The influence of HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV-positive individuals

Objective

This study was performed to investigate the impact of HAART versus no HAART and nucleoside free versus nucleoside containing HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV/HCV co-infected patients. In addition a control group of HCV mono-infected patients undergoing anti-HCV therapy was evaluated.

Methods

Multicenter, partially randomized, controlled clinical trial. HIV-negative and -positive patients with chronic HCV infection were treated with pegylated interferon alfa-2a and ribavirin (800 - 1200 mg/day) for 24 - 48 weeks in one of four treatment arms: HIV-negative (A), HIV-positive without HAART (B) and HIV-positive on HAART (C). Patients within arm C were randomized to receive open label either a nucleoside containing (C1) or a nucleoside free HAART (C2).

Results

168 patients were available for analysis. By intent-to-treat analysis similar sustained virological response rates (SVR, negative HCV-RNA 24 weeks after the end of therapy) were observed comparing HIV-negative and -positive patients (54% vs. 54%, p = 1.000). Among HIV-positive patients SVR rates were similar between patients off and on HAART (57% vs. 52%, p = 0.708). Higher SVR rates were observed in patients on a nucleoside free HAART compared to patients on a nucleoside containing HAART, though confounding could not be ruled out and in the intent-to-treat analysis the difference was not statistically significant (64% vs. 46%, p = 0.209).

Conclusions

Similar response rates for HCV therapy can be achieved in HIV-positive and -negative patients. Patients on nucleoside free HAART reached at least equal rates of sustained virological response compared to patients on standard HAART.     

Anatomy of the perirenal area

The authors comment on the use of the renal bridging septa as a sign in distinguishing compartmentalization of the perinephric space. They also address new concepts regarding the spread of pancreatic effusions and provide information on other anatomic features of the perirenal area.     

Hepatic metastases studied with MR and CT

Examinations of the liver using magnetic resonance (MR) and computed tomography (CT) were performed on 50 patients with hepatic metastases. MR and CT were comparable in their ability to detect metastases, which generally appeared hypointense compared with normal liver parenchyma on T1-weighted MR images and hyperintense on T2-weighted images. The MR imaging techniques that were most reliable in detecting metastases were inversion recovery and a relatively T2-weighted, spin-echo technique (TR = 1,500 msec, TE = 60 msec). We conclude that CT, because of its shorter imaging time, greater spatial resolution, and lower cost, should remain the preferred screening test for hepatic metastases. MR imaging should be reserved for patients with equivocal CT findings and for patients in whom there is persistent clinical suspicion of hepatic metastases despite a negative CT examination.     

Anterior cruciate ligament tears: MR imaging compared with arthroscopy and clinical tests

Seventy-nine magnetic resonance (MR) studies of the knee were reviewed in an evaluation of the ability of MR imaging to demonstrate arthroscopically proved anterior cruciate ligament (ACL) tears. MR findings were also compared with the findings of two commonly applied clinical tests of ACL instability: the Lachman test and the anterior drawer test. The sensitivity of MR imaging was 94% (17 of 18), compared with 78% (14 of 18) for the anterior drawer test and 89% (16 of 18) for the Lachman test. The specificity was 100% for all three. Three MR criteria were applied: irregularity or a wavy contour of the anterior margin of the ligament, high-signal-intensity change within the substance of the ligament on T2-weighted images, and discontinuity of that substance. The sagittal T2-weighted image was especially helpful, producing an "arthrographic" effect, in which the anterior margin of the ACL is outlined by high-signal-intensity joint fluid. By demonstrating ACL and other extrameniscal lesions, MR imaging may help clarify the mechanisms of knee injury.     

Efficacy of percutaneous transluminal coronary angioplasty compared with single-vessel bypass

The use of percutaneous transluminal coronary angioplasty has been increasing rapidly. When the procedure is successful, the clinical relief of symptoms is similar to that achieved with direct coronary artery bypass. It has been suggested that the angioplasty procedure, however, can accomplish these results with potentially less morbidity and mortality, along with a shorter hospital stay. In order to evaluate the results of percutaneous transluminal coronary angioplasty with single-vessel coronary artery bypass, we performed a retrospective review. From January, 1982, to December, 1983, a total of 198 angioplasty procedures were performed. They were successful in 142 patients (71.7%). Emergency bypass was performed in 21 (10.6%) of the 56 patients who had undergone unsuccessful angioplasty procedures. Perioperative myocardial infarction occurred in eight of these patients (38.1%). There were no operative deaths, but there was one death after angioplasty. Elective bypass was performed in 28 of the patients who had angioplasty procedures, with no perioperative myocardial infarctions or operative deaths. Recurrent symptoms developed in 31 (21.8%) of the 142 patients who had undergone initially successful angioplasty. From 1982 to 1983, single-vessel bypass was performed in 143 patients. The internal mammary artery was utilized in 102 patients and the autogenous saphenous vein in 41 patients. There were no perioperative myocardial infarctions or deaths. No patients developed recurrent symptoms during the study interval. Percutaneous transluminal coronary angioplasty is an acceptable alternative to coronary artery bypass in patients with localized lesions that are sufficiently serious to cause symptoms and warrant surgical bypass. However, the angioplasty procedure, when compared to single-vessel coronary artery bypass, may result in an increased incidence of acute myocardial infarction and in a significantly (p less than 0.001) increased incidence of early recurrence of symptoms.     

Transsynovial Drug Distribution: Synovial Mean Transit Time of Diclofenac and Other Nonsteroidal Antiinflammatory Drugs

The synovial mean transit time of diclofenac was determined by two methods from existing plasma and synovial fluid concentration-time data. These data were obtained from single- and multiple-dosing regimens of diclofenac in patients with osteoarthritis and rheumatoid arthritis. Plasma and synovial fluid concentration-time data taken from the literature for four other nonsteroidal antiinflammatory drugs (etodolac, ibuprofen, indomethacin, and tenoxicam) were also analyzed. The two methods of data analysis rely on the determination of the ratio of the area under the synovial fluid concentration-time curve to the area under the plasma concentration-time curve. Both methods can be considered noncompartmental because in determining the first-order exit rate constant for the synovial fluid (the inverse of the synovial mean transit time), an analysis of the overall distribution and elimination characteristics of the drug is unnecessary. Method 1 makes use of the information contained in the postdistributional synovial fluid to plasma concentration ratio whereas method 2 is a linear pharmacokinetic model using a partial-areas analysis. The single dose mean ± S.D. synovial fluid exit rate constant for diclofenac was 0.39 ± 0.33 hr^–1 (n = 6), which was not significantly different from that determined by method 2; which was 0.49 ± 0.52 hr^–1. The steady state mean ± S.D. diclofenac synovial fluid exit rate constants for methods 1 and 2 were 0.43 ± 0.18 and 0.54 ± 0.71 hr^–1 (n = 8), respectively, which were not significantly different. These values of synovial fluid exit rate constants result in a synovial mean transit time for diclofenac that is approximately 2 to 2.5 hours. The synovial mean transit time calculated using method 1 from literature data for etodolac, ibuprofen, indomethacin, and tenoxicam were 6.8, 2.2, 4.8, and 3.5 hours, respectively. The synovial mean transit times calculated by method 2 for the same drugs were 5.3, 3.4, 4.7, and 4.0 hours, respectively. Similar values of the synovial mean transit time of nonsteroidal antiinflammatory drugs were achieved by using either of these two methods, both of which avoid complex equation fitting which is statistically problematic in the frequently data-sparse environment of extravascular sampling.     

Mitogenic properties of a bispecific single-chain Fv-Ig fusion generated from CD2-specific mAb to distinct epitopes [In Process Citation]

The combination of anti-CD2 mAb 9.6 and 9-1, specific for distinct epitopes, induces proliferation of resting human T cells. The mitogenic activity of this mAb mixture depends upon accessory cells and the 9-1 mAb Fc domain. To further study the functional properties of these mAb, their variable regions were cloned and expressed as monospecific single- chain Fv (scFv) proteins fused to the human IgG1 Fc domain (scFvIg). A novel bispecific scFvIg was constructed by cloning the two monospecific scFv binding sites in tandem, with the 9.6 scFv placed N-terminal to the 9-1 scFvIg. Monospecific scFvIg binding to CD2 was comparable to that of the corresponding parental mAb, while the bispecific scFvIg exhibited binding activity similar to that of the 9-1 scFvIg. The combination of 9.6 scFvIg and 9-1 mAb was mitogenic, whereas mixtures including the 9-1 scFvIg were non-stimulatory, confirming the unique properties of the 9-1 IgG3 Fc. Without the IgG3 tail, the bispecific 9.6/9-1 scFvIg was directly mitogenic and was a more potent mitogen than the mAb mixture, but was accessory cell dependent. Unlike the combination of mAb, the bispecific reagent did not directly mobilize calcium in T cells. In comparison to the mAb mixture, bispecific 9.6/9- 1 scFvIg-mediated stimulation of a mixed lymphocyte reaction was significantly more resistant to inhibition of the CD28 co-stimulatory pathway by the inhibitor CTLA-4-Ig. These results show that expression of the 9.6 and 9-1 binding sites together on a bispecific scFvIg increased the mitogenic properties of the mAb and altered the degree of accessory cell signals required for T cell activation.