Costs of multidrug-resistant TB treatment in Finland and Estonia affected by the 2019 WHO guidelines.

BACKGROUND: Multidrug-resistant TB (MDR-TB) is a growing problem in the effort to end the global TB epidemic. In 2019, the WHO adopted a new standardised regiment for MDR-TB, consisting of only oral medications.METHODS: We estimated the impact of the new guidelines on the costs of TB treatment in Estonia and Finland. For both countries, the costs of the two most common new drug regimens were calculated, including drug costs, as well as care- and monitoring-related costs.RESULTS: In Turku, Finland, treatment costs with the old regimen were €178,714; this could either increase by 10% or decrease by 18%, depending on the duration of bedaquiline use (6 months vs. 20 months). In Estonia, treatment costs with the old regimen were €33,664, whereas the new regimens were associated with a 40% increase in overall costs.CONCLUSIONS: The 2019 WHO guidelines have led to significant changes in the costs of MDR-TB treatment in Finland and Estonia. These changes depend mostly on the drug regimen administered and on care-related practices, with important differences between countries and even within the same country due to local practices.

Respiratory tuberculosis incidence and mortality in Estonia: 30-year trends and sociodemographic determinants.

OBJECTIVE: To explore time trends in the incidence and mortality of respiratory tuberculosis (TB) over a 30-year period in Estonia, and to evaluate disease disparities according to sex, age, ethnicity and education. DESIGN: Data from the TB Register and the Causes of Death Register were used to assess time trends in age-standardised incidence and mortality rates. The effect of sociodemographic characteristics on TB risk was modelled using Poisson regression around three population censuses. RESULTS: Respiratory TB incidence and mortality decreased in males and were stable in females in 1987-1991, after which the rates increased sharply in both sexes until 1998 and decreased steadily afterwards. Multidrug-resistant TB (MDR-TB) incidence rose in males until 1998 and in females until 2002, and then started to fall. The incidence of TB and human immunodeficiency virus (HIV) coinfection in males increased until 2007 and decreased thereafter. Less educated people and non-Estonians had a significantly higher relative risk of respiratory TB. CONCLUSION: Estonia, one of the countries most affected by TB in the World Health Organization European Region, has made considerable progress in reducing the risk of respiratory TB, TB-HIV and MDR-TB. Continuing education- and ethnicity-related disparities in TB risk remain a concern.

Beyond multidrug-resistant tuberculosis in Europe: a TBNET study.

The emergence of drug-resistant tuberculosis (TB) is a challenge to TB control in Europe. We evaluated second-line drug susceptibility testing in Mycobacterium tuberculosis isolates from patients with multidrug-resistant, pre-extensively drug-resistant (pre-XDR-TB) and XDR-TB at 23 TBNET sites in 16 European countries. Over 30% of bacilli from patients with pre-XDR-TB showed resistance to any fluoroquinolone and almost 70% to any second-line injectable drug. Respectively >90% and >80% of the XDR-TB strains tested showed phenotypic resistance to pyrazinamide and ethambutol. Resistance to prothionamide/ethionamide was high in bacilli from pre-XDR-TB patients (43%) and XDR-TB patients (49%).

A four-year nationwide molecular epidemiological study in Estonia: risk factors for tuberculosis transmission.

SETTING: Estonia has a high proportion of multidrug-resistant tuberculosis (MDR-TB). It is important to link molecular and epidemiological data to understand TB transmission patterns. OBJECTIVE: To use 24-locus variable numbers of tandem repeat (VNTR) typing and national TB registry data in Estonia from 2009 to 2012 to identify the distribution of drug resistance patterns, Mycobacterium tuberculosis isolate clustering as an index for recent transmission, socio-demographic and clinical characteristics associated with recent transmission, and the distribution of transmission between index and secondary cases. DESIGN: A retrospective nationwide cross-sectional study. RESULTS: Of 912 cases with isolate and patient information, 39.1% of isolates were from the Beijing lineage. Cluster analysis identified 87 clusters encompassing 69.1% of isolates. The largest cluster comprised 178 isolates from the Beijing lineage, of which 92.1% were MDR- or extensively drug-resistant TB (XDR-TB). Factors associated with recent transmission were polyresistant TB, MDR- and XDR-TB, human immunodeficiency virus positivity, Russian ethnicity, non-permanent living situation, alcohol abuse and detention. XDR-TB cases had the highest risk of recent transmission. The majority of transmission cases involved individuals aged 30-39 years. CONCLUSION: Recent TB transmission in Estonia is high and is particularly associated with MDR- and XDR-TB and the Beijing lineage.

Overall and cause-specific mortality among patients with tuberculosis and multidrug-resistant tuberculosis.

OBJECTIVE: To assess overall and cause-specific mortality among patients with tuberculosis (TB) and multidrug-resistant tuberculosis (MDR-TB) in Estonia. DESIGN: A total of 2449 patients diagnosed with active respiratory TB from 1 January 2002 to 31 December 2009 were followed up retrospectively until 31 December 2011. To estimate the risk of death, standardised mortality ratios (SMR) and mortality rate ratios (RR) were calculated. RESULTS: The SMR for all-cause mortality among those diagnosed with TB was 5.30 (95%CI 4.85-5.75) in males and 10.00 (95%CI 8.25-11.74) in females. The relative risk of death from TB was higher among MDR-TB patients (adjusted RR in males 2.98, 95%CI 2.00-4.44, and in females 3.26, 95%CI 1.42-7.50) than among non-MDR-TB patients. Among the cohort of successfully treated patients, the SMR for all-cause mortality was 3.46 (95%CI 3.08-3.84) in males and 6.24 (95%CI 4.86-7.88) in females. Lower education level and foreign ethnicity contributed to the higher risk of mortality. Previous history of successfully treated MDR-TB did not increase the risk of death compared to successfully treated non-MDR-TB. CONCLUSIONS: Mortality among successfully treated TB and MDR-TB patients remained higher than among the general population. It was influenced by foreign ethnicity and lower education but, importantly, not by previous history of MDR-TB.

Predictors of sputum culture conversion among patients treated for multidrug-resistant tuberculosis.

OBJECTIVE: To identify predictors of initial sputum culture conversion, estimate the usefulness of persistent positive cultures at different time points in predicting treatment failure, and evaluate different definitions of culture conversion for predicting failure among patients with multidrug-resistant tuberculosis (MDR-TB) in five countries, 2000-2004. METHODS: Predictors of time to conversion were identified using multivariate Cox proportional hazards regression modeling. Receiver operating characteristic curves were plotted to visualize the effect of using different definitions of 'culture conversion' on the balance between sensitivity and specificity. RESULTS: Overall, 1209/1416 (85%) of patients with baseline positive cultures converted in a median of 3.0 months (interquartile range 2.0-5.0). Independent predictors of less likely conversion included baseline positive smear (hazard ratio [HR] 0.60, 95%CI 0.53-0.68), resistance to pyrazinamide (HR 0.82, 95%CI 0.70-0.96), fluoroquinolones (FQs; HR 0.65, 95%CI 0.51-0.83) or thioamide (HR 0.83, 95%CI 0.71-0.96), previous use of FQs (HR 0.71, 95%CI 0.60-0.83), poor outcome of previous anti-tuberculosis treatment (HR 0.69, 95%CI 0.54-0.88) and alcoholism (HR 0.74, 95%CI 0.63-0.87). The maximum combined sensitivity (84%) and specificity (94%) in predicting treatment failure was based on lack of culture conversion at month 9 of treatment, assuming conversion is defined as five consecutive negative cultures. CONCLUSION: Patients with identified risk factors were less likely to achieve sputum culture conversion during MDR-TB treatment.

Predictors of recurrence of multidrug-resistant and extensively drug-resistant tuberculosis.

OBJECTIVE: To assess the treatment outcome of the first Green Light Committee (GLC) approved countrywide management of multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) in Estonia and to evaluate risk factors contributing to TB recurrence over 8 years of follow-up. DESIGN: Prospective assessment of MDR- and XDR-TB patients starting second-line anti-tuberculosis drug treatment between 1 August 2001 and 31 July 2003, with follow-up until 31 December 2010. RESULTS: In 211 MDR- and XDR-TB patients, treatment success was 61.1%; 22.3% defaulted, 8.5% failed and 8.1% died. TB recurrence among successfully treated patients was 8.5%, with no significant difference between XDR-TB and MDR-TB. TB recurrence was associated with resistance to all injectables (HR 2.27, 95%CI 1.16-5.06, P = 0.046), resistance to a greater number of drugs (HR 1.35, 95%CI 1.11-1.64, P = 0.003), and sputum smear positivity (HR 2.16, 95%CI 1.16-4.00, P = 0.016). A history of previous TB treatment was associated with TB recurrence among successfully treated patients (HR 4.28, 95%CI 1.13-16.15, P = 0.032). CONCLUSIONS: The internationally recommended Category IV treatment regimens are sufficiently effective to cure 75% of adherent MDR- and XDR-TB patients. A history of previous treatment, resistance to all injectable agents and resistance to a greater number of drugs increase the recurrence of MDR- and XDR-TB.

Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment.

Monthly culture is usually recommended to monitor treatment of multidrug-resistant tuberculosis (MDR-TB). As mycobacterial laboratory capacity is limited in many settings, TB programs need evidence to decide whether monthly cultures are necessary compared to other approaches. We simulated three alternative monitoring strategies (culture every 2 or 3 months, and monthly smears alone) in a cohort of MDR-TB patients in Estonia, Latvia, Philippines, Russia and Peru from 2000 to 2004. This retrospective analysis illustrated that less frequent testing delays confirmation of bacteriological conversion. This would prolong intensive treatment, hospitalization and respiratory isolation, increasing cost and toxicity. After conversion, less frequent testing could delay diagnosis of possible treatment failure.

Countrywide management of pulmonary tuberculosis reverses increasing incidence.

OBJECTIVE: To evaluate the impact of countrywide management of tuberculosis (TB) and the availability of second-line drugs (SLDs) on the notification rates of pulmonary TB (PTB) overall and of multidrug-resistant TB (MDR-TB), taking into account human immunodeficiency virus (HIV) co-infection and the national economy in Estonia. DESIGN: Retrospective analysis of notification rates and treatment outcomes of PTB and MDR-TB during 1998-2006. RESULTS: The annual notification rates of both PTB and MDR-TB decreased significantly, by on average 3.3 (P = 0.007) and 1.7 (P = 0.008) cases per 100,000 population, respectively. The accelerating impact of SLD availability on the annual decline was significant for both PTB overall and MDR-TB (P = 0.003 and P = 0.025, respectively). During 1998-2006, an increase in TB-HIV co-infection (P = 0.009) significantly affected the notification rates of both PTB overall and MDR-TB (P < 0.001 and P < 0.001, respectively). The negative impact of TB-HIV co-infection was counterbalanced by the availability of SLDs, the decrease in the MDR-TB rate and the increase in gross domestic product (GDP) per capita, as confirmed by multivariate analysis. CONCLUSION: Countrywide access to SLDs and the coordinated effect of programmatic conditions can, in parallel with increasing GDP, reverse the increasing notification rates of PTB and MDR-TB in the context of an HIV epidemic.