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1 Online data supplement Title: Fluoroquinolone therapy for the prevention of multi-drug resistant tuberculosis in contacts: a cost-effectiveness analysis Authors: Gregory J Fox Olivia Oxlade Dick Menzies E1

2 Supplementary Methods Costs and Utilities The additional cost and the number of additional cases of MDR-TB prevented using the FPT strategy relative to the no treatment strategy was calculated. The outcomes (including costs) were expressed as events (or costs) per 1,000 treated contacts. QALY calculations were based upon weights for disease states were derived studies in relevant populations (E1), shown in Table 1 in the main text. The utility weight for contacts taking FPT therapy was expected to be equivalent to subjects in the no treatment group, consistent with findings among matched contacts of patients with DS-TB treated taking isoniazid preventative therapy (E2). Where relevant, a strategy was considered cost-effective if the incremental cost effectiveness ratio (ICER) was less than the willingness to pay threshold of $50,000 per QALY (E3). Strategies were considered dominant if the expected cost was lower and outcomes were also improved, in which case an ICER was not given. Adverse drug reactions Data from recent randomized controlled trials have demonstrated that long term FQN therapy is safe and well tolerated in treatment of active disease (E4, E5). Consequently, subjects receiving FQN treatment were considered to have a very low risk of developing a severe adverse event (1%) (E6), with a drug related death rate of < 0.01% overall. If subjects developed a severe adverse event, the drug was assumed to be discontinued and therefore ineffective. E2

3 Direct treatment and surveillance costs Direct treatment costs were calculated in $2014 US. Treatment costs were derived from Marks et al (E7) and the 2014 American Hospital Formulary Service Drug information 2014 (E8), adjusted for inflation (8.9% between 2010 and 2014) (9). Costs of six months of FQN The costs of six months of FQN therapy included baseline complete blood count and liver function tests ($ $11.70)*( ), six clinic visits ($38.63 * ( ) * 6) (E7), and the cost of six months of generic levofloxacin ($69.97 for 60 tablets * 3 = $209.91) (E8), a total of $487 per person. Costs of routine surveillance The cost of routine surveillance (no preventive therapy) for those not receiving FQN therapy included four clinic visits over a two-year period ($38.63 * ( ) * 4) and four plain chest radiographs ($30.97 * ( ) * 4), a total cost in $2014 US of $303 per person. Costs of MDR-TB treatment The cost of treatment for MDR-TB were primarily derived from the 2010 treatment costs of Marks et al (E7). The cost of 20 months of 750mg daily brand name levofloxacin, at the drug prices reported by Marks et al ($ per mg, a total of $16,183.93) was deducted from the average cost of treatment ($134,000), and the cost of generic levofloxacin for the same duration was added ($643 in $2010 US) then adjusted for inflation, giving a total treatment cost in $2014 US of $118,459 * ( ), that is $129,001. E3

4 Costs of QMDR-TB treatment The treatment cost of QMDR-TB was derived similarly. The cost of 26 months of 750mg daily brand name levofloxacin, at the drug prices cited by Marks et al ($ per mg, a total of $21,039) (E7) was deducted from the average cost of treatment ($430,000), and the cost of generic levofloxacin given for the same duration was added ($835 in $2010 US) then adjusted for inflation, giving a total treatment cost of $409,796 * ( ), that is $446,268 in $2014 US. Costs of DS-TB treatment The cost of treatment for DS-TB was $17,000 * ( ) (E7), that is $18,513 in $2014 US. Costs of treating severe adverse events The cost of treating severe adverse events was for 7 days of inpatient care at the average rate adjusted for inflation: (7 * $1419) * ( ), a total of $10,817 in $2014 US. E4

5 Supplementary text references E1. de Perio MA, Tsevat J, Roselle GA, Kralovic SM, MH E. Cost-effectiveness of interferon gamma release assays vs tuberculin skin tests in health care workers. Arch Intern Med. 2009;169: E2. Bauer M, Ahmed S, Benedetti A, Greenaway C, Lalli M, Leavens A, Menzies D, Vadeboncoeur C, Vissandjee B, Wynne A, Schwartzman K. The impact of tuberculosis on health utility: a longitudinal cohort study. Qual Life Res E3. Hirth RA, Chernew ME, Miller E, Fendrick AM, Weissert WG. Willingness to pay for a quality-adjusted life year: in search of a standard. Med Decis Making. 2000;20(3): E4. Gillespie SH, Crook A, Mchugh T, Mendel C, Meredith S, Murray S, Pappas F, Phillips P, Nunn A, Consortium ftr. Four-Month Moxifloxacin-Based Regimens for Drug-Sensitive Tuberculosis. N Engl J Med E5. Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, Odhiambo J, Amukoye E, Bah B, Kassa F, N'Diaye A, Rustomjee R, de Jong BC, Horton J, Perronne C, Sismanidis C, Lapujade O, Olliaro PL, Lienhardt C, Project OGfT. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med. 2014;371(17): E6. Liu HH. Safety profile of the fluoroquinolones: focus on levofloxacin. Drug safety 2010;33(5): E7. Marks SM, Flood J, Seaworth B, Hirsch-Moverman Y, Armstrong L, Mase S, Salcedo K, Oh P, Graviss EA, Colson PW, Armitige L, Revuelta M, Sheeran K, Consortium TBES. Treatment practices, outcomes, and costs of multidrug-resistant and extensively drug-resistant tuberculosis, United States, Emerg Infect Dis. 2014;20(5): E5

6 E8. American Society of Health System Pharmacists. American Hospital Formulary Service Drug Information McEvoy G, editor. E6

7 Supplementary Table E1: Incidence of QMDR-TB among infected contacts according to the effectiveness of FPT Incidence of QMDR-TB per 1,000 contacts Effectiveness of FPT No FPT given FPT given Reduction in QMDR- TB with FPT (%) Absolute difference a (% change b ) 10% % 20% % 30% % 40% % 50% % 60% % 70% % 80% % 90% % a Some values may differ slightly on account of rounding. b Percentage reduction under FPT relative to no FPT. Negative values indicate a lower incidence of QMDR- TB under the FPT scenario. FPT = fluoroquinolone preventive therapy. All costs are given in $2014 US. Analyses assuming 60% effectiveness of fluoroquinolone preventive therapy (the base case) are indicated in bold. E7

8 Supplementary Table E2: Sensitivity analysis varying the rate of acquired fluoroquinolone resistance upon the incidence of fluoroquinolone resistant multi-drug resistant disease among infected contacts Incidence of QMDR-TB per 1,000 contacts Proportion of infected contacts taking FPT developing acquired FQN resistance Cases of incident QMDR-TB No FPT Reduction in cases of QMDR-TB with FPT Absolute (%) given FPT given difference (% change b ) 0% % Base case a 1% % 2% % 3% % 4% % 5% % 6% % 7% % 8% % 9% % 10% % a In the base case, used in the main analyses, 1% of contacts treated with FPT acquired additional fluoroquinolone resistance while taking preventive therapy. b Negative values represent cases of QMDR-TB prevented, and positive values represent additional cases of QMDR-TB in the FPT group, compared to the no FPT group. QMDR-TB = multi-drug resistant tuberculosis with additional fluoroquinolone resistance. FQN = fluoroquinolone. FPT = Fluoroquinolone preventive therapy. E8

9 Supplementary Table E3: Projected health system costs of FPT for 6, 9 and 12 months, per 1000 infected household contacts of individuals with MDR-TB Cost according to duration of FPT 6 months 9 months 12 months (baseline case) Health system costs of $487,000 $718,000 $950,000 delivering 6FQN to 1,000 contacts Total health system costs per 1,000 contacts Total cost of no FPT $10,555,343 $10,555,343 $10,555,343 Total cost of FPT $5,292,534 $5,521,343 $5,750,997 Cost difference with FPT * -$5,262,810 -$5,033,484 -$4,804,347 All costs given in 2014 $US. FPT = fluoroquinolone preventive therapy. MDR-TB = multidrug resistant tuberculosis. 6FQN = six months of fluroquinolone, including the purchase of levofloxacin, baseline blood tests and monthly clinic visits for those taking preventive therapy for either 6 months, 9 months or 12 months. * Negative cost difference represents a saving with FPT. E9

10 Supplementary Figure E1: Tornado diagram showing one-way sensitivity analyses showing incremental health system costs of fluoroquinolone preventive therapy EV = -$5,263 Incremental cost of FPT per contact in dollars ($US 2014) This one-way sensitivity analysis shows the incremental costs comparing FPT with no FPT. The vertical line represents the expected incremental cost when the base case of all parameters is used. Negative values represent a reduction in cost in the FPT group. Values are for each contact, and so to obtain values for 1,000 contacts these are multiplied by 1,000. Not all parameters are included only those responsible for the greatest variation are shown. MDR-TB = Multidrug resistant tuberculosis. FPT = fluoroquinolone preventive therapy. EV = expected value. TB = tuberculosis. FQ = fluoroquinolone. AE = adverse events. 6FQ = six months of fluoroquinolone preventive therapy. QMDR-TB = Quinolone Resistant Multidrug resistant TB. E10

11 Supplementary Figure E2: One-way sensitivity analysis of the incremental incidence of MDR-TB, comparing FPT versus no preventive therapy Incremental incidence of MDR-TB (cases of MDR-TB per contact per year) This one-way sensitivity analysis shows the incremental incidence of MDR-TB, comparing FPT with no FPT. The vertical line represents the incremental effects when the base case estimates of all parameters are used. Negative numbers represent a reduction in incidence in the FPT group. Values are for each contact, and so to obtain values for 1,000 contacts these are multiplied by 1,000. Not all parameters are shown, with those responsible for the greatest variation shown. MDR-TB = Multidrug resistant tuberculosis. FPT = fluoroquinolone preventive therapy. EV = expected value (FPT versus no FPT). TB = tuberculosis. FQ = fluoroquinolone. AE = adverse events. 6FQ = six months of fluoroquinolone preventive therapy. QMDR = Quinolone Resistant Multidrug resistant TB. E11

12 Difference in health system costs of preventive therapy per contact compared to no preventive therapy ($2014 US / contact) FPT cost saving Equivalent cost Supplementary Figure E3: Scatter plot showing the health system costs and incidence of MDR-TB among those taking preventive therapy compared with those with no preventive therapy, using probabilistic sensitivity analysis - FPT more effective Difference in the proportion of contacts developing incident MDR-TB with FPT compared to no FPT Equivalent effectiveness The ellipse indicates the 95% Uncertainty Range. The outcomes of 1,000 trials are shown. All points on the graph below the horizontal dashed line, and to the left of the vertical dashed line, are considered cost saving and effective (i.e. dominant), as they represent cost savings and reduced incident MDR-TB with the FPT scenario. FPT = Fluoroquinolone preventive therapy E12