The risks and benefits of structured treatment interruption (STI) in HIV-1-infected subjects are not fully understood. A pilot study was performed to compare STI with continuous highly active antiretroviral therapy (HAART) in chronic HIV-1-infected subjects with HIV-1 plasma RNA levels (VL) <400 copies per ml and CD4 ؉ T cells >400 per l. CD4 ؉ T cells, VL, HIV-1-specific neutralizing antibodies, and IFN-␥-producing HIV-1-specific CD8 ؉ and CD4 ؉ T cells were measured in all subjects. STIs of 1-month duration separated by 1 month of HAART, before a final 3-month STI, resulted in augmented CD8 ؉ T cell responses in all eight STI subjects (P ؍ 0.003), maintained while on HAART up to 22 weeks after STI, and augmented neutralization titers to autologous HIV-1 isolate in one of eight subjects. However, significant decline of CD4 ؉ T cell count from pre-STI level, and VL rebound to pre-HAART baseline, occurred during STI (P ؍ 0.001 and 0.34, respectively). CD4 ؉ T cell counts were regained on return to HAART. Control subjects (n ؍ 4) maintained VL <400 copies per ml and stable CD4 ؉ T cell counts, and showed no enhancement of antiviral CD8 ؉ T cell responses. Despite increases in antiviral immunity, no control of VL was observed. Future studies of STI should proceed with caution.
The models suggest that structured therapy interruption only leads to transient or sustained virus control if the immune effector cells increase during therapy. This increase must more than counterbalance the increase in susceptible target cells induced by therapy. The risk of inducing drug resistance by therapy interruptions or the risk of repopulating the pool of latent cells during drug-free periods may be small if the virus population remains at levels considerably below baseline. However, if the virus load increases during drug-free periods to levels similar to or higher than baseline before therapy, both these risks increase dramatically.
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