Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir.

The combination of didanosine (ddI) and tenofovir (TDF) has potential advantages, but because of several pitfalls (unexpected decreases in CD4+ T cells, increased risk of pancreatitis) its use has been questioned. Since anecdotal cases of transient insulin-dependent diabetes mellitus were seen in our clinic in patients on ddI + TDF-containing regimens, we explored the rate of this complication in more detail. Retrospective analysis of plasma glucose levels in patients who completed 12 months of treatment with three different triple antiretroviral regimens including ddI + TDF, TDF, or ddI was done. Patients taking antidiabetic drugs and/or those with baseline glucose levels >125 mg/dl were excluded. Weight, age, concomitant antiretrovirals, and ddI dose were assessed. At 12 months without treatment changes, fasting glucose levels were compared to baseline. A multivariate analysis was performed to evaluate which variables were associated with glucose elevations. A total of 177 HIV-infected patients were assessed (78 on ddI + TDF, 42 on TDF, and 57 on ddI). Mean baseline features were well balanced between groups for age (mean, 39 years), gender (78% male), CD4+ count (mean, 507 cells/mm3), weight (mean, 67 kg), and glucose level (mean, 95 mg/dl). There were only significant differences between groups for baseline viral load and protease inhibitor (PI) use (13% in the ddI + TDF arm vs. 7% and 9% in the TDF and ddI arms, respectively). At 12 months, 60% of the patients in the ddI + TDF arm were taking ddI 250 mg/day and the rest were on ddI 400 mg/day. At 12 months, hyperglycemia was significantly more frequent in the ddI + TDF arm (33%) when compared to patients on TDF or ddI separately (5% and 10%, respectively). In the multiple linear regression analysis, a lower weight (beta -0.35; 95% CI -0.67 to -0.03; p = 0.033) and use of ddI + TDF (beta: 13.05; 95% CI: 0.2 to 26; p = 0.047) were independently associated with a higher risk of developing hyperglycemia. The risk of hyperglycemia is increased in patients treated with ddI + TDF, particularly in those with lower weight. As high ddI exposure has been associated with endocrine pancreatic dysfunction and diabetes, ddI "overdosing" as result of concomitant TDF use and low weight might explain our findings. These results add a further note of caution to the use of TDF and ddI in combination.

Compatibiliity and stability of furosemide and dexamethasone combined in infusion solutions.

AIM: The goal of palliative care is the achievement of the best quality of life for patients and their families. For this, the administration of drugs by subcutaneous infusion is frequently used since many patients have great difficulties in taking drugs orally and regular intramuscular injections are painful. Usually, drugs are combined in infusion solutions. The objective was therefore to study the compatibility and stability of dexamethasone sodium phosphate (CAS 2392-39-4) and sodium furosemide (CAS 54-31-9) combined in solutions destined to subcutaneous administration in palliative medicine. METHODS: Twelve different solutions were assessed during 15 days. Drug admixtures were prepared in polypropylene syringes using 0.9 % saline as diluent and stored at 4 degrees C and 25 degrees C in the dark. Initial concentrations were 3.33-10.0 mg/ ml for sodium furosemide (dose range 40-120 mg/day) and 0.33-3.33 mg/ml (dose range 4-40 mg/day) for dexamethasone sodium phosphate. Quantification of both drugs was performed by high-performance liquid chromatography. RESULTS: After 5 days of storage at both temperatures, the maximum losses obtained were lower than 10 % for both drugs. However, after 15 days, slight precipitation/turbidity was observed in all mixtures. At this time, maximum losses of 20 % were obtained for both drugs. CONCLUSION: These results confirm the stability of mixtures prepared with sodium furosemide (< or = 120 mg/day) and dexamethasone sodium phosphate (< or = 40 mg/day) for a period of 5 days and with independence of their storage at 4 degrees C or 25 degrees C.

Early monitoring of ribavirin plasma concentrations may predict anemia and early virologic response in HIV/hepatitis C virus-coinfected patients.

Ribavirin (RBV) in combination with pegylated interferon alpha (pegIFN) is currently the standard treatment of hepatitis C virus (HCV) infection. The development of anemia requires a reduction in RBV doses in a substantial proportion of patients, limiting their chances of treatment response. The primary goal of this study was to assess if early monitoring of RBV plasma levels could help to predict anemia as well as early HCV RNA response in HIV/HCV-coinfected individuals. The secondary goal was to evaluate if antiretroviral drugs might influence RBV plasma levels. Plasma RBV concentrations were measured at weeks 4 and 12 in 98 HIV/HCV-coinfected individuals who initiated therapy with pegIFN-2a (180 microg/wk) plus RBV (800-1200 mg/d). RBV plasma levels correlated with RBV dose per kilogram of body weight (P = 0.02). Larger drops in hemoglobin levels were independently associated with higher RBV plasma levels and zidovudine (ZDV) use (P < 0.001). Likewise, higher RBV levels (P = 0.007) and HCV genotype 3 (P < 0.001) were found to be independent predictors of virologic response at week 4. Similar findings were obtained at week 12. Patients receiving ZDV concomitantly showed significantly higher RBV plasma concentrations compared with those who did not (3.28 mug/mL vs. 2.51 mug/mL; P = 0.002). RBV levels were not significantly altered by the coadministration of other nucleoside/nucleotide analogues. In summary, RBV plasma levels correlate with the development of anemia and with the achievement of an early virologic response. Therefore, early therapeutic drug monitoring might help to tailor RBV dosages, improving the efficacy and safety of anti-HCV treatment.

Predictors of virological response to atazanavir in protease inhibitor-experienced patients.

BACKGROUND: Atazanavir (ATV) is the latest approved HIV protease inhibitor (PI). Even though it is very convenient (only two capsules once a day), concerns have risen about its potency. METHOD: The clinical performance of ATV 400 mg once a day was examined in all PI-experienced patients who were included in the ATV expanded access program conducted in a single institution. The predictive value of baseline drug resistance HIV genotypes, ATV plasma trough levels, and the genotypic inhibitory quotient (GIQ) on the virological response at week 24 was assessed. RESULTS: Data from 92 patients were analyzed. ATV was prescribed as part of a rescue intervention (45%), a simplification strategy (11%), or an attempt to ameliorate hyperlipidemias (23%) or other toxicities (16%). Tenofovir (TDF) was concomitantly used with ATV in 78% of patients. None received ritonavir boosting. In patients with detectable viremia at baseline (65%), the median HIV RNA drop was 0.7 logs. The median ATV Cmin was 0.12 microg/mL (IQR, 0.05-0.22 microg/mL), which is clearly above the IC90 (90% inhibitory concentration) for ATV in wild-type viruses. The virological response did not correlate significantly with ATV Cmin. The median number of protease resistance mutations was lower in patients showing virological response than in nonresponders (1 vs. 5; p=.07). A higher HIV RNA drop was associated with a higher GIQ (p=.02; beta=-5.4; 95% CI, -10 to -1). Only 4 patients (4%) discontinued treatment due to ATV-related toxicities (hyperbilirubinemia in 1). Bilirubin levels were associated with ATV plasma concentrations (p=.05; beta=3.2; 95% CI, -0.1 to 6.5). The rate of hypertriglyceridemia and hypercholesterolemia declined significantly with respect to baseline. CONCLUSION: ATV is relatively safe and provides significant virological response in PI-experienced patients, mainly among those with a low number of protease resistance mutations. The GIQ predicts accurately the virological response in patients receiving ATV. Hyperbilirubinemia is associated with higher ATV plasma levels.