JAC Advance Access originally published online on January 30, 2006
Journal of Antimicrobial Chemotherapy 2006 57(3):579-582; doi:10.1093/jac/dki469
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Correspondence |
Antiretroviral activity and safety of lopinavir/ritonavir in protease inhibitor-experienced HIV-infected children with severe-moderate immunodeficiency
Laboratory of Inmunobiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain
* Corresponding author. Tel: +34-91-5868565; Fax: +34-91-5868018; E-mail: mmunoz{at}cbm.uam.es
Keywords: CD4+ , viral load , drug resistance , salvage therapy , immune reconstitution
Sir,
HIV-infected children have an immature immune system that is unable to control HIV-1 replication efficiently.1 Furthermore, many children on highly active antiretroviral therapy (HAART) rapidly experience virological failure allowing the appearance of HIV-1-quasispecies resistant to antiretroviral drugs.2 Lopinavir/ritonavir is a protease inhibitor (PI) that has shown potent antiretroviral activity in PI-experienced HIV-infected children.3–6
We carried out a prospective multicentre study for a period of 18 months to study the effectiveness of salvage therapy with lopinavir/ritonavir in 25 children. The study was conducted according to the Declaration of Helsinki and was approved by the Ethics Committee of our hospital, HGU Gregorio Marañón. The inclusion criteria of 25 children were as follows: (i) CD4+ <25% and <500 cells/mm3; (ii) virological failure to antiretroviral therapy (ART) with a PI and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI); and (iii) viral load (VL) >5000 copies/mL at entry into the study. The study of evaluation, adverse events and dose of lopinavir/ritonavir on children during follow-up were as described previously.4 Response to therapy was evaluated every 3 months by serial %CD4+, %CD8+ and VL measurements.4 There was not a uniform approach regarding ART. Instead, each paediatrician administered the appropriate ART regimen and changed the drugs according to his/her interpretation of the children's data and international guidelines.4
All children were heavily pre-treated with HAART [median (range): 41 (14.6–61.6) months, 4 (1–9) ART-protocol switches, and 8 (4–12) drugs prior to lopinavir/ritonavir therapy]. At baseline, 13 (52%) children had prior diagnosis of AIDS and none of the children progressed to AIDS or death during the follow-up period. No child was lost to follow-up. The new drugs in children with salvage therapy (excluding lopinavir) were 8 nucleoside analogues (NRTI), 3 non-nucleoside analogues (NNRTI) and 2 protease inhibitors (PI). The HAART protocols (NRTIs+...) were 16 with lopinavir/ritonavir, 4 with lopinavir/ritonavir+1 PI (saquinavir, amprenavir or nelfinavir), 1 with lopinavir/ritonavir+2 PI (amprenavir+saquinavir) and 4 with lopinavir/ritonavir+1 NNRTI (efavirenz). As assessed through parental report, adherence was deemed to be good by the clinician in the cohort.
At baseline, median (range) age was 10.9 (3.2–17.1) years. Eleven children had CD4+ <15% and median (range) CD4+ was 16% (1–23). The median (range) log10 VL was 5.17 (4.06–6) copies/mL. Baseline HIV mutations were studied in 21 out of the 25 samples. The median number of PI mutations was 6 (1–10) and the median number of RT mutations was 6 (3–14). All children had mutations associated with PI and 17 children had 
1 PI mutation and 11 children had 6 PI mutations. The list of PI mutations detected were L10F (n = 3), L10I (n = 11), K20M (n = 2), L24I (n = 2), D30N (n = 4), L33F (n = 2), M36I/V (n = 5), M46I (n = 6), M46L (n = 3), I54V (n = 5), L63A/P (n = 15), A71T/V (n = 8); G73S (n = 2), V77I (n = 8), V82A/F (n = 6), I84V (n = 5), N88D (n = 4) and L90M (n = 11).
‘Lopinavir mutation score’ (LMS) and protease-associated mutations (PRAMs) are likely to contribute to the reduced susceptibility to lopinavir, and provide a potential method as a baseline genotype to evaluate the hypothetical virological response to lopinavir/ritonavir.7 At baseline, the prevalence of LMS was 5 (0–9) and the prevalence of PRAMS was 1 (0–3). However, we did not find an association with virological failure by Cox regression analysis possibly due to the low number of children.
VL decreased quickly and it remained low during the follow-up study (Figure 1a) with a median (range) decrease at month 18 of 1.9 (0.15–4.2) log10 VL (copies/mL) (P < 0.001). The percentages of children who achieved a VL <5000 copies/mL and undetectable VL (uVL 
400 copies/mL) during the follow-up study were 63% and 47%, respectively (Figure 1b), and 17 of 25 children achieved uVL during follow-up (Figure 1c). After achieving uVL, 8 of 17 children had a rebound of VL >400 copies/mL (Figure 1c).
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Significant increases in CD4+ were observed. The median (range) increase at month 18 was 15 (–3; 44) %CD4+ (P < 0.001) and 300 (4: 2434) CD4+/mm3 (P = 0.001) (Figure 1d and e). Also, 68% of children had CD4+ >500 cells/mm3 and 58% had CD4+ >25% (Figure 1f). Next, we analysed the CD4+ increase by Kaplan–Meier analysis (Figure 1g). The median time to achieve CD4+ >25% was 12.6 ± 2.6 months and the median time to achieve CD4+ >500 cells/mm3 was 5.96 ± 1.7 months.
Lopinavir/ritonavir was well tolerated. One child temporarily interrupted their ART due to diarrhoea and vomiting during 2 weeks and lopinavir/ritonavir was reintroduced again. Adverse events during the follow-up study were reported in 15 out of 25 (60%) children. The most frequent events were gastrointestinal, diarrhoea in nine (36%) children and vomiting or nausea in four (16%) children. Diarrhoea was considered of grade 1 or 2.
Cholesterol levels did not vary significantly during the follow-up [195 (131–295) mg/dL versus 181 (131–275) mg/dL]. However, children had an increase in non-fasting triglyceride levels during the follow-up [126 (71–476) mg/dL at baseline versus 187 (67–609) mg/dL at month 18; P = 0.022]. Moreover, one child had non-fasting triglyceride levels >300 mg/dL and four children had levels >200 mg/dL. There were no increases in the remaining laboratory parameters (haematology markers, alkaline phosphatase, amylase, creatinine, aminotransferases) during the follow-up.
These children had a high number of HIV mutations that might well be the reason for the prior virological failure.8 During the follow-up study, >45% of children reached uVL (400 copies/mL). These results are in agreement with the experience in heavily pre-treated children on salvage HAART with lopinavir/ritonavir,5,6 and may be considered excellent, despite the fact that most drugs used in combination with lopinavir/ritonavir are supposed to have little activity against the resistant viruses. We also observed a significant increase in the percentage of children with immune-competence (CD4+ >25% or CD4+ >500 cells/mm3). Children were already on PI for many months and a further rise in CD4+ count was observed despite lack of complete virological response.
Lopinavir/ritonavir was well tolerated as reported previously,6 enabling adherence to treatment. The most common drug-related adverse events were of gastrointestinal nature, and the most common laboratory abnormality was lipid elevation. We found that plasma triglycerides were increased but all children were PI-experienced before starting lopinavir/ritonavir regimens. These children could have had increased lipid and cholesterol at entry into the study. The possibility of hypercholesterolaemia in children with other risk factors for cardiovascular diseases should require surveillance during lopinavir/ritonavir therapy.
In conclusion, salvage therapy with lopinavir/ritonavir exhibited safety and tolerability, and it was associated with substantial antiviral activity (
50% of children with VL <400 copies/mL) and immune recovery.
Transparency declarations
The authors do not have commercial or other associations that might pose a conflict of interest.
Footnotes
Participants are listed in the Acknowledgements section. 
Acknowledgements
Sources of financial support: Fundación para la Investigación y la Prevención del SIDA en España (FIPSE) (grant 12456/03); Fundación para la Investigación Sanitaria (FIS) del Ministerio de Sanidad y Consumo (PI040883, PI052479, PI052472, PI052411); Plan Nacional de Salud (SAF 2003-09209, SAF-2004-06778); Red Temática Cooperativa de investigación en SIDA (RIS G03/173) of FIS; and Red Temática Cooperativa de investigación en Genética (RIG C03/07) of FIS. Salvador Resino has staff researcher by FIS (CP04/00090).
Participating hospitals and personnel staff of the Spanish Group of Paediatric HIV Infection are as follows. Madrid: Hospital 12 Octubre: J. T. Ramos, P. Carreño, J. Ruiz, J. Clemente; Hospital Gregorio Marañón: J. M. Bellón, M. D. Gurbindo, M. L. Navarro, A. Alvaro-Meca, S. Resino, M. A. Muñoz-Fernández; Hospital la Paz: M. I. Isabel de José; Hospital Carlos III: P. Martín-Fontelos, M. J. Mellado, J. Villota. Sevilla: Hospital Virgen del Rocio: J. A. León Leal. Barcelona: Hospital S Juan de Dios: C. Fortuny, L. M. Tello; Hospital Valle de Hebrón: J. M. Bertrán, L. García; Hospital del Mar: A. Mur. Alicante: Hospital S Juan: R. González-Montero. Bilbao: Hospital de Cruces: I. Pocheville, C. Gutierrez. Palma de Mallorca: Hospital Son Dureta: L. Ciria, J. Dueñas. Valencia: Hospital La Fe: A. Orti, M. C. Otero, F. Asensi. Zaragoza: Hospital Clínico: M. Gracia. Abbott Laboratories, Spain: E. Cabrero, L. Usán.
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