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JAC Advance Access originally published online on November 19, 2007
Journal of Antimicrobial Chemotherapy 2008 61(1):183-190; doi:10.1093/jac/dkm436
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Long-term response to highly active antiretroviral therapy with lopinavir/ritonavir in pre-treated vertically HIV-infected children

Beatriz Larrú1,*, Salvador Resino1,2, Jose M. Bellón1, M. Isabel de José3, Claudia Fortuny4, M. Luisa Navarro5, M. Dolores Gurbindo5, José Tomás Ramos6, Pere Soler Palacín7, Juan Antonio Léon8, Manuel Asensi9, M. José Mellado10 and M. Ángeles Muñoz-Fernández1

1 Laboratorio de Inmuno-Biología Molecular, Hospital General Universitario ‘Gregorio Marañón’, Madrid, Spain 2 Centro Nacional de Microbiología, Instituto de Salud ‘Carlos III’, Majadahonda, Madrid, Spain 3 Inmuno-Pediatría, Hospital Universitario ‘La Paz’, Madrid, Spain 4 Inmuno-Pediatría, Hospital ‘San Joan de Déu’, Barcelona, Spain 5 Inmuno-Pediatría, Hospital General Universitario ‘Gregorio Marañón’, Madrid, Spain 6 Inmuno-Pediatría, Hospital Universitario ‘12 de Octubre’, Madrid, Spain 7 Inmuno-Pediatría, Hospital ‘Val d'Hebron’, Barcelona, Spain 8 Pediatría-Infecciosas, Hospital Universitario ‘Virgen de Rocío’, Sevilla, Spain 9 Pediatría-Infecciosas, Hospital ‘La Fe’, Valencia, Spain 10 Pediatría-Infecciosas, Hospital Universitario ‘Carlos III’, Madrid, Spain

* Corresponding author. Tel: +34-91-586-8565; Fax: +34-91-586-8018; E-mail: bealarru{at}yahoo.es

Received 13 July 2007; returned 8 September 2007; revised 9 October 2007; accepted 11 October 2007


   Abstract
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Background: Immune recovery after prolonged highly active antiretroviral therapy (HAART) with lopinavir/ritonavir has been reported in adults but not in children. Our study aimed at evaluating the long-term use of lopinavir/ritonavir among children in a clinical setting.

Methods: We carried out a retrospective study on 69 protease inhibitor (PI)-experienced vertically HIV-infected children on HAART containing lopinavir/ritonavir. We analysed the changes in percentage CD4+ cell count (%CD4+) and viral load (VL) and identified prognostic factors to achieve CD4+ >25% and undetectable VL (uVL) (≤400 copies/mL) by logistic regression.

Results: During the first 2 years, we found an increase in the %CD4+ in children with baseline CD4+ between 0% and 15% and those with baseline VL < 30 000 copies/mL. We found a decrease in VL in all groups of children. From second to fourth year, we found an increase in %CD4+ in all the children who had CD4+ <25% and in those with baseline VL > 100 000 copies/mL. We found that %CD4+ at baseline had a strong positive association with achieving CD4+ >25% at 6, 12, 18, 24, 36 and 48 months of follow-up. We also found that length of PI use had a negative association with reaching CD4+ >25% at 24 and 48 months and achieving uVL at 12 and 24 months. VL at baseline had a negative association with achieving uVL at 18 and 24 months.

Conclusions: Our study demonstrates ongoing immune recovery among children on HAART with lopinavir/ritonavir after 4 years of follow-up. Lopinavir/ritonavir, when given as part of a salvage regimen, is safe and well tolerated in HIV-infected children.

Keywords: protease inhibitors , immune reconstitution , viral suppression


   Introduction
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 Introduction
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The introduction of antiretroviral therapy (ART) has achieved a substantial reduction in mortality and morbidity in HIV-infected adults and children.1,2 Lately, ART has become more convenient and effective, but a cure for HIV infection remains elusive and HIV-infected children must take long-term ART.3 In adults, the use of highly active antiretroviral treatment (HAART) can lead to the development of toxic effects and drug resistance.4,5 Therefore, it is important to study ART for prolonged periods among children, so that a better clinical approach can be established.

Moreover, few data exist on how paediatric immune recovery changes over several years on HAART.6,7 It has been suggested that long-term HAART allows CD4+ recovery and viral load (VL) control in HIV-infected children, but there is no evidence from randomized trials on the optimal time to initiate ART.8

Lopinavir/ritonavir is a combination of two protease inhibitors (PIs) which is characterized by high trough concentrations, as a consequence of metabolism inhibition because of ritonavir and a favourable resistance profile that reduces the risk of development of resistance mutations in naive patients.9,10 Current guidelines on paediatric HIV infection recommend its use for both initial and salvage regimens.11 Although its effectiveness in adults after 6 years of treatment has been published recently, there are few data available in HIV-infected children.12,13 Our study aimed at evaluating the effectiveness and safety of HAART with lopinavir/ritonavir during a long-term period among vertically HIV-infected children in a clinical setting.


   Patients and methods
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Population and study design

A retrospective study of 69 vertically HIV-infected children followed from June 2000 to October 2006 was conducted in 8 Spanish paediatric referral hospitals from Madrid, Barcelona, Seville and Valencia. Among all the HIV-1-infected children attending these hospitals, we selected those who were vertically infected and received lopinavir/ritonavir for the first time in a HAART regimen for a duration of at least 12 months, after a therapeutic failure with a previous HAART regimen containing other PIs. We excluded those with undetectable VL (uVL) at baseline and PI-naive patients, so that the study group was more homogeneous. uVL was considered as achieved when the patient had ≤400 copies/mL.

The Ethics Committees of all hospitals involved approved the study. Clinical classification was based on the 1994 revised guidelines of the CDC.14 Children were monitored at least once every 3 months with repeated interviews, physical examinations and blood sample collection for serial biochemical parameters, %CD4+ T cell count (%CD4+), %CD8+ T cell count (%CD8+) and VL measurements. There was no uniform approach regarding the use of other antiretrovirals (ARVs) given together with lopinavir/ritonavir in the HAART regimen. Instead, each paediatrician administered the appropriate ART regimen and changed the drugs according to the condition of the children and following international CDC and European guidelines.15,16

We only included the children in the study while they were taking lopinavir/ritonavir as part of their HAART regimen. The adherence to ARV drugs was measured by each paediatrician by examining the dose taken and through interviews with their parents or tutors. We also collected information on the side effects during the follow-up, including lipodystrophy symptoms.

HIV-1 infection laboratory markers

T-lymphocyte subsets in peripheral blood were quantified by flow cytometry (FACScan, Becton–Dickinson Immunocytometry Systems, San Jose, CA, USA). VL was measured in 200 µL plasma samples using a quantitative assay (Amplicor Monitor, Roche Diagnostic Systems, Brandenburg, NJ, USA).17

Genotypic analysis of HIV-1 isolates

Baseline plasma samples for viral genotype were collected between day –90 (90 days prior to initiation of lopinavir/ritonavir) and day 1. Genotypic HIV-1 drug resistance was determined from plasma-associated HIV-1 RNA using the TruGene HIV-1 Resistance Kit (Visible Genetics, Toronto, ON, Canada). The complete HIV-1 protease gene was analysed using Gene Objects software (Visible Genetics). Drug resistances were defined according to the International AIDS Society-USA consensus panel.18

Statistical analysis

All statistical analyses were performed with SPSS (version 12). All P values were two-tailed. Statistical significance was defined as P < 0.05. Initiation of HAART with lopinavir/ritonavir was defined as the first time they took lopinavir/ritonavir with two or more ARVs. Subsequent changes of HAART with lopinavir/ritonavir were ignored in terms of statistical analysis as long as it still included lopinavir/ritonavir as part of the HAART regimen.

To begin with, we carried out a multivariate analysis to determine the long-term response to HAART with lopinavir/ritonavir. Dependent variables were the mean differences of %CD4+ and log10 VL per year from baseline to the second year on this therapy and also from the second year to the fourth year. We selected these points to analyse the first stage of CD4+ increase and the second stage of stabilization of CD4+. Independent variables were CD4+ stratum (0% to 15%, 15% to 25% and >25%) or VL stratum (0–30 000, 30 000–100 000 and >100 000 copies/mL). This analysis was adjusted by baseline characteristics (age, CD4+, log10 VL and length of PI use).

We performed a logistic regression analysis to determine the odds ratio (OR) to reach a CD4+ >25% or uVL (≤400 copies/mL) at 6, 12, 18, 24, 36 and 48 months of completed follow-up. Independent variables were age, CD4+, log10 VL, length of ART, length of PI use, number of previous PIs, number of primary resistances and ≥6 lopinavir mutation score (LMS) at baseline. We carried out a univariate analysis to determine the prognostic factors at baseline followed by a multivariate analysis to select the most relevant ones (age, CD4+, log10 VL and length of PI use).


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Characteristics of vertically HIV-infected children

Baseline characteristics are summarized in Table 1. All were PI-experienced children and had a median length of previous PI use of 40.4 months (P25; P75: 31.2; 47.3). At baseline, 82.6% of the children had previously taken nelfinavir (median length: 20.4 months, P25; P75: 13.9; 27.6), 58.0% of children had taken indinavir for 21.0 months (10.7; 27.5) and 26.1% of children had taken saquinavir for 11.0 months (25.7; 18.2). The distribution of children according to lopinavir dose was: 39.0% received 230–300 mg lopinavir/m2 every 12 h, 35.1% received 300–400 mg lopinavir/m2 every 12 h, and 3.9% received >400 mg lopinavir/m2 every 12 h.


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  		Table 1. Clinical and demographic characteristics at baseline in the cohort of vertically HIV-infected children on HAART containing lopinavir/ritonavir

 
The median time of lopinavir/ritonavir treatment was 57.1 months (P25; P75: 40.3; 67.6). During follow-up, 6 of 69 children experienced any adverse event with the use of lopinavir/ritonavir: 4 children had grade 3 diarrhoea, 1 child had severe abdominal pain, and another child developed a Cushing syndrome because of co-administration of fluticasone and lopinavir/ritonavir. At the end of the study, 28.6% of the children had any sign of lipodystrophy: 22.7% of them had mild symptoms, 40.1% had moderate symptoms, and 37.2% severe ones. However, only 3 children discontinued the use of lopinavir/ritonavir because of the worsening of lipodystrophy. Cholesterol values remained stable during the follow-up with a median level of 191.0 mg/dL (P25; P75: 168; 223) at month 12 and 178.0 mg/dL (P25; P75: 158.0; 193.0) at month 48. Triglycerides values experienced a mild increase during the follow-up. At month 12, the median value was 133.0 mg/dL (95.2; 189.2), and at month 48, the value was 124.0 mg/dL (84.0; 212.0).

During the follow-up, four patients died, but none of the other children developed AIDS. Patients who died were older than the others (median age: 10.8; min: 6.0 and max: 15.6) and they had lower %CD4+ counts (17.3 ± 6.8) and higher %CD8+ counts (58.0 ± 14) and log10 VL (5.19 ± 0.5). None of these children achieved an adequate immune recovery or viral suppression during the follow-up (data not shown). Three children died from multi-organ failure and one child died of non-Hodgkin’s lymphoma.

HIV genotype baseline

The HIV-1 resistance genotypes were determined for 53 of the 69 children at baseline. Mutations found in HIV protease gene are summarized in Figure 1. The most prevalent primary mutation was L90M followed by I54V. Within secondary mutations, L63A/P was the most frequent, being also the most prevalent protease mutation.


Figure 1
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  		Figure 1. Percentage of children with mutations in HIV protease gene at baseline.

 
Evolution of CD4+ T cells and VL according to stratum at baseline

Figure 2 shows that children with CD4+ <15% at baseline did not achieve CD4+ >25% during follow-up. However, children with baseline VL > 100 000 had CD4+ >25% at month 12. Children with CD4+ >15% at baseline achieved better viral suppression than those with CD4+ <15%. Children with the lowest VL at baseline maintained a better viral suppression during follow-up when compared with those with VL > 30 000 copies/mL at baseline.


Figure 2
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  		Figure 2. Evolution of CD4+ T cells and VL according to stratum at baseline during follow-up.

 
In Table 2, we summarize the mean of changes of %CD4+ and log10 VL (copies/mL) from pre-baseline to second and fourth year according to CD4+ and VL strata at baseline. During the first 2 years on HAART, we only found a significant increase in %CD4+ in children with CD4+ between 0% and 15% and those with VL < 30 000 copies/mL (P < 0.05). Furthermore, we found a significant decrease in VL in all groups of children (P < 0.05). When we considered the last 2 years of follow-up (from second to fourth year), we found a significant increase in %CD4+ in all children who had CD4+ <25% and in those with baseline VL > 100 000 copies/mL. Once more, we found a significant decrease in VL in all groups of children (P < 0.05).


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  		Table 2. Summary of estimated marginal means of change in %CD4+ T cells and log10 VL (copies/mL) of HIV-infected children from baseline to second or fourth year on HAART

 
In the univariate analysis (Table 3), %CD4+ at baseline had a strong positive association with achieving and maintaining CD4+ >25% at 6, 12, 18, 24, 36 and 48 months. However, we found a negative association of length of PI use and number of previous PIs with achieving CD4+ >25% at 6, 12, 18, 24, 36 and 48 months. We found a negative association of age with reaching CD4+ >25% at 6 and 12 months. We also observed a negative association of length of ART with achieving CD4+ >25% at 24, 36 and 48 months. We conducted a multivariate analysis to identify the most relevant factors associated with reaching CD4+ >25%. We found that %CD4+ at baseline had a strong significant positive association with achieving CD4+ >25% at 6, 12, 18, 24, 36 and 48 months. We found that length of PI use had a negative association with reaching CD4+ >25% at 24 and 48 months.


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  		Table 3.. Summary of logistic regression analysis to achieve sustained CD4+ T cell counts higher than 25% at 6, 12, 18, 24, 36 and 48 months

 
Finally, we analysed the long-term response to HAART with lopinavir/ritonavir on viral suppression (Table 4). In the univariate analysis, %CD4+ at baseline had a strong positive association with achieving uVL (≤400 copies/mL) at 6, 12, 18, 24, 36 and 48 months. However, we also found a negative association of length of PI and number of previous PIs with achieving an adequate viral suppression at 6, 12, 18, 24, 36 and 48 months. Besides, we detected a negative association of VL at baseline and length of previous ART with achieving uVL (≤400 copies/mL) at 12, 18, 24 and 36, and 6, 12, 18 and 24, respectively. Moreover, we observed a negative association of having ≥6 LMS with reaching an adequate viral suppression during 12, 18, 24 and 36 months. In the multivariate analysis, we observed that %CD4+ at baseline had a positive association with reaching uVL (≤400 copies/mL) at 36 and 48 months. Furthermore, we found that VL at baseline and length of PI had a negative association with achieving uVL (≤400 copies/mL) at 18 and 24 months and at 12 and 48 months, respectively.


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  		Table 4.. Summary of logistic regression analysis to achieve sustained VL suppression (≤400 copies/mL) at 6, 12, 18, 24, 36 and 48 months

 

   Discussion
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 Patients and methods
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This study shows a sustained and continued immune recovery in vertically HIV-infected children receiving HAART with lopinavir/ritonavir during a median time of almost 5 years, even when plasma HIV-1 RNA is not completely suppressed. Several previous reports have demonstrated the effectiveness of lopinavir/ritonavir in both naive and experienced children.19,20 However, few data about its long-term use are available in children. Recently, Landay et al. have demonstrated ongoing immune reconstitution in adults with sustained viral suppression after 6 years of lopinavir/ritonavir treatment but few studies have been carried out in children.12,13 Besides, our study evaluated lopinavir/ritonavir use in children during a prolonged period in a clinical setting, so its results represent more accurately what happens in clinical practice where lack of adherence or pharmacokinetic interactions might lead to incomplete viral suppression in children.

Our cohort included children with extensive experience in all classes of ARVs and with moderate immune suppression according to CDC categories. Moreover, they had worse nutritional parameters at baseline and, as it has been recently reported by Guillen et al.21 this might be related to lack of previous viral control. Furthermore, the effectiveness of subsequent HAART regimens is usually lower than the first regimen.22 Notwithstanding, HAART with lopinavir/ritonavir in our cohort was associated with a sustained increase in CD4+ counts and decrease in viral replication even in children with lowest %CD4+ or highest VL at baseline.

Side effects of HAART with lopinavir/ritonavir in our study were mild, transient and mainly gastrointestinal. Here, we only reported those side effects that were severe or might cause the discontinuation of treatment. Less than 9% of children included in our study experienced severe adverse events. These data are similar to other studies carried out in HIV-infected children.11,20,23 Hypercholesterolaemia and hypertriglyceridaemia are common side effects reported in adults. Although these side effects appear to be less common in children, as our study also showed, the future risk of cardiovascular diseases in vertically HIV-infected infants may be of concern.24 Thus, a routine monitoring of serum lipid values seems to be advisable during lopinavir/ritonavir treatment in children.3 The most prevalent side effect in our cohort was lipodystrophy in ~30% of children. However, lipodystrophy could also be related to the previous use of other ARTs. In addition, stavudine was the most prevalent nucleoside reverse transcriptase inhibitor (NRTI) at baseline in our cohort (data not shown). As recently reported, NRTIs, particularly stavudine and didanosine, and not only PIs, are related to the development of lipodystrophy in children.4,25

Resistance development due to incomplete viral suppression remains the main obstacle to the success of long-term HIV-treatment.10 In our study, more than 50% of children had any primary mutation in protease gene at baseline, and even though none of them had the I47A/V mutation, the only specific primary mutation selected by lopinavir/ritonavir,26 most of our patients have accumulated several mutations during previous treatment with PIs. L90M was the most frequent primary mutation found, which could be due to the previous treatment with nelfinavir or saquinavir in more than 60% of children. Having more than six mutations27 was associated with inadequate viral suppression. However, small simple size of children with ≥6 LMS (13 children) could have reduced the influence of mutations in HIV-protease gene at baseline to achieve a good long-term response in our cohort.28,29

Few data are available on long-term immune recovery in children and addressing this issue is particularly important to define the optimal time to initiate ART.30 In our study, children with %CD4+ ≤25% at baseline still achieved an increase in %CD4+ at the end of the study. However, immune recovery in patients with %CD4+ ≤25% at baseline was lower during the whole follow-up. Resino et al.8 reported ongoing immune recovery in children after 6 years on HAART but with a plateau in %CD4+ after 2 years and once more, with a lower response in children with fewer %CD4+. In our study, we have identified different predictive factors for short-term immune responses (having %CD4+ ≥25% at 18 months) compared with those with longer-term immune responses (having %CD4+ ≥25% at 48 months). Thus, we observed that %CD4+ at baseline was the most important factor in predicting an adequate immune recovery during the whole follow-up. Soh et al.31 reported that for 1012 children treated with PI, better immune responses were observed among younger children with higher %CD4+. Lengths of PI use or number of previous PIs were also identified as predictive factors of longer-term immune recovery but with a negative correlation. The impact of these factors was corroborated by the multivariate analysis. Age was identified as a predictive factor for achieving a good immune response during the first year on HAART with lopinavir/ritonavir. Better immune recovery has been reported among younger children previously by Walker et al.32 However, due to the lack of babies and small children in our cohort, age was less relevant. Thus, taking into account our results, ART would be more effective in the long-term among HIV-infected children with mild or absent immune suppression. However, the appearance of side effects or lack of adherence that usually developed after long-term ART complicates this issue. Current guidelines on ART in children gives more relevance to %CD4+ above any other parameter to guide paediatric HIV-infection treatment.33 Our study corroborates the importance of %CD4+ to decide when to initiate ART in treatment-experienced children. Nevertheless, there are several limitations in our study such as different ARV schemes before initiation of lopinavir/ritonavir and the use of non-homogeneous HAART regimens, which make it difficult to have a clear understanding of the impact and statistical association between virological/immunological variables and use of lopinavir/ritonavir.

Predictive factors of virological success with lopinavir/ritonavir treatment have been widely studied in adults10,13,34,35 and children.28,36 In our cohort, %CD4+ and length of ART or PI use or number of previous PIs were identified as predictive factors for virological response in the univariate analyses. Nevertheless, its relevance decreases in the multivariate analyses partially due to the interactions between these factors. Baseline VL was associated with virological success at least for a duration of 24 months. Observations corroborate the idea that immune categories in children affect long-term responses whereas VL measures are more effective to predict short-term responses. However, both parameters should be considered in deciding when HIV-infected children should start a salvage regimen.

In summary, this study demonstrates ongoing immune recovery among children on HAART with lopinavir/ritonavir after 4 years of follow-up. This response was greater in less immunocompromised children but it still happens even when viral replication is not fully suppressed. Lopinavir/ritonavir when given as part of a salvage regimen is safe and well tolerated in HIV-infected children.


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This work has been supported by grants from Fondos de Investigación Sanitaria (FIS) del Ministerio de Sanidad y Consumo (PI052476, PI061479); Red RIS RD06-0006-0035; FIPSE (36514/05, 24534/05), Fundación Caja Navarra and Comunidad de Madrid (S-SAL-0159-2006) to M. A. M. F. From FIS (CP04/00090, PI052411) to S. R. Beatriz Larrú has staff researcher by FIS (CM0600054).


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None to declare.


   Acknowledgements
 
Spanish Group of Paediatric HIV Infection: participating hospitals and personnel staff in this paper. Madrid—Hospital Universitario ‘12 Octubre’: J. T. R., S. Guillen, P. Carreño, J. Ruiz, J. Clemente and M. I. Tomé; Hospital General Universitario ‘Gregorio Marañón’: B. L., S. R., J. M. B., M. D. G., M. L. N. and M. A. M.-F.; Hospital Universitario ‘La Paz’: M. I. J.; Hospital Universitario ‘Carlos III’: P. Martín-Fontelos and M. J. M. Barcelona—Hospital ‘San Joan de Déu’: C. F., A. Noguera and C. Muñoz-Almagro; Hospital ‘Val dxHebrón’: P. S. Seville—Hospital Universitario ‘Virgen del Roció’: J. A. León Leal and Ignacio Obando. Valencia—Hospital ‘La Fe’: M. A.


   References
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4 Hartman K, Verweel G, de Groot R, et al. Detection of lipoatrophy in human immunodeficiency virus-1-infected children treated with highly active antiretroviral therapy. Pediatr Infect Dis J (2006) 25:427–31.[CrossRef][Web of Science][Medline]

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11 Ramos JT, De Jose MI, Duenas J, et al. Safety and antiviral response at 12 months of lopinavir/ritonavir therapy in human immunodeficiency virus-1-infected children experienced with three classes of antiretrovirals. Pediatr Infect Dis J (2005) 24:867–73.[CrossRef][Web of Science][Medline]

12 Kline MW, Rugina S, Ilie M, et al. Long-term follow-up of 414 HIV-infected Romanian children and adolescents receiving lopinavir/ritonavir-containing highly active antiretroviral therapy. Pediatrics (2007) 119:e1116–20.[Abstract/Free Full Text]

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15 AIDSinfo. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. http://AIDSinfo.nih.gov (26 October 2006, date last accessed).

16 Ramos JT, de Jose MI, Polo R, et al. Recommendations of the CEVIHP/SEIP/AEP/PNS on antiretroviral treatment in HIV-infected children and teenagers. Enferm Infecc Microbiol Clin (2005) 23:279–312.[CrossRef][Web of Science][Medline]

17 Resino S, Gurbindo M, Bellón J, et al. Predictive markers of clinical outcome in vertically HIV-1 infected infants. A prospective longitudinal study. Pediatr Res (2000) 47:509–15.[Web of Science][Medline]

18 Hirsch MS, Brun-Vezinet F, D’Aquila RT, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. JAMA (2000) 283:2417–26.[Abstract/Free Full Text]

19 Resino S, Bellón JM, Ramos JT, et al. Positive virologic outcome after lopinavir/ritonavir salvage therapy in protease inhibitor-experienced HIV-1-infected children. A prospective cohort study. J Antimicrob Chemother (2004) 54:921–31.[Abstract/Free Full Text]

20 Saez-Llorens X, Violari A, Deetz CO, et al. Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. Pediatr Infect Dis J (2003) 22:216–24.[CrossRef][Web of Science][Medline]

21 Guillen S, Ramos JT, Resino R, et al. Impact on weight and height with the use of HAART in HIV-infected children. Pediatr Infect Dis J (2007) 26:334–8.[CrossRef][Web of Science][Medline]

22 Newell ML, Patel D, Goetghebuer T, et al. CD4 cell response to antiretroviral therapy in children with vertically acquired HIV infection: is it associated with age at initiation? J Infect Dis (2006) 193:954–62.[CrossRef][Web of Science][Medline]

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N. Rakhmanina, J. van den Anker, A. Baghdassarian, S. Soldin, K. Williams, and M. N. Neely
Population Pharmacokinetics of Lopinavir Predict Suboptimal Therapeutic Concentrations in Treatment-Experienced Human Immunodeficiency Virus-Infected Children
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