Results of a Phase 2 Clinical Trial at 48 Weeks (AI424-007): A Dose-Ranging, Safety, and Efficacy Comparative Trial of Atazanavir at Three Doses in Combination with Didanosine and Stavudine in Antiretroviral-Naive Subjects

Abstract

Three dose levels of the protease inhibitor (PI) atazanavir (200, 400, and 500 mg once daily) were compared with nelfinavir (750 mg three times daily) when given both as monotherapy and in combination with didanosine and stavudine in 420 antiretroviral-naive subjects infected with HIV-1. Subjects received monotherapy for 2 weeks, followed by combination therapy for 46 weeks. After 48 weeks, mean change from baseline in HIV RNA (-2.57 to -2.33 log 10 copies/mL), the proportion of subjects with HIV RNA <400 copies/mL (56%-64%) and <50 copies/mL (28%-42%), and mean increases in CD4 cell count (185-221 cells/mm 3) were comparable across treatment groups. Diarrhea was two to three times more common in the nelfinavir group (61% of subjects) than in the atazanavir groups (23%-30% of subjects, <.0001 versus nelfinavir), and jaundice occurred only in atazanavir-treated subjects (6%, 6%, and 12% in the 200-, 400-, and 500-mg groups, respectively) ( <.03 for all atazanavir regimens vs. nelfinavir). Mean percent change from baseline in fasting low-density lipoprotein (LDL) cholesterol was significantly less in the atazanavir groups (-7% to 4%) than in the nelfinavir group (31%) ( <.0001). In conclusion, once-daily atazanavir is a potent, safe, and well tolerated PI that rapidly and durably suppresses HIV RNA and durably increases CD4 cell count in antiretroviral-naive subjects. Through 48 weeks, atazanavir was not associated with clinically relevant increases in total cholesterol, fasting LDL cholesterol, or fasting triglycerides. In comparison, nelfinavir was associated with prompt, marked, and sustained elevations in these parameters of a magnitude that suggests they are clinically relevant.

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

“…The support cited for the suggested cut-off level of 150 ng/ml in treatment-naïve patients was generated in an observational cohort of whom only 33% were protease inhibitor (PI)-naïve [2,26], and other researchers have not been able to validate it [24]. The premarketing dose-ranging monotherapy study of ATV was performed in antiretroviralnaïve subjects with unboosted doses of 200-500 mg q.d., and the results of this study do suggest an increasing potency with increasing exposure over that same dose range [27]. The main source of data on the exposure-response relation of ATV in treatment-naïve subjects, however, is probably the BMS−089 study, where unboosted ATV 400 mg q.d.…”

New Antiretroviral Therapies for Pediatric HIV Infection

“…Two studies have evaluated the efficacy of ATV compared with NFV in antiretroviral-naïve patients. 41,42 Both studies showed similar viral response rates between ATV 400 mg once daily versus NFV (administered either 2 or 3 times a day) as part of combination therapy. One study in treatment-experienced adults showed similar efficacy between once-daily ATV plus saquinavir (SQV) compared to twice-daily SQV plus low-dose RTV when administered as part of combination therapy.…”

“…39 In two studies comparing ATV to NFV, the incidence of common adverse effects and the number of patients who discontinued treatment early was similar in both groups, with two exceptions. 41,42 Diarrhea was significantly more common with NVF therapy and jaundice was reported only with ATV therapy. Reports of adverse effects were similar when ATV plus SQV was compared to SQV plus low-dose RTV.…”

“…Reports of hyperbilirubinemia in clinical trials comparing ATV to NFV occurred in the ATV group only. 41,42 Atazanavir inhibits uridine diphosphate glucuronosyl 1A1 (UTG1A1), the enzyme which is responsible for conjugating bilirubin. The inhibition of UTG1A1 is most likely the mechanism by which ATV causes indirect hyperbilirubinemia.…”

Use of metabolic drugs and fish oil in HIV‐positive patients with metabolic complications and associations with dyslipidaemia and treatment targets

“…Substitution of the PI component of the HAART regimen with an NNRTI, such as nevirapine or efavirenz, has also been explored [53][54][55]. Within the PI class of drugs, ritonavir-boosted atazanavir is a new option with a relatively benign lipid profile [56,57], which may change future treatment strategies in a positive way. However, before HAART modification can take place as an option to lower blood lipids, it has to be determined whether or not the patient has had HIV-1 drug resistance, currently or at any time in the past.…”