Nirupma Trehanpati, Arshi Khanam, Syed Hissar, Rashi Sehgal, Ritu Khosla, Paul David, Ashish kumar, Anupama Prashar, Ankit Bhardwaj, Shyam Kottilil and Shiv Kumar Sarin
Viral load reduction followed by immunomodulation is an emerging approach to improve the treatment outcomes in patients with Chronic Hepatitis B (CHB). Persistent functional defects in Dendritic Cells (DC) have been observed in CHB patients, even with effective antiviral therapy. We investigated the effects of Tenofovir plus Peg-IFN Sequential Therapy (SQT) on functional restoration of innate and adaptive immunity in CHB patients. HBeAg+ve CHB patients were randomized to receive 48weeks of either tenofovir monotherapy (TM; Gr.1, n=30) or tenofovir with addition of PEG interferon from week 12 to 36 followed by tenofovir sequential therapy (SQT; Gr. 2, n=28) for 48 weeks. Biochemical parameters improved significantly with treatment at week 24 in both groups, but HBeAg seroconversion at week 48 occurred more frequently after SQT (21%) than TM (13%). At week 24, the expression and function of TLR7 and TLR9 in DCs were significantly increased in SQT compared to TM (p<0.05). Phagocytic activity of DCs, production of IFN-α and TNF-α by mDCs and pDCs and the expression of specific miRNAs for DC proliferation and maturation like miR155 and miR221, were higher in the SQT (p<0.05). After 24 weeks, SQT restored significantly more circulating CD8Tcells (p=0.02), CD8+CD127+ Tcells (p=0.03) and reduced the PD-1 expression on CD8 T-cells (p=0.04) vs. TM. Our results show that in a short period of 24 weeks, SQT significantly improves functionality of DCs. Upregulation of TLR7 and TLR9 and miR155 in DCs by PEG-IFN-α is a novel mechanism that may be quite significant in mounting an effective antiviral response. Influence of longer duration of SQT and immunomodulation needs to be studied.