Free energy perturbation (FEP) simulations have been widely applied to obtain predictions of the relative binding free energy for a series of congeneric ligands binding to the same receptor, which is an essential component for the lead optimization process in computer-aided drug discovery. In the case of several congeneric ligands forming a perturbation map involving a closed thermodynamic cycle, the summation of the estimated free energy change along each edge in the cycle using Bennett acceptance ratio (BAR) usually will deviate from zero due to systematic and random errors, which is the hysteresis of cycle closure. In this work, the advanced reweighting techniques binless weighted histogram analysis method (UWHAM) and locally weighted histogram analysis method (LWHAM) are applied to provide statistical estimators of the free energy change along each edge in order to eliminate the hysteresis effect. As an example, we analyze a closed thermodynamic cycle involving four congeneric ligands which bind to HIV-1 integrase, a promising target which has emerged for antiviral therapy. We demonstrate that, compared with FEP and BAR, more accurate and hysteresis-free estimates of free energy differences can be achieved by using UWHAM to find a single estimate of the density of states based on all of the data in the cycle. Furthermore, by comparison of LWHAM results obtained from the inclusion of different numbers of neighboring states with UWHAM estimation involving all the states, we show how to determine the optimal neighborhood size in the LWHAM analysis to balance the trade-offs between computational cost and accuracy of the free energy prediction. Even with the smallest neighborhood, LWHAM can improve the BAR free energy estimates using the same input data as BAR. We introduce an overlapping states matrix that is constructed by using the global jump formula of LWHAM and plot its heat map. The heat map provides a quantitative measure of the overlap between pairs of alchemical/thermodynamic states. We explain how to identify and improve the FEP calculations along the edges that most likely cause large systematic errors by using the heat map of the overlapping states matrix and by comparing the BAR and UWHAM estimates of the free energy change.