Published online April 9, 2007
PEDIATRICS Vol. 119 No. 5 May 2007, pp. e1116-e1120 (doi:10.1542/peds.2006-2802)
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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 and Heidi L. Schwarzwald, MDa,b

a Baylor College of Medicine International Pediatric AIDS Initiative, Texas Children's Hospital, Houston, Texas
b Baylor Black Sea Foundation, Constanta, Romania
c Infectious Diseases Hospital, Constanta, Romania


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND. There are no published reports of the long-term safety and effectiveness of highly active antiretroviral therapy for children and adolescents living in resource-limited settings or of large cohorts of HIV-infected children and adolescents 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-containing 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 November 2001 and August 2006 at the Romanian-American Children's Center in Constanta, Romania. The center provides comprehensive primary and HIV specialty 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–experienced 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 (n = 260), +343 (n = 176), and +270 cells per microliter (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 adolescents in resource-limited settings. Lopinavir/ritonavir-containing highly active antiretroviral therapy is a safe, effective, and durable treatment option for antiretroviral drug–experienced older children and adolescents with advanced HIV disease.

Key Words: HIV infection • child • adolescent • lopinavir

Abbreviations: HAART—highly active antiretroviral therapy • BIPAI—Baylor College of Medicine International Pediatric AIDS Initiative

The World Health Organization recently estimated that 800000 children <15 years of age are in immediate need of antiretroviral treatment.1 More than 90% 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 antiretroviral therapy (HAART) for children in these settings.

Lopinavir/ritonavir (Kaletra)-containing HAART is strongly recommended for initial therapy of HIV infection in children by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children of the US Health Resources and Services Administration 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-containing HAART in large cohorts of HIV-infected children and adolescents.

Romania is a middle-income country with a per capita gross domestic product comparable to that of Botswana or Thailand and total health expenditure per capita less than Botswana, Thailand, or South Africa. Thousands of Romanian children were infected horizontally 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 Pediatric AIDS Initiative (BIPAI), Texas Children's Hospital, the Infectious Diseases Hospital Constanta, and the Romanian Ministry of Health and Family built and opened the Infectious Diseases Hospital-BIPAI Outpatient HIV Clinic (also known as the Romanian-American Children's Center) in Constanta in April 2001.4 In 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 comprehensive medical and psychosocial services and antiretroviral drug donations.

A program of child and adolescent HAART was initiated 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 November 2001 and August 2006.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
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 Prevention5 category other than N1 or A1 were considered eligible for treatment. Children already receiving antiretroviral therapy were considered eligible for a change to lopinavir/ritonavir-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 naïve to lopinavir/ritonavir and to ≥1 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 according 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 measuring or counting returned medication and by questioning the parent and/or child at each scheduled clinic visit.

Patients received prophylaxis for Pneumocystis jiroveci pneumonia according to established guidelines,6 and nutritional support and antibiotic therapy were prescribed as needed. Immunomodulators (excluding corticosteroids and intravenous immunoglobulin) were not used.

Patient and Family Education and Support
All of the patients and caregivers were counseled initially and monthly regarding the importance of medication adherence. At the time that HAART was initiated, each child and family was given a 1-page, individualized reference sheet showing actual-size, color photographs of the pills that they would be taking, together with dosing instructions and any other special instructions (eg, diet). Medication boxes were provided, and each family was instructed on their correct use. An illustrated 20-page Romanian language booklet on HIV and antiretroviral therapy was created for use at the center, and it was given to each family as an adjunct to verbal 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 support 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 children and adolescents.

Clinical and Laboratory Monitoring
All of the treated children and adolescents were evaluated 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 ≥3 abnormalities include the following: hemoglobin concentration, <7 g/dL; absolute neutrophil count, <400/uL; alanine aminotransferase, ≥10 times the upper limit of normal; bilirubin, ≥3 times the upper limit of normal; and serum creatinine, >1.1 (age: 3 months to 2 years) or 1.6 mg/dL (age: ≥2 years). Grade ≥3 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 for ≤28 days. If the toxicity improves during that time to less than grade 3, therapy is resumed.

Because of cost considerations, plasma HIV RNA measurements (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
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Population
A total of 414 children and adolescents received lopinavir/ritonavir-containing HAART between November 2001 and August 2006. Table 1 shows selected characteristics of lopinavir/ritonavir-treated children at baseline. 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 adolescents.


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  		TABLE 1 Characteristics of 414 Lopinavir/Ritonavir-Treated Children and Adolescents at Baseline

 

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  		TABLE 2 Antiretroviral Drugs Used in Combination With Lopinavir/Ritonavir

 

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  		TABLE 3 Status of 414 Lopinavir/Ritonavir-Treated Children, August 2006

 
Safety and Clinical Observations
Lopinavir/ritonavir-containing HAART was well tolerated, with 337 (81%) of 414 children remaining on therapy after a median duration of >4 years. Treatment with lopinavir/ritonavir was interrupted on 312 occasions in 220 children. The most common reasons for treatment interruption were clinical adverse events or laboratory abnormalities (87 episodes), temporary unavailability of concomitantly administered antiretroviral medications (63 episodes), death (37 episodes), HIV disease progression (25 episodes), and medication nonadherence (23 episodes). Few clinical adverse events or laboratory abnormalities of at least moderate severity (grade ≥3) 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 lopinavir/ritonavir (Table 3).

Thirty-seven deaths occurred among children receiving lopinavir/ritonavir-containing HAART. Causes of death included tuberculosis (8 cases), progressive encephalopathy (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 (November 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 prospectively 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 152036 copies per milliliter (range: <400–930000 copies 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 ≥1 follow-up count obtained ≥1 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
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
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 particular 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 testing 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 combination 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 (including HIV protease inhibitors) and had moderate or severe HIV-associated clinical symptoms and immunosuppression. These characteristics often are associated with treatment benefit less pronounced than that typically observed in children naïve to antiretroviral therapy and with less advanced HIV disease. Nevertheless, lopinavir/ritonavir-containing HAART was safe and effective. Eighty-one percent of the children remained on therapy after a median duration of >4 years. The mortality 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 observed after 1, 2, 3, and 4 years of treatment. Comparable virus load and CD4+ lymphocyte count findings were reported from a 48-week multicenter clinical trial of 100 children treated with lopinavir/ritonavir-containing 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 vertical HIV infection. Nevertheless, lopinavir/ritonavir-containing HAART seems to be a safe, effective, and durable treatment option for antiretroviral drug–experienced 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 International 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).


   FOOTNOTES
 
Accepted Nov 13, 2006.

Address correspondence to Mark W. Kline, MD, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, CCC1210, Houston, TX 77030. E-mail: mkline{at}bcm.edu

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.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 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 Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Available at: http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf. Accessed 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[CrossRef][ISI][Medline]
  4. Kline MW, Matusa RF, Copaciu L, Calles NR, Kline NE, Schwarzwald HL. Comprehensive pediatric human immunodeficiency virus 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[CrossRef][ISI][Medline]
  5. Centers for Disease Control and Prevention. 1994 revised classification 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 guidelines 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
  7. Kline MW, Matusa RF, Simon CL, Kline NE. Four-year longitudinal study of HIV among children in Constanta, Romania. Presented at: 40th Annual Meeting of the Infectious Diseases Society of America; October 24–27, 2002; Chicago, IL. Abstract 438
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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