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Background Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children Methods An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. Results 22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13–5.19; p = 0.024). Moreover, children Conclusion The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children.

Objective: To evaluate the effect of combined antiretroviral therapy on serum immunoglobulin (Ig) levels in HIV-1 perinatally infected children.Methods: Data from 1250 children recorded by the Italian Register for HIV Infection in Children from 1985 to 2002 were analysed. Since Ig levels physiologically vary with age, differences at different age periods were evaluated as differences in z-scores calculated using means and standard deviations of normal population for each age period. Combined antiretroviral therapy has become widespread in Italy since 1996, thus differences in Ig z-scores between the periods 1985-1995 and 1996-2002 were analysed. Data according to type of therapeutic regimen were also analysed.Results: Between the two periods 1985-1995 and 1996-2002, significant (P < 0.0001) decreases in IgG (6.29 +/- 4.72 versus 4.44 +/- 4.33), IgM (9.25 +/- 13.32 versus 5.61 +/- 7.93), and IgA (10.25 +/- 15.68 versus 6.48 +/- 11.56) z-scores, together with a parallel significant (P < 0.0001) increase in CD4 T-lymphocyte percentages, were found. These decreases were confirmed regardless of whether the children were receiving intravenous Ig or not. Ig z-scores were significantly higher in children receiving mono-therapy than in those receiving double-combined therapy (IgG, P < 0.0001; IgM, P = 0.003; IgA, P = 0.031) and in the latter children than in those receiving three or more drugs (P < 0.0001 for all z-scores). Ig z-scores correlated inversely with CD4 T lymphocyte percentages and, directly, with viral loads.Conclusions: Our data show that in HIV-1 infected children combined antiretroviral therapy leads to reduction of hyperimmunoglobulinemia which parallels restoration of CD4 T-lymphocyte percentage and viral load decrease, which it turn probably reflects improved B-lymphocyte functions.(C) 2004 Lippincott Williams Wilkins.

OBJECTIVE: To define age at entry into Tanner stages in children with perinatal HIV-1 infection. DESIGN: Multicentre longitudinal study including 212 perinatally HIV-1-infected children (107 girls and 105 boys) followed-up during puberty (from 8 and 9 years onwards in girls and boys, respectively). Healthy children (843 girls and 821 boys) provided reference percentiles. P2 or B2 stages in girls and P2 or G2 stages in boys defined onset of puberty. METHODS: The cumulative probability [95% confidence limit (CI)] of entry into each stage at different ages was estimated by the Kaplan-Meier product-limit method; differences were evaluated by log rank test. Relationships were tested using the Spearman's rank correlation coefficient. RESULTS: Ages of girls [years (95%CI)] at P2 [12.9 (12.6-13.2)], P3 [13.4 (13.0-13.8)], P4 [14.6 (14.0-15.2)], B2 [12.7 (12.2-13.2)], B3 [13.3 (12.8-14.0)] and B4 [14.6 (14.0-15.2)] stages were > 97th percentile (> or = 21 month delay) of controls. Ages of boys [years (95%CI)] at P2 [12.6 (12.1-13.1)], P3 [13.9 (13.4-14.4)], P4 [14.9 (14.2-15.6)], G2 [12.1 (11.5-12.7)], G3 [13.6 (13.1-14.1)] and G4 [14.9 (14.1-15.7)] stages were at the 75-97th percentiles (< or = 15 month delay). Age at onset of puberty was not related to clinical and immunological condition, antiretroviral treatment, weigh for height and age at onset of severe disease or immune suppression. CONCLUSION: Perinatal HIV-1 infection interferes with sexual maturation. The mechanisms by which this occurs should be elucidated and intervention strategies designed. Intervention could save much psychological distress, since associated linear growth failure can exacerbate adolescents' feelings of being different and unwell.

There is currently an experts' agreement discouraging interruption of antiretroviral treatment (ART) during the first trimester of pregnancy in women infected with human immunodeficiency virus type 1 (HIV-1). However, this recommendation is poorly supported by data. We evaluated the effects of discontinuing ART during pregnancy on the rate of mother-to-child transmission.Logistic regression models were performed in a prospective cohort of 937 children who were perinatally exposed to HIV-1 to estimate adjusted odds ratios for confounding factors on mother-to-child transmission, including maternal interruption of ART.Among 937 pregnant women infected with HIV-1, ART was interrupted in 81 (8.6%) in the first trimester and in 11 (1.2%) in the third trimester. In the first trimester, the median time at suspension of ART was 6 weeks (interquartile range [IQR], 5-6 weeks) and the time without treatment was 8 weeks (IQR, 7-11 weeks). In the third trimester, the median time at suspension of ART was 32 weeks (IQR, 23-36 weeks) and the time without treatment was 6 weeks (IQR, 2-9 weeks). The plasma viral load was similar in women who had treatment interrupted in the first trimester and in those who did not have treatment interrupted. Overall, the rate of mother-to-child transmission in the whole cohort was 1.3% (95% confidence interval [CI], 0.7%-2.3%), whereas it was 4.9% (95% CI, 1.9%-13.2%) when ART was interrupted in the first trimester and 18.2% (95% CI, 4.5%-72.7%) when ART was interrupted in the third trimester. In the multiple logistic regression models, only interruption of ART during either the first or the third trimester, maternal mono- or double therapy, delivery by a mode other than elective cesarean delivery, and a viral load at delivery4.78 log(10) copies/mL were independently associated with an increased rate of mother-to-child transmission.Discontinuing ART during pregnancy increases the rate of mother-to-child transmission of HIV-1, either when ART is stopped in the first trimester and subsequently restarted or when it is interrupted in the third trimester. This finding supports recommendations to continue ART in pregnant women who are already receiving treatment for their health.

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.

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.

The time at which antiretroviral therapy (ART) should be initiated in children with perinatal human immunodeficiencyvirus (HIV) infection remains controversial. In a cohort study, Berk et al1 reported clinical benefit from mono/dual ART started before 60 days of life in 10 children compared with treatment administered at 61 to 120 days of life in 16 children. The 23 children who received early triple ART were not investigated because none of them progressed to category C diagnosis by 3 years of age. We performed a similar analysis in a cohort study of a larger data set of children with a longer follow-up to evaluate the outcomes of early and very early triple ART.

Summary 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 ≥ 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.

Children with acquired immune deficiency syndrome (AIDS) commonly have recurrent infectious and noninfectious lung complications that ultimately end in death. To study the intensity of alveolar inflammation and to evaluate the clinical utility of bronchoalveolar lavage (BAL) in children with HIV-1 infections, we retrospectively analyzed differential cell counts, lymphocyte subsets, and fibronectin and hyaluronic acid concentrations in BAL fluid of 18 HIV-1-positive children (9 boys, mean age 3.5 years, range 5 months-8 years) with radiological evidence of interstitial lung disease, and 19 control children who had undergone BAL for clinical indications not involving the lung parenchyma (13 boys, mean age 3 years, range 2 months-14 years). BAL fluid from 89% of the HIV-1 infected children showed CD8+ve lymphocytic alveolitis expressing HLA-DR, CD54, and CD 69 antigens. BAL fluid from HIV-infected patients typically contained markedly increased percentages and numbers of lymphocytes (P < 0.0001) and eosinophils (P < 0.04) and significantly higher concentrations of albumin (P < 0.05) and fibronectin (P < 0.0006) than fluids from control children. Whereas BAL cellular components did not differ in P. carinii-positive and P. carinii-negative HIV-1-infected children, fibronectin concentrations were significantly higher in P. carinii-positive than negative children. BAL cell differentials and noncellular components were related neither to severity of disease nor to patients' disease progression. These findings indicate that BAL is useful in studying the intensity of lung inflammation in children with HIV-1 infections and radiologically documented interstitial lung disease, but provides no information on the subsequent clinical course.

HIV infection is thought to exacerbate the virulence of normal saprophytic vaginal microflora. We studied the vaginal ecosystem of HIV patients to detect the quantitative and qualitative variation of vaginal microorganisms. 15 patients (5 with AIDS and 10 with ARC) were investigated. Vaginal candidiasis was more frequent in this group than in the control groups. Gardnerella was present in 60% of patients generally in association with anaerobic bacteria and Mycoplasma. Among anaerobia, Bacteroides sp and other Gram-negative rods were the most common bacteria. Neisseria gonorrhoeae was absent in all patients tested. Chlamydia trachomatis was recovered in two out of the 15 HIV-positive patients. Aerobic Gram-negative flora was 100-fold that of the control group and anaerobic Gram-negative flora 10-fold.

The antigenemia and the patterns of antibodies to core protein (p24) and envelope glycoproteins (gp41, gp120) have been investigated in 81 patients with Human Immunodeficiency Virus (HIV) infection followed prospectively for 24 months. HIV antigen was detectable in 23 (28.4%) patients at entry to the study (13/13 with AIDS and 10/23 with ARC) and in 33 (40.7%) at the end (25/28 with AIDS, 5/12 with ARC e 3/14 with LAS). Anti-p24 were positive in 51 (63.0%) patients at the entry (26/30 symptomless, 13/15 with LAS e 12/23 with ARC) and in 41 (50.6%) at the end of the study (23/27 symptomless, 9/14 with LAS, 7/12 with ARC e 2/28 with AIDS). All patients were positive for anti-gp41 and showed no significant changes in the antibody titers during the two years of follow-up; by contrast, anti-gp120 was undetectable in most patients (26/28) with AIDS. Clinical progression in a high proportion of patients was associated with the appearance of HIV antigen, with the decline of anti-p24 titers and with no antibody reactivity to gp120 glycoprotein.

A retrospective chart review was performed on 118 HIV infected patients with pulmonary tuberculosis hospitalized between 1987 and 1996 in a tertiary care center for Infectious Diseases in Rome. The aims of this study were: a) to evaluate global prevalence of and risk factors for drug-resistant Mycobacterium tuberculosis and multidrug resistant tuberculosis; b) to assess trends in prevalence of drug-resistant tuberculosis over the 10-year study period. Prevalence of drug resistance of first Mycobacterium tuberculosis isolates was tested on Lowenstein-Jensen medium with the proportional method. Of the 118 patients studied, 83 had never been treated for tuberculosis and 35 had already been treated for at least 1 month. The overall prevalence of resistance to one or more drugs was 25% (17% in never treated patients vs 46% in already treated patients; p = 0.002). Five percent of isolates were resistant to both isoniazid and rifampin (1% in never treated patients vs 14% in already treated patients; p = 0.008). Resistance rates to individual drugs were: isoniazid 14%, rifampin 8%, ethambutol 0%, streptomycin 13%. During the study period no significant variations in prevalence of drug-resistant tuberculosis were found. In our area, empiric therapy should include 4 drugs: as well as isoniazid, rifampin and pyrazinamide, we recommend ethambutol. Surveillance of drug-resistant tuberculosis is needed. Directly observed therapy should be considered for HIV patients in order to prevent increases in drug resistance, relapses, and treatment failures.