Since monotherapy is not recommended in treating HIV, HCQ has also been tested in synergy with other drugs commonly used to manage HIV. In this regard, 400 mg/day of HCQ in a combination regimen with 1000 mg/day hydroxyurea and 250–400 mg/day didanosine (dosed per body weight) was administered for 48 weeks to 22 asymptomatic HIV-1 infected patients naïve to antiretroviral treatment. Only 16 out of 22 patients were evaluable. These 16 subjects, at the 12th week, showed a significant reduction in viral load which was maintained until the 48th week. Furthermore, at week 12, an increase in CD4+ percentage was also shown, and this improvement was kept until the 48th week [19]. To evaluate the long-term efficacy and safety of HCQ, hydroxyurea, and didanosine combination, they were also tested on 17 HIV-infected naïve patients for 144 weeks. All subjects received 200 mg HCQ, 500 mg hydroxyurea, and 125–200 mg didanosine twice daily. Of the 17 patients who started treatment, 14 remained until the end of the 144th week. After 114 weeks, viral load was reduced by 1.6 Log10 copies/mL under baseline (p < 0.001), eight patients (47%) had an unnoticeable viral load (< 400 copies/mL), and two patients (12%) had a measurable viral load, but resistance mutations were not detected. Four patients (24%) had both detectable viral load and resistance mutation: one with both 62V and 65R and three with both 74V and 184V mutations; the latter three were assessed as didanosine resistant, while no resistance was found for HCQ. However, in all cases, the viral load remained below the baseline at the 144th week. The CD4+ cell count had increased significantly, while the percentage of CD8 cells was reduced up to the 144th week [20]. This HCQ noticeable impact on immune activation, thereby increasing CD4+ T cells, was also demonstrated in a prospective study conducted on 20 HIV-infected immunologic no responders treated with standard antiretroviral therapy [23]. These results suggested that the combination of HCQ, hydroxyurea, and didanosine could be a valid alternative to the highly active commercial HAART in HIV-patients. Nonetheless, these latter studies have some limitations, such as the small number of subjects included and the absence of a control group. Therefore, it is not possible to determine the contribution made by HCQ to the overall decrease in viral load obtained from the combination of drugs. Anyway, the potential anti-HIV efficacy of HCQ, when added to existing treatment with an antiretroviral regimen, was also confirmed by a case report about a patient with HLA-B27-associated spondyloarthropathy and HIV infection [43].