Costs of inpatient treatment for multi-drug-resistant tuberculosis in South Africa

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1 Tropical Medicine and International Health doi: /tmi volume 18 no 1 pp january 2013 Costs of inpatient treatment for multi-drug-resistant tuberculosis in South Africa Kathryn Schnippel 1, Sydney Rosen 1,2, Kate Shearer 1, Neil Martinson 3,4, Lawrence Long 1, Ian Sanne 1,2 and Ebrahim Variava 5,6 1 Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences,University of the Witwatersrand, Johannesburg, South Africa 2 Center for Global Health and Development, Boston University, Boston, MA, USA 3 Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa 4 School of Medicine, Johns Hopkins University, Baltimore, MD, USA 5 North West Department of Health, Klerksdorp/Tshepong Hospital Complex, Klerksdorp, South Africa 6 Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Abstract background In South Africa, patients with multi-drug-resistant tuberculosis (MDR-TB) are hospitalised from MDR-TB treatment initiation until culture conversion. Although MDR-TB accounts for <3% of incident TB in South Africa, 55% of the public sector TB budget is spent on MDR-TB. To inform new strategies for MDR-TB management, we estimated the per-patient cost (USD 2011) of inpatient MDR-TB treatment. methods All resources used by patients admitted to the MDR-TB hospital with confirmed MDR-TB from March 2009 to February 2010 were abstracted from patient records for up to 12 months after initial admission or until the earliest of final discharge, abscondment or death. Costs of hospital stay/ day were estimated from hospital expenditure records and costs for drugs, laboratory tests, radiography and surgery from public sector sources. 133 patients met study inclusion criteria of whom 121 had complete cost records. results By 12 months, 86% were discharged with culture conversion, 8% died in hospital, 2% were still admitted, and 3% had absconded. The mean hospital stay was 105 days. The mean total cost per patient was $17 164, of which 95% were hospitalisation costs (buildings, staff, etc.) and 2% each for MDR-TB drugs ($380); TB laboratory tests, including drug susceptibility testing ($236); and other costs. conclusions The inpatient cost per patient treated for MDR-TB is more than 40 times the cost of treating drug-susceptible TB in South Africa. There is potential for substantial cost savings from improved management of drug-susceptible TB and shifting to a model of decentralised, outpatient MDR-treatment. keywords multi-drug-resistant, tuberculosis, cost, South Africa, hospitalisation Introduction In recent years, following on severe global epidemics of both HIV and drug-susceptible tuberculosis, multi-drugresistant tuberculosis (MDR-TB) has emerged as a serious health challenge. In 2009, South Africa had 9070 confirmed cases of MDR-TB, second highest globally in total case load (WHO 2011a) and the highest global case load for extensively drug-resistant TB (XDR-TB) at 572 reported cases (Zignol et al. 2012). MDR-TB requires months of treatment and is associated with very high early mortality (Gandhi et al. 2010). Second-line TB treatment is expensive and complicated to administer, with potential for severe adverse events and success rates just above 60% (Orenstein et al. 2009). An estimated 60% of patients with TB in South Africa are co-infected with HIV (WHO 2011b). Although there is limited and conflicting global evidence of an association between HIV and MDR-TB (Suchindran et al. 2009), observational studies from South Africa have reported worse outcomes for MDR-TB patients co-infected with HIV (Brust et al. 2011; Farley et al. 2011). Until late 2011, all patients with MDR- and XDR-TB in South Africa were treated as inpatients at specialised, provincial-level MDR-TB treatment centres. Patients with MDR-TB were hospitalised for 6 months or until they 2012 Blackwell Publishing Ltd 109

2 achieved culture conversion, defined as two consecutive months with culture-negative sputa (Directorate Tuberculosis Control 2007). Discharge was delayed if the patient was in poor clinical condition or had a previous history of treatment interruption, complications or major adverse drug events. While drug-resistant TB of all types comprises less than 5% of incident TB in South Africa, control of drug-resistant TB accounted for 55% of the National Tuberculosis Program (NTP) budget in 2010 (WHO 2011a). A large share of this cost is likely due to the long hospital stays of patients with MDR-TB, which also results in treatment delays due to a shortage of some 740 MDR-TB treatment beds (Directorate Drug- Resistant TB 2011a). There are no empirical estimates, however, of costs of inpatient care for MDR-TB in South Africa, and very limited cost data are available globally. A recent systematic review of the costs of MDR-TB treatment found only four published estimates that met inclusion criteria for the review, and none were from sub-saharan Africa (Fitzpatrick & Floyd 2012). Although new South African guidelines (Directorate Drug- Resistant TB 2011b) recommend that smear-negative MDR-TB patients be treated through an outpatient model of care, most patients with MDR-TB will likely continue to require substantial hospital stays. Without up-to-date information on the cost of treating MDR-TB, it will be difficult for policy makers and programme managers to estimate the cost-effectiveness of alternative treatment models, examine the impact of shorter treatment regimens or plan for implementation of new guidelines. To fill this knowledge gap, we used patient-level data from a provincial MDR-TB treatment centre to estimate the cost of providing inpatient MDR-TB treatment in South Africa. Methods Study site The study was conducted at the Klerksdorp/Tshepong Hospital Complex in North West Province, South Africa, the provincial referral hospital for MDR- and XDR-TB. Initially, patients with MDR-TB and XDR-TB were hospitalised in a 32- and 6-bed ward, respectively, within Klerksdorp Hospital. During the study period, funding from The Global Fund to Fight AIDS, Tuberculosis and Malaria assisted the North West Department of Health to construct new, separate structures for both inpatient wards and an outpatient clinic. Patients are now housed in a 36-bed MDR-TB ward and 20-bed XDR-TB ward at Tshepong Hospital. Full medical records for admitted patients, including laboratory results and drug administration charts, are stored in a file room within the specialised MDR- and XDR-TB wards. Treatment guidelines TB treatment guidelines in effect during the study recommended that phenotypic first-line drug susceptibility testing (DST) be performed for all TB suspects with a history of TB treatment and for contacts of patients with MDR- TB. DST was also performed if patients with TB remained sputum smear positive at the end of 2, 3 or 5 months of first-line TB treatment (TB Control Programme 2008). DST for resistance to second-line drugs was performed for all viable culture isolates that were found to be resistant to both isonaizid (INH) and rifampicin (RIF). Patients with INH and RIF resistance were registered as MDR-TB cases and admitted to the study site wards to initiate treatment. Similar to drug-sensitive TB treatment, MDR- and XDR-TB treatment have an intensive phase and continuation phase. Culture conversion, defined as two consecutive negative culture sputa taken 30 days apart, was used as an indicator of treatment efficacy. This determined the duration of hospitalisation, with hospital discharge at culture conversion. The intensive phase of treatment coincided with hospitalisation, but also continued for 4 months after culture conversion. The standardised regimen for the intensive phase of MDR-TB treatment was daily kanamycin or amikacin injections and terizidone or ethambutol, pyrazinamide, ofloxacin and ethionamide (Directorate Tuberculosis Control 2007). Upon discharge from hospital, all patients received outpatient care including directly observed treatment from a local clinic, with monthly outpatient visits to the MDR-TB hospital. Injections are not part of the continuation phase; all other drugs in the standardised regimen are continued at the same dose. Capreomycin injection (during intensive phase), para-aminosalicylic acid and moxifloxacin were available if patients were resistant to a second-line drug. Most laboratory tests ordered for patients with MDR- TB were performed on site, at the National Health Laboratory Services (NHLS) facility at Tshepong Hospital. This included fluorescent sputum smear microscopy, liquid media cultures and DST for first-line drugs (INH, RIF, ethambutol and streptomycin). DST for resistance to second-line drugs (ethionamide, kanamycin and ofloxacin) was performed at NHLS s central TB referral laboratory in Johannesburg, a 2-h drive from the study site. During the study period, the central referral laboratory began using a line probe assay (LPA) for the identification of mycobacterium tuberculosis (MTB) in culture Blackwell Publishing Ltd

3 isolates while also providing rapid genotypic testing for INH and RIF resistance. Xpert MTB/RIF was not available at the study site during the study period. Study population The study was a medical record review of resource utilisation and outcomes for all patients with MDR-TB admitted between 1 March 2009 and 28 February 2010 with confirmed MDR-TB and for whom the complete patient medical record was available. Patients were excluded if they were under age 18 at the time of admission, were diagnosed with drug allergies or with mono- or poly-resistant TB but not MDR-TB, had initiated MDR-TB treatment at a different site or transferred out of the study site to a different inpatient treatment facility within 12 months of admission to the study site. All patients were followed from their admission until the earliest of the date of final discharge, abscondment or death, up to 12 months after admission. Patients who progressed to a diagnosis of XDR-TB during the 12 months after initiating MDR-TB treatment were retained in the sample. Cost data and analysis For each study subject, we reviewed the medical record to collect data on resources utilised from the date of admission to 12 months after admission. Resources captured included inpatient days; TB and non-tb drugs and fluids, including antiretroviral (ART) medications for HIV; specialist consultations; surgical procedures; chest x-rays and other scans; and TB monitoring tests and other laboratory investigations. For patients who had multiple admissions and intermediate discharges during the 12-month follow-up period, the total number of days admitted over the period was used. These data were used to estimate the total number of units of each resource used by each study subject. The average inpatient cost of MDR-TB treatment was estimated using costing methods recommended by the WHO for TB control (Floyd 2002). Prices of medications including MDR-TB drugs, fluids and laboratory tests and investigations were collected from public sector suppliers of these products and services. Public sector hospital charges were used for specialist consultations, surgical procedures and scans, with the exception of x-rays for which costs were estimated from hospital expenditure records. Personnel costs, medical supply costs and costs for the purchase, maintenance and operation of infrastructure and equipment were collected from hospital expenditure and financial reports. To estimate the cost per patient in our sample, we calculated three types of costs. First, for all patient-specific resource usage (drugs, laboratory tests, fluids, specialist consultations, scans, x-rays and surgical procedures), costs were calculated by multiplying unit costs by quantity of resources used. Second, DR-TB ward-specific costs that could not be attributed to individual patients were estimated as the sum of ward costs for personnel, supplies, equipment and infrastructure, and the total DR-TB ward cost divided by the total number of DR-TB inpatient days to obtain a cost per patient day for DR-TB ward-specific costs. Third, for shared services that the general hospital provides (e.g. hospital administration, laundry and security), we estimated the proportion of all inpatient days and outpatient days for the whole hospital that were spent in the DR-TB ward. We then multiplied the hospital s total cost for shared services by this proportion. For both DR-TB ward-specific costs and shared service costs, we divided the relevant totals by the total number of TB inpatient days to obtain a cost per patient day. The sum of ward-specific and shared costs per inpatient day is referred to as the hotel cost. The total cost per patient in our sample is the cost of patient-specific resource usage plus the daily hotel cost for the length of the admission. Buildings and equipment were discounted at 3% per annum. Costs are reported in 2011 USD, with prior year costs inflated using the South African consumer price index (Statistics South Africa 2012). The average exchange rate for 2011, ZAR 7.23/USD, is used (Oanda 2012). Patient-level data were captured in CSPro v. 4.1 (US Census Bureau). SAS v. 9.3 was used to generate descriptive statistics, analysis of the differences of proportions (chi-squared test) and differences of means (t-test). Ethics approval for this study was received from the Human Research Ethics Committee of the University of the Witwatersrand, the Institutional Review Board of Boston University Medical Center and the Hospital s Research Committee. Results Sample characteristics During the 12-month period of study enrolment, 277 patients registered at the study site; 133 of these met inclusion criteria and were enrolled in the study (Figure 1). The main reason for exclusion was absence of a confirmed MDR-TB diagnosis, which typically indicated mono- or poly-resistant TB but not MDR-TB. The mean age of the study sample was 39.9 years, and 45% were female (Table 1). Nearly all (n = 123, 92%) 2012 Blackwell Publishing Ltd 111

4 Recorded in hospital register 277 Not admitted (treated elsewhere) 3 Non-MDR TB diagnosis 83 < age 18 8 File missing, status unknown 1 NTM 3 Polyresistant 6 INH monoresistant 19 Unconfirmed MDR-TB 3 RIF monoresistant 38 Drugsensitive TB 14 Potentially eligible 182 Initiated MDR-TB treatment at another site 33 Completed inpatient treatment at another site 16 Enrolled in study 133 Known smear status at admission 128 Complete resource utilization records 121 reported being resident in North West Province at admission. 64% were unemployed. A large majority (n = 111, 83%) had a history of previous TB treatment. The mean interval from collection of sputum for DST to laboratory report MDR-TB diagnosis was 84 days; and from sputum collection to hospital admission was 111 days. By definition, all patients were TB culture positive at diagnosis, with INH and RIF resistance confirmed by either DST or LPA or both. 56% of patients were smear positive at diagnosis. Of 133 enrolled study subjects, four did not have a smear microscopy taken on admission and one patient s sputum sample was rejected, leaving a total of 128 subjects with known smear status at baseline. The sample was evenly divided between patients who were smear negative and smear positive at hospital admission. Threequarters of smear-negative patients and more than half of smear-positive patients were HIV infected, of whom 43% were on ART at admission. Low body mass index (BMI) was common, with two-thirds of smear-positive patients and almost one-third of smear-negative patients having BMI <18.5. Anaemia (40%) and diabetes mellitus (10%) were also frequently diagnosed. 69% of smearnegative patients were culture negative at admission, and 72% of smear-negative patients had resistance to only first-line anti-tb drugs. In contrast, 53% of smear-positive patients had resistance to one or more second-line drugs. Outcomes Of the 133 subjects enrolled in the study, 121 had complete information on outcomes and resource utilisation in their medical records. This smaller sample of 121 is used for the remainder of this analysis. After 12 months, 98% of patients who were smear negative at admission and 80% of those who were smear positive had been discharged upon culture conversion (Table 2). Three patients, all of whom were all smear positive at admission and resistant to one or more second-line TB drugs, were still hospitalised at the end of 12 months. Ten patients (8%) died while admitted, all of whom were HIV infected. Four (3%) absconded. Resource utilisation Figure 1 Study enrolment. DR-TB, drug-resistant TB; NTM, non-tuberculosis Mycobacterium; INH, isonaizid; RIF, rifampicin. Patients were hospitalised for an average of 105 days (Table 2). 115/121 patients had at least one chest x-ray, Blackwell Publishing Ltd

5 Table 1 Study population characteristics, by smear status at admission Smear status at admission All subjects (n = 128)* Smear positive (n = 64) Smear negative (n = 64) Age, mean 40 [11] 39 [11] 41 [11] [standard deviation] Female 57 (45%) 26 (41%) 31 (48%) Extrapulmonary TB 21 (16%) 12 (19%) 9 (14%) Low BMI (<18.5) 62 (48%) 43 (67%) 19 (30%) Moderate or severe 48 (38%) 30 (47%) 18 (28%) anaemia Diabetes mellitus 13 (10%) 4 (6%) 9 (14%) HIV infected 83 (65%) 36 (56%) 47 (73%) on ART 36 (43%) 14 (39%) 22 (47%) CD4 cells/ll, 215 [162] 208 [174] 220 [154] mean [SD] Culture results at admission Negative 49 (38%) 5 (8%) 44 (69%) Positive 70 (55%) 56 (88%) 14 (22%) Other (e.g. missing, 9 (7%) 3 (5%) 6 (9%) contaminated) Ever resistant to 2nd line drugs 52 (41%) 34 (53%) 18 (28%) ART, antiretroviral; TB, tuberculosis; BMI, body mass index. *Excludes 5 study subjects of unknown smear status (smear microscopy not performed). Defined as haemoglobin less than 11 g/dl for non-pregnant women and men and less than 10 g/dl for pregnant women, with haemoglobin corrected for elevation. usually at admission; the mean number of chest x-rays was 1.2 per patient. Sputum smears and cultures were, on average, taken monthly. Blood tests, including CD4 monitoring and liver and kidney function screening, were performed for patients without recent test results at admission and only repeated if admission was longer than 6 months or if results were abnormal. Of the 74 patients (61%) with at least one positive TB sputum culture after admission, 64 had anti-tb drug resistance testing performed. Resistance testing was ordered as sets phenotypic DST for four first-line TB drugs and, if the culture isolate was resistant to at least INH and RIF, then DST for three second-line TB drugs was completed by the laboratory. On average, patients were tested once for a set of seven drugs. For 90% of sampled patients, treatment followed the standardised MDR-TB regimen. Patients received an average of 52 injections while hospitalised (i.e. 3.5/ week). Reasons for not receiving injectables included a contra-indication identified by the attending doctor, adverse reactions and reduced frequency and dosage of injectables for patients who were underweight. Nearly all patients received daily vitamins B6 and B-complex. Pain and cough medication and hypnotics were commonly dispensed. Surgical procedures, other scans or investigations and specialist consultations (e.g. audiologist or ophthalmologists) were infrequent in this patient cohort. Two-thirds (66%) of the HIV-infected patients were maintained or initiated on ART during their hospitalisa- Table 2 Patient outcomes, resource utilisation and costs, by smear status at admission All subjects (N = 121) Smear positive (n = 55) Smear negative (n = 61) Smear not done (n = 5) Outcomes 12 months after initial admission Discharged, culture conversion 104 (86%) 44 (80%) 60 (98%)* 0 Absconded 4 (3%) 2 (4%) 0 (0%) 2 (40%) Died in hospital 10 (8%) 6 (11%) 1 (2%) 3 (60%) Still admitted at 12 months 3 (2%) 3 (5%) 0 (0%) 0 Resources utilised (mean [SD]) Number of days in hospital [52.0] [57.8] 95.4 [34.9]* 12.8 [16.9] Number of chest x-rays 1.2 [0.6] 1.4 [0.6] 1.1 [0.5]* 0.6 [0.5] Number of TB cultures 4.1 [1.9] 4.8 [2.0] 3.8 [1.4]* 0.2 [0.4] Number of drug sensitivity tests 6.7 [8.3] 12.2 [8.4] 2.3 [4.7]* 0 Number of injections 52.4 [41.2] 57.0 [42.0] 52.4 [39.7]* 1.2 [1.3] Inpatient costs per patient admitted (mean [SD], USD 2011) All patients admitted $ [8, 625] $ [9, 701] $ [5, 633] $2042 [2, 690] Culture converted, discharged $ [6, 527] $ [1, 020] $ [5, 670] n.a. Absconded $5837 [6, 320] n.a. n.a. n.a. Died in hospital $ [14, 315] n.a. n.a. n.a. Still admitted at 12 months $ [4, 428] n.a. n.a. n.a. TB, tuberculosis. *Significant difference between smear-positive and smear-negative subjects at P-value <0.05. Sample size too small too stratify by these outcomes Blackwell Publishing Ltd 113

6 tion, most (92%) on the standard first-line ARV regimen. Costs The average hotel cost per inpatient day, including room, board, clinical interactions and basic supplies to maintain the hospital wards but excluding all procedures and drugs, was $155 (Table 3). 58% of these costs were specific to the MDR- and XDR-TB ward. Shared services, including hospital administration, laundry and security, accounted for 21% of general hospital expenditure. MDR-TB inpatient days comprised only 8% of the total patient days for the hospital, and therefore, just 1.7% of general hospital expenditure was allocated to the MDR- TB inpatient costs. While the new hospital was being constructed, some admitted patients who had negative smears but who had not yet culture converted were moved to an unused ward at a nearby private mining hospital. A monthly flat fee was paid to the private hospital for the service, with the drugs, laboratories and physician management continuing to be provided by the MDR-TB hospital. The average cost per patient day for this service was $188, or 21% higher than the cost per day at the specialised MDR-TB hospital. Table 3 Hotel costs of inpatient treatment for MDR-TB, per day Cost component USD % of total MDR- and XDR-TB ward-specific $ costs Ward staff, including medical officer $ and nursing staff Ward buildings and grounds $ Ward equipment and furnishings $ Supplies, including laundry, office, $ cleaning and patient meals General hospital expenses allocated $ to MDR-TB patient costs Non-ward hospital staff, including $ administration, pharmacy, admissions and medical records Non-ward-specific hospital buildings $ and grounds Non-ward-specific equipment and $ furnishings Non-medical supplies $ Total hotel costs per day $ MDR-TB, multi-drug-resistant tuberculosis; XDR-TB, extensively drug-resistant tuberculosis. The average cost of inpatient treatment was $ per patient in the first 12 months after initial admission (Figure 2, Table 2). Cost per day in the hospital hotel costs including salaries, buildings, equipment, consumables and supplies accounted for 95% of total costs. Patients who were smear negative at admission cost less than patients who were smear positive, with the difference due largely to the shorter inpatient stays of smearnegative patients (average 95 vs. 125 days). Costs for smear-positive patients were more positively skewed and had a wider variance than those for smear-negative patients. The average cost per patient for MDR-TB laboratory monitoring, including DST, was $236, 1% of the total. Drugs for treating MDR-TB, at $380 per patient, accounted for only 2% of the total. Total patient costs did not differ significantly by HIV status (results not shown). ART costs were a small component of total costs, with a mean cost of $66 per patient on ART. CD4 counts and viral load tests did contribute to HIV-infected patients having higher non-mdr-tb-related costs, at $180 compared to $132; however, these costs account for approximately 1% of the total inpatient costs. Discussion In this study of the costs of inpatient treatment for MDR-TB in South Africa, we found that the average cost of treating a patient who is ultimately discharged with culture conversion that is, a successful treatment outcome exceeds $ This is nearly 40 times the average cost of treating drug-susceptible TB (Sinanovic et al. 2003) and nearly 25 times the cost of a year of first-line ART (Long et al. 2010). Management of drugresistant TB already consumes a majority of the country s total TB control resources. The roll-out of Xpert MTB/ RIF is estimated to increase the number of MDR-TB cases diagnosed by as much as 70% (Meyer-Rath et al. 2012), making it even more urgent to both prevent MDR-TB and to reduce the cost of its treatment. Success rates for treating drug-susceptible TB in South Africa are far below both international and local targets, at 60% for retreatment, 64% for smear-negative TB and 73% for smear-positive TB cases (WHO 2011b). In 2011, the South African National TB Program adopted new guidelines allowing MDR-TB patients meeting specific criteria primarily smear-negative disease and good clinical condition to be treated as outpatients. While this is likely to reduce costs for these patients dramatically, the National Department of Health estimates that only 30 40% of patients with MDR-TB will meet these criteria (Directorate Drug- Resistant TB 2011a). Hospital stays will be shortened for many others, as the new Blackwell Publishing Ltd

7 $60,000 $50,000 $40,000 $30,000 $20,000 Median Mean 75th percentile 25th percentile $10,000 $0 Figure 2 Histogram of total 12-month inpatient costs per MDR-TB patient in 2011 USD. guidelines allow discharge upon smear conversion, rather than culture conversion. Once the new guidelines are fully in effect, substantial cost savings should result for many but not all patients. The findings we report lend urgency to the effort to implement the new guidelines, which will require large-scale training of staff, improved patient monitoring and records systems, patient and community education on infection control, infrastructure improvements, accelerated laboratory processing capacity and decentralisation of the MDR-TB drug supply. We note three main limitations to our findings. First, MDR-TB treatment typically lasts months, with most of this interval spent in outpatient care. Our cost estimates capture only the inpatient component of the treatment regimen. While culture conversion is considered a good interim indicator and inpatient costs are usually far higher than outpatient costs, further research is needed to evaluate the total cost per patient of MDR-TB treatment. Second, by enrolling the study cohort at admission to an MDR-TB hospital, an average of 111 days after they were tested for MDR-TB, there is likely to be a survivor bias. Culture and DST can only be performed at centralised laboratories in South Africa, and both take weeks to generate results. For patients in our sample, the interval between sputum collection and availability of test results averaged 84 days, accounting for most of the delay in admission. A study in KwaZulu Natal, South Africa, that followed patients during the time from sputum collection to hospital admission found that 40% of patients with MDR-TB and 51% of patients with XDR-TB died in the first 30 days following sputum collection (Gandhi et al. 2010). Accelerated diagnosis of MDR-TB made possible by the scale-up of Xpert MTB/ RIF technology may change the profile of the inpatient population and thus of the costs incurred. Finally, the data we present are from a single site in South Africa. There is variation in estimated hospital per patient day equivalent expenditure across South Africa, with an average $213 per day and standard deviation of $45 (Health Systems Trust 2012), and it may be that there is also variation across the MDR-TB facilities. Although these limitations should be kept in mind, the cost estimates presented here provide the best evidence yet of the high cost of treating MDR-TB using an inpatient model of care. These results can be used to estimate the cost-effectiveness of alternative models of care and budget for the large proportion of patients who will continue to require hospitalisation. Our results also have relevance to other high-burden MDR-TB countries. The WHO reports that 24 of 27 high-burden countries require hospitalisation during the intensive phase of treatment (WHO 2011a). In the review of MDR-TB treatment costs mentioned previously, the two countries included that had inpatient models of care, Estonia and Russia, had much higher costs than those that allowed outpatient treatment, Peru and the Philippines (Fitzpatrick & Floyd 2012). For South Africa and other countries, our results thus underscore the importance of implementing 2012 Blackwell Publishing Ltd 115

8 outpatient MDR-TB treatment as quickly as possible, so that the resources currently used for long inpatient stays can be re-allocated to improving first-line TB treatment and prevention. Acknowledgements We thank Dr M van Rensburg, JP Phepheng and the staff of Klerksdorp/ Tshephong Hospital for their assistance. Funding for this study was provided by the South Africa Mission of the US Agency for International Development. KSch and EV received research training funded from Fogarty International Center. The funders had no role in study design, analysis, decision to publish or preparation of the manuscript. References Brust JCM, Lygizos M, Chaiyachati K et al. (2011) Culture conversion among HIV Co-infected multidrug- resistant tuberculosis patients in Tugela Ferry, South Africa. PLoS One 6, e Day C, Barron P, Massyn N, Padarath A & English R (eds) (2012) District Health Barometer 2010/11. Health Systems Trust, Durban. ISBN Number: Directorate Drug- Resistant TB (2011a) Multi-Drug Resistant Tuberculosis: A Policy Framework on Decentralised and Deinstitutionalised Management for South Africa. Infection Control. Directorate Drug- Resistant TB, Pretoria. Directorate Drug- Resistant TB (2011b) Management of Drug- Resistant Tuberculosis: Policy Guidelines. Health Care. Directorate Drug- Resistant TB, Pretoria. Directorate Tuberculosis Control (2007) Management of Drugresistant Tuberculosis in South Africa: Policy Guidelines. Directorate Drug- Resistant TB, Pretoria. Farley JE, Ram M, Pan W et al. (2011) Outcomes of multi-drug resistant tuberculosis (MDR-TB) among a cohort of South African patients with high HIV prevalence. PLoS One 6, e Fitzpatrick C & Floyd K (2012) A systematic review of the cost and cost effectiveness of treatment for multidrug-resistant tuberculosis. Pharmacoeconomics 30, Floyd K (2002) Guidelines for Cost and Cost-effectiveness Analysis of Tuberculosis Control. Guidelines for Cost and Costeffectiveness Analysis of Tuberculosis Control. WHO, Geneva. doi: WHO/CDS/TB/ a. Gandhi NR, Shah NS, Andrews JR et al. (2010) HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. American Journal of Respiratory and Critical Care Medicine 181, Long L, Fox M, Sanne I & Rosen S (2010) The high cost of second-line antiretroviral therapy for HIV/AIDS in South Africa. AIDS 24, Meyer-Rath G, Schnippel K, Long L et al. (2012) The impact and cost of scaling up GeneXpert MTB/RIF in South Africa (ed. MP Nicol) PLoS One 7, e Oanda (2012) USD ZAR Average exchange rate 1 Jan Dec Historical Exchange Rates. currency/historical-rates/ Orenstein EW, Basu S, Shah NS et al. (2009) Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. The Lancet Infectious Diseases 9, Sinanovic E, Floyd K, Dudley L, Azevedo V, Grant R & Maher D (2003) Cost and cost-effectiveness of community-based care for tuberculosis in Cape Town, South Africa. The International Journal of Tuberculosis and Lung Disease 7, S56 S62. Statistics South Africa (2012) Statistical Release: Consumer Price Index, Vol. P0141. Statistics South Africa, Pretoria. Suchindran S, Brouwer ES & Van Rie A (2009) Is HIV infection a risk factor for multi-drug resistant tuberculosis? a systematic review PLoS One 4, e5561. TB Control Programme (2008) South African National Tuberculosis Guidelines. South Africa National Department of Health, Pretoria. WHO (2011a) Towards Universal Access to Diagnosis and Treatment of Multidrug-resistant and Extensively Drugresistant Tuberculosis by 2015: WHO Progress Report WHO, Geneva. WHO (2011b) Global Tuberculosis Control: WHO Report Tuberculosis. WHO, Geneva. doi: ISBN Zignol M, Gemert WV, Falzon D et al. (2012) Surveillance of anti-tuberculosis drug resistance in the world : an updated analysis Bulletin of the World Health Organization 90, Corresponding Author Kathryn Schnippel, Themba Lethu Wing, Helen Joseph Hospital, Perth Road, Westdene 2092 South Africa: Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. Tel.: ; kschnippel@ heroza.org Blackwell Publishing Ltd