Virology analyses of HCV genotype 4 isolates from patients treated with simeprevir and peginterferon/ribavirin in the Phase III RESTORE study.

Simeprevir is a hepatitis C virus NS3/4A protease inhibitor. Hepatitis C virus baseline NS3/4A polymorphisms and emerging mutations were characterized in treatment-naїve and treatment-experienced genotype 4-infected patients treated with simeprevir+peginterferon/ribavirin in the RESTORE study. Population sequencing of the NS3/4A region was performed and in vitro simeprevir activity against site-directed mutants or chimeric replicons with patient-derived NS3 protease sequences was assessed in a transient replicon assay. Simeprevir remained active against most (83/91 [91%]) baseline isolates tested in the chimeric replicon assay. Eight baseline isolates reduced simeprevir activity; these carried I132L or D168E substitutions reducing simeprevir median activity by 4.6- and 39-fold, respectively. Six of these eight isolates were from patients achieving sustained virologic response. Baseline NS3 Q80K polymorphism was not observed in the genotype 4-infected patients. Of the 107 simeprevir-treated patients, 37 did not achieve sustained virologic response for any reason. Of the 32 patients who failed treatment and had sequencing information, 28 (88%) had emerging mutations at NS3 positions 80, 122, 155, 156 and/or 168 at time of failure, similar to those in genotype 1. Emerging mutations were mainly D168V and D168E alone or combined with mutations at position 80. In general, isolates obtained at time of failure displayed high-level in vitro resistance to simeprevir (fold change ≥50) in a chimeric replicon assay with a median simeprevir fold change value of 440, consistent with observed mutations. In conclusion, emerging mutations in genotype 4 patients failing simeprevir+peginterferon/ribavirin treatment were similar to those in genotype 1 and conferred high-level resistance to simeprevir.

Oral allergy syndrome due to nut oleosins

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Incidence of virological failure and emergence of resistance with twice-daily vs every 8-h administration of telaprevir in the OPTIMIZE study.

The OPTIMIZE study demonstrated noninferior efficacy between telaprevir (TVR) twice daily (bid) vs every 8-h (q8h) administration. This analysis compared the selective pressure of both dosing regimens by characterisation of the hepatitis C virus (HCV) variants emerging in genotype 1 (G1) HCV-infected patients who did not achieve sustained virological response (SVR). HCV NS3•4A population sequencing was performed at baseline and time of failure (viral breakthrough, stopping rule or relapse). TVR-resistant variants were classified by fold change in inhibitory concentration (IC50 ). Baseline TVR-resistance was low (<5%) and did not preclude achieving SVR in either arm. The proportion of patients with TVR-resistant variants at time of failure was similar in the bid (15%) and q8h (17%) dosing arms. The majority of variants and virological failures occurred in G1a patients, and mutations V36M, R155K and R155T (G1a), and V36A, T54A and A156S (G1b) were significantly enriched in both treatment arms. The number and type of emerging TVR-resistant variants in non-SVR patients were comparable between treatment arms and were consistent with previous observations. No differences in viral resistance profiles were observed between TVR-based treatment arms in non-SVR patients, indicating a similar selective pressure of TVR bid and q8h dosing.

Pooled week 96 results of the phase III DUET-1 and DUET-2 trials of etravirine: further analysis of adverse events and laboratory abnormalities of special interest.

OBJECTIVES: The aim of the study was to investigate the frequency and severity of adverse events (AEs) and laboratory abnormalities of interest over 96 weeks of treatment with etravirine or placebo in the pooled TMC125 DUET (Demonstrate Undetectable viral load in patients Experienced with ARV Therapy) trials. METHODS: Treatment-experienced, HIV-1-infected patients randomly received etravirine 200 mg twice a day (bid) or placebo, plus a background regimen. The frequency and severity of neuropsychiatric, rash, hepatic and lipid AEs were analysed; frequencies were also adjusted for total patient-years of exposure (PYE). RESULTS: A total of 599 and 604 patients received etravirine and placebo, respectively (median treatment duration 96.0 and 69.6 weeks, respectively). There was no significant difference between the treatment groups in the frequency of neuropsychiatric AEs. However, a significant difference in the frequency of rash was observed (20.5% vs. 11.8%, respectively; P < 0.0001); rash was generally mild to moderate in severity; the rate of discontinuation because of rash was low (2.2% vs. 0% in the etravirine and placebo groups, respectively). The frequency of hepatic AEs was low and similar between the treatment groups (8.7% vs. 7.1%, respectively; P = 0.3370); hepatic enzyme levels did not increase over time. Lipid-related laboratory abnormalities and changes over time in lipid levels were generally comparable between treatment groups. Adjusting for treatment exposure, the frequency of AEs remained similar between treatment groups, with the exception of rash [13.7 vs. 9.3 per 100 PYE; relative risk (95% confidence interval) 1.48 (1.02-1.95)]. CONCLUSIONS: The frequency of AEs of interest was generally similar between the treatment groups, both overall and when adjusted for treatment exposure, with the exception of rash which was more frequent in the etravirine group.

Virological response with fully active etravirine: pooled results from the DUET-1 and DUET-2 trials.

The objective of this subanalysis of the Phase III DUET trials was to examine virological response to an etravirine-containing regimen in patients harbouring virus fully sensitive to etravirine. Full etravirine sensitivity was defined as fold change in 50% effective concentration (FC) ≤3 or weighted genotypic score ≤2. At Week 48 in the etravirine group, 74% of patients with etravirine FC ≤3 and 77% with etravirine genotypic score ≤2 had viral load <50 HIV-1 RNA copies/mL, versus 48% and 46%, respectively, in the placebo group (P < 0.0001). Response rates increased with baseline phenotypic sensitivity score, but were consistently higher with etravirine (56-82%) than placebo (2-72%). Similar observations were made in patients harbouring virus with full etravirine and darunavir sensitivity. Our findings support current recommendations to include three active agents in treatment-experienced patients' regimens.

Increased CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells.

Why HIV-specific CD8(+) T cells ultimately fail to clear or control HIV infection is not known. We show here that HIV-specific CD8(+) T cells exhibit increased sensitivity to CD95/Fas-induced apoptosis. This apoptosis is 3-fold higher compared to CMV-specific CD8(+) T cells from the same patients. HIV-specific CD8(+) T cells express the CD45RA(-)CD62L(-) but lack the CD45RA(+)CD62L(-) T cell effector memory (T(EM)) phenotype. This skewing is not found in CMV- and EBV-specific CD8(+) T cells in HIV-infected individuals. CD95/Fas-induced apoptosis is much higher in the CD45RA(-)CD62L(-) T(EM) cells. However, cytotoxicity and IFNgamma production by HIV-specific CD8(+) T cells is not impaired. Our data suggest that the survival and differentiation of HIV-specific CD8(+) T cells may be compromised by CD95/Fas apoptosis induced by FasL-expressing HIV-infected cells.

Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy.

CONTEXT: Despite suppressive treatment with highly active antiretroviral therapy (HAART), replication-competent virus can still be isolated from peripheral blood mononuclear cells and genital cells of many individuals receiving suppressive HAART. OBJECTIVE: To determine whether free virion RNA can be detected in the blood plasma and/or genital tract fluids from patients receiving suppressive HAART. DESIGN: Prospective cohort study conducted from November 1998 to May 1999. SETTING: Academic medical center. PATIENTS: Human immunodeficiency virus 1-infected individuals (20 men and 2 women) shown in our laboratories to have fewer than 50 copies/mL of HIV-1 RNA in peripheral blood plasma while taking suppressive HAART. MAIN OUTCOME MEASURES: Free virion RNA levels in peripheral blood plasma and genital fluids, quantified using an ultrasensitive reverse transcriptase polymerase chain reaction able to quantify cell-free virion RNA to a lower limit of 5 copies/mL and qualitatively detect viral RNA below this level. RESULTS: In all 22 patients, residual viral RNA could be detected in the peripheral blood plasma (mean level, 17 copies/mL). The presence of viral RNA suggests that ongoing viral replication is occurring, albeit at low levels, in each patient evaluated. Viral RNA levels were lower in most patients' genital fluids compared with blood plasma and in 12 patients were undetectable. CONCLUSIONS: These data suggest that low-level replication of HIV-1 in patients taking suppressive HAART may be demonstrated not only in peripheral blood mononuclear cells but also in peripheral plasma as cell-free virion RNA. Complete ablation of viral replication may require intensification of antiretroviral therapies beyond standard suppressive HAART.

Partner risk: the hidden threat of capitated provider networks.

As provider networks align risk-sharing incentives, they must avoid partner risks that could pose a threat to the network. Partner risk results when actions taken by one or more partners in a network threaten to adversely affect other partners in the network. Such risk can arise from the way partners manage cost drivers under capitation or through passing risk to one another.

Medicaid managed care: problems and promise.

Medicaid spending is an increasing burden on already stressed state budgets. The states find themselves trapped between these growing costs and mounting pressure to ensure access of the underserved to health care services. States are hopeful that managed care is the answer to meeting the seemingly diametric needs of reducing costs while increasing access. However, evidence of performance measured in cost, access, and quality, and financial viability is inconclusive. Nevertheless, there have been some successes and, clearly, Medicaid managed care has potential. The unanswered question is the extent to which states can meet the diverse challenges of both Medicaid and managed care and tap that potential.

Acute and long-term treatment of hypertension with nifedipine in the elderly.

The acute hypotensive effect of nifedipine was evaluated, and the possibility of its long-term use in hypertensives over 60 years of age was studied. Sublingual nifedipine in a dose of 20 mg was given to 28 patients, mean age 73.1 yrs, and blood pressure, heart rate, and plasma drug concentration were monitored at 15 min, and every 30 min thereafter for 3 hrs. Systolic and diastolic blood pressure decreased at 15 min by 22.1 and 7.0 mmHg, respectively, reaching a maximal decrease two hours after drug administration. The decrease in blood pressure level did not correlate with nifedipine plasma concentration, but only with the initial systolic blood pressure. Long-term treatment with nifedipine was initiated in 60 patients, with 45 patients completing the study. Mean age was 66.2 years. An initial dose of 30 mg daily had to be increased to 60-80 mg in one-third of the patients. Monotherapy was not satisfactory in some patients. Blood pressure gradually decreased from 173/99 to 148/85 mmHg at three months, and to 141/84 mmHg at six months. Drug tolerance was fairly good. Nifedipine was withdrawn due to a considerable increase in heart rate in three patients and skin allergy in one. The most frequent adverse symptoms were: rash, headache, and leg oedema. Laboratory tests revealed no changes in urea and creatinine, and an increase in fasting glycaemia. Lipid parameters did not change significantly. These data proved that a single dose of 20 mg of nifedipine produced therapeutic plasma concentration of the drug and good hypotensive effect, positively correlating with initial systolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnostic problems in patients with superior vena cava syndrome]. / Problemy diagnostyczne u chorych z zespolem zyly glównej górnej.

Diagnostical difficulties were shown in 275 patients with the superior vena cava syndrome (SVCS) evaluated in the years 1970-1982. Men consisted 84 percent of the group. In 68 percent the symptoms preceded hospitalization by less than one month. 31 percent of the patients were treated without histopathological verification. In 83 percent the cause of the SVCS was lung cancer. Only in 10 patients (5.3%) non-malignant causes were present. Basing on analysis of their material the authors conclude that it it possible to make a diagnosis of SVCS etiology in the majority of the patients. This is mandatory because the etiology of this syndrome is variable, and the therapy may produce unwarranted and unjustified side effects in many cases.

[Nifedipine level in the blood and its immediate hypotensive effect after its sublingual administration to aged patients]. / Stezenie nifedypiny we krwi a jej dorazny efekt hipotensyjny po podjezykowym podaniu leku u osób w wieku podeszlym.

In 28 aged patients (means = 73.1 years) with arterial hypertension nifedipine has been administered sublingually in a single dose of 20 mg and the hypotensive effect of that drug under the control of its concentration in the blood serum was evaluated. The nifedipine concentration was determined by the use of gas chromatography with electron capture detector. The mean drug concentration increased from 38.1 ng/ml to 82.3 ng/l during the 2nd hour of observation. After 3 hours the lowering of the nifedipine concentration and the decrease of its hypotensive effect was observed. After 15 min from the drug application the systolic pressure lowered by the average 22.1 mmHg whereas the diastolic pressure was 7.0 mmHg lower. The most significant pressure decrease (mean of systolic pressure 52.7 mmHg) 7.03 kPa and that of diastolic pressure 23.2 mmHg (3.1 kPa) occurred after 2 and 1.5 hours. The decrease of pressures after nifedipine correlated with the start-point value of systolic pressure. The frequency of the heart action in the whole group did not altered significantly, however, in individual cases both the acceleration of that action (34 per min) or acceleration (42 systoles per min) was noted. Slight typical side-effects were noted in 5 treated patients. A single-dose sublingual 20 mg nifedipine (Cordafen--Polfa) administration enabled in all the subjects the obtaining of therapeutic drug level in the blood and in the aged patients with hypertension may be regarded as efficacious antihypertensive treatment.

Trends and patterns in lung cancer incidence in four cities of Eastern Europe, 1971-1980.

The trends of age-adjusted and age-specific lung cancer incidence rates showed over the period of 1971-1980 substantial differences in four selected towns of Eastern Europe. The downward age-adjusted trends in males coincided in Berlin with the possible beginning of their downturn in the whole country, while their decline in both sexes in Bratislava could be related to the change of demographis factors. In the other two towns studied--Cracow and Tallinn--the substantial increase of lung cancer incidence in males corresponded with the similar evolution in both respective countries (Poland and Estonia). The rising trends in females in both mentioned towns could be more or less compared with their dramatic increase in some developed countries. The rising trends of age-specific rates in younger age groups of males do not indicate meanwhile the positive influence of low-tar or filter-tipped cigarettes on lung cancer incidence in males observed recently in some countries.