Costs of inpatient treatment for multidrugresistant tuberculosis in south africa

Tropical Medicine and International Health Costs of inpatient treatment for multi-drug-resistanttuberculosis in South Africa Kathryn Schnippel1, Sydney Rosen1,2, Kate Shearer1, Neil Martinson3,4, Lawrence Long1, Ian Sanne1,2 andEbrahim Variava5,6 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, USA3 Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa4 School of Medicine, Johns Hopkins University, Baltimore, MD, USA5 North West Department of Health, Klerksdorp/Tshepong Hospital Complex, Klerksdorp, South Africa6 Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa In South Africa, patients with multi-drug-resistant tuberculosis (MDR-TB) are hospitalised from MDR-TB treatment initiation until culture conversion. Although MDR-TB accountsfor <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) ofinpatient MDR-TB treatment.
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 afterinitial 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 ofwhom 121 had complete cost records.
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 totalcost 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.
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 fromimproved management of drug-susceptible TB and shifting to a model of decentralised, outpatientMDR-treatment.
keywords multi-drug-resistant, tuberculosis, cost, South Africa, hospitalisation with potential for severe adverse events and success rates just above 60% (Orenstein et al. 2009). An estimated In recent years, following on severe global epidemics of 60% of patients with TB in South Africa are co-infected both HIV and drug-susceptible tuberculosis, multi-drug- with HIV (WHO 2011b). Although there is limited and resistant tuberculosis (MDR-TB) has emerged as a serious conflicting global evidence of an association between health challenge. In 2009, South Africa had 9070 con- HIV and MDR-TB (Suchindran et al. 2009), observa- firmed cases of MDR-TB, second highest globally in total tional studies from South Africa have reported worse out- case load (WHO 2011a) and the highest global case load comes for MDR-TB patients co-infected with HIV (Brust for extensively drug-resistant TB (XDR-TB) at 572 reported cases (Zignol et al. 2012). MDR-TB requires Until late 2011, all patients with MDR- and XDR-TB 18–24 months of treatment and is associated with very in South Africa were treated as inpatients at specialised, high early mortality (Gandhi et al. 2010). Second-line TB provincial-level MDR-TB treatment centres. Patients with treatment is expensive and complicated to administer, MDR-TB were hospitalised for 6 months or until they Tropical Medicine and International Health K. Schnippel et al. Costs of MDR-TB inpatient care achieved culture conversion, defined as two consecutive tration charts, are stored in a file room within the specia- months with culture-negative sputa (Directorate Tuberculosis Control 2007). Discharge was delayed if thepatient was in poor clinical condition or had a previous history of treatment interruption, complications or majoradverse drug events.
TB treatment guidelines in effect during the study recom- While drug-resistant TB of all types comprises less than mended that phenotypic first-line drug susceptibility test- 5% of incident TB in South Africa, control of drug-resis- ing (DST) be performed for all TB suspects with a history tant TB accounted for 55% of the National Tuberculosis of TB treatment and for contacts of patients with MDR- Program (NTP) budget in 2010 (WHO 2011a). A large TB. DST was also performed if patients with TB share of this cost is likely due to the long hospital stays of remained sputum smear positive at the end of 2, 3 or patients with MDR-TB, which also results in treatment 5 months of first-line TB treatment (TB Control Pro- delays due to a shortage of some 740 MDR-TB treatment gramme 2008). DST for resistance to second-line drugs beds (Directorate Drug- Resistant TB 2011a). There are no was performed for all viable culture isolates that were empirical estimates, however, of costs of inpatient care for found to be resistant to both isonaizid (INH) and rifam- MDR-TB in South Africa, and very limited cost data are picin (RIF). Patients with INH and RIF resistance were available globally. A recent systematic review of the costs registered as MDR-TB cases and admitted to the study of MDR-TB treatment found only four published estimates that met inclusion criteria for the review, and none were Similar to drug-sensitive TB treatment, MDR- and from sub-Saharan Africa (Fitzpatrick & Floyd 2012).
XDR-TB treatment have an intensive phase and continu- Although new South African guidelines (Directorate ation phase. Culture conversion, defined as two consecu- Drug- Resistant TB 2011b) recommend that smear-nega- tive negative culture sputa taken 30 days apart, was tive MDR-TB patients be treated through an outpatient used as an indicator of treatment efficacy. This deter- model of care, most patients with MDR-TB will likely mined the duration of hospitalisation, with hospital dis- continue to require substantial hospital stays. Without charge at culture conversion. The intensive phase of up-to-date information on the cost of treating MDR-TB, treatment coincided with hospitalisation, but also contin- it will be difficult for policy makers and programme man- ued for 4 months after culture conversion. The standar- agers to estimate the cost-effectiveness of alternative dised regimen for the intensive phase of MDR-TB treatment models, examine the impact of shorter treat- treatment was daily kanamycin or amikacin injections ment regimens or plan for implementation of new guide- and terizidone or ethambutol, pyrazinamide, ofloxacin lines. To fill this knowledge gap, we used patient-level and ethionamide (Directorate Tuberculosis Control data from a provincial MDR-TB treatment centre to esti- 2007). Upon discharge from hospital, all patients mate the cost of providing inpatient MDR-TB treatment received outpatient care including directly observed treat- ment from a local clinic, with monthly outpatient visitsto the MDR-TB hospital. Injections are not part of thecontinuation phase; all other drugs in the standardised regimen are continued at the same dose. Capreomycininjection (during intensive phase), para-aminosalicylic acid and moxifloxacin were available if patients were The study was conducted at the Klerksdorp/Tshepong Hospital Complex in North West Province, South Africa, Most laboratory tests ordered for patients with MDR- the provincial referral hospital for MDR- and XDR-TB.
TB were performed on site, at the National Health Labo- Initially, patients with MDR-TB and XDR-TB were hos- ratory Services (NHLS) facility at Tshepong Hospital.
pitalised in a 32- and 6-bed ward, respectively, within This included fluorescent sputum smear microscopy, Klerksdorp Hospital. During the study period, funding liquid media cultures and DST for first-line drugs (INH, from The Global Fund to Fight AIDS, Tuberculosis and RIF, ethambutol and streptomycin). DST for resistance to Malaria assisted the North West Department of Health second-line drugs (ethionamide, kanamycin and ofloxa- to construct new, separate structures for both inpatient cin) was performed at NHLS’s central TB referral labora- wards and an outpatient clinic. Patients are now housed tory in Johannesburg, a 2-h drive from the study site.
in a 36-bed MDR-TB ward and 20-bed XDR-TB ward at During the study period, the central referral laboratory Tshepong Hospital. Full medical records for admitted began using a line probe assay (LPA) for the identifica- patients, including laboratory results and drug adminis- tion of mycobacterium tuberculosis (MTB) in culture Tropical Medicine and International Health K. Schnippel et al. Costs of MDR-TB inpatient care isolates while also providing rapid genotypic testing for To estimate the cost per patient in our sample, we cal- INH and RIF resistance. Xpert MTB/RIF was not avail- culated three types of costs. First, for all patient-specific able at the study site during the study period.
resource usage (drugs, laboratory tests, fluids, specialistconsultations, scans, x-rays and surgical procedures),costs were calculated by multiplying unit costs by quan- tity of resources used. Second, DR-TB ward-specific costs The study was a medical record review of resource utilisa- that could not be attributed to individual patients were tion and outcomes for all patients with MDR-TB admit- estimated as the sum of ward costs for personnel, sup- ted between 1 March 2009 and 28 February 2010 with plies, equipment and infrastructure, and the total DR-TB confirmed MDR-TB and for whom the complete patient ward cost divided by the total number of DR-TB inpa- medical record was available. Patients were excluded if tient days to obtain a cost per patient day for DR-TB they were under age 18 at the time of admission, were ward-specific costs. Third, for shared services that the diagnosed with drug allergies or with mono- or poly-resis- general hospital provides (e.g. hospital administration, tant TB but not MDR-TB, had initiated MDR-TB treat- laundry and security), we estimated the proportion of all ment at a different site or transferred out of the study site inpatient days and outpatient days for the whole hospital to a different inpatient treatment facility within that were spent in the DR-TB ward. We then multiplied 12 months of admission to the study site. All patients the hospital’s total cost for shared services by this pro- were followed from their admission until the earliest of portion. For both DR-TB ward-specific costs and shared the date of final discharge, abscondment or death, up to service costs, we divided the relevant totals by the total 12 months after admission. Patients who progressed to a number of TB inpatient days to obtain a cost per patient diagnosis of XDR-TB during the 12 months after initiat- day. The sum of ward-specific and shared costs per inpa- ing MDR-TB treatment were retained in the sample.
tient day is referred to as the ‘hotel’ cost. The total costper patient in our sample is the cost of patient-specificresource usage plus the daily hotel cost for the length ofthe admission.
Buildings and equipment were discounted at 3% per For each study subject, we reviewed the medical record annum. Costs are reported in 2011 USD, with prior year to collect data on resources utilised from the date of costs inflated using the South African consumer price admission to 12 months after admission. Resources cap- index (Statistics South Africa 2012). The average tured included inpatient days; TB and non-TB drugs and exchange rate for 2011, ZAR 7.23/USD, is used (Oanda fluids, including antiretroviral (ART) medications for 2012). Patient-level data were captured in CSPro v. 4.1 HIV; specialist consultations; surgical procedures; chest (US Census Bureau). SAS v. 9.3 was used to generate x-rays and other scans; and TB monitoring tests and descriptive statistics, analysis of the differences of propor- other laboratory investigations. For patients who had tions (chi-squared test) and differences of means (t-test).
multiple admissions and intermediate discharges during Ethics approval for this study was received from the the 12-month follow-up period, the total number of days Human Research Ethics Committee of the University of admitted over the period was used. These data were used the Witwatersrand, the Institutional Review Board of to estimate the total number of units of each resource Boston University Medical Center and the Hospital’s The average inpatient cost of MDR-TB treatment was estimated using costing methods recommended by theWHO for TB control (Floyd 2002). Prices of medications including MDR-TB drugs, fluids and laboratory tests and investigations were collected from public sector suppliersof these products and services. Public sector hospital During the 12-month period of study enrolment, 277 charges were used for specialist consultations, surgical patients registered at the study site; 133 of these met procedures and scans, with the exception of x-rays for inclusion criteria and were enrolled in the study which costs were estimated from hospital expenditure (Figure 1). The main reason for exclusion was absence of records. Personnel costs, medical supply costs and costs a confirmed MDR-TB diagnosis, which typically indi- for the purchase, maintenance and operation of infra- cated mono- or poly-resistant TB but not MDR-TB. The structure and equipment were collected from hospital mean age of the study sample was 39.9 years, and 45% were female (Table 1). Nearly all (n = 123, 92%) Tropical Medicine and International Health K. Schnippel et al. Costs of MDR-TB inpatient care reported being resident in North West Province at admis- 72% of smear-negative patients had resistance to only sion. 64% were unemployed. A large majority (n = 111, first-line anti-TB drugs. In contrast, 53% of smear-posi- 83%) had a history of previous TB treatment. The mean tive patients had resistance to one or more second-line interval from collection of sputum for DST to laboratory report MDR-TB diagnosis was 84 days; and from sputumcollection to hospital admission was 111 days. By defini- tion, all patients were TB culture positive at diagnosis,with INH and RIF resistance confirmed by either DST or Of the 133 subjects enrolled in the study, 121 had com- LPA or both. 56% of patients were smear positive at plete information on outcomes and resource utilisation in their medical records. This smaller sample of 121 is used Of 133 enrolled study subjects, four did not have a smear microscopy taken on admission and one patient’s After 12 months, 98% of patients who were smear sputum sample was rejected, leaving a total of 128 sub- negative at admission and 80% of those who were smear jects with known smear status at baseline. The sample positive had been discharged upon culture conversion was evenly divided between patients who were smear (Table 2). Three patients, all of whom were all smear negative and smear positive at hospital admission. Three- positive at admission and resistant to one or more sec- quarters of smear-negative patients and more than half ond-line TB drugs, were still hospitalised at the end of of smear-positive patients were HIV infected, of whom 12 months. Ten patients (8%) died while admitted, all of 43% were on ART at admission. Low body mass index whom were HIV infected. Four (3%) absconded.
(BMI) was common, with two-thirds of smear-positivepatients and almost one-third of smear-negative patients having BMI <18.5. Anaemia (40%) and diabetes mellitus(10%) were also frequently diagnosed. 69% of smear- Patients were hospitalised for an average of 105 days negative patients were culture negative at admission, and (Table 2). 115/121 patients had at least one chest x-ray, Tropical Medicine and International Health K. Schnippel et al. Costs of MDR-TB inpatient care Table 1 Study population characteristics, by smear status at 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 ART, antiretroviral; TB, tuberculosis; BMI, body mass index.
dispensed. Surgical procedures, other scans or investiga- *Excludes 5 study subjects of unknown smear status (smear tions and specialist consultations (e.g. audiologist or ophthalmologists) were infrequent in this patient cohort.
†Defined as haemoglobin less than 11 g/dl for non-pregnant Two-thirds (66%) of the HIV-infected patients were women and men and less than 10 g/dl for pregnant women, with maintained or initiated on ART during their hospitalisa- haemoglobin corrected for elevation.
Table 2 Patient outcomes, resource utilisation and costs, by smear status at admission Outcomes 12 months after initial admission Inpatient costs per patient admitted (mean [SD], USD 2011) 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.
Tropical Medicine and International Health K. Schnippel et al. Costs of MDR-TB inpatient care tion, most (92%) on the standard first-line ARV The average cost of inpatient treatment was $17 164 per patient in the first 12 months after initial admission(Figure 2, Table 2). Cost per day in the hospital – ‘hotelcosts’ including salaries, buildings, equipment, consum- ables and supplies – accounted for 95% of total costs.
The average hotel cost per inpatient day, including room, Patients who were smear negative at admission cost less board, clinical interactions and basic supplies to maintain than patients who were smear positive, with the differ- the hospital wards but excluding all procedures and ence due largely to the shorter inpatient stays of smear- drugs, was $155 (Table 3). 58% of these costs were spe- negative patients (average 95 vs. 125 days). Costs for cific to the MDR- and XDR-TB ward. Shared services, smear-positive patients were more positively skewed and including hospital administration, laundry and security, had a wider variance than those for smear-negative accounted for 21% of general hospital expenditure.
patients. The average cost per patient for MDR-TB labo- MDR-TB inpatient days comprised only 8% of the total ratory monitoring, including DST, was $236, 1% of the patient days for the hospital, and therefore, just 1.7% of total. Drugs for treating MDR-TB, at $380 per patient, general hospital expenditure was allocated to the MDR- accounted for only 2% of the total. Total patient costs did not differ significantly by HIV status (results not While the new hospital was being constructed, some shown). ART costs were a small component of total admitted patients who had negative smears but who had costs, with a mean cost of $66 per patient on ART. CD4 not yet culture converted were moved to an unused ward counts and viral load tests did contribute to HIV-infected at a nearby private mining hospital. A monthly flat fee patients having higher non-MDR-TB-related costs, at was paid to the private hospital for the service, with the $180 compared to $132; however, these costs account drugs, laboratories and physician management continuing for approximately 1% of the total inpatient costs.
to be provided by the MDR-TB hospital. The averagecost per patient day for this service was $188, or 21% higher than the cost per day at the specialised MDR-TBhospital.
In this study of the costs of inpatient treatment forMDR-TB in South Africa, we found that the average costof treating a patient who is ultimately discharged withculture conversion — that is, a ‘successful’ treatment out- Table 3 Hotel costs of inpatient treatment for MDR-TB, come — exceeds $17 000. This is nearly 40 times the average cost of treating drug-susceptible TB (Sinanovicet al. 2003) and nearly 25 times the cost of a year of first-line ART (Long et al. 2010). Management of drug- resistant 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 spe- cific criteria — primarily smear-negative disease and good clinical condition — to be treated as outpatients. While this is likely to reduce costs for these patients dramati- cally, the National Department of Health estimates that only 30–40% of patients with MDR-TB will meet these MDR-TB, multi-drug-resistant tuberculosis; XDR-TB, criteria (Directorate Drug- Resistant TB 2011a). Hospital extensively drug-resistant tuberculosis.
stays will be shortened for many others, as the new Tropical Medicine and International Health K. Schnippel et al. Costs of MDR-TB inpatient care Figure 2 Histogram of total 12-month inpatient costs per MDR-TB patient in 2011 USD.
guidelines allow discharge upon smear conversion, rather that 40% of patients with MDR-TB and 51% of patients than culture conversion. Once the new guidelines are with XDR-TB died in the first 30 days following sputum fully in effect, substantial cost savings should result for collection (Gandhi et al. 2010). Accelerated diagnosis of many but not all patients. The findings we report lend MDR-TB made possible by the scale-up of Xpert MTB/ urgency to the effort to implement the new guidelines, RIF technology may change the profile of the inpatient which will require large-scale training of staff, improved population and thus of the costs incurred. Finally, the patient monitoring and records systems, patient and com- data we present are from a single site in South Africa.
munity education on infection control, infrastructure There is variation in estimated hospital per patient day improvements, accelerated laboratory processing capacity equivalent expenditure across South Africa, with an aver- and decentralisation of the MDR-TB drug supply.
age $213 per day and standard deviation of $45 (Health We note three main limitations to our findings. First, Systems Trust 2012), and it may be that there is also var- MDR-TB treatment typically lasts 18–24 months, with iation across the MDR-TB facilities.
most of this interval spent in outpatient care. Our cost Although these limitations should be kept in mind, the estimates capture only the inpatient component of the cost estimates presented here provide the best evidence treatment regimen. While culture conversion is considered yet of the high cost of treating MDR-TB using an inpa- a good interim indicator and inpatient costs are usually tient model of care. These results can be used to estimate far higher than outpatient costs, further research is the cost-effectiveness of alternative models of care and needed to evaluate the total cost per patient of MDR-TB budget for the large proportion of patients who will con- treatment. Second, by enrolling the study cohort at tinue to require hospitalisation. Our results also have rel- admission to an MDR-TB hospital, an average of evance to other high-burden MDR-TB countries. The 111 days after they were tested for MDR-TB, there is WHO reports that 24 of 27 high-burden countries likely to be a survivor bias. Culture and DST can only be require hospitalisation during the intensive phase of treat- performed at centralised laboratories in South Africa, and ment (WHO 2011a). In the review of MDR-TB treatment both take weeks to generate results. For patients in our costs mentioned previously, the two countries included sample, the interval between sputum collection and avail- that had inpatient models of care, Estonia and Russia, ability of test results averaged 84 days, accounting for had much higher costs than those that allowed outpatient most of the delay in admission. A study in KwaZulu treatment, Peru and the Philippines (Fitzpatrick & Floyd Natal, South Africa, that followed patients during the 2012). For South Africa and other countries, our time from sputum collection to hospital admission found results thus underscore the importance of implementing Tropical Medicine and International Health K. Schnippel et al. Costs of MDR-TB inpatient care outpatient MDR-TB treatment as quickly as possible, effectiveness Analysis of Tuberculosis Control. WHO, Geneva.
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We thank Dr M van Rensburg, JP Phepheng and the staff of Klerksdorp/ Tshephong Hospital for their assistance.
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Floyd K (2002) Guidelines for Cost and Cost-effectiveness Anal- ysis of Tuberculosis Control. Guidelines for Cost and Cost- Corresponding Author Kathryn Schnippel, Themba Lethu Wing, Helen Joseph Hospital, Perth Road, Westdene 2092 SouthAfrica: 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.: +27 11 276 8896; E-mail: kschnippel@heroza.org

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