The study design allowed the impact of the PPV boost in patients from the prime-boost group to be evaluated. For this, we compared frequency and distribution of responders (i.e., patients who experienced both a twofold increase in SPP-specific antibody levels and IgG concentrations > 1 μg/ml), 4 weeks following the administration of either the PCV in the prime-boost group or PPV in the PPV group. The distribution of frequency of responders in the categories 0, 1–2, 3–4 and 5–7 SPP were 9, 20, 22 and 49% in the prime-boost group at week 4 and did not differ significantly from frequency of responders of the PPV-alone strategy at week 8: proportional OR 1.36 (95% CI, 0.82–2.25; P = 0.23). Altogether, these results showed that the PPV boost in patients from the prime-boost group contributed to increase the rate of responders at week 8, as compared to a single PPV administration in patients from the PPV group.
At week 8, compared with the PPV group, SPP-specific IgG concentrations (geometric mean of antibody concentrations) were significantly higher in patients who received the PCV prime followed by the PPV boost for six of seven serotypes shared by the PCV and PPV vaccines: serotypes 4, 9V, 14, 18C, 19F, and 23F. As expected, there were no differences between groups in the IgG antibody concentrations for serotypes 5 and 1 which are not contained in the PCV, indicating that PCV prime did not inhibit any of the PPV unshared subtype responses (Table 2).
The sustainability of SPP-specific IgG responses was evaluated at week 24. Patients from the prime-boost group had significantly higher levels as compared to the PPV-alone group for four of seven SPP shared by the two vaccines (Table 2). The frequency and the distribution of patients who experienced both a twofold increase in SPP levels and IgG concentrations > 1 μg/ml was significantly higher in the prime-boost group as compared with the PPV-alone group. Responders to 0, 1–2, 3–4 and 5–7 SPP were 17, 30, 24 and 30% in the prime-boost group as compared to 23, 40, 27 and 10% in the PPV group: proportional OR, 2.14 (95% CI, 1.30–3.53; P = 0.003) (Fig. 3).
Finally, we analyzed predictive factors of IgG-specific immunological responses to vaccination. In the multivariate model (Table 3), the prime-boost strategy remained significantly associated with a better immunological response. Moreover, smokers and patients co-infected with HCV had a significantly lower chance of being responders to vaccination than others. However, in these categories of patients, the rate of responders remained higher in those who received the prime-boost regimen as compared to recipients of the PPV-alone.
In this randomized, controlled trial, we show that a vaccination combining PCV as a prime followed by a PPV boost led to a higher rate of immunological responders as compared to the administration of a single injection of the currently recommended PPV. Moreover, the prime-boost strategy led to a higher level of SPP-specific IgG against all but one, of the seven polysaccharides shared by the two vaccines. Both vaccine strategies were well tolerated.
Studies evaluating antibody responses to PPV consistently concluded low immunogenicity and lack of efficacy in HIV-infected patients with CD4 cell counts < 500/μl [17,23,24,27–29,41]. Several trials performed in children, who have poor responses to PPV, have shown that the PCV is highly efficacious against invasive disease [34,35,42,43]. Therefore, conjugated vaccines might be a very promising strategy to protect high-risk adults. For example, vaccination of adult HIV-infected patients with conjugated-Hemophilus influenzae b (Hib) vaccine led to a greater antibody response than the Hib polysaccharide vaccine . However, regarding pneumococcal vaccination, results are less clear-cut since no differences in immunological responses elicited by a single dose of PCV compared to PPV were shown in adult patients with CD4 cell counts > 200/μl . This defect in humoral immunity was not overcome by revaccination either by a double dose of PPV [31,32] or by vaccination with one or two doses of PCV [29,41].
As seven SPP are shared by the PPV and PCV, we evaluated whether a prime with PCV would be more effective in obtaining a longer-term response to a boost with PPV. We chose this combination following the demonstration of a booster effect of the PPV after priming with PCV both in HIV and non-HIV infected infants and children [45–47]. Moreover, we hypothesized that this strategy might help to extend the breadth of the antibody response against SPP serotypes. Our design allowed evaluation of the rate of responders to the seven SPP shared by the two vaccines and to SPP 1 and 5 contained only in the PPV. Following administration of the PPV boost in patients primed with PCV, the proportion of responders to 5–7 SPP became 20% higher as compared to the PPV group. Our results contrast with those of another study showing no additional increases in antibody concentrations elicited by a dose of PPV following a first dose of PCV in HIV-infected patients with CD4 cell counts > 200 cells/μl . Several differences between this study and our results may explain these different findings including the timing of the PPV boost 8 weeks following the PCV, the small sample size (18 patients received the combination strategy) and the high rate of lost of follow-up (20%) which jeopardized the power of this study.
Continued uncertainty regarding the nature of SPP vaccine responses that translate into vaccine efficacy in the setting of HIV infection underscores the need to define useful surrogates for vaccine efficacy. The levels of IgG required for protection remain unknown. However, previous studies have shown that vaccine failures are often associated with lack of antibody response [49–51]. We used two different criteria of antibody responses. The first one (twofold increase in IgG levels) has been routinely used in studies of pneumococcal immunization in adults [23,26,48]. However, it does not assess the absolute post-vaccination value which could be a surrogate marker of protection against invasive pneumococcal disease. To overcome this, we used a second and stricter criterion of response which includes both a twofold response and a level of antibody ≥ 1 μg/ml. Our results show that the prime-boost strategy led to higher values of the geometric mean of IgG-specific for six of the seven serotypes shared by the two vaccines, except for SPP 6b, which is known to be an antigen with poor immunogenicity [52,53]. It seems unlikely that the low antibody responses against serotype 6b could have any clinical relevance, because this serotype is rarely found in adults with pneumococcal invasive disease .
Several studies reported that immunological responses to vaccination with either T-cell-dependent antigens or SPP are impaired in HIV-infected adults with low CD4+ cell count [55,56]. In the context of the multiple immune dysregulations that complicate HIV infection, SPP specific suboptimal antibody responses may be less protective. Our results show that a combination strategy including a prime with a T-cell dependent antigen may help to overcome limitations to an effective antibody response in HIV infection. These provide arguments for testing such strategy in patients who less likely may have chance to mount a significant antibody response to SPP such as non-white patients or individuals with low CD4+ cell counts .
Interestingly, we observed that a higher rate of responders was maintained 6 months following vaccination with PCV combined with PPV. This observation might have clinical relevance since a rapid loss of vaccine antibodies is observed in HIV individuals receiving either PCV or PPV-alone . The limited responses after re-immunization of patients with the current PPV do not overcome this loss of antibody titres and reinforce the need for a more immunogenic strategy. As with previous studies, we found that the percentages of responders to SPP dropped in each group of the study six months following the end of the vaccination. Previous studies have shown that the rate of decline of vaccine antibodies against SPP is similar in HIV-infected individuals and healthy controls suggesting that the period of protection following vaccination is dependent on the levels achieved after vaccination [32,41,57]. We found that the levels of IgG specific to four of seven of the SPP shared by the two vaccines remained significantly higher in recipients of the PCV-PPV combination as compared to patients vaccinated with PPV alone. This observation suggests that the period of protection might be significantly prolonged in patients who received a sequential vaccination with PCV and PPV.
We evaluated the impact of the prime-boost strategy in a multicentric trial as close as possible to the practical care of a population of HIV-infected individuals. Although a vast majority of patients were treated with HAART, all patients treated or not with antiviral drugs were eligible to participate to this study. Similarly, there was no restriction based upon the nadir CD4 T cell count, a clear predictive factor of the response to vaccination in HIV-infected patients [18,19,41,55]. We found that the efficacy of the prime-boost strategy remained significantly higher than that of PPV alone when adjusted for CD4 cell counts, viral load and antiviral therapy. In the multivariate analysis, the prime-boost strategy remained associated with better immunological responses in smokers and patients with HCV infection. Several studies have shown that cirrhosis is a risk factor for both pneumococcal infection and low response to vaccination against SPP [58–60]. In addition, HCV infection was found to inhibit humoral response to hepatitis B virus vaccine in patients . More recently, HCV infection was identified as a risk factor for invasive pneumococcal disease in HIV-infected patients . However, to our knowledge, an association between HCV infection status and response to pneumococcal vaccination in HIV-infected patients has not been documented previously. This result would help to identify, among HIV-infected individuals, subjects who likely may have a better benefit of the prime-boost strategy.
Our study provides evidence to support the use of a PCV primed-PPV boosted strategy to overcome limitations of the immunogenicity of the currently recommended immunization with PPV alone. We found that this strategy led to a higher efficacy of the vaccination in frequency, breadth, magnitude and sustainability of antibody responses among HIV-infected adults with CD4 cell counts between 200 and 500 cells/μl.
We would like to thank Dr Bernard Fritzell (Wyeth Pharmaceuticals Vaccines) for his contribution to this paper, Dr Madore DV (Wyeth-Lederlé Rochester, USA) for the evaluation of IgG responses to pneumococcal serotypes, Pr David Goldblatt (Immunobiology Unit, Institute of Child Health, UK) for expertise in the quality control evaluation of IgG responses, and Mrs Inga Tschöpe for checking the results of statistical analysis. We also gratefully acknowledge the contribution of the Data and Safety Monitoring Committee: France Mentré, Philippe Morlat. This study was performed with the financial support of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS).
1. Frankel RE, Virata M, Hardalo C, Altice FL, Friedland G. Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection. Clin Infect Dis 1996; 23:577–584.
2. Gilks CF, Ojoo SA, Ojoo JC, Brindle RJ, Paul J, Batcheler BI, et al
. Invasive pneumococcal disease in a cohort of predominantly HIV-1 infected female sex-workers in Nairobi, Kenya. Lancet 1996; 347:718–723.
3. Nuorti JP, Butler JC, Gelling L, Kool JL, Reingold AL, Vugia DJ. Epidemiologic relation between HIV and invasive pneumococcal disease in San Francisco County, California. Ann Intern Med 2000; 132:182–190.
4. Janoff EN, Breiman RF, Daley CL, Hopewell PC. Pneumococcal disease during HIV infection. Epidemiologic, clinical, and immunologic perspectives. Ann Intern Med 1992; 117:314–324.
5. Redd SC, Rutherford GW 3rd, Sande MA, Lifson AR, Hadley WK, Facklam RR, et al
. The role of human immunodeficiency virus infection in pneumococcal bacteremia in San Francisco residents. J Infect Dis 1990; 162:1012–1017.
6. Jones N, Huebner R, Khoosal M, Crewe-Brown H, Klugman K. The impact of HIV on Streptococcus pneumoniae bacteraemia in a South African population. Aids 1998; 12:2177–2184.
7. Hibbs JR, Douglas JM Jr, Judson FN, McGill WL, Rietmeijer CA, Janoff EN. Prevalence of human immunodeficiency virus infection, mortality rate, and serogroup distribution among patients with pneumococcal bacteremia at Denver General Hospital, 1984–1994. Clin Infect Dis 1997; 25:195–199.
8. Boschini A, Smacchia C, Di Fine M, Schiesari A, Ballarini P, Arlotti M, et al
. Community acquired pneumonia in a cohort of former injection drug users with and without human immunodeficiency virus infection: incidence, etiologies, and clinical aspects. Clin Infect Dis 1996; 23:107–113.
9. McEllistrem MC, Mendelsohn AB, Pass MA, Elliott JA, Whitney CG, Kolano JA, et al
. Recurrent invasive pneumococcal disease in individuals with human immunodeficiency virus infection. J Infect Dis 2002; 185:1364–1368.
10. Barry PM, Zetola N, Keruly JC, Moore RD, Gebo KA, Lucas GM. Invasive pneumococcal disease in a cohort of HIV-infected adults: incidence and risk factors, 1990–2003. Aids 2006; 20:437–444.
11. Heffernan RT, Barrett NL, Gallagher KM, Hadler JL, Harrison LH, Reingold AL, et al
. Declining incidence of invasive Streptococcus pneumoniae infections among persons with AIDS in an era of highly active antiretroviral therapy, 1995–2000. J Infect Dis 2005; 191:2038–2045.
12. Jordano Q, Falco V, Almirante B, Planes AM, del Valle O, Ribera E, et al
. Invasive pneumococcal disease in patients infected with HIV: still a threat in the era of highly active antiretroviral therapy. Clin Infect Dis 2004; 38:1623–1628.
13. Lopez-Palomo C, Martin-Zamorano M, Benitez E, Fernandez-Gutierez C, Guerrero F, Rodriguez-Iglesias M, et al
. Pneumonia in HIV-infected patients in the HAART era: incidence, risk, and impact of the pneumococcal vaccination. J Med Virol 2004; 72:517–524.
14. Tacconelli E, Tumbarello M, de Gaetano K, Cauda R, Ortona L. Highly active antiretroviral therapy decreases the incidence of bacteremia in human immunodeficiency virus-infected individuals. Clin Infect Dis 1998; 27:901–902.
15. Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000; 342:1416–1429.
16. Anonymous. 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Clin Infect Dis 2000; 30:S29–S65.
17. French N, Nakiyingi J, Carpenter LM, Lugada E, Watera C, Moi K, et al
. 23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial. Lancet 2000; 355:2106–2111.
18. Dworkin MS, Ward JW, Hanson DL, Jones JL, Kaplan JE. Pneumococcal disease among human immunodeficiency virus-infected persons: incidence, risk factors, and impact of vaccination. Clin Infect Dis 2001; 32:794–800.
19. Gebo KA, Moore RD, Keruly JC, Chaisson RE. Risk factors for pneumococcal disease in human immunodeficiency virus-infected patients. J Infect Dis 1996; 173:857–862.
20. Fry AM, Facklam RR, Whitney CG, Plikaytis BD, Schuchat A. Multistate evaluation of invasive pneumococcal diseases in adults with human immunodeficiency virus infection: serotype and antimicrobial resistance patterns in the United States. J Infect Dis 2003; 188:643–652.
21. Breiman RF, Keller DW, Phelan MA, Sniadack DH, Stephens DS, Rimland D, et al
. Evaluation of effectiveness of the 23-valent pneumococcal capsular polysaccharide vaccine for HIV-infected patients. Arch Intern Med 2000; 160:2633–2638.
22. Hung CC, Chen MY, Hsieh SM, Hsiao CF, Sheng WH, Chang SC. Clinical experience of the 23-valent capsular polysaccharide pneumococcal vaccination in HIV-1-infected patients receiving highly active antiretroviral therapy: a prospective observational study. Vaccine 2004; 22:2006–2012.
23. Rodriguez-Barradas MC, Musher DM, Lahart C, Lacke C, Groover J, Watson D, et al
. Antibody to capsular polysaccharides of Streptococcus pneumoniae after vaccination of human immunodeficiency virus-infected subjects with 23-valent pneumococcal vaccine. J Infect Dis 1992; 165:553–556.
24. Rodriguez-Barradas MC, Alexandraki I, Nazir T, Foltzer M, Musher DM, Brown S, et al
. Response of human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy to vaccination with 23-valent pneumococcal polysaccharide vaccine. Clin Infect Dis 2003; 37:438–447.
25. Glaser JB, Volpe S, Aguirre A, Simpkins H, Schiffman G. Zidovudine improves response to pneumococcal vaccine among persons with AIDS and AIDS-related complex. J Infect Dis 1991; 164:761–764.
26. Kroon FP, van Dissel JT, Ravensbergen E, Nibbering PH, van Furth R. Antibodies against pneumococcal polysaccharides after vaccination in HIV-infected individuals: 5 year follow-up of antibody concentrations. Vaccine 1999; 18:524–530.
27. Ochs HD, Junker AK, Collier AC, Virant FS, Handsfield HH, Wedgwood RJ. Abnormal antibody responses in patients with persistent generalized lymphadenopathy. J Clin Immunol 1988; 8:57–63.
28. Janoff EN, Douglas JM Jr, Gabriel M, Blaser MJ, Davidson AJ, Cohn DL, et al
. Class specific antibody response to pneumococcal capsular polysaccharides in men infected with human immunodeficiency virus type 1. J Infect Dis 1988; 158:983–990.
29. Ahmed F, Steinhoff MC, Rodriguez-Barradas MC, Hamilton RG, Musher DM, Nelson KE. Effect of human immunodeficiency virus type 1 infection on the antibody response to a glycoprotein conjugate pneumococcal vaccine: results from a randomized trial. J Infect Dis 1996; 173:83–90.
30. Nielsen H, Kvinesdal B, Benfield TL, Lundgren JD, Konradsen HB. Rapid loss of specific antibodies after pneumococcal vaccination in patients with human immunodeficiency virus-1 infection. Scand J Infect Dis 1998; 30:597–601.
31. Tasker SA, Wallace MR, Rubins JB, Paxton WB, O'Brien J, Janoff EN. Reimmunization with 23-valent pneumococcal vaccine for patients infected with human Immunodeficiency virus type 1: clinical, immunologic, and virologic responses. Clin Infect Dis 2002; 34:813–821.
32. Rodriguez-Barradas MC, Groover JE, Lacke CE, Gump DW, LAhart CJ, Pandey JP, et al
. IgG antibody to pneumococcal capsular polysaccharide in human immunodeficiency virus-infected subjects: persistence of antibody in responders, revaccination in nonresponders, and relationship of immunoglobulin allotype to response. J Infect Dis 1996; 173:1347–1353.
33. Mond JJ, Lees A, Snapper CM. T cell-independent antigens type 2. Annu Rev Immunol 1995; 13:655–692.
34. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9 valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003; 349:1341–1348.
35. Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, Legerfield R, et al
. Decline in invasive pneumococcal disease after the introduction of protein polysaccharide conjugate vaccine. N Engl J Med 2003; 348:1737–1746.
36. Stein KE. Thymus-independent and thymus-dependent responses to polysaccharide antigens. J Infect Dis 1992; 165(Suppl 1):S49–S52.
37. Chan CY, Molrine DC, George S, Tarbell NJ, Pauch P, Diller L, et al
. Pneumococcal conjugate vaccine primes for antibody responses to polysaccharide pneumococcal vaccine after treatment of Hodgkin's disease. J Infect Dis 1996; 173:256–258.
38. Wernette CM, Frasch CE, Madore D, Carlone G, Goldblatt D, Plikaytis B, et al
. Enzyme-linked immunosorbent assay for quantitation of human antibodies to pneumococcal polysaccharides. Clin Diagn Lab Immunol 2003; 10:514–519.
39. Whitehead J. Sample sizes calculations for ordered categorical data. Stat Med 1996; 15:1065–1066.
40. McCullach P. Regression models for ordinal data. J Roy Statist Soc 1980; B43:109–142.
41. Kroon FP, van Dissel JT, Ravensbergen E, Nibbering PH, van Furth R. Enhanced antibody response to pneumococcal polysaccharide vaccine after prior immunization with conjugate pneumococcal vaccine in HIV-infected adults. Vaccine 2000; 19:886–894.
42. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al
. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000; 19:187–195.
43. Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS, Okoko JB, et al
. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in the Gambia: randomised, double-blind, placebo-controlled trial. Lancet 2005; 365:1139–1146.
44. Steinhoff MC, Auerbach BS, Nelson KE, Vlahov D, Becker RL, Graham NM, et al
. Antibody responses to Haemophilus influenzae type B vaccines in men with human immunodeficiency virus infection. N Engl J Med 1991; 325:1837–1842.
45. O'Brien KL, Steinhoff MC, Edwards K, Keyserling H, Thoms ML, Madore D. Immunologic priming of young children by pneumococcal glycoprotein conjugate, but not polysaccharide, vaccines. Pediatr Infect Dis J 1996; 15:425–430.
46. Breukels MA, Rijkers GT, Voorhorst-Ogink MM, Zegers BJ, Sanders LA. Pneumococcal conjugate vaccine primes for polysaccharide-inducible IgG2 antibody response in children with recurrent otitis media acuta. J Infect Dis 1999; 179:1152–1156.
47. Veenhoven R, Bogaert D, Uiterwaal C, Brauwer C, Kiezebrink H, Brain J, et al
. Effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study. Lancet 2003; 361:2189–2195.
48. Feikin DR, Elie CM, Goetz MB, Lennox JL, Cadone GM, Romero-Steiner S, et al
. Randomized trial of the quantitative and functional antibody responses to a 7-valent pneumococcal conjugate vaccine and/or 23-valent polysaccharide vaccine among HIV-infected adults. Vaccine 2001; 20:545–553.
49. Simberkoff MS, El Sadr W, Schiffman G, Rahal JJ Jr. Streptococcus pneumoniae infections and bacteremia in patients with acquired immune deficiency syndrome, with report of a pneumococcal vaccine failure. Am Rev Respir Dis 1984; 130:1174–1176.
50. French N, Gilks CF, Mujugira A, Fasching C, O'Brien J, Janoff EN. Pneumococcal vaccination in HIV-1-infected adults in Uganda: humoral response and two vaccine failures. AIDS 1998; 12:1683–1689.
51. French N, Moore M, Haikala R, Kayhty H, Gilks CF. A case-control study to investigate serological correlates of clinical failure of 23-valent pneumococcal polysaccharide vaccine in HIV 1-infected Ugandan adults. J Infect Dis 2004; 190:707–712.
52. Ahman H, Kayhty H, Tamminen P, Vuorela A, Malinoski F, Eskola J. Pentavalent pneumococcal oligosaccharide conjugate vaccine PncCRM is well tolerated and able to induce an antibody response in infants. Pediatr Infect Dis J 1996; 15:134–139.
53. Kayhty H, Ahman H, Ronnberg PR, Tillikainen R, Eskola J. Pneumococcal polysaccharide meningococcal outer membrane protein complex conjugate vaccine is immunogenic in infants and children. J Infect Dis 1995; 172:1273–1278.
54. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis 2000; 30:100–121.
55. Kroon FP, van Dissel JT, de Jong JC, van Furth R. Antibody response to influenza, tetanus and pneumococcal vaccines in HIV-seropositive individuals in relation to the number of CD4+ lymphocytes. AIDS 1994; 8:469–476.
56. Kroon FP, van Dissel JT, Labadie J, van Loon AM, van Furth R. Antibody response to diphtheria, tetanus, and poliomyelitis vaccines in relation to the number of CD4+ T lymphocytes in adults infected with human immunodeficiency virus. Clin Infect Dis 1995; 21:1197–1203.
57. Musher DM, Groover JE, Rowland JM, Watson DA, Struewing JB, Baughn RE, et al
. Antibody to capsular polysaccharides of Streptococcus pneumoniae: prevalence, persistence, and response to revaccination. Clin Infect Dis 1993; 17:66–73.
58. McCashland TM, Preheim LC, Gentry MJ. Pneumococcal vaccine response in cirrhosis and liver transplantation. J Infect Dis 2000; 181:757–760.
59. Mellencamp MA, Preheim LC. Pneumococcal pneumonia in a rat model of cirrhosis: effects of cirrhosis on pulmonary defense mechanisms against Streptococcus pneumoniae. J Infect Dis 1991; 163:102–108.
60. Preheim LC, Mellencamp MA, Snitily MU, Gentry MJ. Effect of cirrhosis on the production and efficacy of pneumococcal capsular antibody in a rat model. Am Rev Respir Dis 1992; 146:1054–1058.
Appendix: Members of the ANRS 114-Pneumovac Study Group
P. Lesprit,Y. Levy (principal investigators); G. Chêne (trial coordinator); N. Sarrazin (trial monitor); G. Pedrono (trial statistician); C. Rabian (trial immunologist); P. Bursachi, M.-J. Commoy, J.-F. Delfraissy, F. Denis, B. Fritzell, C. Goujard, R. Salamon, R. Tubiana, J. P. Viard.
Participating clinical departments and investigators
Hôpital Avicenne, Bobigny: A. Krivitzky, M. Bentata, S. Makki, R. Mansouri, L. Guillevin, B. Jarousse, A.-K. Klutse, G. Obenga, P. Honoré-Berlureau, Y. Baazia and S. Soreda; Hôpital Saint-Louis, Paris: J.-P. Clauvel, E. Oksenhendler, L. Gerard, J. Delgado, J.-M. Molina, N. Colin de Verdière, P. Palmer, I. Madelaine; Hôpital Pellegrin, Bordeaux: M. Dupon, J.-M. Ragnaud, D. Neau, I. Raymond, I. Garrigue, J.-P. Dupin; Hôpital Necker, Paris: Ch. Boitard, J.-P. Viard, S. El Marsafy, R. Lahoulou, A. Mogenet, C. Broissand; Hôpital de Bicêtre, Le Kremlin-Bicêtre: J.-F.Delfraissy, C. Goujard, D. Pereti, Y. Quertainmont, P. Robquin, O. Segeral, S. Poirier, M.-T Rannou, N. Idri, C. Le Tiec; Hôpital Cochin, Paris: D. Sicard, D. Salmon, O. Launay, B. Silbermann, C. Desaint, A. Krivine, C. Guérin; Hôpital Henri-Mondor, Créteil: A. Sobel, Y. Lévy, P. Lesprit, A.-S. Lascaux, Ch. Chesnel, C. Jung, A. Miladi, C. Antoine; Hôpital Pitié-Salpêtrière, Paris: F. Bricaire, Ch. Katlama, I. Boubezari, S. Pierre-François, L. Schneider, C. Seulié, M.-H. Fievet; Hôpital Saint-Antoine, Paris: P.-M. Girard, A.-M. Béglé, F. Besse, R. Mouchotte, A. Charrois, A. Duaguenel-Nguyen; Hôpital Bichat, Paris: P. Yeni, I. Fournier, S. Lariven, B. Phung, P. Ralaïmazava, Ch. Gaudebout, J. Gerbe, D. Descamps, S. LePoole; Hôpital Gui de Chauliac, Montpellier: J. Reynes, P. André, V. Baillat, V. Le Moing, C. Merle, M. Vidal, J.-M. Fondère, I. Roch-Torreilles; Hôpital Hôtel-Dieu, Nantes: F. Raffi, P. Morineau, C. Allavena, B. Bonnet, H. Hue, E. Guarnier, A. Lepelletier; Hôpital Les Oudairies, La Roche sur Yon: P. Perré, O. Aubry, S. Leautez, C. Leroy, I. Suaud, A.-S. Poirier, A. Lepelletier; Hôpital de L'Archet, Nice: P. Dellamonica, V. Rahelinirina, M.-A. Sereni, S. Benhamou, M.-Ch. Rigault; Hôpital Purpan, Toulouse: P. Massip, B. Marchou, M. Alvarez, E. Bonnet, L. Cuzin, M. Obadia, F. Balsarin, M. Barone, M. Heraud, I. Peyranne.
Data and safety monitoring board
F. Mentré, P. Morlat.
Coordinating trial centre
INSERM U593, Bordeaux, France (G. Chêne, N. Sarrazin, G. Pedrono, I. Tschöpe, G. Palmer)
61. Leroy V, Bourliere M, Durand M, Abergel A, Tran A, Baud M, et al
. The antibody response to hepatitis B virus vaccination is negatively influenced by the hepatitis C virus viral load in patients with chronic hepatitis C: a case-control study. Eur J Gastroenterol Hepatol 2002; 14:485–489.