Current challenges and new approaches to implementing optimal management of sickle cell disease in sub-Saharan Africa

Abstract

Sickle cell disease (SCD) is the most common life-threatening monogenic disorder in the world. The disease is highly prevalent in malaria endemic areas with over 75% of patients residing in Sub-Saharan Africa (SSA). It is estimated that, without proper care, up to 90% of children with SCD will not celebrate their fifth birthday. Early identification and enrolment into comprehensive care has been shown to reduce the morbidity and mortality related with SCD complications. However, due to resource constraints, the SSA is yet to implement universal newborn screening programs for SCD. Furthermore, care for patients with SCD in the region is hampered by the shortage of qualified healthcare workers, lack of guidelines for the clinical management of SCD, limited infrastructure for inpatient and outpatient care, and limited access to blood and disease modifying drugs such as Hydroxyurea which contribute to poor clinical outcomes. Curative options such as bone marrow transplant and gene therapy are expensive and not available in many SSA countries. In addressing these challenges, various initiatives are ongoing in SSA which aim to enhance awareness on SCD, improve patient identification and retention to care, harmonize the standards of care for SCD, improve the skills of healthcare workers and conduct research on pertinent areas in SCD in the SSA context. Fortifying these measures is paramount to improving the outcomes of SCD in SSA.

Introduction

Sickle cell disease (SCD) is the most prevalent genetic disorder worldwide. The disease, which is autosomal recessive in nature, occurs due to a single base-pair mutation in the β-globin gene, resulting in the substitution of the amino acid valine (HbA) for glutamic acid (HbS) at position 6 in the β-globin chain [1]. SCD is therefore said to occur when an individual has either inherited 2 copies of HbS (HbSS), has 1 copy of HbS with partial or complete deletion of the other β globin gene (HbS/β-thalassemia) or has 1 copy of HbS with another mutated β globin gene such as HbC or HbD in compound heterozygosity (HbSC, HbSD and others) [2]. Globally, it is estimated that there are over 300,000 births each year of individuals with SCD with over 75% of these being in sub-Saharan Africa (SSA). It is estimated that this number will increase to 404,200 births per year by 2050 with concomitant increase in disease burden in SSA to 85% [3]. Countries with the highest prevalence of sickle allele, above 10%, are almost exclusively found in SSA [3]. The highest prevalence of HbS is seen in Nigeria followed by the Democratic Republic of Congo, Angola and Tanzania. In Tanzania, the prevalence ranges between 13% and 20% and is highest in Northwestern regions around Lake Victoria [4–6]. SCD was acknowledged by the World Health Organisation (WHO) as a disease of public health importance in 2006 due to its high morbidity and mortality, and the resulting significant social and economic implications [7]. Evidence from high income countries indicate that early identification and linkage to comprehensive care can significantly improve the morbidity and mortality due to SCD [8]. However, these interventions are not optimally implemented in many countries in SSA. This article reviews the current status of care for SCD in SSA, innovations made and their progress as well as existing challenges that still need to be addressed.

Clinical presentation of SCD

Clinical presentation of SCD is due to polymerization of deoxygenated HbS leading to recurrent vaso-oclussion and haemolytic anemia [9]. These presentations may be acute or chronic in nature and vary depending on the organ affected. Generally, the spectrum of clinical presentations in SCD includes painful events, recurrent anemia, recurrent infections caused by impaired immunity due to hyposplenism, acute chest syndrome, splenic sequestration, priapism, leg ulcers and end organ damage such as nephropathy, avascular necrosis, heart disease and stroke [10,11]. Individuals with sickle cell trait (HbAS) are usually asymptomatic. Of the SCD genotypes most prevalent in SSA (HbSS, HbS/β-thalassemia and HbSC), it is the homozygous SCD (HbSS; sickle cell anemia) that has the most severe clinical manifestation [2]. Generally, the symptoms of SCD start at around 4 to 6 months of age following a significant replacement of HbF by HbS [1,10,12]

Prevention and early diagnosis of SCD

Premarital counselling, maternal carrier testing, prenatal screening and neonatal screening are effective in prevention and early identification of newborns with SCD. In high income countries, these are offered universally through antenatal and neonatal care programs and the identified neonates with SCD are directly linked to comprehensive care [8].

Newborn screening (NBS) and early infant diagnosis (EID)

Early identification of neonates and infants with SCD and linkage to early interventions have been shown to significantly reduce the mortality and improve the health-related outcomes among children with SCD in high income countries [8,13]. In the sixty-third World Health Assembly in 2010, the WHO urged member countries to raise awareness about the significance of newborn screening (NBS) programs for identification of infants born with congenital diseases as control measures to reduce the burden associated with inherited congenital diseases [14]. Moreover, in the sixtieth session of the WHO African Region (WHO-AFRO) in 2010, a strategy for addressing SCD that prioritized, among others, the NBS programs was developed [15].

Different initiatives for early preventive measures have been employed in SSA. Although not implemented as universal country interventions, NBS for SCD programs are available in countries with high burden of SCD in SSA. The most extensive NBS program is in Ghana which started in 1993 [5,16–19]. Pilot NBS programs have been implemented in Angola, Democratic Republic of Congo, Nigeria,Tanzania, Cameroon, Congo Brazzavile and Madagascar [5,6,9,16,19,20]. Experiences indicate that NBS using heel prick or umbilical cord blood collected on dried blood spot (DBS) cards is generally acceptable and feasible in SSA settings [5,6]

The pilot NBS programs in SSA have uncovered a number of challenges for large-scale roll out. One of the major challenges encountered is timing for screening. Due to short interval of hospital stay between delivery and discharge, and a high number of deliveries per day with the existing shortage of staff in most delivery facilities, it is not uncommon to miss a significant number of babies who are discharged before screening. Further, home deliveries are still common in many countries in SSA where babies involved will have no opportunity for screening after birth [21,22] To maximize the number of babies screened for SCD, other programs have extended screening age to 9 months and utilize the existing immunization clinics to capture babies who were not screened postdelivery [23]. This practice, referred to as Early Infant Diagnosis (EID), takes advantage of the fact that most infants are brought to immunization clinics and that babies identified with SCD up to the age of 9 months can still be linked to comprehensive care before significant complications have occurred [24]. Establishment of dedicated teams for NBS has improved the number of babies screened [17].

Besides logistical challenges in scheduling for screening, shortage of screening materials is another obstacle faced during NBS in SSA settings. Most settings in SSA use Isoelectric Focusing (IEF) as first line test and High-Performance Liquid Chromatography (HPLC) or Haemoglobin Electrophoresis as standard confirmatory tests. However, the cost for IEF is a limiting factor for nationwide scale up of NBS. Studies conducted to assess the efficacy of using less expensive options such as point-of-care (POC) tests such as HemotypeSC and sickle SCAN and DNA-based tests for NBS in Nigeria and Tanzania have revealed that there is a concordance of nearly 100% between POC tests and the gold standard HPLC [18,25,26]. The cost of POC test ranges between 1.4$ to 4.75$ per test [26]. Studies conducted in the Democratic Republic of Congo and Tanzania have shown that DNA-based tests are effective in identifying HbS mutation and cost half the price of IEF [25,27]. Further, these tests are not affected by HbF or blood transfusion hence over-coming the limitations faced by hemoglobin-based tests. However, challenges associated with sample collection, transfer, and storage should be addressed [27].

Giving feedback of results to the parents of newborns with SCD is also challenging. In most settings, communication with parents is done through mobile phones [5,17,18]. Challenges of implementing this mode of communicating results include lack of access to mobile phones by some parents, and in some instances, mothers offering wrong contact information or changing their phone numbers for various reasons such as not being ready to accept the results or fear of being abandoned by their male partners in case their babies are diagnosed with SCD. To improve the feedback process, mobile numbers of next of kin are recorded. In countries where community healthcare workers are available, results are provided to the parents at their home place if parents were not reachable through their mobile phones or do not go back to the healthcare facility for the results as scheduled [17].

Although early enrolment into comprehensive care has led to a significant improvement in morbidity and mortality of children with SCD in high income countries, this impact has not been demonstrated in SSA since the NBS programs are implemented at a limited scale. A large multi-national 5-year implementation project, the Consortium on Newborn Screening in Africa (CONSA), funded by the American Society of Hematology, is currently implemented in 7 SSA countries namely Ghana, Nigeria, Liberia, Uganda, Kenya, Tanzania and Zambia. The project aims to assess the birth incidence of SCD, its effects on mortality, overall 5-year survival as well as sustainability and cost of NBS and early intervention for each CONSA country [28]. Another large ongoing study conducted by the SickleInAfrica Consortium, funded by US National Heart, Lung and Blood Institute (NHLBI), is investigating the feasibility, efficacy and acceptability of POC tests for NBS in Mali, Ghana, Nigeria, Uganda, Tanzania, Zambia, and Zimbabwe. If implemented universally, NBS and its modifications such as EID have the potential to emerge as the culturally acceptable and cost-effective methods for early diagnosis of SCD and timely enrolment of afflicted babies into comprehensive care in SSA [28–31].

Premarital counselling

Premarital counselling is commonly practiced in Middle Eastern countries and it has proven to be among effective early preventive measures for hereditary hemoglobin disorders [32]. The goal of premarital counselling is to enable couples who are carriers of hemoglobinopathies make informed decision on whether or not to proceed with marriage knowing that there is a possibility of having a baby with the disease of interest. In SSA, premarital counselling is commonly practiced for HIV/AIDS and less often conducted in the context of inherited genetic diseases such as SCD. There is paucity of literature regarding premarital counselling for SCD in SSA. In this setting, premarital counselling is provided by certified genetic counsellors where available but also so often by healthcare workers who are not certified genetic counsellors as well as non-healthcare workers such as teachers and religious leaders [33,34]. The shortage of genetic counsellors contributes to limited implementation of this measure. Efforts to increase the number of certified genetic counsellors in SSA are ongoing. In Tanzania, there is a campaign to “break the sickle cycle ” where adolescents and young adults in secondary schools are given SCD education and screened for SCD [35]. This aims to increase awareness on SCD and the importance of knowing SCD status of both partners before having children. To improve premarital counselling for SCD, we suggest integrating premarital counselling for SCD within the already existing and well-established HIV counselling services.

Maternal carrier testing

Maternal carrier testing identifies pregnancies at-risk of SCD. Pregnant women with sickle cell trait or SCD are counselled for prenatal diagnosis or followed up for NBS after delivery. Antenatal clinics are suitable but often underutilized platforms for provision of health education on SCD since pregnant women attend several antenatal visits and can focus without diverting their attention to the newborns. In Tanzania, maternal SCD education and screening were found to be feasible and effective interventions in improving the uptake of NBS [36]. We recommend that maternal carrier testing should be offered to every pregnant woman who does not know her sickle cell status in SSA.

Prenatal diagnosis

Prenatal diagnosis is another measure for SCD prevention routinely practiced in high income countries. Invasive prenatal diagnosis using amniotic fluid or chorionic villus sampling is offered to carrier pregnant women if the father is also known to be a carrier. However, in cases where the father’s genotype is unknown, it poses a challenge to offer invasive prenatal diagnosis to carrier mothers due to perceived procedure-related risk of miscarriage [37]. There are ongoing research and debates regarding the introduction of non-invasive prenatal diagnosis in high income countries. Non-invasive prenatal diagnosis using cell-free foetal DNA circulating in maternal plasma for detection of SCD is predicted to improve uptake of prenatal diagnosis since it eliminates the perceived procedure-related risk of miscarriage [37–39]. Identification of SCD-affected pregnancy allows the parents to make informed decision on whether to terminate or continue with pregnancy to term knowing that their baby will need to be enrolled into comprehensive SCD care after delivery. Prenatal diagnosis is accepted in SSA. However, its applicability is limited to its utility as a measure for early diagnosis with the goal to enrol affected babies into comprehensive care. This is because in most SSA countries, voluntary termination of pregnancy based on the presence of foetal abnormalities is not legally and ethically approved. Medical termination of pregnancy is permitted only for the purpose of saving the mother from grave health threat [40]. Fortunately, there are opportunities for post-natal diagnosis before SCD manifestation which usually starts 4 to 6 months postdelivery, allowing adequate time for screening the new-borns and infants, and timely initiation of interventions through the culturally and ethically acceptable NBS and EID programs [31].

Supportive management

Supportive management is the mainstay of treatment for SCD. Without optimal standards of care, SCD causes significant morbidity and mortality in which 50% to 90% of children die before their 5th birthday [7,9,16,41]. Childhood mortality is several-folds higher in children with SCD compared to those without SCD [42]. In Tanzania, SCD contributes 7% of under-5 mortality [43]. Supportive treatment for SCD aims to reduce the frequency of complications and improve the quality of life [9,44]. It includes pain management, prevention of infections specifically in children below 5 years of age, blood transfusion therapy, use of disease modifying agents such as hydroxyurea (HU), voxelotor, crizanlizumab and L-Glutamine, regular health checks to prevent, identify and manage complications, psychosocial management and health education [9,44–48].

Pain management

Pain is the commonest and usually the earliest clinical presentation of SCD resulting from vaso-occlusion [1]. Pain episodes are important predictors of adverse outcomes in children with SCD [10]. Pain management in SCD follows the WHO analgesic ladder which specifies treatment based on the pain intensity [49]. Mild pain is treated with non-opioids such as non-steroidal anti-inflammatory drugs (NSAIDs) with optional adjuvant analgesia. Weak opioids are added in management of moderate pain whereas strong opioids are added in the management of moderate to severe pain. Assessment, treatment, reassessment, and adjustment of medications according to pain intensity and response to analgesia is recommended [1]. Additionally, the precipitating causes such as stress, infections and dehydration should be managed accordingly [10,50,51]. Whereas the management of mild pain is generally optimal due to readily availability of NSAIDs, the management of severe pain is generally challenging in many healthcare facilities in SSA due to limited availability of opioids [10]. We recommend improved access to opioids for optimization of the clinical management of severe pain in patients with SCD.

Infection prevention

Without interventions, infections are the leading cause of mortality in under-fives with SCD. Due to impaired splenic function, patients with SCD are susceptible to infections with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae [10,52]. Oral penicillin prophylaxis is an effective intervention in preventing against invasive pneumococcal disease [46,53]. In SSA, oral penicillin (Pen V) is recommended to all under-fives with SCD. A study within the SickleInAfrica consortium identified inadequate knowledge and doubt about the necessity of penicillin prophylaxis among healthcare workers as the potential barriers to its large-scale utilization [54]. The consortium is currently undertaking a follow-up implementation study on the uptake and adherence to penicillin. Due to an increase in the irrational use of antibiotics and self-medication habits, penicillin resistance is an emerging challenge that needs to be closely monitored [55]. Penicillin-non-susceptible pneumococci were isolated in several studies conducted in Tanzania [56,57]. To minimize the risk of penicillin resistance, we suggest authorities should tighten control for its usage only by prescription.

Vaccination against S.pneumoniae and H.influenza type b is recommended to all infants with SCD. These vaccines are incorporated in the national vaccination programs for under-fives in most countries in SSA and their uptake is generally excellent, approaching between 78% in Guinea to over 90% in countries such as Tanzania, Uganda, Democratic Republic of Congo, South Africa, Rwanda, Burundi, Ghana, Zimbabwe, Zambia, Senegal, Namibia, Cameroon and Kenya [22]. In Tanzania, pneumococcal conjugate vaccine-13 (PCV-13) and H.influenza type b (Hib) vaccines were incorporated in the extended program of immunization in 2012 and are given at 6, 10, and 14 weeks postdelivery. Hib is given as a pentavalent Diphtheria-Tetanus-Pertussis-Hepatitis B-Hib vaccine. PCV-13 protects against 13 serotypes of S.pneumoniae including 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 18C, and 23F. Pneumococcal infections with multiple serotypes including those not covered by PCV-13 have been observed in SSA and elsewhere [58–60]. Pneumococcal polysaccharide vaccine 23 (PPSV-23) protects against 23 serotypes of pneumococcus. This vaccine is attractive due to its broad coverage of serotypes, but its immunogenicity in early years of life is limited due to the immature immune system [61]. In Tanzania, PPSV-23 is recommended as a booster pneumococcal vaccine since PCV-13-induced immunity wanes off over time [62]. PPSV-23 vaccine is however not incorporated in national immunization programs in many countries and therefore has to be paid for out of pocket. We suggest inclusion of booster doses of PCV-13 and PPSV-23 in children with SCD in the national immunization programs in order to optimize the durability of vaccine-induced protection against the life-threatening pneumococcal disease among children with SCD in SSA.

SCD is prevalent in malaria endemic areas [3]. Malaria infection is among the major causes of morbidity and mortality in patients with SCD in SSA [63]. Although malaria chemoprophylaxis is recommended to all patients with SCD who live in malaria endemic areas [15], the practice varies in different SSA countries. The resistance of Plasmodium falciparum to chloroquine caused many SSA countries to stop using chloroquine prophylaxis [10]. In some countries, malaria prevention is based on non-pharmacological measures including use of insecticide-treated nets, whereas in other countries drugs such as proguanile, mefloquine, sulphadoxine-pyrimethamine and artemether-based therapies are used for malaria prophylaxis [10, 64]. Currently, there is an ongoing study conducted by the SickleInAfrica consortium assessing the practice and efficacy of malaria chemoprophylaxis among the member countries.

Hydroxyurea

Hydroxyurea is the only disease modifying agent that is available in SSA. Its efficacy and effectiveness have been shown in both children and adults with SCD even in SSA settings [65–67]. However, hydroxyurea is underutilized in SSA, even in countries with the highest burden of SCD such as Nigeria, Democratic Republic of Congo, Angola, and Tanzania [66,68–72]. Factors hindering utilization of hydroxyurea in SSA are many and include health systems barriers, healthcare providers’ barriers and patients’ barriers [73–76]. Health system barriers include limited availability, high cost of the drug and not being covered by health insurance schemes. Healthcare providers’ barriers include negative attitudes as well as inadequate knowledge and expertise to prescribe hydroxyurea. Patients’ and caregivers’ barriers include negative beliefs towards hydroxyurea, lack of health insurance coverage and inadequate knowledge regarding hydroxyurea use and SCD in general. Several initiatives to improve use of hydroxyurea in SSA are ongoing. These include provision of free hydroxyurea from various projects, local manufacturing of hydroxyurea, inclusion of hydroxyurea in health insurance schemes and provision of health education on hydroxyurea utilization to healthcare workers, caregivers and patients with SCD [69,72,77]. In Tanzania, various initiatives have been undertaken to improve hydroxyurea utilization. These include inclusion of hydroxyurea in the National Essential Medicines List and National Guidelines for Clinical Management of SCD, and its procurement by the National Medical Stores Department which supplies medicines to all public health facilities. Of recent, restrictions for hydroxyurea provision were removed by the National Health Insurance Fund (NHIF), and there is an ongoing discussion on implementation of universal health insurance which is expected to be an important step towards achieving large-scale access and utilization of HU by all patients with SCD.

Folic acid supplementation

Folic acid is widely used in management of SCD to prevent folate deficiency that may result from increased erythropoiesis [1]. Studies have highlighted mixed evidence of the benefit of folic acid supplementation in SCD patients [78–80]. However, due to high prevalence of macro and micronutrients deficiencies which accounts for up to 45% of child mortality in Africa, folic supplementation is encouraged [81]. In many SSA countries, daily 5mg of folic acid is prescribed to SCD patients. However, it is underutilized in some countries such as Democratic Republic of Congo where more than a half of patients were reported to not use folic acid [71]. We suggest that folic acid supplementation should be prescribed to all SCD patients in SSA.

Blood transfusion

Hospitals require adequate blood supply for proper management of SCD patients with medical complications including acute anemia, stroke, and acute chest syndrome, or complications that require surgical interventions such as emergency splenectomy or elective surgeries such as hip replacement surgery. Recommended interventions to improve blood supply in SSA include encouraging voluntary donation instead of the family replacement donation practice which accounts for more than 80% of all donations, use of social media and mass media to increase awareness and knowledge regarding blood donation, developing blood donor’s retention policy and reduction of unnecessary transfusions [82,83].

Exchange transfusion is a specialized service that is of particular benefit to patients with severe SCD to prevent complications such as acute chest syndrome and stroke [9]. The use of automated exchange blood transfusion is limited in SSA. However, efforts to incorporate manual exchange blood transfusion into routine care is ongoing. In Tanzania, manual exchange blood transfusion was first reported in 2017, and since then it has been performed in both public and private tertiary health facilities in patients with either acute or chronic complications [84]. Shortage of blood and limited resources for extended red cell phenotyping and antibody identification remain major challenges. Since extended red cell phenotyping is not routinely done in many SSA countries, patients with SCD who have history of recurrent blood transfusion are at increased risk of developing red cell alloantibodies and subsequently developing immunological transfusion reactions [85–90].

Screening for stroke

Screening for cerebrovascular disease using trans-cranial doppler (TCD) ultrasound is indicated in children with SCD [50,91]. Patients with high risk of developing cerebro-vascular accident (CVA) are advised to be enrolled in exchange transfusion or chronic top up transfusion programs together with the use of hydroxyurea to ensure reduction of HbS levels to below 30% [9]. Limited availability, affordability and expertise for TCD delay early identification of and interventions for patients with high risk of developing CVA. Currently, TCD ultrasound is available at tertiary hospitals in most countries in SSA. Thus, patients are referred to zonal and national hospitals for TCD ultrasound screening. Increased deployment of TCD ultrasound machines to district and regional hospitals concurrent with training of sonographers should be scaled up in SSA.

Psychosocial care

Being a chronic illness that starts early in childhood, SCD has a significant psychosocial effect on patients and caregivers [92]. Psychosocial factors such as beliefs and practices affect health seeking behaviors, medication use and overall quality of life [74,93,94]. Studies conducted in Sierra Leone and Nigeria indicate that families of patients with SCD experience significant psychosocial burden and distress [92,93] Psychosocial care is recommended in order to improve health related quality of care of patients with SCD [1].

Outpatient care

Currently, in many SSA countries, patients with SCD are attended at general pediatric or medical clinics due to shortage of HCWs such as haematologists, social workers and nurses, and shortage of space for establishment of dedicated SCD clinics. This affects standards of care provided to patients with SCD. Studies conducted in Democratic Republic of Congo have shown that SCD patients who are seen in dedicated SCD clinics receive better healthcare than patients seen in general clinics [71,95]. We propose the establishment of dedicated SCD clinics in all levels of healthcare facilities especially in regions with high prevalence of SCD.

Over time, individuals with SCD are at risk of major organ damage [10]. The commonly affected organs include the heart, kidneys, brain, eyes, and long bones. This necessitates establishment of designated specialized clinics for management of chronic complications associated with SCD in SSA. Although it is not widely implemented, tertiary hospitals in some SSA countries have started to implement specialized clinics for SCD. In Tanzania, there are designated specialized cardiac clinics for SCD with heart complications, as well as designated antenatal clinics for pregnant women with SCD, both located at the Muhimbili National Hospital. To optimize the available resources, the establishment of these designated specialized services in SSA should be based on the needs and clinical epidemiology of the chronic SCD complications in respective countries.

Health education on SCD

Management of patients with SCD will not be successful with limited knowledge and awareness regarding SCD among healthcare workers, caregivers, and patients. Inadequate knowledge is among the major challenges in providing and achieving optimal standards of care to SCD patients. In Tanzania, only a quarter of healthcare workers in regional hospitals were found to have adequate knowledge on supportive management of SCD [96]. The situation is almost the same in other SSA countries such as Nigeria, Ghana, Democratic Republic of Congo and Sierra Leone where healthcare workers, SCD patients and their caregivers were also found to have low level of knowledge on various aspects of SCD management [54,68,74,93,97,98]. Health education has been shown to have a significant effect on increasing the knowledge, improving attitudes, awareness and the quality of care to patients with SCD [99–102]. To improve knowledge, various health education programs are ongoing through SickleInAfrica and other platforms in SSA [103]. Recently, the SickleInAfrica consortium published standards of care recommendations for multi-level management of SCD, from home to tertiary hospitals, in the SSA context [50]. Additionally, PEN-Plus project is providing healthcare workers education and capacity building for clinical services for SCD, diabetes and rheumatic heart disease in SSA [104]. REDAC is another program in SSA that provides healthcare workers training, and educational therapy to parents of patients with SCD in Central Africa and Madagascar [20]. The success of Jamaica, a Low-and-Middle-Income Country (LMIC), in improving outcomes of patients with SCD provides hope that countries in SSA can also achieve better outcomes through systematic implementation of standard of care recommendations [105].

Curative management

Advanced curative therapies for SCD include hemopoietic stem cell transplant (HSCT) and gene therapy [9,106]. Allogeneic HSCT is currently the only approved curative option for SCD with high success rate [107]. Gene therapy options, which are still under development, are designed to introduce correct HbA genes in patients with SCD (thus achieve complete cure) or optimize HbF production (thus achieve functional cure) [108]. One of the approaches for the latter is silencing of BCL11A gene, hence restart HbF production which prevents occurrence of sickling episodes [109]. Gene therapy is a desirable alternative to BMT because it does not involve the use of donor’s stem cells hence can be offered to patients who do not have fully matched related donor. Additionally, it avoids the risks of graft rejection and graft-versus host diseases that are associated with allogeneic BMT [109,110]. The major risk of gene therapy is genotoxicity which has been found to accompany ex vivo gene therapy [111]. In vivo gene therapy is a less complex promising alternative that does not involve chemotherapy conditioning, collection of hemopoietic stem cells from the patient and complex laboratory-based cellular modification, thus can be offered in settings with limited bone marrow transplant units [111,112]. Unfortunately, the implementation of curative options is expensive, and not available in many low and middle income countries in Sub-Saharan Africa where the burden of SCD is greatest [106,113]. To facilitate the availability of gene therapies to all, the Bill and Melinda Gates Foundation entered a memorandum of understanding with National Institute of Health (NIH) in 2019 aiming to expand the access to in vivo gene therapies for SCD and HIV in low and middle income countries [114]. Furthermore, in 2021 the Gates Foundation entered a collaboration with Norvatis Pharmaceutical Company to discover a therapeutic agent that could potentially be administered directly to the patient once, effectively target hemopoietic stem cells, deliver editing machinery to the cells without genotoxicity or immunologic complications and achieving long lasting clinical benefit [115].

Despite the high genetic diversity in Africa, there are very few genome-wide association studies (GWAS) performed in African population. It is estimated that over 80% of gene variants that account for heritability of enhanced HbF expression after birth are still unknown in African population [116]. The GWAS that discovered known HbF modulators such as BCL11A, were performed in individuals of European descent [117]. Scaling up the genomic research and the production of genomic data in Africa will uncover the unknown HbF- modifying loci that are suitable targets for effective induction of HbF in Africans through gene therapy [116,117]. NIH and Wellcome Trust Foundation have funded the Human Heredity and Health in Africa (H3Africa) to facilitate the production of genomic data from African population [118,119]. H3Africa consortium has designed an SNP array derived from whole genome sequences of individuals across Africa. Currently, various projects perform GWAS to investigate the association between genetic variants and diseases such as stroke, cardiovascular diseases, kidney diseases, and sickle cell disease [119]. Additionally, Norvatis Institute for Biomedical Research (NIBR) has recently signed a research and development agreement with Tanzania to develop gene therapy in Tanzania [120]. To facilitate precision medicine in the continent, SSA countries should participate in genomic research to generate data that will be more representative of the geographical variation [118].

Currently, Nigeria, South Africa and Tanzania are the only SSA countries with the capacity of providing bone marrow transplant (BMT) therapy. Nigeria has the most extensive bone marrow transplant registry for SCD patients. The first successful allogeneic BMT for SCD was done in Nigeria in 2011 where a 7 year old was successfully cured of SCD [121,122]. In Tanzania, there are ongoing efforts to identify eligible patients for BMT and their eligible stem cell donors through the SCD Advanced Therapy Clinic run jointly by the Muhimbili University of Health and Allied Sciences (MUHAS), the Muhimbili National Hospital (MNH) and the Jakaya Kikwete Cardiac Institute (JKCI). Another tertiary hospital at the Tanzania capital city of Dodoma, the Benjamin Mkapa Hospital (BMH), has recently launched BMT services for patients with SCD [123]. There is currently paucity of literature regarding implementation of gene therapy initiatives for SCD in SSA. Nonetheless, countries in SSA with the highest burden of SCD agree that gene therapy has the potential to serve as the most effective approach to cure of SCD in the SSA context, especially when approaches employing in-vivo transformation will become available. To facilitate increased involvement in curative therapy initiatives in Tanzania, plans are underway to establish the East African Centre of Excellence for SCD at MUHAS. It is imperative that SSA countries are involved in gene therapy trials concurrent with establishment of capacities for the same, and these efforts must go hand-in-hand with optimization of the infrastructure for supportive care for SCD in the region.

Conclusion

The care for patients with SCD in SSA is currently suboptimal due to a number of challenges including limited resources to implement NBS, shortage of qualified healthcare workers and limited access to medications such as hydroxyurea and opioids, as well as limited access to blood and curative options for SCD. Notwith-standing these challenges, there is notable progress in improving standards of care for patients with SCD such as development of regional multilevel treatment guidelines, initiatives to enhance community and healthcare workers knowledge on SCD, use of POC tests for NBS and early infant diagnosis programs, establishment of dedicated SCD clinics at referral hospitals, efforts to manufacture hydroxyurea locally, and policy changes to accommodate coverage of hydroxyurea by health insurances. Moreover, the participation of SSA countries in gene therapy research and BMT services promises the scale-up of these curative options in SSA.