MIKADO: a multicentre, open‐label pilot study to evaluate the antiretroviral activity and safety of saquinavir with stavudine and zalcitabine

Abstract

BackgroundSince eradication of HIV is unlikely, long-term management of the disease necessitates careful evaluation of the combinations of currently available drugs to determine the most potent and useful rational sequencing of regimens. ObjectiveTo determine the antiretroviral ef®cacy and tolerability of saquinavir soft gelatin capsule (SQV-SGC) plus zalcitabine (ddC) and stavudine (d4T), as ®rst-line treatment in HIV-infected patients. DesignMulticentre, open-label, non-comparative study. Patients and methodsThirty-®ve asymptomatic, HIV-infected adults with no prior antiretroviral treatment, a CD4 count b 250 cells/mL and baseline b 5000 HIV RNA copies/mL were included in the study. Patients received SQV-SGC 1200 mg three times a day (tid), ddC 0.75 mg tid and d4T 30 or 40 mg twice a day (bid) for 24 weeks. Plasma HIV RNA, CD4 and CD8 cell counts, HIV reverse transcriptase and protease resistance genotypes, SQV plasma concentration and tolerability were evaluated. ResultsAt baseline, median HIV RNA (interquartile range) was 4.99 (4.81±5.48) log 10 copies/mL, and median CD4 count was 370 (318±504) cells/mL (n = 35). At week 24, the median decrease in HIV RNA was 3.05 (2.19±3.68) log 10 copies/mL. A viral load below the level of quanti®cation (200 copies/mL and 20 copies/mL) was achieved in 63% and 34% of patients, respectively (intent-to-treat analysis). The only mutations detected were L90M substitutions in two patients. At week 24, the median CD4 count increased (P < 0.0001), and CD8 cell counts decreased (P < 0.0001), relative to baseline. In total, there were ®ve cases of peripheral neuropathy (14%). Mean triglyceride and cholesterol levels remained within normal ranges. ConclusionsTriple therapy with SQV-SGC plus ddC and d4T is a reasonably well tolerated regimen that markedly and rapidly reduces viral load with immunological improvement. This combination is an effective (d4T) have not been combined in therapy regimens. One explanation for this is the suggestion that they may cause neurological toxicity [2,9]. This pilot study was designed therefore to determine the ef®cacy and tolerability of SQV-SGC, plus an NRTI backbone of ddC and d4T, in antiretroviral-naive individuals. Patients and methods Study designThis multicentre, phase III, open-label, non-comparative study was conducted in nine centres in France for 24 weeks, with visits scheduled every 4 weeks. Local ethical committees approved the protocol and patients were required to provide written informed consent before enrolling. Inclusion criteriaAsymptomatic, adult HIV-infected patients with no previous antiretroviral treatment, a CD4 count b 250 cells/mL and a plasma viral load of b 5000 HIV RNA copies/mL at baseline were included in the study. The baseline characteristics of the study patients are presented in Table 1. Treatment regimensPatients received SQV-SGC (Fortovase q ; Roche Pharmaceuticals, Basel, Switzerland) 1200 mg three times a day (tid), ddC (Hivid q ; Roche Pharmaceuticals) 0.75 mg tid and d4T (Zerit q ; Bristol-Myers Squibb Europe...

Nucleoside Reverse Transcriptase Inhibitor Usage and the Incidence of Peripheral Neuropathy in HIV/AIDS Patients

“…ddI+d4T combination was associated with an almost two-fold increase in the relative risk of PN, as assessed by Poisson regression. These data are similar to other reports (Katlama et al, 2001;Reliquet et al, 2001). The usage of other NRTIs such as zidovudine, zalcitabine and lamivudine did not appear to increase the risk of developing PN.…”

“…Several studies have shown that PN is more frequent when didanosine and stavudine are used in combination (Katlama et al, 2001;Lea & Faulds, 1996). Thus, we designed a similar analysis to assess the relative risk of PN.…”

Stampidine as a Novel Nucleoside Reverse Transcriptase Inhibitor with Potent Anti-HIV Activity

“…Katlama et al evaluated the antiretroviral efficacy and tolerability of the PI, saquinavir soft gelatin capsule (SQV-SGC) + zalcitabine (DDC) and STV, as first-line treatment in HIV-infected patients (MIKADO trial) [44].…”

Tolerability and Safety of HIV Protease Inhibitors in Adults

“…18,[72][73][74][75][76] In a recent study of 212 patients receiving PI-based ART, RTVand LPV/RTV-containing regimens caused the highest incidence of hypercholesterolemia and hypertriglyceridemia after 12 months of therapy. 72 These data were confirmed in a study of 353 previously treated patients who received LPV/RTV treatment.…”