Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Fernandes S, Sicuri E, Kayentao K, et al. Cost-effectiveness of two versus three or more doses of intermittent preventive treatment for malaria during pregnancy in sub-saharan Africa: a modelling study of meta-analysis and cost data. Lancet Glob Health 2015; 3: e

2 Supplementary appendix Cost effectiveness of 2 vs 3 or more doses Intermittent Preventive Treatment for malaria during pregnancy in diverse settings in Sub-Saharan Africa: modelling of meta-analysis and cost data Silke Fernandes, MSc 1 ; Elisa Sicuri, PhD 2 ; Kassoum Kayentao, MD 3,4 ; Anne Maria van Eijk, PhD 3 ; Jenny Hill, MSc 3 ; Jayne Webster, PhD 1 ; Vincent Were, MSc 5 ; James Akazili, PhD 6 ; Mwayi Madanitsa, MD 7 ; Feiko O. ter Kuile, PhD 3,5 ; Kara Hanson, PhD 1 * - Supplementary appendix o S_Methods o S_Discussion - S_References

3 Supplementary appendix S_Methods The health provider costs: Drug costs for three tablets of SP were estimated by analysing 2012 data from international procurement databases 1,2 and adjusting for wastage (5%), insurance & freight (10%) and internal transport (10%), giving a cost of US$ 0.20 per dose. National salary scales and average allowance packages for different grades of nurses and midwifes for 2012 were averaged across trial countries and used to calculate the average monthly cost of a nurse. The cost of nurses time to administer the intervention was calculated by multiplying the cost per minute of a nurse by the minutes required to administer a dose of IPTp-SP estimated during real time observations of routine and trial antenatal care (ANC) visits in Kenya (N=40), Ghana (N=18) and Malawi (N=18). Data from one non trial country (Ghana) were used to represent Burkina Faso and Mali, because it was the only West African site in which the authors collected observational data. Household costs: The percentage of women attending ANC never, once, twice and three or more times during their most recent pregnancy were estimated using the most recent Demographic Health Survey (DHS) from each country, which took place in 2010 in Burkina Faso, Malawi and Tanzania 3-5, 2008/2009 in Kenya 6, 2007 in Zambia 7 and 2006 in Mali 8. Exit interviews, conducted in 2009 and 2010 at ANC units in Kenya (N=613) 9 and Mali (N=778) 10, provided an estimate of the direct cost of transport to the health facility and indirect cost of time of an ANC visit including duration of labour (valued at the national agricultural wage) lost due to waiting at and travel time to the health facility. Disability-adjusted-life-years (DALYs): DALYs were calculated with a 3% discount rate, based on conventional practice and no age weighting and using average life expectancy at birth (averaged over the six countries across males and females) for LBW and between years (averaged over 6 countries for females only) for estimating years of life lost due to moderate/severe anaemia and

4 clinical malaria 11. For LBW an attributable neonatal mortality risk of 6.9% (95% CI %) as reported by Marchant et al. for East Africa was applied 12, which is comparable to the median attributable neonatal mortality risk for babies born prematurely at appropriate weight for gestational age in Africa (55.8/ 1000 live births) reported by the Child Health Epidemiology Group 13. The case fatality rate used for malaria during pregnancy was 0.33% 14 and for moderate/severe anaemia 1.0% 15. The length of disability for clinical malaria during pregnancy was assumed to be 3.5 days (range 2-6), 21 days for malaria related anaemia (range 14-42) 15 and lifelong for LBW. Willingness-to-pay (WTP) thresholds: We calculated the probability of IPTp-SP3+ being cost effective at three WTP thresholds. In 1993, WHO first articulated thresholds of $25 and $150 per DALY averted as highly attractive and attractive interventions from a policymaker WTP perspective, respectively, here updated to 2012 values of $39.72 and $ WHO-CHOICE currently uses the value of gross domestic product (GDP) per capita as the threshold for being highly cost-effective and one to three times GDP per capita as being cost effective. 17 One GDP per capita in 2012 averaged over the six countries amounted to US$ Deterministic sensitivity analysis table 1 and figure 2: For three scenarios multiple input variables were changed simultaneously: In simultaneously change relative risk all outcomes/low birth weight, all gravidae the relative risk for all outcomes or only for LBW were set simultaneously for all gravidae to the lower or upper *value found in Table 2. Low and high LBW background risk illustrates the change in the ICER if the baseline risk for LBW in both gravidae subgroups was simultaneously set to the minimum or maximum value shown in Table 2. The last four variables represent a structural change: We looked at the hypothetical scenario of delivering the intervention to primi- and secundigravidae only. We explored the cost-effectiveness when only including HIV negative women rather than all women. The health provider perspective only included the cost of providing and administering IPTp-SP. And finally Direct costs represent the results where the indirect costs of time and transport to ANC were excluded from the analysis.

5 * the upper value for all outcomes in G3+ was capped at 1.0, because there is no evidence that suggests giving more doses of IPTp-SP could result in higher numbers of LBW, severe anaemia or clinical malaria.

6 S_Discussion This section contains a more detailed discussion of our results in the context of varying levels of SP resistance: Although SP resistance is heterogeneous across Africa, the results of the meta-analysis are surprisingly consistent and do not show evidence for heterogeneity by resistance level (or transmission intensity), despite being conducted in areas with both low and high SP resistance, and intense perennial as well as highly seasonal transmission. 18 This was illustrated statistically by the I- square value, which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance). The values for the I-square were 0% for both LBW and mean birth weight, showing clearly that it is valid to pool the data. Thus, the consistency of the effect estimates across the trials suggests the results are generalizable within the limits of the resistance levels included in the studies. However, it does not imply that SP efficacy is unaffected at higher levels of resistance. The effectiveness of IPTp-SP in eastern and southern Africa is indeed threatened by increasing parasite resistance to SP, conferred by the successive acquisition of polymorphisms in dhps and dhfr. Three common mutations in the dhfr genes combined with 2 mutations in dhps confer high-grade resistance (the quintuple mutant haplotype) and their association with the failure of SP treatment in children has rendered SP unsuitable for therapy. Areas where sextuple mutant parasites, harbouring either 4 mutations in dhfr (including the additional dhfr-i164l mutation) or 3 mutations in dhps (including dhps-e581g), exceed 10% of the parasite population have recently been described as super-resistant areas. These areas are currently restricted to 3 hot-spots of resistance in northern Tanzania, western Kenya, and southern Uganda. 19 Evidence from other meta-analysis conducted by the Malaria in Pregnancy Consortium reviewed by WHO at the most recent Evidence Review Group meeting in July 2013, show that even in areas where the quintuple dhfr-dhps mutation is common (>90%), IPTp-SP has remained effective. This persistence of the efficacy of SP in areas where the drug has failed as case-management in patients with clinical malaria likely reflects the pregnant women s acquired immunity and their ability to control infections. The notable exception are super-resistant areas where the additional pfdhps-e581g mutation occurs at >10% (Meghna Desai personal communication, Feiko ter Kuile, personal

7 communications). These data suggested that the A581G mutation in dhps (a proxy of the sextuple mutant) could broadly undermine malaria control efforts in pregnant women across sub-saharan Africa, but that there remains a clear role for IPTp-SP in areas where this mutation is still rare. In the source paper by Kayentao et al, the prevalence of the dhps-k540e mutation, a good proxy of the quintuple dhfr-dhps mutant, varied across sites from 0% to 96% prevalence (0, 0, 14, 46, 46, 86, 96%, respectively) and thus included low-grade and high-grade resistant areas, but excluded superresistance areas. Kayentao s results are consistent with the other meta-analysis conducted for WHO and also finds improvements in birth weight with extra doses of SP, even in areas where the prevalence of the pfdhps-k540e mutation was >90%. Since none of the studies were conducted in areas where the E581G mutation was present, our results cannot be (and haven t been) extrapolated to these super resistant areas. However, with the exception of three super-resistant hotspot areas our results are valid for most areas of sub-saharan Africa. Lastly, it is not clear at what rate SP resistance will increase, or indeed whether high-grade resistance will be maintained in the absence of marked drug pressure now that SP has been withdrawn as first line treatment for clinical malaria and is only used for IPTp in pregnant women in most of Africa. In countries with higher potential drug-pressure, such as those in west-africa that have adopted Seasonal Malaria Chemoprophylaxis with SP plus amodiaquine, parasite populations remain highly sensitive to SP with very low prevalence (0% in Burkina Faso and <1% in Mali) of the quintuple haplotype, approximated by the pfdhps-k540e mutation. 19,20

8 S_References 1. Health MSf. International Drug Price Indicator Guide. Accessed 15 August Fund G. The Global Fund Procurement dashboard. Accessed 15 August Parise ME, Ayisi JG, Nahlen BL, et al. Efficacy of sulfadoxine-pyrimethamine for prevention of placental malaria in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infection. Am J Trop Med Hyg. 1998;59(5): Filler SJ, Kazembe P, Thigpen M, et al. Randomized trial of 2-dose versus monthly sulfadoxine-pyrimethamine intermittent preventive treatment for malaria in HIV-positive and HIV-negative pregnant women in Malawi. The Journal of infectious diseases. 2006;194(3): Tanzania Demographic and Health Survey Tanzania National Bureau of Statistics Kenya Demographic and Health Survey 2008/ National Bureau of Statistics, Nairobi, Kenya. 7. Zambia Demographic and Health Survey Central Statistical Office / MOH 8. Mali Demographic and Health Survey Direction Nationale de la Statistique et de l Informatique, Bamako, Mali. 9. Webster JHJ. 10. Webster J, Kayentao K, Bruce J, et al. Prevention of malaria in pregnancy with intermittent preventive treatment and insecticide treated nets in Mali: a quantitative health systems effectiveness analysis. PloS one. 2013;8(6):e Salomon JA, Vos T, Hogan DR, et al. Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study Lancet. 2012;380(9859): Marchant T, Willey B, Katz J, et al. Neonatal mortality risk associated with preterm birth in East Africa, adjusted by weight for gestational age: individual participant level meta-analysis. PLoS Med. 2012;9(8):e Katz J, Lee AC, Kozuki N, et al. Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis. Lancet. 2013;382(9890): Sicuri E, Bardaji A, Nhampossa T, et al. Cost-effectiveness of intermittent preventive treatment of malaria in pregnancy in southern Mozambique. PloS one. 2010;5(10):e Brabin BJ, Hakimi M, Pelletier D. An analysis of anemia and pregnancy-related maternal mortality. J Nutr. 2001;131(2S-2):604S-614S; discussion 614S-615S. 16. United States Department of Labor. Bureau of Labor Statistics: CPI inflation calculator. Accessed 9 December WHO. CHOosing Interventions that are Cost Effective (WHO-CHOICE): cost effectiveness thresholds. Accessed 8 September Kayentao K, Garner P, van Eijk AM, et al. Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis. JAMA : the journal of the American Medical Association. 2013;309(6): Naidoo I, Roper C. Mapping 'partially resistant', 'fully resistant', and 'super resistant' malaria. Trends in parasitology. 2013;29(10): Coulibaly SO, Kayentao K, Taylor S, et al. Parasite clearance following treatment with sulphadoxine-pyrimethamine for intermittent preventive treatment in Burkina-Faso and Mali: 42-day in vivo follow-up study. Malaria journal. 2014;13(1):41.

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