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Growth hormone deficiency and HIV infection
LETTERS
Growth hormone deficiency and HIV infection To the Editor: Watson and Counts1 describe 2 HIV-infected children with growth failure and growth hormone (GH) deficiency and summarize the 2 cases of the only other such children reported (one by us). We want to provide further follow-up to our previous report,2 which now leads us to question the role of GH therapy for HIV-associated growth failure. At the time of our publication,2 our patient was 10 years old, and her growth velocity had doubled from 2.5 cm/year to 5 cm/year with the administration of GH 2 mg 3 times/week
(Figure). However, further catch-up growth was not seen, and her skeletal maturation remained unchanged over 12 months. Increasing the frequency of the GH injections did not improve her growth velocity, and GH was discontinued at the child’s request. In spite of eventual suppression of plasma HIV viral RNA to <400 copies/mL (as more antiretroviral agents became available), her growth velocity slowed, and her puberty was delayed. After living for 20 years with her perinatally acquired HIV infection, she discontinued her antiretroviral therapy over a period of months; she died of cryptococcal meningitis at 21 years of age.
Figure. NCHS/CDC Growth Chart 2 to 20 years: Girls Version of 05/30/00 (modified 11/21/00) From: http://cdc.gov/growthcharts. Updated growth chart of child with HIV infection and GH deficiency. First 10 years of data were previously published.2 Circle indicates height and weight data points; triangle indicates bone age for height point attached by line; ddI, didanosine; ZDV, zidovudine; NVP, nevirapine; IDV, indinavir.
Letters
559
Like Watson and Counts’ second patient, our patient had onset of growth failure with aberrant GH secretion in mid-childhood; in contrast, she had neither brain dysfunction nor psychiatric illness confounding the cause of her growth failure. We and others have shown that protease inhibitor– based highly active antiretroviral therapy (PI-HAART) improves height z-scores, as well as weight-z scores.3,4 Unfortunately, our patient had likely achieved her final height before PI-HAART became available. We still believe that growth failure is uncommon in HIV-infected children with successful virologic responses to PI-HAART and that, in these few children, GH deficiency should be considered. However, GH replacement therapy may not always lead to as much growth as expected. Geoffrey A. Weinberg, MD Nicholas Jospe, MD Department of Pediatrics University of Rochester School of Medicine and Dentistry Strong Children’s Research Center Golisano Children’s Hospital at Strong Rochester, NY 14642 YMPD1459 10.1016/j.jpeds.2005.02.013
REFERENCES 1. Watson DC, Counts DR. Growth hormone deficiency in HIV-infected children following successful treatment with highly active antiretroviral therapy. J Pediatr 2004;145:549-51. 2. Jospe N, Powell KR. Growth hormone deficiency in an 8-year-old girl with human immunodeficiency virus infection. Pediatrics 1990;86:309-12. 3. Miller TL, Mawn BE, Orav EJ, Wilk D, Weinberg GA, Nicchitta J, et al. The effect of protease inhibitor therapy on growth and body composition in human immunodeficiency virus type 1-infected children. Pediatrics 2001; 107(5):E77. URL: http://www.pediatrics.org/cgi/content/full/107/5/e77. 4. Buchacz K, Cervia JS, Lindsey JC, Hughes MD, Seage GR III, Dankner WM, et al. Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in HIV-infected children. Pediatrics 2001;108(4):E72. URL: http://www.pediatrics.org/cgi/ content/full/108/4/e72.
Hydroxyurea as secondary prevention for stroke in children with sickle cell anemia To the Editor: Ware et al1 described hydroxyurea as a secondary prevention for stroke in children with sickle cell anemia (SCA). I have a few comments that may provide an alternative viewpoint of the results. First, I would like to acknowledge the hard work by Dr. Ware and his colleagues. They have systematically addressed an extremely difficult problem, namely, how to manage patients with sickle cell disease after initial strokes who, for a variety of reasons, will not or can not continue on blood transfusion therapy. Rather than haphazardly selecting different therapeutic options, Ware and his group decided to develop a prospective protocol to assess the utility of hydroxyurea 560
Letters
administration. Such systematic efforts are far and few between in clinical medicine, and this effort should be applauded. Ware et al comment that the rate of secondary strokes for persons treated with hydroxyurea and blood transfusion therapy were comparable. However, I think this comment may be slightly misleading. They quote a secondary stroke rate for hydroxyurea of 5.7 per 100 patient years. In addition, the rate of secondary strokes with blood transfusion therapy is quoted as 2.22 to 6.43 events per 100 patient years. However, the secondary stroke rates from these three articles are not directly comparable. In the study that Ware et al performed, patients had previously been on blood transfusion therapy for an average of approximately 4 years and then subsequently were switched over to hydroxyurea. In both the Scothorn and Pegelow articles, the stroke incidence rate with blood transfusion therapy included the entire period while on transfusion. As was noted in Scothorn et al,2 the highest incidence rate of stroke occurs approximately 2 years after the initial stroke. To compare blood transfusion to hydroxyurea for secondary stroke prevention would require adjustment for the high-risk period of a second stroke. Further, Ware et al appear to give equal weight to the two studies describing the secondary stroke rate for children receiving blood transfusion therapy, Scothorn et al2 and Pegelow et al,3 and only mention the higher of the two rates in the discussion. In the Pegelow3 study, the secondary stroke rate is derived from 60 subjects followed for 192 patient years with an incidence of 4.2 strokes per 100 patient years (95% confidence interval 1.8 to 8.0 strokes per 100 patient years). In the Scothorn2 study, 137 patients were followed for 1382 patient years with an incidence of 2.2 strokes per 100 patients years (95% CI 1.5 to 3.2 strokes per 100 patient years). To mention only the higher of the two rates for stroke is slightly misleading given the more rigorous study design and larger number of patients followed for a longer duration in the Scothorn et al article. In addition, that rate quoted for Pegelow et al was incorrectly stated in the Ware et al article. Pegelow et al quoted a rate of 4.2 strokes per 100 patient years, not 6.4 strokes per 100 patient years. When the two different methods for secondary prevention of strokes are compared, blood or hydroxyurea, the rate of an adverse outcome (stroke) must be noted. In Evidence Based-Medicine,4 the common metric that directly compares this tradeoff is referred to as the numbers needed to harm (NNH).4 Based on these data, if hydroxyurea is used instead of blood, one would anticipate that the NNH would be approximately 25, that is for every 25 patients treated with hydroxyurea, one patient will have a stroke in excess of what would be anticipated if patients were only receiving blood transfusion therapy. Only a formal evaluation of the tradeoffs between stopping blood transfusion therapy and starting hydroxyurea therapy can provide sufficient evidence for the best therapeutic option and determine whether the perceived benefits outweigh the risks. When presented with a choice of therapy, the cost of one additional preventable stroke may not outweigh the benefit of treatment with hydroxyurea. The Journal of Pediatrics
October 2005
Growth hormone deficiency and HIV infection To the Editor: Watson and Counts1 describe 2 HIV-infected children with growth failure and growth hormone (GH) deficiency and summarize the 2 cases of the only other such children reported (one by us). We want to provide further follow-up to our previous report,2 which now leads us to question the role of GH therapy for HIV-associated growth failure. At the time of our publication,2 our patient was 10 years old, and her growth velocity had doubled from 2.5 cm/year to 5 cm/year with the administration of GH 2 mg 3 times/week
(Figure). However, further catch-up growth was not seen, and her skeletal maturation remained unchanged over 12 months. Increasing the frequency of the GH injections did not improve her growth velocity, and GH was discontinued at the child’s request. In spite of eventual suppression of plasma HIV viral RNA to <400 copies/mL (as more antiretroviral agents became available), her growth velocity slowed, and her puberty was delayed. After living for 20 years with her perinatally acquired HIV infection, she discontinued her antiretroviral therapy over a period of months; she died of cryptococcal meningitis at 21 years of age.
Figure. NCHS/CDC Growth Chart 2 to 20 years: Girls Version of 05/30/00 (modified 11/21/00) From: http://cdc.gov/growthcharts. Updated growth chart of child with HIV infection and GH deficiency. First 10 years of data were previously published.2 Circle indicates height and weight data points; triangle indicates bone age for height point attached by line; ddI, didanosine; ZDV, zidovudine; NVP, nevirapine; IDV, indinavir.
Letters
559
Like Watson and Counts’ second patient, our patient had onset of growth failure with aberrant GH secretion in mid-childhood; in contrast, she had neither brain dysfunction nor psychiatric illness confounding the cause of her growth failure. We and others have shown that protease inhibitor– based highly active antiretroviral therapy (PI-HAART) improves height z-scores, as well as weight-z scores.3,4 Unfortunately, our patient had likely achieved her final height before PI-HAART became available. We still believe that growth failure is uncommon in HIV-infected children with successful virologic responses to PI-HAART and that, in these few children, GH deficiency should be considered. However, GH replacement therapy may not always lead to as much growth as expected. Geoffrey A. Weinberg, MD Nicholas Jospe, MD Department of Pediatrics University of Rochester School of Medicine and Dentistry Strong Children’s Research Center Golisano Children’s Hospital at Strong Rochester, NY 14642 YMPD1459 10.1016/j.jpeds.2005.02.013
REFERENCES 1. Watson DC, Counts DR. Growth hormone deficiency in HIV-infected children following successful treatment with highly active antiretroviral therapy. J Pediatr 2004;145:549-51. 2. Jospe N, Powell KR. Growth hormone deficiency in an 8-year-old girl with human immunodeficiency virus infection. Pediatrics 1990;86:309-12. 3. Miller TL, Mawn BE, Orav EJ, Wilk D, Weinberg GA, Nicchitta J, et al. The effect of protease inhibitor therapy on growth and body composition in human immunodeficiency virus type 1-infected children. Pediatrics 2001; 107(5):E77. URL: http://www.pediatrics.org/cgi/content/full/107/5/e77. 4. Buchacz K, Cervia JS, Lindsey JC, Hughes MD, Seage GR III, Dankner WM, et al. Impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in HIV-infected children. Pediatrics 2001;108(4):E72. URL: http://www.pediatrics.org/cgi/ content/full/108/4/e72.
Hydroxyurea as secondary prevention for stroke in children with sickle cell anemia To the Editor: Ware et al1 described hydroxyurea as a secondary prevention for stroke in children with sickle cell anemia (SCA). I have a few comments that may provide an alternative viewpoint of the results. First, I would like to acknowledge the hard work by Dr. Ware and his colleagues. They have systematically addressed an extremely difficult problem, namely, how to manage patients with sickle cell disease after initial strokes who, for a variety of reasons, will not or can not continue on blood transfusion therapy. Rather than haphazardly selecting different therapeutic options, Ware and his group decided to develop a prospective protocol to assess the utility of hydroxyurea 560
Letters
administration. Such systematic efforts are far and few between in clinical medicine, and this effort should be applauded. Ware et al comment that the rate of secondary strokes for persons treated with hydroxyurea and blood transfusion therapy were comparable. However, I think this comment may be slightly misleading. They quote a secondary stroke rate for hydroxyurea of 5.7 per 100 patient years. In addition, the rate of secondary strokes with blood transfusion therapy is quoted as 2.22 to 6.43 events per 100 patient years. However, the secondary stroke rates from these three articles are not directly comparable. In the study that Ware et al performed, patients had previously been on blood transfusion therapy for an average of approximately 4 years and then subsequently were switched over to hydroxyurea. In both the Scothorn and Pegelow articles, the stroke incidence rate with blood transfusion therapy included the entire period while on transfusion. As was noted in Scothorn et al,2 the highest incidence rate of stroke occurs approximately 2 years after the initial stroke. To compare blood transfusion to hydroxyurea for secondary stroke prevention would require adjustment for the high-risk period of a second stroke. Further, Ware et al appear to give equal weight to the two studies describing the secondary stroke rate for children receiving blood transfusion therapy, Scothorn et al2 and Pegelow et al,3 and only mention the higher of the two rates in the discussion. In the Pegelow3 study, the secondary stroke rate is derived from 60 subjects followed for 192 patient years with an incidence of 4.2 strokes per 100 patient years (95% confidence interval 1.8 to 8.0 strokes per 100 patient years). In the Scothorn2 study, 137 patients were followed for 1382 patient years with an incidence of 2.2 strokes per 100 patients years (95% CI 1.5 to 3.2 strokes per 100 patient years). To mention only the higher of the two rates for stroke is slightly misleading given the more rigorous study design and larger number of patients followed for a longer duration in the Scothorn et al article. In addition, that rate quoted for Pegelow et al was incorrectly stated in the Ware et al article. Pegelow et al quoted a rate of 4.2 strokes per 100 patient years, not 6.4 strokes per 100 patient years. When the two different methods for secondary prevention of strokes are compared, blood or hydroxyurea, the rate of an adverse outcome (stroke) must be noted. In Evidence Based-Medicine,4 the common metric that directly compares this tradeoff is referred to as the numbers needed to harm (NNH).4 Based on these data, if hydroxyurea is used instead of blood, one would anticipate that the NNH would be approximately 25, that is for every 25 patients treated with hydroxyurea, one patient will have a stroke in excess of what would be anticipated if patients were only receiving blood transfusion therapy. Only a formal evaluation of the tradeoffs between stopping blood transfusion therapy and starting hydroxyurea therapy can provide sufficient evidence for the best therapeutic option and determine whether the perceived benefits outweigh the risks. When presented with a choice of therapy, the cost of one additional preventable stroke may not outweigh the benefit of treatment with hydroxyurea. The Journal of Pediatrics
October 2005