SUMMARY BackgroundPeginterferon alfa-2a and alfa-2b, the two commercially available pegylated interferons, have different pharmacokinetic properties that produce differing abilities to suppress replication of the hepatitis C virus.

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The frequencies of anti-interferon-beta (IFN-beta) antibody development reported to date in patients treated with different IFN-beta preparations are not readily comparable mainly because of differences in underlying diseases and assay methods. Thus, the frequency of neutralizing antibody (NAb) and binding antibody (BAb) development was analyzed in a sample of sera derived from a homogeneous group of relapsing-remitting multiple sclerosis (RRMS) patients treated with different IFN-beta preparations. The frequency of developing NAb and BAb to IFN-beta varied according to the IFN-beta given. Specifically, the NAb seroconversion frequency was significantly higher in patients treated with Betaferon, Schering AG, Berlin, Germany (31.3%) than in patients treated with both preparations of recombinant IFN-beta 1a (Rebif, Serono, Geneva, Switzerland [7.4%] or Avonex, Biogen, Cambridge, MA [6.3%]). Analysis of BAb seroconversion frequency in the same patients revealed that different IFN-beta preparations may also have different capability to induce BAb development and that BAb are produced during IFN-beta therapy at a significantly higher rate than NAb. Our main conclusion is that different human IFN-beta preparations may possess different immunogenicities, leading to varying frequency of development of antibody to IFN-beta in RRMS.

The aim of this study was to evaluate patterns of antiretroviral resistance of HIV-1 in peripheral blood mononuclear cells (PBMCs) and in the plasma of patients whose therapeutic regimen is failing. Plasma and PBMC samples were collected from 95 HIV-infected patients undergoing long-term treatment. Genotyping of the reverse transcriptase (RT) and protease genes of HIV-1 was undertaken using the fluorescent dideoxy-terminator method. Comparison of the amino acid sequence of the RT and protease genes in cell-associated variants of HIV-1 with that of the plasma revealed that 62 of the 95 patients' samples tested exhibited different genotypic resistance patterns (discordant samples [DSs]). In 27% of samples, the patterns of resistance detected were concordant in both compartments. In 51% of DSs, the greatest number of mutations was found in plasma; however, in 37% of DSs, greater numbers of mutations were found in PBMC DNA. The HIV mutation patterns detected in plasma do not necessarily reflect those found in the cell-associated compartment. The observation that the cellular compartment may contain an archive of the resistance variant makes this reservoir an interesting substrate for analysis of the "resistance potential" in a given patient.

The efficacy of alpha interferon (IFN-␣) in the treatment of severe type II essential mixed cryoglobulinemia (EMC) has been reported previously. In some patients, the development of neutralizing antibodies to recombinant IFN-␣ (rIFN-␣) can affect the clinical response achieved with rIFN-␣; a second treatment with natural IFN-␣ preparations may reinduce the clinical response. In the present study the ability of leukocyte IFN (LeIFN) to restore the response was investigated from a pharmacodynamic viewpoint. Specifically, the pharmacodynamic profiles of different IFN-␣ preparations were studied by measuring the serum neopterin levels and the levels of expression of protein MxA mRNA in in vivo peripheral blood mononuclear cells in two patients with EMC whose resistance to rIFN-␣2a treatment increased concomitantly with the development of neutralizing antibodies. These markers were measured before injection and at 24 and 48 h after a single injection of rIFN-␣2a, consensus IFN [(C)IFN], or LeIFN. No increase or only a slight increase in MxA mRNA levels was detectable after administration of rIFN-␣2a or (C)IFN, whereas a significant increase (>10-fold) in MxA mRNA expression was recorded following administration of LeIFN. The neutralizing antibodies to rIFN-␣2a cross-react with (C)IFN. Sera from these patients neutralized most but not all of the subtypes present in the natural IFN-␣ (LeIFN) mixture, and no significant increase in neopterin levels was observed after these patients were switched to LeIFN treatment. In summary, the data demonstrate that the problem of neutralizing antibodies still exists and that LeIFN may induce an increase in the level of MxA mRNA expression but not an increase in neopterin levels in patients who are resistant to treatment with rIFN-␣2a or (C)IFN.It has been repeatedly reported that antibodies to interferon (IFN) may develop during alpha IFN (IFN-␣) therapy (2). Of the antibodies that bind to different epitopes of the IFN molecule, some are neutralizing antibodies (NABs), as measured in antiviral neutralization assays.The development of NABs against IFN-␣ has been correlated with a decline in therapeutic efficacy in patients with chronic myelogenous leukemia (39), hairy-cell leukemia (40), carcinoid tumors (33, 36), and chronic hepatitis C (7, 21, 31) treated with IFN-␣ and, more recently, in patients with multiple sclerosis treated with IFN-␤ (26, 27, 37). It has also been observed in patients with severe type II essential mixed cryoglobulinemia (EMC), for whom IFN-␣ is a well-established and widely used therapy (9,10,12,32). Several studies have also demonstrated that second-line therapy with natural human IFN-␣ may be effective in restoring the therapeutic response in patients with chronic hepatitis C (5, 13, 31) and in those with cancer (8,20,38,42) who relapse following the production of NABs to rIFN-␣. However, the possibility that switching to alternative IFN-␣ preparations could overcome the NAB-induced fall in the biological and clinical activities of IFN has, so far, rarely b...