Factors associated with catastrophic total costs due to tuberculosis under a designated hospital service model: a cross-sectional study in China.

BACKGROUND: Certain districts and counties in China designated local general hospital as the designated hospital for tuberculosis (TB) management after the promulgation of the Law of Practicing Physicians in 2009. To our knowledge, there is limited research on catastrophic payments of TB patients under this service model, often with inconsistent conclusions. In addition, there has been no published studies from China using the updated 2018 World Health Organization (WHO) definition of catastrophic total costs due to TB. This study used the latest criterion recommended by the WHO to analyze the incidence of catastrophic total costs for households affected by TB under the designated hospital model and explore its influencing factors. METHODS: A cross-sectional analysis was carried out in all ten designated hospitals in Ningbo, China. Eligible pulmonary TB cases confirmed by sputum culture of Mycobacterium tuberculosis were recruited and surveyed from September 2018 to October 2018. We evaluated catastrophic total costs using total costs for TB treatment exceeding 20% of the household's annual pre-TB income. A sensitivity analysis was performed while varying the thresholds. The least absolute shrinkage and selection operator (LASSO) regression were applied to select variables, and multiple logistic regression analysis were used to identify the determinants of catastrophic total costs. RESULTS: A total of 672 patients were included, with a median age of 41 years old. The rate of catastrophic total costs of surveyed households was 37.1%, and that of households affected by MDR was 69.6%. Medical cost accounted for more than 60% of the total cost. 57.7% cases were hospitalized. The hospitalization rates of patients with no comorbidities, no severe adverse drug reactions, and rifampin-sensitive TB were 53.9, 54.9, and 55.3%, respectively. Patients in the poorest households had the highest hospitalization rates (Q1:54.8%, Q2:61.4%, Q3:52.2%, Q4:49.5%, Q5:69.7%, P = 0.011) and the highest incidence of severe adverse drug reactions (Q1:29.6%, Q2:19.6%, Q3:28.0%, Q4:33.7%, Q5:35.3%, P = 0.034). Factors such as elderly, minimum living security, unemployed before or after illness, poor economic status, seeking medical care outside the city, hospitalization, absence of local basic medical insurance coverage and MDR were positively associated with catastrophic costs. CONCLUSION: Substantial proportions of patients and households affected by pulmonary TB faced catastrophic economic risks in Ningbo, China. The existing policies that focus on expanding the coverage of basic medical insurance and economic protection measures (such as cash transfers to compensate low-income households for direct non-medical costs and income loss) might be insufficient. Tailored program that mitigate inappropriate healthcare and address equity of care delivery are worthy of attention.

Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis.

The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2 µg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax ≥ 22 µg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) ≥ 70 µg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.

SIRCLE: a randomised controlled cost comparison of self-administered short-course isoniazid and rifapentine for cost-effective latent tuberculosis eradication.

BACKGROUND: Currently, treatment of latent tuberculosis infection (LTBI) in Australia consists most commonly of a 9-month course of isoniazid (9H). A 3-month course of weekly isoniazid and rifapentine (3HP) has been shown to be as effective as 9 months of daily isoniazid, and associated with less hepatotoxicity; however, rifapentine is not currently available in Australia. Introduction of this regimen would have apparent advantages for people with LTBI in Victoria by safely shortening duration of LTBI therapy. However, the cost benefit of this new therapeutic approach is uncertain. AIM: Cost-analysis of standard and short-course therapy for LTBI in an Australian context. METHODS: Single-centre randomised controlled trial conducted between December 2013-March 2016. Participants underwent 1:1 randomisation to either a 9-month course of daily isoniazid or a 12-week course of weekly isoniazid and rifapentine. The primary outcome measure was total healthcare system costs (in Australian dollars; AUD) per completed course of LTBI therapy. Secondary cost analyses were performed to consider varying assumptions regarding commercial cost of rifapentine. RESULTS: Overall, 34 of 40 (85%) participants in the 9H group and 36/40 (90%) in the 3HR group completed therapy. One patient in the 3HP group was hospitalised for a febrile illness; no hospitalisations were recorded in the 9H group. The cost per completed course of 9H was 601 AUD, while that of 3HP was significantly lower at 511 AUD (P < 0.01). CONCLUSIONS: This study provides cost analysis evidence to support the use of 3HP for the treatment of LTBI in Australia.

Safety and completion of a 4-month course of rifampicin for latent tuberculous infection in children.

SETTING: Children's Tuberculosis Clinic, Houston, Texas. OBJECTIVE: To describe adherence to and tolerability of 4 months of rifampicin (4RMP) compared to 9 months of isoniazid (9INH) in children with latent tuberculous infection (LTBI). DESIGN: Retrospective descriptive case series of children treated for LTBI from 2010 to 2013 by self-administered therapy or directly observed preventive therapy (DOPT) administered by the local health department. RESULTS: Four hundred and four children were treated, 324 (80%) with 9INH and 80 with 4RMP: the mean age was 7.3 years, and 47% were girls. Of these, 37% were identified during contact investigations. DOPT was used in 51% and self-administered therapy in 49%; 81% completed therapy. Completion of self-administered 4RMP therapy was not significantly different from completion rates for children receiving 9INH administered as DOPT (93% vs. 88%, OR 0.6, 95%CI 0.2-1.7), but was significantly higher than in the 9INH self-administration group (OR 7.9, 95%CI 2.7-23.2). Adverse events were rare: 20 (6%) in the 9INH group and 2 (3%) in the 4RMP group, and none was serious. CONCLUSION: Completion rates for 4RMP surpassed those of 9INH for all methods of delivery, except for DOPT, where completion rates were similar. 4RMP was well tolerated. The increased cost of 4RMP over 9INH may be offset by increased effectiveness, as gauged by completion rates.

A user-friendly, open-source tool to project impact and cost of diagnostic tests for tuberculosis.

Most models of infectious diseases, including tuberculosis (TB), do not provide results customized to local conditions. We created a dynamic transmission model to project TB incidence, TB mortality, multidrug-resistant (MDR) TB prevalence, and incremental costs over 5 years after scale-up of nine alternative diagnostic strategies. A corresponding web-based interface allows users to specify local costs and epidemiology. In settings with little capacity for up-front investment, same-day microscopy had the greatest impact on TB incidence and became cost-saving within 5 years if delivered at $10/test. With greater initial investment, population-level scale-up of Xpert MTB/RIF or microcolony-based culture often averted 10 times more TB cases than narrowly-targeted strategies, at minimal incremental long-term cost. Xpert for smear-positive TB had reasonable impact on MDR-TB incidence, but at substantial price and little impact on overall TB incidence and mortality. This user-friendly modeling framework improves decision-makers' ability to evaluate the local impact of TB diagnostic strategies.

Impact of GeneXpert MTB/RIF on patients and tuberculosis programs in a low-burden setting. a hypothetical trial.

RATIONALE: Guidelines recommend routine nucleic-acid amplification testing in patients with presumed tuberculosis (TB), but these tests have not been widely adopted. GeneXpert MTB/RIF (Xpert), a novel, semiautomated TB nucleic-acid amplification test, has renewed interest in this technology, but data from low-burden countries are limited. OBJECTIVES: We sought to estimate Xpert's potential clinical and public health impact on empiric treatment, contact investigation, and housing in patients undergoing TB evaluation. METHODS: We performed a prospective, cross-sectional study with 2-month follow-up comparing Xpert with standard strategies for evaluating outpatients for active pulmonary TB at the San Francisco Department of Public Health TB Clinic between May 2010 and June 2011. We calculated the diagnostic accuracy of standard algorithms for initial empiric TB treatment, contact investigation, and housing in reference to three Mycobacterium tuberculosis sputum cultures, as compared with that of a single sputum Xpert test. We estimated the incremental diagnostic value of Xpert, and the hypothetical reductions in unnecessary treatment, contact investigation, and housing if Xpert were adopted to guide management decisions. MEASUREMENTS AND MAIN RESULTS: A total of 156 patients underwent Xpert testing. Fifty-nine (38%) received empiric TB treatment. Thirteen (8%) had culture-positive TB. Xpert-guided management would have hypothetically decreased overtreatment by 94%, eliminating a median of 44 overtreatment days (interquartile range, 43-47) per patient and 2,169 total overtreatment days (95% confidence interval, 1,938-2,400) annually, without reducing early detection of TB patients. We projected similar benefits for contact investigation and housing. CONCLUSIONS: Xpert could greatly reduce the frequency and impact of unnecessary empiric treatment, contact investigation, and housing, providing substantial patient and programmatic benefits if used in management decisions.

Protease inhibitor-containing antiretroviral treatment and tuberculosis: can rifabutin fill the breach?

OBJECTIVE: To assess how to best manage co-administration of rifabutin (RFB) and human immunodeficiency virus 1 (HIV-1) protease inhibitor (PI) containing antiretroviral treatment (ART). Recommended for initial anti-tuberculosis treatment, rifampicin (RMP) lowers PI concentrations below therapeutic levels, posing significant challenges for ART. As RFB has little effect on PI concentrations, it could be an alternative to RMP. METHODS: A review of the scientific literature on the safety and efficacy of RFB for adult tuberculosis (TB) treatment was conducted, focusing on ART-TB co-therapy. A cost comparison was performed between treatment regimens, and estimates of the burden of TB disease in patients on ART were used to model RFB demand in low- and middle-income countries (LMICs). RESULTS: Eleven clinical studies were identified, comprising 1543 TB patients treated with RFB; 980 (64%) were living with HIV. RFB was as safe and effective as RMP, including in 313 patients receiving co-administered ART (unboosted PIs included indinavir, nelfinavir or saquinavir; a minority received ritonavir [RTV] boosted amprenavir or saquinavir). The total cost for 6 months of all HIV and TB treatment containing RTV-boosted lopinavir (LPV) and RFB is US$410, compared to US$455 if RMP is used with LPV super-boosted with RTV. Our model suggests that demand for RFB in LMICs could be between 10,000 and 18,000 courses by 2012. CONCLUSION: RFB is effective and safe in combination with the PIs studied, cost-saving for co-therapy with currently recommended boosted PIs, and may have a pivotal role in the roll-out of ART. Further research into a daily dose of RFB to simplify dosing regimens and developing fixed-dose combinations can enhance the public sector roll-out of ART.

Impact of treatment completion, intolerance and adverse events on health system costs in a randomised trial of 4 months rifampin or 9 months isoniazid for latent TB.

RATIONALE: Treatment for latent tuberculosis infection with isoniazid for 9 months (9INH) has poor completion and serious adverse events, while treatment for 4 months with daily rifampin (4RIF) has significantly higher completion and fewer adverse events. OBJECTIVES: To compare the health system costs of 4RIF and 9INH. METHODS: In a randomised trial conducted in five Canadian centres, one Brazilian and one Saudi Arabian centre, consenting subjects were randomised to receive 4RIF or 9INH. Health system costs were estimated from healthcare utilisation including scheduled and unscheduled visits, investigations and drugs. All activities for all subjects were evaluated using financial information from 2007 from the Montreal Chest Institute. Costs were expressed in Canadian dollars. RESULTS: Total health system cost per patient allocated to 4RIF was $854 compared with $970 for 9INH (p<0.0001). The average cost per patient for the 328 of 420 (78%) who completed 4RIF therapy was $1094 compared with $1625 for the 254 of 427 (60%) completing 9INH (p<0.0001). Costs were modestly increased in patients with minor intolerance and substantially increased if the treating physician stopped treatment because of possible adverse events. Total costs related to management of adverse events with 9INH were $48 142 compared with $25 684 for 4RIF (p=0.008). Using these data, incremental cost-effectiveness analyses showed that 4RIF would be cost saving and prevent more cases within 2 years if efficacy exceeded 74%, and cost saving if efficacy exceeded 65%. CONCLUSIONS: The 4RIF regimen was significantly cheaper per patient completing treatment because of better completion and fewer adverse events.

Tuberculosis prevention in Mexican immigrants: limitations of short-course therapy.

BACKGROUND: Two months of rifampin and pyrazinamide (RIF/PZA) for tuberculosis prevention has been advocated as a way to improve adherence in mobile populations, such as recent immigrants. However, RIF/PZA requires intensive patient and laboratory monitoring for hepatotoxicity. OBJECTIVES: To describe the feasibility and outcomes of using RIF/PZA for TB prevention during a tuberculosis outbreak in a Mexican immigrant community, where 23 adults and 11 children were treated with RIF/PZA between August 2001 and October 2001. METHODS: Retrospective chart review and interviews with health department employees were conducted to assess completion rates, hepatotoxicity, cost, and feasibility of monitoring. RESULTS: Ten (91%) children and 13 (57%) adults completed RIF/PZA. One child (9%) and four adults (17%) developed drug-induced hepatitis. Cultural barriers affected care. The adults resisted the biweekly blood draw, believing it would "drain them of energy." RIF/PZA, plus monitoring, was twice as costly as 4 months of rifampin. CONCLUSIONS: RIF/PZA was associated with significant hepatotoxicity, poor completion, and cultural barriers to monitoring, and was more costly than standard therapy. Tuberculosis prevention must address potential clinical, cultural, and economic barriers to completion and monitoring of short-course therapy in immigrants.

Value of antimicrobials in the prevention and treatment of tuberculosis in the United States.

OBJECTIVE: To estimate the economic value of antimicrobials for the prevention and treatment of tuberculosis in the United States from 1954 through 1997. DESIGN: Published sources were used to estimate the burden of illness (direct medical costs, reductions in quality of life, and years of life lost) from active tuberculosis (TB) cases diagnosed between 1954 and 1997. Published literature concerning the pre-antimicrobial incidence rate and treatment of TB were extrapolated to estimate the burden of illness that would have occurred in the absence of antimicrobials. RESULTS: Between 1954 and 1997, the use of antimicrobials reduced the number of newly diagnosed cases of active TB by 32% (relative to the number that would have occurred in the absence of antimicrobials), the number of mortalities by 81%, the number of life-years lost by 87%, and the cost of medical treatment by 76%. The total financial burden of illness over this time period (including the value of lost life-years) was reduced from $894 billion (in 1997 dollars) to $128 billion. CONCLUSION: TB antimicrobials had a substantial health impact in the US from 1954 to 1997. This quantitative assessment of the economic impact of innovative biopharmaceutical products demonstrates the importance of continuing medical innovation.

[Pharmacoeconomic model of the use of rifabutin in new cases of pulmonary tuberculosis]. / Farmakoékonomicheskaia model' primeneniia rifabutina u bol'nykh s vpervye vyiavlennym tuberkulezom legkikh.

The formalized procedures to commensurate the results and expenditures were used to make a comprehensive evaluation of the clinical efficiency and economical expediency of purposeful application of rifabutin in new cases of disseminated and destructive pulmonary tuberculosis.

Review of the Indian market of anti-tuberculosis drugs: focus on the utilisation of rifampicin-based products.

SETTING: There is a need to better understand the extent of the utilisation of rifampicin in the market, particularly in fixed-dose combinations (FDC). OBJECTIVE: To review the Indian market of antituberculosis drugs, as this is the largest single market in the world of this therapeutic class. DESIGN: Review and analysis of the sales data proffered by the Indian market audit. Estimated data relating to public sector product usage were utilised in order to obtain a more complete scenario. RESULTS: The use of rifampicin-based products is very important in the Indian market of anti-tuberculosis drugs. Particularly common is the use of FDCs, which represent 62% of anti-tuberculosis drugs sold in the private market. CONCLUSIONS: The Indian market for anti-tuberculosis drugs is very large and well integrated. FDCs are widely used. In addition to double- and triple-drug FDCs, four-drug combinations have recently been introduced into the market. The Indian industry also exports raw materials and pharmaceutical specialities.

Estimate of the global market for rifampicin-containing fixed-dose combination tablets.

SETTING: Despite WHO and IUATLD recommendations to use fixed-dose combination (FDC) tablets for treatment of tuberculosis, more than 75% of all rifampicin used in the public sector globally is administered as single drug tablets. OBJECTIVE: To estimate the potential global market for rifampicin-containing FDCs in the public and private sectors. DESIGN: The public sector market for FDCs was calculated from the number of tuberculosis cases notified to WHO for 1996 and from information on treatment regimens currently used in each country. The private sector market was calculated from the estimated number of treated tuberculosis cases and the treatment regimens presumed to be used in the private sector. RESULTS: The potential global market for the four-drug FDC tablet (rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg) is 305 (90%CI 145-505) million tablets per year, 105 (90%CI 50-160) and 200 (90%CI 95-345) million of which would be distributed in the public and private sectors, respectively. The uncertainty of the estimate remains considerable, as shown by the 90% confidence intervals. CONCLUSION: The study demonstrated a large potential global market for FDCs that should encourage pharmaceutical manufacturers to produce WHO-recommended dosages of FDCs at affordable prices.

Rifapentine: its role in the treatment of tuberculosis.

OBJECTIVE: To review the pharmacokinetics, efficacy, adverse effects, and cost of the newest antitubercular drug, rifapentine. DATA SOURCES: A MEDLINE search using key terms such as rifapentine, rifampin, isoniazid, Mycobacterium tuberculosis, and pyrazinamide was conducted for the time period 1966-November 1998. STUDY SELECTION: Animal data were used for basic information and human studies were selected for inclusion if they were randomized, controlled studies assessing efficacy, or if they were single- or multiple-dose studies assessing the pharmacokinetics of rifapentine. Background articles on the pathophysiology of tuberculosis and cost of care and noncontrolled studies assessing drug interactions were also included. DATA SYNTHESIS: Compared with an oral solution, the relative bioavailability of rifapentine is 70% following oral admninistration of tablets. Food increased bioavailability by 55%. Rifapentine accumulated significantly in human macrophages and its elimination half-life was longer than that of rifampin. Comparative studies of rifapentine and rifampin in humans during intensive- and continuation-phase treatment of tuberculosis suggest that at currently accepted doses, rifapentine was slightly less effective than rifampin. The most significant drug interaction with rifapentine involves indinavir: the maximum concentration and AUC of indinavir are reduced by 55% and 70%, respectively, when rifapentine is coadministered with indinavir. Adverse events of rifapentine may occur less frequently at the currently recommended 600-mg dose as compared with rifampin; however, the difference was not statistically significant. If only drug costs were evaluated during the six-month treatment of tuberculosis, rifapentine is more expensive than rifampin. CONCLUSIONS: Rifapentine can be administered twice weekly during the intensive phase of tuberculosis treatment and then once weekly during the continuation phase of treatment. This may improve patient adherence over some other treatments and possibly reduce costs of treatment by preventing development of resistant tubercular strains due to nonadherence. Rifapentine is well tolerated, with most patients experiencing adverse effects at a similar rate as rifampin. Rifapentine induces cytochrome P450 somewhat less than rifampin, although few drug interaction studies have been done with rifapentine. Its efficacy at the currently approved dosage of 600 mg may be slightly lower than that of rifampin. Studies are needed to determine if equal or greater efficacy can be achieved with higher doses of rifapentine. Rifampin is less expensive than rifapentine. Further pharmacoeconomic studies are needed to evaluate costs of relapse and failure in patients receiving these agents.

[Comparative study on efficacy of regimens including streptomycin or ethambutol].

OBJECTIVE: To evaluate the advantages and disadvantages of regimens of 2E3H3R3Z3/4H3R3(EMB regimen) and 2S3H3R3Z3/4H3R3(SM regimen) in tuberculosis control program. METHOD: Retrospective, cross-sectional and prospective studies were carried out in Shijiazhuang city, Hebei province from January 1994 to June 1996. RESULT: There was no significant difference between the two regimens in efficacy, relapse rate and full course supervision. The EMB regimen was found more applicable than the SM regimen, and the SM regimen caused more side effects than the EMB regimen. Streptomycin skin test had a 4.5% positive rate, and using SM costs 84% more than using EMB. One of the drawbacks found in the SM regimen was that only in 42.9% of the rural sanitation units the disinfection standard could be fulfilled, and the patients preferred the EMB regimen to the SM regimen. CONCLUSION: The EMB regimen is more applicable than the SM regimen in the tuberculosis control program.