Availability and affordability of medicines and diagnostic tests recommended for management of asthma and chronic obstructive pulmonary disease in sub-Saharan Africa: a systematic review

Background Early accurate diagnosis and sustainable availability of affordable medicines and diagnostic tests is fundamental in optimal management of asthma and chronic obstructive pulmonary disease (COPD). We systematically reviewed original research articles about availability and affordability of medicines and diagnostic tests recommended for management of asthma and COPD in sub-Saharan Africa (SSA). Methods We searched PubMed, Scopus and African Journal Online for original research articles conducted in SSA between 2000 and March 2018 containing information about availability and affordability of any recommended medicine and diagnostic test for asthma and COPD. Results The search yielded 9 eligible research articles. Availability of short-acting beta agonists (SABA), inhaled corticosteroids (ICS) and short acting anti-muscarinic agents (SAMA) ranged between 19.9–100%, 0–45.5% and 0–14.3% respectively. Combination of ICS-long acting beta agonists (LABA) were available in 0–14.3% of facilities surveyed. There was absence of inhaled long acting anti-muscarinic agents (LAMA) and LAMA/LABA combinations. Spirometry and peak expiratory flow devices were available in 24.4–29.4% and 6.7–53.6% respectively. Affordability of SABA and ICS varied greatly, ranging from < 2 to 107 days’ wages while ICS–LABA combinations, SAMA and oral theophylline plus leukotriene receptor antagonists cost 6.4–17.1, 13.7 and 6.9 days’ wages respectively. Conclusion Availability and affordability of medicines and diagnostics recommended for the management of asthma and COPD is a big challenge in SSA. Research about this subject in this region is still limited. More robustly performed studies are required to further understand the magnitude of inequity in access to these medicines and diagnostic tests in SSA and also to formulate simple pragmatic solutions to address this challenge.


Burden of asthma and COPD: Globally and in sub-Saharan Africa
The global burden of chronic respiratory disorders (CRD) particularly asthma and chronic obstructive pulmonary disease (COPD) continues to increase especially in low-and middle income countries (LMIC), posing a substantial public health threat [1]. The 2015 Global Burden of Diseases, Injuries and Risk Factors (GBD) study reported an increase in the prevalence of asthma and COPD by 12.6% and 44.2% respectively from 1990 to 2015. This was associated with an increased rate of mortality due to COPD [2]. In 2015, 3.2 million people and 0.4 million people died from COPD and asthma worldwide respectively. This represents an 11.6% increase in COPD-related deaths and a 26.7% decrease in asthmarelated deaths when compared to estimates in 1990 [2]. The majority of these deaths were reported in LMIC.
Smoking (both active and passive), ambient particulate matter, household pollution and occupational triggers were identified as the key risk factors and contributors to DALYS for both asthma and COPD [2].
Increasing trends of morbidity due to asthma and COPD have also been reported in sub-Saharan Africa (SSA). Regarding the prevalence of asthma in Africa, a systematic review by Adeloye et al. [3] of 45 relevant studies published between 1990 and 2012 estimated about 74.4 million, 94.8 million and 119.3 million asthma cases in the total population in 1990, 2000 and 2010 respectively. A higher crude prevalence of asthma was noted in the urban areas compared to the rural areas.
A systematic review conducted in 2011 by Finney et al. [4] reported estimates of COPD to vary between 4 and 25%. This data was obtained from 9 studies that were performed in 4 countries (Nigeria, South Africa, Malawi and Cape Verde). Only one study used a population based representative sampling approach. Another systematic review performed by Adeloye et al. [5] in 2012 that included 13 eligible studies (5 of which were based on spirometry data) reported a prevalence of COPD of 13.4% using spirometric data and 4% using non spirometric data. The most recent community surveys that have been conducted between 2013 to-date to ascertain the burden of COPD in Cameroon, Malawi, Nigeria, Uganda and Tanzania have reported prevalence of 2.4%, 7.7%, 4.2%, 16.2% and 17.5% respectively [6][7][8][9][10].
To effectively address the public health concern that asthma and COPD pose in SSA, health systems should be well structured to prevent, diagnose early and optimally manage these conditions. Consistent availability of affordable medicines and diagnostic tests is a fundamental component in the management of asthma and COPD in clinical practice. The Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend the use of inhaled short acting beta agonists (SABA), inhaled short acting anti muscarinic agents (SAMA), inhaled long acting anti muscarinic agents (LAMA), inhaled long acting beta agonists (LABA) and LAMA combinations, inhaled corticosteroid (ICS)-LABA combinations, ICS monotherapies, oral methylxanthines, oral leukotriene receptor antagonists (LTRA), pneumococcal vaccination and phosphodiesterase-4 inhibitors as the mainstay pharmacological therapies in the management of asthma and COPD [11,12].
Citing the evident increase in morbidity and mortality due to asthma and COPD in SSA, it is essential to document the current status of availability and affordability of these medicines and diagnostic tests recommended for management of asthma and COPD in SSA. This will help in the guiding the formulation and implementation of pragmatic solutions to address the challenges of poor availability and high cost of these medicines and diagnostic tests.
Availability and affordability of medicines and diagnostic tests recommended for the management of asthma and COPD in SSA has not been systematically studied to-date. We, therefore undertook a systematic review of relevant original studies performed between 2000 and March 2018 that investigated availability and affordability of these medicines and diagnostic tests in SSA.

Methods
A comprehensive literature search of PubMed, Scopus and African Journal Online was performed for original research articles in English language performed between 2000 and March 2018 with an objective of determining the scope of availability and affordability of key medicines and diagnostic tests recommended in the management of asthma and COPD in SSA. References of the selected original research articles and published review articles were further searched for additional original research articles. We also searched the first 1000 Google scholar searches for original research articles.
Studies included were original research articles that contained information about availability and affordability of any known important medicine and diagnostic test for the management of asthma and COPD, was conducted in SSA between 2000 and March 2018 and published in English language.
Availability of any medicine (s) or diagnostic test (s) was expressed as a percentage of health facilities where it was present at the time of the study. Affordability was expressed as the total number of days' wages it would cost the lowest paid unskilled government worker to pay for a diagnostic test or a months' cost of the medicine. This information was documented precisely as reported in the eligible original research article. The classes of medicines of interest were those belonging to these categories: inhaled SABA, SAMA, LAMA, ICS, SABA-SAMA combinations, LABA-LAMA combinations, ICS-LABA combinations, oral methylxanthines and LTRA. Studies that also contained information about the availability and affordability of spacer devices were also included due to their role in drug delivery especially in young children and elderly patients. The diagnostic tests of interest were spirometry and peak expiratory flow devices.
The following search terms were used: access OR affordability OR pricing OR cost OR availability AND "essential medicines" OR drugs OR therapies OR medicines AND tests OR diagnostic OR imaging AND asthma OR "chronic obstructive pulmonary disease" OR COPD OR "chronic respiratory disorders" AND Africa. The titles and abstracts of all studies were initially assessed for eligibility. Full texts of those studies that initially met the inclusion criteria were obtained and screened by 2 independent reviewers (DK and RES) and then exported to Endnote citation manager. Three extra authors (RN, WW and BK) independently reviewed the selected original research articles for the eligibility and key information about study setting and design and information about availability and affordability using a data extraction form. We excluded original research articles published in other languages other than English, studies whose full texts could not be accessed for full analysis and review articles.
The methodological quality of the identified studies was assessed by 2 independent reviewers (DK and RES) using the Newcastle-Ottawa scale. A maximum score of 6 and 9 was used for the selected cross sectional and case-control and cohort studies respectively [13].
The PRISMA guidelines for the reporting of systematic reviews were followed (Table 1) [14]. This systematic review was registered in PROSPERO (registration number: CRD42018093391).

Results
A total of 796 published articles were identified after searching the 3 databases. Thirty-two duplicates were removed, leaving 764 articles. The titles and abstracts of 764 articles were screened. Of these, 737 articles were excluded because they lacked the information of interest. Full texts of 27 articles were assessed for eligibility and only 6 articles met the inclusion criteria. Three papers were added after searching Google Scholar, references of the eligible original articles and published review articles, making a total of 9 eligible original research articles which were included in the systematic review [15][16][17][18][19][20][21][22][23] ( Fig. 1-Flow diagram summarizing the identification of eligible articles).

Study characteristics and methodological quality
All eligible studies were cross sectional in nature. Six of the studies (67%) were performed in a single African country (Malawi, Uganda-2 different studies, Nigeria, Ghana, South Africa) [15-17, 19, 20, 23]. The rest were multi-country studies performed in both an African country and other LMIC outside Africa [18,21,22]. In these multi-country studies, only data reported from the African countries was obtained.
The eligible original studies included in the systematic review are summarised in Table 2.

Oral low dose theophylline and LTRA
Varying levels of availability of oral theophylline and LTRA were reported by 2 studies [16,17]. In a study performed in Uganda, availability of oral theophylline and LTRA was 16.9% and 60.8% respectively [16] compared to 76.5% and 5.9% respectively in a study performed in Nigeria [17].

Inhaled LAMA (tiotropium)
Only 1 study investigated availability of inhaled tiotropium, reporting its absence in all health facilities surveyed [16].

Availability of medicines used in symptom control of COPD only (inhaled LABA monotherapy, SABA-SAMA combinations and LAMA and LABA combinations)
Availability of all the above medicines was studied by only 1 study, documenting comparable very low levels of availability of inhaled LABA monotherapies and SABA-SAMA combinations of 10% and 10.8% respectively. No surveyed health facility had any inhaled LABA-LAMA combination [16].
No study investigated the availability of LABA-LAMA-ICS triple combinations, pneumococcal vaccines and phosphodiesterase 4 inhibitors which are essential medicines in the management of COPD.

Spacers
Due to the important role of spacers in drug delivery in the management of asthma and COPD in children and elderly patients, we also included information about their availability from 4 studies [16,17,19,23]. With the exception of a study performed in South Africa where spacers were available in 72.9% of the surveyed 46 primary healthcare facilities, the rest of the studies reported very low levels of availability of 0% in Ghana [19], 18.5% and 19.2% for adult and paediatric spacers respectively in Uganda [16] and 20.6% in Nigeria [17].

Availability of diagnostic tests for asthma and COPD
Only 4 studies contained findings about the availability of the diagnostic tests [16,17,19,23]. Availability of peak expiratory flow devices was reported about in all the 4 studies (6.7% in Uganda, 13% in Ghana, 38% in Nigeria and 53.6% in South Africa). Availability of      [16] and Nigeria (29.4%) [17].

Affordability of medicines used in management of exacerbations of both asthma and COPD (inhaled SABA and SAMA monotherapies) Inhaled SABA (salbutamol)
In a multi-centre study by Babar et [21]. In another study done in Uganda, the LPG salbutamol inhaler cost 2.2 days' wages [16].

Affordability of medicines used in symptom control of both asthma and COPD (ICS, ICS-LABA combinations, low dose theophylline, LTRA and inhaled LAMA) Ics
A disparity in the affordability of generic and innovator ICS was observed in the study by Babar [16].

ICS-LABA combinations, SAMA-SABA combinations, low dose theophylline and LTRA
Only 1 study contained information about the affordability of the above medicines [16]. Regarding ICS-LABA combinations, the reported cost of the LPG formoterol/beclometasone, salmeterol/fluticasone propionate and formoterol-budesonide was 6.4 days' wages, 10.2 days' wages and 17.1 days' wages respectively. Inhaled SAMA-SABA (ipratropium-salbutamol combination) cost 10.7 days' wages while oral LTRA and low dose theophylline both cost 6.9 days' wages. Adult and paediatric spacers cost 12.9 and 7.5 days' wages respectively [16].

Affordability of diagnostic tests of asthma and COPD
One study evaluated affordability of spirometry which cost up to 27.8 days' wages [16].

Discussion
To our knowledge, this systematic review provides the first comprehensive assessment of availability and affordability of internationally recommended medicines and diagnostic tests in management of asthma and COPD in SSA. It also evidently demonstrates that studies investigating this key area in SSA are still limited and availability of affordable medicines and diagnostic tests still remains a substantial challenge in clinical practice in the region.
We noted considerable heterogeneity in the study results and health facilities surveyed. Poor availability was widely noted with SAMA, SAMA-SABA combinations, ICS, LAMA, LAMA-LABA combinations and diagnostic tests (spirometry and peak expiratory flow devices). The paucity of studies investigating access to LAMA and LAMA-LABA combinations, which are vital medicines in reducing COPD symptoms and future exacerbations is also revealing. This poor access to medicines for asthma and COPD has been highlighted in SSA and other LMIC and it carries substantial public health implications [24][25][26][27]. Availability of SABA (salbutamol inhaler) and LABA-ICS combination was > 70% in Uganda, Nigeria, Sudan and Eriteria [16,17,22] and > 45% in Uganda and Nigeria [16,17]. The fairly good availability could explain the frequent use of SABA that has been described in patients with asthma and COPD in clinical practice.
Poor access to spirometry as a cornerstone for diagnosis and assessment of treatment response in patients with asthma and COPD as noted by this systematic review still remains a challenge. The poor availability of spirometry in health facilities and inadequate proficiency in interpretation of spirometric readings by healthcare workers in clinical practice has been widely documented as an impediment to optimal management of asthma and COPD in SSA [26][27][28]. The absence of adequate numbers of skilled personnel to perform spirometry and interpret its findings could also partly explain its low availability in SSA.
A dearth of studies about affordability of the medicines and diagnostic tests for asthma and COPD in SSA is also of great concern. The majority of the medicines (controller therapies) especially in the private sector and innovator brands remain unaffordable for most patients in SSA. Several reasons could explain the poor availability and high costs of the majority of the medicines and diagnostic tests in SSA. There exists a knowledgepractice gap among healthcare practitioners in SSA resulting into patterns of clinical practice that are not in conformity with international treatment guidelines [27,29]. Low prescribing rates of these medicines by healthcare practitioners directly or indirectly influence their availability both in the public and private sector. Exclusion of these medicines from the national essential medicine lists (EML) and treatment guidelines could also explain the poor availability in SSA. One survey that investigated the number of asthma and COPD essential medicines on the national EML of 32 LMIC (including some countries in SSA) noted that the median number of essential medicines was 7, with a range of 0-22. Notably, no African country included LABA to their national EML. Few low income countries (LIC) included inhaled anti cholinergic agents (20%). None of the LIC included therapies recommended in step 4 and 5 of asthma management by the GINA guidelines. Only a third of them included at least 1 medicine recommended in the step 2 and 3 of COPD management by the GOLD guidelines [30].
The high cost of the medicines and diagnostic tests in SSA could be explained by lack of local price regulatory frameworks or legislation, absence or poor access to national health insurance schemes that can provide the medicines at subsided fees, low scale of local pharmaceutical production of generic medicines and absence of public and private co-financing initiatives to reduce costs of drugs.

Strengths and limitations of the systematic review
One significant strength of this systematic review is being the first review to offer comprehensive information about the extent of availability and affordability of medicines and diagnostic tests of asthma and COPD in SSA. Despite this, some of the limitations are heterogeneity of the study findings and health facilities surveyed and the low methodological quality of the eligible original studies.

Conclusion
A better understanding of the magnitude and reasons to explain the challenge of poor availability and high cost of these medicines and diagnostic tests in SSA is important to guide better implementation of pragmatic solutions and guidelines. Poor availability and unaffordability of medicines and diagnostic tests recommended for the management of asthma and COPD in SSA could be addressed through increasing awareness about the burden of both conditions and their optimal management among healthcare practitioners, improving local manufacturing of cheap good quality generic medicines, updating national EML and treatment guidelines, improving supply chain and forecast and sustained and equitable government financing of health budgets. Implementation of health policies like national health insurance schemes, regulation of local retail prices of chronic diseases and introduction of preferential registration procedures for locally manufactured generic drugs by drug regulatory institutions can help address the challenge of high costs of medicines of asthma and COPD in SSA.
Due to differences in economic status of countries in SSA, more robust country-specific large studies about access to affordable essential medicines and diagnostic tests are needed to further appreciate the magnitude of this public health problem in this region.