The first randomized, double-blind, placebo-controlled clinical trial about the anti-HIV-1 activity of HCQ was published in 1995. In this study, 40 asymptomatic HIV-infected patients received either 800 mg/day HCQ or placebo for eight weeks. All patients treated with antiretroviral therapy (HAART = zidovudine (ZDV), 2′,3′-dideoxyinosine, or 2′,3′-dideoxycytidine) and stopped taking it four weeks before the clinical trial start. Unlike placebo, at the eighth week, HCQ displayed a reduction in HIV-1 RNA total plasma levels in 12 out of 19 patients. Furthermore, the percentage of CD4+ T cells decreased significantly in the placebo group and remained stable during the treatment with HCQ, indicating a probable stabilization of immune function in the HCQ group. HCQ administration also induced a decrease in serum interleukin 6 (IL-6) and immunoglobulin G (IgG). However, no significant changes were found in the IgA and IgM levels [17]. The anti-HIV-1 effect of HCQ was also compared with that of ZDV, a nucleoside reverse transcriptase inhibitor, in a randomized, placebo-controlled clinical trial conducted on 72 HIV-l-infected asymptomatic patients. All subjects were treated for 16 weeks with 800 mg/day HCQ (n = 35) or 500 mg/day ZDV (n = 37). As in the previous study, patients who had received HAART stopped taking it four weeks before the clinical trial’s outset. After 16 weeks, total plasma HIV-1 RNA levels were reduced in both the ZDV group and HCQ group, although the extent of anti-HIV-l activity in HCQ patients was lower than that observed in ZDV subjects. However, eight subjects in the Azithromycin (AZM) group showed an increase in HIV-1 RNA levels in the 16th week, indicating the rapid emergence of viral resistance. Contrarily, in the HCQ group, increased antiviral activity was revealed after 16 weeks rather than after 8 weeks, and no subject showed an increase in HIV-1 RNA levels at either 8 or 16 weeks of treatment. This evidence suggests that no resistance developed under HCQ therapy or that it might develop more slowly than under ZDV. A reduction in serum p24 antigen levels in both ZDV and HCQ groups was also described, while only in the HCQ group could a decrease in IL-6 and IgG levels be observed [18]. This reduction of IgG levels displayed after HCQ treatment in both studies may be significant since autoantibodies contribute to CD4+ cell depletion and autoimmune diseases observed in HIV infection.