Correspondence
Protease Inhibitors and Mortality among Children and Adolescents Infected with HIV-1
N Engl J Med 2002; 346:1026-1027March 28, 2002
- Article
To the Editor:
The article by Gortmaker et al. about combination therapy including protease inhibitors in children with human immunodeficiency virus type 1 (HIV-1) infection (Nov. 22 issue)1 includes no data about the side effects of protease inhibitors. The homology of the catalytic region of HIV protease with cytoplasmic retinoic acid–binding protein 1 and low-density lipoprotein receptor–related protein may allow protease inhibitors to interfere with these proteins, which may be the cause of the metabolic and somatic alterations that develop in patients treated with protease inhibitors (dyslipidemia, insulin resistance, and lipodystrophy).2 There is also evidence that protease inhibitors directly inhibit the uptake of glucose in insulin-sensitive tissues, such as skeletal muscle.2 Moreover, the bone mineral loss induced by protease inhibitors may retard the growth of HIV-infected children and adolescents.
An attractive approach to the management of the somatic and metabolic alterations induced by protease inhibitors is to switch to triple-therapy regimens that do not include a protease inhibitor. The switch from regimens containing protease inhibitors to regimens containing nonnucleoside reverse-transcriptase inhibitors may result in some benefit in terms of the levels of circulating lipids, bone mineral density, and lipodystrophy without causing substantial viral rebound.3 Unfortunately, Gortmaker et al. include no data on switching from protease inhibitors or related follow-up data. Despite the reduction in mortality from AIDS-related diseases, the side effects of protease inhibitors could influence the growth of HIV-infected children and adolescents and increase both the incidence of metabolic and cardiovascular complications4 and related costs for care and rehabilitation.
4 ReferencesGiuseppe Barbaro, M.D.
University La Sapienza, 00161 Rome, Italy
g.barbaro@tin. it 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;345:1522-1528
Full Text | Web of Science | Medline2
Carr A ,Cooper DA . Adverse effects of antiretroviral therapy. Lancet 2000;356:1423-1430
CrossRef | Web of Science | Medline3
Dube MP ,Sprecher D ,Henry WK , et al. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin Infect Dis 2000;31:1216-1224
CrossRef | Web of Science | Medline4
Barbaro G ,Fisher SD ,Lipshultz SE . Pathogenesis of HIV-associated cardiovascular complications. Lancet Infect Dis 2001;1:115-124
CrossRef | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Barbaro that there are potentially substantial adverse effects associated with all antiretroviral therapies, including protease inhibitors, as we tried to point out. The Pediatric AIDS Clinical Trials Group Protocol 219 (PACTG 219) is a prospective cohort study designed to examine not only the benefits of antiretroviral therapy, but also the potential adverse effects of such treatment. We agree with Dr. Barbaro that these effects require close scrutiny, now that it has been demonstrated that combination antiretroviral therapy can significantly reduce the previously high mortality associated with HIV disease in children. Further study is clearly needed to identify adverse outcomes related to specific drugs and to determine whether such outcomes are related to the disease or to other factors. However, we must recognize that, if it were not for the success of these highly active antiretroviral therapies, concern about the long-term consequences of therapy might not be relevant.
Considerable disagreement remains as to whether switching regimens can reverse all the changes in metabolism and body composition that have been observed in patients receiving regimens that include protease inhibitors. An important issue is whether some of these changes, such as the loss of bone mineral density or changes in body composition, may be directly related to the underlying disease and not just to the therapeutic interventions used to treat HIV.
The results of another study by the PACTG 219 team indicated that the use of combination therapies containing protease inhibitors was not associated with retardation of growth in height or weight,1 although another report provides evidence of osteonecrosis.2 Most of the metabolic abnormalities cited by Dr. Barbaro have been described in adult populations. We share his concern that the same abnormalities could adversely affect the quality of life for HIV-infected children. These long-term issues related to toxic effects will be a focus of future analyses of the data being generated by PACTG 219.
2 ReferencesSteven L. Gortmaker, Ph.D.
Michael Hughes, Ph.D.
Harvard School of Public Health, Boston, MA 02115Wayne M. Dankner, M.D.
Duke University Medical Center, Durham, NC 277101
Buchacz K ,Cervia JS ,Lindsey JC , et al. Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in HIV-infected children. Pediatrics 2001;108:E72-E72
CrossRef | Web of Science | Medline2
Gaughan DM, Mofenson LM, Hughes MD, Seage GR, Oleske JM. Avascular necrosis of the hip (Legg-Calve-Perthes disease) in HIV-infected children in long-term follow-up PACTG Protocol 219. In: Program and abstracts of the Eighth Conference on Retroviruses and Opportunistic Infections, Chicago, February 4–8, 2001. abstract.
