Richard B Pollard1, Jürgen K Rockstroh2, Giuseppe Pantaleo3, David M Asmuth1, Barry Peters4, Adriano Lazzarin5, Felipe Garcia6, Kim Ellefsen3, Daniel Podzamczer7, Jan van Lunzen8, Keikawus Arastéh9, Dirk Schürmann10, Bonaventura Clotet11, W David Hardy12, Ronald Mitsuyasu13, Graeme Moyle14, Andreas Plettenberg15, Martin Fisher16, Gerd Fätkenheuer17, Margaret Fischl18, Babafemi Taiwo19, Ingebjørg Baksaas20, Darren Jolliffe21, Stefan Persson22, Oyvind Jelmert23, Arnt-Ove Hovden24, Maja A Sommerfelt24, Vidar Wendel-Hansen25, Birger Sørensen24. 1. Division of Infectious Diseases, UC Davis Medical Center, Sacramento, CA, USA. 2. Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I, Immunologische Ambulanz, Bonn, Germany. 3. Division of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland. 4. Harrison Wing, St Thomas' Hospital, London, UK. 5. Department of Infectious Diseases, Ospedale San Raffaele and Vita-Salute University, Milan, Italy. 6. Infectious Diseases and AIDS Units, Hospital Clinic/IDIBAPS, University of Barcelona, Barcelona, Spain. 7. HIV Unit, Infectious Disease Service, Hospital Universitari de Bellvitge, Barcelona, Spain. 8. Universitätsklinikum Hamburg Eppendorf, Ambulanzzentrum Infektiologie, Hamburg, Germany. 9. EPIMED-Gesellschaft für Epidemiologische und Klinische Forschung in der Medizin mbH/Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany. 10. Department of Internal Medicine, Division of Infectious Diseases and Pulmonary Medicine, Charité-University Medicine Berlin, Berlin, Germany. 11. Irsicaixa Foundation, UAB, UVic, Hospital Universitari "Germans Trias i Pujol", Badalona, Catalonia, Spain. 12. Division of Infectious Diseases Cedars-Sinai Medical Center, Los Angeles, CA, USA. 13. UCLA CARE Center, University of California, Los Angeles, CA, USA. 14. Kobler Clinic, Chelsea and Westminster Hospital, London, UK. 15. ifi-Institut, an der Asklepios-Klinik St Georg, Hamburg, Germany. 16. Brighton and Sussex University Hospital, HIV/GUM Research, Elton John Centre, Brighton, UK. 17. Klinik I für Innere Medizin, Klinikum der Universität zu Köln, Cologne, Germany. 18. University of Miami School of Medicine AIDS Clinical Research Unit, Miami, FL, USA. 19. Division of Infectious Diseases, Northwestern University, Chicago, IL, USA. 20. Mericon AS, Skien, Norway. 21. Aptiv Solutions, Abingdon, UK. 22. SP PharmaConsulting, Uppsala, Sweden. 23. Bionor Laboratories, Skien, Norway. 24. Bionor Pharma ASA, Oslo, Norway. 25. Bionor Pharma ASA, Oslo, Norway. Electronic address: post@bionorpharma.com.
Abstract
BACKGROUND: Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1. METHODS: Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789. FINDINGS:174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. INTERPRETATION: The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. FUNDING: Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.
RCT Entities:
BACKGROUND: Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24(Gag), in adults infected with HIV-1. METHODS: Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load <50 copies per mL) with CD4 cell counts of 400 × 10(6) cells per L or greater. The trial was done at 18 sites in Germany, Italy, Spain, the UK, and the USA. Participants were randomly assigned (2:1) to Vacc-4x or placebo. Group allocation was masked from participants and investigators. Four primary immunisations, weekly for 4 weeks, containing Vacc-4x (or placebo) were given intradermally after administration of adjuvant. Booster immunisations were given at weeks 16 and 18. At week 28, cART was interrupted for up to 24 weeks. The coprimary endpoints were cART resumption and changes in CD4 counts during treatment interruption. Analyses were by modified intention to treat: all participants who received one intervention. Furthermore, safety, viral load, and immunogenicity (as measured by ELISPOT and proliferation assays) were assessed. The 52 week follow-up period was completed in June, 2011. For the coprimary endpoints the proportion of participants who met the criteria for cART resumption was analysed with a logistic regression model with the treatment effect being assessed in a model including country as a covariate. This study is registered with ClinicalTrials.gov, number NCT00659789. FINDINGS: 174 individuals were screened; because of slow recruitment, enrolment stopped with 136 of a planned 345 participants and 93 were randomly assigned to receive Vacc-4x and 43 to receive placebo. There were no differences between the two groups for the primary efficacy endpoints in those participants who stopped cART at week 28. Of the participants who resumed cART, 30 (34%) were in the Vacc-4x group and 11 (29%) in the placebo group, and percentage changes in CD4 counts were not significant (mean treatment difference -5·71, 95% CI -13·01 to 1·59). However, a significant difference in viral load was noted for the Vacc-4x group both at week 48 (median 23,100 copies per mL Vacc-4x vs 71,800 copies per mL placebo; p=0·025) and week 52 (median 19,550 copies per mL vs 51,000 copies per mL; p=0·041). One serious adverse event, exacerbation of multiple sclerosis, was reported as possibly related to study treatment. Vacc-4x was immunogenic, inducing proliferative responses in both CD4 and CD8 T-cell populations. INTERPRETATION: The proportion of participants resuming cART before end of study and change in CD4 counts during the treatment interruption showed no benefit of vaccination. Vacc-4x was safe, well tolerated, immunogenic, seemed to contribute to a viral-load setpoint reduction after cART interruption, and might be worth consideration in future HIV-cure investigative strategies. FUNDING: Norwegian Research Council GLOBVAC Program and Bionor Pharma ASA.
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