Introduction
The virological response to highly active antiretroviral therapy (HAART) is now well documented in clinic populations of patients with HIV infection [1–6 viral load with a median time to undetectable levels of approximately 4 months. It has been suggested that the achievement and maintenance of prolonged viral suppression is directly related to the long-term efficacy of HAART [7 viral load may start to rise in a substantial proportion of patients [1,5,8–10 11,12 13,14 15,16 17,18 19,20
The aims of this study were to describe the rate of virological rebound among 2444 HIV-infected patients in the EuroSIDA study, and to investigate the factors related to virological rebound.
Methods
Patients
The EuroSIDA study is a prospective, European study of patients with HIV-1 infection in 70 centres across Europe (including Israel, see Appendix ) and now including Argentina. Details of the study have been published elsewhere [21 3 in the previous 4 months, a booked clinic appointment and who were older than 16 years at the time of enrolment. The CD4 lymphocyte count restriction was removed for cohorts IV and V. Information was provided on a standardized data collection form at baseline and every 6 months thereafter. Follow-up was to Spring 2002, with information from up to 16 forms available for cohort I, 13 for cohort II, 10 for cohort III, five for cohort IV and one for cohort V. At each follow-up visit, details on all CD4 lymphocyte counts measured since the last follow-up and viral load measurements were collected. For each patient, the date of starting and stopping each antiretroviral drug was recorded, as was the use of drugs for prophylaxis against opportunistic infections. The dates of diagnosis of all AIDS-defining illnesses have also been recorded, including those diagnoses made subsequent to the initial diagnosis, using the 1993 clinical definition of AIDS from the Centers for Disease Control [22
Statistical methods
HAART was defined as starting a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) for the first time, combined with at least two nucleoside reverse transcriptase inhibitors (NRTI), or starting triple NRTI therapy with abacavir. For viral load measurements, the Roche was the predominant method used in 64% of centres, nucleic acid sequence-based amplification was used in 16%, and the Chiron branched DNA approach was used in 20%. For the purposes of this analysis, a more general definition of an undetectable viral load was defined as below 400 copies/ml, regardless of whether the viral load was measured to a greater degree of sensitivity. Patients were followed from the first date of viral load below 400 copies/ml after the initiation of HAART, providing this occurred within 12 months of starting HAART, until the date of the first of two consecutive viral loads above 400 copies/ml, or until the date of the last viral load measure, for patients whose viral load did not rebound. Patients were excluded from these analyses if their viral load became undetectable on HAART before prospective follow-up in the EuroSIDA study began. Patients were grouped according to whether they were treatment naive or experienced at starting HAART. Chi-squared tests and non-parametric tests such as the Wilcoxon test were used to compare the characteristics of patients included in analyses.
The categorical variables considered were sex, exposure group, race, region of Europe, clinical status (i.e. whether patients had ever received an AIDS diagnosis), the number of antiretroviral drugs included in the HAART regimen, specific drugs included in the regimen, date of starting HAART, NRTI combinations, HAART regimen (i.e. single PI regimen, dual PI regimen, NNRTI regimen or mixed regimen), limit of detection of viral load used and a change (i.e. starting a new antiretroviral drug or stopping any antiretroviral drug) in any of the antiretroviral drugs included in the initial HAART regimen. Continuous variables included the date of starting HAART, CD4 lymphocyte count and viral load at or before starting HAART (and within 12 months of starting HAART), CD4 lymphocyte count at the date of viral suppression, time to achieve viral suppression from starting HAART, age, time with AIDS, and the percentage increase in the CD4 lymphocyte count between starting HAART and achieving suppression. Additional variables were examined for treatment-experienced patients, namely, the number of new NRTI started at the date of starting HAART (i.e. the number of NRTI to which patients had never previously been exposed), the number of NRTI ever taken, specific NRTI taken, the time since starting antiretroviral therapy, and what previous antiretroviral therapy they had been exposed to (i.e. monotherapy only, dual therapy only or both mono and dual therapy).
Kaplan–Meier estimates were used to examine the cumulative probability of virological rebound over time, both overall and stratified by previous treatment experience. The incidence rates of viral rebound (number of virological rebounds/number of person-years follow-up; PYFU) in different periods of follow-up and according to previous NRTI experience were calculated and differences between groups were assessed using Poisson regression. Cox proportional hazards models, stratified by centre, were used to determine which factors were independently related to virological rebound, both overall among all patients, and within treatment-naive and experienced patients.
Poisson regression was performed using STATA (version 7), all other analyses were performed using SAS (Statistical Analysis Software, version 6.12; Cary, NC, USA).
Results
Table 1 describes the patients included in the study, stratified by previous treatment. Of 2444 patients, 623 (25.5%) were treatment naive before starting HAART. There were some differences between groups according to previous treatment. Over 70% of patients from eastern Europe were treatment naive (79 patients, 73.1%) compared with 28.3% of patients from northern Europe, 20.5% from central Europe and 20.5% from southern Europe (P < 0.001, chi-squared test). The more intensive treatment regimens tended to have been in patients who were treatment experienced before HAART, with 100% of those on five antiretroviral drugs being treatment experienced before starting HAART (P < 0.001, chi-squared test). Treatment-naive patients tended to start HAART later in time, experience a higher percentage increase in CD4 lymphocyte count by the time of viral suppression, and have higher levels of viraemia at starting HAART (P < 0.0001, P < 0.0001, P < 0.0001, respectively, Wilcoxon tests). The median age was 38 years [interquartile range (IQR) 33.3–45.2), the median CD4 cell count at starting HAART was 244 cells/mm3 (IQR 125–358), and the median CD4 cell count at virological suppression was 300 cells/mm3 (IQR 180–430). The median time to viral suppression was 3 months (IQR 2–7). A total of 560 patients had been diagnosed with AIDS (22.9%), and the most common nucleoside combination used was zidovudine and lamivudine (853 patients, 34.9%).
Table 1: Selected characteristics of 2444 patients included in analyses.
The most commonly used PI was indinavir (928 patients, 38.0%), followed by ritonavir (540 patients, 22.1%), and saquinavir hard gel (392 patients, 16.0%). Nevirapine was used in 303 patients (12.4%) and efavirenz in 166 patients (6.8%), whereas abacavir was used by 125 patients (5.1%). Table 2 describes the previous treatment of the 1821 patients who were treatment experienced at starting HAART. The first treatment with antiretroviral drugs occurred a median of 37 months before starting HAART (IQR 18–61). The majority of patients had been treated with both monotherapy and dual combination therapy before HAART (1069 patients, 58.7%), and almost all patients had previously received zidovudine (1704 patients, 93.6%). A total of 701 patients (38.5%) did not start any new NRTI (i.e. NRTI they had never previously been treated with) at starting HAART, and 479 patients (26.3%) were able to start HAART with two or more new NRTI in the HAART regimen.
Table 2: Treatment-experienced patients (N = 1821).
The viral load rebounded in 1031 patients (42.2%) during a median follow-up of 23 months (IQR 7–47). Of those who experienced virological rebound, 151 (14.6%) were treatment naive. Fig. 1 describes the progression to virological rebound, using Kaplan–Meier estimates. The progression is shown overall and stratified by treatment experience. There appears to be an initially high rate of virological rebound, which slows down with increasing time from HAART; for example, among all patients, at 12 months 27.9% of patients were estimated to have experienced virological rebound [95% confidence interval (CI) 26.1–29.7)] and at 24 months this increased to 37.5% (95% CI 35.5–39.5). Patients with previous antiretroviral treatment experienced viral load rebound at a significantly faster rate than those patients who were treatment naive at starting HAART (P < 0.0001, log-rank test).
Fig. 1.:
  Virological rebound after suppression on highly active antiretroviral therapy. –– All; ––▪–– treatment experienced; ––*–– treatment naive.
Among all patients, regardless of previous treatment experience, there was a clear, statistically significant trend for a decreasing rate of virological rebound as the time since initial suppression increased [rate ratio (RR) 0.63; 95% CI 0.60–0.67, P < 0.0001]. Overall, the rate of virological rebound in the first 6 months after initial suppression was 33.5 per 100 PYFU (95% CI 30.1–36.9), almost four times higher than the rate of virological rebound at or after 24 months after initial suppression (incidence of 8.6 per 100 PYFU, 95% CI 7.4–9.8). Fig. 2 describes the incidence of virological rebound according to both time from initial suppression and previous treatment experience. The incidence of rebound was significantly higher among treatment-experienced patients, but both groups showed a similar decline in incidence with increasing time from initial suppression. Overall, the incidence of virological rebound among treatment-naive patients was less than half that of treatment-experienced patients (RR 0.47; 95% CI 0.40–0.46, P < 0.0001). In all time periods the rate of virological rebound among treatment-naive patients remained approximately half that of treatment-experienced patients.
Fig. 2.:
  Incidence of virological rebound (more than 400 copies/ml). ARV, Antiretroviral; CI, confidence interval; PYFU, patient-years of follow-up.
In Cox models, the association with outcome was tested for all variables in univariate models and those that were significant (P < 0.1) were then included in multivariate models. All models were stratified by centre. Both changing treatment and CD4 lymphocyte count were included as time-updated covariates. The results are shown in Table 3 . After adjustment, patients on four or five-drug regimens were significantly more likely to experience virological rebound than those on three drugs [relative hazard (RH) 1.29; 95% CI 1.08–1.54, P = 0.0049 and 1.98; 95% CI 1.48–2.64, P < 0.0001, respectively], as were patients who made any change to their HAART regimen (RH 1.59, 95% CI 1.39–1.82, P < 0.0001). Compared with patients whose viral load was below 400 copies/ml when starting HAART, all other patients were more likely to experience virological rebound (excluding patients for whom we did not know the viral load at starting HAART). Patients starting a single-NNRTI regimen were more likely to have a rebound in viral load (RH 1.36; 95% CI 1.07–1.73, P = 0.011), when compared with patients starting HAART with a single PI-based regimen. Compared with treatment-experienced patients, those who were treatment naive were significantly less likely to experience virological rebound (RH 0.56; 95% CI 0.46–0.68, P < 0.0001). It was also interesting to note that patients whose viral load was known to be below 50 copies/ml at the date of initial suppression were significantly less likely to experience virological rebound than patients whose viral load was undetectable at 400 copies/ml (RH 0.54; 95% CI 0.44–0.67, P < 0.0001). Older patients, those who started HAART more recently, and those with higher current CD4 lymphocyte counts were significantly less likely to experience virological rebound (Table 3 ).
Table 3: Relative risk of virological rebound after initial suppression on highly active antiretroviral therapy (< 400 copies/ml).
The analysis was repeated for treatment-experienced patients, and the results are also shown in Table 3 . Additional variables included in this analysis were the number of NRTI ever taken, what regimens the patients had tried (i.e. mono, dual or both), and also the time since starting antiretroviral therapy. None of these additional variables were of significance in univariate analyses. The only variable related to the risk of virological rebound was the number of new NRTI included in the HAART regimen. In multivariate analyses, the results of the analyses were very similar to when all patients were included in the analysis. In addition, the risk of virological rebound was 19% lower for each new NRTI added to the HAART regimen (RH 0.81, 95% CI 0.74–0.88, P < 0.0001).
A Cox model including all patients was constructed that redefined the baseline date to be 1 January 1995, and patients were then left-censored until the date of initial virological suppression. This analysis allowed the decreasing rate of virological rebound over time to be formally tested after adjustment for the other factors related to virological rebound. In univariate analyses, there was a 15% decreased risk of virological rebound with each additional 6 months since initial virological suppression (RH 0.85, 95% CI 0.81–0.89, P < 0.0001). This confirmed the results of Fig. 2 , in which there was strong evidence of a decrease in the rate of virological rebound over time. After adjustment for the factors related to virological rebound shown in Table 3 , there remained a 27% decreased risk of virological rebound with each additional 6 months since initial suppression (RH 0.73, 95% CI 0.64–0.84, P < 0.0001).
Several sensitivity analyses were also performed to investigate how sensitive the results were to minor changes in the definitions used. In the first sensitivity analysis, patients were censored at the date of changing any aspect of their initial HAART regimen. As some patients changed therapy before their initial virological suppression, this reduced the number of patients included in the analysis to 1944, of whom 404 (20.8%) experienced virological rebound. Highly consistent results to those shown in Table 3 were found. In a further analysis, patients were eligible for inclusion in analyses if they achieved their initial virological suppression within 6 months of starting HAART. This reduced the number of patients included in the analysis to 1726, of whom 678 experienced virological rebound (39.3%). The results were once again highly consistent. Further analysis excluded patients whose viral load was unknown or was below 400 copies/ml at starting HAART, excluding all patients who started saquinavir hard gel (because of its poor bioavailability), and defining failure as a single viral load above 400 copies/ml, all with similar results As a different limit of detection was used in different centres, the analyses were repeated using a definition of virological success and rebound of 200 or 50 copies/ml for all centres. Each analysis produced very similar results, and all results were consistent with those shown in Table 3 (further details available on request).
Discussion
EuroSIDA is one of the largest European observational studies of patients with HIV-1 infection. The study has found a substantial number of patients who had a rebound in viral load after initial virological suppression on HAART regimens, but the rate of virological rebound decreased over time, suggesting that if the viral load does not rebound in the initial months after virological suppression, there is less risk of virological rebound over time as the time from suppression increases. Whereas treatment-naive patients had the lowest risk of virological rebound, treatment-experienced patients who could add new antiretroviral drugs to their HAART regimen were also significantly less likely to experience virological rebound than those who did not add new antiretroviral drugs to their HAART regimen.
It has been well established that previously treated patients who start HAART tend to experience a poorer virological response to HAART [1–5,23 24 25,26 16 27 10,15,19,27
Patients on more intensive antiviral treatment regimens were significantly more likely to have a rebound in viral load , which could be partly explained by compliance or side-effects. The treatment schedule and side-effect profile of a five-drug HAART regimen is likely to be significantly more complicated [11,12 viral load . However, even after adjustment for the lower limit of detection used, patients who swapped any drug in their HAART regimen were more likely to experience virological rebound, suggesting that this cannot explain all of the increased risk of virological rebound. Again, this may raise questions about compliance or side-effects, as physicians may change drugs in order to increase compliance or reduce side-effects, but problems of drug resistance may already have started, or tolerance to side-effects may already have decreased substantially.
Patients with the lowest levels of viral load (i.e. measured to below 50 copies/ml), were significantly less likely to experience virological rebound than those whose viral load was below 400 copies/ml. Patients with viral loads measured to a lower level (such as 200 or 50 copies/ml) would be included in the analyses and not defined as a virological failure until their viral load rebounded above 400 copies/ml, even if individual centres may classify them as failing treatment with viral rebounds to above 50 copies/ml. There is conflicting evidence on the importance of low levels of viral rebound, or ‘blips’ on long-term virological suppression [28,29 viral load have also suggested that the long-term durability of virological response depends on achieving low levels of viraemia [30,31 viral load . Adding new drugs when forming a HAART regimen has previously been shown to affect the virological response to HAART favourably [1,32
A further important finding was that the rate of virological rebound decreased over time, both in naive and treatment-experienced patients. The difference in virological rebound over time between treatment-experienced and treatment-naive patients persisted beyond 2 years. This has previously been shown for other observational cohorts [20,33 viral load more quickly. Another more speculative explanation is that the declining rate of virological rebound reflects the decline in newly activated infected cells, as the pool of latently infected cells becomes reduced, but this would seem to be inconsistent with the observed low rate of decline in the numbers of latently infected cells [34
Patients taking NNRTI were more likely to experience virological rebound. The majority of patients were taking nevirapine as their first NNRTI-containing HAART regimen. Several observational studies, including EuroSIDA, have reported a superior virological response to HAART in efavirenz-containing regimens compared with nevirapine [35–37
There are several caveats to note. We required that patients respond to their initial regimen within 12 months. It could be argued that patients should respond to HAART within the first 6 months of therapy [11,12 4 viral load measurements may be more frequent than in clinical practice. In sensitivity analyses, when we required that the initial HAART success occurred within the first 6 months, our conclusions remained unaltered. In addition, we used a global definition of virological rebound using 400 copies/ml, even though in some cases, we had viral loads measured using a sensitivity of 200 or 50 copies/ml. However, we repeated our analyses using different definitions of virological rebound, including an analysis that selected patients whose viral load was measured using a sensitivity of 50 copies/ml, and by defining virological failure on the basis of a single viral load above the limit of detection, and all showed remarkably similar results.
In summary, we found a higher rate of virological rebound in treatment-experienced patients compared with treatment-naive patients, and a decrease in the rate of virological rebound over time. The long term follow-up of large cohorts such as EuroSIDA is essential to monitor whether virological rebound eventually results in immunological failure and subsequent clinical failure.
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Appendix
The multicentre study group on EuroSIDA (national coordinators in parenthesis)
Argentina : (M. Losso), A. Duran, Hospital J.M. Ramos Mejia, Buenos Aires, Argentina.
Austria : (N. Vetter) Pulmologisches Zentrum der Stadt Wien, Vienna, Austria.
Belgium : (N. Clumeck) P. Hermans, B. Sommereijns, Saint-Pierre Hospital, Brussels, Belgium; R. Colebunders, Institute of Tropical Medicine, Antwerp, Belgium.
Czech Republic : (L. Machala) H. Rozsypal, Faculty Hospital Bulovka, Prague, Czech Republic.
Denmark : (J. Nielsen) J. Lundgren, T. Benfield, O. Kirk, Hvidovre Hospital, Copenhagen, Denmark; J. Gerstoft, T. Katzenstein, B. Røge, P. Skinhøj, Rigshospitalet, Copenhagen, Denmark; C. Pedersen, Odense University Hospital, Odense, Denmark.
Estonia : (K. Zilmer) Tallinn Merimetsa Hospital, Tallinn, Estonia.
France : (C. Katlama) M. De Sa, Hôpital de la Pitié-Salpétière, Paris, France; J.-P. Viard, Hôpital Necker-Enfants Malades, Paris, France; T. Saint-Marc, Hôpital Edouard Herriot, Lyon, France; P. Vanhems, University Claude Bernard, Lyon, France; C. Pradier, Hôpital de l'Archet, Nice, France.
Germany : (M. Dietrich) C. Manegold, Bernhard-Nocht-Institut for Tropical Medicine, Hamburg, Germany; J. van Lunzen, H.-J. Stellbrink, Eppendorf Medizinische Kernklinik, Hamburg, Germany; V. Miller, S. Staszewski, J.W. Goethe University Hospital, Frankfurt, Germany; F.-D. Goebel, Medizinische Poliklinik, Munich, Germany; B. Salzberger, Universität Köln, Cologne, Germany; J. Rockstroh, Universitäts Klinik, Bonn, Germany.
Greece : (J. Kosmidis) P. Gargalianos, H. Sambatakou, J. Perdios, Athens General Hospital, Athens, Greece; G. Panos, I. Karydis, A. Filandras, 1st IKA Hospital, Athens, Greece.
Hungary : (D. Banhegyi) Szent LĂ¡slĂ³ Hospital, Budapest, Hungary.
Ireland : (F. Mulcahy) St James's Hospital, Dublin, Ireland.
Israel: (I. Yust) M. Burke, Ichilov Hospital, Tel Aviv, Israel; S. Pollack, Z. Ben-Ishai, Rambam Medical Center, Haifa, Israel; Z. Bentwich, Kaplan Hospital, Rehovot, Israel; S. Maayan, Hadassah University Hospital, Jerusalem, Israel.
Italy : (S. Vella, A. Chiesi) Istituto Superiore di Sanita, Rome, Italy; C. Arici, Ospedale Riuniti, Bergamo, Italy; R. PristerĂ¡, Ospedale Generale Regionale, Bolzano, Italy; F. Mazzotta, A. Gabbuti, Ospedale S. Maria Annunziata, Florence, Italy; R. Esposito, A. Bedini, UniversitĂ di Modena, Modena, Italy; A. Chirianni, E. Montesarchio, Presidio Ospedaliero A.D. Cotugno, Naples, Italy; V. Vullo, P. Santopadre, UniversitĂ di Roma ‘La Sapienza', Rome, Italy; P. Narciso, A. Antinori, P. Franci, M. Zaccarelli, Ospedale Spallanzani, Rome, Italy; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan, Italy; A, D'Arminio Monforte, Ospedale L. Sacco, Milan, Italy.
Latvia : (L. Viksna) Infectology Centre of Latvia, Riga, Latvia.
Lithuania : (S. Chaplinskas) Lithuanian AIDS Centre, Vilnius, Lithuania.
Luxembourg : (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg.
Netherlands : (P. Reiss) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, the Netherlands.
Norway : (J. Bruun) A. Maeland, V. Ormaasen, UllevĂ¥l Hospital, Oslo, Norway.
Poland: (B. Knysz) J. Gasiorowski, Medical University, Wroclaw, Poland; A. Horban, Centrum Diagnostyki i Terapii AIDS, Warsaw, Poland; D. Prokopowicz, A. Wiercinska-Drapalo, Medical University, Bialystok, Poland; A. Boron-Kaczmarska, M. Pynka, Medical Univesity, Szczecin, Poland; M. Beniowski, Osrodek Diagnostyki i Terapii AIDS, Chorzow, Poland; H. Trocha, Medical University, Gdansk, Poland.
Portugal : (F. Antunes) Hospital Santa Maria, Lisbon, Portugal; K. Mansinho, Hospital de Egas Moniz, Lisbon, Portugal; R. Proenca, Hospital Curry Cabral, Lisbon, Portugal.
Romania : (D. Duiculescu) Spitalul de Boli Infectioase si Tropicale Dr Victor Babes, Bucarest, Romania; A. Streinu-Cercel, Institute of Infectious Diseases, Bucarest, Romania.
Slovakia : (M. Mikras) Derrer Hospital, Bratislava, Slovakia.
Spain : (J. GonzĂ¡lez-Lahoz) B. Diaz, T. GarcĂa- Benayas, L. Martin-Carbonero, V. Soriano, Hospital Carlos III, Madrid, Spain; B. Clotet, A. Jou, J. Conejero, C. Tural, Hospital Germans Trias i Pujol, Badalona, Spain; J.M. Gatell, J.M. MirĂ³, Hospital Clinic i Provincial, Barcelona, Spain.
Sweden : (A. Blaxhult) Karolinska Hospital, Stockholm, Sweden; A. Karlsson, Södersjukhuset, Stockholm, Sweden; P. Pehrson, Huddinge Sjukhus, Stockholm, Sweden.
Switzerland : (B. Ledergerber) R. Weber, University Hospital, ZĂ¼rich, Switzerland; P. Francioli, A. Telenti, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; B. Hirschel, V. Soravia-Dunand, Hospital Cantonal Universitaire de Geneve, Geneve, Switzerland; H. Furrer, Inselspital Bern, Bern, Switzerland.
Ukraine : (N. Chentsova) Kyiv Centre for AIDS, Kyiv, Ukraine.
United Kingdom : (S. Barton) St Stephen's Clinic, Chelsea and Westminster Hospital, London, UK; A.M. Johnson, D. Mercey, Royal Free and University College London Medical School, London (University College Campus), UK; A. Phillips, C. Loveday, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus), UK; A. Pinching, J. Parkin, Medical College of Saint Bartholomew's Hospital, London, UK; J. Weber, G. Scullard, Imperial College School of Medicine at St Mary's, London, UK; M. Fisher, Royal Sussex County Hospital, Brighton, UK; R. Brettle, Western General Hospital, Edinburgh, Scotland, UK.
Virology group
C. Loveday, B. Clotet (Central coordinators) plus ad hoc virologists from participating sites in the EuroSIDA Study.
Steering committee
F. Antunes, A. Blaxhult, N. Clumeck, J. Gatell, A. Horban, A. Johnson, C. Katlama, B. Ledergerber (Chair), C. Loveday, A. Phillips, P. Reiss, S. Vella.
Coordinating centre staff
J. Lundgren (Project leader), I. Gjørup, O. Kirk, N. Friis-Moeller, A. Mocroft, A. Cozzi-Lepri, D. Mollerup, M. Nielsen, A. Hansen, D. Kristensen, L. Kolte, L. Hansen, J. Kjær.
