Background: HIV-associated immune injury is hypothesized to increase the risk of preclinical disability and frailty via inflammatory pathways. We investigated the role of CD4 þ T cell depletion and clinical AIDS on preclinical disability and frailty in HIV-positive women with a history of combination antiretroviral therapy (cART) and HIV-negative women. Methods: This was a cross-sectional study nested within the Women's Interagency HIV Study (WIHS), a prospective cohort study initiated in 1994 across five U.S. cities. Questionnaires and tests were performed by 573 HIV-negative and 1206 HIV-positive women. Prevalence ratios were computed using regression models. Results: Severe CD4 þ cell depletion was an independent predictor of slowness, weakness, and frailty in HIVpositive women compared with HIV-negative women. Women with CD4 þ counts <100 cells=mm 3 were 0.13 seconds slower to complete 4 meters (95% CI 0.06-0.21), 1.25 kg weaker (95% CI À2.31-À0.19), and had 2.7 times higher prevalence of frailty (95% CI 1.46-5.01).Conclusions: This study is one of the largest studies to administer performance-based tests to investigate disability and frailty in HIV-positive women. HIV-positive women with intact immune systems and without a history of clinical AIDS were no different from HIV-negative women on tests of slowness, weakness, and frailty phenotype.
Without regard to cycle phase, MIS was similar during early follicular phase and highly correlated with early follicular FSH and inhibin B in women with and without HIV. Measurement of serum MIS offers a simplified method of determining ovarian reserve using specimens obtained without menstrual phase timing. Furthermore, using biologic measures of reproductive aging, we found no evidence that HIV infection influences ovarian aging.
Regardless of continuing or discontinuing stavudine, HIV-infected women demonstrate decreases in weight and body circumference measurements over time. The lower limb seems to be most affected by stavudine exposure, with stabilization observed more than 2 years after discontinuation.
Introduction: Large randomized trials in pediatric ALL show that multiple doses of E.Coli asparaginase (ASP) given throughout post remission phase are associated with improved outcome. ASP is routinely incorporated into most front line adult ALL protocols. PEG-asparaginase (PEG-ASP) is E.coli ASP, which is linked to polyethylene glycol reducing the risk of hypersensitivity reactions and prolonging the half life compared to the native forms. In children multiple doses of PEG-ASP produce less neutralizing antibodies than equivalent doses of native E. coli ASP with similar toxicity (Avramis Blood 99:1986Avramis Blood 99:2002). Information on PEG-ASP in adults is very limited. In a previous study we showed that in adult ALL, a single IV dose of PEG-ASP given at induction produces a long duration of serum ASP enzymatic activity and concomitant asparagine depletion with similar toxicity to equivalent multiple doses of E.coli ASP. We currently report in adults the pharmacokinetics (PK), antibody production and toxicity of multiple doses of PEG-ASP given throughout the treatment of patients with newly diagnosed previously untreated ALL. Methods: We used a modified augmented BFM ALL protocol consisting of 8 cycles of multi-agent chemotherapy followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Serum samples were taken weekly for three weeks for ASP enzymatic activity after PEG-ASP dosing in induction phase 1 (dose 1) and in delayed re-inductions I and II (doses 4 and 6, respectively). Results: 18 patients aged 19–57 (median 28) years with newly diagnosed ALL (precursor B cell - 14, T -4) were studied. All 18 patients (100%) achieved a CR after induction phase I. Six patients discontinued the protocol because of undergoing allogeneic stem-cell transplantation. The number of doses of PEG-ASP was: all 6 doses- 4 pts, 4-3 pts., 2–5 pts., 1– 6 pts. Total number of doses was 52. T ½ was 7±4.7 days (n=18) after the fist dose increasing to 11.9±5.9 days (n=11) after dose 4 and 6. In the first cycle the AUC and MRT were lower while the Vd, Vdss and total clearance (Clt) were higher compared to the subsequent cycles. The change in PK parameters over time is most likely due to Michaelis-Menten (M-M) rate-limiting step on the elimination of the drug. Peak serum levels did not change significantly between the cycles. Anti-ASP antibodies were not detected in any patient-cycles. Grade 3/4 toxicities were hyperbilirubinemia - 3 pts (3 doses), elevated liver enzymes - 10 pts (13 doses), hyperglycemia - 7 pts (10 doses), allergy, pancreatitis, neuropathy, and fatigue - 1 pt (1 dose) each. All toxicities were reversible. We saw no pattern of increasing toxicity in subsequent doses of PEG-ASP. Only two patients had relapsed (median follow up of 15 months). Conclusion: multiple doses of PEG-ASP can be given IV to adults (age<57 years) and provide a very long duration of post remission ASP enzymatic activity. The M-M kinetics suggest that multiple doses of PEG-ASP lead to gradually increasing trough levels resulting in longer depletion of asparagine and glutamine levels and possibly better clinical activity, without being associated with increased toxicity or neutralizing antibody production.
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