Unboosted atazanavir-based therapy maintains control of HIV type-1 replication as effectively as a ritonavir-boosted regimen.

BACKGROUND: Triple combination therapy based on a ritonavir (RTV)-boosted protease inhibitor plus two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) has improved outcomes in HIV type-1 (HIV-1)-infected patients. For patients unable to tolerate these regimens, alternative therapeutic approaches are needed. METHODS: We report a comparative, open-label study in treatment-naive patients who underwent initial induction treatment with a triple combination including RTV-boosted atazanavir (ATV; 300/100 mg once daily). Patients who achieved an HIV-1 viral load <50 copies/ml after the induction period were then randomized in the maintenance phase either to continue on current treatment or to switch to unboosted ATV 400 mg once daily (plus two NRTIs unchanged). RESULTS: A total of 252 patients entered the induction phase, of whom 172 were eligible for randomization in the maintenance phase (ATV/RTV n=85 and ATV n=87). The unboosted ATV regimen demonstrated non-inferior efficacy to the ATV/RTV regimen with 78% and 75% of patients, respectively, maintaining virological suppression (HIV-1 RNA <50 copies/ml) up to week 48 after randomization (difference estimate 2.9, 95% confidence interval -9.8-15.5). Time to virological failure and change from the end of the induction phase in mean CD4(+) T-cell counts were also similar between the treatment arms. Although both regimens were well-tolerated, unboosted ATV was associated with fewer adverse events, fewer total bilirubin abnormalities and an improved lipid profile compared with ATV/RTV. CONCLUSIONS: An HIV-1 combined treatment regimen based on unboosted ATV is a feasible treatment option for patients with established virological control who are unable to tolerate triple combination therapy including ATV/RTV.

Simultaneous analysis of several antiretroviral nucleosides in rat-plasma by high-performance liquid chromatography with UV using acetic acid/hydroxylamine buffer Test of this new volatile medium-pH for HPLC-ESI-MS/MS.

Zalcitabine (ddC), lamivudine (3TC), didanosine (ddI), stavudine (d4T), carbovir (CBV), zidovudine (AZT), tenofovir (PMPA) and its administrated form (tenofovir diisoproxyl fumarate, TDF), are nucleosides currently approved in HIV therapy. To facilitate pharmacokinetics studies, a specific reversed-phase high-performance liquid chromatography (HPLC) method was developed for their analysis in rat plasma. The method involved a quantitative recovery of these drugs from rat plasma by solid-phase extraction on Oasis HLB Waters cartridges followed by optimised HPLC separation on an Atlantis dC18 column with acetic acid-hydroxylamine buffer (ionic strength 5mM, pH 7)-acetonitrile elution gradient. Quantitation was performed by HPLC/UV at 260 nm. Linear calibration curves were obtained within a 30-10,000 ng/mL plasma concentration range. Correlation coefficients (r2) greater than 0.992 were obtained by least-squares regression and limits of quantification were in 30-90 ng/mL concentration range. Quantitative parameters (accuracy, intra-day repeatability and inter-day reproducibility) yielded satisfactory results. Finally, a new buffer, obtained with acetic acid and hydroxylamine, has been tested in HPLC/ESI-MS/MS and appears to be an efficient volatile buffer in the medium 5-7 pH range. Indeed, at pH 7 and low ionic strength (5 mM), its buffer capacity is one hundred times higher to that obtained for the usual acetic acid/ammonia buffer.

Didanosine in HIV-1-infected patients experiencing failure of antiretroviral therapy: a randomized placebo-controlled trial.

BACKGROUND: The antiviral efficacy of didanosine in patients experiencing virological failure is not well known. METHODS: A total of 168 patients (139 men and 29 women) receiving stable antiretroviral therapy with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 1000-100,000 copies/mL were randomly assigned to have didanosine (n=111) or placebo (n=57) added to their currently failing regimen for 4 weeks. The primary efficacy end point was the change in HIV-1 RNA level from baseline to week 4. RESULTS: At baseline, the median HIV-1 RNA level was 3.8 log(10) copies/mL, the median CD4 cell count was 378 cells/mm(3), and the median number of nucleoside reverse-transcriptase inhibitor-associated mutations (NAMs) was 4. At week 4, a significant decrease in the median HIV-1 RNA level was observed in the didanosine group, compared with that in the placebo group (-0.56 vs. +0.07 log(10) copies/mL, respectively) (P<.0001). A total of 33 patients (31%) in the didanosine group, compared with 3 (6%) in the placebo group, had HIV-1 RNA levels <400 copies/mL (P<.001). Significant antiviral activity of didanosine was observed in patients with up to 5 NAMs at baseline. Diarrhea occurred in 5 patients (5%) in the didanosine group and 2 patients (4%) in the placebo group. CONCLUSIONS: In HIV-1-infected patients experiencing failure of antiretroviral therapy, didanosine retains short-term antiviral activity.

Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients.

OBJECTIVE: To determine the concentrations of intracellular active anabolites of stavudine (d4T) and didanosine (DDI) and their interpatient variability in HIV-infected patients and to explore relationships between plasma and intracellular forms. METHODS: This pilot study included 28 antiretroviral-naive HIV-infected patients who received d4T (40/30 mg twice daily), ddI (400/250 mg daily) and efavirenz (600 mg daily). After 6 months of therapy, 7 ml of blood was collected between 0.5 and 16.2 h and 2.5 and 28.5 h after the last dose of d4T and ddI, respectively. Plasma samples were obtained for the determination of d4T and ddI concentrations. Peripheral blood mononuclear cells were prepared for measuring intracellular d4T and ddI triphosphates (d4T-TP and ddA-TP, respectively). RESULTS: d4T-TP and ddA-TP concentrations were above the limit of quantification in 25 of 26 compliant patients: median d4T-TP was 31 fmol/10(6) cells (range, 0-99) and median ddA-TP was 8 fmol/10(6) cells (range, 0-23). The half-life of d4T-TP was calculated as 7 h. Interpatient variability in d4T-TP and ddA-TP concentrations was 48% and 58%, respectively. A significant relationship was observed between plasma d4T and intracellular d4T-TP. No relation was found between ddI and ddA-TP. A linear relation was observed between the intracellular concentrations of d4T-TP and ddA-TP. CONCLUSION: This is the first time that data have been obtained on intracellular concentrations of d4T-TP and ddA-TP, their intracellular pharmacokinetics and interpatient variability. Other similar studies with more patients are needed to enhance knowledge of the intracellular pharmacology of the nucleoside reverse transcriptase inhibitors.

Infectious diseases as a trigger in thrombotic microangiopathies in intensive care unit (ICU) patients?

OBJECTIVE: Thrombotic microangiopathy (TMA) has been associated with a large number of underlying diseases. We conducted a descriptive, retrospective study including all TMA adult patients admitted to our ICU, with a particular interest in infectious episodes as a trigger of TMA. PATIENTS: All adult patients (30) with a diagnosis of TMA admitted to the medical ICU at Saint-Louis Hospital (Paris, France) between 1992 and 1998 were retrospectively included. METHODS: All patients with clinical and microbiological evidence of bacterial infection were treated with intravenous antibiotics. The specific treatment of TMA consisted in solvent/detergent-treated plasma administration by plasma exchange or high volume plasma infusion (30 ml/kg per day) in fractionated doses. RESULTS: Among the 30 adult patients studied, TMA in 16 (53%) was associated with microbiologically documented infection. An acute infection was found in 8/9 patients with an HIV-related TMA, in 2/6 patients with a systemic lupus erythematosus (SLE)-related TMA and in 3/6 patients with TMA associated with other disorders. In three patients, an acute infectious disease was the only cause associated with the TMA. Four other patients had clinical manifestations suggesting an infection process but without bacteriological documentation. Escherichia coli was isolated in 7/16 cases and verotoxin was found in the stools of two other patients. All patients were treated with plasma administration and those with evidence of infection were systematically and intensively treated with antibiotics. Eventually 8 patients died (27%), 20 (67%) reached complete remission and 2 partial remission. CONCLUSION: Bacterial infections are commonly observed amongst TMA patients hospitalized in ICUs and may act as a trigger of this disease. Screening for infection is a requirement in patients with TMA, either idiopathic or associated with other conditions.

Systemic candidiasis in intensive care units: a multicenter, matched-cohort study.

OBJECTIVE: To determine the impact of systemic candidiasis on the mortality and length of hospital stay of intensive care unit (ICU) patients and the associated workload. DESIGN: Multicenter, retrospective, matched-cohort study. SETTING: Data were retrieved from a computerized database that prospectively collected clinical data submitted by 32 ICUs in the Paris, France area. PATIENTS: A total of 149 stays with systemic candidiasis, including 104 candidemia, on ICU admission were identified in a 3-year period (1995-1997) among 49,063 admissions (3 per 1,000 admission). A total of 121 cases were matched with patients with no evidence of systemic Candida infection during the hospitalization period under study (same ICU, date of ICU admission, age, sex, simplified acute physiology score (SAPS II), location of the patient before admission, type of admission). RESULTS: Patients with systemic candidiasis had longer ICU length of stays than controls (25 vs 10 d; P =.001) with a relative risk for death of 2.27 (95% confidence interval, 1.64-3.11; P =.001). There was no difference between patients with systemic candidiasis with or without positive blood culture. CONCLUSIONS: Systemic Candida infections increased mortality and morbidity in severely ill patients. Optimizing management of such infections is imperative.