Compared to Curse etc I am by no means an experienced player but I learnt some stuff. Firstly, I used HS121 in beginners world. Since it was beginners world it is no match to here but my calculations show it can still be very very profitable. On the other hand this is "conditional" profitability. What I mean is, except for some very absurd planes, under right circumstances any plane can be profitable. Even Concorde.
For high fuel consuming planes to be profitable, they have to carry a lot passengers quickly. HS121 is one of the fastest planes so that's a plus. The 3B variant (which I find much better than other variants) carry a lot as well, but to be profitable it should be in high density configuration. This brings 2 other questions: Is there competition? If there is competition, passengers will not like to sit in your high density seats so there should be no competition. Second question is, where is the demand? When you put HD configuration on a HS121 its range decreases to around 800 nm if I remember correctly.
So, if there is no competition and there is enough demand in 800 nm range you can put HD configuration on HS1213B and make profit. But there is the most important thing which is already mentioned. Fly to dense routes. This means, avoid once-a-day routes if you can. I had routes where 3-4 HD configuration HS1213Bs were running 4x a day. That way you will make money. If you have to fly thin routes, if there is competition or if range does not allow HD HS1213B, switch to a more efficient plane.
Just my 2 cents.