The immature immune system of human immunodeficiency virus (HIV)-infected children is unable to control HIV replication allowing higher plasma viral loads than adults. Virologic failure and the emergence of HIV quasispecies resistant to antiretroviral (ARV) drugs compromise the available treatment options. To date, 25 compounds have been licensed for HIV infection in adults1 and 17 in the pediatric population.2 The use of protease inhibitors (PIs) has led to a decrease in HIV-related morbidity and mortality. Fosamprenavir (FPV), approved in 2003 for adults and 2007 for pediatric patients, is a potent PI that, boosted with ritonavir (FPV/r), has shown potent ARV activity in ARV-naive adults,3–5 ARV-naive and pretreated pediatric subjects aged 2 to 18 years.6,7
Our aim was to assess the virologic, immunologic, and clinical response to a FPV/r-based regimen in combination with nucleoside reverse transcription inhibitors (NRTIs) and PIs and/or non-nucleoside reverse transcription inhibitors (NNRTIs) in ARV-naive and ARV-experienced children and adolescents with previous virologic failure and on highly active antiretroviral treatment (HAART). In addition, we addressed the safety and tolerability of FPV/r in this cohort.
PATIENTS AND METHODS
A multicenter retrospective study of vertically HIV-infected children (2–12 years old) and adolescents (13–15 years old) of the HIV Spanish Pediatric Cohort (CoRISpe) receiving treatment with FPV/r followed up at least 1 year was carried out. Patients were included in 1 of the 2 following categories: (i) ARV-naive and (ii) ARV-experienced individuals with at least one episode of virologic failure and on HAART. Baseline was considered FPV/r initiation. A weight-adjusted dose of 30 mg/kg twice daily was chosen for naive patients from 4 to 18 years old and 18 mg/kg twice daily for pretreated patients >6 years old. Visits were scheduled every 3 to 6 months. Demographics, clinical, and laboratory parameters were recorded longitudinally. Clinical category was based on the Center for Disease Control and Prevention guidelines. Ethical approval for the survey was obtained from the Ethical Committees of all hospitals and informed consent was obtained from parents or guardians. Several biologic samples were provided by the Spanish HIV BioBank belonging to the Spanish AIDS Research Network (RIS).8 Plasma HIV-1 ribonucleic acid (RNA) was measured using the commercial quantitative Amplicor Monitor assay (Roche Diagnostic Systems) with a detection limit of 50 copies/mL while plasma HIV-2 RNA was measured using the commercial Nuclisens Easy Q (version 1.1) assay (EasyQ; bioMérieux) as previously described.9 CD4+ T-lymphocytes were quantified by flow cytometry (Coulter, Madrid, Spain). Values were recorded as absolute numbers/percentage and medians were calculated with their interquartile range. Mann-Whitney U test was used to compare continuous variables. P-values were 2-tailed and statistical significance was defined as P < 0.05. SPSS (v.12; SPSS Inc., Chicago, IL) was used.
Twenty vertically HIV-infected patients born from 1991 to 2004 fulfilling the inclusion criteria were enrolled from 2003 to 2007 (Annex). Six (30%) were therapy-naive and 14 (70%) therapy-experienced. Median age was 6 (2–9) and 10 years, (6–13), respectively. The majority of patients were female (70%; n = 14) and Caucasian (85%; n = 17) (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A374). Only one child (from Ecuador) harbored HIV-2 subtype A.
At baseline, median HIV-1 RNA was 37,250 (4.6 log10) copies/mL (16,599–68,321) in naive and 21,990 (4.4 log10) copies/mL (1920–78,283) in pretreated patients. Median CD4+ T-cell count was 376 (17%) cells/μL (180–862) and 722 (31%) cells/μL (502–1266), respectively. CD4+ T-cell percentage was higher in pretreated patients compared with naive ones (P = 0.007). Three (50%) out of 6 naive patients presented a moderate immunologic suppression (200–499 cells/μL) and 1 of 6 (17%) severe suppression (<200 cells/μL) who harbored a resistant virus acquired through vertical transmission. Two (14%) of 14 pretreated patients presented moderate immune suppression. Four (20%) out of 20 subjects (1 naive and 3 pretreated) were classified into C clinical category (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A374). The naive child harboring a resistant virus showed mutations to NRTIs (D67N, K70R, T215Y, K219Q), NNRTIs (K103N, G190A), and PIs (L90M, I54V). ARV-experienced patients had a median duration of HAART exposure of 94.6 months (59.8–131.1) and 6 of 14 (43%) developed mutations to NRTIs (M41L, D67N, K70R, L74V, M184V, L210W, T215Y, K219Q), NNRTIs (K103N, Y181C, G190A, P225H), and to PIs (M46I/L, V82A, L90M).
The median time of follow-up with FPV/r was 180 weeks (134.5–229.1), with 17 of 20 (85%) patients exposed >129 weeks. Only one patient received unboosted (without ritonavir) FPV. Backbone ARV treatment was 2 NRTI being the most common drugs lamivudine and abacavir. Eighteen (90%) out of 20 patients (6 naive and 12 pretreated) reached undetectable HIV-1 RNA: 15 (75%) within the first 4 months and 3 at the fifth, sixth, and eleventh month, respectively. Seventy-eight percent of patients (4 naive and 10 pretreated) maintained undetectable HIV-1 RNA. Three of them were enrolled in the HIV-infected adults Spanish Cohort (CoRIS) at the end of the study and a simplification regimen was performed replacing FPV-based regimen by Atripla. In 2 pretreated children with insufficient viral response, FPV therapy was replaced by etravirine, darunavir, and maraviroc. Nevertheless, a decrease in HIV-1 RNA ≥2 log10 was detected during follow-up.
At the end of the study, median increase from baseline in CD4+ T-cell counts was observed in 5 of 6 naive and 8 of 14 ARV-experienced patients (Δ217 cells/μL and Δ251 cells/μL, respectively). Among the 7 patients experiencing a decrease in T-cells, one naive child had 492 cells/μL, while the rest maintained a CD4+ T-cell value ≥500 cells/μL. Laboratory abnormalities, ARV adherence, and ARV-related adverse events are summarized in Table, Supplemental Digital Content 1, http://links.lww.com/INF/A374. The child who developed a severe skin rash, initially considered an abacavir reaction, was negative for HLA-B*5701 genetic variation. Four (20%) subjects permanently interrupted FPV-based therapy (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A374), but only one because of high-resistance to FPV: the emergence of the I54L mutation after 197 weeks conferred, along with baseline resistance mutations (M46L, V82A, L90M), complete resistance to the drug. One patient received unboosted FPV and showed a long (197 weeks) virologic and immunologic response as observed in patients having boosted FPV.
An increasing number of HIV-infected children and adolescents are failing the available treatment options. Currently, the recently approved PIs FPV (Lexiva), tipranavir (Aptivus), and darunavir (Prezista) for the pediatric population are still being evaluated in ongoing clinical trials, representing potential new drug alternatives to HIV-1 infection treatment in children and adolescents.7,10,11 The rather limited studies published so far in pediatric population on FPV-based regimen correspond to the APV20003 and APV29005 (interim data) clinical trials6,7 and no information on FPV/r use in routine clinical practice has been published to date. Notably, the present study represents the first epidemiologic survey characterizing the clinical, virologic, and immunologic response to a combined FPV/r therapy in naive and ARV-experienced HIV-infected pediatric patients followed up for more than a median of 180 weeks in a clinical set-up. Evidences support that FPV/r exerts its effect in both naive and ARV-experienced children according to recent trials.6,7 The study population was comparable in terms of age, gender, ethnicity, baseline viral load with the APV29005 (interim data) group. Concerning immunologic status, no data are available in the APV29005 (interim data) trial to perform a comparison between the 2 groups (estimated study completion date: December 2012). The virologic response achieved mainly during the first 4 months of follow-up was potent and durable, with a proportion of responders higher than previously reported.7 However, as early evidenced, poor adherence and initial resistance mutations might compromise the effectiveness of FPV-based therapy. A long-term sustained immunologic improvement was observed, as highlighted by others.4 Nevertheless, a considerable proportion of HIV-infected subjects entered the study with a minimally compromised immune system. The low rate of adverse events related to FPV/r regimen confirmed its safe profile as previously reported.7 The emergence of resistance mutations to FPV/r occurred late during follow-up, in agreement with observations described in HIV-1 infected adults,4 suggesting high genetic barrier to this drug. Further analyses involving larger cohorts remain necessary.
Although the limited size of the study population represents the main shortcoming, our results are supported by clinical trials in adults,3–5 children, and adolescents,6,7 being our study the longest carried out to date evaluating FPV/r efficacy. Moreover, 2 interesting cases never described earlier are presented. The first case is represented by a severely immunocompromised naive child who harbored a HIV-1 resistant virus at enrolment. FPV/r was associated with long-term clinical benefit, although a viral load rebound was observed at 120 weeks. The second case is an HIV-2 infected patient who showed good response to FPV/r therapy.
The authors thank the patients in this study for their participation and the HIV BioBank belonging to the Spanish AIDS Research Network (RIS) and collaborating centers for the clinical samples provided.
1. De Clercq E. Anti-HIV
drugs: 25 compounds approved within 25 years after the discovery of HIV
. Int J Antimicrob Agents
3. Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV
-1-infected patients. J Acquir Immune Defic Syndr
4. Gathe JC Jr, Wood R, Sanne I, et al. Long-term (120-week) antiviral efficacy and tolerability of fosamprenavir
/ritonavir once daily in therapy-naive patients with HIV
-1 infection: an uncontrolled, open-label, single-arm follow-on study. Clin Ther
5. Eron J Jr, Yeni P, Gathe J Jr, et al. The KLEAN study of fosamprenavir
-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV
infection over 48 weeks: a randomised non-inferiority trial. Lancet
6. Chadwick E, Borkowsky W, Fortuny C, et al. Safety and antiviral activity of fosamprenavir
/ritonavir once daily regimens in HIV
-infected pediatric subjects ages 2 to 18 years (48-week interim data, study APV20003). In: 14th Conference on Retroviruses and Opportunistic Infections; February 25–28, 2007; Los Angeles, CA. Abstract 719.
7. Cunningham C, Freedman A, Read S, et al. Safety and antiviral activity of fosamprenavir
-containing regmens in HIV
-infected 2- to 18-year-old pediatric subjects (Interim Data, Study APV29005). In: 14th Conference on Retroviruses and Opportunistic Infections; February 25–28, 2007; Los Angeles, CA. Abstract 718.
8. Garcia-Merino I, de Las Cuevas N, Jimenez JL, et al. The Spanish HIV
BioBank: a model of cooperative HIV
9. Rodes B, Sheldon J, Toro C, et al. Quantitative detection of plasma human immunodeficiency virus type 2 subtype A RNA by the Nuclisens EasyQ Assay (version 1.1). J Clin Microbiol
10. Salazar JC, Cahn P, Yogev R, et al. Efficacy, safety and tolerability of tipranavir coadministered with ritonavir in HIV
11. Bologna R, Rugina S, Cahn P, et al. Safety and efficacy of darunavir co-administered with low-dose ritonavir in treatment-experienced children
at week 24. In: 15th Conference on Retroviruses and Opportunistic Infections; February 3–6, 2008; Boston, MA. Abstract 78LB.
Hospital Universitari “La Fe,” Valencia (7 patients), Hospital Universitario “La Paz,” Madrid (4 patients), Hospital Universitario “Doce de Octubre,” Madrid (3 patients), Hospital Regional Universitario “Carlos Haya,” Málaga (2 patients), Hospital “Virgen del Rocio,” Sevilla (2 patients), Hospital Universitario “Carlos III,” Madrid (1 patient), Hospital Universitario de Getafe, Madrid (1 patient).
Spanish Group of Pediatric HIV Infection: Participating Hospitals and Personnel Staff in This Paper
Hospital General Universitario “Gregorio Marañón,” C. Palladino; V. Briz; S. J. de Ory; D. García Alonso; M. D. Gurbindo; M. L. Navarro; and M. A. Muñoz-Fernández. Hospital Universitari “La Fe,” S. Negre Policarpo; Laura Fernandez Silveira. Hospital Universitario “La Paz,” M. I. de José. Hospital Universitario “Doce de Octubre,” M. I. González-Tomé. Hospital Regional Universitario “Carlos Haya,” D. Moreno. Hospital Infantil Unversitario “Virgen del Rocío,” J. A. León Leal. Hospital Universitario de Getafe, J. T. Ramos. Hospital Universitario “Carlos III,” M. J. Mellado.