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  International AIDS Conference
July 13-16, 2003, Paris
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Recombinant Human Growth Hormone (r-hGH)
Reported by Judith Aberg, MD , Washington University, St Louis, Missouri and the ACTG
  Dr. Donald Kotler and colleagues presented 2 posters on the use of r-hGH in patients with HIV-associated wasting on HAART. r-hGH was approved as a treatment for HIV-associated wasting prior to the introduction of HAART. Neverthelesss, the use of rHGH is limited due to a scarcity of data suggesting it may improve lipodystophy and its high costs. Another major concern has been the association of insulin resistance with r-hGH which potentially could exacerbate the development of insulin resistance associated with protease inhibitor therapy.
G Moyle5, D Kotler1, J Gertner2, E Daar3, JC Melchior4, F O'Brien2 and E Svanberg6 1 St Luke's Roosevelt Hospital, New York, USA; 2 Serono, Inc., Rockland, MA, USA; 3 Harbor-UCLA Research and Education Institute, UCLA School of Medicine, Torrance, CA, USA; 4 Department of Medicine: Infectious Diseases and Clinical Nutrition, Raymond Poincarre Hospital and University Paris- Ouest-Ile-de-France, France; 5 Chelsea and Westminster Hospital London, UK; and 6 Serono International, Geneva, Switzerland
The objectives of this study were to confirm clinical efficacy of r-hGH in improving body composition of patients with HIV-associated wasting and to establish optimal dose for r-hGH (Serostim). Of note, the primary endpoint was the effect of r-hGH on physical performance (bicycle ergometry work output) and not on measures of body composition. HIV seropositive patients with 10% weight involuntary loss, body mass index (BMI) <20, or weight <90% ideal body weight were randomized (1:1:1) in a 12 week multi-center, double blind, placebo controlled study of r-hGH 6 mg daily (DD), 6 mg alternate days (AD), or placebo (P). At baseline and after treatment, body composition was assessed by dual energy X-ray absorptiometry (DXA) or by bioelectrical impedance spectroscopy (BIS).
757 (253DD, 257AD, 247P) subjects started and 646 (201DD, 219AD,226P) completed 12 weeks of treatment. Analysis was performed on only 555 patients who completed 12 weeks of therapy and was at least 80% compliant with study treatment. Subjects were white (77%) men (91%), mean age 41 years. 87.6% were on HAART. At baseline, median BMI and body weight were 20.8 kg/m2 and 65.6 kg respectively (2.2 lbs=1 kg). Median lean body mass (LBM) and total body fat were 52.76 kg and 8.26 kg respectively. After 12 weeks, median body weight increased by 2.20 kg in the DD group and by 1.51 kg in the AD group compared with about 0.5 kg in the placebo group (both p<0.0001 vs P). LBM determined by BIS increased by 4.57 kg in DD and 2.69 kg in AD (both P<0.0001 vs P). BMI was restored to >20 kg/m2 in 10%.8% of patients in the P group, 25.8% in the AD group and 45.5% in the DD group. Although I am not sure how to interpret that, given the median baseline BMI was 20.8 kg/m2 prior to any treatment.
Total and trunk fat mass by DXA decreased 1.22 kg and 0.78 in the AD group and 1.43 kg and 1.06 in DD respectively. No change was noted in the placebo arm. Trunk to limb fat ratio decreased in both treatment arms. Viral load remained stable over the 12 weeks of therapy. 6 mg r-hGH AD was slightly better tolerated with fewer adverse events (related to fluid retention, interstitial fluid redistribution, glucose homeostasis, arthralgias and myalgias) than 6 mg DD.
Of the 111 (14.7%) patients who withdrew from the study, 46 did so because of adverse events primarily due to fluid retention however 2 withdrew due to high blood sugars. A total of 11 serious adverse events (SAE) in the AD group and 17 SAEs in the DD group occurred. The investigators attributed only 3 of the 28 SAEs to study drug. The investigators concluded r-hGH , 6 mg DD was superior to 6 mg AD on increasing body weight and improving body composition of HIV wasting patients in the HAART era. 6 mg AD was slightly better tolerated than 6 mg DD.
HAART-era is a misnomer in the sense that not all the subjects are on HAART. It is true that these subjects are being offered r-hGH when HAART is readily available yet for whatever reason, 69 (12%) subjects were not receiving HAART. One could argue that patients with wasting not on HAART are quite different metabolically/physiologically from those on HAART and should have been excluded from this study. Also, the final analysis is quite different from most studies. Typically, an analysis is performed as an intent-to-treat and all randomized patients are counted. They then not only looked at the patients who completed 12 weeks of therapy, they further discarded 91 patients who they determined (unclear how) were less than 80% adherent to study treatment; hence the analysis is quite biased. Could it be that the 91 patients were not that adherent due to adverse effects? It would be helpful to know what the true ITT analysis is or for that matter, a complete OTT analysis. Also, the primary endpoint of this study was the effect of r-hGH on physical performance measured by bicycle ergometry work output and those results were not presented.
DP Kotler1, GJ Moyle2, J Gertner3, N Muurahainen3, E Svanberg4 and C Olivier4 1 Columbia University and St. Lukes-Roosevelt Hospital Center, New York, USA; 2 Chelsea and Westminster Hospital, London, UK; 3 Serono, Inc., Rockland, MA, USA; and 4 Serono International A.S., Geneva, Switzerland
This second study is examining the effects of r-hGH on fasting blood sugar. This is very confusing as to whether this is a different study from the one presented above or whether there are 2 studies that just happen to have the same patient numbers! One would assume that they could have performed the fasting blood sugars on the study above, but for whatever reason, this is a different dosing. In the abstract, they describe the same cohort as above however in the poster they describe dosing as 0.1 mg/kg daily or 0.1 mg/kg on alternate days. Given the median body weight, this would amount to 6.5 mg. This study is described as a randomized, double-blind, placebo-controlled trial with inclusion criteria as above except that it states subjects must be on antiretroviral therapy for at least 8 weeks prior to inclusion. They then state that over 85% of the patients were receiving HAART. This again poses a problem if the premise of this study is whether r-hGH could potentially worsen insulin resistance or hyperglycemia associated with protease inhibitors. Those not on HAART should have been excluded from the study. Patients with pre-existing diabetes or fasting glucose >120 mg/dl (6.66 mmol/l) were excluded.
Moving forward, at the end of the 12 weeks of study treatment, subjects could then either continue double-blind treatment for an additional 36 weeks with those on placebo being randomized to either daily or alternate day r-hGH or receive daily open-label r-hGH for an additional 12 weeks.
In this study, the demographics were given for all 757 subjects and as above, 555 were considered evaluable. Subjects were men (91%), mean age 41 years. 86% were on HAART. At baseline, median BMI and body weight were approximately 21 kg/m2 and 65.6 kg respectively. A total of 646 subjects completed the initial double-blind study and entered the extension phase. So, now I really do not understand why the analysis was done on only 555 yet 646 are continuing on. Then, 249 subjects were re-randomized to rhGH DD or AD for 36 wks and 397 subjects received open-label DD for 12 wks. Fasting blood sugar (FBS) was measured at baseline and wks 4, 8, 12, 16, 24 and 48. Cases of hyperglycemia were managed with dose reduction of r-hGH or temporarily holding r-hGH. If a subject remained hyperglycemic, r-hGH was permanently discontinued.
The baseline mean FBS in the DD, AD and P arms were 90.4 mg/dL, 92.0 mg/dL and 92.6 mg/dL respectively. The mean changes in FBS during the 12 week study were 9.7 mg/dL, 5.6 mg/dL and 2.0 mg/dL respectively. A dose-dependant increase in glucose was seen on rhGH that did not require withdrawal, discontinuation, or corrective therapy in most pts. During wks 1-12, between 20-28% of patients on DD developed increased glucose compared to 17-18% of patients on AD and 10-11.5% of patients on placebo. Most values were in a low range (i.e. 110-140 mg/dL). 2.4 % on DD, 3.1% on AD, and 1.8% on P developed FBS in the range of 141-250 mg/dL. One new-onset case of diabetes (on DD) and 2 cases of pronounced hyperglycemia (one each on AD and DD) were reported, for which one required hospitalization. During the initial 12 week phase, one subject withdrew because of hyperglycemia and one withdrew because of development of diabetes. After week 12, one subject on AD and 4 subjects on DD withdrew because of hyperglycemia. During the full 48 weeks of the study, hyperglycemia was reported in 9 subjects on placebo , 12 on AD and 33 on DD.
The investigators concluded that the elevations in FBS were modest and rarely serious. They recommended that glucose levels must be determined before treatment and closely monitored. Although we do not know if and when insulin resistance may lead to diabetes, the intent of this study was to determine whether r-hGH could substantially worsen the insulin resistance that has been reported with protease inhibitors yet fasting insulin levels were not obtained for this study. In the introduction, the investigators state, "Administration of r-hGH, however, tends to increase insulin resistance, which may result in hyperglycemia and potential worsening of pre-existing diabetes; furthermore, treatment with protease inhibitor-based therapy may result in a predisposition towards increased insulin resistance. It is thus important to evaluate the effects of r-hGH on glucose homeostasis in HIV-positive patients receiving HAART." I could not agree more. But then why not measure insulin levels or other measure of glucose such as 2 hr OTT in patients on protease inhibitors receiving r-hGH? Again, we have the problems of interpreting mixed data including the 69 subjects not on HAART and we really do not know how many of those on HAART were actually on a protease-inhibitor based regimen. Then, we also have the 91 other subjects that were excluded in the analysis because of adherence difficulties yet allowed to continue study through 48 weeks.
As the investigators note, it is critical to monitor FBS in this population. Unfortunately, the population who may benefit the most from its effects on body composition are also the ones most likely to have metabolic syndrome characterized by elevated lipids and insulin resistance. Therefore, this therapy may pose more harm than good. Given its high cost, biased statistical analyses and adverse effects, these studies do not warrant the routine use of r-hGH in clinical practice. Further studies in a sub-population with lipodystrophy on protease inhibitors are needed.