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Those calling for Covid restrictions to be eased are "factually wrong," Mark Drakeford has insisted.
The first minister warned "the storm of Omicron" had arrived in Wales as positivity rates hit "astronomically high" levels.
On Friday, he announced no changes would be made to restrictions, amid calls from some industry and scientific experts for rules to be eased.
"We must be prepared for cases to rise even higher," he said.
The comments come after a senior epidemiologist, who has advised the Welsh and UK governments, called for restrictions to be dropped to pre-Omicron levels.
Cardiff University's Prof John Watkins had said booster jabs meant the threat was no worse than that posed by Delta, and the while Omicron was more transmissible it was less severe and patients were less likely to die.
However, the first minister said the idea that Omicron is an illness we can afford to "take lightly" does not "bare any connection to the actual position we are facing".
Mr Drakeford told BBC Radio Wales those calling for restrictions to be eased were "very straightforwardly, and factually wrong".
In Wales nightclubs are closed, with limits on hospitality businesses, sporting events and who people can meet indoors and outdoors.
The decision to limit outdoor gatherings, including organised exercise groups, has previously been criticised by the UK health minister, and there have been concerns that hospitality rules could see people head across the border to England to socialise.
Public Health Wales has reported 7,915 new Covid cases and 21 further deaths.
The seven day rolling case rate per 100,000 has continued to climb to 2,324, compared to 2,228 reported on Thursday.
The testing positivity rate - the percentage of Covid test returning a positive result - has fallen very slightly to 51.2%.
There were 625 patients with confirmed Covid in hospital beds - an 82% increase on a week ago.
However, NHS bosses have said this includes "a lot" of "incidental" Covid patients, who are in hospital for non-Covid reasons but test positive for Covid.
But Mr Drakeford said this "doesn't make any difference to the hospitals" as they must still "treat every one of those patients as a coronavirus patient".
The first minister said the Omicron wave meant "we have a tough few weeks ahead and we are not in a position to withdraw any of the protections".
"We have a higher number of people falling ill with coronavirus in Wales than at any other time in the whole of the pandemic, astronomically high positivity rates, hospitalisations going up every day," he said.
"This variant may not be as severe as we had initially feared but the speed at which it is travelling and its infectiousness continue to be cause for concern," he added.
He urged people to limit the number of people they meet, take lateral flow tests before going out, and make getting a booster vaccine a priority.
On those eligible for a vaccine that have chosen not to receive one, Mr Drakeford said they are "expecting someone else to put themselves in harms way to look after them, and it simply isn't fair."
Dr Rowena Christmas, head of the Royal College of GPs in Wales, told BBC Radio Wales that while the rules were difficult hospitals were at "bursting point".
"The numbers are absolutely huge, so I think we have to continue as we are at least for the time being," she said.
UK Hospitality Cymru warned this week that without extra money and lighter restrictions businesses would be left in "peril", with ministers responding that a emergency financial support package will be available from 10 January.
A government spokesman said they would continue to consider whether additional emergency business support funding was needed.
'Critical breaking point'
Gary Lulham, boss of Sin City nightclub in Swansea, said while he did not expect any changes the news was "devastating" for an industry that was already at a "critical breaking point".
He added that without significant financial support there would be "hundreds of thousands" of people at the end of the month who "won't be able to pay their rent, or be able to put food on the table for themselves or their kids".
The Welsh Conservatives urged ministers to provide urgent support for businesses, and said restrictions on outdoor sporting events should be relaxed.
Andrew RT Davies, Welsh Tory leader in the Senedd, called for "greater flexibility" on restrictions for hospitality settings.
"I think all people have done is move that socialising indoors into house party environments which are unregulated environments," he said.
"I do think there is scope to lift some of the restrictions in that particular area."
He also called for Welsh ministers to scrap "ridiculous" fines for workers who go into the workplace when they could work at home.
Mr Drakeford had previously defended the fines saying they were in place the last time there was a work from home obligation, that "no fines were issued at all" during that period and "they are designed to protect workers, not to penalise them".