Cost analysis of implementing HIV drug resistance testing in Kenya: a case study of a service delivery site at a tertiary level hospital in Kenya

Background

Unprecedented increased access to antiretroviral therapy (ART) is one of the greatest milestones in the fight against the HIV epidemic, resulting in reduced mortality from AIDs-related causes and a global decline in HIV incidence (UNAIDS, 2019). However, this success is threatened by emergence of HIV drug resistance (HIVDR). The World Health Organization (WHO) reports greater than 10% pretreatment drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) among adult patients starting on a first-line ART regimen. This rate is higher in children below 18 months, with over half of newly diagnosed infants harboring resistance to NNRTIs. The prevalence of acquired HIVDR among patients on ART ranges from 3% to 29% (WHO, 2019). Moreover, recent studies in Kenya have shown an upward trend in both transmitted and acquired HIVDR (Hassan et al., 2019; Kantor et al., 2018; Milne et al., 2019).

ART is delivered through the public health approach in most low- and middle-income countries, where standardized drug regimens are administered with simplified laboratory monitoring using tests such as HIV viral load and CD4 count assays (Lessells et al., 2013; De Luca et al., 2013; Phillips et al., 2018). Access to HIVDR testing is limited for patients in resource-limited settings such as Kenya due to high costs involved and inadequate laboratory capacity (Kennedy et al., 2016; Nkengasong et al., 2018; Petti et al., 2006). On the other hand, HIVDR testing is offered routinely in resource-rich setting to inform clinical management of people living with HIV (Dunn et al., 2011; Günthard et al., 2019). However, considerable effort has been made to monitor population level of HIVDR in low- and middle-income countries by implementing HIVDR surveys according to WHO guidelines. These surveys have been crucial in informing national ART guidelines; for example, data on the high prevalence of pretreatment drug resistance to NNRTIs has been critical in the transitioning from an NNRTI-based first-line regimen to a regimen that consists of dolutegravir (DTG) in sub-Saharan countries (WHO, 2019).

Funding for HIV programming in Sub-Saharan countries is provided by multilateral development partners including the US President’s Emergency Plan for AIDs Relief (PEPFAR), the Global Fund and the World Bank, among others (Ministry of Health, 2015; Mwai, 2017; Olakunde et al., 2019; Schneider et al., 2016). These multilateral partners have acknowledged the integral role played by quality medical laboratory services within health systems, precipitating mobilization of significant amounts of funding earmarked for laboratory systems strengthening in resource-limited settings (Abimiku, 2009; Hamel et al., 2015; Nkengasong et al., 2018). This support has led to great improvement in HIV diagnostic and monitoring services, inter-laboratory networks, systems, governance, and institutions, evident by the increased number of laboratories that have the capacity to perform molecular diagnostics for HIV viral load and early infant diagnosis (EID), as well as HIV genotyping. Furthermore, these partners have been at the forefront in supporting development of national laboratory policy and strategic plans, and improving quality in these laboratories (Nkengasong et al., 2018; Hamelet al., 2015).

In Kenya, there are 10 laboratories across the country that support HIV viral load and EID testing through a PEPFAR and Global Fund funded specimen referral network, and only four of these have capacity to perform HIVDR testing. However, there is a paucity of costing data from these laboratories and no detailed cost analysis has been done (Inzaule et al., 2013). Some of the essential costs when performing a costing analysis include equipment costs, personnel costs, and utilities costs. Previous studies have included reagents cost and consumables cost in their estimations, excluding major cost categories (Acharya et al., 2014; Inzaule et al., 2013; Novitsky et al., 2015; Zhou et al., 2011). A detailed cost analysis provides a deeper understanding of the costs of HIVDR to the health systems. Moreover, cost information is important in development of business plans, projections, planning, budgeting, pricing and resources allocation. Finally, it gives a good guide on the affordability of HIVDR testing inclusion in the standard package of HIV testing in Kenya to alleviate the rising number of cases of HIVDR.

In this study we estimate the unit cost of HIVDR testing, identify the cost drivers for the HIVDR test, explore opportunities for cost saving and document challenges and lessons learnt in implementation of HIVDR testing.

Methods

Results

HIVDR unit cost

Activity-based costing for HIVDR testing was performed at MIDR Laboratory by collecting cost data for each step in the drug resistance testing. The cost for performing HIVDR testing was US$ 271.78 per test, where capital costs took the biggest share at $102.42, followed by reagents and consumables at $101.5 (Table 1 and Figure 1). Other costs included personnel ($46.81), utilities ($14.69), maintenance cost of equipment ($2.37) and quality assurance program ($4.00) (Gachogo et al., 2020a).

Table 1. Cost breakdown for each category.

Costs in USD.

Item	Cost per test	%
Capital cost*	102.42	37.68
Reagents + consumables	101.48	37.35
Personnel	46.81	17.22
Utilities	14.69	5.41
Maintenance cost of equipment	2.37	0.87
Quality assurance program	4.00	1.47
Total cost	271.78	100.00

* The most costly component of HIV resistance testing.

Figure 1. Distribution of cost of HIV drug resistance testing in capital, reagents + consumables, personnel, utilities, maintenance cost of equipment, and quality assurance program categories.

Unit cost is $271.8.

Cost per laboratory process

The sequencing step had the largest cost of $160.94 per test, while DNA/RNA amplification had the second largest cost of $56.14. DNA/RNA extraction, gel electrophoresis, sequence analysis and sample collection had a cost of $22.79, $10.34, $19.16 and $2.41, respectively (Table 2 and Figure 2).

Table 2. Cost breakdown by laboratory processes.

Costs in USD.

Item	DNA/RNA extraction	DNA/RNA amplification	Gel electrophoresis	Sequencing*	Sequence analysis	Sample collection	Total cost
Capital cost	7.66	4.48	6.55	82.57	1.21	0.10	102.56
Reagents + consumables	5.42	37.30	1.47	55.63	0	1.67	101.48
Personnel	4.68	9.36	1.87	15.44	15.44	0.47	47.27
Utilities	4.39	3.96	0.20	5.20	0.41	0.11	14.28
Maintenance cost of equipment	0.24	0.24	0.09	0.78	0.78	0.02	2.15
Quality assurance program	0.40	0.80	0.16	1.32	1.32	0.04	4.03
Total cost in USD	22.79	56.14	10.34	160.94	19.16	2.41	271.78
% Total cost	8.38	20.66	3.8	59.22	7.05	0.89	100

* The most expensive step in HIV drug resistance testing.

Figure 2. Distribution of costs of HIV drug resistance testing laboratory processes, including DNA/RNA extraction, DNA/RNA amplification, gel electrophoresis, sequencing, sequence analysis, and sample collection.

Unit cost is $271.78.

Cost of the modified HIVDR assay

The laboratory validated a low-cost assay, whereby reagents volumes used during the amplification and sequencing steps were half the recommended volumes by the manufacturer. The test performance was in agreement with the original assay as previously reported (Magomere et al., 2019). The unit cost as a result of halving reagents volumes at the amplification and sequencing step was $233.81, a reduction from $271.78 of the original assay. There was a notable reduction for the amplification and sequencing costs to $38.38 and $140.70 from $56.14 and $160.94, respectively. There was no change in costs for the other steps in HIVDR testing (Table 3 and Figure 3).

Table 3. Cost breakdown of the modified assay.

Item	DNA/RNA extraction	DNA/RNA amplification	Gel- electrophoresis	Sequencing	Sequence analysis	Sample collection	Total cost
Capital cost	7.66	4.48	6.55	82.57	1.24	0.1	102.60
Reagents + consumables	5.42	19.3	1.47	35.38	0	1.67	63.24
Personnel	4.68	9.36	1.87	15.34	15.44	0.47	47.27
Utilities	4.39	3.96	0.2	5.2	0.41	0.11	14.28
Maintenance cost of equipment	0.24	0.47	0.09	0.78	0.78	0.02	2.39
Quality assurance program	0.40	0.8	0.16	1.32	1.32	0.04	4.03
Total cost in USD	22.79	38.381	10.34	140.702	19.16	2.41	233.813
% Total cost	9.74	16.41	4.42	60.18	8.21	1.03	100

¹ Halving reagent volumes at DNA/RNA amplification step reduces the cost of this step from $56.14 to $38.38.

² Halving reagent volumes at sequencing step reduces the cost of this step from $160.94 to 140.70.

³ Halving reagent volumes at DNA/RNA amplification and sequencing steps reduce the HIV drug resistance test cost to $ 233.81 from $ 271.78.

Figure 3. Cost distribution of the modified assay among HIV drug resistance processes including capital, reagents + consumables, personnel, utilities, maintenance cost of equipment and quality assurance program.

Total unit cost is $233.81.

Sensitivity analysis

The costs presented assume that the laboratory runs 1000 HIVDR tests per year with no machine breakdown or waste of supplies. Considering that variation in input costs would have an impact on the input costs, a one-way sensitivity analysis for 20% variations to cost categories was performed. Variations to capital, reagents, and personnel inputs had a major impact on the unit cost, whereas variations to utilities, maintenance and quality assurance results had no significant impact on the unit cost. A 20% variation to capital and reagents results in changes of up to 7.5% in unit cost; approximately a $20 difference (Figure 4).

Figure 4. Tornado graph for one-way sensitivity analysis, costs in USD.

Grey represents 20% reduction in the input costs, while dark grey represents 20% increase in the input costs. Unit cost is $271.78.

Discussion

The aim of this study was to establish a detailed cost profile for HIVDR testing from a provider’s perspective and identify cost drivers. We also report the challenges encountered and lessons learnt during the implementation of HIVDR testing at the MIDRL. The cost of performing HIVDR testing was estimated to be $271.78 per test. The cost estimate represents all the inputs required for performing HIVDR testing including; capital, personnel, reagents, consumables, quality assurance program and service contracts for the laboratory equipment for performing 1000 tests per year. Previous studies did not include all cost categories, making it difficult to compare costs for offering drug resistant tests across many laboratories (Acharya et al., 2014; Alemán et al., 2015; Inzaule et al., 2013; Novitsky et al., 2015). In this study, we offer a framework for performing laboratory cost analyses that makes it easy to compare cost categories between different laboratories. A previous study from KEMRI/CDC, Kenya, performed a cost analysis of their in-house assay and established the unit cost to be approximately $113.33, with $109.31 as the cost of reagents and consumables (Inzaule et al., 2013). The analysis included the costs of reagents and consumables and the cost of maintaining the equipment but did not account for capital, personnel and external quality assurance program costs. Considering the reagent and consumable costs, there was a correlation in the cost results for these items, as our study estimated the cost to be $101.50. The slight difference could be attributed to time difference in performing the cost analysis. In addition, the previous study estimated the equipment maintenance cost to be $4.02, while the present study estimates a cost of $2.37 for this category. Some of the studies performed in other parts of the world found considerably lower reagents and consumables costs than those estimated by this study. For instance, the costs reported in India and Cuba were $85.00 and $87.80, respectively (Acharya et al., 2014; Alemán et al., 2015). Conversely, one study reported higher reagent costs than those found in the present study; the estimated cost was $139.75 per test (Novitsky et al., 2015).

To answer the question of the cost drivers for HIVDR testing, the costs were categorized according to the processes involved in HIVDR testing, including sample collection, RNA extraction and amplification, gel electrophoresis, sequencing, and sequencing analysis. In terms of cost categories, capital cost took the biggest share of pie at $102.42 (37.68%), followed by reagents plus consumables at $101.50 (37.35%). High capital costs could be attributed to sub-optimal utilization of the sequencing platform. It should be noted that the equipment required for HIVDR testing can be leveraged to perform more patient tests that support HIV care and treatment, therefore bringing down the cost of equipment attributed to HIVDR testing. Our cost analysis was based on an estimated projection of 1000 HIVDR tests per year, which is a gross underestimation of the laboratory’s capacity. If the laboratory operated optimally, offering approximately ~6720 tests per year, the capital cost would reduce ~6.7 fold. The reagent costs were considerably high as a result of acquiring the sequencing machine at no upfront cost. This bound the laboratory to only procure reagents and consumables from the machine provider. This commitment denies the laboratory an opportunity to practice strategic purchasing, which would be a key factor in lowering the cost of reagents. This is not unique to HIVDR testing; a study done in Kenya to estimate cost of HIV viral load and EID reported high reagent costs as a result of machine acquisition on a placement basis (Cintron et al., 2017).

A comparison with other studies was impossible as most of the previous cost analysis included reagents and consumables costs only, omitting other categories such as capital, personnel, utilities and quality control program costs (Alemán et al., 2015; Inzaule et al., 2013; Novitsky et al., 2015). In terms of cost per process, the sequencing step, which involves purification of PCR products, cycle sequencing, purification of sequencing products and sequence detection, was the most costly step in HIVDR testing at $160.94 (59.22%). This is in keeping with other studies evaluating the cost of HIVDR testing. Other studies report $59.88 (52.92%) and $50 (58.82%) as the cost for the sequencing step (Acharya et al., 2014; Inzaule et al., 2013). The one-way sensitivity analysis performed illustrates a cost saving opportunity, for example through negotiating lower reagent prices and maximizing utilization of the sequencing platform, therefore ensuring sustainable use of health financing resources.

Comparing the cost of the HIVDR test to a HIV viral load test used in monitoring and management of people living with HIV, the HIVDR testing cost is higher. A study in Kenya estimates HIV viral load test at $24.63 for non-point-of-care viral load testing and $29.74 for point-of-care HIV viral load testing (Cintron et al., 2017). This is attributed to additional processes in HIVDR test, that is, nested PCR and cycle sequencing processes. These increase the amount of cost inputs used in HIVDR testing, especially staff hands-on time.

The study evaluated the effects of reducing the reagents volume on the cost and performance characteristics of the HIVDR testing in view of reagents being one of the cost drivers for HIVDR testing. On the cost of the HIVDR testing, there was a significant reduction in the cost from $271.78 to $247.30; a ~13.97% reduction in the cost per test. This assay modification led to a ~37.68% reduction in reagent costs. Of note is the concordance of the two assays in their performance characteristics, which increases the confidence in adoption of this cost saving undertaking by the laboratories that would like to increase their efficiency in offering the HIVDR testing service (Magomere et al., 2019). The new assay performance characteristics met the WHO HIVDR validation criteria (WHO, 2018). Cost computation using Viroseq reagents, which are FDA approved and an alternative to in-house Thermofisher (Illinois, US) reagents, gave a cost of $379.46 per test, with reagents taking the biggest share of the cost at 55.13% ($209.18). This illustrates a lower cost of HIVDR testing using Thermofisher reagents by $107.68. These findings are in keeping with other studies where the cost of HIVDR per test was lower when using the in-house system compared to the Viroseq system (Acharya et al., 2014; Inzaule et al., 2013; Zhou et al., 2011). For instance, one study reported a $132.86 difference in the two systems, while another reported a $165.01 difference (Inzaule et al., 2013).

One of the challenges encountered during the implementation of HIVDR testing was high staff turnover. This is attributed to advanced molecular skills required for sample analysis in HIVDR testing. There are a few laboratory specialists equipped with these skills, making them highly sought after in the job market. This is a challenge in a low resource set up as training personnel on this area is quite expensive (Abimiku, 2009; Kennedy et al., 2016; Nkengasong et al., 2018; WHO, 2010). To counteract this challenge, one of the staff won a training grant to learn HIVDR testing from a laboratory that was already established. The sequencing machine provider is also bound by the contract to train the laboratory staff to the highest level possible and provide machine service when due. Maintaining a good working relationship with other laboratories performing the test helps in the exchange of new ideas and also facilitates an inter-laboratory proficiency testing program.

Unlike HIV viral load and EID, HIVDR testing is not included in the Global Access Program, which has helped in the scaling up of HIV viral load and EID testing in Kenya at a relatively low cost (WHO, 2014). This raises sustainability concerns owing to recent reduced donor funding for HIV programs. However, HIVDR testing services can leverage on already established sample referral networks, human resources, laboratory equipment and database for HIV viral load. The multiple possible applications of the sequencing platform provides opportunities to deploy it for other tests and services, therefore reducing the overall running costs. Sensitization of key stakeholders involved in management of people living with HIV through regular stakeholders meetings has been instrumental in uptake of HIVDR test.

Other challenges experienced during the implementation of drug resistance testing included frequent electricity disconnections, which was solved by installing a backup generator to ensure a constant supply of power. This corroborates other previous studies that highlighted similar findings in resource limited settings (Kennedy et al., 2016; Nkengasong et al., 2018). Furthermore, supply chain insufficiency, which delayed timely delivery of reagents, consumables, and laboratory equipment, was a major setback in implementing HIVDR testing. Finally, the premixed PCR master-mixes limited the flexibility of their use for other tests.

Strengths of the study

This report presents findings from a complete cost analysis performed in the early stages of implementation of HIVDR testing, hence giving a good picture of the costs involved in the process. This report will further serve as a useful resource for planning and budgeting information for better resource management for similar projects in future. The inclusion of the cost-saving assay evaluation makes the study one of a kind, as it provides an evidence of cost reduction and comparable performance characteristics for both assays.

Study limitations

The study estimated costs from the provider’s perspective, thus limiting the inclusion of cost incurred by patients. The study design also excluded transport costs incurred for the transport of samples from peripheral health facilities to the testing laboratory in Nairobi. Furthermore, the cost analysis was carried out in only one facility, hence hindering the comparison across facilities offering HIVDR testing. This study presents a partial economic evaluation; a complete economic evaluation would give a clearer picture on the cost-effectiveness of HIVDR testing versus the status quo. Finally, at the time of the study the laboratory was not operating at full capacity, which increases the unit cost of HIVDR testing. It is conceivable that once uptake for the HIVDR test increases, the additional volumes would translate to reduced costs.

Conclusion

The MIDRL has implemented HIVDR testing capacity for patients failing ART at a cost of $271.78 per test. The most important cost driver is expenditure on capital cost, which is likely to reduce when utilization of the equipment increases. It has also been demonstrated that there are opportunities for cost saving through assay modifications such as selective reagent volume reduction.

Data availability