Figure 2 shows the proportion of the first 2 years of follow-up spent on specific antiretrovirals stratified by group. Patients had been for the majority of time exposed to nucleosides (lamivudine and thymidine analogues) and protease inhibitor (mainly indinavir) with no appreciable differences between the groups.
Table 1 also shows the prevalence of resistance detected in the time window 0.5–2 years after cART initiation in patients in group C, both in terms of prevalence of specific mutations (or family of mutations) and according to an interpretation of their genotypic results (using the Rega interpretation systems, v6.4.1 and 7.1). In a minority of patients, prevalence was calculated cumulating the results obtained in two tests (n = 144, 15%) or at least three tests (n = 38, 4%). The majority of tests used in this analysis (91%, n = 885) were performed in the central laboratory.
The percentage of patients with double-class and triple-class resistance mutations was 58 and 21%, respectively. In more than one-third of the patients in group C, less than one drug included in the regimen received at baseline was predicted to retain activity against the patients' virus and 63% of the patients had less than seven drugs, among all those available at that specific point in time, which were predicted to be fully active.
There were 829 new AIDS events and 571 deaths during 38 814 person-years of follow-up (PYFU) for an overall crude incidence of new AIDS and death of 3.6 per 100 PYFU [95% confidence interval (CI): 3.4–3.8]. The Kaplan–Meier estimates of the overall cumulative proportion of people with a new AIDS diagnosis or death were 4.6% (95% CI: 4.1–5.0) by 1 year, 16.0% (95% CI: 15.2–16.8) by 5 years and 25.3% (95% CI: 23.7–26.9) by 8 years.
Figure 3a shows the Kaplan–Meier estimates stratified by groups (A, B and C); by 96 months from baseline, the proportion of patients with a new AIDS diagnosis or death was 20.3% (95% CI: 17.7–22.9) in group A, 30.4% (95% CI: 27.8–33.0) in B and 35.3% (95% CI: 31.2–39.4) in C (log-rank test P = 0.0001). This analysis shows a clear difference in risk of new AIDS and death when comparing patients with and without evidence of virological failure. This was confirmed in the multivariable analysis adjusted for potential confounders (relative hazard of group C vs. group A: 1.46, 95% CI: 1.18–1.80, P = 0.0005 and relative hazard of group B vs. group A: 1.40, 95% CI: 1.17–1.67, P = 0.0002). Within group C, patients who showed the highest risk of new AIDS and death were those who both rebounded and were tested while still on treatment (relative hazard vs. group A: 1.33, 95% CI: 1.04–1.70, P = 0.02).
Figure 3b shows the estimate comparing again patients in group A with those in group C who were, in turn, categorized according to the level of drug class resistance mutations detected by baseline (no resistance, single-class, double-class and triple-class resistance mutations). Within group C, patients with triple-class resistance mutations were those with the highest risk of new AIDS and death and there was a significant difference between groups (log-rank P = 0.0001). Table 2 shows the multivariable analysis corresponding to the Kaplan–Meier curves shown in Fig. 3b as well as a number of other models using alternative definitions of resistance described in the ‘Methods’. This analysis carried strong evidence that, even after adjusting for a large number of potential confounders, including CD4 cell count at baseline and calendar year of baseline, patients who accumulated resistance mutations to two or more drug classes over the first 2 years of cART were at higher risk of subsequently experiencing AIDS or death than those with no evidence of virological failure. Of note, when looking at specific drug classes, our analysis did not identify a particular drug class driving the association between accumulation of resistance and clinical outcome (Table 2).
Interestingly, the association between the virus predicted susceptibility and the risk of new AIDS and death was less strong than that observed with our simple definition of triple-class resistance. Compared with patients with no evidence of viral failure, the difference was significant for those receiving at baseline a regimen including less than one active drug and for those who had less than seven active drugs that could be used in future regimens.
The estimate of the risk of new AIDS and death associated with the detection of triple-class resistance mutations as compared with no evidence of virological failure was consistent in a number of sensitivity analyses: relative hazard was 2.27 (95% CI: 1.56–3.30, P = 0.0001) when using only genotypic tests performed retrospectively in the central EuroSIDA laboratory, relative hazard, 1.46 (95% CI: 0.44–4.90, P = 0.54) in patients who started cART when they were ART-naive (n = 2712 patients and 245 clinical events), relative hazard, 1.33 (95% CI: 0.42–4.23, P = 0.63) in those who initiated cART with two nucleosides with either a NNRTI or a protease inhibitor/r (n = 1629, 136 events) and relative hazard, 1.43 (95% CI: 0.83–2.47, P = 0.20) in those who started when they were already under active follow-up in EuroSIDA (n = 1700, 284 events).
Patients with triple-class resistance mutations were at increased risk of new AIDS alone (relative hazard: 2.27, P = 0.002) compared with patients without virological failure. Consistent results were found for the endpoint death alone, although the power of this analysis was low (data not shown).
The relationship between the emergence of HIV drug resistance in patients on ART and the risk of clinical outcome has been the subject of various analyses from cohort studies often using differing approaches [7–15]. Potentially as a result of the use of different methods of analysis as well as other factors, the results of these studies have been somewhat conflicting.
Our study provides strong evidence for an association between HIV drug resistance emerging on treatment and subsequent risk of new AIDS and death. The main strength of this analysis is the use of a large and well characterized cohort of patients with both genotypic resistance data and long-term prospective clinical follow-up.
The issue of trying to establish whether there is an association between emergence of HIV drug resistance and risk of clinical progression is complicated by several factors. First, the fact that resistance can only, in general, be measured using standard assays in people with viral load above a certain cut-off (typically ≥500 copies/ml). As a consequence of this, people who are tested for resistance on treatment in clinical cohort studies are potentially per se a selected population of patients at higher risk of disease progression compared, for example, with those with sustained virological suppression, regardless of whether drug resistance has been selected by ART or not. This introduces a limitation in that results can only be generalized to the population of patients routinely tested for resistance who may be not representative of all patients enrolled in the clinical cohort. Second, the lack of detectable resistance in a person experiencing virological failure on therapy is typically a marker of patients' poor adherence, which, in turn is associated with poor clinical outcome. Previous analyses [7,8] compared the risk of clinical progression between people with virological failure and no detectable resistance mutations (patients likely to be poorly adherent) with that of patients with evidence of resistance at virological failure (patients with reduced benefit from therapy due to resistance). The interpretation of such analysis is not straightforward, as it seems difficult to predict a priori which of these two groups may experience, in the long run, the worst clinical outcome. In contrast, our alternative analysis design allowed the inclusion, and the use as the comparator group, of patients with undetectable viral load. Interestingly, our analysis carried evidence that patients in whom no resistance mutations could be detected at failure (4% of tested) tended to be at increased risk of new AIDS and death compared with patients without virological failure, suggesting that poor adherence may have a long-term detrimental effect on the clinical outcome. However, of course, poor adherence cannot be assumed to be the only explanation for treatment failure in the presence of viral rebound with no detection of resistance and in our cohort, in which the majority of patients started ‘old generation’ antiretrovirals, issues such as drug potency and cellular resistance may have played a role .
Furthermore, there is the issue of which statistical approach may be best to answer this clinical question; viral load is likely to be both a time-dependent confounder and an intermediate factor for the relationship between accumulation of resistance and clinical outcome [26–32]. In such a situation, marginal structural modelling (MSM)  is preferable to standard survival analysis with time-dependent covariates  if the aim is to estimate the true magnitude of the association of interest. However, because resistance can be measured only in patients with raised viral load and because current assays can only detect mutations present in the dominant virus, it is likely that the analysis of the determinants of drug resistance may produce unreliable inverse probabilities of weighting. Also, although MSM is ideally suited to estimate the net effect of an intervention (typically the initiation of treatment) on the outcome, testing for resistance it is not an intervention per se but rather a tool that is used to guide treatment interventions and therefore the causal question is not well defined [20,21,33].
Before drawing conclusions, some possible limitations of our analysis need to be mentioned. First, the fact that resistance to drug classes was based on the sequencing of reverse transcriptase and encoding protease genomes alone so that for people with resistance in other regions of HIV (e.g. gag) or to newly approved classes of drugs (fusion-inhibitor, integrase-inhibitors and CCR5 antagonists) we may have underestimated the number of drug classes to which their virus populations were resistant. However, only eight patients were exposed to T20 before baseline and none to the other newer drugs. Second, the majority of the genotypic tests were performed retrospectively on stored plasma samples and Group C may have not been representative of the whole population of viraemic patients in EuroSIDA. Nevertheless, we did not find major differences in their risk of new AIDS and death comparing patients in Group C (with genotypic test) with those of group B (without genotypic test, Fig. 3a). Third, although we used multiple genotypic tests for some individuals, sensitivity of current routine genotypic assays is low so that the real level of resistance may have been underestimated. However, if anything, as a consequence of this bias, our estimate of the difference in risk of clinical progression between groups may have also been underestimated. Finally, ours is an historical analysis including mainly patients who started cART before the year 2000 and results may not be generalized to patients starting cART more recently who may have the benefit of experiencing the newer classes of drugs. However, the estimate of the association between detection of triple-class resistance and risk of new AIDS and death in patients who started regimens recommended by current guidelines was consistent with that of our main analysis, though not statistically significant. This lack of significance is likely to be due to low statistical power of the analysis as a consequence of the low incidence of triple-class resistance mutations in this subgroup of patients. This assessment should, therefore, be repeated in the future as data of patients starting cART with currently recommended regimens will accumulate.
Our analysis shows evidence that the detection of resistance in patients on therapy is associated with their long-term clinical outcome. In particular, our data show that there is an 55% increase in the risk of new AIDS and death in patients who, by 2 years of starting their first cART, accumulated resistance to two classes of antiretrovirals and an 80% increase in those who accumulated resistance to nucleosides, NNRTI and protease inhibitor. Because we only studied baseline factors, the potential mechanisms behind this association need to be further investigated. Adherence may be one of the likely explanations of our findings and we cannot rule out residual confounding by health-seeking behaviour, quality of care or other so far unrecognized factors.
These findings are consistent with those of other studies [7–11] and extend the results of another study in which a more stringent definition of class resistance was used . Our analysis, however, does not support the previous observation that emergence of resistance to NNRTI is associated with a greater risk of subsequent death than the emergence of resistance to nucleosides or protease inhibitor [14,15]. Of note, the NNRTI-specific effect on clinical outcome in these other studies was found using MSM  or standard survival analysis with time-dependent covariates  and could be also reproduced in EuroSIDA using these methods (data not shown). Further work is required to identify possible causes for this discrepancy.
In conclusion, our findings further support the view that experiencing early virological failure with drug resistance is a prognostic sign for poorer long-term clinical outcome. This is likely to be due to both a tendency for those with drug resistance to be poorly adherent (and therefore patients' education about the risk of resistance associated with less than perfect adherence should be reinforced) and a direct effect of resistance on subsequent outcome; further research is needed to separate the effect of these two distinct potential mechanisms.
Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), the 5th Framework (QLK2-2000-00773) and the 6th Framework (LSHP-CT-2006-018632) programs. Current support also includes unrestricted grants by Bristol-Myers Squibb, GlaxoSmithKline, Roche, Gilead, Pfizer, Merck and Co., Tibotec and Boehringer-Ingelheim. The participation of centres from Switzerland was supported by a grant from the Swiss Federal Office for Education and Science.
Over the past few years, some of the authors have received reimbursement, fees and/or funding for attending symposiums, speaking, advisory board membership, organising educational activities, consulting and/or research from Abbott (A.N.P., J.D.L.), Boeringher Ingelheim (A.N.P., J.D.L.), Bristol-Myers Squibb (A.N.P., J.D.L., A.M.), Gilead Sciences (A.N.P., J.D.L.), GlaxoSmithKline (A.C.-L., A.N.P., J.D.L.), Pfizer Pharmaceutical (A.N.P., J.D.L.), Roche (A.C.-L., A.N.P., J.D.L.), and Tibotec (A.N.P., J.D.L.). None of the other authors have declared a conflict of interest. None of the authors hold any shares in any of the companies.
Presented at 10th European AIDS Conference/EACS; Dublin 17–20 November 2005; Abstract PS6/4.
Role of each author
Design of the study (J.D.L., O.K., A.M., A.N.P.)
Data collection (J.D.L., O.K., A.L., A.W.-D., A.K.)
Analysis design (A.C.-L., A.N.P.)
Statistical analysis of the data (A.C.-L.)
Genotypic testing (B.C., L.R.)
Contribution to the writing of the paper (A.C.-L., A.N.P., B.C., A.M., L.R., O.K., A.L., A.W.-D., A.K. and J.D.L.)
The EuroSIDA Study Group
The names of the national coordinators are given in parenthesis.
(M. Losso), A. Duran, Hospital JM Ramos Mejia, Buenos Aires, Argentina.
(N. Vetter), Pulmologisches Zentrum der Stadt Wien, Vienna, Austria.
(I. Karpov), A. Vassilenko, Belarus State Medical University, Minsk, Belarus.
(N. Clumeck), S. De Wit, B. Poll, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp, Belgium.
K. Kostov, Infectious Diseases Hospital, Sofia, Bulgaria.
J. Begovac, University Hospital of Infectious Diseases, Zagreb, Croatia.
(M. Ristola), Helsinki University Central Hospital, Helsinki, Finland.
(L. Machala), H. Rozsypal, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen, Czech Republic.
(J. Nielsen), J. Lundgren, T. Benfield, O. Kirk, Panum Institute, Copenhagen; J. Gerstoft, T. Katzenstein, A.-B. E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense; L. Oestergaard, Skejby Hospital, Aarhus, Denmark.
(K. Zilmer), West-Tallinn Central Hospital, Tallinn; J. Smidt, Nakkusosakond Siseklinik, Kohtla-Järve, Estonia.
(C. Katlama), Hôpital de la Pitié-Salpétière, Paris; J.-P. Viard, Hôpital Necker-Enfants Malades, Paris; P.-M. Girard, Hospital Saint-Antoine, Paris; J.M. Livrozet, Hôpital Edouard Herriot, Lyon; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l'Archet, Nice; F. Dabis, Unité INSERM, Bordeaux, France.
(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; S. Staszewski, JW Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne, Germany.
(J. Kosmidis), P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Hospital; H. Sambattakou, Ippokration Genereal Hospital, Athens, Greece.
(D. Banhegyi), Szent Lásló Hospital, Budapest, Hungary.
(F. Mulcahy), St. James's Hospital, Dublin, Ireland.
(I. Yust), D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; S. Pollack, G. Hassoun, Rambam Medical Center, Haifa; S. Maayan, Hadassah University Hospital, Jerusalem, Israel.
(A. Chiesi), Istituto Superiore di Sanità, Rome; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; C. Arici, Ospedale Riuniti, Bergamo; 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; A. Chirianni, E. Montesarchio, M. Gargiulo, Presidio Ospedaliero AD Cotugno, Monaldi Hospital, Napoli; G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Ospedale L. Sacco, Milan; A. d'Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan, Italy.
(B. Rozentale), P. Aldins, Infectology Centre of Latvia, Riga, Latvia.
(S. Chaplinskas), Lithuanian AIDS Centre, Vilnius, Lithuania.
(R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg, Luxembourg.
(P. Reiss), Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, Netherlands.
(J. Bruun) A. Maeland, V. Ormaasen, Ullevål Hospital, Oslo, Norway.
(B. Knysz), J. Gasiorowski, Medical University, Wroclaw; A. Horban, Centrum Diagnostyki i Terapii AIDS, Warsaw; D. Prokopowicz, A. Wiercinska-Drapalo, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk, Poland.
(F. Antunes), E. Valadas, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon.Romania: (D. Duiculescu), Spitalul de Boli Infectioase si Tropicale: Dr Victor Babes, Bucarest, Portugal.
(A. Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; E. Vinogradova, St Petersburg AIDS Centre, St Peterburg; S. Buzunova, Novgorod Centre for AIDS, Novgorod, Russia.
(D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade, Serbia.
(M. Mokráš), D. Staneková, Dérer Hospital, Bratislava, Slovakia.
(J. González-Lahoz), V. Soriano, L. Martin-Carbonero, P. Labarga, Hospital Carlos III, Madrid; B. Clotet, A. Jou, J. Conejero, C. Tural, Hospital Germans Trias i Pujol, Badalona; J.M. Gatell, J.M. Miró, Hospital Clinic i Provincial, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona, Spain.
(A. Karlsson), Karolinska University Hospital, Stockholm; P.O. Persson, Karolinska University Hospital, Huddinge; L. Flamholc, Malmö University Hospital, Malmö, Sweden.
(B. Ledergerber), R. Weber, University Hospital, Zürich; P. Francioli, M. Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, E. Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel, Switzerland.
(E. Kravchenko), N. Chentsova, Kiev Centre for AIDS, Kiev, Ukraine.
(S. Barton), St. Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, D. Mercey, Royal Free and University College London Medical School, London (University College Campus); A. Phillips, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); M. Murphy, Medical College of Saint Bartholomew's Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St. Mary's, London; M. Fisher, Royal Sussex County Hospital, Brighton; R. Brettle, Western General Hospital, Edinburgh, United Kingdom.
Virology group: B. Clotet (central coordinator) plus ad hoc virologists from participating sites in the EuroSIDA Study.
Steering committee: F. Antunes, B. Clotet, D. Duiculescu, J. Gatell, B. Gazzard, A. Horban, A. Karlsson, C. Katlama, B. Ledergerber (chair), A. d'Arminio Monforte, A. Phillips, A. Rakhmanova, P. Reiss (vice-chair), J. Rockstroh.
Coordinating centre staff: J. Lundgren (project leader), O. Kirk, A. Mocroft, N. Friis- Møller, A. Cozzi-Lepri, W. Bannister, M. Ellefson, A. Borch, D. Podlevkareva, J. Kjær, L. Peters, J. Reekie
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
clinical progression; drug resistance mutations; virological failure