Among the 2708 patients, 447 (17%) progressed clinically; either in terms of developing a first AIDS-defining event (n = 137, 31%), a new AIDS-defining event after the initial AIDS diagnosis (n = 179, 40%) or death (n = 131, 29%). The most common AIDS-defining events were oesophageal candidosis (19%) and non-Hodgkin lymphoma (12%); all other events occurred in less than 10% of the patients. In the ritonavir group, 106 patients progressed (19%), whereas 201 (15%) and 140 (17%) did so in the indinavir and saquinavir hgc groups, respectively. There was no difference in type of event according the PI used (P = 0.55). The incidence of clinical progression was 8.4 (95% CI, 6.8–10.0) for ritonavir, 6.8 (95% CI, 5.9–7.7) for indinavir and 7.9 (95% CI, 6.6–9.2) events/100 person–years of follow-up for saquinavir hgc; (ritonavir versus indinavir:P = 0.09; ritonavir versus saquinavir hgc P = 0.63; and indinavir versus saquinavir hgc:P = 0.19). The incidences were based on 1261, 2937 and 1774 person–years of follow-up, respectively, and the overall loss to follow-up throughout the study period (not seen since January 1999) was 9.4, 7.5 and 12.6%, respectively). Further, the incidence of clinical progression did not differ between the treatment groups when assessed in CD4 and pVL strata according to the latest measurements (data not shown).
The proportion of patients who had experienced clinical progression at 12 months was 11.9% (95% CI, 9.2–14.6) for ritonavir; 9.2% (95% CI, 7.6–10.8) for indinavir; and 11.9% (95% CI, 9.7–14.1) for saquinavir hgc; log-rank test, P = 0.20 (Fig. 3). To analyse potential differences in clinical outcome between the three treatment groups, Cox proportional hazards models were established. When adjusting for differences in factors at baseline, patients starting indinavir were at a statistically significant 23% lower risk of progressing clinically compared with those starting saquinavir hgc (P = 0.043). Patients starting ritonavir were at 17% lower risk compared with the saquinavir group, although this result was not statistically significant (Table 3). Other prognostic baseline factors were age, CD4 cell count, body weight, haemoglobin, prior AIDS diagnosis, and number of new drugs initiated when starting HAART (Table 3). Factors not significantly associated with clinical progression in univariate models (P < 0.10) were not included in the final multivariate model. In particular, HIV transmission category was not a significant prognostic factor and did not change the results of the multivariate model if included.
In the highly selected subset of patients with a pVL measurement in the 6 months prior to starting the PI, this covariate was also included in the model. Adjusting for the same factors as in the original model and additionally pVL only changed the relative risks (RH) slightly (although it changed the P-values quite substantially due to smaller numbers). When pVL was included, RH for ritonavir compared with saquinavir hgc was 0.92 (95% CI, 0.59–1.45;P = 0.72); and for indinavir compared with saquinavir hgc, 0.89 (95% CI, 0.60–1.30;P = 0.53); and the corresponding relative hazards without inclusion of pVL were 0.92 (95% CI, 0.59–1.44;P = 0.71) and 0.88 (95% CI, 0.60–1.29;P = 0.53), respectively. Baseline pVL was not a significant prognostic factor for clinical progression (RH = 1.12; 95% CI, 0.95–1.31 per log10 higher;P = 0.17).
Again including all patients, the RH of clinical progression in the first 12 months of HAART and thereafter was also investigated. These models were adjusted for identical factors as in Table 3. In the first 12 months of HAART, patients starting ritonavir or indinavir were at a 22 and 32% lower risk of clinical progression, RH = 0.78 (95% CI, 0.54–1.12;P = 0.17) and 0.68 (95% CI, 0.50–0.93;P = 0.02), respectively compared with those starting saquinavir hgc. After 12 months of HAART, the risk of clinical progression did not differ significantly, RH = 1.00 (95% CI, 0.61–1.63;P = 0.99) and 1.01 (95% CI, 0.65–1.58;P = 0.95), respectively.
When using the latest values of CD4 cell count, weight, and haemoglobin in order to include changes in these markers which occurred after starting HAART, there was no longer any difference (see Table 3 right column for comparison) in the risk of clinical progression according to the type of PI initiated: RH (ritonavir versus saquinavir hgc) = 0.93 (95% CI, 0.67–1.29;P = 0.66), and RH (indinavir versus saquinavir hgc) = 0.94 (95% CI, 0.70–1.26;P = 0.70). When the latest pVL was included (in the subset in which this was available), the RHs were 0.97 (95% CI, 0.67-1.42;P = 0.89), and 1.02 (95% CI, 0.74-1.43;P = 0.89) respectively. Therefore, after adjustment for the poorer initial virological and immunological response seen among patients starting saquinavir hgc, there were no differences in the risk of clinical progression between ritonavir, indinavir and saquinavir hgc.
We have documented that use of saquinavir hgc as part of a HAART regimen is associated with a significantly inferior clinical outcome compared with indinavir which was consistent with and in the same direction as the differences in CD4 cell count and pVL responses. Differences in the marker responses explained fully the higher rate of clinical progression seen among patients starting saquinavir hgc.
Other studies have reported on the inferior virological outcome of saquinavir hgc capsules compared with other PIs [7–14]. The consistency of this finding across several independent observational studies, where patterns of saquinavir hgc use have varied widely, together with the known low bioavailability of saquinavir hgc capsules , indicates that the association is largely due to the inferior potency of saquinavir hgc and not to bias due to confounding by indication. Thus this seems to be an example of where observational studies have reliably identified a difference in efficacy between drug regimens. This finding does not include the better-absorbed saquinavir soft gel capsules which have recently replaced saquinavir hgc nor the ritonavir-boosted saquinavir hgc therapy where the pharmacological properties are dramatically improved [21–23].
No randomized trials and observational studies have reported on long-term immunological and clinical outcome according to the PI used. In our study, the CD4 response corresponded in general to the pVL response. In a multivariate Cox model of clinical progression, patients starting indinavir were at a 23% lower risk of clinical progression relative to those starting saquinavir hgc. The difference between ritonavir and saquinavir hgc was nearly at the same level as that of indinavir versus saquinavir hgc, but the difference was not significant, perhaps due to the smaller number of patients starting ritonavir.
Our results are not fully in agreement with a previous study which did not find a tendency of an inferior clinical response among patients starting Saquinavir hgc relative to other PIs in spite of significant differences in virological response . There is no obvious reason for this discrepancy between the studies, but chance may play a role. Providing a substantially longer follow-up with a median follow-up of 30 months after starting HAART, the present study allows for estimating longer-term clinical outcome and for a better precision of the size of effect, RH = 0.77 (95% CI, 0.60–0.99) in the present study compared with 1.10 (95% CI, 0.81–1.49) for saquinavir hgc versus indinavir . In our study, the difference in clinical progression seemed to get weaker with increasing time, as a post-hoc analysis fond that the effect was only present within the first 12 months of HAART. However, there was no significant interaction between the effects of calendar time and type of PI on the clinical outcome, and the CD4 cell response remained consistently lower in the saquinavir group compared with the indinavir group. Therefore, to further analyse the longer-term differences, continuous monitoring is warranted.
It is possible that antiretroviral therapy is modified according to changes in surrogate markers, so that patients who experience inferior immunological and/or virological responses are switched to a more potent drug combination before experiencing clinical progression. This would limit our ability to detect real clinical differences between the PI groups. In accordance with this, the differences in virological response decreased with increasing time on HAART. Further, the CD4 cell count, which showed less pronounced differences between the PI groups than the pVL, might be more important for the prognosis than pVL [24–26].
Our results are based on the principle of intent-to-treat, which is a trial concept, though in many clinical trials even an intent-to-treat analysis will exclude patients after they discontinue treatment, as such patients are not routinely assessed for viral load or CD4 cell counts [1,27,28]. In an observational study as EuroSIDA, this information is readily available, and in addition, the loss to follow-up rate is very low in EuroSIDA (< 5% per year). Thus, patients who modify treatment are still included in the analyses, rather than excluding their data or registering them as a failure . Inclusion of data after discontinuation of the initial PI provides important information, as a given treatment might influence the outcome of a subsequent therapy due to the development of resistance. Factors such as adherence, poor absorption and potency of a given antiretroviral drug might therefore affect the outcome of a subsequent regimen, and the inferior immunological and virological responses of Saquinavir hgc might lead to compromised responses to the following regimens .
Several reservations in the interpretation of the findings in the present study are necessary. First of all, this is not a randomized clinical trial, and there are many different reasons governing the decision to start an individual PI which would not be a bias in a randomized trial, but which may affect the results of an observational study [15,16,31]. For example, experience with PI treatment has rapidly advanced and patients starting a PI regimen in 1998 may be more likely to start three new drugs compared to patients starting in 1996. We have attempted to adjust for such factors in our analyses, but other potential confounders may remain that we were not able to adjust for. Additional adjustment for pVL in the subgroup of patients with available pVL at the time of starting the initial PI only caused minor changes in the risk of clinical progression in the three treatment arms. As an important point, the key baseline factors for the three treatment groups were fairly well balanced, and this was particularly so between the groups of indinavir and saquinavir hgc. Therefore the statistical adjustments are likely to remove the influence of confounding from these factors . Furthermore, as discussed above, our results concerning virological outcome are consistent with those from several other cohorts .
No randomized trial has been conducted to analyse these potential differences in long-term clinical prognosis of different PI-containing regimen [1,2]. Therefore, observational cohorts might be the only source for providing data on this issue . Being a large observational cohort, representing a variety of centres over most of Europe with heterogeneity in the approach to therapy and a substantial total follow-up time, the EuroSIDA study has the capacity of addressing the question of potential differences in the clinical outcome as well as the immunological and virological outcome according to which treatment the patient has received .
The patients in EuroSIDA make up an unselected part of the patient population at the participating centres, representing most parts of Western Europe, which contrasts the often highly selected patients included in randomized trials. However, it should be kept in mind that although the patients in EuroSIDA probably better reflect the general HIV-infected population than the patients of the randomized clinical trials, many of the EuroSIDA centres are large clinics and often university-associated. Such centres might have earlier access to new therapies, access to HAART through clinical trials and expanded access, more regular follow-up visits and assessments, and are therefore likely to represent a high quality of clinical practice.
In conclusion, among patients starting their initial PI regimen, saquinavir hgc is associated with inferior virological and immunological responses relative to indinavir. We documented consistent differences in the long-term clinical response with those in virological and immunological responses. The poorer clinical outcome among patients starting saquinavir hgc could be fully explained by changes in markers on HAART.
Sponsorship: The European Commission BIOMED 1 (CT94-1637) and BIOMED 2 (CT97-2713) programmes were the primary sponsors of the EuroSIDA study. Unrestricted grants were also provided by Pharmacia Upjohn, Glaxo Wellcome, Roche, and Merck. The participation of centres from Switzerland was supported by a grant from the Swiss Federal Office for Education and Science.
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The EuroSIDA Study Group
The multicentre study group on EuroSIDA (national coordinators in parenthesis).
Austria (N. Vetter) Pulmologisches Zentrum der Stadt Wien, Vienna. Belgium (N Clumeck) P. Hermans, B. Sommereijns, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine Antwerp. Czech Republic (L. Machala) H. Rozsypal, Faculty Hospital Bulovka, Prague. Denmark (J. Nielsen) J. Lundgren,T. Benfield, O. Kirk, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, B. Røge, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense. France (C. Katlama) C. Rivière, Hôpital de la Pitié-Salpétière, Paris; J.-P. Viard, Hôpital Necker-Enfants Malades, Paris; T. Saint-Marc, Hôpital Edouard Herriot, P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l'Archet, Nice. Germany (M. Dietrich) C. Manegold, Bernhard-Nocht-Institut for Tropical Medicine, Hamburg; J. van Lunzen, Eppendorf Medizinische Kernklinik, Hamburg; V. Miller, S. Staszewski, J.W. Goethe University Hospital, Frankfurt; F.-D. Goebel, Medizinische Poliklinik, Munich; B. Salzberger, Universität Köln, Cologne; J. Rockstroh, Universitäts Klinik Bonn. Greece (J. Kosmidis) P. Gargalianos, H. Sambatakou, J. Perdios, Athens General Hospital, Athens; G. Panos, M. Astriti, 1st IKA Hospital, Athens. Hungary (D. Banhegyi) Szent Lásló Hospital, Budapest. Ireland (F. Mulcahy) St. James's Hospital, Dublin. Israel (I. Yust) D. Turner, Ichilov Hospital, Tel Aviv; S. Pollack, Z. Ben-Ishai, Rambam Medical Center, Haifa: Z. Bentwich, Kaplan Hospital, Rehovot; S. Maayan, Hadassah University Hospital, Jerusalem. Italy (S. Vella, A. Chiesi) Istituto Superiore di Sanita, Rome; F. Suter, A. Cremaschi, Ospedale Riuniti, Bergamo; R. Pristerá, Ospedale Generale Regionale, Bolzano; F. Mazzotta, F.Vichi, Ospedale S. Maria Annunziata, Florence; B. DeRienzo, A. Bedini, Università di Modena, Modena; A. Chirianni, E. Montesarchio, Presidio Ospedaliero AD. Cotugno, Naples; V. Vullo, P. Santopadre, Università di Roma La Sapienza, Rome; C. Arici, P. Franci, P. Narciso, A. Antinori, M. Zaccarelli, Ospedale Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; A. D'Arminio Monforte, Osp. L. Sacco, Milan. Luxembourg (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg. Netherlands (P. Reiss) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway (J. Bruun) A. Maeland, Ullevål Hospital, Oslo. Poland (B. Knysz) J. Gasiorowski, Medical University, Wroslaw; A. Horban, Centrum Diagnostyki i Terapii AIDS, Warsaw; R. Rogowska-Szadkowska, Medical University, Bialystok; A. Boron-Kaczmarska, Medical Univesity, Szczecin; M. Beniowski, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk. Portugal (F. Antunes) Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; R. Proenca, Hospital Curry Cabral, Lisbon. Spain (J. González-Lahoz) R. Polo, V. Soriano, 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. Sweden (A. Blaxhult) Karolinska Hospital; B. Heidemann, Södersjukhuset; P. Pehrson, Huddinge Sjukhus, Stockholm. Switzerland (B. Ledergerber) R. Weber, University Hospital, Zürich; P. Francioli, A. Telenti, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, V. Soravia-Dunand, Hospital Cantonal Universitaire de Geneve, Geneve. United Kingdom (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, C. Loveday, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); A. Pinching, J. Parkin, 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, City Hospital, Edinburgh.
Steering committee: J. Nielsen (chair), N. Clumeck, M. Dietrich, J.M. Gatell, A. Horban, A.M. Johnson, C. Katlama, B. Ledergerber, C. Loveday, A. Phillips, P. Reiss, S. Vella.
Coordinating centre staff: J. Lundgren (project leader), I. Gjørup, T. Benfield, O. Kirk, A. Mocroft, D. Mollerup, M. Nielsen, A. Sørensen, H. Buch, L. Madsen, L. Teglbjærg.