Sergio Pauluzzi

Self-reported symptoms and medication side effects influence Adherence to highly active antiretroviral therapy in persons with HIV infection

Objectives: To identify variables predictive of nonadherence to highly active antiretroviral therapy (HAART) and to assess whether self‐reported symptoms or medication side effects are related to adherence. Design: Cross‐sectional multicenter study Adherence Italian Cohort Naive Antiretrovirals [AdICONA] within the Italian Cohort Naive Antiretrovirals (ICONA). Methods: Participants receiving HAART completed a 16‐item self‐administered questionnaire to assess nonadherence in the last 3 days as well as the type and intensity of 24 common HIV‐ and HAART‐related symptoms experienced during the last 4 weeks. Results: From May 1999 to March 2000, 358 persons were enrolled: 22% reported nonadherence and were less likely to have HIV RNA <500 copies/ml (odds ratio = 0.51; 95% confidence interval: 0.31‐0.85). Frequency of moderate/severe symptoms or medication side effects in nonadherent participants ranged from 3.6% to 30%. On univariate analysis, nausea, anxiety, confusion, vision problems, anorexia, insomnia, taste perversion, and abnormal fat distribution were significantly associated with nonadherence. Nonadherent persons had a higher mean overall symptom score (12.3 ± 9.2 versus 8.1 ± 6.6; p < .001) and mean medication side effect score (2.9 ± 2.7 versus 1.9 ± 1.9; p < .001) when compared with adherent participants. In the multivariate analysis, nausea (p = .003); anxiety (p = .006); younger age (p = .007); unemployment (p < .001); not recalling name, color, and timing of drugs (p = .009); running out of pills between visits (p = .002); and being too busy (p = .03) were independently associated with nonadherence in the last 3 days. Conclusions: In addition to patient characteristics, medication‐related variables, and reasons for nonadherence, patient‐reported symptoms and medication side effects were significantly associated with adherence to HAART.

Secondary Mutations in the Protease Region of Human Immunodeficiency Virus and Virologic Failure in Drug-Naive Patients Treated with Protease Inhibitor-Based Therapy

The role of mutations in protease (PR) and reverse-transcriptase (RT) of human immunodeficiency virus (HIV) in predicting virologic failure was assessed in 248 antiretroviral-naive HIV-positive patients who began a PR inhibitor-containing antiretroviral regimen. Genotypic testing was performed on plasma samples stored before the start of therapy. Twenty-seven patients (10.9%) had mutations in the RT, 5 (2%) carried primary mutations in the PR, and 131 (52.8%) showed only secondary PR mutations. Virologic failure at week 24 occurred in 62 (25.0%) of 248 patients. There was a statistically significant correlation between virologic failure and the number of PR mutations (P= .04, chi(2) test). Mutations at codons 10 and 36 of PR (present in 39.3% and 40.0% of patients in whom treatment failed, respectively) were identified by stepwise logistic regression as the strongest predictors of virologic failure (odds ratio, 2.20; 95% confidence interval, 1.30-3.75; P= .004). If confirmed in independent studies, this result may justify the increased use of HIV genotyping in drug-naive patients requiring antiretroviral therapy.

Unusual Presentation of Life-Threatening Toscana Virus Meningoencephalitis

This case report describes a brother and a sister with severe meningoencephalitis caused by Toscana virus (TOSv). The clinical presentation was characterized by stiff neck, deep coma, maculopapular rash, diffuse lymphadenopathy, hepatosplenomegaly, renal involvement, tendency to bleeding, and diffuse intravascular coagulation. The boy had epididymo-orchitis. Recovery with neurologic sequelae as hydrocephalus was observed. Microbiological diagnosis was obtained by serological tests and reverse transcriptase-polymerase chain reaction. Sequencing of polymerase chain reaction products from the S and M segments was carried out. TOSv may be a causative agent in severe meningoencephalitis.

Prevalence of HBV, HDV and HCV hepatitis markers in HIV-positive patients

Since HIV infection could condition the natural history of parenterally transmitted viral hepatitis (HBV, HCV, HDV), with possibly differing effects in different risk groups, we decided to retrospectively examine sera from a cohort of 637 HIV seropositive patients in different stages of infection, seen from 1985 to 1992, to study the prevalence and temporal course of these infections. Virological markers of HBV, HCV and HDV were determined by ELISA and RIBA methods. The severity of HIV infection was higher in homosexuals than in drug addicts. Prevalence of antiHBc antibodies was 82% in drug addicts and 77% in homosexuals, whereas antiHCV antibodies prevalence was 72% in drug addicts and only 7% in homosexuals (p<0.000001). When only antiHBc-positive patients were considered, there was a significant difference in antiHBs antibodies between drug addicts (DA) and homosexuals (OR for DA 0.29, 95% CI 0.08/0.83,p=0.02), suggesting that drug addicts are less able to produce a protective response. This fact cannot be explained by the severity of HIV infection (which was higher among the homosexual group) and suggests some immunodepressive effect of drug abuse. Delta infection was only detected in the drug addict group, and the prevalence was low. Finally, we cannot confirm the interference of HCV infection with the speed of HBsAg clearance: in this study the prevalence of HBsAg was almost the same in HCV-positive and negative patients.

Prospective randomized clinical trial of teicoplanin for empiric combined antibiotic therapy in febrile, granulocytopenic acute leukemia patients.

The increasing prevalence of bacteremia caused by gram-positive bacteria in granulocytopenic acute leukemia patients prompted us to evaluate, in a prospective randomized trial, the role of teicoplanin, a new glycopeptide antibiotic, when it was added to amikacin plus ceftazidime, as an empiric therapy of fever in these patients. Of 47 evaluable episodes, 22 were treated with the teicoplanin regimen and 25 were treated with the combination of amikacin and ceftazidime. The overall response to therapy of patients treated with teicoplanin was slightly better (82% improvement) than that obtained with amikacin plus ceftazidime (52%). The response rate of patients with gram-positive bacteremias was 80% (4 of 5) to the regimen that included teicoplanin; 25% (1 of 4) of the patients treated with amikacin plus ceftazidime responded to treatment; and for patients with gram-negative bacteremias, the response rates were, respectively, 100% (4 of 4) and 70% (7 of 10). The better results obtained with amikacin-ceftazidime-teicoplanin treatment were most evident in patients with profound (less than 100/mm3) and persistent neutropenia (83 versus 30% improvement). Furthermore, a good response rate of patients with gram-positive bacteremias (seven of eight; 87% improvement) was achieved in a small group of bone marrow transplant patients who were all treated with amikacin-ceftazidime-teicoplanin. No severe side effects were documented in any patient. Teicoplanin, as a drug administered as a single daily dose, seems to be a safe and useful anti-gram-positive agent when used in combination with amikacin-ceftazidime as an empiric therapy of febrile episodes in granulocytopenic acute leukemia patients.

Interferon-Alpha Is Effective in the Treatment of HIV-1–Related, Severe, Zidovudine-Resistant Thrombocytopenia: A Prospective, Placebo-controlled, Double-Blind Trial

Thrombocytopenia is relatively common in patients infected with human immunodeficiency virus type 1 (HIV-1), and it occurs in patients belonging to all major risk groups, such as homosexuals, intravenous drug users, and hemophiliacs [1-3]. Thrombocytopenia occurs in 5% to 15% of asymptomatic patients; 6% to 24% of these patients have serious thrombocytopenia (counts < 30 109/L [2, 4]) and clinical bleeding [2, 4, 5]. The general consensus is to not treat patients with less severe thrombocytopenia because of the low risk for bleeding and the possibility of spontaneous remissions [6-9]. However, the treatment of severe thrombocytopenia is mandatory in view of the frequent, serious bleeding manifestations [2, 4, 5]. The mechanism of HIV-1related thrombocytopenia is not completely understood but immunologic mechanisms (antiplatelet antibodies or circulating immune complexes, or both) and megakaryocyte viral infection may play a role [10]. Although the response to treatment of HIV-1related thrombocytopenia does not appear to differ substantially from that observed in adults with idiopathic chronic thrombocytopenia, there are limitations when using conventional therapeutic approaches. Steroids and other immunosuppressive agents (for example, vincristine, cyclophosphamide) [11, 12] can facilitate the development of opportunistic infections or can lead to the flaring up of infectious hepatitis, which is often present in these patients [13, 14]; steroids have also been reported to accelerate the progression of Kaposi sarcoma [15, 16]. Splenectomy enhances the risk for subsequent infection, especially severe sepsis [17], and in some patients a late relapse of thrombocytopenia may occur [18]. High-dose intravenous immunoglobulins represent an effective treatment in most patients, but the effect is short-lasting in almost all of them, and the high costs and the need for intravenous administration limit their use [9, 19]. Finally, alternative approaches, such as dapsone [20], protein A immunoadsorption [21], or anti-rhesus factor IgG [19], have been tested in limited series and uncontrolled studies (or both). It is now well established that zidovudine (azidothymidine) can effectively enhance the platelet count of patients with HIV-1related thrombocytopenia. A remission of thrombocytopenia during zidovudine administration has been shown in several case series [22-24] and in one placebo-controlled, prospective clinical study [25]. However, between 30% and 40% of patients with thrombocytopenia are resistant to full-dose (1000 mg/d) zidovudine treatment [23, 24, 26, 27]. It is not clear that higher doses of zidovudine affect thrombocytopenia [28, 29]; in addition, higher doses are potentially toxic [30]. Some anecdotal reports and small, uncontrolled case series have recently suggested that interferon- can correct the thrombocytopenia of patients with HIV-1 infection [9, 14, 31-33], even in patients not responding to zidovudine treatment [31, 33]. However, no studies have analyzed, under carefully controlled conditions, the efficacy, toxicity, and kinetics of the response to interferon- in patients with zidovudine-resistant, HIV-1related thrombocytopenia. We tested whether interferon- can increase the platelet count in patients with zidovudine-resistant, HIV-1related severe thrombocytopenia and assessed the kinetics of the interferon- effects and the possible toxicity of interferon in association with zidovudine in a randomized, placebo-controlled clinical study. Methods Selection of Patients Patients were considered eligible for the study if they were seropositive for HIV-1 by the enzyme-linked immunosorbent assay and the Western-blot technique and had a platelet count less than 25 109/L on at least two occasions separated by more than 2 weeks. In addition, thrombocytopenia had to be refractory to a 1-month course of full-dose (1000 mg/d) zidovudine treatment and to previous therapeutic attempts with one of the following: corticosteroids, splenectomy, vincristine, danazol, high-dose intravenous IgG, or anti-ID immunoglobulins. The main exclusion criteria were pregnancy or breast-feeding; the acquired immunodeficiency syndrome; concomitant serious diseases not related to HIV-1 infection (cardiomyopathy, seizure, stroke, psychosis); presence of antinuclear, anti-smooth-muscle, antimitochondrial, or anti-liver-kidney microsome 1 antibodies; and granulocyte counts less than 1 109/L or hemoglobin levels less than 80 g/L. Women of childbearing potential were advised to practice effective methods of birth control. Assessment before study included a medical history, physical examination, electrocardiogram, chest radiograph, and the following laboratory tests: measurement of hemoglobin, hematocrit, mean corpuscular volume, leukocyte count, differential leukocyte count, platelet count, serum glucose, blood urea nitrogen, serum creatinine, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serologic tests for hepatitis B and C, prothrombin time, activated partial thromboplastin time, bleeding time, and urinalysis. Fifteen consecutive patients satisfying the criteria for entry into the study were enrolled between April and October 1992 in four centers belonging to four different hospitals in Central Northern Italy. Written, informed consent was obtained from each patient before enrollment in the study; the study protocol was approved by the Ethics Committee of the Umbria Region. Treatment Patients were enrolled in a double-blind, crossover, placebo-controlled, randomized study in which they were treated with either subcutaneous lymphoblastoid interferon- (Wellferon, Burroughs Wellcome, Italy) or 1 mL of subcutaneous saline solution (placebo). Therapy was administered to the patients in hospital by specially trained nurses. The treatment code was known only to the nurse, and the doctors, nurses involved in patient management, and the patients were all blinded to the study code. All patients received subcutaneous injections of placebo or interferon-, 3 million units, three times a week for 4 weeks. During the following 4 weeks, they did not receive any injections (washout period); they were then switched to the opposite treatment for another 4 weeks. After treatment discontinuation, patients were followed for a final 4-week period (washout period). Patients were randomly assigned to either sequence of the crossover design. The study lasted 16 weeks; during this time patients were seen weekly for clinical evaluations including a physical examination, a review of subjective complaints, and standard hematologic tests including platelet counts. All patients received, throughout the study period, zidovudine therapy at 200 mg three times a day. Bleeding times, immune studies, and p24 antigen, hematologic, renal, and hepatic tests were done at weeks 0, 4, 8, 12, and 16. Evaluation Criteria The primary end point, established before the beginning of the study, was the variation in the number of circulating platelets. A secondary end point was the clinical response to interferon- treatment, defined as follows: 1) complete response: platelet count more than 100 109/L; 2) partial response: platelet count more than 50 109/L and less than 100 109/L; 3) failure: platelet count less than 50 109/L. A cut-off level of 50 109 platelets/L was chosen to define treatment failure because conventionally hemorrhage is rare when counts are greater than this limit. Other secondary end points included the bleeding time, p24 antigen levels in serum, CD4 and CD8 counts, 2-microglobulin levels in serum, and platelet-associated IgG. Laboratory Data Platelet counts were determined on ethylenediaminetetraacetic acid-anticoagulated venous blood samples by using electronic particle counters (Coulter Counter, STKR, Hialeah, Florida for the four centers). Platelet counts were measured on each patient using the same instrument throughout the study. Bleeding time was carried out according to Mielke and colleagues [34] by the use of a standardized template (Simplate II, General Diagnostics, Morris Plains, New Jersey). The registration of the bleeding time was followed for a maximum of 30 minutes; when the bleeding time exceeded 30 minutes, it was considered to be equal to 30 minutes for the statistical analysis. CD4 and CD8 lymphocyte counts were determined by two-color flow cytometry using monoclonal antibodies (Leu 2-3+, Leu 2+3-; Leu 4+Dr-; Becton Dickinson, Franklin, New Jersey) on whole blood samples. Serum p24 core antigen was determined by enzyme immune assay (New England Nuclear, du Pont, Rockville, Maryland); the least detectable amount with this assay is 4.4 pg/mL of serum. Serum 2-microglobulin was assayed by enzyme immune assay (Behring, Scoppito, Italy). Serum platelet antibodies were detected with the indirect platelet suspension immunofluorescence test [35]. Determinations of hemoglobin, complete blood counts, serum glucose, blood urea nitrogen, creatinine, liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, -glutamyltranspeptidase, and total bilirubin), prothrombin time, and activated partial thromboplastin times were carried out according to standard procedures. Data Collection and Statistical Analysis All investigators, nurses, and laboratory personnel involved in patient and sample management were blinded to treatment groups until all end points were determined at the end of the study. First-order carryover identifies the residual effect of a given treatment at the time of the second baseline (before the beginning of the second treatment), whereas second-order carry-over indicates any residual effect of the first treatment at the time of the second treatment. Data required by the study protocol were collected and recorded in case report forms by the investigators at each of the participating centers. The case report forms were then submitted to clinical research personnel at the

The pp65 antigenaemia test as a predictor of cytomegalovirus-induced end-organ disease in patients with AIDS

Objective:To evaluate the predictive value of pp65 antigenaemia quantitative test for cytomegalovirus (CMV) end-organ disease in patients with advanced HIV infection. Design and patients:A prospective study in AIDS patients or HIV-infected subjects with CD4 count < 150 × 106/l or CD4 percentage < 10% was carried out. Patients with a history of CMV disease or positive viraemia or antigenaemia tests, and subjects under anti-herpes suppressive therapy were excluded. Clinical, ophthalmoscopic, biochemical and virological (antigenaemia test) evaluations were performed at baseline and every 1–3 months until the onset of CMV end-organ disease. Setting:Institutional tertiary care centre. Results:Forty-nine patients were evaluable for this study. End-organ disease was observed in 13 patients, 11 with at least one positive test, two with persistently negative assays. Thirteen patients without CMV disease had at least one positive test, whereas 23 always had negative tests. The 12-month Kaplan–Meier estimate of the incidence of CMV disease in our population was 30.9%, and was 75% in antigenaemia-positive subjects. The negative predictive value (NPV) of the test was 92%, and the positive predictive value (PPV) was 45.8%. However, the NPV of quantitative (> 20 cells) antigenaemia assay was 92.1%, and the PPV was 90.9%. Conclusions:The antigenaemia test is a quick, simple and easy to perform assay for diagnosing CMV infection. The NPV is fairly good, as is the PPV when the quantitative method (> 20 positive cells) is used. This test could be used as an alternative to polymerase chain reaction in order to select patients at higher risk of CMV disease who can be treated with pre-emptive anti-CMV therapy.

Role of antigenemia assay in the early diagnosis and prediction of human cytomegalovirus organ involvement in AIDS patients

The role of an antigenemia assay in the diagnosis and prediction of human cytomegalovirus (HCMV) disease in AIDS patients was evaluated. The clinical history of 62 patients with advanced HIV infection from whom a total of 248 blood samples were drawn and tested by the HCMV antigenemia assay was examined retrospectively. Between December 1992 and January 1994, 28 episodes of HCMV disease with organ involvement were recorded; the antigenemia assay was positive in 23 of them (82.1 %). In particular, this test was positive in 11 of 12 (91.6 %) first episodes and in 3 of 3 (100 %) recurrent episodes occurring in patients not receiving maintenance therapy. The same test was positive in 9 of 13 (69.2 %) recurrent episodes occurring in patients receiving maintenance therapy. The first occurrence of HCMV disease was always preceded by a positive antigenemia assay 2 and 4 months before diagnosis (in all 7 patients of the 7 for whom a blood sample was available before HCMV disease). A positive antigenemia test result was not always followed by organ involvement, but a high positive cell count (>100/200,000 polymorphonuclear leukocytes) strongly correlated with the appearance of HCMV disease in the following 1 to 3 months (100 % of cases). The antigenemia assay is a useful and reliable indirect method for the diagnosis and prediction of HCMV endorgan disease in severely and persistently immunocompromised AIDS patients.

Viridans streptococci septicemia in cancer patients: a clinical study.

Viridans streptococci septicemia was documented in ten cancer patients, 7 of whom were neutropenic (< 1000/mmc). Pneumonia was presumed to be the source of bacteremia in six patients. Viridans streptococci isolated from sputum culture in an immunocompromised host must be regarded as the potential etiological agent, then further characterized and checked for antibiotic sensitivity.

Post operative surveillance of human hydatidosis: evaluation of immunodiagnostic tests

Summary We investigated the kinetics of antibodies detected by indirect hemagglutination (IHA), IgE Elisa and immunoelectrophoresis (IEP) in patients with hydatid disease operated on and continuously followed in the pre‐operative and post‐operative periods. In the pre‐operative phase the IgE Elisa test was found to be adequately sensitive (68.4%) compared with IHA (79%), with a ratio of IgE Elisa/IHA positivity of 87%, while IEP was positive in 55.3% of cases (IEP/IHA ratio = 70%). During post‐operative follow‐up IHA became negative late in patients who were cured (7 out of 11 were still positive after 4 yrs), whereas IEP and IgE Elisa became negative within 2 yrs of operation (apart from 1 patient with a persisting positive IgE Elisa 3 yrs later). However, IgE Elisa appeared clearly more sensitive in revealing postoperative recurrences (13 out of 13 patients had positive IgE Elisa, vs. 6 out of 13 IEP).