We have been traveling for about a year and a half without any problems with the tonneau cover open while the using the 5th wheel. This included trips from Michigan to Arizona, Tennessee, Indiana, and around Michigan.
You will have to check that the cover doesn't inch forward towards your rear TV window due to the backdraft (you will be using only two clips versus the normal four clips). I added a strip of foam at the front of my truck bed to give me more surface contact with the top (I have plastic side rail protectors).
Just be sure to check your hitch with the cover open.
I must admit that I don't have any experience with driving over rough terrain. There might be a problem with deep pot holes that cause extreme movement of the truck. You may not want to do this if you drive off road a lot.