Adherence to Growth Hormone Therapy: A Practical Approach

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1 HORMONE RESEARCH IN PÆDIATRIC S Original Paper Received: October 14, 2013 Accepted: December 12, 2013 Published online: Adherence to Growth Hormone Therapy: A Practical Approach M. Bozzola a S. Pagani a L. Iughetti d C. Maffeis c E. Bozzola b C. Meazza a a Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia ; b Pediatrics Department, Bambino Gesù Children s Hospital, Rome ; c Department of Life and Reproduction Sciences, University of Verona, Verona, and d Department of Pediatrics, University of Modena and Reggio Emilia, Modena, Italy Key Words Growth hormone deficiency Growth hormone therapy Insulin-like growth factor I Compliance Adherence Abstract Background: Early detection of suspected poor adherence to growth hormone (GH) therapy is crucial to achieve normal final height in GH-deficient (GHD) patients. Patients: 106 children (73 M, 33 F) with a median age of ± 3.48 years (mean ± standard deviation score (SDS)) exhibited short stature ( 1.76 ± 0.64 SDS) and a delayed bone age (8.68 ± 3.42 years). Severe GHD was found in 28, while partial GHD was seen in 78 cases, with low IGF-I values. Recombinant human GH was administered by daily subcutaneous injection at a dosage of 21 μg/kg in prepubertal and 25 μg/kg in pubertal patients. Results: Poor adherence was suspected in a number of patients, but clearly demonstrated in only 4 cases with persistent reduced height velocity in spite of a corrected therapeutic regimen. These patients admitted incomplete adherence to GH injections and clinical and anthropometric measurements revealed their poor response to therapy. Conclusions: To efficaciously improve adherence in GHD patients, it is mandatory to regularly interview patients; a non-aggressive approach might be utilized to ensure effective communication with patients and their parents S. Karger AG, Basel Introduction The objectives of growth hormone (GH) treatment are to correct impaired growth during childhood and achieve normal peak bone mass during adolescence [1, 2]. The recommended GH dose is calculated based on body weight and can vary according to specific pathologies including GH deficiency (GHD), Turner syndrome, small for gestational age, Prader-Willi syndrome, chronic renal insufficiency and neonatal panhypopituitarism [3]. In case of GHD, treatment with GH should be initiated early and be monitored by a pediatric endocrinologist every 4 6 months to verify growth velocity and identify possible side effects. In addition, prompt initiation of GH treatment prevents hypoglycemia in GHD neonates. Moreover, early replacement therapy increases growth velocity allowing the patient to achieve their genetic height potential and avoid social handicaps associated with short stature [2]. Poor adherence to treatment is a common problem during the management of most chronic diseases, such as GHD. No general consensus on the definition of good adherence has been reported because of the great variation in methods employed for measuring it (i.e. direct evaluation of drug levels or its metabolites, or indirect evaluation of prescription refills, clinical response and electronic devices) [4]. Moreover, these methods are inconvenient for karger@karger.com S. Karger AG, Basel /14/ $39.50/0 Mauro Bozzola, MD Dipartimento di Medicina Interna e Terapia Medica Università di Pavia, Fondazione IRCCS Policlinico San Matteo Piazzale C. Golgi 2, IT Pavia (Italy) unipv.it

2 patients or imprecise, underscoring the difficulty for physicians to accurately assess the degree of adherence [5, 6]. In fact, an adherence rate of 80 or 95% has been fixed as a cut-off [7]. The causes of non-adherence are often unknown and may be due to the different lifestyles of the parents, including socioeconomic status, academic level and type of relationship with the child s physician. Other factors influencing adherence include the complexity of treatment regimens, long-term nature of the therapy and discomfort or pain associated with injections [8, 9]. In the present study we examined adherence to GH therapy in GH-treated patients in whom growth failure was observed after a period of good growth response. Furthermore, we propose new strategies for the management of non-adherence in long-term GH therapy to prevent growth failure. Color version available online Pa t i e n t s We followed 106 GHD children (73 M, 33 F) with a median age of ± 3.48 years (mean ± SD). GHD was established, after excluding other causes of growth failure, and considering the basis of short stature, reduced growth rate, delayed bone age and insufficient GH response to at least two classical pharmacological stimuli (peak <10 ng/ml) according to international guidelines [3]. These patients exhibited short stature (height 1.76 ± 0.64 standard deviation score (SDS)), a body mass index (BMI) of 1.15 ± 2.52 SDS, and a bone age of 8.68 ± 3.42 years. Severe GHD (GH peak <5 ng/ml) was found in 28 patients, while partial GHD (GH peak <10 ng/ml) [3, 10] was observed in 78 cases, with low IGF-I circulating values. Recombinant human GH was administered by daily subcutaneous injection at a dosage of 21 μg/kg in prepubertal and 25 μg/kg in pubertal patients. GH substitutive treatment was continued for 5.43 ± 3.01 years and monitored every 6 months by evaluating anthropometric and laboratory parameters (i.e. IGF-I levels, A 1c fraction of glycosylated hemoglobin, adrenal and thyroid function), and assessing compliance. R e s u l t s Fig. 1. Growth failure in an adolescent with a decrease in serum IGF-I values. In 11 out of 106 GHD patients, growth failure was observed after a period of good growth response to longterm GH therapy. In these patients, we first verified the adequate dosage of the medication, the possible onset of other chronic diseases such as celiac disease, and the presence of anti-gh antibodies. Finally, we carefully interviewed the patient and parents in order to verify compliance to GH treatment. In all cases, GH dosage was adequate for body weight and pubertal status. The parents of 7 patients admitted poor adherence, although the patients were unwilling to openly confirm their parent s declarations. The degree of non-adherence varied from missing occasional doses per week to discontinuing the therapy. In the other 4 patients it was more difficult to understand the cause of the decrease in growth rate. They were all patients with GHD, a normal karyotype, without any chronic conditions including celiac or Crohn s disease and had a normal MRI of the hypophysis. Furthermore, we did not observe any abnormal laboratory parameters during their follow-up. Patient 1 The first patient was diagnosed when she was 3 years old. She started GH replacement therapy at age 3 and after 8.5 years of good response we observed a significant reduction in growth velocity ( fig. 1 ), associated with an unexpected decrease in serum IGF-I values (from 677 ng/ ml at the age of 11.1 years to ng/ml 6 months later). After a careful interview, the patient admitted to having discontinued the therapy for 7 8 months, because of therapeutic fatigue. 2 Bozzola/Pagani/Iughetti/Maffeis/Bozzola/ Meazza

3 Color version available online Color version available online Fig. 2. Growth failure in an adolescent with intermittent adherence. Fig. 3. Growth failure in an adolescent who confirmed non-adherence to GH therapy. Patient 2 In the second pubertal patient (diagnosed when he was 5.1 years old) after 8 years of good response to GH treatment, an unexpected decrease in growth velocity ( fig. 2 ) was observed with no changes in serum IGF-I values (604 ng/ml at the age of 13.1 years and ng/ml 6 months later). Following a careful interview with the patient, we discovered that the patient had missed injections and only a couple of weeks before the visit had started GH injections again. This explained why IGF-I levels had not decreased. Subsequently, the patient agreed to adhere to his medication schedule and showed catch-up growth in the following period. Patient 3 The third patient (diagnosed when he was 5.5 years), after 8 years of GH treatment, at the age of 13.8 years, showed a growth arrest suggesting a GH resistance condition ( fig. 3 ). Therefore, we suggested that he discontinue therapy. One month later, an additional endocrinological evaluation confirmed the partial GHD (GH peak 7.4 ng/ ml after glucagon), low serum IGF-I levels (235 ng/ml, 1.17 SDS), normal thyroid and adrenal function and absence of anti-gh antibodies. Following a careful interview, the patient admitted non-adherence to GH therapy that caused the growth arrest. He restarted treatment and 6 months later his growth velocity increased and IGF-I values rose to 586 ng/ml. Patient 4 The last patient, a 12-year-old girl with partial GHD, showed after 4 years of good response to GH treatment (at the age of 16 years) an unexpected progressive decrease in growth velocity, notwithstanding an increase in GH dosage (from 0.25 to 35 mg/kg/week) and good compliance ( fig. 4 ). In this subject we found anti-gh antibodies (titer 1/1,850; cut-off 1/100) confirmed 6 months later (titer 1/2,035) with a subsequent decrease to 1/950 after 3 months of therapy discontinuation [11]. Adherence and GH Treatment 3

4 Fig. 4. Growth failure in a girl showing high values of circulating anti-gh antibodies. Table 1. Suggestions for the management of non-adherence in GHD children treated with GH Non-aggressively interview the patient and his/her family in order to assess the adherence status Discuss the reasons for non-adherence Eventually change the device or the treatment regimen Educational intervention and motivational support D i s c u s s i o n In the present paper we present 4 cases of GHD children who exhibited, after some years of good response, reduced effectiveness of GH therapy (in terms of growth velocity), due to non-adherence to treatment. Cutfield et al. [12] have shown that GH treatment non-compliance with is common and associated with reduced linear growth, leading to a mean final height generally below that of the parents and/or the general population [13]. In GHD children, the success of therapy depends on a correct diagnosis and the ability of the patients and their parents to carefully adhere to the recommended treatment regimen. Some children show a suboptimal response for several reasons including lack of child-adjusted GH doses, irregular injection frequency and mistakes in drug administration [14, 15] (due to missing an occasional dose or missing several doses) [7]. Although needle-free devices are supposed to improve therapy adherence, no differences in adherence were observed between patients who had been allocated a needle-free injection device and those allocated a multi-dose injection pen [16]. Moreover, an alternative approach could be the use of electronic injection devices with a dosage counter [17]. In general, it is difficult for physicians to carefully assess the degree of adherence [5], since patients often affirm adherence to the prescribed therapeutic procedure. While complete non-adherence to GH therapy is relatively easy to detect on the basis of growth failure and/or a sudden decrease in circulating growth factors, such as IGF-I, suboptimal and intermittent adherence are more difficult to assess. This is frequently the case in pubertal patients who are also unwilling to admit non-adherence [18]. A very recent study has reported a higher adherence rate in prepubertal than in pubertal children who were allocated these devices (96.5 and 89.1%, respectively; p < 0.005) [19]. In fact, 3 of our patients who did not admit that they had stopped the injections were pubertal. Furthermore, 1 of the patients stopped the injections and decided to restart them some days before the visit in order to normalize IGF-I levels. When a pediatric endocrinologist is faced with a patient who, after some years of good response to GH treatment, shows a reduction in linear growth, we suggest to firstly exclude chronic diseases, such as Crohn s disease or celiac disease, which could have emerged, negatively influencing growth. Then, the development of anti-gh antibodies should be evaluated, which could inhibit the effect of exogenous GH, as was the case in our patient No. 4. Finally, non-adherence should be evaluated. As no method can directly assess adherence to GH treatment, the simplest and most efficacious means of detecting the real degree of adherence is to regularly interview the patients. However, a single intervention is not sufficient, but several strategies should be available to reduce issues contributing to poor adherence ( table 1 ). At first, a soft approach should be utilized to understand whether the decreased growth rate is actually due to nonadherence, then it is important to identify the reasons 4 Bozzola/Pagani/Iughetti/Maffeis/Bozzola/ Meazza

5 (complex treatment regimen, pain, etc.) by discussing with patients and their family other therapeutic possibilities. For example, if the non-compliance is due to pain associated with drug injections, the use of a needle-free device should be suggested. Appropriate motivational support is essential to ensure that the child s and parents commitment to GH treatment does not diminish over time. Therefore, educational interventions that explain the importance of GH treatment and final outcomes are considered very useful [20]. Co n c l u s i o n s Poor adherence to GH treatment is an important problem in clinical practice because it is associated with reduced growth velocity, and is often underappreciated by physicians. Since a gold-standard method is not available for detecting the real degree of adherence, the simplest and most efficacious means is to regularly interview whether the patient is adherent. Patients and parents should be actively encouraged and educated to carefully adhere to prescribed therapeutic procedures to avoid short final stature. Acknowledgement The authors are grateful to Ms. Laurene Kelly for English revision of the manuscript. Disclosure Statement The authors have no conflicts of interest to disclose. References 1 Lanes R: Long-term outcome of growth hormone therapy in children and adolescents. Treat Endocrinol 2004; 3: Harris M, Hofman PL, Cutfield WS: Growth hormone treatment in children: review of safety and efficacy. Paediatr Drugs 2004; 6: Growth Hormone Research Society: Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 2000; 85: Norgren S: Adherence remains a challenge for patients receiving growth hormone therapy. Pediatr Endocrinol Rev 2009; 6: Stephenson BJ, Rowe BH, Haynes RB, Macharia WM, Leon G: The rational clinical examination. Is this patient taking the treatment as prescribed? JAMA 1993; 269: Ingersoll KS, Cohen J: The impact of medication regimen factors on adherence to chronic treatment: a review of literature. J Behav Med 2008; 31: Osterberg L, Blaschke T: Adherence to medication. N Engl J Med 2005; 353: Haverkamp F, Johansson L, Dumas H, Langham S, Tauber M, Veimo D, Chiarelli F: Observations of nonadherence to recombinant human growth hormone therapy in clinical practice. Clin Ther 2008; 30: Cromer BA, Tarnowski KJ: Noncompliance in adolescents: a review. J Dev Behav Pediatr 1989; 10: Bozzola M, Meazza C: Growth hormone deficiency: diagnosis and therapy in children. Expert Rev Endocrinol Metab 2010; 5: Meazza C, Schaab M, Pagani S, Calcaterra V, Bozzola E, Kratzsch J, Bozzola M: Development of antibodies against growth hormone (GH) during rhgh therapy in a girl with idiopathic GH deficiency: a case report. J Pediatr Endocrinol Metab 2013; 26: Cutfield WS, Derraik JG, Gunn AJ, Reid K, Delany T, Robinson E, Hofman PL: Noncompliance with growth hormone treatment in children is common and impairs linear growth. PLoS One 2011; 6:e Lustig RH: Optimizing growth hormone efficacy: an evidence-based analysis. Horm Res 2004; 62: Bajpai A, Menon PS: Growth hormone therapy. Indian J Pediatr 2005; 72: Cutfield W, Lindberg A, Albertsson-Wikland K, Chatelain P, Ranke MB, Wilton P: Final height in idiopathic growth hormone deficiency: the KIGS experience. KIGS International Board. Acta Paediatr Suppl 1999; 88: Verrips GH, Hirasing RA, Fekkes M, Vogels T, Verloove-Vanhorick SP, Delmarre-Van de Waal HA: Psychological responses to the needle-free Medi-Jector or the multidose Disetronic injection pen in human growth hormone therapy. Acta Paediatr 1998; 87: Bozzola M, Colle M, Halldin-Stenlid M, Laroque S, Zignani M: Treatment adherence with the easypod TM growth hormone electronic auto-injector and patient acceptance survey results from 824 children and their parents. BMC Endocr Disord 2011; 11: Fernández-Pérez L, Nóvoa J, Ståhlberg N, Santana-Farré R, Boronat M, Marrero D, Henríquez-Hernández L, Norstedt G, Flores- Morales A: The effect of in vivo growth hormone treatment on blood gene expression in adults with growth hormone deficiency reveals potential biomarkers to monitor growth hormone therapy. Clin Endocrinol 2010; 72: Hartmann K, Ittner J, Müller-Rossberg E, Schönau E, Stephan R, Ullrich KP, Hoppe B, Ramseger R, Brämswig J: Growth hormone treatment adherence in prepubertal and pubertal children with different growth disorders. 2013; 80: Gold DT, McClung B: Approaches to patient education: emphasizing the long-term value of compliance and persistence. Am J Med 2006; 119:S32 S37. Adherence and GH Treatment 5