Group B children
Among HIV-1 infected children enrolled in the Register, born after 1 January 1996, and never lost to follow-up, 131 patients received combined ART with three or more drugs after 6 months of age. Data from 28 children, who were not included in group B because of low compliance to the therapy, were analysed separately. Thus group B included 103 children (49 children in CDC category N, 25 in category A, and 29 children in category B) (Fig. 1). The median age at the start of ART was 2.1 years (range, 0.8–4.4 years). The median follow-up time was 4.8 years (range, 1.2–6.2 years). There was no difference between group A and group B children regarding the proportion of mothers receiving ART during pregnancy (53.3% versus 50.0 %), the proportion of Caesarean (43.0% vs. 43.0%) or premature (< 32 gestational weeks) (23.3% versus 33.0%) delivery, and the proportion of children receiving prophylactic treatment with antiretroviral drugs after birth (53.3% versus 50.0%).
Data from 29 children (6 children in CDC category N, 16 in category A, and 7 in category B) who never received ART were analysed. The median follow-up time was 3.7 years (range, 0.3–6.4 years).
Effects of combined ART on plasma HIV-1 loads, CD4, and CD8 T-lymphocyte percentages in group A (early treatment) infants
In early treated infants the median viral load prior to the beginning of therapy was 5.84 log10 RNA copies/ml (range, 3.38–7.20 log10 RNA copies/ml). Viral load reached undetectable levels in 22 (72.3%) infants, and in all of these viral load remained undetectable during the entire follow-up period. Undetectable viral load was reached in 19 of 22 (86.3%) infants with baseline CD4 T-lymphocyte percentage ≥ 25% versus three of eight (37.5%) infants with CD4 T-lymphocyte percentage < 25% (P = 0.016). Mean baseline CD4 T-lymphocyte percentage was 34.15 ± 13.71%. All infants showed good immunologic response to therapy: CD4 T-lymphocyte percentage at the last determination was ≥ 25% in 29 infants, in the remaining one it was 24%. CD8 T-lymphocyte percentage was 23.93 ± 7.13% at baseline and did not significantly change over time (Table 2).
Data from two non-compliant children (CDC Category A1 and B2) were analysed separately. They were prescribed a nelfinavir-containing regimen and have been followed up for 7 and 13 months. Viraemia was 6.01 and 5.70 log10 copies RNA/ml at baseline and 4.41 and 4.08 log10 copies RNA/ml at last follow-up, respectively. CD4 T-lymphocyte percentage was 28 and 29% at baseline and 32 and 24% at last follow-up. Clinically, they presented with hepatomegaly and a severe bacterial infection, respectively.
Differences in plasma HIV-1 loads, CD4, and CD8 T-lymphocyte percentages between group A (early treatment) and group B (deferred treatment) infants
Differences in plasma HIV-1 loads, CD4, and CD8 T-lymphocyte percentages between group A and group B children at each age period are reported in Table 2. No significant difference was seen at baseline. In contrast, group A children showed significantly lower viral loads than group B children at all timepoints. An undetectable viral load was reached in 22 of 30 (73.3%) group A and 31 of 103 (30.1%) group B children (P < 0.0001). Higher CD4 T-lymphocyte percentages were evident among group A children at 13–24 (P < 0.0001), 25–36 (P < 0.0001), 37–48 (P = 0.003) months of age (Table 2). Moreover, no group A versus 20 of 103 (19.4%) group B children (P = 0.02) showed CD4 T-lymphocyte percentage < 15% at one time point during follow-up. Group A children displayed lower CD8 T-lymphocyte percentages than group B children at all follow-up times (Table 2).
Data from 28 non-complaint children who were prescribed deferred ART were analysed. No significant difference in viral loads (median, 5.68 log10 copies RNA/ml; range, 2.81–6.51 log10 copies RNA/ml; P = 0.530 versus compliant children) or CD4 T-lymphocyte percentages (31.94 ± 13.38%; P = 0.826 versus compliant children) was evidenced at baseline. By contrast, non-compliant children showed significantly higher viral loads at all timepoints [4.65 (range, 2.85–6.69) log10 copies RNA/ml, P = 0.046; 4.52 (range, 1.90–6.00) log10 copies RNA/ml, P = 0.028; 4.60 (range, 1.67–5.88) log10 copies RNA/ml, P = 0.005; 4.25 (range, 1.67–5.65) log10 copies RNA/ml, P = 0.005; 3.97 (range, 1.67–6.24) log10 copies RNA/ml; P = 0.042. respectively]. At the same follow-up times CD4 T-lymphocyte percentages were 23.71 ± 13.38% (P = 0.011 versus compliant children); 24.07 ± 10.35% (P = 0.037); 24.77 ± 9.59% (P = 0.007); 23.91 ± 9.04% (P = 0.015); 26.87 ± 8.59% (P=0.262); 24.35±10.17% (P = 0.174) respectively.
Long-term non progressors
Among the 29 children who never received ART, CD4 T-lymphocyte percentages were 33.78 ± 15.71% in the first year of life and did not differ from those of group A and group B children (P = 0.620). Subsequently, CD4 T-lymphocyte percentages were lower than those of group A children [27.75 ± 11.22 in the second (P < 0.0001 versus group A children); 28.12 ± 12.96 in the third (P = 0.003 versus group A children); 28.03 ± 9.04 in the fourth (P = 0.001 versus group A children); and 27.06 ± 6.71 (P = 0.002 versus group A children) in the fifth year of life]. Meadian baseline viral load was 5.47 log10 copies RNA/ml (range, 2.00–6.84 log10 copies RNA/ml) and did not differ from those of group A and group B children (P = 0.518). Subsequent viral loads were higher (P < 0.001) than those of group A children [first year, median 4.88 (range, 3.30–5.86); second year, median, 6.84 (range, 1.67–5.88); third year, median 4.32 (range, 1.67–5.10); fourth year: 4.41 (range, 2.01–5.10); fifth year: 3.85 (range, 3.95–2.78) 5.47 log10 copies RNA/ml].
Differences in clinical events between group A (early treatment) and group B (deferred treatment) infants
No CDC category A, B or C clinical event occurred among group A children over the follow-up period. In contrast 44 group B children showed a decline in the CDC category (9 patients falling to category A, 19 to category B, and 16 to category C) and one of these children died. In total 204 category A, 77 category B, and 59 category C clinical events occurred; 20 of these latter events occurred after the initiation of ART. In particular, category C events were esophageal candidiasis (n = 3); cytomegalovirus (CMV)-related disease (n = 6); extrapulmonary cryptococcosis (n = 1); chronic cryptosporidiosis (n = 1) Pneumococcus carinii pneumonia (n = 3), bacteraemia (n = 2), bacterial pneumonia (n = 13), other severe bacterial infections (n = 12), progressive multifocal leukoencephalopathy (n = 2), HIV-1 related encephalopathy (n = 16).
Kaplan–Meier analyses with log-rank test revealed significant differences in CDC category A (P = 0.0002), category B (P = 0.0003) and category C (P = 0.0018) event-free survivals between group A and B children (Fig. 2).
This study reports the Italian experience with early versus later institution of combined-ARV in asymptomatic or moderately symptomatic HIV-1 infected infants.
Because in adults primary infection is usually restricted to the first 6 months from onset , we considered primary infection in infants to be limited to the first 6 months of life and defined early ART as a treatment initiated within this age period.
The results obtained highlight that starting combined ART within the first 6 months of life in HIV-1 perinatally infected children allows avoidance of clinical manifestation, preserved CD4 T-lymphocyte percentage, and no increase in CD8 T-lymphocyte percentage, at least for the first years of life. Moreover, viral load fell to undetectable levels in more than 70% of early-treated infants. Bearing in mind the natural history of disease progression in infants [4–6], starting treatment after 6 months of age also resulted in relevant virologic, immunologic, and clinical benefits but these were substantially less that those in early-treated infants. In particular, early-treated infants displayed lower viral loads than infants receiving deferred therapy and an undetectable viral load was reached in a higher proportion of children. In addition, we found early ART to be associated with a better preservation of CD4 T-lymphocyte percentage. About one-fifth of infants receiving deferred treatment, but no early-treated infant, presented severe immunologic deterioration (CDC category 3) over the observation period. The immunologic benefits of early ART appeared clearly within the first 4 years of life. Lack of a significant difference in CD4 T-lymphocyte percentage at older ages may be due to the limited number of study patients. Alternatively, when combined ART was initiated in the children receiving deferred therapy, they may have displayed their great potential for immune reconstitution (which is a well-known peculiarity in childhood ), allowing them to re-establish the pool of CD4 T lymphocytes. Interestingly, early-treated infants showed lower CD8 T-lymphocyte percentages than infants receiving deferred treatment.
Clinical benefits from early ART were also shown. Early-treated infants presented no CDC category A, B, or C events, unlike children receiving deferred treatment.
Early ART has been recently proposed for the treatment of asymptomatic or moderately symptomatic infants with HIV-1 infection . As the rate of viral replication during the first months of life is correlated with disease outcome , early therapeutic intervention, which keeps the virus at low levels during primary infection, might lead to a better long-term viral suppression and preserved immune system function. Moreover, one possible goal of early ART is the prevention of HIV-mediated damage of the developing nervous system which is particularly frequent in infants . Additionally, data from early treated children were compared to those from LTNP. No difference was evident at baseline, confirming the difficult-to-predict disease progression in young children . Subsequently, higher CD4 T-cell percentages and lower viral loads were observed in early treated children at all follow-up times.
This finding, if confirmed by randomized studies, may further support the early therapy strategy. To date no randomized trial has investigated the impact of early ART in infants and few studies are available [9–14]. Recent observations [9,12] found that early treatment in infants reduced viral load below the threshold levels required for the onset of a humoral HIV-1 immune response and most of the early-treated infants lacked of a specific HIV-1 immune response. Nonetheless, early ART did not appear to prevent the establishment of a reservoir of latently infected cells . Similar to our results, in these studies CD4 T-lymphocyte counts normalized or remained normal and viral loads were undetectable in the majority of children. This is in contrast with a study on 20 infants  that found good clinical and immunologic outcome in all children, despite 70% of virologic failure at week 72 associated with emergence of genotypic resistance. In a recent non-randomized open-label trial on 25 early-treated infants and 27 controls , there was no significant association between age at initiation of therapy and the likelihood of viral suppression at week 16 or 48. Nevertheless, association became significant after 4 years.
No previous study has investigated differences in CD8 T-lymphocyte percentages between infants receiving early or deferred combined ART. These cells play a key role in controlling viral replication and the baseline CD8 T lymphocyte percentage was found to predict response to therapy . In our study infants receiving early treatment maintained unchanged CD8 T-lymphocyte percentages while those receiving deferred treatment displayed elevated CD8 T-lymphocyte percentages. Elevated CD8 T lymphocytes  and disruptions of their subsets  have been reported in HIV-1 infected children. During combined ART substantial but incomplete recovery of these alterations occurs in children [25,26]. This may, at least partially, explain the persistently higher CD8 T-lymphocyte percentages in children with deferred therapy. On the contrary, in early-treated infants we found that ART maintained the normal pool not only of CD4 but also of CD8 T-lymphocytes.
Our investigation is the largest and longest study on effects of early ART in perinatally HIV-1 infected infants. Our data seem to indicate virologic, immunologic, and clinical benefits from early ART as compared with deferred therapy in the first years of life. Nevertheless, our study is observational and, therefore, has some limitations. In particular, detailed information on viral resistance and side effects was not available. However, the fact that no early-treated infant interrupted the treatment over the follow-up period suggests that this was well tolerated. Also, early-treated children received many different treatment regimens and so it was not possible to derive conclusions about this. Children born in recent years may have received a higher dose of nelfinavir. Indeed, this event may be plausible and may explain the high rate of children with viral suppression in our population but, unfortunately, we do not have sufficient data to investigate this issue. Finally, we observed that the two groups of children receiving early or deferred treatment could display some differences, as suggested by disparity in compliance rates. The high rate of compliant children in the early-treated group may contribute to the high rate of viral suppression in our population compared with other studies . It is possible that patients treated earlier were cared for by more ‘aggressive’ Centres or had parents who were more actively engaged in the medical care system. This could result in better adherence and better outcomes. To avoid this potential bias only compliant children were included in the statistical analyses and data from non-complaint children were considered separately. Moreover, we checked that early treated children were not clustered into a limited number of Centres, but followed by many different Centres through the Country. Large randomized studies, monitoring also for the occurrence of viral resistance and long-term side effects are needed to further clarify this issue.
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P. Osimani, R. Cordiali (Ancona), D. De Mattia, M. Manzionna, C. Di Bari (Bari), M. Ruggeri (Bergamo), M. Masi, A. Miniaci, F. Specchia, M. Ciccia, M. Lanari, F. Baldi (Bologna), L. Battisti (Bolzano), C. Fiorino (Brescia), C. Dessì, C. Pintor, M. Dedoni, M.L. Fenu, R. Cavallini (Cagliari), E. Anastasio, F. Merolla (Catanzaro), M. Sticca (Como), G. Pomero (Cuneo), T. Bezzi, E. Fiumana (Ferrara), F. Bonsignori, P. Gervaso, E. Seini (Firenze), M.T. Cecchi (Forlì), D. Cosso, A. Timitilli (Genova), M. Stronati (Mantova), A. Plebani, R. Pinzani, I. Bongianin, A. Viganò, V. Giacomet, P. Erba, F. Salvini, G.V. Zuccotti, M. Giovannini, G. Ferraris, R. Lipreri, C. Moretti (Milano), M. Cellini, M.C. Cano, P. Paolucci (Modena), E. Bruzzese, G. De Marco, L. Tarallo, F. Tancredi (Napoli), M. Pennazzato, O. Rampon (Padova), E.R. Dalle Nogare, A. Sanfilippo, A. Romano, M. Saitta (Palermo), I. Dodi, A. Barone (Parma), A. Maccabruni, (Pavia), R. Consolini, A. Legitimo (Pisa), C. Magnani (Reggio Emilia), P. Falconieri, C. Fundarò, O. Genovese, A. Panzanella, A.M. Casadei, A. Martino, C. Concato, G. Anzidei, G. Bove, S. Cerilli, S. Catania, C. Ajassa (Roma), A. Ganau (Sassari), L. Cristiano (Taranto), A. Mazza, A. Di Palma (Trento), F. Mignone, C. Riva, C. Scorfaro (Torino), V. Portelli (Trapani), M. Rabusin (Trieste), A. Pellegatta (Varese), M. Molesini (Verona).
Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
combined antiretroviral therapy; infants; HIV-1 infection