Mid/late April is a great time to go to Cuba - liovely and hot without the humidity that you get in high summer. Mozzies can be a problem of an evening but a good insect repellent does the trick - malaria is not an issue.
As to location, this depends a lot on what you are looking for from your holiday and what you enjoy doing. The cayos are all very isolated from local Cuban life - if you are wanting to get out and about and experience the local life and culture, then the cayos aren't a good idea. The only Cubans you meet will be people working in the hotel. If this isn't important to you then they can be ideal and the hotels appear to all be of a good standard. Varadero is also predominantly a large commercial, tourist orientated resort but it does offer more opportunities to see something of local life but not that much more.
A few pointers on what makes a good holiday for you would help us all provide you with more detailed replies.
SM