What if Spike and Drusilla went to Brazil and stayed together, Spike not coming to Sunnydale for Lovers Walk?
I think it would be doubtful that Spike would ever return at all then, given his return in S4 was only due to his breakup with Dru. And no Spuffy, so a definite upside.
It would have been fun to see Spike and Dru return as a couple as the true Big Bads of, say, S6.
Spike and Dru could find happy meals with legs anywhere in the populated world. They may find that it is more fulfilling to set up a dynasty of death in some unsuspecting little town where they have free rein to do whatever they like. Or they might travel the world - I could see an episode where they go to Argentina and Spike is immediately arrested as British spy from the Falkland Islands and Dru has to intervene by killing all the guards. (The British cast of Fifth Gear had a lot of trouble at the border of Chile and Argentina when doing a series on travel around South America.)
The remaining seasons of Buffy certainly did not need Spike's presence in the form that it was written.