1 Clinica delle Malattie Infettive, Policlinico-University of Bari Italy, Bari 70124; 2 Clinica Dermatologica, Policlinico-University, Bari, Italy
Received 18 September 2003; returned 16 December 2003; revised 13 January 2004; accepted 14 January 2004
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Abstract |
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Materials and methods: Six patients were evaluated. Five of them underwent cutaneous biopsies using a 4 mm punch. Sections were stained with haematoxylineosin, periodic acid-Schiff stain and Verhoeffs stain. Moreover, immunohistochemical studies were carried out using CD20, CD45Ro and CD34 antibodies.
Results: Four different macroscopic patterns were presented: (a) no evidence of cutaneous lesions; (b) transient infiltrative lesions which auto-resolved within 24 h; (c) transient nodular lesions which auto-resolved within 715 days; and (d) stable lesions after more than 30 days with a scleroderma-like aspect. Histological examination showed three patterns: (1) an acute urticaria/vasculitis-like pattern with inflammation of the fat tissue; (2) a sub-acute pattern with an initial dermal sclerosis; (3) a chronic scleroderma-like pattern with connective tissue disposed around the adnexa, whose structure was intact. The immunohistochemical study evidenced a prevalence of T lymphocytes and a moderate neoangiogenesis.
Conclusions: In our experience, after a rather long period of treatment, cutaneous reactions comprised a variety of features largely independent of the virological and immunological outcome. The adnexa was unaltered in all patients, this indicating a tendency to a possible regression of the sclerotic lesions. Therefore, patients should be encouraged to rotate the sites of injection thus permitting the tissues to regenerate.
Keywords: antiretroviral therapy, HIV-1 fusion inhibitors, peptide inhibitors
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Introduction |
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The aim of this study was the clinical and histopathological evaluation of ISRs in patients treated with enfuvirtide for 80 weeks.
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Materials and methods |
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Epidemiological, immunological and virological data at baseline, together with the optimized background (OB) of the six patients are summarized in Table 1. Five of the six patients underwent cutaneous biopsies using a 4 mm punch (PFM GmbH, Koln/Surth, Germany). The samples were fixed in 10% buffered formalin and paraffin-embedded. Four micrometre sections were stained with haematoxylineosin, periodic acid-Schiff stain and Verhoeffs stain for the study of the elastic fibres. Moreover, to investigate the lymphocytic infiltration and neoangiogenesis, immunohistochemical studies were carried out using CD20 (clone L26, DAKO s.p.a., Milan, Italy), CD45Ro (clone UCHL1, DAKO s.p.a., Milan, Italy) and CD34 antibodies (QBEND10, Bio Optica, Milan, Italy).
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Results |
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Of the six patients, only one without clinical lesions denied consent for the punch biopsy. In the patient with clinical pattern (b), the biopsy was carried out 12 h after injection at that site; in the patient with pattern (c) after 7 days and in the three patients with pattern (d) after 1 month.
Histological examination carried out on the remaining five patients showed three distinct morphological patterns: (1) within 12 h after the inoculation (patient 1), an acute urticaria/vasculitis-like pattern characterized by polymorphic inflammatory infiltration with a rich eosinophil component, especially around the vessels was observed in addition to involvement of the fat tissue with interstitial and lobular inflammation; (2) a sub-acute pattern characterized by moderate lymphocytic infiltration, particularly around the vessels, and an initial derma sclerosis was observed after 7 days from inoculation (patient 6); (3) a chronic scleroderma-like pattern was characterized by absence of inflammatory infiltration and progressive sclerosis of the derma; in the latter, connective tissue was typically disposed around the adnexa, whose structure was intact (patients 3, 5 and 2).
In all patients, the immunohistochemical study showed a prevalence of T lymphocytes (CD45Ro) on B lymphocytes (CD20) and a moderate neoangiogenesis (CD34).
Details regarding the histological examination are shown in Table 2.
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Discussion |
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The analysis of data from a Phase III study has shown that ISRs occur in 97.9% of patients. In most patients (85.6%), the reaction appears during the first week of treatment. These reactions generally did not worsen over time and few patients had infections at the injection site. In total, 13% of patients had severe pain which limited normal activities and required analgesics. Average duration of an individual ISR was about 7 days. Treatment discontinuation rate as a result of ISRs was 3% and less than 1% of patients discontinued therapy because of difficulty with self-administered injections. The most frequent signs and symptoms of a local ISR were pain and/or discomfort (94.6%), induration (89.3%), erythema (89.0%), nodules or cysts (75.9%).14
Another study examined the ISR histology in seven patients with different clinical features: four with palpable nodules, one with erythema, one with induration and one without any clinical reaction.7 The time from injection to biopsy ranged from 3 to 40 h. In all cases, inflammatory infiltrates consistent with a localized hypersensitivity reaction with conspicuous eosinophils, histiocytes, rare lymphocytes and plasma cells were found. Moreover, there was focal pallor and some fragmentation of the connective tissue in all patients. In some areas, the inflammatory cells included histiocytes with some multinucleate forms aggregated around the areas of collagen degradation resembling a palisade granulomatous response, as seen in granuloma annulare. Focal lipophagic fat necrosis and haemorrhage were also observed, consistent with a trauma component. Fibrosis and widening of subcutaneous septa were found in a diabetic patient. All specimens were positive for enfuvirtide, with the highest positivity seen in areas where the inflammatory response was most dense. Enfuvirtide was also observed on the collagen fibres in areas where collagen degradation was present. Moreover, in all specimens except one, most of the lymphocytes present were T cells, but CD20 staining showed rare B cells and CD68 staining showed the presence of macrophages. No significant increase in lymphocytes above the normal was seen (S-100, CD1a, CD30).
In our experience, after a rather long period of treatment with enfuvirtide, cutaneous reactions comprised a variety of features ranging from a transient acute pattern, to scleroderma-like lesions. As illustrated in Table 2, the clinical and histological features of the ISR seem largely independent of the virological and immunological outcome. In fact, at the start of therapy, an advanced stage of the disease from the immunological and virological point of view was demonstrated in all patients (Table 1). After 80 weeks of treatment, two patients (4 and 2) significantly improved, whereas the viral load and CD4 cell count in the remaining patients did not substantially change. Moreover, the adnexa was unaltered even in patients with signs of cutaneous sclerosis, a fact which might indicate a tendency to possible regression of the sclerotic lesions. Therefore, patients should be encouraged to rotate the sites of injection thus permitting tissues to regenerate. Previous evidence suggests that rotating the sites of injection (abdomen, arm, thigh) results in comparable pharmacokinetic and absorption profiles.8
In conclusion, although observations on larger patient samples are warranted, our data seem to indicate that a wide array of responses to ISRs can be observed and that an iatrogenic scleroderma is not the rule, even with long-term follow-up.
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Acknowledgements |
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Footnotes |
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References |
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8 . Lalezari, J. P., Patel, I. H., Zhang, X. et al. (2003). Influence of subcutaneous injection site on the steady-state pharmacokinetics of enfuvirtide (T-20) in HIV-1-infected patients. Journal of Clinical Virology 28, 21722.[CrossRef][ISI][Medline]