Promoting The Integrated Community Case Management of Under-Five Pneumonia In Nigeria: A Cost-Benet Analysis

While evidence-based recommendations for the management of under-ve pneumonia at the community level were made by the World Health Organisation, the implementation remains poor in Nigeria. Initiatives to promote the integrated community case management (iCCM) of pneumonia through the proprietary and patent medicine vendors (PPMVs) have been poorly utilized possibly due to low nancial support and perceived benet. This study provides cost and benet estimates and implications of promoting the iCCM through the PPMVs’ education and support. The outcome of this study will help inform healthcare decisions in Nigeria. This study was a cost-benet analysis using simulation-based decision-analytic Markov model. Two approaches were compared, the current scenario which is the use of amoxicillin dispersible tablet (DT) and amoxicillin DT plus promotion. Health outcomes include disability-adjusted life years averted (converted to monetary benet) and severe pneumonia hospitalisation cost averted. Both the cost and benet were expressed in 2018 US dollars.


Abstract
Background While evidence-based recommendations for the management of under-ve pneumonia at the community level were made by the World Health Organisation, the implementation remains poor in Nigeria. Initiatives to promote the integrated community case management (iCCM) of pneumonia through the proprietary and patent medicine vendors (PPMVs) have been poorly utilized possibly due to low nancial support and perceived bene t. This study provides cost and bene t estimates and implications of promoting the iCCM through the PPMVs' education and support. The outcome of this study will help inform healthcare decisions in Nigeria.

Methods
This study was a cost-bene t analysis using simulation-based decision-analytic Markov model. Two approaches were compared, the current scenario which is the use of amoxicillin dispersible tablet (DT) and amoxicillin DT plus promotion. Health outcomes include disability-adjusted life years averted (converted to monetary bene t) and severe pneumonia hospitalisation cost averted. Both the cost and bene t were expressed in 2018 US dollars.

Results
The incremental bene t-cost ratio of promoting the iCCM was 1.37, while the total net-bene t was $3.31 (95% CI: $2.08 -4.76) million from the whole country perspective, which will offset over three-quarter of the promotion cost. Implementing the promotion exercise at a cost above $6.82 million will not be a worthwhile decision.

Conclusion
Promoting the iCCM for the treatment of pneumonia in children under-ve through education and support of the PPMVs holds promises to harness the bene ts amoxicillin DT and provide a high return on investment. A nationwide promotion exercise should be considered especially in remote areas of the country.

Background
The World Health Organisation (WHO) recommends the use of oral amoxicillin dispersible tablet (DT) as the rst-line agent in the management of uncomplicated cases of under-ve pneumonia at the community level and parenteral penicillin and gentamicin as rst-line in severe cases [1], but implementation in Nigeria remains low especially in rural communities.
The Nigerian Ministry of Health in collaboration with the Maternal and Child Survival Program (MCSP), and the WHO has implemented the Saving One Million Lives project [2]. This project aims to support community case management of illness such as pneumonia, malaria and diarrhoea as a strategy to improve treatment access and coverage especially for children living in rural areas [3]. The integrated community case management (iCCM) strategy enables assessment, classi cation, treatment and referral of pneumonia, diarrhoea and malaria cases [4]. The United Nations agencies and other donor agencies have supported the implementation of the iCCM in Nigeria [2]. Following the implementation of the national iCCM guidelines in the year 2013, the occurrence of childhood illness has reduced, and management of pneumonia improved but implementation remains poor [2]. A plausible reason for the poor result was the initial focus of iCCM promotion on community health workers and less focus on the proprietary and patent medicine vendors (PPMVs) who are ubiquitous in the communities. The PPMVs are drug vendors without formal training in pharmacy and are issued a licence by the Pharmacist Council of Nigeria (PCN) to retail non-prescription medications. The iCCM strategy has led to the removal of amoxicillin DT from the prescription-only medicine list to enable the PPMVs to have access to the drug for the treatment of non-severe childhood pneumonia at the community level [5]. In Nigeria, this decision was also supported by the fact that majority of the populace in rural areas visit PPMVs for medical advice, diagnosis, medications and general health management due to their low service cost and accessibility [6,7]. A study in Uganda has also shown that PPMVs are indispensable at the rural communities [8]. The coalition promoting the iCCM foresaw a problem of abuse and increased resistance to amoxicillin DT due to the possibility of irrational dispensing. This foreseen challenge called for the need to educate PPMVs (due to their low medical knowledge) who will sell the amoxicillin DT to most patients. The training of PPMVs involves basic education about signs of pneumonia including danger signs, use of respiratory rate timers, how to dose the drug and when to refer patients in complicated cases to healthcare facilities.
The MCSP in collaboration with the United States Agency for International Development (USAID) made an education outreach in the year 2017 in four local government areas (Idah, Okehi, Izzi and Ohaozara) of two states in Nigeria (Kogi state and Ebonyi state) to test the feasibility of promoting iCCM through the PPPVs [9]. The training held also included education on management of diarrhoea and malaria at the community level and when to refer patients to healthcare facilities [9]. In addition to supporting one of the training in Kogi state, Nemel Pharmaceuticals Limited, an indigenous pharmaceutical company of Nigeria in the year 2018 sponsored the iCCM training through the PCN in few local government areas of Enugu state and the Federal Capital Territory of Nigeria [9]. The outreach reported over 90% turn out of the expected trainees. Following the successful implementation of the training, the PPMVs national executive committee demanded promotion in other PPMVs locations. However, the promotion was decelerated possibly due to fund limitation and low perceived bene t [9]. This lacuna calls for evidence-based analysis of its bene t to encourage the government and donor agencies buy-in. This problem has informed the need for health economic evaluation of the promotion exercise to assess whether scale-up of education and support of PPMVs in the practice of iCCM for under-ve pneumonia management will be bene cial to Nigeria.
This study, therefore, aimed to evaluate the cost and bene t of promoting iCCM for the management of pneumonia for children under ve years in Nigeria through education and support of PPMVs.

Study setting and sample size
The study was carried out using a decision-analytic Markov cohort model and depicted the Nigerian scenario. The population used in the study was an estimated size of 34.6 million Nigerian children under ve years. This gure was based on the 2018 population report [10]. This population was used as the starting population in the model (well state) but at risk of having childhood pneumonia.

Study perspective
The study used retrospective data related to Nigeria to estimate the bene t and cost of promoting iCCM through the PPMVs. The cost was estimated from the payers' perspective (government, donor agencies or third-party payer).

Interventions
A. Amoxicillin DT: In this scenario (current scenario), amoxicillin DT is given to patients with non-severe pneumonia (moderate pneumonia) where the child has fast breathing pneumonia at a dose of 80mg/kg/day in two divided doses for 5 days.
B. Amoxicillin DT plus promotion: In addition to amoxicillin DT for 5 days as in the current scenario above, this scenario (promotion scenario) involves the training of the PPMVs on signs of pneumonia including danger signs, use of respiratory rate timers, how to dose the drug and when to refer patients in complicated cases to healthcare facilities. It also includes the free distribution of one respiratory rate timer to each PPMV shop.

Choice of model and assumptions
We used a simulation-based decision-analytic Markov model in our analysis with a yearly cycle for 5 years. The states in the model were: well state, moderate (clinical) pneumonia, severe pneumonia and death [11,12]. The starting age in the model was under-one year. The model was developed using Nigerian-speci c data. The transition probabilities of moving to moderate and severe states were estimated from the national incidence rates from a global systematic review [1,11]. Yearly incidence rates were converted to yearly probabilities using the formula, P = 1 -where P = probability, r = rate and t = time (year). The mortality rate from all-cause of disease and from pneumonia were obtained from the 2017 Institute of Health Metrics and Evaluation report for Nigeria [13]. In the model, children will start from the well state and with each cycle, they may remain well, move to moderate or severe pneumonia or may die as shown in Figure 1. Based on recent education programs to PPMVs conducted by the MCSP, the USAID and the PCN described earlier and elsewhere [9], we estimated that one health educator will train 10 PPMVs per day (in two sessions); 4 training sessions (2 days) will be held per week per health educator; 16 training sessions will be held per month per health educator and 176 training sessions will be held per annum (11 months) per health educator. The experience from the recent outreach revealed that at least a day-spacing is necessary for trainers to prepare for and travel to the next training venue. We assumed that for each PPMV shop, one representative will be trained. The number of PPMV shops was obtained from a recent survey in Nigeria as 24.58 per 100,000 population [14]. Thus, 55 health educators will be required based on this estimate. We included two extra educators in case of unforeseen shortfall of educators which brings the total to 57 educators. Based on Nigeria's 6 geopolitical zones, 8 educators were assigned to each of four geopolitical zones (north-central; northeast; south-east; and south-south). A total of 12 and 11 educators were assigned to north-west and south-west zone respectively due to their relatively high population with north-west having the highest in Nigeria. One educator will be stationed in the northern region in case of any surge or demand while the other in the southern region. Two vehicles; two computers and two electronic projectors will be allocated to each geopolitical zone. The outreach in 2018 showed that at least ve educators were needed for each training to carter for the number of the trainees.
The PPMV shops and community pharmacies are the major providers of health service at the community level for non-severe health conditions in Nigeria. The survey by the MCSP and the USAID showed that care-seeking at PPMVs shops for fever, diarrhoea, cough or pneumonia was 43% in Nigeria and was used in this study [9]. Overall care-seeking at health facilities was found to be about 40% [2,9]. Details of the assumptions are shown in Table 1 and Additional le 1. The model simulated cost and outcome within the period of 0 to 5 years for a population of 34.6 million at risk of having pneumonia. Cost and bene t (health outcome) were discounted at a rate of 5% [17].
The measure of effectiveness (relative risk ratio) The effectiveness of promoting iCCM for pneumonia was modelled as relative risk. The relative risk ratio was obtained from a recent study in Uganda that compared the effect of promotion (through PPMVs education and support with a diagnostic kit and amoxicillin DT) to no promotion [8]. Details of parameters inputs and distribution are shown in Table 2.

Health outcome
The primary bene t of the promotion was measured in terms of disability-adjusted life years (DALY) averted. The DALY calculation was based on 2017 global burden of disease study and we used recently updated disability weights for moderate and severe pneumonia [18]. The DALY was calculated as the sum of the years of life lived with disability (YLD) from morbidity and the years of life lost (YLL) from mortality. The DALYs were calculated for each cycle and accumulated over the time horizon of ve years and averaged to obtain the mean DALY per patient. In calculating the monetary value of a DALY, we used the Harvard-led guideline for conducting a bene t-cost analysis project [19]. The valuation was based on ''value of statistical life year'' (VSLY) with one DALY averted valued at 1.3 times the GNI per capita of a country in sub-Saharan Africa. The secondary outcome was measured as the cost of hospitalisation due to severe pneumonia averted. The cost was estimated from the payers' perspective. The cost component for the current scenario (amoxicillin DT) includes the cost of amoxicillin DT (1*10 pack) for children ≤ 1 year (2 -12 months) or 2*10 pack (for children ≥ 1≤ 5 years) which are the recommended pack sizes [22]. In the promotion scenario, the cost components include amoxicillin DT as in the current scenario above plus the cost of the promotion. The administrative cost components for promotion were obtained from WHO-CHOICE [15] for  Table 2 and Additional le 1.

Data analysis
We estimated the cost per treatment course. Based on the report of 0.29 episodes of pneumonia per child year in developing countries [24], we then estimated the cost per annum which was used in the model. The cost data, transition probabilities, relative risk and utilities were made probabilistic using the appropriate distributions as shown in Table 2. The DALY was calculated by combining the YLD and YLL for each cycle year. YLD = number of cases duration till remission or death disability weight [25,26]. YLL = number of deaths due to pneumonia life expectancy at the age of death [26]. The standard life expectancy of < 1 year (54.7) and 1 -4 years of (57.9) was obtained from the Nigerian life table [27]. The DALYs across each cycle was summed and averaged to obtain the standard DALYs which was used in the probabilistic sensitivity analysis (PSA). The DALYs averted was calculated as the difference between the DALYs lost in the current scenario (amoxicillin DT) and the promotion scenario (amoxicillin DT plus promotion). Half cycle correction using the life table method was employed in the model [28]. The PSA was used to assess simultaneous uncertainty in the variables. This approach is well suited to express overall parameters uncertainty [29]. To assess how simultaneous change of several variables affects the cost and bene t, a Monte-Carlo simulation (1000 iterations) was performed (a type of multivariate sensitivity analysis). This technique runs many simulations by repeatedly drawing samples from probability distributions of input variables. Data were analysed using Microsoft 365 Excel.

Costs and bene ts
From the analysis, the mean cost per patient following the current scenario (amoxicillin DT) was $0.49 (95% CI: $0.48 -0.50) while the promotion scenario (amoxicillin DT plus promotion) was $8.77 (95% CI: $8.58 -8.96). The incremental cost per patient treatment for scaling up promotion was $8.29 (95% CI: $8.10 -8.50). The estimated cost of promoting the iCCM through the PPMVs was $3.41 (95%CI: $3.40 -3.42) million. The DALY averted per patient due to the promotion of iCCM for the management of pneumonia was 0.004, which translates to a bene t of $11.31 (95% CI: $10.27 -12.35) per patient, and a net bene t of $2.54 (95% CI: $1.50 -3.58) per patient, and a total bene t of $4.41 (95% CI: $3.99 -4.80) million for the country. With a 2018 gross national income per capita of $1960, the bene t-cost ratio (BCR) of the promotion was 1.29, while the incremental BCR was 1.37 per patient. The result showed that the difference in the number of cases of severe pneumonia between the current scenario and the promotion scenario was 146,837 cases (in favour of the promotion scenario). The number of severe pneumonia hospitalisations averted based on 40% care-seeking at health facilities was 58,735 cases.
Following the WHO guideline for the treatment of severe pneumonia and the paediatrician association of Nigeria guideline [30], the cost of hospitalisation for severe pneumonia is $39.35 (25.39 -51.20) per case, which will yield a bene t of $2.31 (95% CI: $1.49 -3.38) million from the cost of severe hospitalisation averted. These translate to a total bene t $6.72 (95% CI: 5.48 -8.18) million and a net bene t of $3.31 (95% CI: $2.08 -4.76) million, which will offset 97% of the cost of promotion. The results are summarised in Table 3.
To test the effect of uncertainty of our assumptions on the outcome, we used a conservative approach of sensitivity analysis by increasing the cost of promotion by 25%, 50% and 100% (2 times increase). The sensitivity test showed that a 25% increase in the cost of the promotion will still be bene cial (BCR = 1.10). Worse-case scenarios of 50% and a 100% increase in the cost were still bene cial, with BCR of 0.93 and 0.74, but total net-bene t of $1.75 and $0.4 million respectively. However, a 125% (2.25 times) increase in the investment yielded a net-loss of $0.46 million. Table 3: Per patient cost, bene t and bene t-cost ratio of the promotion Discussion While evidence-based recommendations for the management of under-ve pneumonia were made by the WHO, the implementation remains poor in Nigeria. Initiatives to promote the iCCM through the PPMVs has been poorly utilized possibly due to low nancial support and perceived bene t. No study has quanti ed its cost and bene t in Nigeria, a region with high pneumonia incidence and mortality. This study provided costs and bene ts estimates and implications that will guide decision making in the country. The study showed that iCCM promotion through the PPMVs using the method described will be bene cial to Nigeria. Our analysis shows that 97% of the cost of the promotion will be offset if the scaleup of the promotion is initiated.
The analysis was based on a speci c price of amoxicillin DT. There is a need for price regulation of the drug. The Nigerian government or donors can provide customized packs of amoxicillin DT to PPMVs and a x an indelible price tag on the mono-packs of the drug (with the PPMVs mark-up included). For instance, a pack of 1*10 tablets supplied at $0.23 will have an indelible price tag of $0.28 (20% mark-up) on the packs so that the PPMVs retailers sell at a xed price. The caretakers of patients who come to buy the drug, on seeing the price tag already know what to pay. This additional support will further guarantee the success of iCCM promotion through PPMVs. This will impel the PPMVs as they will be motivated to make more sales while implementing the service. On the other hand, the Nigerian GDP will grow as more lives are saved.
The PPMV education outreach conducted in 2017 and 2018 incorporated education for malaria and diarrhoea management also. Thus, no additional resources need to be invested to provide education for malaria and diarrhoea management to the PPMVs. This implies that the actual cost for promoting underve pneumonia management can become approximately one-third of the estimated amount in this study, which will lead to cost-saving.
This study has some limitations. The assumptions in estimating the cost of promoting iCCM through PPMVs might vary should implementation be done. The study estimates and assumptions were based on the recent outreach. The sensitivity analysis showed that at a high cost of promotion up to 100% increase, the bene t will outweigh the cost. However, implementation cost above 2 times the estimated cost in this study will not be bene cial to Nigeria. Thus, at a cost of promotion above $6.82 million, the cost will outweigh the bene t and as such, the promotion will not be a worthwhile decision. Secondly, our estimate did not capture alternate treatment cost in case of the rst-line failure. It also failed to capture the treatment approach for human immunode ciency virus (HIV) patients with pneumonia or patients at risk of HIV [1,30]. Thirdly, we did not include the treatment of chest indrawing pneumonia with amoxicillin DT since it is not covered in the iCCM tool. We assumed that treatment failures at iCCM level will be referred to health facilities and, in this case, amoxicillin DT would likely not be repeated but parenteral medications.
Nigeria is the giant of Africa, but the country has lost so many human resources and funds due to lack of information and right implementation practice. Most useful healthcare implementations are poorly sustained. The high mortality rate of children under-ve in the country calls for a pragmatic approach to ameliorate the problem. Being the "future of tomorrow", protecting the Nigerian children under-ve should not be negotiated, otherwise, the frontier of 'gigantism and dwar sm of Africa' for Nigeria will become narrower.

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