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Background Patients with human immunodeficiency virus (HIV) infection and a history of Pneumocystis carinii pneumonia are at high risk for relapse if they are not given secondary prophylaxis. Whether secondary prophylaxis against P. carinii pneumonia can be safely discontinued in patients who have a response to highly active antiretroviral therapy is not known.
Methods We analyzed episodes of recurrent P. carinii pneumonia in 325 HIV-infected patients (275 men and 50 women) in eight prospective European cohorts. Between October 1996 and January 2000, these patients discontinued secondary prophylaxis during treatment with at least three anti-HIV drugs after they had at least one peripheral-blood CD4 cell count of more than 200 cells per cubic millimeter.
Results Secondary prophylaxis was discontinued at a median CD4 cell count of 350 per cubic millimeter; the median nadir CD4 cell count had been 50 per cubic millimeter. The median duration of the increase in the CD4 cell count to more than 200 per cubic millimeter after discontinuation of secondary prophylaxis was 11 months. The median follow-up period after discontinuation of secondary prophylaxis was 13 months, yielding a total of 374 person-years of follow-up; for 355 of these person-years, CD4 cell counts remained at or above 200 per cubic millimeter. No cases of recurrent P. carinii pneumonia were diagnosed during this period; the incidence was thus 0 per 100 patient-years (99 percent confidence interval, 0 to 1.2 per 100 patient-years, on the basis of the entire follow-up period, and 0 to 1.3 per 100 patient-years, on the basis of the follow-up period during which CD4 cell counts remained at or above 200 per cubic millimeter).
Conclusions It is safe to discontinue secondary prophylaxis against P. carinii pneumonia in patients with HIV infection who have an immunologic response to highly active antiretroviral therapy.
The risk of recurrence of P. carinii pneumonia is substantially higher than the risk of primary P. carinii pneumonia.12 This increase in risk is almost certainly due to the fact that the immune system is more profoundly compromised in patients in whom pneumonia has already developed, and to the presence of residual P. carinii organisms in the lungs despite a clinical response to therapy.13 Thus, recommendations regarding the safety of discontinuing primary prophylaxis cannot simply be extrapolated to the discontinuation of secondary prophylaxis.
We therefore analyzed data on eight European cohorts of HIV-infected patients who had been successfully treated for an episode of P. carinii pneumonia, whose CD4 cell count had risen to more than 200 per cubic millimeter, and who subsequently discontinued chemoprophylaxis against recurrent P. carinii pneumonia.
Methods
Participating Cohort Studies
Our analysis included data from eight large prospective European cohort studies (Table 1), all of which have been approved by local ethics committees, use standardized methods of data collection, and schedule follow-up visits at least once every six months. Additional measurements of peripheral-blood CD4 cell counts and plasma levels of HIV type 1 (HIV-1) RNA, determined at the time of routine evaluations at the 162 participating clinics, are also recorded. One of the eight studies, the EuroSIDA study, is a multicenter study and may include patients who are also members of the other cohorts. Therefore, each of the other cohort studies verified that none of its patients were also enrolled in the EuroSIDA study.
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We included patients with HIV-1 infection who had previously been given a definitive or presumptive diagnosis of P. carinii pneumonia and had received secondary prophylaxis against recurrent pneumonia, which was discontinued between October 1996 and January 2000, during highly active antiretroviral treatment after their CD4 cell counts had risen to more than 200 per cubic millimeter. The decision to discontinue prophylaxis was the result of consultation between individual patients and their physicians and reflected the assumption that the increased CD4 cell counts induced by highly active antiretroviral therapy were indeed clinically protective. In some countries, discontinuation of secondary prophylaxis against P. carinii pneumonia was even formulated in official treatment guidelines.
Secondary prophylaxis was defined as treatment with any drug with known activity against P. carinii or Toxoplasma gondii and included trimethoprim–sulfamethoxazole, inhaled pentamidine, dapsone, pyrimethamine, and atovaquone. Highly active antiretroviral therapy was defined as therapy with at least one protease inhibitor or non–nucleoside-analogue reverse-transcriptase inhibitor in combination with at least two nucleoside-analogue reverse-transcriptase inhibitors. Patients whose CD4 cell counts for the six months preceding the discontinuation of secondary prophylaxis were unavailable and patients who were unavailable for follow-up were excluded from the analysis.
End Points
Recurrence of P. carinii pneumonia, diagnosed definitively or presumptively, after the discontinuation of secondary prophylaxis was the primary end point of the study. A diagnosis was considered definitive if P. carinii was found on microscopical analysis of induced sputum or bronchoalveolar-lavage fluid or on histologic examination of a specimen of lung tissue. The diagnosis of P. carinii pneumonia was considered presumptive if results from invasive pulmonary diagnostic procedures were not available. At a minimum, a presumptive diagnosis required a recent history of dyspnea on exertion or nonproductive cough, an appropriate response to any of the standard recommended treatments for P. carinii pneumonia, and the absence of evidence of bacterial pneumonia.
The secondary end points of the study were bacterial pneumonia, death or any new illness classified as defining the acquired immunodeficiency syndrome (AIDS), CD4 cell counts of less than 200 per cubic millimeter, and reinstitution of secondary prophylaxis — all occurring after the discontinuation of secondary prophylaxis. A diagnosis of bacterial pneumonia required documentation of a compatible clinical history, including an acute onset of pulmonary symptoms, and typical pulmonary infiltrates on a chest radiograph, together with a response to antibacterial drugs with no known activity against P. carinii. Furthermore, most study groups performed a careful retrospective chart review of all patients to identify single episodes of bacterial pneumonia and to confirm the other study end points.
Statistical Analysis
Patient selection and data extraction were performed at the data centers of the participating cohort studies. Data on a predefined set of anonymous demographic, laboratory, and clinical variables from the selected patients were then pooled and analyzed centrally. Follow-up was measured from the date of discontinuation of secondary prophylaxis against P. carinii pneumonia until the date of the last clinical follow-up, the date of reinitiation of secondary prophylaxis, or the date of diagnosis of recurrent P. carinii pneumonia. In a separate analysis, follow-up was restricted to the periods when CD4 cell counts remained at or above 200 per cubic millimeter. The closing date for the analysis was April 19, 2000. Recurrent cases of P. carinii pneumonia and bacterial pneumonia were assumed to have a Poisson distribution, and exact confidence intervals were calculated for the incidence. The length of time to the documentation of a CD4 cell count of less than 200 per cubic millimeter and the length of time to the reinitiation of secondary prophylaxis were analyzed by the Kaplan–Meier method. All reported P values are two-sided. We used Stata software (version 6.0, Stata, College Station, Tex.) for statistical analyses.
Results
A total of 325 patients fulfilled the inclusion criteria. Their characteristics at the time of the discontinuation of secondary prophylaxis against P. carinii pneumonia are shown in Table 2. The median age was 38 years, and 85 percent of the patients were men. The median CD4 cell count at the time secondary prophylaxis was discontinued was 350 per cubic millimeter; the median nadir CD4 cell count had been 50 per cubic millimeter. Highly active antiretroviral therapy included a single protease inhibitor and two nucleoside-analogue reverse-transcriptase inhibitors in 74 percent of the patients. Two protease inhibitors or a non–nucleoside-analogue reverse-transcriptase inhibitor, together with at least two nucleoside-analogue reverse-transcriptase inhibitors, were used in 17 percent and 9 percent of patients, respectively.
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The evolution of CD4 cell counts from the diagnosis of P. carinii pneumonia to the start of highly active antiretroviral therapy, the discontinuation of secondary prophylaxis, and the last available CD4 cell count are shown in Figure 1. The median increase in CD4 cell counts from the nadir to the value at the time secondary prophylaxis was discontinued was 283 per cubic millimeter. After secondary prophylaxis was discontinued, the CD4 cell counts increased further by a median of 50 per cubic millimeter, but in 27 patients (8 percent) they dropped to less than 200 per cubic millimeter (Table 3). The probability that a patient would have a CD4 cell count of less than 200 per cubic millimeter 12 and 24 months after secondary prophylaxis was discontinued was 8 percent (95 percent confidence interval, 5 to 12 percent) and 14 percent (95 percent confidence interval, 9 to 23 percent), respectively. In 20 (74 percent) of the 27 patients whose CD4 cell counts fell to less than 200 per cubic millimeter after discontinuation of secondary prophylaxis, the last available CD4 count (after a median of eight months) was again well above 200 cells per cubic millimeter, with a median of 316 cells per cubic millimeter.
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No diagnoses of recurrent P. carinii pneumonia were recorded during 374 person-years of follow-up in the absence of secondary prophylaxis (Table 3). The incidence was therefore 0, with an upper 99 percent confidence limit of 1.2 per 100 person-years of follow-up. For 355 person-years of follow-up, CD4 cell counts were at or above 200 per cubic millimeter, resulting in an upper 99 percent confidence limit of 1.3 per 100 person-years.
One patient decided to stop highly active antiretroviral therapy but resumed secondary prophylaxis; in this patient, a presumptive diagnosis of P. carinii pneumonia with a CD4 cell count of 12 per cubic millimeter was made six months later. Five patients had a new AIDS-defining illness, and four patients died during follow-up. A diagnosis of bacterial pneumonia was made in 7 of the 222 patients from the seven cohorts that had collected this information.
Reinstitution of Secondary Prophylaxis
Fifteen of 325 patients (5 percent) began secondary prophylaxis again during follow-up, including 11 patients whose CD4 cell counts remained above 200 per cubic millimeter (Figure 2). For most of these 11 patients, the reason for the reinstitution of secondary prophylaxis was a decline in CD4 cell counts, which frequently occurred in conjunction with incomplete control of HIV replication.
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This study supports the hypothesis that the CD4 cell recovery associated with highly active antiretroviral therapy leads to profoundly improved protection against opportunistic infections that are common in patients with HIV infection who have low CD4 cell counts.20,21 If CD4 cell recovery were not associated with protection against recurrent P. carinii pneumonia, we would have expected — on the basis of historical data — that more than 50 percent of the patients would have a relapse of P. carinii pneumonia during follow-up.12 However, P. carinii pneumonia did not develop in any of the patients after secondary prophylaxis was discontinued.
Several studies have previously addressed this issue, with similar results,7,8,10,22 but none of these studies were conclusive, given their small samples and hence their wide confidence intervals. The upper 99 percent confidence limit of the incidence of P. carinii pneumonia in the present study was only 1.2 cases per 100 person-years of follow-up. Thus, although we cannot exclude the possibility that P. carinii pneumonia may develop in patients who discontinue secondary prophylaxis, the risk is very low. Similarly, although a relatively low risk of a primary episode of P. carinii pneumonia was found in patients with CD4 cell counts above 200 per cubic millimeter,9,23,24,25 the threshold CD4 cell count for instituting primary prophylaxis was set at 200 per cubic millimeter.26 Guidelines for the initiation or discontinuation of prophylaxis (which define the group of patients in whom it is not needed) will always be based on the evaluation not only of the relative benefits but also of the risks of the prophylactic treatment. Potential problems associated with prophylaxis are diverse and drug-specific and include hypersensitivity to sulfonamides,27,28 the development of drug-resistant P. carinii 29,30 and bacteria,31 the high cost (especially of inhaled pentamidine32 and atovaquone33), and the number of additional pills that must be taken.
A particular concern regarding the discontinuation of trimethoprim–sulfamethoxazole is the loss of protection against common bacterial infections.34 In this study, the incidence of bacterial pneumonia after the discontinuation of secondary prophylaxis against P. carinii pneumonia was only 2.7 episodes per 100 person-years of follow-up. This rate is considerably lower than was reported in a study undertaken before highly active antiretroviral therapy became available,35 despite the fact that we used quite liberal criteria to identify possible cases of bacterial pneumonia. However, we cannot rule out the possibility that patients who are at higher risk for bacterial pneumonia might benefit from antibacterial chemoprophylaxis, such as may be provided by continued use of trimethoprim–sulfamethoxazole. We also did not observe any cases of cerebral toxoplasmosis, an infection that may also be prevented by prophylaxis against P. carinii pneumonia.36
Most patients in this study had been taking combination antiretroviral-drug therapy for more than one year before prophylaxis was discontinued. Thus, their physicians apparently were concerned about discontinuing secondary prophylaxis prematurely, since P. carinii pneumonia is a severe infection associated with a 10 to 15 percent case fatality rate.25,37 Therefore, caution should be exercised in extrapolating our findings to persons who have smaller increases in CD4 cell counts or have been treated for shorter periods with highly active antiretroviral therapy.
Our study does not directly address the question of when secondary prophylaxis should be restarted, but it does provide some clues. Almost 10 percent of all patients had a decrease in the CD4 cell counts to less than 200 per cubic millimeter, a threshold below which prophylaxis against P. carinii pneumonia is generally recommended.11 As compared with the remaining patients, those in whom secondary prophylaxis against P. carinii pneumonia was reinstituted or whose CD4 cell counts decreased to less than 200 per cubic millimeter already had lower CD4 cell counts when secondary prophylaxis was discontinued (data not shown). Thus, patients who discontinue secondary prophylaxis against P. carinii pneumonia when their CD4 cell counts are marginally above 200 per cubic millimeter, particularly if they have subsequent negative trends in their CD4 cell counts or evidence of increased HIV replication, should be carefully monitored for decreases in CD4 cell counts to less than 200 per cubic millimeter and hence the need for reinstitution of secondary prophylaxis.
Several limitations of our study should be noted. First, it was not a controlled clinical trial but a compilation of data from several observational cohorts; there may have been undetected differences between the cohorts. However, clinical suspicion and diagnosis of P. carinii pneumonia are an integral part of routine care at the sites participating in this study, and it is unlikely that any cases of P. carinii pneumonia remained undiagnosed. Most of the cases of P. carinii pneumonia in this study (83 percent) were definitively diagnosed on the basis of microscopy rather than clinical suspicion. All the studies have well-implemented quality-control procedures to ensure the correct transfer of data from patients' records to the cohort data base. Although our study was not randomized, such a design would not have improved the interpretability of the findings, since no case of recurrent P. carinii pneumonia was diagnosed.
In conclusion, as has been demonstrated for primary prophylaxis, secondary prophylaxis against P. carinii pneumonia can be safely discontinued in patients with HIV infection who have had a response to highly active antiretroviral therapy (indicated by a CD4 cell count above 200 per cubic millimeter) with a minimal risk of recurrent P. carinii pneumonia.
The EuroSIDA study was supported by grants from the European Commission BIOMED 1 (CT94-1637) and BIOMED 2 (CT97-2713) programs, from Pharmacia & Upjohn, Glaxo Wellcome, Roche, and Merck, and from the Swiss Federal Office for Education and Science (for the Swiss sites). The Swiss HIV Cohort Study was supported by a grant (3345-062041) from the Swiss National Science Foundation. The ATHENA study was supported by a grant (CURE/97-46486) from the Health Insurance Fund Council, Amstelveen, the Netherlands. The Frankfurt HIV Cohort was supported by a grant from the Bundesministerium für Bildung und Forschung and Glaxo Wellcome Research. The ICONA network was supported by an unrestricted educational grant from Glaxo Wellcome, Italy.
Source Information
From the Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland (B.L.); the Royal Free and University College Medical School, London (A.M.); the Division of Infectious Diseases, Tropical Medicine, and AIDS and the National AIDS Therapy Evaluation Center, Academic Medical Center, University of Amsterdam, Amsterdam (P.R.); the Division of Infectious Diseases, University Hospital Bern, Bern, Switzerland (H.F.); the Department of Infectious Diseases, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark (O.K., J.D.L.); the Center of Internal Medicine, J.W. Goethe University, Frankfurt, Germany (M.B.); the Infectious Diseases Department, San Raffaele Hospital, Milan, Italy (C.U.-F.); the Tropical and Infectious Diseases Department, Hôpital l'Archet, Nice, France (C.P.); the Institute of Infectious and Tropical Diseases, University of Milan, Milan, Italy (A.d'A.M.); and the Department of Internal Medicine, Division of Infectious Diseases and AIDS, University Medical Center Utrecht, Utrecht, the Netherlands (M.M.E.S.). Presented in part at the 7th Conference on Retroviruses and Opportunistic Infections, January 30–February 2, 2000, San Francisco.
Address reprint requests to Dr. Ledergerber at the Division of Infectious Diseases, University Hospital, CH-8091 Zurich, Switzerland, or at infled{at}usz.unizh.ch.
References
The members of the eight study groups were as follows: The Multicenter Study Group on EuroSIDA — Austria: N. Vetter (national coordinator), Vienna; Belgium: N. Clumeck (national coordinator), P. Hermans, B. Sommereijns, Brussels; R. Colebunders, Antwerp; Czech Republic: L. Machala (national coordinator), H. Rozsypal, Prague; Denmark: J. Nielsen (national coordinator), T. Benfield, T. Katzenstein, B. Røge, P. Skinhøj, Copenhagen; France: C. Katlama (national coordinator), C. Rivière, J.-P. Viard, Paris; T. Saint-Marc, P. Vanhems, Lyons; Germany: M. Dietrich (national coordinator), C. Manegold, J. van Lunzen, Hamburg; V. Miller, S. Staszewski, Frankfurt; F.-D. Goebel, Munich; B. Salzberger, Cologne; J. Rockstroh, Bonn; Greece: J. Kosmidis (national coordinator), P. Gargalianos, H. Sambatakou, G. Panos, G. Boulmetis, M. Astriti, Athens; Hungary: D. Banhegyi (national coordinator), Budapest; Ireland: F. Mulcahy (national coordinator), Dublin; Israel: I. Yust (national coordinator), D. Turner, Tel Aviv; S. Pollack, Z. Ben-Ishai, Haifa; Z. Bentwich, Rehovot; S. Maayan, Jerusalem; Italy: S. Vella and A. Chiesi (national coordinators), V. Vullo, P. Santopadre, C. Arici, P. Franci, P. Narciso, A. Antinori, M. Zaccarelli, Rome; F. Suter, A. Cremaschi, Bergamo; R. Pristerá, Bolzano; F. Vichi, Florence; B. DeRienzo, A. Bedini, Modena; A. Chirianni, E. Montesarchio, Naples; R. Finazzi, Milan; Luxemburg: R. Hemmer (national coordinator), T. Staub, Luxemburg; the Netherlands: J. Wubbels, Amsterdam; Norway: J. Bruun (national coordinator), A. Maeland, Oslo; Poland: B. Knysz (national coordinator), J. Gasiorowski, Wroclaw; A. Horban, Warsaw; R. Rogowska-Szadkowska, Bialystok; A. Boron-Kaczmarska, Szczecin; M. Beniowski, Chorzow; H. Trocha, Gdansk; Portugal: F. Antunes (national coordinator), K. Mansinho, R. Proenca, Lisbon; Spain: J. González-Lahoz (national coordinator), R. Polo, V. Soriano, Madrid; B. Clotet, A. Jou, J. Conejero, C. Tural, Badalona; J. Gatell, J. Miró, Barcelona; Sweden: A. Blaxhult (national coordinator), B. Heidemann, P. Pehrson, Stockholm; Switzerland: V. Soravia-Dunand, Geneva; United Kingdom: S. Barton (national coordinator), A. Johnson, D. Mercey, A. Phillips, C. Loveday, M. Johnson, A. Pinching, J. Parkin, J. Weber, G. Scullard, London; M. Fisher, Brighton; R. Brettle, Edinburgh; AIDS Therapy Evaluation Project Netherlands — W. Bronsveld, Alkmaar; H. Weigel, K. Brinkman, P. Frissen, J. ten Veen, M. Hillebrand, S. Schieveld, J. Mulder, E. van Gorp, P. Meenhorst, A. van Eeden, F. Claessen, R. Perenboom, S. Danner, J.K. Eeftinck Schattenkerk, E. Gisolf, M. Godfried, M. Jambroes, J. Lange (study coordinator), J. van der Meer, J. Nellen, D. Notermans, N. Pakker, T. van der Poll, M. van Praag, J. Prins, M. Reijers, T. Ruys, M. van der Valk, E. van der Ven, A. Verbon, G.J. Weverling, F. Wit, F. de Wolf (study coordinator), J. Wubbels, Amsterdam; C. Richter, Arnhem; R. Vriesendorp, R. Kauffman, E. Kogger, The Hague; B. Bravenboer, Eindhoven; C. ten Napel, K. Pogany, Enschede; H.G. Sprenger, G. Law, Groningen; R.W. ten Kate, Haarlem; M. Leemhuis, Leeuwarden; F. Kroon, Leiden; G. Schrey, S. van der Geest, A. van der Ven, Maastricht; P. Koopmans, M. Keuter, D. Telgt, Nijmegen; M. van der Ende, I. Gyssens, S. de Marie, Rotterdam; J. Juttman, C. van der Heul, Tilburg; J. Borleffs, I. Hoepelman, C. Jaspers, K. Schurink, Utrecht; W. Blok, Vlissingen; Swiss HIV Cohort Study — M. Battegay, H. Bucher, P. Erb, T. Klimkait, C. Rudin, Basel; M. Gorgievski, Bern; M. Egger, Bristol, United Kingdom; B. Hirschel, L. Perrin, V. Schiffer, Geneva; P. Bürgisser, P. Francioli (study coordinator), F. Paccaud, G. Pantaleo, P. Sudre, M. Rickenbach, A. Telenti, Lausanne; E. Bernasconi, J.C. Piffaretti, Lugano; R. Amiet, W. Fierz, C. Kind, P. Vernazza, St. Gall; M. Flepp, H. Günthard, M. Opravil, P. Grob, U. Lauper, J. Schupbach, R. Weber, Zurich; Danish Cohort of Patients Stopping Prophylaxis — J. Gerstoft, Copenhagen; N. Obel, Aarhus; H. Nielsen, Aalborg; C. Pedersen, Odense; Frankfurt HIV Cohort — S. Staszewski, V. Miller, E. Helm, Frankfurt, Germany; HSR Cohort — A. Lazzarin, Milan, Italy; DMI-2 Study Group at Nice University Hospital — P. Dellamonica, P.M. Roger, J.P. Cassuto, A. Pesce, J.G. Fuzibet, F. Sanderson, Y. Le Fichoux, J. Cottalorda, J.F. Michiels, Nice, France; Italian Cohort of Patients Naive to Antiretrovirals — M. Montroni, G. Scalise, A. Costantini, M.S. Del Prete, Ancona; U. Tirelli, G. Nasti, Aviano; G. Angarano, L.M. Perulli, Bari; F. Suter, C. Arici, Bergamo; F. Chiodo, F.M. Gritti, V. Colangeli, C. Fiorini, L. Guerra, Bologna; G. Carosi, G.P. Cadeo, F. Castelli, C. Minardi, D. Vangi, Brescia; S. Caprioli, G. Migliorino, Busto Arsizio; P.E. Manconi, P. Piano, Cagliari; T. Ferraro, L. Cosco, Catanzaro; E. Pizzigallo, F. Ricci, Chieti; G.M. Vigevani, L. Pusterla, Como; G. Carnevale, A. Pan, Cremona; P. Viganò, G.C. Ghiselli, Cuggiono; F. Ghinelli, L. Sighinolfi, Ferrara; F. Leoncini, F. Mazzotta, S. Ambu, S. Lo Caputo, Florence; B. Grisorio, S. Ferrara, Foggia; P. Grima, P. Tundo, Galatina; G. Pagano, N. Piersantelli, A. Alessandrini, R. Piscopo, Genoa; M. Toti, S. Chigiotti, Grosseto; F. Soscia, L. Tacconi, Latina; A. Orani, G. Castaldo, Lecco; A. Scasso, A. Vincenti, Lucca; A. Scalzini, F. Alessi, Mantua; M. Moroni (study coordinator), A. Lazzarin, A. Cargnel, F. Milazzo, L. Caggese, V. Testori, F. Delfanti, B. Carini, B. Adriani, S. Garavaglia, C. Moioli, Milan; R. Esposito, C. Mussini, Modena; N. Abrescia, A. Chirianni, O. Perrella, M. Piazza, M. DeMarco, V. Montesarchio, E. Manzillo, S. Nappa, Naples; P. Cadrobbi, R. Scaggiante, Padua; A. Colomba, T. Prestileo, Palermo; G. Filice, L. Minoli, F.A. Patruno Savino, R. Maserati, Pavia; S. Pauluzzi, A. Tosti, Perugia; F. Alberici, M. Sisti, Piacenza; F. Menichetti, A. Smorfa, Pisa; C. De Stefano, A. La Gala, Potenza; T. Zauli, G. Ballardini, Ravenna; L. Bonazzi, M.A. Ursitti, Reggio Emilia; R. Ciammarughi, M. Arlotti, Rimini; L. Ortona, F. Dianzani, A. Antinori, G. Antonucci, S. D'Elia, G. Ippolito, P. Narciso, N. Petrosillo, G. Rezza, V. Vullo, A. De Luca, A. Del Forno, M.R. Capobianchi, M. Zaccarelli, P. De Longis, M. Ciardi, E. Girardi, G. D'Offizi, F. Palmieri, P. Pezzotti, M. Lichter, Rome; M.S. Mura, M. Mannazzu, Sassari; P. Caramello, A. Sinicco, M.L. Soranzo, D. Giacobbi, M. Sciandra, B. Salassa, Turin; D. Torre, Varese; A. Poggio, G. Bottari, Verbania; E. Raise, S. Pasquinucci, Venice; F. De Lalla, G. Tositti, Vicenza; F. Resta, A. Chimienti, Taranto; A. Cozzi Lepri, London, United Kingdom.
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