Immunological and Virological Effects of Structured Treatment Interruptions following Exposure to Hydroxyurea Plus Didanosine

Both hydroxyurea (HU) and structured treatment interruptions (STI) have been investigated as therapeutic approaches to enhance immune responses in chronically HIV-infected individuals. HIV-specific T cell responses as well as T cell activation were analyzed longitudinally in 31 HIV-infected individuals who had been treated for the prior 12 months with didanosine (ddI) plus HU and thereafter completed three STI cycles consisting of 2 months off and 2 months on ddI-HU. Similar increases in plasma HIV-RNA were seen in each of the three cycles off therapy, whereas CD4 counts remained fairly stable along the study period. T cell activation paralleled the evolution of plasma HIV-RNA during the first STI cycle and waned afterward. At baseline most patients presented a high level of CD8⁺ responses to different HIV peptide pools and 23% of them had CD4⁺ responses to Gag and/or Env. The level of CD8⁺ responses against each pool was stable and did not increase during STI cycles, while CD4 responses tended to decline. However, the contribution of Nef-specific response to the total CD8 response tended to increase. In a multivariate model, both a higher baseline plasma HIV-RNA and a higher level of Nef-specific response contribution to the total CD8⁺ response were independently associated with lower plasma HIV-RNA increases during each of the three STI cycles. Nef-specific CD8⁺ responses might contribute to a better virological control of HIV replication following treatment interruptions in HIV-infected individuals and might be boosted by the immunomodulatory effect of HU.