The contribution of drug import to the cost of tuberculosis treatment: A cost analysis of longer, shorter, and short drug regimens for Karakalpakstan, Uzbekistan

Tuberculosis (TB) programs depend on a continuous supply of large amounts of high-quality TB drugs. When TB programs procure TB drugs from international suppliers, such as the Global Drug Facility, they can incur import costs for international transport, customs clearance, and national transport. We assessed the drug costs and import costs of 18 longer (≥18 months), 10 shorter (9-12 months), and 8 short (≤6 months) drug regimens for drug-sensitive (DS) and multidrug-resistant (MDR)-TB treatment. Costs per regimen were estimated by multiplying recommended drug amounts with 2021 Global Drug Facility prices and drug import costs of a TB program in Karakalpakstan, Uzbekistan. The standard short-course treatment of DS-TB requires taking 730 fixed-dose combination tablets, which weigh 0.79 kg and cause an import cost of $4.19 (9.8$43). A new 4-month DS-TB regimen requires taking 1358 tablets, which weigh 1.1 kg and cause an import cost of $6.07 (2.6$233). MDR-TB regimens that last between 24 weeks and 20 months involve 546-9368 tablets and injections. The drugs for these MDR-TB regimens were estimated to weigh 0.42-96 kg and cause an import cost of $2.26-507 per drug regimen (0.29-11$360-15,028). In a multivariable regression analysis, an additional treatment month increased the import cost of a drug regimen by $5.45 (95$133 (95% CI: 47 to 219). The variable and potentially sizable import costs of TB regimens can affect the financial needs of TB programs. Drug regimens that are shorter and all-oral tend to reduce import costs compared to longer regimens and regimens including an injectable drug

Programme costs of longer and shorter tuberculosis drug regimens and drug import: a modelling study for Karakalpakstan, Uzbekistan

Background: The introduction of new and often shorter tuberculosis (TB) drug regimens affects the cost of TB programmes. Methods: We modelled drug purchase and import costs for 20-month, 9-month and 4- to 6-month TB drug regimens based on 2016–2020 treatment numbers from a TB programme in Karakalpakstan, Uzbekistan, and 2021 Global Drug Facility prices. Results: On average, 2225±374 (±sd) people per year started TB treatment, 30±2.1% of whom were diagnosed with drug-resistant forms of TB. Transitioning from a 6-month to a 4-month drug-susceptible (DS)-TB drug regimen increased the TB programme's annual DS-TB drug cost from USD 65±10 K to USD 357±56 K (p<0.001) and its drug import cost from USD 6.4±1.0 K to USD 9.3±1.4 K (p=0.008). Transitioning from a 20-month all-oral multidrug-resistant (MDR)-TB drug regimen to a 9-month MDR-TB drug regimen with an injectable antibiotic decreased the TB programme's annual MDR-TB drug cost from USD 1336±265 K to USD 266±53 K (p<0.001) and had no significant effect on the drug import cost (USD 28±5.5 K versus USD 27±5.4 K; p=0.88). Purchasing (USD 577±114 K) and importing (USD 3.0±0.59 K) the 6-month all-oral MDR-TB drug regimen cost more than procuring the 9-month MDR-TB drug regimen but less than the 20-month all-oral MDR-TB drug regimen (both p<0.01). Conclusion: Introducing new and shorter TB drug regimens could increase the cost of TB programmes with low drug resistance rates and decrease the cost of TB programmes with high drug resistance rates

Modelling the effect of short-course multidrug-resistant tuberculosis treatment in Karakalpakstan, Uzbekistan

Background: Multidrug-resistant tuberculosis (MDR-TB) is a major threat to global TB control. MDR-TB treatment regimens typically have a high pill burden, last 20 months or more and often lead to unsatisfactory outcomes. A 9-11 month regimen with seven antibiotics has shown high success rates among selected MDR-TB patients in different settings and is conditionally recommended by the World Health Organization. Methods: We construct a transmission-dynamic model of TB to estimate the likely impact of a shorter MDR-TB regimen when applied in a low HIV prevalence region of Uzbekistan (Karakalpakstan) with high rates of drug resistance, good access to diagnostics and a well-established community-based MDR-TB treatment programme providing treatment to around 400 patients. The model incorporates acquisition of additional drug resistance and incorrect regimen assignment. It is calibrated to local epidemiology and used to compare the impact of shorter treatment against four alternative programmatic interventions. Results: Based on empirical outcomes among MDR-TB patients and assuming no improvement in treatment success rates, the shorter regimen reduced MDR-TB incidence from 15.2 to 9.7 cases per 100,000 population per year and MDR-TB mortality from 3.0 to 1.7 deaths per 100,000 per year, achieving comparable or greater gains than the alternative interventions. No significant increase in the burden of higher levels of resistance was predicted. Effects are probably conservative given that the regimen is likely to improve success rates. Conclusions: In addition to benefits to individual patients, we find that shorter MDR-TB treatment regimens also have the potential to reduce transmission of resistant strains. These findings are in the epidemiological setting of treatment availability being an important bottleneck due to high numbers of patients being eligible for treatment, and may differ in other contexts. The high proportion of MDR-TB with additional antibiotic resistance simulated was not exacerbated by programmatic responses and greater gains may be possible in contexts where the regimen is more widely applicable

Inpatient signs and symptoms and factors associated with death in children aged 5 years and younger admitted to two Ebola management centres in Sierra Leone, 2014: a retrospective cohort study

Background Médecins Sans Frontières (MSF) opened Ebola management centres (EMCs) in Sierra Leone in Kailahun in June, 2014, and Bo in September, 2014. Case fatality in the west African Ebola virus disease epidemic has been highest in children younger than 5 years. Clinical data on outcomes can provide important evidence to guide future management. However, such data on children are scarce and disaggregated clinical data across all ages in this epidemic have focussed on symptoms reported on arrival at treatment facilities, rather than symptoms and signs observed during admission. We aimed to describe the clinical characteristics of children aged 5 years and younger admitted to the MSF EMCs in Bo and Kailahun, and any associations between these characteristics and mortality. Methods In a retrospective cohort study, we included data from children aged 5 years and younger with laboratoryconfi rmed Ebola virus disease admitted to EMCs between June and December, 2014. We described epidemiological, demographic, and clinical characteristics and viral load (measured using Ebola virus cycle thresholds [Ct]), and assessed their association with death using Cox regression modelling. Findings We included 91 children in analysis; 52 died (57·1%). Case fatality was higher in children aged less than 2 years (76·5% [26/34]) than those aged 2–5 years (45·6% [26/57]; adjusted HR 3·5 [95% CI 1·5–8·5]) and in those with high (Ct<25) versus low (Ct≥25) viral load (81·8% [18/22] vs 45·9% [28/61], respectively; adjusted HR 9·2 [95% CI 3·8–22·5]). Symptoms observed during admission included: weakness 74·7% (68); fever 70·8% (63/89); distress 63·7% (58); loss of appetite 60·4% (55); diarrhoea 59·3% (54); and cough 52·7% (48). At admission, 25% (19/76) of children were afebrile. Signs signifi cantly associated with death were fever, vomiting, and diarrhoea. Hiccups, bleeding, and confusion were observed only in children who died. Interpretation This description of the clinical features of Ebola virus disease over the duration of illness in children aged 5 years and younger shows symptoms associated with death and a high prevalence of distress, with implications for clinical management. Collection and analysis of age-specifi c data on Ebola is very important to ensure that the specifi c vulnerabilities of children are addressed

The impact of pyrazinamide resistance on the treatment outcome of patients with multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan

Pyrazinamide (PZA), is regarded as an important agent in the management of multi-drug resistant tuberculosis (MDR-TB) (defined as resistance to at least rifampicin and isoniazid) and has been shown to reduce treatment duration for drug-sensitive TB (1). Since the inclusion of PZA in a MDR-TB regimen adds significantly to both the pill burden and the side effects, (mainly arthralgia and hepatitis), it is logical to limit usage to patients where PZA has a proven effect. The current World Health Organisation (WHO) recommendation is to include PZA in MDR-TB regimens unless there is demonstrated evidence of resistance (2). However, large-scale data supporting this recommendation are lacking. No evidence was shown of an association between a successful outcome and PZA susceptibility for MDR-TB patients treated with a full intensive phase PZA standard WHO regimen in a high MDR-TB burden setting. Furthermore, there was no evidence of a dose-response association between a successful outcome and different PZA treatment regimens in the intensive phase. The major limitations was the low power for the main analysis and the retrospective and observational nature of the study contributing to an increased risk of bias. A possible explanation for the results might be that PZA treatment mainly has its effect in shortening a regimen (7) instead of improving outcomes or that patients had sufficient likely effective drugs in their regimen. The generalisability would be limited to settings with low HIV prevalence and where there is a high background prevalence of SLD resistance. This study provides provocative but insufficient evidence to warrant changing PZA treatment protocols, although the evidence relating to PZA for the WHO 2016 guideline is weak. Until further evidence emerges supporting these findings, it seems prudent to continue including PZA in standard MDR-TB regimens unless resistance is certain. We recommend research into alternative add-on agents in settings with high PZA resistance

Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan

Background In 2016, WHO guidelines conditionally recommended standardised shorter 9–12 month regimens for multidrug-resistant tuberculosis (MDR-TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan. Methods Consecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between 1st September 2013 and 31st March 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion. Results Of 146 enrolled, 128 patients were included: 67 female (52.3%), median age 30.1 (IQR 23.8–44.4) years. At the end of treatment, 71.9% (92/128) patients achieved treatment success, with 68% (87/128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failure with fluoroquinolone resistance amplification in 8 patients (8/22, 36.4%); 12 (9.4%) loss to follow-up; 2 (1.5%) deaths. Recurrence occurred in one patient. 14 patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (aOR 6.13, 95% CI 2.01;18.63) and adherence<95% (aOR 5.33, 95% CI 1.73;16.36) were associated with unsuccessful outcome in multivariable logistic regression. Conclusions Overall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of DST-confirmed susceptibility

ShORRT (Short, all-Oral Regimens for Rifampicin-resistant Tuberculosis) Research Package

TDR in close collaboration with the Global TB Programme at WHO and technical partners the WHO Global TB Programme is leading the development of ShORRT (Short, all-Oral Regimens For Rifampicin-resistant Tuberculosis), an operational research package to assess the effectiveness, safety, feasibility, acceptability, cost and impact (including on health-related quality of life) of the use of all-oral shorter drug regimens for adults and children with MDR/RR-TB

Treatment outcomes in global systematic review and patient meta-analysis of children with extensively drug-resistant tuberculosis

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999–2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required

Treatment and outcomes in children with multidrug-resistant tuberculosis: a systematic review and individual patient data meta-analysis.

CAPRISA, 2018.Abstract available in pdf