Anna De Bona

Filgrastim to treat neutropenia and support myelosuppressive medication dosing in HIV infection

Background: Patients with HIV infection frequently experience disease or treatment‐related myelosuppression leading to neutropenia. Neutropenia often leads to dose‐reduction or discontinuation of important myelosuppressive therapy. Objective: To examine the efficacy and safety of filgrastim for reversing neutropenia and determine the effect of this on use of myelosuppressive medications. Design: Open‐label, non‐comparative, multicentre study in 200 HIV‐positive patients with neutropenia [absolute neutrophil count (ANC) < 1.0×109/l]. Filgrastim was started at 1 &mgr;g/kg/day subcutaneously for 28 days. This initial treatment phase was followed by a maintenance phase, using 300 &mgr;g on 1‐7 days/week. In both phases the dose of filgrastim was adjusted to achieve an ANC of 2‐5×109/l. Results: Filgrastim reversed neutropenia in 98% of patients (ANC ≥2×109/l), with a median time to reversal of 2 days (range 1‐16) and a median dose of 1 &mgr;g/kg/day (range 0.5‐10). Most patients (96%) achieved reversal of neutropenia with a filgrastim dose of ≤ 300 &mgr;g/day (≤1 vial/day). Normal ANCs were then maintained with a median of 1 &mgr;g/kg/day (range 0.22‐10.6) during the treatment phase and 3×300 &mgr;g vials/week (range 1‐7) during the maintenance phase. Ganciclovir, zidovudine, co‐trimoxazole and pyrimethamine were the drugs most frequently considered to be causing neutropenia, and 83% of patients received one or more of these in the study. Filgrastim allowed > 80% of patients to increase or maintain dose‐levels of these four medications or add them to their therapy. The number of these four medications received per patient increased by > 20% during filgrastim therapy. Filgrastim was well tolerated. CD4, CD8 and total lymphocyte counts all increased slightly, and there was no difference in HIV‐1 p24 antigen levels. Conclusion: Filgrastim rapidly reverses neutropenia and maintains normal ANC in patients with HIV infection. This allows greater use of myelosuppressive medications without the potentially life‐threatening complications of neutropenia.

Liver fibrosis in HIV-positive patients with hepatitis C virus: Role of persistently normal alanine aminotransferase levels

Background:Liver fibrosis requiring treatment in HIV/hepatitis C virus (HCV)-coinfected patients with persistently normal alanine aminotransferase (ALT) values (PNAL) is currently not well defined; in this study clinical and histologic features of PNAL were compared with those of subjects with elevated ALT (EAL). Methods:A total of 326 liver biopsies of HIV/HCV-coinfected patients, performed from 1997-2003, were retrospectively identified. Subjects with at least 3 consecutive normal ALT determinations during a prebiopsy follow-up of 12 months were grouped as PNAL (24 patients) and compared with EAL subjects (302 patients). Liver biopsy was classified with the modified Ishak score. Results:Age, HCV viral load, and genotype, CD4 T-cell count, and antiretroviral drugs did not show a statistical difference between the 2 groups. Statistical significance was found when comparing mean grading (1.4 ± 1.8 vs. 7.2 ± 2.6, P < 0.0001) and staging (1.4 ± 1.79 vs. 2.5 ± 1.7, P < 0.0003) between PNAL and EAL subjects. The proportion of PNAL patients fulfilling histologic criteria for anti-HCV treatment (25% with stage 2-6) was also significantly different from EAL subjects (69%; P = 0.0001). At multivariate analysis, only age, CD4 count (>500 vs. ≤500 cells/mL), and patients group (EAL vs. PNAL) were found to be independently associated with a fibrosis score of ≥2. Conclusion:Liver fibrosis requiring treatment was found in 25% of HIV/HCV-coinfected subjects with PNAL values.

Acute self-limiting hepatitis C after possible sexual exposure: Sequence analysis of the E-2 region of the infected patient and sexual partner

We describe a case of symptomatic acute infection with HCV in a woman whose sexual partner had chronic hepatitis C. The patient cleared HCV RNA 8 weeks after the onset of acute hepatitis and was found to be persistently HCV-RNA negative during 90 weeks of follow-up. Part of the E-2 region of HCV was directly sequenced in the patient and her sexual partner. Four local controls with subtype-1a infection and 9 1a isolates obtained from GenBank were analyzed. The average nucleotide divergence between the sequences of the infected patient and her sexual partner was 5.1%, compared with an average nucleotide divergence of 19.4% (range 16.6-21.8%) between the sequences of the patient and those of controls. Comparison of the phylogenetic trees in the partial E-2 region showed that the sequence of the patient was closely related to that of her sexual partner. Our findings suggest that the infection was transmitted to the patient from her sexual partner. The resolution of acute hepatitis C in this case was probably related to the host rather than to intrinsic characteristics of the HCV genome.We describe a case of symptomatic acute infection with HCV in a woman whose sexual partner had chronic hepatitis C. The patient cleared HCV RNA 8 weeks after the onset of acute hepatitis and was found to be persistently HCV-RNA negative during 90 weeks of follow-up. Part of the E-2 region of HCV was directly sequenced in the patient and her sexual partner. Four local controls with subtype-1a infection and 9 1a isolates obtained from GenBank were analyzed. The average nucleotide divergence between the sequences of the infected patient and her sexual partner was 5.1%, compared with an average nucleotide divergence of 19.4% (range 16.6-21.8%) between the sequences of the patient and those of controls. Comparison of the phylogenetic trees in the partial E-2 region showed that the sequence of the patient was closely related to that of her sexual partner. Our findings suggest that the infection was transmitted to the patient from her sexual partner. The resolution of acute hepatitis C in this case was probably related to the host rather than to intrinsic characteristics of the HCV genome.

Neurobrucellosis with spinal cord abscess of the dorsal tract: a case report

Neurologic manifestations of brucellosis occur in 2-5% of patients.l.* The clinical pictures of neurobrucellosis are characteristically protean: they include meningoencephalitis, meningovascular complications, parenchymatous dysfunctions, peripheral neuropathy/radiculopathy and various degrees of behavioral abnormalities, sometimes leading to acute psychosis. From the clinical series available, meningitis has been referred as the most frequent presentation of neurobrucellosis, occurring in at least the 50% of cases;‘,” meningitis is most often acute, but subacute or chronic presentations are not rare and may lead to disseminated encephalomyelitis with diffuse central nervous system (CNS) demyelinization.3*4 In contrast, Bruceh abscess formation within the CNS has been described up to now in just one child with multiple brain abscesses.’ We here report the first case of neurobrucellosis with intramedullary abscess in an adult. A 24-year-old man from Sicily was admitted to the regional Hospital for high degree continuous fever and night sweats; fever had lasted for about two months and had been treated with a one-week course of oral prednisolone, before the patient was admitted to hospital. The patient remembered eating some fresh goat’s cheese in the recent past. Thus, brucellosis was suspected and the Brucella melitensis serum agglutination test (SAT) was performed. This was positive at a 1:SOO titer. A six-week cycle of rifampin 600 mglday and doxycycline 100 mg b.i.d. was given; both the fever and the agglutinins normalized. Six months later he complained of abrupt onset of fever, hypostenia of the left leg, and paresthesias of the right leg, with consequent impaired walking. A contrast-enhanced magnetic resonance imaging (MRI) of the brain and the spinal cord showed a focal lesion of 15 mm diameter within the dorsal tract of the spinal cord, near to the third intervertebral space; the abscess was surrounded by perilesional edema, had a partially liquid core and a ring enhancement was evident after Gadolinium in-

The 118i Reverse Transcriptase Mutation Is the Only Independent Genotypic Predictor of Virologic Failure to a Stavudine-containing Salvage Therapy in Hiv-1-infected Patients

Summary: Patients infected with HIV-1 with more than 1000 HIV-1 RNA copies/mL, who were genotyped within 3 months before starting stavudine and treated for at least 3 months with a stable stavudine-containing highly active antiretroviral therapy, were selected from our database to identify the determinants of response to stavudine. Nonresponse was defined as a failure to achieve HIV-1 RNA level of less than 400 copies/mL or a reduction of more than 2 log10 by week 12. Univariate logistic analysis was used to elicit the failure-associated reverse transcriptase mutations (scored 1 to develop a genotype score). Eighty-one patients were eligible for the analysis, including 75 (93%) who previously received zidovudine. Thirty-five (43%) were nonresponders. Univariate logistic analysis revealed the following failure-associated mutations: 41L (P = 0.0001), 44D (P = 0.02), 118I (P = 0.0006), 184V (P = 0.04), 210W (P = 0.0004), and 215Y (P = 0.002) for a median stavudine score of 2. Failure was observed in 7 (18.9%) of 37 patients with a score less than 2, compared with 28 (63.6%) of 44 patients with a score of 2 or greater (P < 0.0001). The multivariable analysis showed that the 118I mutation (P = 0.04) was the only independent genotypic predictor of failing on a stavudine- containing highly active antiretroviral therapy.

Recombinant interferon-alpha therapy and meno-metrorrhagia

month later. One week later uterine bleeding restarted; repeated for a four-month history of meno-metrorrhagia and sub- sequent anaemia; thereafter, she received a combined blood examinations were normal as before. During this oral contraceptive with resolution of the haemorrhage. second episode of meno-metrorrhagia soluble inter- Ten months later, while she was still taking an oral con- leukin-2 receptor