77% of Romanians infected with HIV receive antiretroviral therapy, with the challenge of maintaining long-term therapeutic success (the viral load becoming/remaining undetectable). The main purpose of this study was to provide comparative analysis of the long-term virological response to therapeutic regimens containing pharmacokinetically enhanced darunavir (DRV) with ritonavir (RTV) or cobicistat (COBI). The second aim was to evaluate the viral resistance profile to therapy, by number/type/frequency of viral mutations. This retrospective study was conducted on 462 patients infected with subtype F HIV-1, registered at the “Matei Bals” National Institute of Infectious Diseases, between 2018 and 2021: 384 patients received (among other ARV) DRV 600 mg, enhanced with RTV 100 mg (twice daily) and 78 patients received DRV 800 mg boosted with COBI 150 mg (once daily). The virological response was measured by determining the viral load (HIV-1 RNA copies/mL), while the incidence of viral resistance to therapy was assessed by genotyping tests. Comparing the patients with undetectable viremia, from the 1st visit to the 3rd one, the outcomes showed that at the last visit, 84.6% subjects in the DRV/c group achieved virological efficiency over those from DRV/r group (76.8%). The differences observed between this time points are statistically significant p < 0.05. DRV/c administered in combination with other ARV, in subtype F HIV-1 infected patients, proved to be more virologically effective, maintaining a favorable long-time result. When comparing the outcomes of the two groups, a statistically significant difference of p < 0.05 was obtained. 32 patients (27 from DRV/r group and 5 from DRV/c group) were evaluated with persistent HIV-1 ARN plasma load > 1000 copies/mL, during all 3 clinical visits. They formed a research sub-group evaluated in terms of resistance to therapy and were reported as virological failures. 28.12% of the sub-group with persistent HIV-1 RNA > 1000 copies/mL were from the DRV/r group and only 3.12% from the DRV/c group. Drug mutations (DRM) involved in antiretroviral resistance/sensitivity occurred both in the protease gene, and in the reverse transcriptase gene, with the involved ARV classes being protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors. 16 different types of mutations were evaluated in the PR gene and 20 mutations were evaluated in RT gene.