Managing multidrug-resistant tuberculosis in South Africa: a budget impact analysis.

SETTING: In South Africa prior to 2016, the standard treatment regimen for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) was 24 months long and required daily injectable aminoglycoside (IA) treatment during the first 6 months. Recent evidence supports the replacement of IA with well-tolerated oral bedaquiline (BDQ) and a shortened 9-12 month regimen.DESIGN: Using a Markov model, we analyzed the 5-year budgetary impact and cost per successful treatment outcome of four regimens: 1) IA long-course, 2) oral long-course, 3) IA short-course, and 4) oral short-course. We used the South African MDR/RR-TB case register (2013-2015) to assess treatment outcomes for the then-standard IA long-course. Data on the improvement in outcomes for BDQ-based regimens were based on the literature. Costs were estimated from the provider perspective using costs incurred to provide decentralized treatment for MDR-TB at a Johannesburg hospital.RESULTS: Based on our analysis, by 2023, the cost/successful outcome for the four regimens was respectively 1) US$7374, 2) US$7860, 3) US$5149, and 4) US$4922. The annual total cost of each regimen was US$37 million, US$43 million, US$26 million, and US$28 million.CONCLUSION: Despite the high cost of BDQ, a BDQ-based shortened regimen for the treatment of MDR/RR-TB will result in improved treatment outcomes and cost savings for South Africa.

Discordant rifampicin susceptibility results are associated with Xpert® MTB/RIF probe B and probe binding delay.

SETTING: Xpert® MTB/RIF is the first-line diagnostic test for Mycobacterium tuberculosis and rifampicin (RIF) resistance in South Africa. OBJECTIVE: To describe the rates of Xpert RIF resistance not confirmed on follow-up testing, as well as the patient and test characteristics associated with discordant results. DESIGN: Retrospective review of patients with isolates showing Xpert RIF resistance. Line-probe assay, phenotypic drug susceptibility testing or repeat Xpert were all considered confirmatory tests of RIF resistance. 'Discordance' was defined as a patient with RIF resistance identified on initial Xpert testing, with a subsequent confirmatory test indicating RIF susceptibility. Associations were analysed using Pearson χ² difference of proportions and modified Poisson regression. RESULTS: RIF discordance occurred in 22/263 subjects and was associated with Xpert probe B, probe binding delay, as opposed to probe dropout, and probe binding delays (ΔCt) of between 4 and 4.9. CONCLUSION: Discordant RIF resistance was common in our cohort and was associated with Xpert probe delay and use of probe B.

Can patients afford the cost of treatment for multidrug-resistant tuberculosis in Ethiopia?

SETTING: Ethiopia has a high prevalence of tuberculosis (TB) and is one of the countries with the highest burden of multidrug-resistant TB (MDR-TB). OBJECTIVE: To understand the costs that patients incur in obtaining diagnosis and treatment for MDR-TB. DESIGN: In March 2013, interviews were conducted with 169 MDR-TB patients at three hospitals in Ethiopia to identify the cost to patients and the impact on employment and family income. RESULTS: The average MDR-TB patient incurred a total cost of US$1378, which represented 25 months of a mid-treatment household income of US$54. The impact on the patient's employment and on overall patient and family income was generally catastrophic: 74% of all respondents reported losing their jobs, 66% of patients lost household income, and household income was reduced by 38%. To help cover the costs, 38% of patients sold some type of property, while 7% leased out property and 41% took out loans, any of which could jeopardize their future financial situation even further. CONCLUSION: Despite services being officially free of charge, most patients incurred catastrophic costs and suffered significant income loss as a result of obtaining diagnosis and treatment for MDR-TB.

Direct costs of managing adverse drug reactions during rifampicin-resistant tuberculosis treatment in South Africa.

OBJECTIVE: To estimate the provider costs of managing adverse drug reactions (ADRs) to standard long-course treatment for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) according to South African guidelines. METHODS: We parameterised a published Markov health state model for MDR/RR-TB with guidelines-based, bottom-up public-sector provider costing of ADR management. Frequency of ADR occurrence was extracted from the literature. Costs were estimated over 10 years, discounted 3% annually and tested using probabilistic sensitivity analysis. RESULTS: On average, guidelines-based costing of moderate ADRs weighted by the frequency of occurrence was US$135.76 (standard deviation [SD] US$17.18) and the cost of serious ADRs was US$521.29 (SD US$55.99). We estimated that the incremental costs of ADR management were US$380.17 annually per patient initiating MDR/RR-TB treatment. The incremental costs of ADR management for the public health sector in South Africa was US$4.76 million, 8.3% of the estimated cohort costs of MDR/RR-TB treatment ($57.55 million) for the 2015 cohort of 12 527 patients. CONCLUSIONS: Management of multiple ADRs and serious ADRs, which are common during the first 6 months of standard, long-course MDR/RR-TB treatment, substantially increases provider treatment costs. These results need to be taken into account when comparing regimen costs, and highlight the urgent need to identify drug regimens with improved safety profiles.

Persistently high early mortality despite rapid diagnostics for drug-resistant tuberculosis cases in South Africa.

OBJECTIVE: To describe the timing and predictors of mortality among multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients reported in the South African electronic drug-resistant TB register (EDRweb), 2012-2014. DESIGN: We present time-to-event survival analysis and Cox proportional hazards regression. Identity numbers were matched to the National Vital Statistics Register. RESULTS: Of the 20 653 patients included in the analysis (median age 35 years, interquartile range 28-43), over half were male (n = 10 944, 53.0%). Most were human immunodeficiency virus (HIV) positive (n = 14 174, 68.9%), most of whom were on antiretroviral therapy (ART; n = 12 471, 88.0%). At 24 months, 4689 patients had died (22.7%); 2072 deaths (44.2%) were reported within 12 weeks of initiating treatment for MDR/RR-TB. From week 12 to week 24, there were 717 deaths/18 048 persons; 59.5% of mortality occurred within the first 24 weeks. During the first 12 weeks, the adjusted hazard rate (aHR) for mortality was highest among patients with a missing baseline culture result (aHR 3.78, 95%CI 2.94-4.86) and among HIV-positive, ART-naïve patients (aHR 3.40, 95%CI 2.90-3.99). Patients initiating MDR/RR-TB treatment within 4 weeks of diagnosis had higher mortality than those with delayed initiation (aHR 1.57, 95%CI 1.41-1.75). CONCLUSION: In EDRweb, mortality is highest in the first few weeks after MDR/RR-TB treatment initiation.

Incident tuberculosis in HIV-positive children, adolescents and adults on antiretroviral therapy in South Africa.

OBJECTIVE: To evaluate the association between age and incident tuberculosis (TB) among human immunodeficiency virus (HIV) infected patients receiving antiretroviral treatment (ART) in South Africa. DESIGN: Prospective cohort analysis among HIV-infected patients initiating ART between April 2004 and April 2012. Generalized estimating equations (GEE) were used with modified Poisson regression clustered by treatment site as a function of sex, age, nucleoside reverse transcriptase inhibitor, CD4 count, hemoglobin levels and year of ART initiation. Cumulative incidence functions stratified by age and controlling for death as a competing risk were used to graphically display incident TB. RESULTS: Although non-significant, GEE models showed that patients aged <1 year had a 40% increase in risk of TB compared to those aged 30-39.9 years. Results also showed that male patients, those with low CD4, those with low hemoglobin and those who initiated ART before 2010 were at increased risk of TB. CONCLUSIONS: Our results show that patients aged <1 year, males, patients with low CD4 and those with low hemoglobin at ART initiation are at increased risk of incident TB in the first 24 months of ART. Given the known transmission risk factors for children living in households with a TB contact, reducing TB incidence in HIV-positive adults could substantially impact the risk of TB in young children.