Effective use of hydroxyurea for SCA in low-resource countries

Abstract

Purpose of Review.

Over the past several decades, hydroxyurea has emerged as a safe 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 safe, feasible, and beneficial treatment in low-resource countries. Hydroxyurea is therefore vital to reaching the targets for control of SCA outlined by the World Health Organization. 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.

INTRODUCTION

Hydroxyurea (hydroxycarbamide) is a potent, disease-modifying therapy for sickle cell anemia (SCA). Initially reported almost 40 years ago [1], numerous prospective clinical trials have documented consistent laboratory and clinical benefits of hydroxyurea in all age groups [2–6], with best results observed in young children with SCA who are treated at maximum tolerated dose [7,8]. Hydroxyurea induces fetal hemoglobin production, which inhibits sickle hemoglobin polymerization and prevents erythrocyte sickling with additional salutary effects on leukocytes and endothelium [9]. Predictable hydroxyurea treatment effects include decreased hemolytic anemia, reduced inflammation, fewer acute and chronic disease complications, improved quality of life, and overall prolonged survival [10]. In 2014, the National Heart, Lung, and Blood Institute of the National Institutes of Health published evidence-based guidelines that include clear and definitive treatment recommendations: offer hydroxyurea to all children with SCA, regardless of current clinical severity, and treat adults with expanded clinical indications [11]. Similar guidelines have recently been issued by the American Society of Hematology [12] and the British Society of Haematology [13].

In 2020, hydroxyurea is now unquestionably the standard of care for SCA in the developed world. In low-resource countries, however, where the burden of disease is greater [14,15], treatment options are limited, and many patients with SCA die early in childhood [16]. Hydroxyurea is safe, efficacious, affordable, and scalable, making it an ideal treatment option for low-resource countries [9]. Unfortunately, despite repeated demonstrations of hydroxyurea treatment efficacy – defined as significant benefits in clinical trial settings – there is a drastic paucity of hydroxyurea utilization, knowledge, and availability in low-resource countries, leading to a subsequent reduction in treatment effectiveness – meaning widespread access with true reduction in morbidity and mortality for real-world patients. In this review, we discuss the need for broad and bold implementation strategies to address the gaps between clinical efficacy and the actual effectiveness of hydroxyurea, to make this life-saving medication available to all who need it. As new and potentially curative treatments for SCA are being developed, it is imperative that we first develop the capacity to utilize hydroxyurea effectively around the globe, before another generation of lives is lost.

TEXT OF REVIEW

WHO Recommendations

In 2006 and 2010, the World Health Organization (WHO) issued formal position statements regarding the status of SCA care and treatment in sub-Saharan Africa [17,18]. These documents described a woeful state of neglect globally, but also outlined a multi-pronged strategy to provide care for patients suffering from this disease. To meet their targeted goals, the WHO recommended the development of national strategies guided by a series of priority interventions to improve the surveillance, diagnosis, and treatment of SCA.

Although efforts to improve early diagnosis coupled with life-saving immunizations and antibiotic prophylaxis can greatly reduce the morbidity and mortality of SCA, only disease-modifying therapy with hydroxyurea can reduce the disease burden. A full decade has passed since the WHO targets were set, and while some progress has been made in several countries, efforts to control SCA and to fulfill the WHO guidelines are incomplete without wide access to hydroxyurea. The time is now to augment the efforts of the international community to increase the utilization of hydroxyurea treatment for SCA. Table 1 includes the WHO-recommended interventions written for sub-Saharan Africa that are relevant to the safe and expanded use of hydroxyurea in low-resource countries.

Table 1.

WHO recommended priority interventions for Sickle Cell Anemia (SCA) that involve hydroxyurea treatment

Recommendation	Rationale	Comment
Improved Healthcare Provision
Clinical management for patients of all ages	Hydroxyurea is a potent disease-modifying therapy with clinical benefits including reduced painful crises, stroke, malaria, transfusions, and mortality	Guidelines for managing hydroxyurea at all ages must be appropriately adapted to low-resource settings
Laboratory management	Hydroxyurea at maximum tolerated dose provides optimal clinical efficacy, but requires laboratory resources for complete blood count and differential	These tests are also needed as part of general monitoring of individuals with SCA
Training of health professionals	Health care professionals must be educated on the pathophysiology and clinical management of SCA, and how hydroxyurea reduces the disease burden	Training on the utilization of hydroxyurea must be incorporated into this foundation, including familiarity with dosing, benefits, and potential side-effects
Research promotion	Research studies conducted within low-resource settings are needed to increase the fund of knowledge, build local capacity, and improve patient outcomes	High-quality hydroxyurea research requires infrastructure, training, and partnerships between government and academia, especially from high-income countries
Accessibility of Healthcare Services
Provision of affordable medicines	Hydroxyurea is an affordable medication in high-income countries, but its modest price is not affordable by families living in low-resource settings	Medication pricing must be lowered to ensure affordability, through interventions by pharmaceutical companies and global agencies, in partnership with Health Ministries
Geographic access	Hydroxyurea can be distributed to patients living far from established clinics, but clinical and laboratory monitoring should occur at least quarterly	Clinical models with laboratory support are required in both rural and urban settings, ideally with substantial management provided in primary health settings
Financial access	SCA should be included in national frameworks for the management of noncommunicable diseases	This includes the sustainable provision and financing of hydroxyurea as the only available disease-modifying therapy and its associated monitoring
Capacity building	Efforts to increase the availability of hydroxyurea should be encompassed within the context of building comprehensive treatment programs	Education and training will require written guidelines from WHO and other groups, plus on-site training
Public and Political Support
Public awareness	The benefits of hydroxyurea treatment, including improved quality of life, need to be communicated to families to increase diagnosis, genetic testing, and treatment.	Reduction of the stigma and pessimism for SCA as a life-threatening illness by having a viable treatment cannot be overstated.
Advocacy for resource mobilization	As public awareness of SCA and effective treatment increases the demand for hydroxyurea, the supply of hydroxyurea must also increase to prevent shortages and price inflation	International partnerships must ensure adequate global production and distribution of hydroxyurea
Political advocacy	As the benefits of hydroxyurea treatment become recognized, advocacy efforts must increase for proper governmental support of medication availability and access	Public awareness will mobilize resources for hydroxyurea and launch advocacy for future treatment options currently in development
Targets for 2020
Adopt comprehensive health care management	WHO member states should include hydroxyurea in their national SCA control programs *	Hydroxyurea is the best disease-modifying therapy available to date, with proven efficacy in patients of all ages
Develop national control programs	Payment for hydroxyurea prescriptions and monitoring should be covered in national comprehensive health care plans **	Barriers to treatment include costs of hydroxyurea and periodic laboratory monitoring

^*Goal: 25% of member states;

^**50% of member states

Efficacy in low-resource countries

Over the past decade, partly in response to the WHO recommendations, several clinical trials involving hydroxyurea treatment for SCA have been conducted in low-resource settings, primarily in the Caribbean and sub-Saharan Africa (Table 2). All of these studies were initiated by investigators from developed countries, typically from academic institutions in the United States [19–31]. Taken together, published data from these trials have consistently documented both the safety and the remarkable efficacy of hydroxyurea to reduce the morbidity and mortality of SCA. Fears about excessive treatment-related adverse events, in particular an increased risk of severe malaria infections [32], have proven to be unfounded and long-term safety data are reassuring. Data from the recent NOHARM and REACH treatment cohorts have documented clinical efficacy in sub-Saharan Africa with reduced risks of malaria, stroke, transfusions, and death in association with hydroxyurea treatment [23,25,26].

Table 2.

Clinical research trials involved low-resource settings within the Caribbean and sub-Saharan Africa. NA = not available.

Research Trial	Acronym	CT.gov	Location	Reference
Sparing Conversion to Abnormal TCD Elevation	SCATE	NCT01531387	Jamaica, Brazil	19
Stroke Prevention in Nigeria	SPIN	NCT01801423	Nigeria	20
Realizing Effectiveness Across Continents with Hydroxyurea	REACH	NCT01966731	Angola, Democratic Republic of Congo, Kenya, Uganda	21–23
Novel use Of Hydroxyurea in an African Region with Malaria	NOHARM	NCT01976416	Uganda	24–26
Risk Clinical Stratification of Sickle Cell Disease in Nigeria	NA	NCT02149537	Nigeria	27
European Sickle Cell Disease Cohort – Hydroxyurea	ESCORT-HU	NCT02516579	French Guiana	NA
Expanding Treatment for Existing Neurological Disease	EXTEND	NCT02556099	Jamaica	28
Primary Prevention of Stroke in Children with SCD in sub-Saharan Africa II	SPRING	NCT02560935	Nigeria	NA
Moderate dose hydroxyurea for Secondary Stroke Prevention in Children with Sickle Cell Disease in sub-Saharan Africa	SPRINT	NCT02675790	Nigeria	NA
Stroke Avoidance in Children from REpublica Dominicana	SACRED	NCT02769845	Dominican Republic	29, 30
Optimizing Hydroxyurea Therapy in Children with SCA in Malaria Endemic Areas	NOHARM MTD	NCT03128515	Uganda	31

Increasing hydroxyurea use

The evidence that supports hydroxyurea treatment for patients with SCA living in low-resource countries, particularly in sub-Saharan Africa, is compelling. To increase hydroxyurea use, however, efforts must intentionally address critical barriers to implementation, including increasing awareness, acceptance, uptake, and affordability. Maximizing the effectiveness of hydroxyurea in developing countries will require development and distribution of evidence-based guidelines that are appropriately adapted to low-resource settings, training of the medical workforce, establishment of basic laboratory and clinical infrastructure supported by sustainable payment models, amplification of public awareness and advocacy efforts, and widespread access to affordable medication. Specific gaps to address include the following topics:

Endorsement.

Increasing the utilization of hydroxyurea in developing countries starts with ensuring that physicians and other healthcare providers are aware and convinced that hydroxyurea is a safe medication and that treatment is strongly recommended for patients with SCA. A clear statement of recommendation for using hydroxyurea issued by the Ministry of Health or another governing body, ideally within a national treatment guideline, would establish access to hydroxyurea as an important treatment goal and lay the foundation for widespread change.

Training.

Local healthcare providers should be educated about SCA and trained on hydroxyurea treatment guidelines adapted to low-resource settings. Without explicit training, clinical practice will vary based on personal style, educational background, and local resources and lead to substandard, or even harmful, outcomes.

Until hematology subspecialty care is more rigorously established within medical training, the initial target should be general practitioners: physicians, medical or clinical officers, nurse practitioners, and other trained and licensed providers.

Medical and nursing school curricula and textbooks should be updated to provide information about the pathophysiology of the disease and principles of management. Existing prescribers should complete written, in-person, or online trainings; national certification exams in high-prevalence areas should expect that healthcare providers understand and are comfortable with hydroxyurea treatment and monitoring.

Finally, to sustainably address the gap in the hematology workforce, fellowships that specialize in hematology are necessary. Training programs are already being developed across Africa through international North-South and South-South collaborations. Programs such as the American Society of Hematology Visitor Training Program can help provide a cadre of physicians who are trained to treat patients with SCA and properly use hydroxyurea. To ensure the ongoing production of knowledge, research within low-resource countries should be supported in driving scientific inquiry, collaborating with international partners, and incorporating the voices of their patients [33, 34].

Guidelines.

Effective prescribing and monitoring of hydroxyurea must be adapted and simplified to be appropriate for low-resource settings and applicable to patients at all stages of life. These guidelines should be accessible and straightforward, such that multiple levels of healthcare providers can be trained to reliably follow the guidelines.

It is not enough for guidelines to exist; they must also be widely distributed. Distribution of guidelines is an ideal role for an international organization with recognized authority. For example, to assist healthcare providers, the WHO develops and distributes disease-specific guidelines, which are freely available online and in print. Furthermore, because many medical staff are not trained in pediatrics, the WHO also produces a widely-used, pediatric resource called the Pocketbook of Hospital Care for Children [35]. Unfortunately, there is a notable absence regarding the care of patients with SCA in WHO guidelines and within this pediatric pocketbook, which urgently needs to be rectified.

Dosing.

A critical adjunct to proper training of healthcare providers about hydroxyurea treatment relates to the medication itself, specifically its proper dosing and monitoring. Figure 1 illustrates a pragmatic hydroxyurea treatment algorithm, adapted mainly from evidence-based practices in high-income countries [11–13] and data from low-resource countries [23,25]. This simplified treatment protocol gives an overview of dosing goals and includes areas of flexibility with optional monitoring. Studies that assess practical dosing in real-world settings will help determine an effective treatment strategy that is feasible, safe, and beneficial, and will address barriers to wider use [36–38].

Figure 1.

Pragmatic hydroxyurea dosing algorithm for low-resource countries. The benefits and risks of hydroxyurea should be discussed with patients and families before initiating therapy. * recommended but not required ** target ANC range is 2.0–3.0 ×10⁹/L

Toxicities.

There are numerous theoretical concerns about adverse effects of hydroxyurea including infertility, mutagenicity, carcinogenicity, or teratogenicity. Fortunately, decades of safe treatment in many thousands of patients have documented no increased risks for any of these outcomes.

Regarding the use of hydroxyurea during pregnancy, there is no evidence to support teratogenicity in humans, especially when considering that hydroxyurea exposure frequently occurs in the first trimester, before mothers realize they are pregnant and notify their healthcare providers. Additionally, hydroxyurea during the third trimester of pregnancy may be beneficial to maintain maternal health and improve pregnancy outcomes for both mother and child [12]. Despite evidence for normal pregnancy outcomes following hydroxyurea exposure [39], the current standard of care is to discontinue hydroxyurea in pregnant women and those attempting to conceive.

Lastly, hydroxyurea use while breastfeeding has historically been contraindicated, yet a recent study documented that hydroxyurea transfer into breastmilk occurs at a very low amount [40], and well below the safe thresholds established by WHO [41, 42]. Accordingly, the current dogma that hydroxyurea therapy is contraindicated during lactation needs to be revised; this treatment shift is particularly important for low-resource countries. As such, we recommend breastfeeding mothers to continue hydroxyurea.

Program Building.

To follow the above guidelines and effectively utilize hydroxyurea, local programs will need to develop sustainable models of care delivery and clinical infrastructure. Each catchment area should have a comprehensive central unit with trained staff, functioning laboratory, and a sustainable medication supply that is accessible to both rural and urban patient populations (Table 3). Existing district hospitals that already serve as clinical hubs are logical places to establish programs. As regions develop further, laboratory monitoring for patients who live farther from the district hospital could be decentralized and performed at local hospitals. Where possible, funding for clinical staff, medication supply, and laboratory monitoring must be included in national insurance coverage plans, so that this life-saving treatment is affordable for low-income patients who need it the most.

Table 3.

Basic requirements of a sickle cell treatment program in low-resource settings

	Essential requirements	Where available
Personnel	Trained and licensed prescriber (physician, clinical officer) Lab technician Nurse Community health worker	Nurse practitioner Social worker Genetic counselor Psychologist
Laboratory equipment and reagents	Hemoglobin electrophoresis Complete blood count (CBC) White blood cell differential Malaria testing (RDT or blood smear)	Reticulocyte count Alanine transaminase (ALT) Serum creatinine Quantitative fetal hemoglobin (HbF)
Pharmacy	Trained and licensed pharmacist Pill cutter	Liquid formulations of hydroxyurea

The CBC (also known as the full blood count) should include hemoglobin, mean corpuscular volume (MCV), leukocytes, and platelet count. RDT = rapid diagnostic kit

Public awareness and stigma.

In addition to educating physicians about hydroxyurea, patients and families also must accept the treatment; stigma about both SCA and hydroxyurea treatment are important barriers to the effective use of hydroxyurea. In the United States, health-related stigma can contribute to suffering, delay the seeking of treatment, and lead to medication non-compliance [43–47].

In low-resource countries, where knowledge about SCA is less widely available, the burden of stigma may be higher, amplifying impedance to self-care and hydroxyurea adherence. Increased public awareness through patient and family support groups, school nurse programs, and youth groups should be encouraged with particular attention to supporting affected females, who may face higher rates of stigma in certain countries [48].

Stigma is not only promoted at the community level; a country’s laws have the power to perpetuate stigma or to protect patients from it. As such, providers should remain aware of the policies in place that make it more challenging for their patients to access treatment and to maintain their privacy. For example, patients should not need to obtain their hydroxyurea at separate pharmacies or to have their illness identified during laboratory monitoring. From the individual patient to the healthcare staff and from the community to the government, people should be educated and supported in understanding the disease to promote adherence and reduce stigma.

Drug access and affordability

Hydroxyurea is included on both the WHO Model List of Essential Medicines [49] and the Model List of Essential Medicines for Children [50], which include medications that are deemed fundamental for addressing the most important public health needs globally. These lists are intended to provide guidance to Ministries of Health and other stakeholders in low-resource countries regarding safe, efficacious, and cost-effective medications that should be available in each country. These lists are not mandates, however, and WHO provides no funding to obtain these medications or negotiate drug prices with pharmaceutical companies. Consequently, despite this medication’s presence on these lists, most countries have not registered hydroxyurea formally on their national drug formularies for treatment of SCA. In a recent review of medication availability in South-East Asia, 5 out of 11 countries reviewed had hydroxyurea in their individual national formularies, with a notable absence on India’s list, a country that shares a large SCA disease burden [51].

Of note, on the List of Essential Medicines, this medication is listed as “hydroxycarbamide” which is one of many alternative names for hydroxyurea and is listed as indicated for “hemoglobinopathies,” but not specifically for SCA. This nomenclature may be confusing to stakeholders who do not know that these drug names are interchangeable or that the main hemoglobinopathy suitable for hydroxyurea therapy is SCA, thus serving as an additional barrier to endorsement. We propose that the WHO change the listing of this medication from hydroxycarbamide to hydroxyurea in the List of Essential Medicines and state specifically that treatment is useful for SCA.

The cost of hydroxyurea serves as an additional barrier to access in local pharmacies in low-resource settings. Currently, in the United States the price of hydroxyurea is relatively inexpensive, but is highly variable among specific products. For example, current costs (February 2020) for a 500mg hydroxyurea capsule range from $0.78 for generic to $1.52 for brand-name products. Specialty formulations include $52.51 for 1000mg dispersible tablets and $2.00 for liquid formulations (100mg/mL).

A final barrier relates to the availability of hydroxyurea as a pharmaceutical-grade, chemical product on a global scale. Currently hydroxyurea is produced by 6 main manufacturers within 3 regions (China, India, Europe) [52]. Although several companies can distribute the purified compound around the world, more companies need to synthesize and produce the raw compound for medicinal use. Compounding can be completed on small or large scales, and solving this challenge requires creative solutions, such as the academic partnership with a pharmacy school in Tanzania [53] or public-private collaborations as proposed in Ghana [54]. Manufacturing within sub-Saharan Africa is a high priority, to lower distribution costs and to empower the continent to provide life-saving treatment for millions of individuals living with SCA.

CONCLUSIONS

SCA disproportionately affects individuals who live in low-resource countries around the world where, for a multitude of reasons, the majority of patients die in childhood. This massive and neglected loss of lives is not only tragic, but also regrettable, considering the existence of technology to perform early diagnosis, interventions to prevent its complications, and therapy to modify the disease course, specifically hydroxyurea. Over a decade ago, the World Health Organization released a statement outlining priority interventions to provide comprehensive healthcare to patients with SCA, but advancements toward these targets have been inexplicably slow. We contend that without developing the local capacity to provide hydroxyurea to all individuals with SCA, progress will continue to stagnate, screening programs will be futile, and the opportunity to save the current generation of patients with SCA will be lost. Hydroxyurea is the only inexpensive and scalable treatment for SCA currently available, and must be provided as the primary, disease-modifying treatment to serve as a foundation for potentially curative future therapies.

KEY POINTS.

1. To increase access of hydroxyurea for SCA, recommendations for its use should be clear, prescribers must be educated about safe dosing and monitoring, and treatment guidelines must be adapted and simplified for low-resource settings.

2. For capacity building, clinical infrastructure must be developed so that central clinics with trained staff and functioning laboratories are accessible to patients across designated catchment areas.

3. Unaddressed stigma regarding SCA is an important barrier to hydroxyurea use and adherence, and interventions aimed at community education and socialization are crucial for the well-being of these suffering patients.

4. Social support and advocacy groups should be reinforced to increase public awareness, improve the quality of life of patients with SCA, promote adherence to hydroxyurea, and provide ongoing support for resources allocated to treatment of the disease.

5. Affordable access to hydroxyurea should be ensured through clarified recommendations for national formularies, national coverage of the medication and laboratory monitoring, and increased drug production and distribution for low-resource countries.