A systematic review on hydroxyurea therapy for sickle cell disease in India

The abnormalities associated with the globin chain of haemoglobin give rise to a group of disorders called haemoglobinopathies, the most common of which include sickle cell disease (SCD) and β-thalassaemia. Sickle haemoglobin (HbS) polymerizes on deoxygenation, leading to distortion and sickle shape of the red blood cells1. India accounts for approximately 40,000 sickle homozygous births every year2. SCD is a notable contributor of childhood mortality and premature death in the adult population2-4, thus inflicting a substantial economic burden on the affected families and the health sector. The sickle cell gene in India represents an occurrence of the HbS mutation known as the Asian haplotype5 and is widely distributed in central, western and eastern States of the sub-continent along with some parts of southern India6,7. The carrier frequency of the sickle cell gene is even higher in some parts of the central, western and southern States in India7. SCD in Indians is believed to have a relatively milder clinical presentation, compared to that among Africans8 due to various reasons such as the high prevalence of the putative potential genetic modifiers such as Arab Indian (AI) β-globin haplotype, high foetal haemoglobin (HbF) levels, the coinheritance of α-thalassaemia and high polymorphic frequency of Xmn1 gene site9-15. Evidence suggests that low socio-economic conditions and poverty could lead to adverse outcomes of the disease10,16.

The National Health Mission (NHM), Government of India (GoI) initiated the SCD programme in high-burden districts, directed at the mass screening of tribal groups along with the provision of care utilizing public health facilities17. Despite screening, the availability and accessibility of established therapies such as preventive and therapeutic hydroxyurea (HU) and pneumococcal immunization in public health institutions are sub-optimal18. The NHM suggests 10-15 mg/kg/day of HU in a single daily dose to be initiated after two years of age. The dose can be escalated every 6-8 wk, if no major toxicity is observed until the desired endpoints (viz. decrease in pain, increase in HbF by 15-20 per cent, increase in Hb level if severely anaemic, improved wellbeing and acceptable myelotoxicity). The maximum tolerated dose (MTD) is 35 mg/kg/day17.

Preliminary review of literature suggested that the management of SCD in India appears to vary and the studies are mostly conducted in a certain population/region only. Therefore, in the context of the treatment of SCD patients with HU, the present review was conducted to assess the efficacy and toxicity of HU in Indian sickle cell patients.

Material & Methods

Data sources: We searched biomedical literature databases of PubMed, Scopus and Cochrane Library for various studies published during the last 20 years (between January 2001 and October 2021), using the keywords, namely sickle cell anaemia (SCA), SCD, hydroxyurea (HU), hydroxycarbamide and India in different combinations.

Data extraction: The abstracts of all the selected studies, identified through web search, were reviewed independently by two authors (A.P. and S.B.) and the final decision of selecting the articles was reached by consensus. While extracting the data, relevant parameters such as author’s name, journal name, year of publication, study design, objectives, methodology, results and outcomes and other factors that can affect outcomes were carefully noted in an excel sheet. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA, http://www.prisma-statement.org) as per the IJMR guidelines for systematic reviews & meta-analysis. With the search strategy, a total of 93 articles were identified, of which 14 studies fulfilled the review criteria and were thus selected. A detailed evidence table was prepared from these 14 studies. The efficacy and effectiveness of HU therapy were taken together as the studies were not easily distinguishable.

Inclusion/exclusion criteria: All prospective, retrospective, observational cohort, descriptive, prospective and randomized placebo-controlled trials reporting the efficacy and toxicity of HU therapy for SCD in India were included in the study. Studies on SCD that did not include the efficacy and toxicity of HU therapy in India were excluded from the present review. Data from unpublished studies, non-peer reviewed journals and from publications which reported data from previously included studies, were also excluded from the current review.

Quality assessment & risk of bias: The quality of the randomized and non-randomized studies was assessed by using a modified methodological quality checklist developed by Downs and Black19. The checklist consisted of 27 questions on reporting, external validity, internal validity bias confounding and power. Twenty six questions were scored as yes (=1) or no/unable to determine (=0) and one question of power was scored on a 3-point scale. The overall study quality was categorized as excellent (23-28), good (18-22), fair (13-17) and poor (<13). The discussion between the authors was sought to resolve the disagreements, when the difference in scoring was more than one.

Statistical analysis: The percentage agreement between the independent reviewers and Cohen’s kappa coefficient were calculated using IBM SPSS^® Statistics for Windows, version 19 (IBM Corp., Armonk, NY, USA).

Results

Data synthesis: Of the 93 articles identified using the search strategy, two studies were identified as duplicate and removed. Of the remaining 91 studies, 71 records were further removed after screening as these were either conducted in animals or were irrelevant (Figure). From the remaining 20 records, two retrospective studies, one review and one descriptive study, which did not assess the efficacy of HU therapy along with one case study of two patients, were further excluded. Fourteen20-33 articles met the inclusion criteria and were chosen for further qualitative analysis (Tables I and II). Study design of the 14 studies included prospective cohort (n=11), cross-sectional (n=2) and double-blind randomized controlled (n=1) trial. The percentage agreement and the inter-rater variability (Cohen’s kappa coefficient) ranged between 70-89 and 0.4-0.8 per cent, respectively. The source of participants, inclusion criteria and patient characteristics were well defined in all the studies. Adherence to interventions was good and properly reported in nine (64.2%) studies20,21,23,25,26,28,30,32,33.

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Figure

Summary of literature search and review process as per the PRISMA guidelines. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

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While selected 10 studies20,22-24,26,27,29,30,32,33 assessed the efficacy/toxicity of HU therapy in SCD, two articles each were on beta-thalassaemia21,28 and HbSD-Punjab25,31. Of the total 14 studies reviewed, five (35.7%) studies20,22,27,29,31 were conducted in paediatric patients, six (42.8%)21,24,25,30,32,33 in adults patients and three (21.4%) in others26-28 in paediatric as well as adult patients with SCD. The duration of both observation and the follow up of patients, however, varied in the studies.

Efficacy & effectiveness of hydroxyurea (HU): It was noted that the majority of the studies indicated the efficacy of low-dose HU therapy in reducing the frequency of pain crises, blood transfusions and hospitalization. Of the 14 studies, 12 used the fixed-dose method20,22-26,28-33, and two used the standard dose escalation method21,27. In the two studies that used the dose escalation method, while one study started with a low dose of 10 mg/kg/day and escalated to 15 mg/kg/day, the other one started from 15 mg/kg/day and escalated to 30 mg/kg/day21,27. On the other hand, of the 12 studies that used the fixed dose method, eight (57.14%) studies showed a beneficial effect of low fixed dose (10 mg/kg/day) of HU in reducing vaso-occlusive crisis (VOC) and transfusion requirements in the treated patients20,22,23,25,26,28,32,33 and four (28.6%) used a standard dose of 20 mg/kg/day24,29-31. The frequency of pain crises decreased significantly in 12 (75%) studies20-31. In five prospective studies22,23,29,30,33, the VOC declined from 4.92 to 1.098 events/yr after HU therapy. The requirement of blood transfusion reportedly decreased in 10 (62.5%) studies20-23,25-29,33. The frequency of hospitalization also decreased as reported in six studies20,21,23,28-30. The randomized controlled trial (RCT)20 conducted with the fixed low-dose HU (10 mg/kg/day) was found to be effective in ameliorating SCA-related events with 95, 94.6 and 93.1 per cent reductions in the rates of VOC, blood transfusions and hospitalizations, respectively, when compared with the placebo group20. The duration of hospitalization was less in the HU group (3.1±1.2) compared to the counterparts in the placebo group (7.1±2.1 days)20.

A cohort study by Deshpande et al27 observed a significant reduction in the number of pain crises which required hospitalization across age groups. A decline in the requirement for blood transfusion in all patients was also reported, however, it was significant only in the age group of 11-20 yr27. Another study measured the efficacy of low-dose HU in paediatric and adult SCA and reported a significant reduction in the painful crises in both the groups. The control and HU therapy groups had different painful crisis rates at the end of two years, with the control and HU groups having 4.8 and 0.5 crises per year, respectively, showing a difference of 89.6 per cent. Ninety five per cent of patients who received HU treatment became transfusion independent26. A study conducted by Italia et al21, in patients with severe manifestations reported that after two years of HU therapy, 78 per cent of patients showed clinical improvement with a reduction of VOC and transfusion requirements.

Predictors of response: The HbF level was recorded in 12 (75%) studies20-23,25-32, all of which reported an elevation in the HbF levels. The mean per cent HbF across these studies increased from 15.8 to 21.4 per cent. Jain et al23, in a study on children with SCA, showed a higher increase in HbF levels in patients with lower baseline HbF levels, suggesting that HbF response to HU is variable. Italia et al21 showed a significant correlation between clinical improvement and the HbF and F-cell response. There was a positive correlation between the rise in HbF level and the reduction in episodes and severity of sickle cell crises.

Toxicity of hydroxyurea (HU): Compliance, adverse effects and inadequate follow up for monitoring play as significant barriers to HU therapy34. Compliance to treatment was reported in nine (64.2%) studies4,21,23,25,26,28,30,32,33. Drug toxicities and adverse events were indicated in 10 (71.4%) studies. Follow up compliance was reportedly good in seven (50%) studies20,21,23,25-27,32 and loss to follow up was reported in five (35.7%) studies22,28-30,33. Four studies21,24,25,27, on the other hand, did not report any toxicities.

Thrombocytopenia and neutropenia were the most common toxicities observed in the nine studies20,22,23,26-28,30,31,33. A few studies22,23,29,33 reported renal and hepatic dysfunction, but whether this was due to HU or as a consequence of SCD requires further evaluation. There are, however, inadequate data regarding the long-term risk of HU and its impact on fertility and reproduction. Dehury et al28 observed minimal gonadal toxicity. Sahoo et al32 found a significant alteration in seminal fluid parameters exacerbated by low-dose HU therapy in male SCD patients in the age group of 15-45 yr. Pigmentation of skin and nail and other adverse events like nausea were also reported in these studies.

Discussion

This systematic review evaluates the efficacy of HU therapy and its toxicity in SCD patients in India. This review included one ‘excellent’20 and six ‘good’23,24,26,29-31 quality studies, as assessed by the cumulative scores obtained by two independent authors using Downs and Black Checklist19. Although HU was found to be beneficial in reducing the VOC, blood transfusion and requirement of hospitalization, much ground still remains to be covered in the better documentation of HU for SCD in Indian patients. A majority (57.14%) of the published evidence from India have reportedly initiated and continued with the low and fixed dose of HU (10 mg/kg/day) in severely affected children and also showed a significant reduction in the recurrent painful episodes, need for frequent blood transfusion and of the frequency of hospitalization along with other SCA related crises20,22,23,25,26,28,32,33. Furthermore, transient cytopenia was the most common side effect observed, which required temporary discontinuation of HU in 6 studies22,23,26,28,30,33.

In context of dose escalation of HU as prescribed by NHM17, the authors believe that while this may confer additional clinical benefits, due to limited facilities to monitor toxicity, administering a higher dose may become a barrier to the treatment. Therefore, dose escalation may be advisable only if there is no reduction in the pain crisis and the requirement of blood transfusion. From this systematic review it also emerged that there was a better compliance with the low dose, which can be further reinforced with the coordinated efforts between a physician and his patients. Thus, on the basis of an RCT20 and other observational studies20,22,23,25,26,28,32,33 highlighting the beneficial effects of low- and fixed-dose HU therapy in SCD patients, it can be concluded that MTD may not be necessary to achieve a therapeutic effect.

A case study35 of two female sickle beta-thalassaemia patients on HU therapy who managed through their pregnancies after discontinuing HU therapy was identified, however, this study was not able to contribute to drawing inference related to teratogenic effect of HU due to its limited extrapolation.

Through this systematic review, several key gaps and challenges associated with HU therapy in a resource-limited setting like India were identified. Although considerable work has been done in India on SCD, these studies remain limited to a handful of centres and hence have limited impact at the national level. The National Heart, Lung and Blood Institute guidelines36 offered that HU should be utilized more broadly, including HU initiation in all infants with sickle cell, at nine months of age, regardless of clinical severity, with regular counselling, whereas in India, the healthcare providers initiate HU therapy to only symptomatic SCD children due to fear of toxicity as well as lack of availability of paediatric dose. Due to the unavailability of low-dose HU tablets, initiating a low/standard-dose treatment became a tedious task for the service providers as the available HU tablets (500 mg) need to be opened up, weighed accordingly and provided in new packages23. In India, even with high HbF levels, severe manifestations among some SCD patients have been reported, where the role of genetic modifiers needs to be studied. A variation in the dosage of HU therapy due to a lack of a definite regimen was also reflected in these studies.

In order to address these gaps and challenges, multi-centric RCTs that can compare the low dose with standard dose and doses up to MTD are required while assessing the pharmacokinetics while also exploring the role of genetic modifiers. There is a paucity of evidence on the long-term benefits of HU in preventing chronic complications of SCD and its effects on fertility and reproduction as a long-term follow up of the patients on HU therapy is lacking. Thus, it becomes imperative to evaluate the long-term safety profile of HU in both children and adults.

There are several limitations in our study. The studies reviewed included patients enrolled from various age groups and with severe clinical manifestations. Furthermore, one double-blind RCT20 could be retrieved from the search.

This review suggests that there is need to conduct research focusing on varied ethnicity in different areas with a clear distinction of the tribal/non-tribal population, as patients’ response across the population could vary. This will not only help in identifying the SCD burden but will also help in identifying the various genetic modifiers across different populations responsible for phenotypic variability. Therefore, more studies are required on individual pharmacokinetic, pharmacodynamic and pharmacogenomic differences contributing to the phenotypic variability in both the dosing of and response to HU therapy. There is also a need in India to develop guidelines based on consensus, especially regarding the dose and duration of HU therapy. These guidelines can be further refined, as and when new data become available. Early detection, treatment and general awareness about SCA in the community are also needed, which can be achieved by community education and partnership as well as better access to healthcare facilities for all economic classes.