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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.

Type and prevalence of zidovudine (ZDV) resistance mutations in HIV-1-infected children in clinically stable condition and on ZDV monotherapy were analyzed to evaluate the effect of switching to didanosine (ddI) monotherapy or to ZDV plus ddI on the pattern of mutations and on the clinical outcome. Monthly clinical and laboratory controls for HIV-1 infection status were performed; at enrollment and every 4 to 6 months after treatment randomization mutant proviral sequences were evaluated in all the children, whereas viral burden was performed only in a small subgroup of patients randomly selected in each of the three treatment groups. ZDV resistance-associated proviral DNA mutations were defined as low-level resistance (LLR) mutations or medium/high-level resistance (MHLR) mutations; clinical outcome was considered as stable or deteriorating. Results showed that at entry into the study the duration of ZDV therapy was significantly correlated with the presence of mutations, and that the level of resistance given by mutations was associated with the severity both of symptoms and immunodeficiency. After randomization to treatment, in patients with mutations that confer LLR a better clinical outcome with ddI monotherapy than with ZDV plus ddI and ZDV alone was observed in the subsequent 6 months, whereas in patients with mutations that confer MHLR no significant difference among the three treatment groups was found. Data showed also that levels of viral burden at the time of changing therapy are related to clinical outcome if measured by plasma viral load. These results suggest that genotypic resistance assays, together with viral load, may prove useful for rational treatment decisions both at the start of therapy and with failure.

Mucocutaneous diseases are more frequent in HIV/AIDS-infected children than in the normal population. We analyze mucocutaneous disorders with atypical presentations in a large population of HIV-infected children, with or without full-blown AIDS, compared to a population of HIV seroreverted children. The majority of these cutaneous disorders have an infectious etiology and their frequency is related to the degree of deterioration of the immune system. Some diseases commonly observed in adults are rare in children; neoplasms are an exception.

Prolonged treatment with antiretroviral agents directed against reverse transcription (RT) in patients with HIV-1 infection results in the emergence of virus variants with reduced sensitivity containing mutations in the HIV-1 RT gene. Development of zidovudine (ZDV)-related mutations was studied in a cohort of 24 vertically infected pediatric patients receiving ZDV therapy. Monthly clinical and immunologic evaluation was accompanied by direct sequencing of the HIV-1 RT gene every 4 months. A correlation was observed between the emergence of mutations and the duration of therapy. Mutation at codon 41 was found only in the presence of mutation at codon 215. The presence of the mutations Met41-->Leu and Thr215-->Tyr/Phe did not appear to be related to disease progression. These findings suggest that the mere presence of mutations in the HIV-1 RT gene alone during ZDV monotherapy is not a reliable prognostic marker in the absence of other clinical and virologic information.

The objective of this study was to compare the safety, tolerability and clinical response of once- versus twice-daily administration of didanosine given at a dosage of 270 mg/m2/day in children with symptomatic HIV-associated disease who were intolerant to or clinically deteriorated on zidovudine monotherapy. We carried out a randomized, open-label multicentre trial. Didanosine was supplied in buffered tablets, which could be chewed or dispersed in liquid. The children were recruited from 16 paediatric departments participating in the Italian Register for HIV Infection in Children. A total of 53 children (median age 5.5 years) started trial treatment; 26 were given didanosine twice daily and 27 once daily; 85% had AIDS and 98% had clinically deteriorated while on zidovudine therapy. Similar safety and tolerability results were demonstrated for the two schemes of therapy. A total of 11 children (20.7%) required discontinuation of didanosine for severe adverse events (five children (19.2%) in the twice-daily group; six children (22.2%) in the once-daily group, log-rank P = 0.81). Severe hepatic toxicity was uncommon (5.6%) while mild to moderate hepatic dysfunction was demonstrated in about 17% of the participants, without any difference between the two groups. Haematological toxicity was common (about 40% of the children, 11 in the twice- and 19 in the once-daily group) but never severe. Clinical pancreatitis and retinal lesions were never demonstrated. There was no significant difference in progression to death or to a new opportunistic infection between the two treatment regimens (log-rank P = 0.54). The modification of surrogate efficacy parameters during the study period was similar in the two groups. However, weight gain was poorer in children treated once daily. This study suggests that the safety and tolerability of 270 mg/m2/day of didanosine given once daily is substantially similar to that of the traditionally recommended schedule of two divided doses. Owing to the small sample and to the severity of the clinical condition of the children enrolled, no definite conclusions on the comparative efficacy of the two regimens can be drawn.

Objective: In HIV-1-infected children, active cytomegalovirus (CMV) infection can cause severe clinical manifestations and accelerate progression of HIV disease. However, sufficient quantities of blood samples may not be available either for culture or detection of CMV DNA or antigens in white blood cells. The aim of this study was to investigate the diagnostic and prognostic significance of detecting CMV DNA in serum samples from HIV-1-infected children., Design: Sera from 55 children (18 boys), aged 2-130 months (mean, 49.8 months), with perinatal HIV-1 infection and clinical manifestations attributable to CMV infection were tested for CMV DNA by nested polymerase chain reaction and for class-specific CMV antibodies [immunoglobulin (Ig) G, IgA, IgM] by enzyme-linked immunosorbent assay. The children were followed up for 2 days to 59 months (mean, 25.5 months)., Results: CMV infection was demonstrated in 43 children (74.5%), 18 of whom (42%) were positive for CMV DNA. During the follow-up, 13 children with CMV infection (30.2%) died, including 11 (84.6%) who were positive for CMV DNAemia just before death. Of these children, seven died soon after hospitalization without antiviral treatment, and four died despite therapy with ganciclovir or foscarnet. Post-mortem CMV inclusions were revealed in seven out of eight children who underwent autopsy. The two other children who died also had progressive CMV disease and received ganciclovir until death. In comparison with CMV-seropositive children without CMV DNAemia, children with CMV DNAemia showed significantly shorter mean survival time (42.5 versus 60 months; P < 0.01), lower final CD4+ T-cell count (218 versus 499 x 10(6)/1; P < 0.01) and higher mortality rate (P < 0.0001)., Conclusions: The detection of CMV DNA in serum is of value for diagnosis of active CMV infection in HIV-1-positive children, and CMV DNAemia is a good prognostic indicator of severe outcome of HIV disease.