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Pier-Angelo Tovo

Publications and source records attributed to Pier-Angelo Tovo.

At least 19 recordsLinked to original sources
PubMed2007

Cancer rates after year 2000 significantly decrease in children with perinatal HIV infection: a study by the Italian Register for HIV Infection in Children.

PURPOSE: To evaluate the impact of highly active antiretroviral therapy (HAART) on cancer incidence in HIV-infected children throughout a 20-year period. PATIENTS AND METHODS: An observational population study was conducted on 1,190 perinatally HIV-infected children enrolled onto the Italian Register for HIV Infection in Children from 1985 to 2004 and never lost to follow-up (total observation time, 10,037.66 years). Cancer rates were calculated in the pre-HAART (1985 to 1995), early HAART (1996 to 1999), and late HAART (2000 to 2004) periods and compared using Poisson regression adjusted for age. The proportion of HAART-treated children increased from 4.1% in 1996 to 60.4% in 1999 and to 81.5% in 2004. In the same time frame, the proportion of children receiving HAART for at least 2 years increased from 3.1% to 77.0%. RESULTS: Overall, 35 cancers occurred. Cancer rates were 4.49 (95% CI, 2.37 to 6.64), 4.09 (95% CI, 1.68 to 6.50), and 0.76 (95% CI, 0.00 to 1.80) per 1,000 children per year in 1985 to 1995, 1996 to 1999, and 2000 to 2004, respectively. Notably, there was no significant difference comparing the periods from 1985 to 1995 and 1996 to 1999 (P = .081). By contrast, cancer rates were significantly lower in the period from 2000 to 2004 than in 1996 to 1999 (P < .0001). Results were confirmed by separately analyzing data from children observed from birth (P = .418 for 1985 to 1995 v 1996 to 1999; P = .001 for 1996 to 1999 v 2000 to 2004). CONCLUSION: Dramatically reduced cancer rates were observed only in the late HAART period in parallel to the increasing proportion of children receiving HAART therapy.

Antiretroviral Therapy, Highly Active↗
PubMed2006

Evolution of hepatitis C viral quasispecies and hepatic injury in perinatally infected children followed prospectively.

Perinatal infection with hepatitis C virus (HCV) is characterized by a wide range of alanine aminotransferase (ALT) levels. The mechanisms responsible for this variability are unknown. We examined whether the evolution of the HCV quasispecies was associated with different ALT profiles in perinatally infected children. Sequences within HCV envelope 1 and 2 genes, inclusive of the hypervariable region 1, the viral load, and the nascent humoral immunity were analyzed in serial serum samples from 12 perinatally infected children prospectively followed for a median of 53 months. These patients were selected to represent two different ALT patterns during the first year of life: 6 had high levels (maximum values ranging from 4.2 to 30 times the normal upper limit), and 6 had normal or slightly elevated levels (< 2 times the normal upper limit). Two patterns of viral evolution were identified according to the ALT profiles. Biochemical evidence of hepatic injury was invariably associated with a mono- or oligoclonal viral population, whereas mild or no liver damage correlated with the early emergence of a heterogeneous viral quasispecies. Consistent with selective immune pressure, amino acid changes occurred almost exclusively within the hypervariable region 1 and were temporally associated with antibody seroconversion; at this time, the difference in genetic diversity between the two groups was highly significant (P = 0.002). The two patterns of viral evolution persisted over time and did not correlate with viral load or genotype. Our study demonstrates that, in perinatally infected children, the evolution of HCV quasispecies correlates with hepatic injury. The sequences reported in this paper have been deposited in the GenBank database (accession nos. DQ 504441-DQ 507112).

Alanine Transaminase↗
PubMed2006

Virologic, immunologic, and clinical benefits from early combined antiretroviral therapy in infants with perinatal HIV-1 infection.

OBJECTIVE: To investigate the impact of early versus deferred combined antiretroviral treatment (ART) in asymptomatic or moderately symptomatic [Centers for Disease Control and Prevention (CDC) category N, A or B] infants with perinatal HIV-1 infection. METHODS: A multi-centre nationwide case-control study was conducted. Data from 30 infants treated with combined ART with three or more drugs before 6 months of age were compared with data from 103 infants starting ART with three or more drugs after 6 months of age. The median follow-up time was 4.1 years (range, 1.0-6.5 years). RESULTS: No difference was evident in the first available viral load and CD4 T-lymphocyte percentage between the two groups of children. Early-treated infants showed significantly lower viral loads than infants receiving deferred treatment at all the follow-up periods. A higher proportion of early-treated infants than infants receiving deferred treatment (73.3% versus 30.1%; P < 0.0001) reached an undetectable viral load. Higher CD4 T-lymphocyte percentages were found in early-treated infants at 13-24 (P < 0.0001), 25-36 (P < 0.0001), and 37-48 (P = 0.003) months of age. No early-treated infant versus 20 of 103 (19.4%) infants receiving deferred ART (P = 0.02) showed a CD4 T-lymphocyte percentage of less than 15% at one time point during follow-up. No CDC category A, B or C clinical event occurred in early-treated infants over the follow-up period while 44 of 103 (42.7%) infants receiving deferred treatment presented a decline in the CDC category. Kaplan-Meier analyses revealed significant differences in CDC category A (P = 0.0002), B (P = 0.0003), and C (P = 0.0018) event-free survivals. CONCLUSION: The data suggest virologic, immunologic, and clinical benefits from early administration of ART.

Age Factors↗
PubMed2006

Accuracy of HCV-RNA PCR tests for diagnosis or exclusion of vertically acquired HCV infection.

The aim of the study was to estimate the sensitivity, specificity, positive (PPV) and negative (NPV) predictive values, and likelihood ratios for HCV-RNA PCR tests for the early diagnosis or exclusion of HCV infection in vertically exposed children. Data were included for children with confirmed HCV infection status from a European multi-center study. Confirmation was dependent on antibody status at or beyond 18 months, the 'gold standard' measure of infection status against which the use of qualitative HCV-RNA PCR tests was assessed. Of the 547 children included in this analysis, 193 were HCV-infected and 354 were not. Sensitivity of the HCV-RNA PCR test was low at birth (22%), but increased to 85% by 6 months. Specificity of RNA PCR was constant over age at 98%. The PPV of the PCR test rose from 33% at birth to 78% at 9 months of age, while NPV ranged from 96% to 99%. The high positive likelihood ratios from 1 month of age indicate strong evidence to diagnose infection but the negative likelihood ratios were consistent with weak evidence to exclude infection. The results suggest that the first qualitative HCV-RNA PCR test should be delayed until after the first month of life given the low sensitivity in the first few weeks. Although a negative test result after this time indicates probable absence of infection, this should be confirmed with a negative anti-HCV antibody test between 9 and 15 months of age as negative PCR results can be observed in infected children with fluctuations in viremia.

Age Factors↗
PubMed2006

Intracranial aspergillosis in children successfully treated with antifungal therapy and surgical intervention.

Invasive aspergillosis is an uncommon but often lethal complication in immunocompromised patients. Despite the progress obtained with new antifungal drugs, intracranial aspergillosis often requires a combined medical and surgical approach. Most cases previously reported in immunocompromised children were fatal. We describe 4 immunosuppressed children with intracranial aspergillosis successfully treated with surgery and antifungal long-term therapy.

Adolescent↗
PubMed2005

Lower mother-to-child HIV-1 transmission in boys is independent of type of delivery and antiretroviral prophylaxis: the Italian Register for HIV Infection in Children.

The relationship between infant's gender and rate of HIV-1 mother-to-child transmission (MTCT) was evaluated in a prospective cohort of 4151 children (2166 boys and 1985 girls) born to HIV-1-infected mothers enrolled in the Italian Register for HIV Infection in Children. Logistic regression models were performed to estimate crude odds ratios (ORs) and adjusted odds ratios (AORs) and 95% CIs for factors potentially influencing MTCT separately for the period 1985-1995 and the period 1996-2001. To evaluate rates of MTCT by gender in specific subgroups, separate logistic regression models by mode of delivery and antiretroviral prophylaxis were performed. Among children born in 1985-1995, 15.5% boys (95% CI: 13.6-17.7) and 17.9% girls (95% CI: 15.7-20.3) were infected (P = 0.1181). After 1995, a lower proportion of boys (3.1% [95% CI: 2.0-4.4]; AOR: 0.43 [95% CI: 0.26-0.71], P = 0.0008) than girls (AOR: 6.3%, 95% CI: 4.8-8.1) was infected. Lower AORs for boys persisted independently of elective cesarean delivery (AOR: 0.31, 95% CI: 0.14-0.71); other than elective cesarean (AOR: 0.38, 95% CI: 0.19-0.78) and antiretroviral prophylaxis (zidovudine monotherapy (AOR: 0.11, 95% CI: 0.03-0.38); none (AOR: 0.43, 95% CI: 0.21-0.90). No difference was observed when combined therapy in the mother was administered (AOR: 1.14, 95% CI: 0.30-4.32), but results were likely to be biased by the very low rate of infected children in this group. A lower proportion of HIV-1-infected boys in children born after 1995 was found. Factor(s) intrinsic to gender (rather than type of delivery or maternal antiretroviral prophylaxis) may be involved, because the risk of infection in boys was lower independent of interventions. A possible explanation is that, among infected fetuses, more girls survive up to the end of pregnancy and may take advantage of the benefits of preventive strategies.

Anti-HIV Agents↗
PubMed2005

Antileishmanial activity of HIV protease inhibitors.

The proteasomes of some protozoa are possible targets for chemotherapy. Leishmaniasis is a major health problem in human immunodeficiency virus (HIV) co-infected subjects. Two HIV protease inhibitors (PI), indinavir and saquinavir, have been shown to block proteasome functions; we therefore investigated their effects on the growth of two Leishmania spp. (Leishmania major and Leishmania infantum). After 24 h of treatment, both drugs exhibited a dose-dependent antileishmanial activity, with 50% lethal dose (LD50) values of, respectively, 8.3 microM and 7 microM on L. major; minor activity was observed on L. infantum. These results add new in vitro insights into the wide-spectrum efficacy of PI and suggest studying their action on amastigote forms of leishmania within macrophages in order to validate their potential contribution against opportunistic infections in treated seropositive patients.

Animals↗
PubMed2005

The management of HCV infected pregnant women and their children European paediatric HCV network.

BACKGROUND/AIMS: As evidence accumulates relating to mother-to-child (vertical) transmission of hepatitis C virus (HCV), it is timely to draw up guidelines for the clinical management of HCV infected pregnant women and their children. METHODS: A review of evidence from the European Paediatric HCV Network (EPHN) prospective study of HCV infected women and their children and other published studies. Meeting of EPHN clinical experts to reach a consensus on recommendations for management. Each recommendation was graded according to the level of evidence. RESULTS/CONCLUSIONS: Although several risk factors for mother-to-child transmission have been identified, none are modifiable and there are currently no interventions available to prevent vertical transmission of HCV. Data on timing of loss of maternal antibodies and reliability of diagnostic tests inform the optimum follow-up schedule for confirmation or exclusion of infection in children born to HCV infected women. Based on the current evidence, routine antenatal screening for HCV should not be introduced and neither elective caesarean section nor avoidance of breastfeeding should be recommended to HCV infected women to prevent mother-to-child transmission of HCV. HCV/HIV co-infected women should follow existing HIV guidelines.

Europe↗
PubMed2005

Growth in the first 5 years of life is unaffected in children with perinatally-acquired hepatitis C infection.

OBJECTIVES: To identify the effect of vertical hepatitis C virus (HCV) infection or exposure on growth in childhood. STUDY DESIGN: Children (n=1203) born to HCV-infected mothers were followed up from birth prospectively in centers of the European Paediatric Hepatitis C virus Network. Z-scores compared height- and weight-for-age in HCV-infected and -uninfected children, adjusting for other factors using linear regression. We also quantified the effect of maternal chronic infection with HCV on childhood growth. RESULTS: There was no significant effect of vertical HCV infection on growth (height P=.223, weight P=.095) nor a significant effect of maternal chronic infection with HCV (height P=.733, weight P=.274). Prematurity and maternal injecting drug use were associated with a significant reduction in height (P < .001) and weight (P < .001) in all HCV-exposed children. CONCLUSIONS: This population of HCV exposed infants has higher rates of maternal injecting drug use and prematurity than standard populations and so there are implications for growth of these children, but this is not a direct result of HCV infection or exposure to chronic maternal HCV infection.

Adult↗
PubMed2005

Hepatitis B virus and hepatitis C virus infections in children.

PURPOSE OF REVIEW: To analyse the most relevant recent information on efficacy, duration and coverage of anti-hepatitis B virus vaccination; correlates of mother-to-child hepatitis C virus transmission; the natural history and outcomes of hepatitis B and C virus infections in children; the efficacy and safety of specific therapies. RECENT FINDINGS: Insufficient hepatitis B virus vaccine coverage and incomplete or delayed vaccine cycles need improvement in many countries. Hepatitis B virus mutants may explain some fulminant hepatitis in perinatally infected infants and vaccine failures. No interventions to prevent vertical hepatitis C virus transmission have been identified. Spontaneous clearance of hepatitis B is lower in children than in adults, while the rates appear to be similar for hepatitis C. The disease progression is slower for both infections in childhood. Several studies support the efficacy and safety of interferons and lamivudine in chronic hepatitis B or of interferons and ribavirin in chronic hepatitis C in children, but the optimal therapy remains unclear. SUMMARY: There are doubts as to the long-term persistence of anti-hepatitis B immunization in low-endemicity areas. Routine hepatitis C virus testing in pregnancy is not recommended as there are no available prophylactic measures. Although hepatitis B and C virus infections are usually asymptomatic or with mild manifestations in childhood, concerns around their long-term clinical impact suggest the need for early treatment. Children should preferably be treated in the context of targeted trials for a better understanding of the efficacy and tolerance of drugs currently used in adults.

Antiviral Agents↗
PubMed2005

Persistently high IgA serum levels are a marker of immunological or virological failure of combined antiretroviral therapy in children with perinatal HIV-1 infection.

Non-expensive and low-complexity surrogate markers for monitoring the response to combined antiretroviral therapy (combined-ART) are needed in poor-resource settings where routine assessment of CD4+ T-lymphocyte count and viral load can not be afforded. We longitudinally evaluated Ig serum levels in 234 HIV-1 infected children receiving combined-ART with > or = 3 drugs. Since Ig levels physiologically vary with age, differences at different age periods were evaluated as differences in z-scores calculated using the mean and standard deviation of the normal population for each age period. Data from 17 (7.3%) children with immunological failure and from 54 (23.1%) children with virological failure of combined-ART were compared with data from not-failed children. At baseline children with immunological failure showed higher IgM z-scores (P = 0.042) than children without. After 3-12 months of therapy immunologically failed children displayed higher viral loads (P < 0.0001) and IgA (P = 0.043) z-scores than not-failed children. Similarly, at the same follow-up time, children with virological failure showed lower CD4(+) T-lymphocyte percentages (P = 0.005) and higher IgA z-scores (P < 0.0001) than not-failed children. No difference in IgG or IgM z-scores was evidenced between failed and not-failed children after 3-12 months of therapy. In conclusion, IgA serum level is a cheap and low-complexity marker of immunological or virological failure of combined-ART which might be adopted in poor-resource settings.

Adolescent↗
PubMed2005

Excluding hepatitis C virus (HCV) infection by serology in young infants of HCV-infected mothers.

AIM: To identify the age at which HCV infection can be accurately excluded by serology in young children born to HCV-infected mothers and to determine an appropriate schedule of antibody testing, most informative to clinical practice. METHODS: Children born to HCV-infected mothers were followed in centres of the European Paediatric HCV Network. Turnbull survival analysis techniques were used to estimate the age at which HCV-uninfected children will lose maternally acquired HCV antibodies. Factors associated with age at antibody loss were assessed in logistic regression. RESULTS: In 1104 children followed from birth and later confirmed to be HCV uninfected, an estimated 57% will have lost passively acquired HCV antibodies before 6 mo of age and an estimated 95% by 12 mo. Maternal HCV viraemia antenatally was associated with later, and maternal HIV-HCV co-infection with earlier loss of antibody. Actual antibody testing of uninfected children at 12 mo identified 82% of those tested to be anti-HCV negative. CONCLUSIONS: Serological confirmation of HCV uninfection remains necessary given the uncertainty in the specificity of virological tests. These results suggest that, in most children, HCV infection can be ruled out with serological testing at an earlier age than previously thought, and that nearly all children born to HCV-infected mothers will have lost passively acquired maternal antibodies by 1 y of age. Antibody loss was significantly later among children born to HCV viraemic mothers. The earlier loss of HCV antibodies in children born to HIV co-infected mothers may be due to HIV treatment.

Age Factors↗
PubMed2005

The HIV protease inhibitors nelfinavir and saquinavir, but not a variety of HIV reverse transcriptase inhibitors, adversely affect human proteasome function.

BACKGROUND: In HIV-infected patients some clinical and immunological benefits of antiretroviral therapy, which frequently include a combination of HIV protease inhibitors (PIs) and reverse transcriptase inhibitors (RTIs), cannot be solely explained by the drugs' action on viral enzymes. Proteasomes constitute the central protease of the ubiquitin ATP-dependent pathway involved in many cellular processes, as well as in HIV maturation and aggressiveness. OBJECTIVE: To explore whether the PIs nelfinavir and saquinavir and the RTIs abacavir, nevirapine, delavirdine, stavudine and didanosine affect proteasome function in vitro and in vivo. METHODS: Peptidase activity of purified human 26S and 20S proteasomes was assayed with and without the drugs at different concentrations. Intracellular proteasome proteolytic activity was evaluated by searching for ubiquitin-tagged proteins in HL60 cells incubated with and without the drugs. RESULTS: At therapeutic dosages, nelfinavir and saquinavir inhibited proteasome peptidase activity and caused intracellular accumulation of polyubiquitinated proteins, a hallmark of proteasome proteolytic inhibition in vivo; the RTIs failed to evoke either effect. CONCLUSION: Proteasomes are targeted by the two PIs but not the RTIs. Therefore, in HIV-infected patients the beneficial effect of a therapy including one of the two PIs should partly rely on inhibition of host proteasome function.

HIV Protease Inhibitors↗
PubMed2005

Zidovudine administration during pregnancy and mitochondrial disease in the offspring.

Prophylactic administration of zidovudine (ZDV) to mother-child pairs reduces HIV transmission. ZDV can impair mitochondrial (mt) DNA polymerase gamma, leading to mtDNA depletion. Signs of mitochondrial dysfunction have been observed in a few children with prenatal exposure to nucleoside analogues, although no mtDNA depletion was demonstrated. Other studies failed to confirm mitochondrial disorders in children who were exposed to antiretroviral agents in utero. A child, whose HIV-infected mother received ZDV from the fourth month of pregnancy, developed neonatal encephalomyopathy, anaemia and hyperlactataemia. At 2 weeks of age, a muscle biopsy exhibited red-ragged-like fibres, proliferation of abnormal mitochondria and a 90% depletion of mtDNA without qualitative abnormalities. At 6 months, the depletion was less profound (about 50% of normal values). Severe psychomotor delay and visual disturbances persisted at 30 months, but they were greatly reduced at 5-year follow-up. These laboratory and clinical findings clearly demonstrated that mtDNA alteration was acquired and not consequent to an inherited disorder. Fetal exposure to ZDV may have caused the mtDNA depletion, which, although temporary, led to irreversible but not progressive brain damage.

Anti-HIV Agents↗
PubMed2003

Inter-laboratory comparison of HCV-RNA assay results: implications for multi-centre research.

To investigate whether it is appropriate to assume comparability of hepatitis virus C (HCV)-RNA results across laboratories in multi-centre studies, nine laboratories of the European Paediatric HCV Network participated in an international proficiency study of HCV-RNA assays. A panel of 12 samples of different dilutions and genotypes was sent to each laboratory and tested with qualitative and/or quantitative HCV-RNA assays according to local procedures. Commercial assays were used in seven laboratories and in-house assays in two. All six laboratories in which a commercial qualitative assay was used were proficient, as were four of six runs (in five laboratories) in which a commercial quantitative assay was used. The proficiency of the laboratories where in-house assays were used could not be assessed according to the VQC definition because of differences in the methods used. Overall, there were several false-negative results, but only one false-positive result with a quantitative assay and none with a qualitative assay. The false-negative results may have implications for the diagnosis of infection, and highlight the need for an antibody test to be performed at 18 months to confirm the absence of infection. The results of qualitative assays were generally consistent across laboratories but it was difficult to evaluate and compare the results of quantitative assays. Multivariate analysis of data collected in multi-centre studies should therefore allow for centre and/or assay used.

Child, Preschool↗
PubMed2002

The human 26S proteasome is a target of antiretroviral agents.

BACKGROUND: Proteasomes constitute the degradative machinery of the ubiquitin/adenosine triphosphate-dependent proteolytic pathway, which is involved in many cell functions, including immune response and apoptosis, and in HIV maturation and infectivity. OBJECTIVE: To examine whether proteasomes are targeted by antiretroviral agents. METHODS: Chymotrypsin-like, trypsin-like and peptidyl-glutamyl-peptide hydrolysing activities of purified human 26S and 20S proteasomes, the latter depleted or enriched in 11S regulator, were assayed after incubation with indinavir, lamivudine and zidovudine at 1-80 microM alone and in combination. To assess the drug effects on cellular functions regulated by proteasomes, the accumulation of ubiquitin-tagged proteins, the processing of the nuclear factor kappa B precursor p105, and the degradation of the inhibitor of nuclear factor kappa B, isoform alpha (IkappaBalpha) were evaluated by Western immunoblotting in Jurkat cells after incubation for 6 h with the drugs above. RESULTS: Trypsin-like and mostly chymotrypsin-like activities of purified 26S proteasome were inhibited by each drug from 10 to 80 microM, more by double combinations and mostly by the triple combination. The peptidyl-glutamyl-peptide hydrolysing activity of the 26S proteasome and the three peptidase activities of the 20S proteasome, depleted or enriched in 11S regulator, were unaffected. The accumulation of ubiquitin-tagged proteins, reduced IkappaBalpha degradation and p105 processing were appreciable in intact cells with the triple drug combination. CONCLUSION: The human 26S proteasome is a target of antiretroviral agents. This suggests that the antiviral action and some clinical and immunological benefits of combined antiretroviral therapy rely not only on its known effects on viral enzymes, but also on host cell components.

Anti-HIV Agents↗