Browsing by Subject "Hydroxyurea"
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Item Cost-Effectiveness of Hydroxyurea for Sickle Cell Anemia in a Low-Income African Setting: A Model-Based Evaluation of Two Dosing Regimens(Springer, 2023) Teigen, David; Opoka, Robert O.; Kasirye, Phillip; Nabaggala, Catherine; Hume, Heather A.; Blomberg, Bjørn; John, Chandy C.; Ware, Russell E.; Robberstad, Bjarne; Pediatrics, School of MedicineBackground and objective: The disease burden of sickle cell anemia (SCA) in sub-Saharan African (SSA) countries is substantial, with many children dying without an established diagnosis or proper treatment. The global burden of SCA is increasing each year, making therapeutic intervention a high priority. Hydroxyurea is the only disease-modifying therapy with proven feasibility and efficacy suitable for SSA; however, no one has quantified the health economic implications of its use. Therefore, from the perspective of the health care provider, we estimated the incremental cost-effectiveness of hydroxyurea as a fixed-dose regimen or maximum tolerated dose (MTD) regimen, versus SCA care without hydroxyurea. Methods: We estimated the cost of providing outpatient treatment at a pediatric sickle cell clinic in Kampala, Uganda. These estimates were used in a discrete-event simulation model to project mean costs (2021 US$), disability-adjusted life years (DALYs), and consumption of blood products per patient (450 mL units), for patients between 9 months and 18 years of age. We calculated cost-effectiveness as the ratio of incremental costs over incremental DALYs averted, discounted at 3% annually. To test the robustness of our findings, and the impact of uncertainty, we conducted probabilistic and one-way sensitivity analyses, scenario analysis, and price threshold analyses. Results: Hydroxyurea treatment averted an expected 1.37 DALYs and saved US$ 191 per patient if administered at the MTD, compared with SCA care without hydroxyurea. In comparison, hydroxyurea at a fixed dose averted 0.80 DALYs per patient at an incremental cost of US$ 2. The MTD strategy saved 11.2 (95% CI 11.1-11.4) units of blood per patient, compared with 9.1 (95% CI 9.0-9.2) units of blood per patient at the fixed-dose alternative. Conclusions: Hydroxyurea at MTD is likely to improve quality of life and reduce the consumption of blood products for children with SCA living in Uganda. Compared with a fixed dose regimen, treatment dosing at MTD is likely to be a cost-effective treatment for SCA, using realistic ranges of hydroxyurea costs that are relevant across SSA. Compared with no use of the drug, hydroxyurea could lead to substantial net savings per patient, while reducing the disease morbidity and mortality and increasing quality of life.Item Decision Making in Fertility Preservation Prior to Pursuing Curative Treatments for Sickle Cell Disease(2023-03-24) Collins, Angela J.; Noel, Josey; Abraham, Olivia; Hornberger, Sydney; Rahim, Mahvish Q.; Jacob, Seethal A.; Saraf, Amanda J.AUTHORS: Angela Collins, MPH(1), Josey Noel(1), Olivia Abraham(1), Sydney Hornberger(1), Mahvish Rahim MD, MBA, MSCR(1,2), Seethal Jacob MD, MS, FAAP(1,2), Amanda Saraf DO(1,2). AFFILIATIONS: (1) Indiana University School of Medicine, Indianapolis, IN. (2) Department of Pediatrics, Riley Hospital for Children, Indianapolis, IN. ABSTRACT: RELEVANT BACKGROUND: Sickle cell disease (SCD) is one of the most commonly inherited hemoglobinopathies, often well controlled on Hydroxyurea (HU). Curative therapy options exist with stem cell transplant (SCT) and gene therapy. While both the underlying condition and routine therapy such as HU is thought to impact fertility, the chemotherapy used for both SCT and gene therapy can result in permanent sterility. Infertility can have a negative impact on long-term measures of quality of life. As a result, fertility preservation ought to be offered to all patients with SCD planning for curative treatment. Ovarian tissue cryopreservation and mature oocyte or embryo cryopreservation are fertility preservation options available for pre and postpubescent females respectively. Testicular tissue cryopreservation (TTC) is an experimental option for prepubescent males and sperm cryopreservation is utilized for postpubescent males. CASE DESCRIPTION: We present three cases of patients with SCD who pursued fertility preservation prior to receiving curative therapy with a myeloablative preparative regimen. Patient 1 is a prepubescent 8-year-old male with SCD controlled with HU who opted for TTC as fertility preservation prior to receiving a matched sibling SCT. Patient 2 is a 13-year-old male with SCD controlled with HU who opted for TTC following a failed sperm banking attempt prior to haploidentical SCT. Patient 3 is an 18-year-old female with SCD controlled with HU and Voxelator who opted to have eggs harvested prior to gene therapy. CLINICAL SIGNIFICANCE: As highlighted by these cases, continued research on safe and effective fertility preservation as well as counseling about both the impact of the underlying disease on fertility and treatment-related fertility risks is imperative to improve long-term quality of life measures. CONCLUSION: These patients demonstrate a need for further emphasis on fertility risk counseling in this patient population and ensuring that discussions regarding preservation options is standard of practice at every institution.Item Development and Validation of the Patient/Caregiver Reported Hydroxyurea Evaluation of Adherence for Life (HEAL) Scale(Dove Press, 2022-12-10) Janson, Isaac A.; Bloom, Ellen M.; Hampton, Kisha C.; Riehm Meier, Emily; Rampersad, Angeli G.; Kronenberger, William G.; Psychiatry, School of MedicineIntroduction: Hydroxyurea reduces the incidence of vaso-occlusive episodes, stroke, and respiratory, cardiac, and renal damage in sickle cell disease by increasing fetal hemoglobin. However, because suboptimal adherence to hydroxyurea limits its effectiveness, understanding patient-specific barriers to hydroxyurea adherence could help improve adherence and health outcomes in patients with sickle cell disease. The aim of this single-site, prospective, IRB-approved study was to validate a 24-item patient- and caregiver-reported hydroxyurea treatment adherence questionnaire, the Hydroxyurea Evaluation of Adherence for Life (HEAL) scale. Methods: A sample of 24 adults with sickle cell disease and 16 caregivers of children with sickle cell disease completed the HEAL scale, and a subset of the original sample provided a second HEAL scale for test-retest reliability. HEAL scale results were validated against global adherence ratings from participants and health-care providers, records of access to pill bottles, and laboratory values for fetal hemoglobin and absolute neutrophil count. Results and discussion: Results demonstrated excellent internal consistency for the HEAL Total score and eight (3-item) subscale scores (Dose, Remember, Plan, Cost, Understand, Effectiveness, Laboratory, and Pharmacy), as well as strong test-retest reliability for all HEAL scores except the Cost subscale. HEAL Total scores correlated significantly with validity measures, including global adherence ratings and lab values. The HEAL scale offers significant clinical potential for understanding adherence in individual sickle cell disease patients and significant research potential for characterizing adherence in persons with sickle cell disease who are treated with hydroxyurea.Item Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness(Ferrata Storti Foundation, 2017-12) Zhu, Xingguo; Hu, Tianxiang; Ho, Meng Hsuan; Wang, Yongchao; Yu, Miao; Patel, Niren; Pi, Wenhu; Choi, Jeong-Hyeon; Xu, Hongyan; Ganapathy, Vadivel; Kutlar, Ferdane; Kutlar, Abdullah; Tuan, Dorothy; Radiation Oncology, School of MedicineHydroxyurea (HU), the first of two drugs approved by the US Food and Drug Administration for treating patients with sickle cell disease (SCD), produces anti-sickling effect by re-activating fetal γ-globin gene to enhance production of fetal hemoglobin. However, approximately 30% of the patients do not respond to HU therapy. The molecular basis of non-responsiveness to HU is not clearly understood. To address this question, we examined HU-induced changes in the RNA and protein levels of transcription factors NF-Y, GATA-1, -2, BCL11A, TR4, MYB and NF-E4 that assemble the γ-globin promoter complex and regulate transcription of γ-globin gene. In erythroblasts cultured from peripheral blood CD34+ cells of patients with SCD, we found that HU-induced changes in the protein but not the RNA levels of activator GATA-2 and repressors GATA-1, BCL11A and TR4 correlated with HU-induced changes in fetal hemoglobin (HbF) levels in the peripheral blood of HU high and low responders. However, HU did not significantly induce changes in the protein or RNA levels of activators NF-Y and NF-E4. Based on HU-induced changes in the protein levels of GATA-2, -1 and BCL11A, we calculated an Index of Hydroxyurea Responsiveness (IndexHU-3). Compared to the HU-induced fold changes in the individual transcription factor protein levels, the numerical values of IndexHU-3 statistically correlated best with the HU-induced peripheral blood HbF levels of the patients. Thus, IndexHU-3 can serve as an appropriate indicator for inherent HU responsiveness of patients with SCD.Item Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa(Massachusetts Medical Society, 2020-06) John, Chandy C.; Opoka, Robert O.; Latham, Teresa S.; Hume, Heather A.; Nabaggala, Catherine; Kasirye, Phillip; Ndugwa, Christopher M.; Lane, Adam; Ware, Russell E.; Pediatrics, School of MedicineBACKGROUND Hydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown. METHODS In a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events. RESULTS Children received hydroxyurea at a fixed dose (94 children; mean [±SD] age, 4.6±1.0 years) or with dose escalation (93 children; mean age, 4.8±0.9 years); the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P<0.001). Children in the dose-escalation group had fewer sickle cell–related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia. CONCLUSIONS Among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety.Item Hydroxyurea reduces infections in children with sickle cell anemia in Uganda(American Society of Hematology, 2024) Namazzi, Ruth; Bond, Caitlin; Conroy, Andrea L.; Datta, Dibyadyuti; Tagoola, Abner; Goings, Michael J.; Jang, Jeong Hoon; Ware, Russell E.; Opoka, Robert; John, Chandy C.; Pediatrics, School of MedicineAfter starting hydroxyurea treatment, Ugandan children with sickle cell anemia had 60% fewer severe or invasive infections, including malaria, bacteremia, respiratory tract infections, and gastroenteritis, than before starting hydroxyurea treatment (incidence rate ratio, 0.40 [ 95% confidence interval, 0.29-0.54 ]; P < .001 ).Item P-039: Alternative Dosing and Prevention of Transfusions (Adapt): A Prospective Trial Evaluating Transfusion Utilization and the Feasibility of Pharmacokinetic Hydroxyurea Dosing in Children with Sickle Cell Anemia in Uganda(Wolters Kluwer, 2022-08-16) Power-Hays, A.; Namazzi, R.; Kato, C.; Conroy, A.; Hume, H.; John, C.; Stuber, Ma S.; Lane, A.; Latham, T.; Opoka, R.; Ware, R.; Pediatrics, School of MedicinePurpose: Blood transfusions are a scarce resource globally and particularly in sub-Saharan Africa. Without disease-modifying therapy, in sub-Saharan Africa sickle cell anemia (SCA) has excess morbidity, mortality, and healthcare resource utilization, specifically requiring a high reliance on blood transfusions. Hydroxyurea is a safe medication for the treatment of SCA that can decrease rates of blood transfusions. The widespread use of hydroxyurea in sub-Saharan Africa is limited in part, however, by logistical challenges in determining an individual patient’s optimal dose. Pharmacokinetic (PK) dosing of hydroxyurea may streamline the dosing process, maximizing the clinical benefits and minimizing toxicities, while reducing the time and resources needed to determine the optimal dose. We hypothesize that hydroxyurea treatment will be associated with a 50% reduction in blood transfusion rate in children with SCA, compared to pre-treatment utilization, and that determining a PK-based hydroxyurea starting dose will be feasible in 80% of participants. Materials and methods: To test this hypothesis, we will conduct the Alternative Dosing and Prevention of Transfusions (ADAPT) trial, a prospective cohort study of children with SCA in Jinja, Uganda (Figure). Transfusion rates and indications will be prospectively recorded during a 3-month pre-treatment period and compared to a 12-month treatment period. Every participant will undergo baseline hydroxyurea PK testing using timed serum collections based on our published sparse-sampling method and HPLC analysis. If generated, the participant will start on their PK-guided dose; when PK testing is not feasible, the participant will be started on 20 mg/kg/day per Ugandan guidelines. Regardless of starting dose (PK or default), all participants will undergo the same laboratory monitoring schedule with dose escalation and adjustments as necessary. Hydroxyurea will be purchased from a local commercial source using 500mg capsules. Results: The primary endpoint will be incidence rate ratio of transfusions per 100-patient years during hydroxyurea treatment as compared with the pre-treatment period. Based on sample size analysis, a total of 100 children with SCA (HbSS genotype), aged 1 to 10 years, will be enrolled in ADAPT. A student’s t-test will be performed to compare the rate of transfusions per 100 patient-years prior to and during hydroxyurea treatment. The secondary endpoints include feasibility of determining a PK-based starting dose and the rates of transfusions, clinical events, dose-limiting toxicities, and dose adjustments in participants on PK-based versus default start dose. Conclusion: Overall, the potential for hydroxyurea to reduce the rate of blood transfusions in children with SCA will have important individual and public health implications. Determining the feasibility and accuracy of PK-dosing of hydroxyurea could simplify the safe and effective treatment of SCA. ADAPT is a collaborative research partnership that will provide important data toward increasing the use of hydroxyurea in Uganda and potentially across sub-Saharan Africa.Item Stroke Training, Research, and Education Toward Capacity With Hydroxyurea (Stretch)(2024-05) Latham, Teresa Smith; Czabanowska, Katarzyna; Babich, Suzanne M.; Ware, Russell E.; Yego-Kosgei, FaithBackground and Purpose: Sickle cell anemia (SCA) is an inherited hematological disease characterized by chronic pain, susceptibility to infections, and significant morbidity and mortality, particularly among children living in resource-limited settings. Stroke is a complication of SCA that can be prevented through transcranial Doppler (TCD) ultrasonography, a screening tool that identifies children at risk, and treatment with hydroxyurea. This study will inform how public health leaders can mitigate stroke risk among children with SCA in sub-Saharan Africa and how TCD screening fits into a larger context of providing safe, effective care. Methods: Stroke Training, Research, and Education Toward Capacity with Hydroxyurea (STRETCH) utilized a qualitative design that included semi-structured interviews with TCD examiners and stakeholders. There were 17 interviews with TCD examiners who participated in a training and supervision program, TCD trainers, and clinical care providers from 6 countries across sub-Saharan Africa. Interviews were coded and analyzed for themes that were used to identify effective training and program strategies, and to develop a capacity-building model for resource-limited settings. Results: Participants reported satisfaction with the training program, noting that in-person training with sub-Saharan Africa-based examiners was preferable to initial training using a web-based platform, and that ongoing training, supervision, and technical support through collaboration between US-based and Africa-based teams was conducive to skill development. Participants described the major clinical and socioeconomic impact of SCA on children, families and communities and emphasized the role of hydroxyurea in preventing complications and decreasing burden on health systems. Results indicate a call to action for improved education for clinicians, families, and community leaders and stakeholder support for health policy to facilitate access to hydroxyurea. Conclusion: The complexities of healthcare infrastructure and the morbidity and mortality associated with SCA in resource-limited settings warrant a multifaceted approach to capacity building. The STRETCH model integrates education, policy development, and access to hydroxyurea as a holistic approach that leverages geographical partnerships and builds on existing resources in sub-Saharan Africa. By simultaneously addressing education, policy, and access barriers, public health leaders can work collaboratively toward building sustainable capacity that improves outcomes for children with SCA in these settings.Item Zinc for infection prevention in children with sickle cell anemia: a randomized double-blind placebo-controlled trial(American Society of Hematology, 2023) Namazzi, Ruth; Opoka, Robert; Conroy, Andrea L.; Datta, Dibyadyuti; Tagoola, Abner; Bond, Caitlin; Goings, Michael J.; Ryu, Moon-Suhn; Cusick, Sarah E.; Krebs, Nancy F.; Jang, Jeong Hoon; Tu, Wanzhu; Ware, Russell E.; John, Chandy C.; Biostatistics and Health Data Science, School of MedicineData from small clinical trials in the United States and India suggest zinc supplementation reduces infection in adolescents and adults with sickle cell anemia (SCA), but no studies of zinc supplementation for infection prevention have been conducted in children with SCA living in Africa. We conducted a randomized double-blind placebo-controlled trial to assess zinc supplementation for prevention of severe or invasive infections in Ugandan children 1.00-4.99 years with SCA. Of 252 enrolled participants, 124 were assigned zinc (10 mg) and 126 assigned placebo once daily for 12 months. The primary outcome was incidence of protocol-defined severe or invasive infections. Infection incidence did not differ between treatment arms (282 vs. 270 severe or invasive infections per 100 person-years, respectively, incidence rate ratio of 1.04 [95% confidence interval (CI), 0.81, 1.32, p=0.78]), adjusting for hydroxyurea treatment. There was also no difference between treatment arms in incidence of serious adverse events or SCA-related events. Children receiving zinc had increased serum levels after 12-months, but at study exit, 41% remained zinc deficient (<65 μg/dL). In post-hoc analysis, occurrence of stroke or death was lower in the zinc treatment arm (adjusted hazard ratio (95% CI), 0.22 (0.05, 1.00); p=0.05). Daily 10 mg zinc supplementation for 12 months did not prevent severe or invasive infections in Ugandan children with SCA, but many supplemented children remained zinc deficient. Optimal zinc dosing and the role of zinc in preventing stroke or death in SCA warrant further investigation.