[Sickle cell disease in the Democratic Republic of the Congo: what are the barriers to treatment using hydroxyurea?] / Drépanocytose en République Démocratique du Congo: quels sont les obstacles à un traitement par hydroxyurée?

INTRODUCTION: hydroxyurea is the unique medication that has been proven to prevent complications in patients with sickle cell disease and is approved by the Food and Drug Administration. This medication requires a prescription to be dispensed, it must be available and at an affordable price. The purpose of this study was to determine the availability and market price of hydroxyurea in the Democratic Republic of the Congo and to make a comparison between these two aspects in a small city, such as Mbujimayi, and in a big city, such as Lubumbashi. METHODS: we conducted a cross-sectional study in the context of a face-to-face survey involving 188 Congolese pharmacies from 1st April to 1st September 2017. RESULTS: hydroxyurea was available at 41/188 (22%) participating pharmacies, but more frequently at those of a big city than at those of a small city (34/96 versus 7/92). Most patients got a prescription (36/41; 88%). The average price of hydroxyurea was $15 (from $10 to $35 a blister packs of 25 capsules), which was higher than the purchasing power of the majority of sickle cell patients. Hydroxyurea is still an imported product from Europe, the United States or Asia. CONCLUSIONS: hydroxyurea is one of the main treatments to slow down disease progression in sickle cell patients. Nevertheless, in the Democratic Republic of the Congo, its availability could be improved, in particular in small cities, and its price is still too high.

Effective use of hydroxyurea for sickle cell anemia in low-resource countries.

PURPOSE OF REVIEW: Over the past several decades, hydroxyurea has emerged as a well tolerated and potent disease-modifying therapy for children and adults with sickle cell anemia (SCA). Strong, evidence-based recommendations from the National Institutes of Health, American Society of Hematology, and British Society of Haematology document that hydroxyurea is now standard of care treatment for SCA. In low-resource settings, however, hydroxyurea is rarely utilized due to lack of availability, inadequate treatment guidance, and excessive costs. RECENT FINDINGS: Research trials conducted within the Caribbean and sub-Saharan Africa confirm the efficacy of hydroxyurea as a well tolerated, feasible, and beneficial treatment in low-resource countries. Hydroxyurea is therefore vital to reaching the targets for control of SCA outlined by the WHO. To maximize its utilization toward real-world effectiveness, specific attention must be given to healthcare provider education and training, public and institutional awareness, and medication access and affordability. SUMMARY: Efforts to introduce hydroxyurea effectively into low-resource countries should urgently address the lack of treatment guidelines, gaps in knowledge and clinical infrastructure, and medication inaccessibility. Partnerships among governmental, academic, pharmaceutical, and charitable organizations must tackle these barriers so that all individuals living with SCA worldwide can benefit from hydroxyurea.

Treatment patterns and economic burden of sickle-cell disease patients prescribed hydroxyurea: a retrospective claims-based study.

BACKGROUND: This study aimed to evaluate sickle-cell disease (SCD) treatment patterns and economic burden among patients prescribed hydroxyurea (HU) in the US, through claims data. METHODS: SCD patients with pharmacy claims for HU were selected from the Medicaid Analytic Extracts (MAX) from January 1, 2009 - December 31, 2013. The first HU prescription during the identification period was defined as the index date and patients were required to have had continuous medical and pharmacy benefits for ≥6 months baseline and 12 months follow-up periods. Patient demographics, clinical characteristics, treatment patterns, health care utilization, and costs were examined, and variables were analyzed descriptively. RESULTS: A total of 3999 SCD patients prescribed HU were included; the mean age was 19.24 years, most patients were African American (73.3%), and the mean Charlson comorbidity index (CCI) score was 0.6. Asthma (20.3%), acute chest syndrome (15.6%), and infectious and parasitic diseases (20%) were the most prevalent comorbidities. During the 12-month follow-up period, 58.9% (N = 2357) of patients discontinued HU medication. The mean medication possession ratio (MPR) was 0.52, and 22.3% of patients had MPR ≥80%. The average length of stay (LOS) for SCD-related hospitalization was 13.35 days; 64% of patients had ≥1 SCD-related hospitalization. The mean annual total SCD-related costs per patient were $27,779, mostly inpatient costs ($20,128). CONCLUSIONS: Overall, the study showed the patients had significant unmet needs manifest as poor medication adherence, high treatment discontinuation rates, and high economic burden.

Health Care Costs and Thromboembolic Events in Hydroxyurea-Treated Patients with Polycythemia Vera.

BACKGROUND: Patients with polycythemia vera (PV) are at increased risk of thromboembolic events (TEs), which are key contributors to reduced overall survival compared with the age- and sex-matched general population. In addition to aspirin and phlebotomy to maintain hematocrit level < 45%, many patients receive cytoreduction with hydroxyurea (HU), which is associated with improved survival and may reduce the risk of cardiovascular events and TEs. However, 1 in 4 patients become resistant to or intolerant of HU. In the general population, prophylaxis and treatment following arterial and venous thromboses are associated with increased health care resource utilization and costs. OBJECTIVE: To describe the health care resource utilization and costs associated with TEs in patients with PV treated with HU in the United States. METHODS: This retrospective cross-sectional analysis of the Truven Health Analytics MarketScan Research Databases included adult patients with a PV diagnosis who were newly treated with HU and continuously enrolled in medical and pharmacy benefit plans for ≥ 12 months pre- and post-index. HU treatment administration, persistence, adherence, and related adverse events, as well as TEs, were reported during the 12-month follow-up period. HU treatment patterns were further analyzed in a subgroup analysis comparing patients with and without a ≥ 45-day gap in HU treatment. Health care resource utilization and costs were analyzed in a subgroup analysis comparing patients who had TEs in the 12-month follow-up period with those who did not. Tests for statistically significant differences across the comparison groups were conducted, including chi-square tests for categorical variables and t-tests for continuous variables. RESULTS: The records of 1,322 patients with PV were included in this study. Mean age was 66.0 years; 51.3% were men; and 14.0% had a history of TEs. During the first year of HU treatment, 764 (57.8%) patients had a treatment gap of ≥ 45 days; however, treatment adherence was similar between those with and those without a gap (85.2% vs. 90.7%, respectively). TEs occurred in 216 (16.3%) patients within 12 months of HU initiation. Health care resource utilization was higher for patients with TEs versus those without, including the proportion of patients requiring inpatient services (50.9% vs. 18.4%; P < 0.001) and emergency room visits (48.1% vs. 26.3%; P < 0.001) and the mean number of inpatient admissions (1.7 vs. 1.3; P = 0.004); office visits (18.9 vs. 14.1; P < 0.001); and prescriptions (45.8 vs. 36.2; P<0.001). In addition, total mean health care costs ($45,040 vs. $16,438; P < 0.001); inpatient costs ($18,952 vs. $4,794; P < 0.001); outpatient costs ($20,844 vs. $8,046; P < 0.001); and outpatient pharmacy costs ($5,244 vs. $3,598; P = 0.002) were higher among patients with TEs than those without. CONCLUSIONS: Patients with PV receiving treatment with HU remain at risk for TEs. The occurrence of TEs during the 12-month follow-up in this patient population was associated with higher health care resource utilization and costs. DISCLOSURES: This study was funded by Incyte Corporation. Parasuraman and Paranagama are employees and stockholders of Incyte Corporation. Shi and Bonafede are employees of Truven Health Analytics, which was awarded a research contract to conduct this study with and on behalf of Incyte Corporation. Study concept and design were contributed by all of the authors, who also interpreted the data and wrote and revised the manuscript. Bonafede and Shi collected the data. This study was presented as an abstract at the Academy of Managed Care Pharmacy NEXUS Annual Meeting on October 26-29, 2015, in Orlando, Florida.

Hydroxyurea use in prevention of stroke recurrence in children with sickle cell disease in a developing country: A cost effectiveness analysis.

We undertook a cost effectiveness analysis (CEA) of hydroxyurea (HU) in preventing stroke recurrence and/or death. We followed 43 children with sickle cell disease from 2000 to 2009 after having a first clinical stroke, of whom 10 opted for HU therapy. HU use led to decreased stroke recurrence and death without significantly increasing the annual cost of care per patient (J$83,250 vs. J$76,901, P = 0.491). The incremental cost effectiveness ratio (ICER) for prevention of stroke recurrence amounted to J$169,238 (US$1,900), while that for death prevention equalled J$635,843 (US$7,140). HU may be recommended when safe and affordable transfusion therapy is not feasible.

Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia.

BACKGROUND AND OBJECTIVE: In the BABY HUG trial, young children with sickle cell anemia randomized to receive hydroxyurea had fewer episodes of pain, hospitalization, and transfusions. With anticipated broader use of hydroxyurea in this population, we sought to estimate medical costs of care in treated versus untreated children. METHODS: The BABY HUG database was used to compare inpatient events in subjects receiving hydroxyurea with those receiving placebo. Unit costs were estimated from the 2009 MarketScan Multi-state Medicaid Database for children with sickle cell disease, aged 1 to 3 years. Inpatient costs were based on length of hospital stay, modified by the occurrence of acute chest syndrome, splenic sequestration, or transfusion. Outpatient expenses were based on the schedule required for BABY HUG and a "standard" schedule for 1- to 3-year-olds with sickle cell anemia. RESULTS: There were 232 hospitalizations in the subjects receiving hydroxyurea and 324 in those on placebo; length of hospital stay was similar in the 2 groups. Estimated outpatient expenses were greater in those receiving hydroxyurea, but these were overshadowed by inpatient costs. The total estimated annual cost for those on hydroxyurea ($11 072) was 21% less than the cost of those on placebo ($13 962; P = .038). CONCLUSIONS: Savings on inpatient care resulted in a significantly lower overall estimated medical care cost for young children with sickle cell anemia who were receiving hydroxyurea compared with those receiving placebo. Because cost savings are likely to increase with age, these data provide additional support for broad use of hydroxyurea treatment in this population.

The clinical effectiveness and cost-effectiveness of primary stroke prevention in children with sickle cell disease: a systematic review and economic evaluation.

BACKGROUND: Sickle cell disease (SCD) is a recessive genetic blood disorder, caused by a mutation in the ß-globin gene. For children with SCD, the risk of stroke is estimated to be up to 250 times higher than in the general childhood population. Transcranial Doppler (TCD) ultrasonography is a non-invasive technique which measures local blood velocity in the proximal portions of large intracranial arteries. Screening with TCD ultrasonography identifies individuals with high cerebral blood velocity; these children are at the highest risk of stroke. A number of primary stroke prevention strategies are currently used in clinical practice in the UK including blood transfusion, treatment with hydroxycarbamide and bone marrow transplantation (BMT). No reviews have yet assessed the clinical effectiveness and cost effectiveness of primary stroke prevention strategies in children with SCD identified to be at high risk of stroke using TCD ultrasonography. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of primary stroke prevention treatments for children with SCD who are identified (using TCD ultrasonography) to be at high risk of stroke. DATA SOURCES: Electronic databases were searched from inception up to May 2011, including the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), EMBASE, the Health Technology Assessment (HTA) database, ISI Web of Science Proceedings, ISI Web of Science Citation Index, the NHS Economic Evaluation Database (NHS EED) and MEDLINE. REVIEW METHODS: The assessment was conducted according to accepted procedures for conducting and reporting systematic reviews and economic evaluations. A de novo Markov model was developed to determine the cost-effectiveness of TCD ultrasonography and blood transfusion, where clinically appropriate, in patients with SCD. RESULTS: Two randomised controlled trials met the inclusion criteria involving a study population of 209 participants. One compared blood transfusion with standard care for children who are identified as being at high risk of stroke using TCD ultrasonography. In this trial, one patient in the transfusion group had a stroke (1/63) compared with 11 children in the standard care group (11/67). The other trial assessed the impact of halting chronic transfusion in patients with SCD. Sixteen patients in the transfusion-halted group had an event (16/41) (two patients experienced stroke and 14 reverted to abnormal TCD velocity); there were no events in the continued-transfusion group (0/38). No meta-analyses of these trials were undertaken. No relevant economic evaluations were identified for inclusion in the review. The de novo modelling suggests that blood transfusions plus TCD scans (compared with just TCD scans) for patients with SCD at high risk of stroke, aged ≥ 2 years, may be good value for money. The intervention has an incremental cost-effectiveness ratio of £24,075 per quality-adjusted life-year gained, and helps avoid 68 strokes over the lifetime of a population of 1000 patients. The intervention costs an additional £13,751 per patient and generates 0.6 extra years of life in full health per patient. The data available for the economic analysis are limited. Sensitivity analyses and validation against existing data and expert opinion provide some reassurance that the conclusion of the model is reliable but further research is required to validate these findings. LIMITATIONS: The main limitations relate to the availability of published clinical data; no completed randomised controlled trials were identified which evaluated the efficacy of either BMT or hydroxycarbamide for primary stroke prevention. Both the clinical and cost data available for use in the economic analysis are limited. Sensitivity analyses and validation against existing data and expert opinion provide some reassurance that the conclusions of the model are reliable, but further research is required to validate these findings. CONCLUSIONS: The use of TCD ultrasonography to identify children at high risk of stroke, and treating these children with prophylactic blood transfusions, appears to be both clinically effective and cost-effective compared with TCD ultrasonography only. However, given the limitations in the data available, further research is required to verify this conclusion. Several research recommendations can be proposed from this review. Clinically, more research is needed to assess the effects and optimal duration of long-term blood transfusion and the potential role of hydroxycarbamide in primary stroke prevention. From an economics perspective, further research is required to generate more robust data on which to base estimates of cost-effectiveness or against which model outputs can be calibrated. More data are required to explain how utility weights vary with age, transfusions and strokes. Research is also needed around the cost of paediatric stroke in the UK. STUDY REGISTRATION: PROSPERO CRD42011001496. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease.

While laboratory and clinical benefits of hydroxyurea for patients with sickle cell disease (SCD) are well-established, few data describe the extent and implications of non-adherence. We sought to assess adherence to hydroxyurea among patients with SCD and investigate associations between adherence and clinical and economic outcomes. Insurance claims of North Carolina Medicaid enrollees (6/2000-8/2008) with SCD were analyzed. Inclusion criteria included age < 65 years, continuous Medicaid enrollment ≥ 12 months before and following hydroxyurea initiation, and ≥ 2 hydroxyurea prescriptions. Three hundred twelve patients, mean age 21 (± 12.2) years, met inclusion criteria and 35% were adherent, defined as a medication possession ration (MPR) ≥ 0.80; mean MPR was 0.60. In the 12 months following hydroxyurea initiation, adherence was associated with reduced risk of SCD-related hospitalization (hazard ratio [HR] = 0.65, p = .0351), all-cause and SCD-related emergency department visit (HR = 0.72, p = .0388; HR = 0.58, p =.0079, respectively), and vaso-occlusive event (HR = 0.66, p = .0130). Adherence was associated with reductions in health care costs such as all-cause and SCD-related inpatient (-$5,286, p < .0001; -$4,403, p < .0001, respectively), ancillary care (-$1,336, p < .0001; -$836, p < .0001, respectively), vaso-occlusive event-related (-$5,793, p < .0001), and total costs (-$6,529, p < .0001; -$5,329, p <.0001, respectively). Adherence to hydroxyurea among SCD patients appears suboptimal and better adherence is associated with improved clinical and economic outcomes.

Cost-effectiveness of hydroxyurea in reducing the frequency of pain episodes and hospitalization in pediatric sickle cell disease.

In a cohort of children with sickle cell disease (SCD) and vaso-occlusive pain visits served through South Carolina's Medicaid system over a 6-year period (N 5 523), we compared the number of vaso-occlusive pain or acute chest syndrome (ACS)/pneumonia episodes, and outpatient or acute service costs in those treated or not treated with hydroxyurea (HU). HU may be an underused intervention for SCD in this practice setting, for a variety of reasons. Treatment with HU varied greatly, appears to have been administered to more severely ill children, but was associated with a reduction in vaso-occlusive pain episodes, hospitalizations,and total costs of care within the HU cohort during a 2-3 year period of active HU treatment. Those receiving care through specialized SCD clinics were less likely to have pain or acute care episodes(RR 5 0.79, P < 0.0001; RR 5 0.90, P 5 0.01). Compared with the non-HU cohort, the HU group evinced a significantly higher risk of experiencing vaso-occlusive pain episodes (RR 5 3.32, P < 0.0001)and ACS/pneumonia episodes (RR 5 2.66, P < 0.0001), and higher outpatient,inpatient/emergency, and total service costs (RR 5 1.85, 2.11,2.10, and P < 0.0001, respectively) over time. HU is clinically effective in reducing pain episodes, hospitalizations, and total care costs, but those receiving it might be more severely ill.

Periodic erythroexchange is an effective strategy for high risk paediatric patients with sickle-cell disease.

We performed an 11 year retrospective study on 34 sickle-cell paediatric patients, focusing on efficacy, safety and costs of an exchange transfusion program in 13 high risk patients. A good clinical control with improvement in patients' quality of life, no disease related complications, no significant iron overload and no procedure related side effects were observed during periodic erythroexchange. Costs of periodic erythroexchange versus chronic transfusion regimen were comparable. Periodic erythroexchange appeared a good alternative to chronic transfusion regimen for controlling the most severe forms of disease, particularly in patients who do not tolerate or do not respond to hydroxyurea.

Treatment of hypereosinophilic syndromes with prednisone, hydroxyurea, and interferon.

The hypereosinophilic syndromes continue to challenge our clinical acumen and skills. Prednisone, hydroxyurea, and interferon alpha 2b are three of the oldest agents that allow control of eosinophilia and its devastating clinical consequences. They still work. As our experience with them has grown, it has become evident that use of these agents in combination will control eosinophilia in most patients. Moreover, with time, the doses can frequently be reduced. Even with the advent of newer agents for treatment of hypereosinophilic syndromes, these three medications still afford an excellent, cost-effective avenue for disease management.

Hospitalization rates and costs of care of patients with sickle-cell anemia in the state of Maryland in the era of hydroxyurea.

The multicenter study of hydroxyurea (MSH) in sickle-cell anemia (SCA) demonstrated that patients treated with hydroxyurea (HU) had a 44% decrease in hospitalizations when compared with those taking placebo. A subsequent study looking at the cost-effectiveness of HU showed that decreased hospitalizations for painful crisis accounted for the majority of cost savings in those taking HU. The purpose of this study was to examine whether the expected decrease in hospital utilization occurred after the approval of HU in Maryland. We used data collected by the Maryland Health Services Cost Review Commission to obtain SCA discharge data for Maryland from FY1995 through FY2003. We also reviewed the inpatient and outpatient charts of all adults with SCA admitted to a large university hospital during 2003. Hospitalization rates for adults with SCA in Maryland have increased significantly since approval of HU. While the total costs of inpatient care in Maryland are estimated to have increased by 31% above inflation from 1995 to 2003, the costs of inpatient care for adult SCA patients has increased by almost 60% above inflation. By comparison, there has been no significant increase in the pediatric hospitalization rate. We found that 70% of patients in one hospital who were appropriate candidates for HU were not taking the medication. Hospital utilization among adults with SCA has increased significantly. There are likely many factors that have played a role in this increase. One factor that appears to be involved is the underutilization of HU.

Pharmacotherapy of essential thrombocythaemia: economic considerations.

The clinical course of essential thrombocythaemia (ET) is mainly outlined by a predisposition to both thromboembolic, and more rarely, haemorrhagic complications. The individual clinical course is, however, variable, ranging from an event-free course to life-threatening thromboembolic episodes. In order to treat ET patients economically, it is necessary, above all, to consider if cytoreductive therapy is really indicated. Risk stratification according to clinical criteria such as age, previous ET-related events and platelet count may help to define patients at risk. In low-risk ET patients, a watch-and-wait strategy seems to be feasible. There is a clear indication for cytoreductive therapy in high risk ET patients as demonstrated in a Phase III clinical trial. Because of the lack of Phase III trials, it is not clear which of the cytoreductive drugs - hydroxyurea, pipobroman, IFN-alpha, pegylated-IFNs or anagrelide - is the best therapeutic option. Factors that influence the choice out of the available drugs are efficacy, safety and cost. The efficacy and safety data of the available drugs for ET are derived from Phase II studies or observational studies. IFN-alpha is the most expensive drug. Newer drugs like anagrelide or pegylated-IFNs are still expensive, but may have a better cost-benefit effect in patients < 60 years of age. Two cost-effectiveness analyses revealed a result in favour of anagrelide, however, in these cost-effectiveness models, assumptions were based on non-randomised trials. For patients > 60 years of age, hydroxyurea may be the best therapeutic option with regard to both the efficacy and cost-effectiveness.

Cost-effectiveness considerations in the treatment of essential thrombocythemia.

Factors that influence the choice of anagrelide, hydroxyurea, or interferon-alfa (IFN-alpha) for treatment of essential thrombocythemia include efficacy, toxicity, and cost. Anagrelide has the US Food and Drug Administration's approval to be used for treating patients with thrombocythemia secondary to chronic myeloproliferative disorders. In contrast, the use of IFN-alpha and hydroxyurea are considered "off-label." We performed an incremental cost-effectiveness analysis to compare anagrelide, hydroxyurea, and IFN-alpha for treating essential thrombocythemia, in terms of estimated impact on life expectancy. The case used for this analysis was of a 40-year-old man with essential thrombocythemia. Clinical assumptions were based on information obtained from nonrandomized clinical trials, and the economic assumptions were derived from information abstracted from observational studies. Lifelong treatment use of anagrelide versus hydroxyurea would cost approximately $72,000 per additional year of life gained, while the use of IFN-alpha was found to be both more costly and less effective than anagrelide. The results were very sensitive to the risk of leukemia caused by hydroxyurea, with an incremental cost-effectiveness of anagrelide compared with hydroxyurea of $156,969 per additional year of life gained if the lifetime leukemia risk drops from a baseline of .08 to.05. Given that many commonly used medical interventions cost in the range of $50,000 to $100,000 per year of life gained, and the generally poor outcome associated with treatment-related leukemia that can result from hydroxyurea, anagrelide could be considered a therapeutic alternative that is clinically effective at an acceptable cost.

Hydroxychloroquine, hydroxycarbamide, and didanosine as economic treatment for HIV-1.

Most people who have HIV-1 and live in less-developed countries cannot afford standard combination antiretroviral therapy, and more economical approaches to treatment are therefore needed. We treated 22 patients who were infected with HIV-1 (viral load < 100000 copies/mL and CD4 count >150 cells/microL) with hydroxychloroquine (200 mg), hydroxycarbamide (hydroxyurea) (500 mg), and didanosine (125-200 mg), taken twice daily. Treatment was well tolerated, with few serious adverse events. Viral load showed a sustained decrease of 1 3 log, and CD4 count was maintained (percentage increase; 2 9%) over 48 weeks in the 16 evaluable patients. This new combination of drugs could be suitable for countries that have restricted resources, but should first be further investigated.