I tried a few HIPS type programs. I don't remember for sure if DefenseWall was one of them since it was awhile ago. I didn't notice one that didn't give off funky side effects after a few times opening closing my apps. Also as I mentioned any real knowledgeable hack is going to kill your booting mechanism and go beneath this type of defense. That's one reason I never use "Browser Helper Objects" since that's what hosed my system.
The short of it is, if you really need an image backup anyway, then why surf with a prophylactic all the time? They're way less than perfect and have to reduce machine performance by definition. Also I think they give a false sense of security. People tend to surf into hazardous waters just to see if the protection resists the intrusion.
If I found a seemless one I might try it, but all the ones I tried, even the paid version trial editions, I got weird action in my browser. I couldn't see running that all the time. But everyone has different comfort levels. I think what's really needed is a system image that's burned into firmware, not flashed. You have a configured system with your base apps burned into a chip. If things get hosed, you power down, power up, then hit the "Re-Image" button to lay that back on the HD. It would just save messing with external drives. But that would be more for like an office where there were hundreds of machines with a standard set of apps. Then people would just back up data.
edit: but since the author of Sandboxie is recommending av in combination with Sandboxie for 64 bit sytems there may be a good reason to do it. Esp. if you could configure it in such a way as to minimize the performance hit. But some authors like the author of BD Rebuilder won't even listen to your issues if you are running av. There's just no way to tell if the program has an issue or the av is interfering when you have 2 or more variables in the equation. I would never try to do video conversions or other intensive stuff with av on. Then again I don't have a CPU with more than 4 cores to try it. Maybe if you have enough horsepower you can eat the performance hit. These are just my prejudices gained from experience. Not some scientific study or anything.