There are a couple decent options here. I like the no nag option, but if a nag is required:
There's no need for the driver to do a specific thing to keep autopilot engaged. Think of a screensaver. ANY input to the computer will turn off the screensaver. I think ANY input could keep autopilot engaged.
1. Any change to ANY setting on the car (volume, window opening, tap on the touchscreen, turn signal, TACC distance adjustment, pedal input, etc.) could reset a nag timer, because that means the driver is conscious. Suppose that nag timer is 3 minutes (a reasonable value IMHO). If you make an adjustment to SOMETHING within every 3 minutes, you'd see no nags at all. That will get you a long way, I think.
2. After three minutes of no control change of any kind, a little message appears on the dash and prompts you if you want to continue autopilot. Again, ANY input to the car resets the timer, since it indicates the driver (or someone else in the car) is conscious.
3. If the message is not responded to within 30 seconds, Music fades out (if playing), a gentle tone sounds, and the car again waits for any input. If there is no input after 15 seconds, a loud, annoying alarm tone plays for perhaps 5 seconds in an attempt to wake the driver. If there is still no input of any kind, one must assume an incapacitated driver, in which case the car should make an attempt to pull over safely. (I think it may be possible to do this with current hardware using hazard lights, the camera, sonar, and very slow lane changes). The car would then prompt Tesla to call you, and if there is no response, contact 911 and send an ambulance to your car.
This way, if a nag is required, it starts out in the least annoying manner and gets progressively more annoying as the concern that the driver is asleep or incapacitated grows.
This would be a good balance to minimize annoyance but still have some sort of confirmation for safety reasons.
You can't eliminate every danger or corner case, but I think these steps would be reasonable and fairly non-invasive.