Objectives:The impact of highly active antiretroviral therapy (HAART) on hepatitis C virus (HCV) is unknown. We analysed changes in HCV RNA and the frequency of hepatotoxicity in co-infected patient enrolling in AIDS Clinical Trials Group trials, and determined whether HCV impairs successful immune reconstitution in these populations.Design/methods:In a prospective analysis of co-infected patients completing at least 16 weeks of HAART in four trials, and co-infected patients with available stored plasma from two other completed HAART trials, HCV RNA was measured at baseline and to week 48. A retrospective analysis of immune recovery in 40 HCV-RNA-positive and 129 HCV-RNA-negative patients from a single trial was performed.Results:Prospective analysis: 60 patients completed at least 16 weeks of HAART. The mean HCV-RNA level increased 0.35 log10IU/ml at week 16 and 0.43 log10IU/ml at week 48. When stratified by baseline CD4 cell count, subjects’ HCV-RNA levels increased 0.43 and 0.59 log10IU/ml at weeks 16 and 48 for entry CD4 cell counts < 350 cells/mm3, but only 0.26 and 0.1 log10IU/ml at weeks 16 and 48 for entry CD4 cell counts > 350 cells/mm3. Severe alanine aminotransferase elevations occurred in only 3.3%. Retrospective analysis: HCV co-infection had no effect on the overall mean CD4 cell increase at weeks 16 or 48 compared with uninfected controls.Conclusion:In HCV-co-infected patients undergoing HAART, immune recovery is associated with a persistent increase in HCV RNA, especially with baseline CD4 cell counts < 350 cells/mm3. HCV co-infection did not antagonize the CD4 cell response to HAART.