Running a large lateral imbalance will also cost you fuel/performance. Holding in the aileron and rudder to offset the roll moment, whether by hand or trim, will incur a larger drag penalty than when neutral. Effectively the same as driving with the hand brake on. It probably also increases wear on the componants put into a constant load when designed to be neutral most of the time. I can imagine something like a Lance with the outer tanks would need a lot of roll trim if you ran one tank dry over the other almost full.