Resistance to HIV integrase strand transfer inhibitors in Argentina: first interim survey.

OBJECTIVE: No data on resistance to HIV integrase strand transfer inhibitors (InSTIs) in Argentina are available as access to these drugs and to integrase genotypic resistance test is limited. We aimed to evaluate the clinical profile of patients who underwent an integrase genotypic resistance test, prevalence of InSTI resistance mutations and predicted efficacy of raltegravir, elvitegravir and dolutegravir in our country. METHODS: Retrospective multicentric pilot survey from January 2011 to November 2017 of InSTI-failing patients assisted at two private and one public healthcare institutions located in Buenos Aires city, Argentina. RESULTS: Sixty seven patients were included. Patients had a median of 5 (4-7) prior treatments. All patients had InSTI-containing regimens (median exposure of 22.5 months); 94% were under raltegravir therapy and 71.9% had InSTI-resistance mutations. Predominant major mutations were N155H (35.1%), Q148H/R (15.8%) and G140A/S (14%). Considering Stanford HIVdb program, extremely low and identical activity of raltegravir and elvitegravir was described while dolutegravir remained either partially or fully active in 97.7% of patients. CONCLUSIONS: Integrase resistance test was prescribed almost exclusively in heavily pretrated raltegravir-exposed patients. The three main mutational pathways were described, with a predominance of N155H. Despite almost null susceptibility and extensive cross resistance was shown among raltegravir and elvitegravir, dolutegravir remains active in the majority of patients.

Antifungal stewardship in a tertiary-care institution: a bedside intervention.

Antifungal stewardship (AFS) programmes are needed in tertiary-care hospitals. Our aim is to describe a bedside non-restrictive AFS programme, and to evaluate its economic impact. During the first year of the AFS a bundle of non-interventional measures were implemented. During the second year an infectious diseases specialist visited 453 patients receiving candins, liposomal amphotericin B, voriconazole or posaconazole. Monthly costs were studied with an interrupted time series (ITS) analysis. The main prescribing departments were haematology (35%), medical departments (23%), and intensive care units (20%). Reasons to start antifungal therapy were: targeted therapy (36%), prophylaxis (32%), empirical therapy (20%) and pre-emptive therapy (12%). At the initial visit, diagnostic advice was provided in 40% of cases. The most common therapeutic recommendations were to de-escalate the antifungal drug (17%) or to suspend it (7%). Annual total antifungal expenditure was reduced from US$3.8 million to US$2.9 million over the first 2 years, generating net savings of US$407,663 and US$824,458 per year after considering the cost of additional staff required. The ITS analyses showed a significant economic impact after the first 12 months of the intervention (p 0.042 at month 13), which was enhanced in the following 24 months (p 0.006 at month 35). The number of defined daily doses decreased from 66.4 to 54.8 per 1000 patient-days. Incidence of candidaemia was reduced from 1.49 to 1.14 (p 0.08) and related mortality was reduced from 28% to 16% (p 0.1). A collaborative and non-compulsory AFS program based on bedside intervention is an efficacious and cost-effective approach that optimizes the use of AF drugs.

Modeling of human corticosteroid binding globulin. Use of structure-activity relations in soft steroid binding to refine the structure.

PURPOSE: We propose a model for human corticosteroid binding globulin that is capable of explaining at the molecular level the experimentally observed binding affinities of four ligands. A new method of analyzing data from docking studies is proposed. METHODS: Displacement of radioactive ligand by competitive binding gives the experimentally determined binding affinities of the competitors. A theoretical model, based on homology with crystallographically determined structures, was studied in an automated docking procedure for the determination of theoretical affinities. The docking runs were analyzed by a hybrid principal component-clustering analysis. RESULTS: Of the two binding sites considered, only one--that in the vicinity of Cys 60--can reproduce the experimentally observed order of binding affinities although the lowest energies are found at the site in the vicinity of Cys 228. CONCLUSIONS: Models proposed for proteins should be always conditioned to take into account experimentally observed results. In the current work, we have shown that an informed analysis of theoretical docking studies can lead to a more logical model of the protein, one that can explain and give a deeper understanding of the stereochemical requirements of binding.

Combination therapy with hydroxyurea versus without hydroxyurea as first line treatment options for antiretroviral-naive patients.

PURPOSE: This study analyzed whether combination therapy with hydroxyurea (HU) could be considered as first line treatment for antiretroviral-naive patients. METHOD: The prospective open-label study was carried out from March 1996 to May 2000. The antiretroviral treatments were treatment 1-didanosine 400 mg/day, stavudine 60/80 mg/day, and HU 500 mg/day; treatment 2-two nucleosides plus a protease inhibitor; treatment 3-didanosine, indinavir, and HU (500-1,000 mg/day). The viral load (VL) and CD4 determinations were performed at weeks 24, 48, 72, and 96. RESULTS: The sample comprised 284 patients. The distribution of patients by levels of VL and CD4 were similar in the three treatment groups. At week 24, patients receiving T1 and T3 achieved higher percentages of undetectable VL (89% and 81%, respectively) with no significant differences (p =.127) between them. The T2 group showed a lower proportion (58%) of undetectable VL, which was significantly lower than T1 (p <.0001) and T3 (p <.0007). At week 48, the results were similar to week 24. At week 96, nearly all patients had undetectable viral load (UVL). The analysis of adverse effects showed that the T2 group at week 48 had a greater proportion of adverse effects that was significantly different from T1 (p =.0026); T3 had intermediate values with no significant difference from T2 (p =.45) and from T1 (p =.048). At week 48, T1 showed higher adherence level with significant difference from the other two treatments. CONCLUSION: Patients were followed for some 96 weeks and, with an intention-to-treat analysis, were found to do better virologically and Clinically in treatment groups containing HU. The combination of antiretroviral drugs with HU may be an excellent option as initial therapy because of its strong antiretroviral action, its lower rate of adverse effect, and the smaller cost as compared to other regimens.

Development of the definitive kidney in the cynomolgus monkey (Macaca fascicularis).

Formation of the definitive kidney in Macaca fascicularis embryos was investigated using light and electron microscopy. Appearance of the definitive kidney at stage 14 was indicated by the ureteric bud invading the metanephrogenic blastema. Glomerular capillaries originate from the connective tissue that surrounds the developing renal vesicle. At 46-100 days gestational age the more developed glomeruli show thinning of the capillary endothelium, thickening of the basal membrane, and presence of pedicels, suggesting a capability of renal function.

Efficacy and toxicity of pentostam against Panamanian mucosal leishmaniasis.

We tested the World Health Organization (WHO) recommended treatment for mucosal leishmaniasis in 16 Panamanians with disease due to Leishmania braziliensis panamensis. Disease was mild in this population because it was limited to the nasal mucosa and only one patient had septal perforation. The patients were administered 20 mg antimony (in the form of Pentostam) per kg intravenously each day for 28 days. Ten patients completed therapy and were cured at 12 month follow-up. Three patients completed therapy, healed their lesions, but relapsed at the six or 12 month follow-up. Three patients terminated therapy prematurely because of liver enzyme elevations in conjunction with either EKG abnormalities or musculoskeletal complaints; none of these patients were healed. This study indicates that in patients with mild mucosal leishmaniasis, the WHO regimen is curative in 77% patients who complete treatment and in 63% of all patients.