Antonio Boschini

Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load.

Objective:To characterize HIV-infected patients with neurosymptomatic cerebrospinal fluid (CSF) ‘escape’, defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA more than 1-log higher than plasma RNA. Design:Retrospective case series. Setting:Four urban medical centers in the United States and Europe. Participants:Virologically controlled HIV-infected patients on antiretroviral therapy (ART) with progressive neurologic abnormalities who were determined to have CSF ‘escape’. Intervention:Optimization of ART based upon drug susceptibility and presumed central nervous system exposure. Main outcome measures:Levels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, and MRI findings. Results:Ten patients presented with new neurologic abnormalities, which included sensory, motor, and cognitive manifestations. Median CSF HIV RNA was 3900 copies/ml (range 134–9056), whereas median plasma HIV RNA was 62 copies/ml (range <50 to 380). Median CD4+ T-cell count was 482 cells/&mgr;l (range 290–660). All patients had been controlled to less than 500 copies/ml for median 27.5 months (range 2–96) and five of 10 had been suppressed to less than 50 copies/ml for median 19.5 months (range 2–96). Patients had documentation of a stable ART regimen for median 21 months (range 9–60). All had CSF pleocytosis or elevated CSF protein; seven of eight had abnormalities on MRI; and six of seven harbored CSF resistance mutations. Following optimization of ART, eight of nine patients improved clinically. Conclusion:The development of neurologic symptoms in patients on ART with low or undetectable plasma HIV levels may be an indication of CSF ‘escape’. This study adds to a growing body of literature regarding this rare condition in well controlled HIV infection.

Cancer risk among men with, or at risk of, HIV infection in southern Europe.

Objective:To evaluate the cancer risk in southern European men with, or at risk of, HIV infection. Design:An analysis of longitudinal data to assess time-dependent rare events. Methods:Data from a cohort of HIV seroconverters, and from two hospital-based HIV seroprevalent cohorts were combined and analysed. The number of cancer cases observed was compared with the expected number, obtained from cancer incidence rates among men in the general population. Age-standardized incidence ratios (SIR) and their 95% confidence intervals (CI) were computed. Results:A total of 19 609 person-years of observation were accumulated among HIV-positive men, and 7957 person-years among HIV-negative men. Among HIV-positive men, statistically significant increased SIR were seen for Hodgkins disease (HD) (SIR = 8.7), liver cancer (SIR = 11.0), and cancer of the salivary glands (SIR = 33.6). An excess of lung cancer was seen among intravenous drug users (IDU), but not among homosexual men. When the risk of all non-AIDS-defining cancers was considered, HIV-positive men had a nearly twofold excess (95% CI: 1.2–2.8). A risk of similar magnitude emerged among HIV-negative IDU (95% CI: 1.0–4.5), largely attributable to lung cancer and HD. Conclusion:These findings confirm that HIV infection increases the risk of HD, whereas they suggest that the risk of hepatocellular carcinoma may also be enhanced by HIV infection. The observation of an elevated risk of lung cancer in both HIV-positive and HIV-negative IDU points to personal behaviours unrelated to HIV infection.

Clinical Cryptosporidiosis and Human Immunodeficiency Virus (HIV)-Induced Immunosuppression: Findings from a Longitudinal Study of HIV-Positive and HIV-Negative Former Injection Drug Users

The natural history of cryptosporidiosis was investigated during a waterborne outbreak among 1731 members of a drug rehabilitation community in Italy; 19.6% of the members were positive for human immunodeficiency virus (HIV). Demographic and clinical information and pre-outbreak serum samples were available. Clinical data were analyzed, stratifying the study population by HIV serostatus and CD4 cell count. The attack rate of clinical cryptosporidiosis was 13.6% among HIV-negative individuals and 30.7% among HIV-positive individuals, although in the latter, it varied according to CD4 cell count. Clinical symptoms and their duration were also related to CD4 cell count. Chronic symptoms were observed in only 16 individuals (15.4%), who all had <150 CD4 cells at the onset of the illness. Among a systematic sample of 198 individuals, 14.1% already had anti-Cryptosporidium antibodies before the outbreak, and 51.2% developed specific antibodies during the outbreak. The development and clinical manifestations of cryptosporidiosis were strongly influenced by the level of HIV-induced immunosuppression.

Safety and immunogenicity of influenza vaccination in individuals infected with HIV

Influenza can cause severe complications in HIV infected individuals leading to increases in hospitalisation and mortality. Vaccination is recommended for such individuals, but some studies reported that immunisation against influenza may stimulate an increase of HIV viral load and decrease of CD4+ cells count. A review of published studies, including our study carried out in HIV former drug addicts, indicates that vaccination against influenza is well tolerated in both children and adult individuals with HIV, but response to vaccination is lower than that observed in immunocompetent individuals. Most studies, including our own, show that vaccination does not induce significant changes in viral load and CD4+ cell counts. In studies reporting modifications of such parameters there is a general agreement that the increased viral replication is usually transient and unable to determine a clear, measurable progression of the underlying HIV disease. Therefore, vaccination against influenza can be safely administered to HIV infected people.

Safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine in HIV-1 infected former drug users

The immunogenicity of 23-valent pneumococcal polysaccharide vaccine was assessed in 57 HIV-1 infected former intravenous drug users and in 20 HIV-1 negative controls. The effect of vaccination on HIV-1 infection was studied in a subgroup of 38 patients, 60% of whom under highly active antiretroviral therapy (HAART). Antibody to capsular polysaccharides from Streptococcus pneumoniae serotypes 3, 4, 6B, 19F, 23 F, and changes in CD4+ count, HIV-1 RNA, proviral DNA and HIV-1 phenotype were measured in pre- and post-vaccination samples. Vaccinations were well-tolerated. The rate of responders was higher (P<0.05) in HIV-1 negative than in HIV-1 infected individuals. No difference in antibody response was found within HIV-1 infected patients stratified according to CD4+ counts. Post-vaccination antibody geometric mean concentrations (GMCs) to the five antigens were higher (P<0.05) than baseline in HIV-1 negative subjects, but not in HIV-1 positive individuals. Those with CD4+ >500 cells/mm(3) showed a significant increase of antibody against type 3 only. Immunisation caused no significant changes in CD4+ counts and in either plasma HIV-1 RNA nor proviral DNA levels. Pneumococcal vaccination does not induce virological or immunological deterioration in HIV infected patients, but the antibody response to a single dose of vaccine is poor.

Phenotypic characteristics and tendency to apoptosis of peripheral blood mononuclear cells from HIV+ long term non progressors

The aim of this study was to analyze (i) phenotype, (ii) in vitro spontaneous and induced apoptosis, (iii) glutathione (GSH) intracellular content and (iv) inhibitors of apoptosis of potential therapeutical use in peripheral blood mononuclear cells (PBMC) from HIV+ long term non progressors (LTNP), in comparison with progressors (HIV+P) and seronegative controls (HIV−). Three groups of subjects were studied: 15 HIV+P (patients losing >150 CD4+/year), 9 LTNP (subjects infected by HIV for at least 7 years without clinical and immunological signs of progression, with a mean of 898 CD4+/μL) and 18 HIV−. All subjects were living in a large community for former drug addicts, and were matched for age and sex. We used flow cytometry for analyzing PBMC phenotype and apoptosis; high performance liquid chromatography for measuring intracellular GSH content. PBMC phenotype of LTNP shared characteristics with those of both HIV− and HIV+P. Indeed, LTNP showed a normal number CD4+ cells (an inclusion criteria), but significantly increased numbers of CD8+ lymphocytes, activated T cells, CD19+, CD5+ B lymphocytes and CD57+ cells, as well as a decrease in CD19+, CD5− B lymphocytes and CD16+ cells. In LTNP, spontaneous apoptosis was similar to that of HIV− and significantly lower than that of HIV+P. Adding interleukin-2 (IL-2) or nicotinamide (NAM) significantly decreased spontaneous apoptosis in LTNP and HIV+P. Pokeweed mitogen-induced apoptosis was also similar in LTNP and HIV−, but significantly lower than that of HIV+P. In HIV+P, but also in LTNP, spontaneous apoptosis was inversely correlated to the absolute number and percentage of CD4+ cells and directly correlated to the number and percentage of activated T cells present in peripheral blood. GSH intracellular content was greatly decreased in PBMC from HIV+P and slightly, but significantly, reduced in LTNP. Adding 2-deoxy-D-ribose, an agent provoking apoptosis through GSH depletion, to quiescent PBMC resulted in similar levels of massive cell death in the three groups. This phenomenon was equally prevented in the three groups by N-acetyl-cysteine but not by IL-2. A complex immunological situation seems to occur in LTNP. Indeed, PBMC from LTNP are characterized by a normal in vitro tendency to undergo apoptosis despite the presence of a strong activation of their immune system, unexpectedly similar to that of HIV+P. Our data suggest that NAM and IL-2 are possible candidates for reducing spontaneous apoptosis in HIV infection.

Consecutive Epidemics of Q Fever in a Residential Facility for Drug Abusers: Impact on Persons with Human Immunodeficiency Virus Infection

Two large outbreaks of Q fever occurred in 1987 and 1988 in an agricultural community for the rehabilitation of drug users. Approximately 40% of the residents were human immunodeficiency virus (HIV)-positive. Two hundred thirty-five residents presented with clinical evidence of a flulike syndrome that was confirmed to be Q fever; moreover, a large proportion of residents developed an asymptomatic infection. Clinical signs and symptoms were rather nonspecific: fever, malaise, and muscle pain that were often associated with pulmonary symptoms. Single or multiple opacities were detected, with mild interstitial inflammation evident on chest roentgenograms. The source of infection was the sheepfold, which is part of the stock-farming activity of the community. Both outbreaks occurred just after lambing had begun. Residents who were exposed during the first epidemic were protected in the second one. The attack rate among HIV-positive residents was significantly higher than that among HIV-negative residents in the first outbreak, whereas only a slight, marginally significant difference was observed in the second outbreak. The clinical features of Q fever did not differ between HIV-positive and HIV-negative individuals. No cases of relapse or chronic disease were observed.

Response to 2009 pandemic and seasonal influenza vaccines co-administered to HIV-infected and HIV-uninfected former drug users living in a rehabilitation community in Italy.

BACKGROUND 2009 A(H1N1) pandemic influenza vaccination was recommended as a priority to essential workers and high-risk individuals, including HIV-infected patients and people living in communities. METHODS HIV-infected and HIV-uninfected former drug-users (18-60 years old) living in a rehabilitation community (San Patrignano, Italy) received one dose of a MF59-adjuvanted 2009 pandemic influenza vaccine and one dose of a 2009-2010 seasonal trivalent inactivated influenza vaccine (containing A/Brisbane/59/2007(H1N1), A/Brisbane/10/2007(H3N2), B/Brisbane/60/2008) simultaneously. Antibodies against each vaccine antigen were determined at the time of vaccination and one and six months post-vaccination by hemagglutination-inhibition test. RESULTS 49 HIV-infected and 60 HIV-uninfected subjects completed the study. Most (98%) HIV-infected participants were on antiretroviral treatment, the median CD4+ cell count was 350 (IQR 300)cells/μl and viremia was suppressed in 91.8% of cases. One month post-vaccination, no significant changes in immune-virological parameters were observed. One month post-vaccination, the immune responses to both pandemic and seasonal vaccine met the EMA-CPMP criteria for immunogenicity of influenza vaccines in both HIV-infected and HIV-uninfected subjects. No difference in vaccine responses was observed between the two groups. Six months after vaccination, the percentages of vaccinees with antibody titres ≥1:40 and antibody geometric mean titres significantly decreased in both groups. However, they were significantly lower in HIV-infected than in HIV-uninfected vaccinees. In subjects who had been primed to seasonal influenza the year before (through either vaccination or natural infection), levels of antibodies against 2009 A(H1N1) were higher than those measured in unprimed subjects, both one month and six months post-vaccination. CONCLUSIONS The co-administration of a single dose of 2009 pandemic MF59-adjuvanted influenza vaccine with a seasonal vaccine provided a protective immune response in both HIV-infected and HIV-uninfected individuals. Subjects who had been primed to seasonal influenza in the year preceding the pandemic had a more vigorous and long-lasting antibody response to 2009 pandemic vaccine.

Disseminated rhodococcus equi infection in HIV infection despite highly active antiretroviral therapy

BackgroundRhodococcus equi (R.equi) is an acid fast, GRAM + coccobacillus, which is widespread in the soil and causes pulmonary and extrapulmonary infections in immunocompromised people. In the context of HIV infection, R.equi infection (rhodococcosis) is regarded as an opportunistic disease, and its outcome is influenced by highly active antiretroviral therapy (HAART).Case presentationWe report two cases of HIV-related rhodococcosis that disseminated despite suppressive HAART and anti-rhodococcal treatment; in both cases there was no immunological recovery, with CD4+ cells count below 200/μL. In the first case, pulmonary rhodococcosis presented 6 months after initiation of HAART, and was followed by an extracerebral intracranial and a cerebral rhodococcal abscess 1 and 8 months, respectively, after onset of pulmonary infection. The second case was characterized by a protracted course with spread of infection to various organs, including subcutaneous tissue, skin, colon and other intra-abdominal tissues, and central nervous system; the spread started 4 years after clinical resolution of a first pulmonary manifestation and progressed over a period of 2 years.ConclusionsOur report highlights the importance of an effective immune recovery, despite fully suppressive HAART, along with anti-rhodococcal therapy, in order to clear rhodococcal infection.

Targeting Candidates for Directly Administered Highly Active Antiretroviral Therapy: Benefits Observed in HIV-Infected Injecting Drug Users in Residential Drug-Rehabilitation Facilities

The purpose of this study was to evaluate retrospectively the potential benefits of directly administered antiretroviral therapy (DAART) in HIV-infected former injecting drug users (ex-IDUs) admitted to residential drug rehabilitation facilities. We compared 106 of these patients consecutively admitted in 12 communities where DAART was administered (DAART group) to two matched control groups of ex-IDUs undergoing self-administered ART: 106 subjects in other 10 communities (SAT group) and 106 outpatients at hospital infectious-disease wards where community patients were referred after discharge (OUT group). We estimated the proportion of patients with high adherence and the hazard ratio (HR) of 20% or more increase in the CD4(+) cell count and of reaching an undetectable viral load. The proportion of patients with high adherence to treatment was highest in the DAART group. The probability of 20% or more increase in the CD4(+) cell count was significantly lower in the two control groups versus the DAART group (SAT group HR=0.32; OUT group HR=0.43). The HR of observing an undetectable HIV-RNA level versus DAART was significantly lower in the OUT group (HR: 0.71; 95% confidence interval [CI]: 0.52-0.97) but did not reach statistical significance for the SAT group (HR: 0.99; 95% CI: 0.74-1.33). Our findings after a 24-month follow-up, suggest that DAART in HIV-infected patients of drug-rehabilitation communities improves adherence, immunologic, and virologic outcome toward free outpatients. Even if our retrospective 36-month data do not show a prolonged viral suppression in these patients, DAART may be considered a valuable therapeutic and educational strategy in this particular target group.