Search
Research Article

# Cost-Effectiveness Study of Three Antimalarial Drug Combinations in Tanzania

• To whom correspondence should be addressed. E-mail: virginia.wiseman@lshtm.ac.uk

Affiliation: Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom

X
• Affiliation: Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom

X
• Affiliations: National Institute for Medical Research, Dar-es-Salaam, Tanzania, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom

X
• Affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom

X
• Published: October 10, 2006
• DOI: 10.1371/journal.pmed.0030373

## Abstract

### Background

As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO) and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs). Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations.

### Methods and Findings

An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ), AQ with sulfadoxine-pyrimethamine (AQ+SP), AQ with artesunate (AQ+AS), and artemether-lumefantrine (AL) in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28). All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ) revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US$1.70 or a net saving of US$22.40 per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy.

### Conclusions

In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is not necessarily the case in parts of Africa where recrudescence following SP and AQ treatment (and their combination) is lower so that the relative advantage of ACTs is smaller, or where diagnostic services are not accurate and as a result much of the drug goes to those who do not have malaria.

## Editors' Summary

### Background.

For many years, malaria was treated with a course of a single drug. This type of treatment made it easy for malaria parasites to become resistant to antimalarial drugs. This is a major factor contributing to the continuing high death rate from the disease. However, although parasites can easily adapt to resist one drug, adapting to combinations of two or three drugs is much harder. Scientists have therefore developed combinations of antimalarial drugs. One component of these combinations is artemisinin—derived from a Chinese shrub. However, these combination therapies are much more expensive than the older treatments.

The regions worst affected by malaria—Africa and Asia—are also the poorest. And, in these areas, where both individual and government resources are scarce, antimalarial treatments must be cost-effective as well as clinically effective.

### What Do These Findings Mean?

Despite being more expensive, newer drugs can be cost-effective where alternatives fail. Although AL was the most cost-effective in places (such as Tanzania) where the malaria parasites are highly resistant to SP and AQ, the picture is likely to change for other areas. In West Africa, for example, AQ resistance is lower, and AQ+SP and AQ+AS would probably be more cost-effective. And in areas where both these combinations are just as good as AL in preventing recurring disease, they would be more cost-effective than AL. However, since AQ and SP have been used singly for many years, the likelihood is that resistance to these drugs will continue to increase. Accurate diagnosis turns out to be very important for maintaining the cost-effectiveness of combination antimalarial therapies. This will be essential if they are to be incorporated as a sustainable part of local health policies. The researchers also point out that, depending on which perspective is taken (provider or patient), the cost-effectiveness of treatments differs, making it important to compare like with like.

### Results

The programme costs for each treatment are shown in Table 1. For the provider, the higher unit price of AL meant that the cost of implementing this treatment was higher than for the others. For patients and their families, current treatment with SP and treatment with AQ were the most costly, due to the need for retreatment. The indirect costs to patients and their families were the largest component of programme costs for all treatments.

Cost-effectiveness data are shown in Table 2. By day 14, AL was revealed to be the most effective treatment with 495 cases averted. By day 28 the effectiveness of all treatments had fallen but AL remained most effective, averting 382 cases of malaria. Comparing cost-effectiveness ratios for the three combination treatments against monotherapy (AQ) revealed that from a societal perspective AL was most cost-effective at day 14; resulting in a gross saving of US$1.51 or a net saving of US$22.24 per case averted. At day 28 the difference between the two most cost-effective treatments of AL and AQ+AS was negligible; both resulted in gross savings of approximately US$1.70 or a net saving of US$22.40 per case averted. From a provider perspective, AL was most costeffective at days 14 and 28.

The greatest resource savings were associated with AL. From a societal perspective, total savings were US$10,261 at day 14 and US$7,919 at day 28. The equivalent figures from a provider perspective are US$2,520 at day 14 and US$1,944 at day 28. For all treatments, savings were higher at day 14 compared with day 28. The greatest reduction in savings to society between days 14 and 28 was reported for AQ (61%). Comparing the three combination treatments against monotherapy (AQ) showed that from a societal perspective AL was again most-cost-effective at day 14. By day 28 there was only a minor difference between AL and AQ+AS.

The results of the sensitivity analysis are shown in Table 3. The effectiveness of all treatments was strongly influenced by accuracy of diagnosis. For example, assuming that 70% of all patients treated for malaria do not in fact have malaria, the number of incremental cases averted using AL falls from 325 to 98 at day 28 while programme costs remain the same. Each combination treatment is compared to monotherapy, which is also assumed to experience a 70% reduction in accuracy of diagnosis. So while cost-effectiveness falls, combinations such as AL remain better value for money relative to monotherapy by saving more resources and averting more cases of malaria. Changing the subsistence wage rate also led to notable changes in costs, but this, again, did not change the fact that combination treatments such as AL continued to be more cost-effective than monotherapy. Altering drug prices or the discount rate had little effect on the findings of this study.

### Discussion

This is, to our knowledge, the first field-based study to compare the cost-effectiveness of the three available drug combinations recommended by a consultative group of WHO for deployment by countries when they move from monotherapy [2]. For each treatment, two sets of cost-effectiveness ratios were presented. The first set were gross estimates that did not take into account potential resource savings; the second set did (i.e., net cost-effectiveness ratios). Both sets of ratios indicate that, whilst AL is the most expensive drug, in this context of malaria that is highly resistant to both SP and AQ, it is the most-cost-effective of the four malaria treatments. Despite the drop in the effectiveness of all treatments between days 14 and 28 due to a combination of reinfection and recrudescence of malaria, savings at day 28 for AL are one-third higher than the initial programme costs faced by providers and patients.

This clear and striking finding has to be interpreted with three notes of caution, all of which are important in trying to generalise the messages of the study. Firstly, and obviously, AL is the most cost-effective drug despite being the most expensive because it is significantly more effective than other options and is therefore likely to reduce the need for further treatment. This will not, however, necessarily be the case in parts of Africa where recrudescence following SP and AQ treatment (and their combination) is lower, so the relative advantage of this ACT is smaller [19,20]. In particular, where rates of AQ resistance are lower—which they are especially in West Africa—both AQ+AS and AQ+SP will be relatively more cost-effective, and where these combinations are as clinically effective as AL in preventing recrudescence they will be more cost-effective than AL.

Diagnostic accuracy has important operational implications. Our results show that accuracy of diagnosis plays an important role in the estimation of effectiveness of combination therapy for malaria. If cost-effectiveness of ACTs is undermined in this way then political support for them is unlikely to be sustained. In this study, double-read research microscopy was used to confirm malaria and only those with a positive result received treatment. In practice, however, microscopes are not widely used in many parts of Africa and clinical diagnosis tends to be the norm. Moreover, recent studies in Tanzania and elsewhere provide evidence that, in practice, many patients with a negative result go on to be treated for malaria [21]. Drawing on local data demonstrating that between 23% and 70% of all those with a negative test will in fact, be given an antimalarial (H. Reyburn, personal communication), we explored the impact on cost-effectiveness of these misdiagnosis rates. If approximately 70% of patients are wrongly diagnosed with malaria (and in low-transmission settings the proportion can be even higher), then the cost per case averted for AQ+SP compared to AQ rise three-fold. AL and AQ+AS remain dominant over AQ but the economic case for these treatments is weakened since cases averted have fallen and cost savings remain the same. Given the importance of accuracy of diagnosis, we have disaggregated all cost and effects so that cost-effectiveness ratios can be easily recalculated to take account of different levels of diagnostic accuracy. Improving diagnostic accuracy becomes a critical issue if ACTs are to be made more cost-effective and their deployment is to be sustainable.

While resource savings are a legitimate outcome of many interventions they tend inevitably to be less precise than estimates of programme costs. For example, adherence levels may be higher under trial conditions. The data from this study come from an effectiveness study conducted in a setting similar to outpatient practice in children, with drugs taken unsupervised at home, rather than efficacy data from trials where all doses are supervised, but families may have perceived trial-based treatment to be of a higher quality and this may promote adherence and, in turn, cases of malaria averted. The lack of payment for ACTs in the trial reflects the current policy in Tanzania. However, the influx of these drugs in the private sector may give families an incentive to save or to sell extra drugs instead of taking the correct dose [9]. These downward pressures on resource savings will to some extent be countered by other factors such as savings to patients and their families resulting from spending less time travelling to hospital, waiting at hospital for treatment, or caring for sick children at home.

In this study all cost and cost-effectiveness estimates are shown from two perspectives: societal and provider. Depending on the perspective taken the results differ substantially. For example, both the programme costs and the resource savings to patients and their families are greater than those to the health service. This translates into lower cost-effectiveness ratios under a societal perspective than under a provider one. When comparing these results with cost-effectiveness ratios for other malaria control or health interventions it is important to ensure that, as far as possible, like is being compared with like and the starting point for this should be the perspective of the evaluation. Again, we have shown estimates based on both perspectives to allow readers to adopt the one that most suits the context in which they are working.

Finally, it has been suggested that a cost-effectiveness ratio less than double the annual income per capita might be an acceptable threshold value for most governments deciding which intervention to fund [22]. The findings from this study fall well below the average annual per capita income of US$120 for Tanzania [23]. “Thresholds,” however, are only a guide to decision-makers. Medicines such as AL require considerable upfront investment in order to realise any benefits, and in particular are likely to need investment in improving diagnostic accuracy. It is difficult to see how most African governments can meet this challenge alone given that they currently devote less than US$5 per person annually to public health [24]. This study demonstrates that in areas of Africa where monotherapy is failing badly, ACTs, despite being more expensive than monotherapy, can be very cost-effective provided that the drugs are prescribed only to those with malaria. The external investment, which will be needed to subsidise drugs even at current costs, and to improve targeting to those with malaria, is clearly justified on the basis of these data.

### Acknowledgments

The authors would like to thank the participants in this study for sharing their valuable time, and the Superintendent and staff of Muheza Designated District Hospital. We also thank Mohammed Fue, our data collector; Brian Beard for assistance with data management; and Fred Matovu for staff supervision. Logistical support was provided by Dr. William Mwengee and the Bombo and Teule Hospitals in Tanzania. The authors appreciate the helpful comments provided by Dr. Stephen Jan, Professor Anne Mills, and three anonymous referees.

### Author Contributions

VW, TKM, and CJMW designed, and MK subsequently modified, the original study. TKM and CJMW collected and analysed clinical data. MK collected economic data. VW and MK analysed economic data with input from CJMW and TKM. All authors interpreted and wrote the paper. VW is the guarantor of this study.

### References

1. 1. White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, et al. (1999) Averting a malaria disaster. Lancet 353: 1965–1967.
2. 2. World Health Organization (2001) Antimalarial drug combination therapy: Report of a technical consultation. Geneva: WHO. 33 p.
3. 3. Goodman C, Coleman PG, Mills AJ (1999) Cost-effectiveness of malaria control in sub-Saharan Africa. Lancet 354: 378–385.
4. 4. Yeung S, Pongtavornpinyo W, Hastings IM, Mills AJ (2004) Antimalarial drug resistance, Artemisinin-based combination therapy, and the contribution of modelling to elucidating policy choices. Am J Trop Med Hyg 71(Suppl 2): 179–186.
5. 5. Whitty CJ, Allan R, Wiseman V, Ochola S, Nakyanzi-Mugisha MV, et al. (2004) Averting a malaria disaster in Africa—Where does the buck stop? Bull WHO 82: 381–384.
6. 6. Wiseman V, Onwujekwe O, Matovu F, Mutabingwa T, Whitty C (2005) Differences in willingness to pay for amodiaquine+artesunate, amodiaquine+sulfadoxine-pyrimathamine, artemether-lumefantrine or monotherapy: Experiences from Tanzania. Bull WHO 83: 845–852.
7. 7. Arrow KJ, Panosian CB, Gelband H, editors. (2004) Saving lives, buying time: Economics of malaria drugs in an age of resistance. Washington (DC): National Academy Press.
8. 8. Morel C, Lauer J, Evans DB (2005) Achieving the millennium development goals for health: Cost effectiveness analysis of strategies to combat malaria in developing countries. BMJ 331: 1299.
9. 9. Mutabingwa TK, Anthony D, Heller A, Hallett R, Ahmed J, et al. (2005) Amodiaquine alone, amodiaquine + sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: A four-arm randomized effectiveness trial. Lancet 365: 1474–1480.
10. 10. Maxwell CA, Chambo W, Mwaimu M, Magogo F, Carneiro IA, et al. (2003) Variation in malaria transmission and morbidity with altitude in Tanzania and with introduction of alphacypermethrin treated nets. Malar J 10: 28.
11. 11. Alilio MS, Kitua A, Njunwa K, Medina M, Ronn AM, et al. (2004) Malaria control at the district level in Africa: The case of Muheza district in northeast Tanzania. Am J Trop Med Hyg 71: 205–213.
12. 12. Mutabingwa T, Nzila A, Mberu E, Nduati E, Winstanley P, et al. (2001) Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania. Lancet 358: 1218–1223.
13. 13. Green A (1999) An introduction to health planning in developing countries. 2nd Ed. Oxford: Oxford University Press.
14. 14. Sanofi-Aventis and Drugs for Neglected Diseases initiative (DNDi) (2005) A collaborative agreement between DNDi foundation and Sanofi-Aventis to develop a new, easy to use malaria drug at target price below one dollar. Available at: http://en.sanofi-aventis.com/images/44_2​5583.pdf. Accessed: 01 September 2006.
15. 15. World Health Organization (2006) Procurement of artemether-lumefantrine through the WHO. Available at: http://www.who.int/malaria/cmc_upload/0/​000/015/789/CoA_website5.pdf Accessed: 01 September 2006.
16. 16. Kindermans JM, Pecoul B, Perez-Casas C, Den Boer M, et al. (2002) Changing national malaria treatment protocols in Africa: What is the cost and who will pay? Case studies: Burundi, Kenya, Rwanda, Tanzania and Uganda. Medecins Sans Frontiers. 2002 Feb. Available at: http://www.accessmed-msf.org/prod/public​ations.asp?scntid=25220021844238&content​type=PARA&. Accessed: 01 September 2006.
17. 17. Johns B, Baltussen R, Hutubessy R (2003) Programme costs in the economic evaluation of health interventions. Cost Eff Resour Alloc 1: 1.
18. 18. Borghi J, Thapa B, Osrin D, Jan S, Morrison J, et al. (2005) Economic assessment of a women's group intervention to improve birth outcomes in rural Nepal. Lancet 366: 1882–1884.
19. 19. Staedeke SG, Mpimbaza A, Kamya MR, Nzarubara BK, Dorsey G, et al. (2004) Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: Randomised clinical trial. Lancet 364: 1950–1957.
20. 20. Barat L, Chipipa J, Kolczak M, Sukwa T (1999) Does the availability of blood slide microscopy for malaria at health centers improve the management of persons with fever in Zambia? Am J Trop Med Hyg 60: 1024–1030.
21. 21. Reyburn H, Mbatia R, Drakeley C, Carneiro I, Mwakasungula E, et al. (2004) Over diagnosis of malaria in patients with severe febrile illness in Tanzania: A prospective study. BMJ 329: 1212–1218.
22. 22. Garber AM, Phelps CE (1997) Economic foundations of cost-effectiveness analysis. J Health Econ 16: 1–31.
23. 23. Kimemia P (2000) An overview of the performance of the East African economies since 1985: Implications for the new initiative on East African co-operation. Afr Sociol Rev 4: 119–137.
24. 24. Equinet (2004) Equinet Newsletter. 39. 01 May 2004. Available at: http://www.equinetafrica.org/. Accessed 01 September 2006.
25. 25. Budlender (2002) Why should we care about unpaid care work? A guidebook prepared for the United Nations Development Fund for Women, Southern African Region Office, Harare, Zimbabwe. Available at: http://www.idrc.ca/uploads/user-S/112811​20221Debbie_Budlender-_Unpaid_CARE_work.​pdf. Accessed 01 September 2006.

Ambra 2.10.3 Managed Colocation provided
by Internet Systems Consortium.