Strategies to decrease viral load rebound, and prevent loss of CD4 and onset of resistance during structured treatment interruptions

Background: Toxicity and other drug adherence-related factors have contributed to decreased compliance to antiretroviral regimens amongst HIV-infected patients. Irregular therapy disruption causes loss of CD4 T cells, onset of drug resistance and rapid rebound of plasma viral load (VL). However, an appropriate choice of drugs and properly scheduled structured treatment interruptions (STIs) may limit VL rebound, maintain CD4 counts and minimize resistance. Methods: We conducted a clinical study of STIs, RIGHT 901, involving 60 drug-naive patients with chronic HIV infection (CD4 > 300, VL > 10000) randomized to receive didanosine-stavudine-indinavir (IDV group) or didanosine-stavudine-hydroxyurea (HU group), for 12 weeks. Subsequently, all patients were randomized again to start STI (short induction) or to continue the therapy for an additional 24 weeks before starting STI (long induction). Both groups underwent four STI cycles and then stopped therapy as long as viraemia remained below 10000 copies/ml before reinitiating another four cycles of STI. Results: During continuous therapy VLs were suppressed at similar rates in both the HU and IDV groups, while a blunted CD4 count was documented in the HU group. Following the first stop median VL rebounded close to baseline values in both groups, however, during the following STI median VL rebound decreased in the HU group, while in the IDV group VL continued to rebound to values close to baseline, and the difference between the two groups was statistically significant. Moreover, patients treated with HU had a constant and stable CD4 increase during STI, whereas CD4 counts fluctuated in the IDV group, with sharp falls during treatment interruptions and partial CD4 recovery following treatment restart. Even in the presence of IDV resistance predisposing mutations at baseline, no genotypic change in the protease sequence was observed during STI. A relevant mutation in the reverse transcriptase sequence (K70R) emerged in one patient interrupting treatment after 36 weeks of continuous therapy and in one patient after four STI cycles. Side effects (no major events) were similar among groups. Conclusions: An appropriate choice of STI schedule and regimens containing drugs less prone to resistance and/or able to prevent CD4 fluctuation may contribute to optimizing STI for chronically infected patients with respect to limiting viral rebound, improving CD4 counts and maintaining a resistance profile comparable to continuous highly active antiretroviral therapy.