It is generally agreed that antiretroviral therapy should be aimed at suppressing HIV replication.1-3 The predictive value of HIV viral load on disease progression has been well-established,4-8 and recent recommendations for the treatment of HIV infection in children have included treatment options that are based largely on considering maximum effect on viral replication.9 An early clinical trial10 showed that the use of didanosine monotherapy was inferior to combinations of zidovudine (ZDV)/didanosine and ZDV/lamivudine (3TC). These conclusions were largely based on changes in CD4 counts and evidence of progression of HIV-associated immunosuppression. More recent experience with children has stressed the impact of proposed new therapies on viral load.11-15 For example conclusions that protease inhibitor-containing regimens such as ZDV/3TC/ritonavir or stavudine (d4T)/ritonavir were better than double nucleoside analogue therapy were drawn from an interim analysis of AIDS Clinical Trials Group 338. This analysis showed that 57 to 61% of children given combinations of drugs that included a protease inhibitor experienced a reduction to an undetectable HIV viral load whereas only 14% of children given ZDV/3TC treatment had this response.13 Together with the experience reported in treating adults with HIV infection,16,17 these trials have laid the foundation for considering the use of regimens containing three antiretrovirals, at least one of which is a protease inhibitor, to maximize the reduction in viral load and therefore the efficacy of antiretroviral therapy in HIV-infected children.
The response of children with HIV infection, particularly those with perinatally acquired infection, to antiretroviral therapy may not be identical with that in adults. First there may be differences in the metabolism of drugs, and therefore the pharmacokinetics of agents used to treat HIV infection when comparing children with adults. Second the biology of HIV infection in infants may be different from that of adults. Differences in early responses to infection and onset of immunodeficiency associated with HIV support that these differences exist. Infants acquiring HIV infection perinatally have HIV RNA viral loads that typically peak during the first 2 months of life and then decline slowly during the next 2 years of life.18-20 In contrast adults have peak viral loads after acute infection that decline rapidly to steady state concentrations within weeks to months after infection.21-23 For these reasons assuming that the experience with therapies in adults will be the same as that experienced by infants and children could be wrong.
Recommendations for treating HIV-infected infants and children that include three antiretroviral agents have been made before a complete analysis of large scale, blinded controlled trials examining the efficacy of regimens containing three drugs.9, 24 As this experience has evolved infants and children have been offered regimens containing multiple antiretrovirals, including protease inhibitors. Measurement of HIV load has served as an important criterion for monitoring this therapy. Our experience was reviewed to characterize the effect of these therapies and specifically to measure how changes in antiretroviral therapy impacted on HIV load in these children.
MATERIALS AND METHODS
Study population. Reviewing The Program for Children with AIDS database identified children who acquired HIV infections from their mother and in whom antiretroviral therapy was changed after June 1, 1996, and before October 31, 1997. Clinical characteristics and laboratory findings were collected for each child by a retrospective review of their medical record.
Definitions of outcomes and changes in therapy. Analysis of outcome of a change in therapy was categorized based on the degree and length of decrease in viral load after a change in therapy. Successful response was defined as a reduction of viral load of at least 0.7 log10 RNA copies/ml that lasted for at least 3 months.
Changes in antiretroviral therapy were categorized as a single, double or triple drug change. A single drug change was considered to have occurred when one antiretroviral drug to which the child was naive, was added to his/her regimen. Likewise double and triple drug changes were considered only for drugs to which the patient was naive. These changes were characterized independent of the total number of antiretroviral drugs the patient was receiving before the change. A patient was considered naive to a drug if he/she had received the medication for <1 week. Changes in therapy were discussed at weekly case management conferences attended by care providers familiar with the patient and his/her family. Decisions for changes in therapy reflected the consensus of a group of providers who remained constant during the period studied.
Laboratory testing. Quantitative HIV RNA measurements were performed on plasma by Labcorp (New York, NY) using the Amplicor HIV RNA assay. Plasma was routinely obtained on these patients at 3- to 6-month intervals as part of their health care. T cell subset measurements were obtained at the same time this testing was performed. Lymphocyte subsets were assessed by standard two color fluorescence-activated cell sorter analysis.
Immunologic categories. Immunologic categories were determined with the age-appropriate CD4+ T lymphocyte cutoff values using CDC 1994 guidelines. The lowest value was used to determine the immunologic category.
Statistical analysis. Discontinuous data for patient groups were compared by chi square analysis. Mean values calculated for patient groups were compared using Student's t test.
Seventy-two changes in antiretroviral therapy in 54 children were identified during the period analyzed. The mean duration of evaluation after the change in therapy was 12.4 months (range, 4 to 17 months). Of the 72 changes made in therapy, 29 of these resulted in a successful response. None of the changes involved use of a nonnucleoside reverse transcriptase inhibitor. None of the children characterized as having a successful response required a subsequent change in their therapy during the period studied. Seven children had changes that were initially unsuccessful and subsequently had changes that succeeded.
The characteristics of patients before change in therapy are shown in Table 1. No differences in distribution of immune category or viral load before changing therapy were evident in comparing those children who had successful response with those with an unsuccessful response. The mean age of children with an unsuccessful response to change was 1.5 years less than that of children who responded to the change in their therapy. However, this difference was not significant. The seven children who initially did not successfully respond to a change in therapy but ultimately did respond were indistinguishable with regard to the characteristics listed in Table 1 with the exception of age. These children were younger than other responders (3.0 ± 1.8 vs. 8.3 ± 4.0; P < 0.01) and nonresponders (3.0 ± 1.8 vs. 5.5 ± 3.1; P < 0.03).
Analysis of outcome of change with regard to the number of drugs changed is shown in Table 2. Changes involving three drugs were more likely to be associated with successful response than changes involving one drug. This trend was observed whether or not the drug change involved a protease inhibitor. However, all successful responses that occurred with a single drug change occurred when that change involved a protease inhibitor. Children who had changes involving two nucleoside reverse transcriptase inhibitors were more likely to have a successful response than children who had a change involving a single nucleoside reverse transcriptase inhibitor (10 of 27 vs. 0 of 13; P = 0.01).
Trends in the number of antiretrovirals given to patients were evident in this analysis. At the beginning of the period studied 26 of the 54 children identified were receiving 2 or more agents. By the end of the study period all 54 were receiving 2 or more agents. Furthermore analysis of the number of drugs used in regimens of children that ultimately responded to therapy demonstrated that 19 of the 29 patients who had a successful response were receiving 3 drugs whereas only 8 of 25 children who never responded successfully were receiving regimens containing 3 antiretrovirals (P < 0.02 by chi square).
Children who responded to changes in their therapy had a mean decrease in viral load of 1.45 ± 0.59 log10 RNA copies/ml for a mean duration of 11.9 ± 3.6 months. Reduction of viral load by >100-fold or a reduction to undetectable amounts (<400 copies/ml) occurred in 12 patients. This response was more likely in children who responded to therapy if they were receiving regimens containing protease inhibitors than in children receiving regimens that did not contain protease inhibitors (11 of 21 vs. 1 of 8; P = 0.05). Analysis of the degree of reduction in viral load further suggested a benefit of receiving a protease inhibitor. The mean decrease in viral load was 1.63 ± 0.60 log10 RNA copies/ml in children who had a successful response to therapy containing protease inhibitors and 0.99 ± 0.12 log10 RNA copies/ml in children who responded to regimens not containing protease inhibitors (Fig. 1). None of the 8 children who responded successfully to changes in therapy and were receiving regimens with 2 nucleoside analogues had a >1.3 log10 RNA copies/ml decrease in viral load. In comparison 16 of 21 children receiving regimens containing protease inhibitors had a >1.3 log10 RNA copies/ml decrease in viral load (P < 0.005 by Fisher's exact test).
Reduction of viral load was enduring in children who responded (Fig. 2). In those children who responded, reduction of viral load by >0.7 log10 RNA copies/ml occurred within 4 months of the change in 28 of the 29 children who responded. In 15 of the 29 children who responded, the viral load at the end of the period of evaluation was less than or equal to the lowest viral load measured in the child during this period. Four of the 10 children who had undetectable viral loads at the end of the period of evaluation had been evaluated for >1 year. Children receiving a protease inhibitorcontaining regimen evaluated for >10 months had a mean decrease of 1.41 ± 0.59 log10 in viral load. This was significantly greater than the mean decrease of 1.02 ± 0.09 log10 (P = 0.05) that was realized by children receiving regimens that did not include a protease inhibitor.
Consistent with observations that decreasing viral load is associated with improvement in CD4 lymphocyte depletion, CD4 counts increased in 22 and more than doubled in 14 of the 29 children who had a >0.7 log10 RNA copies/ml decrease in viral load. Twenty-four of 29 children who responded to therapy based on a viral load decrease increased their CD4 percentage of peripheral lymphocytes. Twenty-one of 22 children whose CD4 number increased also had an increase in CD4 percentage. Twelve of these 22 children had an increase in CD4 percentage of 10% or more (range, 10 to 29%; median, 15%). The mean increase of CD4 lymphocyte number and percentage in these 22 children whose CD4 number increased was 378 cells/mm3 and 12%, respectively. In contrast an increase in CD4 lymphocyte number occurred in 12 and more than doubled in only 2 of the 25 children who did not respond to a change in therapy based on viral load measurements. Eleven of these 25 nonresponders had an increase in CD4 percentage and only 5 had an increase of 10% or more.
Experience with 54 HIV-infected children who had changes made in their antiretroviral therapy demonstrates that combination regimens can have a profound and lasting effect on HIV plasma load. In 10 children these changes resulted in undetectable viral load measurements. Observations presented here suggest that significant and enduring reduction in viral load is more likely to occur when changes involve three agents rather than changes involving one. Furthermore this experience suggests that children prescribed protease inhibitors as part of their change in therapy have a better response than children who do not receive this class of antiretrovirals. Fifty-nine percent (19 of 32) of children prescribed protease inhibitors had a >0.7 log10 reduction in their viral load that persisted for longer than 3 months. In this experience 9 of the 10 children whose viral load became undetectable were prescribed protease inhibitors. The mean decrease in viral load of children who responded to changes that included a protease inhibitor was 4.4-fold greater than the mean decrease associated with changes that did not include these agents.
This experience does not reflect a controlled trial aimed at assessing the efficacy of combination antiretroviral therapy and of protease inhibitors in children. It is clear that establishing the impact of protease inhibitors and highly active antiretroviral therapy on prognosis in HIV-infected children awaits conclusion of ongoing multicentered, collaborative trials. The retrospective analysis of our experience, however, does suggest that protease inhibitors and triple drug therapy hold great promise in controlling HIV infection in perinatally infected children. This promise has been suggested by large scale, controlled trials in adults. Experience reported here is consistent with that reported in adults and should be reassuring that combination antiretroviral therapy can influence HIV replication in children to a degree that has been reported in adults.
It may be that the degree and endurance of reduction in viral load associated with changes in antiretroviral therapy is greater than that which was described with the experience reported here. Limitations of this review include being uncertain about patient adherence to prescribed regimens and not being able to characterize viral genotype and associated resistance to anti-retroviral agents. Failure to adhere to therapy and the development of resistance are two possible explanations for poor responses to the changes prescribed in our patients. Ongoing analysis of children in whom therapy is being changed is aimed at addressing both of these issues. It may be that improving adherence to newly prescribed regimens and guiding changes in therapy by analysis of resistance of virus to antiretrovirals will result in greater and more consistent reduction in viral loads when changes in therapy are made. The influence of these factors may be more evident when results are reported from large, multicentered, controlled trials. These trials are likely to define the effects of antiretroviral therapy on HIV infection. It is possible that comparing the results of these trials with experiences similar to the one reported here will serve the purpose of assessing how closely the potential for these therapies to impact on HIV infections resembles the effects of these therapies as they become part of routine practice.
The experience reported here underscores that therapy established as a standard of care in adults is likely to be highly effective in children. Results support the recent recommendations9, 24 for offering three antiretroviral agents and including protease inhibitors in these regimens in treating HIV-infected infants and children.
Support for this project was provided in part by the Arthur Ashe Endowment Fund (MP) and the Foundation for Treatment of Children with AIDS (RJL). We thank F. Marshall, M.D., J. J. Stavola, M.D., A. M. Dunn, P.N.P. and A. Fernandez, M.D., for their help in caring for these children and in collecting the data presented.
1. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life span, and viral generation time. Science 1996;271:1582-5.
2. Havlir DV, Richman DD. Viral dynamics of HIV: implications for drug development and therapeutic strategies. Ann Intern Med 1996;124:984-94.
3. Lange JMA. Current problems and the future of antiretroviral drug trials. Science 1997;276:548-50.
4. Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in the plasma. Science 1997;272:1167-70.
5. O'Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+
lymphocyte counts and the risk of progression to AIDS. N Engl J Med 1996;334:426-31.
6. Mofenson LM, Korelitz J, Meyer WA, et al. The relationship between serum human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1 -infected children. J Infect Dis 1997;175:1029-38.
7. Palumbo PE, Raskino C, Fiscus S, et al. Predictive value of quantitative plasma HIV RNA and CD4+
lymphocyte count in HIV-infected infants and children. JAMA 1998;279:756-61.
8. Valentine ME, Jackson CR, Vavro C, et al. Evaluation of surrogate markers and clinical outcomes in two-year follow-up of eighty-six human immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J 1998;17:18-23.
9. Centers for Disease Control (CDC). Guidelines for the use of antiretroviral agents in pediatric HIV infection. MMWR 1998;47(RR-4):15-26.
10. James JS. Major pediatric study stopped early: combination treatment better (AIDS Clinical Trials Group 300). AIDS Treat News 1997;274:5-6.
11. Kline MW, Fletcher CV, Brundage RC, et al. Combination therapy including soft gelatin capsules in HIV-infected children [Abstract 229]. In: Program and abstracts of the Fifth Conference on Retroviruses and Opportunistic Infections, Chicago, IL, February 1 to 5, 1998.
12. Mueller BU, Nelson RP, Sleasman J, et al. A Phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection. Pediatrics 1998;101:335-43.
13. Yogev R, Stanley K, Nachman SA, Pelton S, McIntosh K, Wiznia A. Virologic efficacy of ZDV + 3TC vs.
d4T + ritonavir (RTV) vs.
ZDV + 3TC + RTV CTG in stable antiretroviral experienced HIV-infected children (Pediatric ACTG Trial 338). In: Program and abstracts of the 37th International Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, September 28 to October 1, 1997.
14. Gersten M, Peterson AK, Hendricks A, et al. A comparison of the safety and efficacy of Viracept (nelfinavir mesylate) in HIV-infected children and adults. In: Sixth European Conference on Clinical Aspects and Treatment of HIV Infection, Hamburg, Germany, October 11 to 15, 1997.
15. Dobroszycki J, Rosenber M, Lambert G, et al. The effects of HAART in a group of HIV-infected infants. In: 35th Annual Meeting of the Infectious Disease Society of America, San Francisco, September 13 to 16, 1997.
16. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337:734-9.
17. Hammer SM, Squires KE, Hughes MD, et al. A Controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997;337:725-33.
18. Palumbo PE, Kwok S, Waters S, et al. Viral measurement by polymerase chain reaction-based assays in human immunodeficiency virus-infected infants. J Pediatr 1995;126:592-5.
19. Shearer WT, Quinn TC, LaRussa P, et al. Viral load and disease progression in infants infected with human immunodeficiency virus type 1. N Engl J Med 1997;336:1337-42.
20. McIntosh K, Shevitz A, Zakhun D, et al. Age- and time-related changes in extracellular viral load in children vertically infected by human immunodeficiency virus. Pediatric Infect Dis J 1996;15:1087-91.
21. Shacker TW, Hughes JP, Shea T, Coombs RW, Corey L. Biological and virologic characteristics of primary HIV infection. Ann Intern Med 1998;128:613-20.
22. Report of the NIH Panel to Define Principles of Therapy of HIV Infection and Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents: US Department of Health and Human Services. MMWR 1998;47(RR-5):21-35.
23. Lisziewicz J, Jessen H, Finzi D, Siliciano RF, Lori F. HIV-1 suppression by early treatment with hydroxyurea, didanosine, and a protease inhibitor. Lancet 1998;352:199-200.
24. Antiretroviral therapy and medical management of pediatric HIV infection. Pediatrics (Suppl) 1998;102:1005-62
25. Centers for Disease Control. Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR 1994;43(RR-12)1-10.