Browsing by Author "Ware, Russell E."
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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 Decreased parasite burden and altered host response in children with sickle cell anemia and severe anemia with malaria(American Society of Hematology, 2021) Henrici, Ryan C.; Sautter, Casey L.; Bond, Caitlin; Opoka, Robert O.; Namazzi, Ruth; Datta, Dibyadyuti; Ware, Russell E.; Conroy, Andrea L.; John, Chandy C.; Pediatrics, School of MedicinePlasmodium falciparum malaria causes morbidity and mortality in African children with sickle cell anemia (SCA), but comparisons of host responses to P falciparum between children with SCA (homozygous sickle cell disease/hemoglobin SS [HbSS]) and normal hemoglobin genotype/hemoglobin AA (HbAA) are limited. We assessed parasite biomass and plasma markers of inflammation and endothelial activation in children with HbAA (n = 208) or HbSS (n = 22) who presented with severe anemia and P falciparum parasitemia to Mulago Hospital in Kampala, Uganda. Genotyping was performed at study completion. No child had known SCA at enrollment. Children with HbSS did not differ from children with HbAA in peripheral parasite density, but had significantly lower sequestered parasite biomass. Children with HbSS had greater leukocytosis but significantly lower concentrations of several plasma inflammatory cytokines, including tumor necrosis factor α (TNF-α). In contrast, children with HbSS had threefold greater concentrations of angiopoietin-2 (Angpt-2), a marker of endothelial dysregulation associated with mortality in severe malaria. Lower TNF-α concentrations were associated with increased risk of postdischarge mortality or readmission, whereas higher Angpt-2 concentrations were associated with increased risk of recurrent clinical malaria. Children with SCA have decreased parasite sequestration and inflammation but increased endothelial dysregulation during severe anemia with P falciparum parasitemia, which may ameliorate acute infectious complications but predispose to harmful long-term sequelae.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 Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia(ASH, 2017) Opoka, Robert O.; Ndugwa, Christopher M.; Latham, Teresa S.; Lane, Adam; Hume, Heather A.; Kasirye, Phillip; Hodges, James S.; Ware, Russell E.; John, Chandy C.; Pediatrics, School of MedicineHydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416.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.Item Zinc for Infection Prevention in Sickle Cell Anemia (ZIPS): study protocol for a randomized placebo-controlled trial in Ugandan children with sickle cell anemia(BioMed Central, 2019-07-26) Datta, Dibyadyuti; Namazzi, Ruth; Conroy, Andrea L.; Cusick, Sarah E.; Hume, Heather A.; Tagoola, Abner; Ware, Russell E.; Opoka, Robert O.; John, Chandy C.; Pediatrics, School of MedicineBACKGROUND: Sickle cell anemia (SCA) is the most common inherited hemoglobinopathy worldwide. Infection is a major cause of illness and death in children with SCA, especially in sub-Saharan Africa where an estimated 50-90% of affected children die before their fifth birthday. Interventions to reduce the incidence and severity of infections are needed urgently. A high proportion of adults and children with SCA are zinc-deficient, and zinc deficiency leads to impaired immunity and an increased risk of infection. Zinc supplementation has been shown to decrease the risk of infection in adolescents and adults, but there are no data on the effectiveness of zinc for prevention of infection in children < 5 years of age with SCA. METHODS/DESIGN: The study will be a randomized, placebo-controlled, double-blind clinical trial in which 250 Ugandan children 1.00-4.99 years of age with SCA will receive daily zinc supplementation (10 mg oral dispersible tablet) or identical placebo for 12 months. DISCUSSION: If this trial shows a reduction in severe or invasive infection incidence, it would be the basis for a multi-site, multi-country clinical trial to assess real-world safety and efficacy of zinc in African children with SCA. Since zinc is safe, inexpensive, and easy to administer, this trial has the potential to improve the health of hundreds of thousands of African children with SCA through reduction of infection-related morbidity and mortality.