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In this study, we investigated the inhibition of SARS-CoV-2 spike glycoprotein with HIV drugs and their combinations. This glycoprotein is essential for the reproduction of the SARS-COV-2 virus, so its inhibition opens new avenues for the treatment of patients with COVID-19 disease. In doing so, we used the VINI in silico model of cancer, whose high accuracy in finding effective drugs and their combinations was confirmed in vitro by comparison with existing results from NCI-60 bases, and in vivo by comparison with existing clinical trial results. In the first step, the VINI model calculated the inhibition efficiency of SARS-CoV-2 spike glycoprotein with 44 FDA-approved antiviral drugs. Of these drugs, HIV drugs have been shown to be effective, while others mainly have shown weak or no efficiency. Subsequently, the VINI model calculated the inhibition efficiency of all possible double and triple HIV drug combinations, and among them identified ten with the highest inhibition efficiency. These ten combinations were analyzed by Medscape drug-drug interaction software and LexiComp Drug Interactions. All combinations except the combination of cobicistat_abacavir_rilpivirine appear to have serious interactions (risk rating category D) when dosage adjustments/reductions are required for possible toxicity. Finally, the VINI model compared the inhibition efficiency of cobicistat_abacivir_rilpivirine combination with cocktails and individual drugs already used or planned to be tested against SARS-CoV-2. Combination cobicistat_abacivir_rilpivirine demonstrated the highest inhibition of SARS-CoV-2 spike glycoprotein over others. Thus, this combination seems to be a promising candidate for the further in vitro testing and clinical trials.