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AIDS:
doi: 10.1097/01.aids.0000200529.64113.3e
Clinical Science

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

Chiappini, Elenaa; Galli, Luisaa; Tovo, Pier-Angelob; Gabiano, Clarab; Gattinara, Guido Castellic; Guarino, Alfredod; Baddato, Raffaelee; Giaquinto, Carlof; Lisi, Catiusciag; de Martino, Maurizioa; The Italian Register for HIV Infection in Children

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Author Information

From the aDepartment of Paediatrics, University of Florence, Florence, Italy

bDepartment of Paediatrics, University of Turin, Turi, Italy

cBambino Gesù Children's Hospital, Rome, Italy

dDepartment of Paediatrics, Federico II University, Naples, Italy

eDepartment of Paediatrics, University of Brescia, Brescia, Italy

fDepartment of Paediatrics, University of Padua, Padua, Italy

gDepartment of Statistics, University of Florence, Florenc, Italy.

*See Appendix.

Received 21 December, 2004

Accepted 10 June, 2005

Correspondence to M. de Martino, Coordinator of the Italian Register for HIV Infection in Children, Department of Paediatrics, University of Florence, Via Luca Giordano, 13, I-50132 Florence, Italy. Tel: +39 055 566 2494; fax: +39 055 570 380; e-mail: maurizio.demartino@unifi.it

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Abstract

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.

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Introduction

The introduction of combined antiretroviral therapy (ART) led to significant reduction of morbidity and mortality in children with HIV-1 infection [1]. Based on the European [2] and US [3] guidelines, children with clinical or immunologic deterioration should receive ART. Controversy remains regarding the early treatment in infants with no or mild/moderate signs or normal immunologic status [2,3]. In vertically infected children the diagnosis is commonly made during the first months of life allowing paediatricians to start therapy only during primary infection. The risk of disease progression is higher in children than in adults, with 15–20% of HIV-1 infected children progressing to AIDS or death within the first year of life [4–6]. Moreover, in children under 2 years of age neither CD4 T-lymphocyte percentage nor viral load can identify those at higher risk of disease progression, supporting the universal treatment strategy [7]. However, issues of the possible selection of resistant viral mutants, lack of adherence, major toxicity, and adverse effects of early ART need to be considered [3].

A limited number of studies has investigated the impact of early ART in HIV-infected infants, and the most of them are limited to a few cases [8–14]. With the aim of investigating the impact of early versus deferred combined ART on asymptomatic or moderately symptomatic infants {category N, A or B of the Centers for Disease Control and Prevention (CDC) classification [15]} with perinatal HIV-1 infection we conducted a multi-centre nationwide study.

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Methods

Data collection

Data were collected by the Italian Register for HIV Infection in Children, which is a nationwide multi-centre study of children perinatally exposed to HIV-1 instituted in 1985 by the Italian Association of Paediatrics [1,4,16]. The data source is a network of paediatric clinics distributed throughout Italy. The data are transmitted to the two co-ordinating centres at Departments of Paediatrics of the Universities of Florence and Turin. Information concerning data collection has been described in detail elsewhere [1,4,16]. Briefly, the standard registration form consists of demographic and perinatal data. Both the registration and the follow-up forms contain data regarding infectious status, clinical condition, laboratory tests and treatment. All data are collected prospectively every 6–12 months and then entered into a specific database at the co-ordinating centres. We previously documented that combined ART became widespread in Italy after 1996 [1]. Thus, data collected from 1 January 1996 to 31 December 2003 were analysed. Clinical HIV-1 stage was classified according to the CDC recommendations [13]. Infection was defined by the persistence of HIV-1 antibodies after 18 months of age or by the detection, on at least two occasions, of virus markers (proviral DNA, or viral RNA). Viral loads were evaluated quantitatively by Amplicor HIV Monitor test and results were expressed as log10 HIV-1 RNA copies/ml. CD4 and CD8 T-lymphocyte counts were measured using the standardized fluorescent-activated cell sorting technique. Based on the US guidelines for the use of antiretroviral agents in children [3], CD4 and CD8 T-lymphocyte percentages, rather than their absolute counts, were taken into account as these percentages more accurately reflect their immune status. HIV-1-related clinical events were evaluated according to the CDC definition [15]. Compliance with therapy was assessed using addressed standardized questionnaires as described in detailed elsewhere [17]. This study was approved by review boards and ethics committees for the participating institutions.

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Treatment

The specific therapy offered was left to the discretion of single participating centres. The criteria adopted were those discussed and agreed during annual meetings and those of the CDC [18] and the Italian [19] paediatric guidelines for ART in children.

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Patients

Since 1996 the use of combined ART has become widespread in Italy and the use of three or more drugs became more common at that time [1]. Moreover, preliminary analysis showed that all of the children receiving early combined ART were born after January 1, 1996. Therefore, it was decided to include in the study only children born after this date.

All of the study patients were children with perinatal HIV-1 infection enrolled in the Register at birth and never lost to follow-up, satisfying the following conditions: (i) treated with combined ART with three or more antiretroviral drugs, including at least one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor; (ii) in clinical category CDC N, A, or B within the first 6 months of age; (iii) with good compliance to therapy.

Children were divided into two groups: group A included children receiving early ART, before 6 months of age, and group B included children receiving deferred ART, started after 6 months of age. In addition, data from children who had never received ART (long term non-progressors; LTNP) and from non-compliant children were analysed.

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Statistical analysis

Age and viral loads were expressed as median and range. CD4 and CD8 T-lymphocyte percentages were expressed as means and standard deviations. Children receiving early or deferred ART were compared by viral load, CD4, and CD8T-lymphocyte percentages using the Mann–Whitney or the independent sample t test. When the HIV-1 RNA levels were below the lower quantification limit of the assay, a value was assigned equal to the lower quantification limit when analyzed as a quantitative variable. Kaplan–Meier analysis with log-rank test was performed to analyse differences in survival free from CDC clinical events. The statistical analyses were performed using the SPSS software package (SPSS 11.5; SPSS, Chicago, IL, USA). P < 0.05 was considered statistically significant.

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Results

Characteristics of study children
Group A children

Between 1 January 1996 and 31 December 2003, 40 infants commenced ART with three or more drugs before 6 months of age (Fig. 1). Two infants with low compliance to the therapy and eight infants in CDC category C were not included in group A. Therefore, data from 30 infants (12 in CDC category N; 13 in category A, and 5 in category B) were analysed (Fig. 1). Individual patient characteristics and treatment regimens are shown in Table 1. The median age at the start of ART was 3.6 months (range, 0.8–5.8 months). The median follow-up was 4.1 years (range, 1.0–6.5 years). All infants were still receiving combined ART with three or more drugs at the last check.

Fig. 1
Fig. 1
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Table 1
Table 1
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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%).

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Long-term non-progressors

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).

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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).

Table 2
Table 2
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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.

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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.

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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].

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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).

Fig. 2
Fig. 2
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Discussion

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 [20], 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 [21]), 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 [3]. As the rate of viral replication during the first months of life is correlated with disease outcome [3], 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 [22]. 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 [7]. 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 [12]. 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 [13] 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 [14], 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 [23]. 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 [23] and disruptions of their subsets [24] 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 [9]. 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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Appendix
Participants

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).

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Keywords:

combined antiretroviral therapy; infants; HIV-1 infection

© 2006 Lippincott Williams & Wilkins, Inc.

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