Dwarf mistletoe (Arceuthobium vaginatum subsp. cryptopodum (Engelm.) Hawksworth and Wiens) infestation results in severe loss of wood volume in the ponderosa pine forests (Pinus ponderosa Laws.) of ...Colorado. In this research equations were developed which describe the relationship between dwarf mistletoe incidence, severity and stand structure. The effect and inter-relationship between inter-tree competition and dwarf mistletoe was also described for irregular, multi-aged stands using growth and mortality of two-inch diameter classes as predetermined response variables. Stand structure had a significant effect (P $<$.05) on the relationship between dwarf mistletoe incidence and severity. The ratio of the percent trees infected to stand dwarf mistletoe rating (DMR) was significantly higher for even-aged stands than for multi-aged stands. A component of total stand basal area was used to describe inter-tree competition. BASL, which is the sum of the basal area of the trees in a given size class plus basal area of all trees of larger d.b.h., was a useful predictor of competition for small trees (d.b.h. $\leq$ 10 in.) but not for larger trees (d.b.h. $>$ 10 in.). For larger trees, stand basal area (BA) was a statistically significant (P $<$.05), but weak, predictor of competition. For small trees, BA was significant but not as good a predictor as BASL. Growth of trees of all sizes decreased steadily (beginning when trees were moderately infected) to 50% (at the heaviest infection levels) of the expected growth for uninfected trees. Percent of trees in a d.b.h. class heavily infected with dwarf mistletoe was positively correlated with 10 year mortality rates. For infected trees with d.b.h. $<$ 10 in., competition and d.b.h. were also useful predictors of mortality. A higher level of intertree competition (BASL) resulted in higher mortality rates while mortality declined exponentially with increasing tree d.b.h. The results show that stand density and structure interact together to impact growth and mortality.
AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus ...either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (
), and a proportional residual variability model was selected. The final mean parameter estimates were as follows:
= 2.87 h
, CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F (
< 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.
Efavirenz is currently suggested as an alternative to recommended antiretroviral (ARV) regimens by the Department of Health and Human Services for the treatment of HIV-1 in ARV-naive patients. A ...mid-dosing interval therapeutic range between 1000 and 4000 ng/mL for efavirenz has been proposed in the literature, with patients more likely to experience virologic failure below this range and adverse effects above. The current study reports an analysis of virologic outcome between those above, below, or within the reported efavirenz therapeutic range (1000-4000 ng/mL) and within subgroups.
This analysis examined efavirenz plasma concentrations obtained from participants enrolled in AIDS Clinical Trials Group Study A5202. This investigation divided subjects into those who experienced virologic failure and those who did not. These subjects were further separated to investigate those who had "high," "within," or "low" plasma concentrations, based on the therapeutic range. The association between virologic failure and plasma concentration was statistically examined in addition to the variables: race/ethnicity, sex, assigned nucleos(t)ide reverse transcriptase inhibitor backbone, age at study entry, history of intravenous drug use, weight, and screening HIV-1 RNA stratification level.
In univariate analyses, a statistically significant difference was found when comparing the efavirenz concentration groups, (22 failures among the "low" concentration group 19%, 65 failures among the "within" concentration group 12%, and 11 failures among the "high" concentration group 9%) when evaluating virologic failure as an outcome (P = 0.04). In addition, the proportion of participants with virologic failure differed across race/ethnicity groups (P = 0.03) with black non-Hispanic participants observed to have the highest rate (17%). Efavirenz concentration group, race/ethnicity, age, weight, and the interaction between efavirenz concentration group and weight were found to be significantly associated with virologic failure in multivariable logistic regression analysis.
The proposed efavirenz therapeutic range, combined with the impact of a patient's weight, is associated with virologic failure in HIV-infected ARV-naive individuals in the United States. Additional analysis is recommended to determine the most appropriate concentration value that defines the lower limit of the efavirenz therapeutic range.
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