ARTICLE
Long-term Follow-up of 414 HIV-Infected Romanian
Children and Adolescents Receiving Lopinavir/
Ritonavir-Containing Highly Active
Antiretroviral Therapy
Mark W. Kline, MDa,b, Sorin Rugina, MDc, Margareta Ilie, MDc, Rodica F. Matusa, MDc, Ana-Maria Schweitzer, MAa,b, Nancy R. Calles, BSN, RNa,b,
Heidi L. Schwarzwald, MDa,b
aBaylor College of Medicine International Pediatric AIDS Initiative, Texas Children’s Hospital, Houston, Texas;bBaylor Black Sea Foundation, Constanta, Romania; cInfectious Diseases Hospital, Constanta, Romania
Financial Disclosure: Dr Kline and the Baylor College of Medicine International Pediatric AIDS Initiative receive grant support from Abbott Laboratories for program activities in Romania and Africa.
ABSTRACT
BACKGROUND.There are no published reports of the long-term safety and
effective-ness of highly active antiretroviral therapy for children and adolescents living in resource-limited settings or of large cohorts of HIV-infected children and adoles-cents treated long-term (⬎48 weeks) with lopinavir/ritonavir-containing highly active antiretroviral therapy.
OBJECTIVES.The purpose of this work was to evaluate the long-term outcomes of
treatment of HIV-infected children and adolescents with lopinavir/ritonavir-con-taining highly active antiretroviral therapy in a resource-limited setting.
METHODS.We studied an inception cohort of 414 HIV-infected children receiving
lopinavir/ritonavir-containing highly active antiretroviral therapy between No-vember 2001 and August 2006 at the Romanian-American Children’s Center in Constanta, Romania. The center provides comprehensive primary and HIV spe-cialty care and treatment to all known HIV-infected children and adolescents living in Constanta. We measured safety and effectiveness by the percentage of children remaining on treatment, rates of mortality, and changes in plasma HIV RNA concentrations and CD4⫹lymphocyte counts.
RESULTS.The study population consisted predominantly of antiretroviral drug–
ex-perienced older children and adolescents with advanced HIV disease. Treatment was well tolerated, with 337 children (81%) remaining on therapy after a median duration of ⬎4 years. Thirty-seven deaths occurred; the death rate compared favorably to prospectively collected historical data. The most recent on-treatment plasma HIV RNA concentration was ⬍400 copies per milliliter in 192 of 265 children tested. The mean baseline CD4⫹ lymphocyte count was 292 cells per microliter (n⫽299); the mean change from baseline was⫹266 (n⫽284),⫹317
www.pediatrics.org/cgi/doi/10.1542/ peds.2006-2802
doi:10.1542/peds.2006-2802
Key Words
HIV infection, child, adolescent, lopinavir
Abbreviations
HAART— highly active antiretroviral therapy
BIPAI—Baylor College of Medicine International Pediatric AIDS Initiative
(n⫽260), ⫹343 (n⫽176), and⫹270 cells per micro-liter (n⫽ 121) after 1, 2, 3, and 4 years of treatment, respectively.
CONCLUSIONS.Highly active antiretroviral therapy can be
administered safely and effectively to children and ado-lescents in resource-limited settings. Lopinavir/ritona-vir-containing highly active antiretroviral therapy is a safe, effective, and durable treatment option for antiret-roviral drug– experienced older children and adolescents with advanced HIV disease.
T
HE WORLD HEALTH Organization recently estimated that 800 000 children ⬍15 years of age are in im-mediate need of antiretroviral treatment.1 More than90% of these children live in low- and middle-income countries. There are no published reports of the long-term safety and effectiveness of highly active antiretro-viral therapy (HAART) for children in these settings.
Lopinavir/ritonavir (Kaletra)-containing HAART is strongly recommended for initial therapy of HIV infec-tion in children by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Chil-dren of the US Health Resources and Services Adminis-tration and National Institutes of Health.2 Approval of
the drug for children was based largely on the results of a 48-week study of its safety and efficacy in 100 HIV-infected children 6 months to 12 years of age.3
There are no published reports of the long-term (⬎ 48-week) safety and effectiveness of lopinar/ritonavir-con-taining HAART in large cohorts of HIV-infected children and adolescents.
Romania is a middle-income country with a per cap-ita gross domestic product comparable to that of Bo-tswana or Thailand and total health expenditure per capita less than Botswana, Thailand, or South Africa. Thousands of Romanian children were infected horizon-tally with HIV in the late 1980s through the transfusion of whole human blood unscreened for HIV, often by reuse of disposable needles.
The Baylor College of Medicine International Pediat-ric AIDS Initiative (BIPAI), Texas Children’s Hospital, the Infectious Diseases Hospital Constanta, and the Ro-manian Ministry of Health and Family built and opened the Infectious Diseases Hospital-BIPAI Outpatient HIV Clinic (also known as the Romanian-American Chil-dren’s Center) in Constanta in April 2001.4In a unique
partnership arrangement, the government of Romania supports the medical care and antiretroviral treatment of HIV-infected children and adolescents in the center through its national program, complemented by BIPAI and Baylor Black Sea Foundation-supported compre-hensive medical and psychosocial services and antiret-roviral drug donations.
A program of child and adolescent HAART was
initi-ated at the Romanian-American Children’s Center in November 2001. Today, 476 children and adolescents receive HAART at the center, more than in any other European center. We report the long-term outcomes of treatment in 414 HIV-infected children and adolescents who received lopinavir/ritonavir-containing HAART at the Romanian-American Children’s Center between No-vember 2001 and August 2006.
METHODS
Criteria for Treatment and Drug Administration
Children and adolescents received lopinavir/ritonavir-containing HAART in an open manner, by prescription, according to package insert instructions. Children in any US Centers for Disease Control and Prevention5category
other than N1 or A1 were considered eligible for treat-ment. Children already receiving antiretroviral therapy were considered eligible for a change to lopinavir/ritona-vir-containing HAART if they had evidence of clinical, virologic, and immunologic HIV disease progression.
Drugs used in combination with lopinavir/ritonavir were chosen on the basis of patient treatment history; genotyping for resistance mutations was not performed. Every child was naı¨ve to lopinavir/ritonavir and to ⱖ1 other agent that was being used in combination. Many children had been treated previously with other HIV protease inhibitors.
All of the antiretroviral medications were stored ac-cording to package insert instructions. Weight and body surface area were determined every 4 weeks, and the drug dose was changed when indicated by an increase or decrease in weight. Adherence was monitored by mea-suring or counting returned medication and by ques-tioning the parent and/or child at each scheduled clinic visit.
Patients received prophylaxis for Pneumocystis jiroveci
pneumonia according to established guidelines,6and
nutritional support and antibiotic therapy were pre-scribed as needed. Immunomodulators (excluding corticosteroids and intravenous immunoglobulin) were not used.
Patient and Family Education and Support
counseling. This booklet contains a glossary of key terms and is written at a sixth- or seventh-grade educational level. A mobile, multidisciplinary medical/psychosocial team visited children and families in the community⬃5 days each week. Center staff identified children and families who they felt might benefit from this more intensive schedule of follow-up at home and in the community. These home visits permitted monitoring of antiretroviral medication storage, administration and adherence, and factors in the home and family that might impact treatment. Five separate parent-led sup-port groups met on a regular basis with members of the health care team. These meetings provided a forum for discussion of a variety of medical, psychosocial, and other issues and served as an immense source of support for families coping with the care of chronically ill chil-dren and adolescents.
Clinical and Laboratory Monitoring
All of the treated children and adolescents were evalu-ated clinically and with routine laboratory tests on a monthly basis. The Division of AIDS Toxicity Table for Grading Severity of Pediatric Adverse Experiences was used as a rough guide for the management of presumed drug-associated toxicities. In brief, this table grades a variety of potential study drug-associated clinical and laboratory adverse events on a 4-point scale from grade 1 (least severe) to grade 4 (most severe). Laboratory values constituting grade ⱖ3 abnormalities include the following: hemoglobin concentration,⬍7 g/dL; absolute neutrophil count, ⬍400/uL; alanine aminotransferase,
ⱖ10 times the upper limit of normal; bilirubin,ⱖ3 times the upper limit of normal; and serum creatinine, ⬎1.1 (age: 3 months to 2 years) or 1.6 mg/dL (age:ⱖ2 years). Grade ⱖ3 instances of presumed study drug-associated toxicity or intolerance are managed according to a dose-modification scheme that mandates the interruption of antiretroviral drug therapy forⱕ28 days. If the toxicity improves during that time to less than grade 3, therapy is resumed.
Because of cost considerations, plasma HIV RNA mea-surements (Roche Molecular Systems, Branchburg, NJ) were performed only on a subset of treated children and adolescents until ⬃2005, when the test became available more routinely. In general, CD4⫹lymphocyte counts were obtained at baseline and intervals of⬃6 to 12 months.
RESULTS
Study Population
A total of 414 children and adolescents received lopina-vir/ritonavir-containing HAART between November 2001 and August 2006. Table 1 shows selected
charac-teristics of lopinavir/ritonavir-treated children at base-line. Table 2 shows the drugs used in combination with lopinavir/ritonavir. The median duration of follow-up was 51 months (range: 8 –57 months). Table 3 shows the current treatment status of these children and adoles-cents.
Safety and Clinical Observations
Lopinavir/ritonavir-containing HAART was well toler-ated, with 337 (81%) of 414 children remaining on therapy after a median duration of⬎4 years. Treatment with lopinavir/ritonavir was interrupted on 312 occa-sions in 220 children. The most common reasons for treatment interruption were clinical adverse events or laboratory abnormalities (87 episodes), temporary un-availability of concomitantly administered antiretroviral medications (63 episodes), death (37 episodes), HIV dis-ease progression (25 episodes), and medication nonad-herence (23 episodes). Few clinical adverse events or laboratory abnormalities of at least moderate severity (grade ⱖ3) and of possible or probable relationship to lopinavir/ritonavir therapy were observed, consisting principally of intractable vomiting (11 episodes) and hepatitis (3 episodes). Treatment was interrupted in 11 cases because of adverse events or intolerance attributed to concomitantly administered antiretroviral drugs. Six cases of lipodystrophy were diagnosed. Seventy-seven children permanently discontinued therapy with lopina-vir/ritonavir (Table 3).
Thirty-seven deaths occurred among children
receiv-TABLE 1 Characteristics of 414 Lopinavir/Ritonavir-Treated Children and Adolescents at Baseline
Variable Data
Age, y
Mean 13
Range 5–18
Gender, male/female,n(%) 222 (54)/192 (46)
Route of HIV acquisition,n(%)
Horizontal 350 (85)
Vertical 29 (7)
Unknown 35 (8)
Treatment history
Naı¨ve,n(%) 35 (8)
Experienced,n(%) 340 (82)
NRTIs/NNRTIs alone,n 126
Protease inhibitors,n 214
Unknown,n(%) 39 (9)
CDC clinical category,n(%)
A 8 (2)
B 320 (77)
C 86 (21)
CDC immunologic category,n(%)
1 57 (14)
2 183 (44)
3 134 (32)
Unknown,n(%) 40 (10)
ing lopinavir/ritonavir-containing HAART. Causes of death included tuberculosis (8 cases), progressive en-cephalopathy (4 cases), cytomegalovirus disease (3 cases), and pneumonia (2 cases). A specific cause of death was not known in approximately half of the cases; none of the deaths was thought to be related in any way to antiretroviral therapy. Most of the deaths occurred among children with advanced HIV disease at the time that HAART was initiated; 14 deaths (38%) occurred within 16 weeks of starting HAART. Twenty-five deaths occurred during the first half of the study period (No-vember 2001 through December 2003); only 12 deaths occurred during the second half of the study period (January 2004 through August 2006). The mortality rate observed during these 2 time periods was⬃3.3 per 100 patient-years and 1.2 per 100 patient-years, respectively. We observed an average annual mortality rate of⬃13% in a cohort of HIV-infected children followed prospec-tively in Constanta over a 4-year period ending in May 2002.7
Virologic and Immunologic Observations
Only 97 children and adolescents had plasma HIV RNA concentrations measured immediately before beginning lopinavir/ritonavir-containing HAART. In this subgroup, the mean baseline plasma HIV RNA concentration was 152 036 copies per milliliter (range:⬍400 –930 000 cop-ies per milliliter). The most recent on-treatment plasma HIV RNA concentration was⬍400 copies per milliliter in 192 (72%) of 265 children tested (median duration on treatment:⬎3 years). Seventy-two children did not have
a recent plasma HIV RNA concentration available for inclusion in the data set.
The mean baseline CD4⫹ lymphocyte count for the 299 children, who have both a baseline count and ⱖ1 follow-up count obtained ⱖ1 year after initiation of lopinavir/ritonavir-containing HAART was 292 cells per microliter (range: 1–1433 cells per microliter). The mean change from baseline in CD4⫹ lymphocyte count was
⫹266 (n⫽284),⫹317 (n⫽260),⫹343 (n⫽176), and
⫹270 cells per microliter (n⫽121) after 1, 2, 3, and 4 years of treatment, respectively (for all comparisons,P⬍
.0001).
DISCUSSION
We report the long-term follow-up of 414 children and adolescents who received lopinavir/ritonavir-containing HAART at the Romanian-American Children’s Center in Constanta between November 2001 and August 2006. We believe that this may be the largest reported long-term experience with the use of HAART of any kind for HIV-infected children and adolescents living in a low- or middle-income country. In addition, it may represent the world’s largest experience with the use of this par-ticular drug in children.
We treated children and adolescents with HAART by prescription, in a routine pediatric outpatient setting, without the benefit of antiretroviral drug resistance test-ing to guide therapeutic decisions. Treatment history alone dictated which antiretroviral drugs were given concomitantly with lopinavir/ritonavir. Many children who previously had received zidovudine and lamivudine were treated with stavudine and didanosine, a combina-tion of nucleoside reverse transcriptase inhibitors rarely used today.
Most of the children and adolescents that we treated with lopinavir/ritonavir-containing HAART had been treated previously with other antiretroviral drugs (in-cluding HIV protease inhibitors) and had moderate or severe HIV-associated clinical symptoms and immuno-suppression. These characteristics often are associated with treatment benefit less pronounced than that typi-cally observed in children naı¨ve to antiretroviral therapy and with less advanced HIV disease. Nevertheless, lopi-navir/ritonavir-containing HAART was safe and effec-tive. Eighty-one percent of the children remained on therapy after a median duration of⬎4 years. The mor-tality rate that we observed in this cohort compares favorably with the rate observed among HIV-infected children living in Constanta between 1998 and 2002. Seventy-two percent of children tested had plasma HIV RNA concentrations ⬍400 copies per milliliter after a median duration of treatment of⬎3 years, and marked CD4⫹ lymphocyte count increases were ob-served after 1, 2, 3, and 4 years of treatment. Compara-ble virus load and CD4⫹ lymphocyte count findings were reported from a 48-week multicenter clinical trial
TABLE 2 Antiretroviral Drugs Used in Combination With Lopinavir/ Ritonavir
Antiretroviral Drugs No. of Children,n(%)
ZDV/3TC 178 (43)
d4T/ddI 126 (30)
d4T/3TC 37 (9)
3TC/abacavir 15 (4)
d4T/nevirapine 14 (3)
3TC/ddI 10 (2)
Other 34 (8)
ZDV indicates zidovudine; 3TC, lamivudine; d4T, stavudine; ddI, didanosine.
TABLE 3 Status of 414 Lopinavir/Ritonavir-Treated Children, August 2006
Status No. of Children,n(%)
On therapy 337 (81)
Permanently off therapy 77 (19)
Death 37
Medication nonadherence 23
Persistent vomiting 11
Hepatitis 3
Parental request 2
of 100 children treated with lopinavir/ritonavir-contain-ing HAART.3
Because of the unique epidemiology of pediatric HIV infection in Romania,4 the children and adolescents
that we treated with lopinavir/ritonavir-containing HAART were relatively old (mean age: 13 years), and most had acquired the infection horizontally. We are limited in our ability to comment on the generalizability of our findings to infants and young children with ver-tical HIV infection. Nevertheless, lopinavir/ritonavir-containing HAART seems to be a safe, effective, and durable treatment option for antiretroviral drug– expe-rienced older children and adolescents with advanced HIV disease. HAART can be administered safely and effectively to children and adolescents in resource-limited settings.
ACKNOWLEDGMENTS
This work was supported in part by the Abbott Fund’s Step Forward program, the Fogarty International Center of the National Institutes of Health (Baylor AIDS Inter-national Training and Research Program grant 5 D43 TW01036), and by the National Institute of Allergy and Infectious Diseases (Baylor Center for AIDS Research grant AI36211).
REFERENCES
1. World Health Organization. Progress in scaling up access to HIV treatment in low and middle-income countries, June 2006. Available at: www.who.int/hiv/toronto2006/FS_Treatment_en. pdf. Accessed August 21, 2006
2. Working Group on Antiretroviral Therapy and Medical Man-agement of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Available at: http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf. Ac-cessed August 21, 2006
3. 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 –224
4. Kline MW, Matusa RF, Copaciu L, Calles NR, Kline NE, Schwarz-wald HL. Comprehensive pediatric human immunodeficiency vi-rus care and treatment in Constanta, Romania: implementation of a program of highly active antiretroviral therapy in a resource-poor setting.Pediatr Infect Dis J.2004;23:695–700
5. Centers for Disease Control and Prevention. 1994 revised clas-sification system for human immunodeficiency virus infection in children less than 13 years of age.MMWR Morb Mortal Wkly Rep.1994;43(RR-12):1–10
6. Centers for Disease Control and Prevention. 1995 revised guide-lines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virus.MMWR Morb Mortal Wkly Rep. 1995; 44(RR-4):1–11
DOI: 10.1542/peds.2006-2802 originally published online April 9, 2007;
2007;119;e1116
Pediatrics
Schweitzer, Nancy R. Calles and Heidi L. Schwarzwald
Mark W. Kline, Sorin Rugina, Margareta Ilie, Rodica F. Matusa, Ana-Maria
Therapy
Receiving Lopinavir/Ritonavir-Containing Highly Active Antiretroviral
Long-term Follow-up of 414 HIV-Infected Romanian Children and Adolescents
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DOI: 10.1542/peds.2006-2802 originally published online April 9, 2007;
2007;119;e1116
Pediatrics
Schweitzer, Nancy R. Calles and Heidi L. Schwarzwald
Mark W. Kline, Sorin Rugina, Margareta Ilie, Rodica F. Matusa, Ana-Maria
Therapy
Receiving Lopinavir/Ritonavir-Containing Highly Active Antiretroviral
Long-term Follow-up of 414 HIV-Infected Romanian Children and Adolescents
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