Rationale: Isoniazid given daily for 9 months is the standard treatment for latent tuberculosis infection (LTBI), but its effectiveness is limited by poor completion rates. Shorter course regimens and regimens using directly observed therapy result in improved adherence but have higher upfront costs.
Objectives: To evaluate the costs and cost-effectiveness of regimens for the treatment of LTBI.
Methods: We used a computerized Markov model to estimate total societal costs and benefits associated with four regimens for the treatment of LTBI: self-administered isoniazid daily for 9 months, directly observed isoniazid twice-weekly for 9 months, directly observed isoniazid plus rifapentine once weekly for 3 months, and self-administered rifampin daily for 4 months. In the base-case analysis, subjects were assumed to have newly positive tuberculin skin tests after recent exposure to infectious tuberculosis.
Measurements and Main Results: We determined the costs of treatment, quality-adjusted life-years gained, and cases of active tuberculosis prevented. In the base-case analysis, rifampin dominated (less costly with increased benefits) all other regimens except isoniazid plus rifapentine, which was more effective at a cost $48,997 per quality-adjusted life year gained. Isoniazid plus rifapentine dominated all regimens at a relative risk of disease 5.2 times the baseline estimate, or with completion rates less than 34% for isoniazid or 37% for rifampin. Rifampin could be 17% less efficacious than self-administered isoniazid and still be cost-saving compared with this regimen.
Conclusions: In our model, rifampin is cost-saving compared with the standard therapy of self-administered isoniazid. Isoniazid plus rifapentine is cost-saving for extremely high-risk patients and is cost-effective for lower-risk patients.
The Centers for Disease Control and Prevention describes several different regimens for the treatment of latent tuberculosis infection in adults, but how they compare in terms of costs and effectiveness is largely unknown.
Four months of rifampin is more effective and less expensive than standard therapy with 9 months of isoniazid. Three months of isoniazid plus rifapentine is likely to be a cost-effective alternative if this regimen proves effective.
Rifapentine is a rifamycin derivative with a half-life amenable to weekly administration (10). It is approved for use in the continuation phase of treatment for active TB given once-weekly in combination with isoniazid (11, 12) and has been considered as a treatment for latent TB infection (LTBI). One small study has been completed (13), and a large multicenter trial is underway to determine the efficacy of once-weekly isoniazid plus rifapentine in preventing active TB among high-risk latently infected individuals (clinicaltrials.gov ID NCT00023452).
The cost of this potential new regimen remains an issue. Rifapentine is substantially more expensive than isoniazid and rifampin (M. Kelbaugh, personal communication, December 21, 2007), and the recommendation for DOT adds additional costs. However, increased completion rates of the shorter therapy could compensate for the higher cost if more cases of active TB were prevented (8). In an effort to inform public health policy, we have developed a decision model to examine the overall costs of using these four regimens to treat LTBI given the different resource needs, adherence rates, and effectiveness.
We created a Markov model using TreeAge Pro (release 1.2, 2008; TreeAge Software, Inc., Williamstown, MA) to compare the costs, benefits, and cost-effectiveness of four different treatment regimens for treating a hypothetical cohort of individuals with LTBI (Figure 1): (1) Isoniazid 300 mg given as daily self-administered therapy for 9 months (9H); (2) Isoniazid 900 mg given twice weekly by DOT for 9 months (9H-DOT); (3) Isoniazid 900 mg + rifapentine 900 mg given once weekly by DOT for 12 weeks (3HP); (4) Rifampin 600 mg given as daily self-administered therapy for 4 months (4R). We also included a “no treatment” strategy for comparison. We assumed the patient population was recently infected with TB (e.g., contacts to an infectious case) and that all patients were adults with an average age of 39 years.
We assumed that individuals assigned to a regimen were moved to “off treatment” if they completed their regimen, became nonadherent, experienced a treatment-limiting adverse event, developed active TB, or died (Figure 1). Individuals who developed active TB were at risk of death from TB during the period of TB treatment. After the treatment course, patients were considered cured and moved to the post-TB state. We assumed that no patient developed TB more than once.
Expected value calculations were used to analyze the model using cycles of 1 month duration. Payoffs were calculated for costs, number of active cases, and quality-adjusted life-years (QALYs). We followed the recommendations of the Panel on Cost Effectiveness in Health and Medicine as appropriate (14) and assumed that a strategy was a good use of our economic resources if the incremental cost-effectiveness ratio was $50,000 per QALY or less. Costs and QALYs were discounted at 3%. All costs were converted to 2008 U.S. dollars using the Gross Domestic Product deflator (15).
The base-case analysis estimates and sources for transition probabilities are shown in Table 1, and baseline estimates for costs are shown in Tables 2 and 3. Further information on the estimates used in our analysis can be found in the online supplement.
|Lifetime risk of TB||0.06||0.06–0.4||(2–4, 16)|
|TB risk reduction from 9H-SAT or DOT|
|TB risk reduction from 3HP|
|3 months||0.93||0.60–0.93||(5, 13)|
|TB risk reduction from 4R***|
|Probability of stopping from toxicity|
|Isoniazid-containing||0.014||0.001–0.2||(5, 6, 27, 28)|
|Probability of hospitalization for toxicity|
|Probability of death from drug toxicity|
|Probability of extended treatment (active disease)||0.124||(11)|
|Probability of death from TB||0.03||(20, 32)|
|Number of secondary cases per active case||1.2||0–1.2||(5, 33)|
|Quality of life adjustments (life-years)|
|Treatment of active TB||0.90||0.64–0.93||(32)|
| Prior TB||0.95||0.85–1||(Assumed)|
|Monthly visit costs|
|Nursing visit ($31.97/h)||$17.41||(34)|
|Total visit cost||$66.35||$59.72–$73.00|
|Outreach worker ($16.75/h)||$16.75||(36, 37)|
|Patient time (6 min @ $14.86/h)||$1.49||(36, 37)|
|Driving (10 mi at $0.40/mi)||$4.08||(36, 37)|
|Total DOT cost||$22.32||$0–$33.47|
|Isoniazid, 300 mg||$0.02||(M. Kelbaugh, personal communication)|
|Rifapentine, 150 mg||$2.20||(M. Kelbaugh, personal communication)|
|Rifampin, 300 mg||$0.46||(M. Kelbaugh, personal communication)|
|Pyridoxine, 50 mg||$0.01||(M. Kelbaugh, personal communication)|
|Total monthly costs|
|3HP (with DOT)||$167.82|
| Hospitalization (7 d)||$5,320.77||$4,250–$8,000||(23)|
|Patient time, hours||10||$14.86||$1,634.60||(36)|
|Total inpatient treatment||$9,995.81||$5,000–50,000||(36)|
|Outpatient treatment (mo 1 and 2)|
|Drug, doses||8||$9.06||$72.48||Table 2|
|DOT, visits||8||$22.32||$178.53||Table 2|
|Nursing (30 min)||0.5||$31.97||$15.99||(36)|
|Patient time per monthly visit, hours||1.5||$14.86||$22.29||(36)|
|Total outpatient (mo 1 and 2)||$309.51||$245.00–460.00|
|Outpatient treatment (mo 3+)|
|Drug, doses||8||$0.99||$7.92||Table 2|
|DOT, visits||8||$22.32||$178.53||Table 2|
|Nursing (30 min)||0.5||$31.97||$15.99||(36)|
|Patient time per monthly visit, hours||1.5||$14.86||$22.29||(36)|
|Total outpatient treatment (mo 3+)||$244.95||$195.00–370.00|
|Contact tracing/testing (90% of contacts screened)||5.2||$100.33||$469.52||$375.00–715.00||(22, 23)|
|Total per case—6 months||$12,511.71|
|Total per case—9 months||$13,246.57|
The results from the base-case analysis are shown in Tables 4 and 5. Rifampin (4R) was the least expensive regimen, with an average lifetime cost per contact of $495.21. All regimens reduced costs compared with no treatment except for directly observed isoniazid ($2,002.40 vs. $1,527.30 for 9H-DOT and no treatment, respectively). Compared with no treatment, 9H, 9H-DOT, 4R, and 3HP prevented 43.7, 54, 52, and 56.3 additional cases per 1,000 contacts treated, respectively. All four drug regimens provided increased life expectancy (Table 4).
Average Lifetime Cost Per Contact
Incremental Cost Per Contact
Incremental Effectiveness (QALY)
Cases Per 1,000 Contacts, n
Cases Prevented*, n
Average Lifetime Cost Per Contact
Incremental Cost Per Contact
Incremental Effectiveness (QALY)
Incremental Cost-Effectiveness Ratio
In an analysis of the cost-effectiveness of the alternative strategies, all regimens were dominated (i.e., more expensive with a lower quality-adjusted life expectancy) by 4R, except 3HP, which was more effective than 4R, at a cost of $48,997 per QALY in the base-case analysis (Table 5 and Figure 2). Compared with 9H, 3HP was more effective, at a cost of $25,207 per QALY (Figure 2). Cost-effectiveness results were not sensitive to adjustments in the utility scores over the specified range.
Figure 2 shows the cost-effectiveness plots for the regimens under different assumptions of the relative risk of activation. Increasing the underlying risk of activation resulted in more cases of active TB and therefore higher costs for all regimens, with the greatest cost increases in regimens that prevented the fewest cases. At double the relative risk of activation, 4R and 3HP dominated all other regimens, and 3HP was more effective than 4R, at a cost of $20,099 per QALY. At a relative risk of activation above 5.2 times baseline (consistent with the risk associated with old, healed TB on chest radiograph ), 3HP dominated all other options. 9H-DOT was cost-effective compared with 9H above a relative risk of 5.2 times baseline and was cost-saving compared with 9H at a relative risk of 10 times baseline but was never cost-effective compared with 4R or 3HP.
In one-way sensitivity analyses of adherence, 4R dominated all regimens except 3HP as long as the completion rate for 4R was greater than 54% (base case value = 80%), compared with base-case estimates for other regimens. 3HP dominated all other regimens in situations where poor adherence to both of the self-administered regimens was present (completion rates of 34 and 37% for 9H and 4R, respectively).
When estimated risk reductions from treatment were varied over the range of possible values, rifampin maintained a cost advantage even with substantially reduced efficacy. 4R could be up to 17% less efficacious than 9H and still be less expensive and more effective than 9H. If the risk reduction from 3HP was less than the base-case estimate of 93% (i.e., less efficacious than 9H), the incremental cost-effectiveness ratio crossed the $50,000 per QALY cost-effectiveness threshold.
Results were not sensitive to changes in the probabilities of severe toxicity, hospitalization from toxicity, or death from toxicity over the specified ranges.
Because the costs associated with DOT had an impact on the up-front expenditures of the two regimens that used this strategy, we conducted sensitivity analyses to determine threshold values of cost and adherence estimates. First, in a simple, one-way sensitivity analysis, we determined that DOT had to cost less than $1.00 per dose (base-case value = $22.32) before 3HP would become less expensive than, and therefore dominate, 4R. Next, we considered the impact of not using DOT for 3HP, in which case the cost of delivering the doses would be $0. (We did not include 9H-DOT in this analysis because without DOT it would be equivalent to 9H.) Without DOT, completion rates for 3HP would have to be at least 88% to remain cost-effective and at least 93% to be cost-saving, due mostly to the higher cost of rifapentine.
We then examined the effects of a price reduction for rifapentine on the results of our model. If costs for DOT are included, there is no threshold cost for rifapentine below which 3HP becomes cost-saving. If direct observation is not used, 3HP would become cost-saving at or below a price of $0.46 per rifapentine pill (the same cost per pill as rifampin) at a completion rate of 80%.
The primary results were not sensitive to the costs of treatment of active disease (including hospitalization). They were also not sensitive to the costs of toxicity included in the analysis.
In our analysis, 4R was the least expensive regimen for the treatment of LTBI. Over the patient's lifetime, the 4R regimen was less expensive and more effective than the current standard of care (i.e., 9H) over a wide range of estimates for adherence and efficacy. Although more expensive than 4R or 9H, 3HP was more effective, at a cost of $48,997 per QALY compared with 4R and $25,207 compared with 9H, and would therefore be considered cost-effective using our threshold of $50,000 per QALY. Furthermore, this regimen became cost-saving for patients at very high risk or at extreme likelihood of treatment nonadherence. For example, patients with HIV infection have a risk of activation approximately 10 times the baseline estimate (16), so 3HP may be cost-saving in these individuals. However, the cost-effectiveness of 3HP at baseline risk was highly sensitive to its efficacy relative to 9H and to our estimates for adherence. If the ongoing large clinical trial shows that 3HP is less efficacious than 9H, its use would likely be restricted to these highest-risk individuals unless the price is reduced and self-administered therapy is considered an acceptable option.
Isoniazid given by DOT for 9 months was very expensive in our model and did not compare favorably to the other regimens. Nonetheless, this regimen may be useful in instances where nonadherence to self-administered therapy is likely and rifamycins are contraindicated, such as in patients taking boosted HIV protease inhibitors. Additionally, two studies looking at the cost-effectiveness of observed isoniazid in drug users found it to be cost-saving compared with no therapy (17, 18). In both instances, however, the costs of DOT were very low because the procedures were performed by clinic staff already seeing the patients for other purposes, and no shorter regimens were compared.
Our model is the first to directly compare all three CDC-recommended regimens for the treatment of LTBI. Our data are consistent with recent cost data obtained by Aspler and colleagues in a randomized, controlled trial of isoniazid versus rifampin (19). Based on their cost projections, 4 months of rifampin could be 20% less efficacious than isoniazid and still be cost-saving. Conversely, Kahn and colleagues compared isoniazid, rifampin, and rifampin plus pyrazinamide in recent immigrants and found that rifampin was more costly than isoniazid for most patients (but more effective), although their estimated drug costs for rifampin were substantially higher than our current data ($97.70/mo vs. $27.70/mo). A notable difference between this study and ours is their focus on drug resistance patterns. We assumed that everyone in our model was infected with organisms susceptible to all drugs. However, because isoniazid resistance is the most common resistance pattern seen in the United States (20), incorporation of susceptibility patterns into our model would have biased the results further toward rifampin monotherapy.
One significant limitation to our study is the fact that limited data exist to derive point estimates for the efficacy and adherence to 3HP. We used a wide range of parameters in sensitivity analyses, but adherence rates for this regimen without DOT have never been published. In one retrospective study comparing adherence to daily and weekly self-administered alendronate, patients taking the weekly regimen were more adherent over a 1-year period (21), but whether this pattern would be shared with 3HP in a population of patients with LTBI is unknown. If TB programs begin to use isoniazid plus rifapentine in the future without direct observation, publication of data on adherence would be necessary to evaluate its overall utility.
In our model, the costs for each regimen were driven largely by the costs associated with active cases. We used a conservative approach, attempting to reproduce the current costs of treating active TB as much as possible. Other studies have used data from Brown and colleagues (22) in their estimates of the cost of treating an active case, but in that study an average of 77% of patients were hospitalized for an average of 20 days. More recent data from Taylor and colleagues (23) suggest that many fewer patients are hospitalized and for shorter periods, and we used these estimates in our study. There is also some controversy over the total costs associated with active TB. Most studies only include the costs of acute treatment of active disease. However, Pasipanodya and colleagues (24) demonstrated significant respiratory impairment after the treatment of active TB (2), and the societal costs associated with this morbidity may be over $150,000 per case (23). If these costs are included, our model predicts that 3HP would be more effective and less expensive even for very low-risk individuals (data not shown).
Isoniazid remains the standard of care for treating LTBI in adults in the developed world. However, if the efficacy of isoniazid plus rifapentine is confirmed in the ongoing clinical trial, our model suggests that this combination will be a more effective and less expensive alternative for high-risk individuals, particularly those with HIV, and will be cost-effective even for lower-risk patients. Meanwhile, our results indicate that increased use of 4 months of rifampin in place of 9 months of isoniazid to treat LTBI would be cost-saving for most programs in the United States and Canada.
|1.||Centers for Disease Control and Prevention. Guidelines for the investigation of contacts of persons with infectious tuberculosis: recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005;54:1–47.|
|2.||Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Recomm Rep 2000;49:1–51.|
|3.||Comstock GW. Frost revisited: the modern epidemiology of tuberculosis. Am J Epidemiol 1975;101:363–382.|
|4.||Horsburgh CR Jr. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004;350:2060–2067.|
|5.||International Union against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull World Health Organ 1982;60:555–564.|
|6.||LoBue PA, Moser KS. Use of isoniazid for latent tuberculosis infection in a public health clinic. Am J Respir Crit Care Med 2003;168:443–447.|
|7.||Menzies D, Dion MJ, Rabinovitch B, Mannix S, Brassard P, Schwartzman K. Treatment completion and costs of a randomized trial of rifampin for 4 months versus isoniazid for 9 months. Am J Respir Crit Care Med 2004;170:445–449.|
|8.||Jasmer RM, Snyder DC, Chin DP, Hopewell PC, Cuthbert SS, Antonio PE, Daley CL. Twelve months of isoniazid compared with four months of isoniazid and rifampin for persons with radiographic evidence of previous tuberculosis: an outcome and cost-effectiveness analysis. Am J Respir Crit Care Med 2000;162:1648–1652.|
|9.||Lardizabal A, Passannante M, Kojakali F, Hayden C, Reichman LB. Enhancement of treatment completion for latent tuberculosis infection with 4 months of rifampin. Chest 2006;130:1712–1717.|
|10.||Weiner M, Bock N, Peloquin CA, Burman WJ, Kahn A, Vernon A, Zhao Z, Weis S, Sterling TR, Hayden K. et al. Pharmacokinetics of rifapentine at 600, 900, and 1,200 mg during once-weekly tuberculosis therapy. Am J Respir Crit Care Med 2004;169:1191–1197.|
|11.||Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, Gordin F, Horsburg CR, Horton J, Kahn A. et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002;360:528–534.|
|12.||Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, Fujiwara P, Grzemska M, Hopewell PC, Iseman MD. et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003;167:603–662.|
|13.||Schechter M, Zajdenverg R, Falco G, Barnes GL, Faulhaber JC, Coberly JS, Moore RD, Chaisson RE. Weekly rifapentine/isoniazid or daily rifampin/pyrazinamide for latent tuberculosis in household contacts. Am J Respir Crit Care Med 2006;173:922–926.|
|14.||Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel on Cost-effectiveness in Health and Medicine. JAMA 1996;276:1253–1258.|
|15.||Gross Domestic Product Deflator Inflation Calculator. Budget of the United States Government, Fiscal year 2005, historical tables [Internet]. (accessed October 16, 2008). Available from:|
|16.||Moss AR, Hahn JA, Tulsky JP, Daley CL, Small PM, Hopewell PC. Tuberculosis in the homeless: a prospective study. Am J Respir Crit Care Med 2000;162:460–464.|
|17.||Gourevitch MN, Alcabes P, Wasserman WC, Arno PS. Cost-effectiveness of directly observed chemoprophylaxis of tuberculosis among drug users at high risk for tuberculosis. Int J Tuberc Lung Dis 1998;2:531–540.|
|18.||Perlman DC, Gourevitch MN, Trinh C, Salomon N, Horn L, Des J. Cost-effectiveness of tuberculosis screening and observed preventive therapy for active drug injectors at a syringe-exchange program. J Urban Health 2001;78:550–567.|
|19.||Aspler A, Dion MJ, Long R, Trajman A, Yang J, Al Jahdali H, Khan K, Gardam M, Wobeser W, Hoeppner V, et al. Costs and cost-effectiveness of a randomized trial of 4 months rifampin versus 9 months of isoniazid for treatment of latent tuberculosis infection (LTBI) [abstract]. Am J Respir Crit Care Med 2008;177:A790.|
|20.||Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2006. (Accessed September 9, 2007.) Available from: .|
|21.||Rabenda V, Mertens R, Fabri V, Vanoverloop J, Sumkay F, Vannecke C, Desaef A, Verpooten GA, Reginster JY. Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women. Osteoporos Int 2008;19:811–818.|
|22.||Brown RE, Miller B, Taylor WR, Palmer C, Bosco L, Nicola RM, Zelinger J, Simpson K. Health-care expenditures for tuberculosis in the United States. Arch Intern Med 1995;155:1595–1600.|
|23.||Taylor Z, Marks SM, Rios Burrows NM, Weis SE, Stricof RL, Miller B. Causes and costs of hospitalization of tuberculosis patients in the United States. Int J Tuberc Lung Dis 2000;4:931–939.|
|24.||Pasipanodya JG, Miller TL, Vecino M, Munguia G, Bae S, Drewyer G, Weis SE. Using the St. George respiratory questionnaire to ascertain health quality in persons with treated pulmonary tuberculosis. Chest 2007;132:1591–1598.|
|25.||Miller TL. A cost analysis of tuberculosis and its prevention in Tarrant County, Texas [MS thesis]. University of North Texas, 2007.|
|26.||Kohn MR, Arden MR, Vasilakis J, Shenker IR. Directly observed preventive therapy: turning the tide against tuberculosis. Arch Pediatr Adolesc Med 1996;150:727–729.|
|27.||Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999;281:1014–1018.|
|28.||Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006;174:935–952.|
|29.||Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A double-blind placebo-controlled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Am Rev Respir Dis 1992;145:36–41.|
|30.||Menzies D, Long R, Trajman A, Dion MJ, Yang J, Al Jaldali H, Memish Z, Khan K, Gardam M, Hoeppner V, et al. Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial. Ann Intern Med 2008;149:689–697.|
|31.||Page KR, Sifakis F, de Montes OR, Cronin WA, Doherty MC, Federline L, Bur S, Walsh T, Karney W, Milman J, et al. Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study. Arch Intern Med 2006;166:1863–1870.|
|32.||State of North Carolina Tuberculosis Control Program. 2007 tuberculosis statistics for North Carolina. (Accessed December 19, 2008.) Available from: .|
|33.||Salpeter EE, Salpeter SR. Mathematical model for the epidemiology of tuberculosis, with estimates of the reproductive number and infection-delay function. Am J Epidemiol 1998;147:398–406.|
|34.||Guo N, Marra CA, Marra F, Moadebi S, Elwood RK, FitzGerald JM. Health state utilities in latent and active tuberculosis. Value Health 2008;11:1154–1161.|
|35.||Salpeter SR, Sanders GD, Salpeter EE, Owens DK. Monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 35 years of age: a risk-benefit and cost-effectiveness analysis. Ann Intern Med 1997;127:1051–1061.|
|36.||Burman WJ, Dalton CB, Cohn DL, Butler JR, Reves RR. A cost-effectiveness analysis of directly observed therapy vs self-administered therapy for treatment of tuberculosis. Chest 1997;112:63–70.|
|37.||Snyder DC, Chin DP. Cost-effectiveness analysis of directly observed therapy for patients with tuberculosis at low risk for treatment default. Am J Respir Crit Care Med 1999;160:582–586.|