCB-Pharma. R. Camacho has received travel grants and or participated in advisory boards for the following companies: Abbott, Boehringer Ingelheim, Bristol Myers Squibb, Glaxo Smith Kline. M. Salminen has given presentations for the following companies: Abbott, Roche J.C. Schmit has received travel and study grants or participated in advisory boards from the following companies: Abbott, Boehringer Ingelheim, Bristol Myers Squipp, Glaxo Smith Kline, Roche, UCB-Pharma. A. Sonnerborg has received study grants and/or participated in advisory boards for the following companies: Abbott, Jansen-Cilag, Glaxo Smith Kline, Medivir, Roche. A.M. Vandamme has received travel grants from Abbott, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Glaxo Smith Kline, Merck, Roche and has participated in advisory boards of Abbott, Bayer, Boehringer Ingelheim and Gilead. A.M.J. Wensing has received travel grants, given presentations or participated in advisory boards for the following companies: Abbott, Boehringer Ingelheim Bristol Myers Squibb, Glaxo Smith Kline, Roche, Schering Plough.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
Europe; HIV-1; resistance; transmission