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To describe the management of primary HIV infection (PHI), focusing on changes in the design of therapies and time to initiation of antiretroviral treatment, the clinical outcome, and the immuno-virological response over time to highly active antiretroviral therapy (HAART) and its tolerance.In the French PRIMO multicentre cohort, 291 patients presenting with PHI were enrolled between 1996 and 2001. Data were analysed to describe treatment prescription habits over a period of 5 years, and response to and tolerance of treatment.The proportion of patients who initiated treatment during PHI decreased from 92% in 1996 to 56% in 2001. At 6 months, whatever the initiated treatment, 74% of treated patients achieved a plasma viral load < 400 HIV-1 RNA copies/mL and 53% achieved a viral load of < 50 copies/mL. Prescription of protease inhibitor (PI)-sparing regimens has become more frequent since 1999. Despite a similar virological response, patients in the PI-containing group tended to experience a greater 1-year increase in CD4 cell count than those in the non-nucleoside reverse transcriptase (NNRTI)-containing group (218 cells/μL versus 157 cells/μL, respectively). An adverse event was recorded in 51% of treated patients. The most frequent events were gastrointestinal disorders (71%), lipodystrophy (27%) and mood disorders (19%). The main reason for modifying or stopping therapy was the occurrence of an adverse event.Limitations of therapy and poor tolerance to antiretroviral regimens have changed physician attitudes in PHI. This suggests the need for evaluation of better-tolerated regimens and new therapeutic strategies.