点击显示 收起
Maternal-Child and Adolescent Center for Infectious Disease and Virology, University of Southern California Keck School of Medicine, Los Angeles
Pediatric Pharmacology Unit, University of California, San Diego
University of Miami School of Medicine, Miami, Florida
University of Colorado Health Sciences Center, Denver
Children's Hospital and Medical Center, University of Washington, Seattle
Department of Biostatistics, Harvard School of Public Health
Children's Hospital and Harvard Medical School, Boston, Massachusetts
Pediatric, Adolescent and Maternal AIDS Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development
Pediatric Medical Branch, Therapeutics Research Plan, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
We assessed CD4 cell recovery in 175 children with advanced human immunodeficiency virus disease who had received a 4-drug antiretroviral regimen and were categorized as viral load (VL) responders (VLRs), partial VLRs, or non-VLRs. Median CD4 cell counts increased from baseline to week 48, and, among children with maximal follow-up, increases in CD4 cell counts were sustained to week 96 among VLRs and partial VLRs but not among non-VLRs. For VL rebounders still in the study, CD4 cell counts remained increased for 32 weeks after VL rebound. Sustained immunologic benefits can be achieved even with partial VL response in children with advanced disease.
With the introduction of highly active antiretroviral therapy (HAART), there have been significant decreases in morbidity and mortality in adults and children infected with HIV [1, 2], even when there is incomplete viral suppression [3]. Studies of adults suggest that, even with partial reduction of viral load (VL), patients may have both immunologic and clinical benefits [4, 5]. These benefits are especially important since complete viral suppression, to undetectable levels, is achieved in 70% of treatment-naive subjects [6] and in fewer treatment-experienced adults [6, 7]. We describe here the 1- and 2-year immunologic outcomes in relation to VL responses in a clinical trial of several HAART regimens administered to children with rapidly progressive or advanced HIV disease.
Subjects, materials, and methods.
Pediatric AIDS Clinical Trials Group 366 was a partially randomized, open-label study in which patients were assigned to 5 treatment groups on the basis of prior experience with antiretroviral (ARV) class drugs (table 1). Subjects were required to be naive to 2 drugs, of which 1 was nevirapine (NVP), nelfinavir (NFV), or ritonavir (RTV). Nucleoside reverse-transcriptase inhibitor (NRTI)experienced children were stratified by age and CD4 cell percentage and then were randomized to receive either NFV or RTV along with NVP and 2 NRTIs. Enrollment occurred between May 1998 and January 2000 at 50 sites, after institutional review board approval and informed consent were obtained. Children 6 months21 years old were eligible if, while receiving ARV therapy for >8 weeks, they had progressive or advanced HIV disease (plasma HIV-1 RNA level, >50,000 copies/mL; CD4 cell percentage, <15%; or 50% decrease in CD4 cell percentage or CD4 cell count within 6 months, growth failure, or central nervous system disease).
Subjects whose HIV-1 RNA levels decreased to <400 copies/mL from baseline to average week 12/16 were considered to be viral load responders (VLRs); those who had HIV-1 RNA levels 400 copies/mL but who had a reduction in VL of at least 0.75 log10 copies/mL were considered to be partial VLRs; all others were considered to be non-VLRs. VLRs and partial VLRs remained in the study to week 96/100. Non-VLRs withdrew from the study unless, after discussion with study chairs, they were considered to show clinical benefits. After 16 weeks in the study, subjects with VL rebounddefined as an increase of at least 0.75 log10 copies/mL above the VL nadir and an HIV-1 RNA level of >10,000 copies/mL, which was confirmed with repeated testing within 4 weekswithdrew from the study unless clinical benefits were confirmed, as above.
Subjects were examined monthly for 6 months, then every 2 months for 6 months, and then every 3 months for 12 months. CD4 cell subsets and VL measurements were performed at pre-entry, entry, and at every study visit. Those reported to have moderate or severe cutaneous reactions or irreversible life-threatening laboratory toxicities stopped study drugs and withdrew from the study. Lymphocyte phenotyping and VL measurements were performed in laboratories certified by the Quality Assurance Programs of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS.
Results.
The study cohort included 200 children. At week 12/16, 56 (28%) were classified as VLRs, and 13 (23%) of these 56 children had VL rebound; 56 (28%) were classified as partial VLRs, and 30 (54%) of these 56 children had VL rebound. Among those children with VL rebound, 23 (5 VLRs and 18 partial VLRs) had early rebound at weeks 1632, and 20 (8 VLRs and 12 partial VLRs) had late rebound at weeks 3296. The remaining children were classified as non-VLRs (63/200 [31.5%]) or withdrew from the study because of toxicity or other reasons (25/200 [12.5%]). One hundred of the original 200 children continued in the study to week 96/100. This included 35 VLRs, 24 partial VLRs, 10 and 14 VLRs and partial VLRs with VL rebound, respectively, and 17 non-VLRs. There were no deaths among any of the study subjects, and only 1 child had progression after week 16.
Demographic and clinical characteristics at baseline and follow-up, for the 175 children who remained in the study, are shown by response category in table 1. The majority were black or Hispanic and 213 years old. Overall, at enrollment, children had high VLs (median, 4.9 log10 copies/mL), low CD4 cell counts (median, 338 cells/mm3), and low CD4 cell percentages (median, 17%); 35% had advanced clinical disease, and 42% had advanced immunologic disease, as defined by the Centers for Disease Control and Prevention [8]. Non-VLRs had lower observed median baseline CD4 cell percentages and CD4 cell counts than did either VLRs or partial VLRs and, thus, appeared more likely to have advanced immunologic or clinical disease. Overall, there was a median decrease of 1.3 log10 copies/mL in HIV-1 RNA level by week 12/16 among the 175 children who remained in the study, with median decreases ranging from 0.1 log10 copies/mL among non-VLRs to 2.4 log10 copies/mL among VLRs with VL rebound. Similar decreases were noted at weeks 48/52 and 96/100 for VLRs and partial VLRs still in the study but not for those with VL rebound.
We further examined the subset of VLRs and partial VLRs with VL rebound who remained in the study (figure 1B). In this subset, we determined changes in CD4 cell counts in relation to the time of VL rebound (±32 weeks from time 0 or the time of rebound, by use of the definition of VL rebound outlined in Subjects, materials, and methods). As expected, both VLRs and partial VLRs with VL rebound demonstrated large median increases in CD4 cell counts before VL rebound (peak at week -8: VLRs, 260 cells/mm3; partial VLRs, 184 cells/mm3). This was followed by a 16-week period of decrease in CD4 cell counts, although the sample size varied after VL rebound. After that period, immunologic benefits appeared to be maintained, especially for at least half of the 18 partial VLRs who remained in the study for 32 weeks after rebound. Importantly, rebounders who remained in the study maintained an overall median increase of 153 CD4 cells/mm3, even 32 weeks after rebound.
Discussion.
HIV-infected children with advanced disease often have limited treatment options and frequently continue to receive an ARV regimen despite limited antiviral response. Clinicians may perceive a clinical benefit in these children, such as weight gain or resolution of clinical manifestations (for instance, oral candidiasis or diarrhea), even when there is ongoing viral replication. Certainly, the decreases in both morbidity and mortality, despite incomplete viral suppression in >50% of children and adults, suggest immunologic benefits that may, in fact, be protective against or delay disease progression, even with incomplete viral suppression [13]. The results of the present study demonstrate striking increases in CD4 cell counts for up to 2 years, not only in children who achieved undetectable HIV-1 RNA levels (<400 copies/mL) but also in those who had only a partial VL response (a reduction of at least 0.75 log10 copies/mL but 400 copies/mL). Importantly, even children with VL rebound had sustained immunologic benefits for 6 months or longer. This is in sharp contrast to the non-VLRs (at least those who remained in the study), who showed no median increases in CD4 cell counts but whose median CD4 cell counts were maintained at or above baseline.
Studies of adults and children have demonstrated both immunologic and clinical benefits for those who initiate HAART, even without complete viral suppression [4, 5, 911]. Partial VLRs, frequently referred to as those with "discordant responses," are noted to have increases in CD4 cell counts of 100 cells/mm3 and clear clinical benefits [4, 5]. In fact, discontinuation of treatment in such patients has resulted in decreases in CD4 cell counts and clinical progression [12, 13]. The children in our study had greater increases in CD4 cell counts than did adults, and, importantly, increases continued even after 1 year of treatment, suggesting long-term immunologic benefits, even with partial VL responses [14]. Interestingly, some children with VL rebound were found to have high and sustained CD4 cell counts for up to 6 months after VL rebound. Such sustained immunologic responses among partial VLRs or those with VL rebound are rarely seen among adults, perhaps because of differences in thymic reserve.
The findings of the present study suggest that, when a new viral set-point is established, even with decreases in HIV-1 RNA levels of 0.75 log10 copies/mL, there is a new steady state between HIV replication and CD4 cell destruction. In children, this results in significant immune reconstitution. The mechanisms for these findings may include reduced viral fitness and replicative capacity because of combinations of mutations that make the virus less pathogenic and good thymic reserve.
There are several limitations to the present study. First, although we used strict definitions for response groups and although VLRs and partial VLRs were followed for almost 2 years, not all patients were followed after week 12/16. Second, non-VLRs and rebounders remained in the study only when clinical benefits were observed. This may have resulted in a bias toward immunologic responders. Nevertheless, 28 non-VLRs were followed for at least 1 year, and they showed no increase in CD4 cell counts. Third, our cohort was quite heterogeneous, such that both protease inhibitor and nonnucleoside reverse-transcriptase inhibitornaive and experienced children were included. However, even with this heterogeneity, we demonstrated a close association between reduction in VL and CD4 cell response.
These findings have important implications for clinicians managing the care of children with HIV, since current treatment guidelines suggest change in treatment if the HIV-1 RNA level is not suppressed to undetectable levels after 46 months or in the case of VL rebound [15]. The present study has suggested that significant immune reconstitution can be achieved even in children who do not reach undetectable VLs or who have VL rebound. The immune repletion may give children with few treatment options the needed advantage to prevent further disease progression.
Pediatric AIDS Clinical Trials Group (PACTG) 366.
The principal investigators and the sites listed below participated in PACTG 366 and are listed in order of the number of patients enrolled: University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark: Paul Palumbo and Arry Dieudonne; Duke University Medical Center, Durham, North Carolina: Ross McKinney, Jr., and Margaret Donnelly; University of Puerto Rico, San Juan: Irma Febo and Lisette Lugo; Washington Hospital Center, Washington, DC: Phillip Goldstein; University of California, San Francisco, San Francisco: Diane W. Wara and Deborah Trevithick; University of Massachusetts Medical School, Worcester: John L. Sullivan and Katherine Luzuriaga; State University of New York, Downstate Medical Center, Brooklyn: Edward L. Handelsman; University of Miami School of Medicine, Miami, Florida: Savita Pahwa; St. Jude Children's Research Hospital, Memphis, Tennessee: Patricia M. Flynn and F. Sholar Clark; University of Mississippi Medical Center, Jackson: Hannah Gay and Sondra Sadler; University of California Los Angeles Medical Center, Pediatric Infectious Disease Department, School of Medicine, Los Angeles: Yvonne Bryson; Children's Memorial Hospital, Chicago, Illinois: Ram Yogev and Ellen G. Chadwick; Metropolitan Hospital Center, Department of Pediatrics, New York, New York: Mahrukh Bamji; Children's Hospital of Boston, Infectious Diseases, Boston, Massachusetts: Sandra K. Burchett and Kenneth McIntosh; Texas Children's Hospital, Houston: William Shearer; Robert Wood Johnson University Hospital, New Brunswick, New Jersey: Sunanda Gaur; Howard University Hospital, Department of Pediatrics, Washington, DC: Sohail Rana and Deepika Darbari; Children's Diagnostic & Treatment Center of South Florida, Ft. Lauderdale: Ana M. Puga and Susan M. Widmayer; University of Miami, Department of Pediatrics, Miami, Florida: Gwendolyn B. Scott and Charles D. Mitchell; New York University School of Medicine, New York: William Borkowsky and Sulachni Chandwani; Children's Hospital of Philadelphia, Philadelphia, Pennsylvania: Richard M. Rutstein and Carol A. Vincent; Schneider Children's Hospital, New Hyde Park, New York: Vincent Bonagura; Ramon Ruiz Aranu University Hospital, Bayamon, Puerto Rico: Rosaura Aguayo; State University of New York Health Science Center at Syracuse, Syracuse: Kathie Contello and Maureen Famiglietti; Los Angeles County/University of Southern California Medical Center, Los Angeles: Andrea Kovacs; Johns Hopkins University Hospital, Baltimore, Maryland: Deborah Persaud and Nancy Hutton; Columbia University Medical Center, New York, New York: Marc Foca and Alice Higgins; Tulane University School of Medicine, New Orleans, Louisiana: Margarita Silio and Thomas Alchediak; Harlem Hospital Center, Department of Pediatrics, New York, New York: Elaine J. Abrams and Delia Calo; Cornell Medical Center, New York, New York: Gary Noel; University of Alabama at Birmingham, School of Medicine, Department of Pediatrics, Birmingham: Robert F. Pass and Marilyn J. Crain; University of Illinois College of Medicine, Chicago: Kenneth C. Rich and Karen Hayani; Emory University Hospital, Atlanta, Georgia: Steven Nesheim; Virginia Commonwealth UniversityMedical College of Virginia, Richmond: Suzanne R. Lavoie and Tima Smith; University of California, San Diego, Department of Pediatrics, La Jolla: Stephen A. Spector and Lisa Stangl; Bronx-Lebanon Hospital, Department of Pediatrics, Bronx, New York: Saroj Bakshi and Mavis Dummitt; Medical University of South Carolina, Pediatric Department, Charleston: George Johnson; Yale University School of Medicine, New Haven, Connecticut: Warren Andiman and Sostena Romano; University of Colorado Health Sciences Center, Department of Pediatrics, Denver: Myron Levin; Children's Hospital Columbus, Columbus, Ohio: Michael Brady; and Boston Medical Center, Boston, Massachusetts: Stephen I. Pelton and Ellen R. Cooper.
References
1. Gortmaker SL, Hughes M, Cervia J, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N Engl J Med 2001; 345:15228. First citation in article
2. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:85360. First citation in article
3. Grabar S, Le Moing V, Goujard C, et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med 2000; 133:40110. First citation in article
4. Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure of protease inhibitorbased regimens in patients with human immunodeficiency virus infection. J Infect Dis 2000; 181:94653. First citation in article
5. Kaufmann D, Pantaleo G, Sudre P, Telenti A. CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART). Swiss HIV Cohort Study. Lancet 1998; 351:7234. First citation in article
6. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available at: http://aidsinfo.nih.gov/guidelines/. Accessed 7 April 2005. First citation in article
7. Hammer SM, Vaida F, Bennett KK, et al. Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. JAMA 2002; 288:16980. First citation in article
8. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992; 41:119. First citation in article
9. Ghaffari G, Passalacqua DJ, Caicedo JL, Goodenow MM, Sleasman JW. Two-year clinical and immune outcomes in human immunodeficiency virus-infected children who reconstitute CD4 T cells without control of viral replication after combination antiretroviral therapy. Pediatrics 2004; 114:e60411. First citation in article
10. Nikolic-Djokic D, Essajee S, Rigaud M, et al. Immunoreconstitution in children receiving highly active antiretroviral therapy depends on the CD4 cell percentage at baseline. J Infect Dis 2002; 185:2908. First citation in article
11. Soh CH, Oleske JM, Brady MT, et al. Long-term effects of protease-inhibitor-based combination therapy on CD4 T-cell recovery in HIV-1-infected children and adolescents. Lancet 2003; 362:204551. First citation in article
12. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001; 344:47280. First citation in article
13. Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med 2003; 349:83746. First citation in article
14. Hunt PW, Deeks SG, Rodriguez B, et al. Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 2003; 17:190715. First citation in article
15. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Available at: http://aidsinfo.nih.gov/guidelines/. Accessed 24 March 2005. First citation in article