July 26, 2005
As the known long-term toxicities of highly active antiretroviral therapy (HAART) continue to mount, researchers have returned to the pre-HAART era search for methods of bolstering the immune system.
Are there ways to improve immunity and lengthen the lifespan of persons infected with HIV that don't involve viral suppression? Can we effectively control the effects of this virus over decades without causing lipodystrophy, diabetes and coronary artery disease? Two sentinel studies presented at the 3rd IAS meeting in Rio showed that recombinant human growth hormone may just fit the bill.
Progressive HIV disease is associated with a decrease in CD4+ T cells that brings an associated risk of opportunistic infections and death. Because the thymus is the primary site of T-cell development, it may be a key player in restoring immune function in HIV-infected people. While the thymus is generally thought to be active only early in human development, evidence suggests that thymic reserve persists into adulthood and may be called into action as the need arises.
Growth hormone and its proximal mediator, insulin-like growth factor 1 (IGF-1), play key roles in T-cell production. It has been found that in immunodeficient animals, they accelerate immune reconstitution. In rodents, they can reverse thymic involution and age-related declines in thymic production of T cells.
Laura A. Napolitano et al previously extended these findings to humans in a small uncontrolled prospective study of 5 adults immunodeficient from HIV. Administration of growth hormone was associated with a reversal of thymic involution and with a resultant increase in the number of circulating naive CD4+ T cells, which correlate with immune response to neoantigens.1
Napolitano's group, from The Gladstone Institute of Virology and Immunology and University of California, San Francisco, now expanded these findings to a prospective, randomized trial of recombinant human growth hormone given to 20 HIV-infected adults. They presented preliminary results of a 2-year prospective randomized open-label crossover study.
To be eligible for the trial, HIV-infected adults had to have CD4+ cell counts under 400 cells/mm3 and HIV viral loads below 1,000 copies/mL while on effective antiretroviral therapy, without intensification, for at least 1 year. Patients were excluded for abundant thymus (thymus score >3), diabetes mellitus or an abnormal glucose tolerance test, neoplasia, carpal tunnel syndrome, pancreatitis and active cardiac disease.
Ten patients entered each arm, with no statistically significant difference in median values for age (arm 1/2 - 54/48 years), duration of stable antiretroviral therapy (2.7 years), CD4+ cell counts (230/178), HIV viral loads (75), thymic score (1), thymic density (-90/-91 Hounsfield units), and race (mostly Caucasian). Study participants stayed on antiretroviral therapy and underwent computed tomography (CT) scanning of the thymus every 6 months and analysis of their peripheral lymphocytes every 1 to 3 months. IL-7 and IGF-1 immunoassays were also performed at unspecified intervals.
For 6 months, arm 1 received 3 mg a day of growth hormone by subcutaneous injection. This was followed by a decreased dose of growth hormone at 1.5 mg a day for the next 6 months.
At 1 year, these patients crossed over with the 10 patients in arm 2 who had been observed only on antiretroviral therapy and had not received growth hormone. The arm 2 patients now received growth hormone, administered by the same schedule as above while the arm 1 patients entered the observation only stage.
Helical CT scans were read by a thoracic radiologist blinded to study participant arm. Thymic scores ranged from 1 for minimal, barely recognizable to 5 for mass-like, concerning for hyperplasia or thymoma. Agreement between scores and CT-based density estimation was strong with r = 0.76 with P<.0001. A random intercept model with log transformation of non-normal variables was used to estimate the effects of growth hormone therapy.
Seven patients in arm 2 crossed over to growth hormone therapy, with 1 excluded for growth hormone intolerance. Growth hormone therapy has been associated with increased thymic mass. Thymic scores increased with growth hormone therapy, but not with observation (+1.51 versus -0.02 with P = .004). Thymic density increased with therapy (+28 Hounsfield units versus +2 with P = .03) as did thymic volume (+3% versus -2.5% with P = .13), suggesting thymic involution may be reversed in HIV.
Growth hormone is associated with a marked increase in naive CD4+ cells,1 suggesting that the radiographic changes are associated with enhanced thymopoiesis and increased total CD4+ T cells.
Naive CD4+ cells increased by 69% in arm 1 patients who had been receiving growth hormone for 1 year. This compared to a 9% increase in the observation arm (P = .0002), with total CD4+ cell count increasing by 19% versus 1% (P = .09). The increased CD4+ cell count was associated with a growth hormone-induced rise in circulating IGF-1 suggesting IGF-1 may mediate some growth hormone effects on the human immune system.
Naive and total CD4+ T cells increased by 95% and 25%, respectively, in those with a >3-fold rise in IGF-1 from pre-growth hormone levels and only 19% and 6% in those with a <3-fold rise (naive with P = .01 and total with P = .25).
IL-7 levels were examined, as they have been found to be decreased in growth hormone-deficient adolescents raising the possibility that growth hormone directly or indirectly interacts with IL-7. In this study, IL-7 levels were 62% higher in growth hormone recipients, although these levels decreased over time.
Growth hormone was not associated with a gain in naive CD8+ cells, as they may arise from extra-thymic sites, while phenotypically naive CD4+ cells are dependent on the thymus for production. Alternatively, the phenotypical markers used for analysis here may be inadequate to correctly identify all CD8+ naive cells. Growth hormone had no effect on circulating B lymphocytes or natural killer cells.
Seventy-one adverse effects have been reported to date, with 45 of those in growth hormone recipients. Growth hormone recipients reporting adverse effects within the past 3 months included 17 reporting grade 2 generalized arthralgias and myalgias, diaphoresis, fatigue and insomnia.
Five growth hormone recipients experienced carpal tunnel syndrome symptoms, 2 edema, 7 transaminitis, 2 fasting and 2 non-fasting hyperglycemia and 2 hyperamylasemia (all were grade 2 in severity). One grade 3/4 hyperamylasemia and 4 hypertriglyceridemias also occurred.
One patient was discontinued from the trial for the onset of diabetes mellitus at 1 month and 1 for carpal tunnel syndrome at 6 months.
ACTG 5174 Study
Kim Smith presented a larger, similar trial of recombinant human growth hormone on behalf of the ACTG 5174 study group. To be eligible patients had to have a CD4+ cell count below 350, have a HIV viral load below 400, and be on HAART for at least a year.
Sixty patients were then randomized 1:1 to arm A, which received HAART and growth hormone by subcutaneous injection at 1.5 mg/day for 48 weeks or arm B, which received HAART alone for 24 weeks with the addition of growth hormone at 3 mg a day for 24 weeks. Thymic CT scans were performed on 11 patients in arm A and 9 in arm B at baseline and week 24. Statistical analysis was done using Wilcoxon signed-rank.
Mean baseline CD4+ cell counts were 223 and 219, respectively. Most patients were male Caucasians with a median age of 47 and HIV viral loads below 50 after a mean of 4.7 years of antiretroviral therapy.
Six patients discontinued trial, one for debilitation and the other 5 for various non-medical reasons. Arm A tended towards increases in total (P = .054) and naive (P = .093) CD4+ cell counts from baseline to week 24, while arm B had no significant change. By week 48, both arms had significant increases in both total and naive CD4+ cell count. From baseline to week 48, median changes for arms A/B in total and naive CD4+ cell counts were +36/+26 and +55/+23, respectively (P<.002 for each).
In arm B, the median change in naive CD4+ cell count from baseline to week 24, while patients were on HAART alone, was +5 with a change of +24 from weeks 24 to 48 when 3 mg of growth hormone daily was added to HAART (P<.001). The lower dose of growth hormone took longer to achieve the desired effect of increasing naive CD4+ T cells.
Seven of 11 patients in arm A (64%) increased their thymic size after 24 weeks of growth hormone at 1.5 mg/day (P = .06) and 7 of 9 patients in arm B (78%) did the same after 24 weeks of growth hormone at 3.0 mg per day (P = .016).
Examination of recent thymic immigrants by TREC (thymic recombinant excision circles) showed a 1 log change in arm A versus a half log in arm B by week 48. Adverse events were infrequent, with carpal tunnel being the most common reason for study discontinuation (6 patients). Grade 3 or higher adverse effects were infrequent, with hypertriglyceridemia the most common noted.
The use of growth hormone was associated with a gain in thymic mass and circulating naive and total CD4+ T lymphocytes in HIV-infected adults. This suggests growth hormone may induce de novo T-cell production in HIV-infected adults.
Smith raised a number of important questions in her presentation. Will these CD4+ T cells respond to neoantigens, recall antigens and HIV-specific antigens? Will these increases in CD4+ T cells persist after discontinuation of the growth hormone? Does growth hormone have potential as an immune booster or vaccine adjuvant?
While the data is clearly intriguing, large prospective trials in diverse patient populations are needed to determine optimal dosing of growth hormone and to prove safety and efficacy before we rush to change treatment practices.
The long-term toxicities of growth hormone, such as diabetes, may be compounded in patients already on HAART and thus need to be carefully studied. Given the rise in often serious antiretroviral therapy-associated side effects that we are currently seeing, further studies of drugs such as growth hormone -- which strengthen immunity via alternative mechanisms -- are much needed.
Abstract: Treatment with growth hormone leads to improvement in total and naive CD4 lymphocyte recovery in HIV-infected subjects with incomplete immune reconstitution on HAART (Oral TuOa0203)
Authored by: K Smith, R Wang, R Bosch, D Margolis, A Tenorio, R Pollard, V Stocker, B Gross, I Frances, N Muurahainen, ACTG 5714 Protocol Team A
Affiliations: Rush University Medical Center, Chicago, United States of America; Harvard School of Public Health, Boston, United States of America; UT Southwestern Medical Center, Dallas, United States of America; UC Davis Medical Center, San Diego, United States of America; AACTG Operations Center, Silver Spring, United States of America; University of Michigan, Ann Arbor, United States of America; Serono, Inc, Rockland, United States of America
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