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Little is known about time trends, predictors, and consequences of changes made to antiretroviral therapy (ART) regimens early after patients initially start treatment.We compared the incidence of, reasons for, and predictors of treatment change within 1 year after starting combination ART (cART), as well as virological and immunological outcomes at 1 year, among 1866 patients from the Swiss HIV Cohort Study who initiated cART during 2000-2001, 2002-2003, or 2004-2005.The durability of initial regimens did not improve over time (P = .15): 48.8% of 625 patients during 2000-2001, 43.8% of 607 during 2002-2003, and 44.3% of 634 during 2004-2005 changed cART within 1 year; reasons for change included intolerance (51.1% of all patients), patient wish (15.4%), physician decision (14.8%), and virological failure (7.1%). An increased probability of treatment change was associated with larger CD4+ cell counts, larger human immunodeficiency virus type 1 (HIV-1) RNA loads, and receipt of regimens that contained stavudine or indinavir/ritonavir, but a decreased probability was associated with receipt of regimens that contained tenofovir. Treatment discontinuation was associated with larger CD4+ cell counts, current use of injection drugs, and receipt of regimens that contained nevirapine. One-year outcomes improved between 2000-2001 and 2004-2005: 84.5% and 92.7% of patients, respectively, reached HIV-1 RNA loads of <50 copies/mL and achieved median increases in CD4+ cell counts of 157.5 and 197.5 cells/μL, respectively (P < .001 for all comparisons).Virological and immunological outcomes of initial treatments improved between 2000-2001 and 2004-2005, irrespective of uniformly high rates of early changes in treatment across the 3 study intervals.