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A Prospective Trial of Structured Treatment Interruptions in Human Immunodeficiency Virus Infection
Catherine Fagard, MD;
Annette Oxenius, PhD;
Huldrych Günthard, MD;
Felipe Garcia, MD;
Michelle Le Braz, RN;
Gabriel Mestre, MD;
Manuel Battegay, MD;
Hansjakob Furrer, MD;
Pietro Vernazza, MD;
Enos Bernasconi, MD;
Amalio Telenti, MD;
Rainer Weber, MD;
Dominique Leduc, MD;
Sabine Yerly, PhD;
David Price, MD;
Sara J. Dawson, PhD;
Thomas Klimkait, MD;
Thomas V. Perneger, MD;
Angela McLean, PhD;
Bonaventura Clotet, MD;
José M. Gatell, MD;
Luc Perrin, MD;
Montserrat Plana, MD;
Rodney Phillips, MD;
Bernard Hirschel, MD; for the Swiss HIV Cohort Study
Arch Intern Med. 2003;163:1220-1226.
Background According to the "autovaccination hypothesis," reexposure to human immunodeficiency virus (HIV) during treatment interruptions may stimulate the HIV-specific immune response and lead to low viremia after withdrawal of highly active antiretroviral treatment (HAART). Many patients who started HAART earlier in their disease course than is currently recommended would like to discontinue, but it is unknown whether it is safe to do so.
Objectives To determine whether repeated treatment interruptions of HAART (1) stimulated the cytotoxic HIV-specific immune response and whether such stimulation correlated with low viremia off treatment, and (2) were safe with respect to clinical complications, development of viral resistance, and decline in CD4 cell counts.
Design Interventional study with before-after comparison.
Setting Outpatient clinics of university hospitals in Switzerland and Spain.
Patients A total of 133 patients receiving HAART, with a median CD4 cell count of 740/µL, and whose viral load had been undetectable for a median of 21 months.
Interventions HAART was interrupted for 2 weeks, restarted, and continued for 8 weeks. After 4 such cycles, treatment was indefinitely suspended 40 weeks after study entry.
Main Outcome Measures HIV-specific cytotoxic T-cell responses were evaluated by interferon  enzyme-linked immunospot analysis. The proportion of "responders" (viral load <5000 copies/mL) was measured at weeks 52 and 96. HIV-related diseases and CD4 cell counts were recorded.
Results Seventeen percent of patients (95% confidence interval, 11%-25%) were responders at week 52, and 8% at week 96. Low pre-HAART viral load and lack of rebound during weeks 0 to 40 predicted response. HIV-specific CD8+ T cells increased between week 0 (median, 343 spot-forming cells per million peripheral blood lymphocytes [SFC/106 PBL]) and week 52 (median, 1930 SFC/106 PBL), but there was an inverse correlation between response and the number of spot-forming cells. Eighty-five (64%) of 133 patients stopped therapy for at least 12 weeks, and 55 (41%) for at least 56 weeks. The median CD4 cell count decreased from 792/µL to 615/µL during the first 12 weeks without treatment, but stabilized thereafter. One patient (0.75%) developed drug resistance necessitating salvage treatment. There were no AIDS-related clinical complications.
Conclusions Results of this study do not favor the autovaccination hypothesis. Treatment interruptions did not provoke clinical complications, and there was little drug resistance. Comparative trials will have to show what benefit, if any, is associated with intermittent, as opposed to continuous treatment.
From the Division of Infectious Diseases (Drs Fagard and Hirschel and Ms Le Braz), the Laboratory of Virology (Drs Yerly and Perrin), and the Quality of Care Unit (Dr Perneger), Geneva University Hospital, Geneva, Switzerland; Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, England (Drs Oxenius, Price, Dawson, and Phillips); Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine, University Hospital, Zurich, Switzerland (Drs Günthard and Weber); Infectious Disease Service, Clinical Institute of Infections and Immunology, Hospital Clinic, Barcelona, Spain (Drs Garcia, Mestre, Gatell, and Plana); Center for HIV Research, Outpatient Department of Internal Medicine, University Hospital, Basel, Switzerland (Drs Battegay and Klimkait); Division of Infectious Diseases, Inselspital, Berne, Switzerland (Dr Furrer); Medizinische Klinik, University Hospital, St Gallen, Switzerland (Dr Vernazza); Ospedale Civico, Lugano, Switzerland (Dr Bernasconi); Division of Infectious Diseases, CHUV, Lausanne, Switzerland (Dr Telenti); Centre Hospitalier, Hôpital d'Ambilly, d'Ambilly, France (Dr Leduc); Wellcome Trust Center for Epidemiology of Infectious Disease and Zoology Department, Oxford, England (Dr McLean); and Germans Trias i Pujol, Hospital Universitari i Fundacio irsiCaixa, Badalona/Barcelona, Spain (Dr Clotet). The authors have no relevant financial interest in this article.
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