Effectiveness and safety of modified fully oral 9-month treatment regimens for rifampicin-resistant tuberculosis: a prospective cohort study.

BACKGROUND: In 2020, WHO guidelines prioritised the use of a standard fully oral short treatment regimen (STR) consisting of bedaquiline, levofloxacin or moxifloxacin, ethionamide, ethambutol, high-dose isoniazid, pyrazinamide, and clofazimine for the management of rifampicin-resistant tuberculosis. A high prevalence of resistance to constituent drugs precluded its widespread use by countries in the WHO European region. We evaluated three 9-month fully oral modified STRs (mSTRs) in which ethionamide, ethambutol, isoniazid, and pyrazinamide were replaced by linezolid, cycloserine, or delamanid (or a combination). METHODS: This multicountry, prospective, single-arm, cohort study examined the effectiveness and safety of mSTRs for fluoroquinolone-susceptible, rifampicin-resistant pulmonary tuberculosis in 13 countries in the WHO European region during 2020-23. We enrolled adults and children of all ages with bacteriologically confirmed rifampicin-resistant, fluoroquinolone-susceptible pulmonary tuberculosis, and children (aged 0-18 years) with clinically diagnosed disease and a confirmed contact with rifampicin-resistant, fluoroquinolone-susceptible tuberculosis. Participants aged 6 years or older received one of two regimens: bedaquiline, linezolid, levofloxacin, clofazimine, and cycloserine; or bedaquiline, linezolid, levofloxacin, clofazimine, and delamanid. Children younger than 6 years received delamanid, linezolid, levofloxacin, and clofazimine. Participants were followed up for 12 months after successful treatment completion to detect recurrence and death. The primary outcome was the cumulative probability of not having an unsuccessful study outcome (defined as treatment failure, on-treatment loss to follow-up, death, or recurrence) before 22 months of study follow-up. The primary safety outcome was the incidence of each adverse event of interest (peripheral neuropathy, optic neuritis, myelosuppression, hepatitis, prolonged QT interval, hypokalaemia, and acute kidney injury) of grade 3 or higher severity during the treatment course. FINDINGS: Between Aug 28, 2020 and May 26, 2021, 7272 patients were screened and 2636 were included in the treatment cohort. 1966 (74·6%) were male, 670 (25·4%) were female, and median age was 43 years (IQR 33-53). Treatment success was recorded for 2181 (82·7%) participants. The cumulative probability of not having an unsuccessful study outcome 22 months after treatment initiation was 79% (95% CI 78-81). Increasing age (adjusted hazard ratio 2·61 [95% CI 1·70-4·04] for people aged >64 years vs 35-44 years), HIV-positive status (1·53 [1·16-2·01]), presence of bilateral cavities (1·68 [1·29-2·19]), smoking history (1·34 [1·05-1·71]), baseline anaemia (1·46 [1·15-1·86]), unemployment (1·37 [1·04-1·80]), elevated baseline liver enzymes (1·40 [1·13-1·73]), and excessive alcohol use (1·47 [1·14-1·89]) were positively associated with unsuccessful study outcomes. In the safety cohort of 2813 participants who received at least one dose, 301 adverse events of interest were recorded in 252 (9·0%) participants with the most frequent being myelosuppression (139 [4·9%] participants, 157 [52·2%] events). INTERPRETATION: The high treatment success and good safety results indicate considerable potential for the use of mSTRs in programmatic conditions, especially for individuals not eligible for the current WHO-recommended 6-month regimen and in settings with a need for alternative options. FUNDING: The Global Fund to Fight AIDS, Tuberculosis and Malaria; United States Agency for International Development; Government of Germany; and WHO. TRANSLATION: For the Russian translation of the abstract see Supplementary Materials section.

Pregnancy and Birth Outcomes in Patients With Multidrug-Resistant Tuberculosis Treated With Regimens That Include New and Repurposed Drugs.

Among 43 pregnant women receiving multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment with bedaquiline and/or delamanid, 98% had favorable treatment outcomes. Of 31 continued pregnancies, 81% had live births with no reported malformations, and 68% of neonates had normal birth weights. Effective MDR/RR-TB treatment during pregnancy can improve maternal outcomes without harming neonates.

HIV co-infection increases the risk of post-tuberculosis mortality among persons who initiated treatment for drug-resistant tuberculosis.

Little is known regarding the relationship between common comorbidities in persons with tuberculosis (TB) (including human immunodeficiency virus [HIV], diabetes, and hepatitis C virus [HCV]) with post-TB mortality. We conducted a retrospective cohort study among persons who initiated treatment for rifampicin-resistant and multi/extensively drug-resistant (RR and M/XDR) TB reported to the country of Georgia's TB surveillance during 2009-2017. Exposures included HIV serologic status, diabetes, and HCV status. Our outcome was all-cause post-TB mortality determined by cross-validating vital status with Georgia's death registry through November 2019. We estimated adjusted hazard rate ratios (aHR) and 95% confidence intervals (CI) of post-TB mortality among participants with and without comorbidities using cause-specific hazard regressions. Among 1032 eligible participants, 34 (3.3%) died during treatment and 87 (8.7%) died post-TB treatment. Among those who died post-TB treatment, the median time to death was 21 months (interquartile range 7-39) post-TB treatment. After adjusting for confounders, the hazard rates of post-TB mortality were higher among participants with HIV co-infection (aHR=3.74, 95%CI 1.77-7.91) compared to those without HIV co-infection. In our cohort, post-TB mortality occurred most commonly in the first three years post-TB treatment. Linkage to care for common TB comorbidities post-treatment may reduce post-TB mortality rates.

The Relationship between Insulin Resistance and Thyroid Volume in Georgia.

Patients with insulin resistance (IR) have a higher thyroid volume therefore the aim of our study is to examine the correlation between IR and thyroid volume in the residents of Georgia. METHODS: 413 patients with a mean age of 37.3 ± and 11.4 years were included in this study. Out of those, 120 were males, and 293 were females who were studied retrospectively. They had hyperinsulinemia and were referred to the clinic from 2017 to 2019. The factors studied were age, sex, body mass index (BMI), clinical signs, thyroid ultrasound, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipids, fasting insulin, fasting glucose, thyroid stimulating hormone (TSH), Free thyroxine (FT4), and Zinc (Zn). RESULTS: IR was detected in 252 individuals. The frequency of men with insulin resistance was significantly higher than in the control group - 72.50%, and 56.31%, respectively (F = 9.55, p= 0.0021). Mean thyroid volume in the patients with IR was significantly higher compared to the controls 20.52 + 6.39 cm3 and 15.25 + 6.55 cm3, respectively (p < 0.001). Hyperinsulinemia had a significant positive correlation with Goiter r = 0.445, p < 0.0001. The associated factors for hyperinsulinemia are: Goiter (1) - OR = 5.12 (95% CI:3.02-8.69); Cholesterol - OR = OR = 3.31 (95% CI: 1.54-7.14); Triglycerides - OR = 3.23 (95% CI:1.02-10.28); Obesity (1)- OR = 3.94 (95% CI: 2.23-6.98); Thyroid structural changes (1) - OR = 2.01 (95% CI: 1.12-3.60); ALT/AST-OR = 4.53 (95% CI: 2.33-8.80); Zn decreased Odds Ratio hyperinsulinemia - OR = 0.95 (95% CI: 0.94-0.97). CONCLUSION: Hyperinsulinemia is the most common cause of diffuse goiter and the heterogeneous structure of the thyroid. The volume of the thyroid gland shows a significant positive association with the characteristics of metabolic syndrome and increased thyroid volume predictors of metabolic syndrome.

Correlation Between Vitamin B12 Deficiency and Autoimmune Thyroid Diseases.

BACKGROUND: Autoimmune thyroid diseases (AITD) are the most prevalent organ-specific autoimmune disorders. Vitamin B12 plays an important role in the proper functioning of the immune system. The aim of this study was therefore to investigate the correlation between vitamin B12 deficiency and AITD. MATERIALS AND METHODS: A total of 306 patients (aged 18-65 years, mean - 37.6 ± 11.3 years and comprising 87 males and 219 females) were studied retrospectively (observational study). Patients were divided into groups: with and without vitamin B12 deficiency, and with and without AITD. Differences between groups were evaluated by Fisher's exact test for qualitative variables and by Student's t-test for quantitative variables. Correlations for quantitative factors were determined by the Pearson correlation coefficient and for qualitative factors by Spearman correlation analysis. The sensitivity and specificity of vitamin B12 deficiency for AITD were calculated by ROC analysis. RESULTS: The vitamin B12 level was significantly lower in patients with AITD (and 200.70 + 108.84) compared to controls (393.41+150.78 p<0.0001). Patients with vitamin B12 deficiency were characterized by significantly higher mean values of anti-TPO (236.60+455.74) compared to controls (39.51+165.57 p<0.0001). Vitamin B12 levels were inversely correlated to anti-TPO levels (r=- 0.233, p<0.001). Roc analysis of vitamin B12 as a diagnostic test for AITD gave the area under curve as 0.881 (95% CI: 0.839-0.924), a sensitivity of - 0.947, a specificity of - 0.768, and a cutoff value of - 178.9. CONCLUSION: The vitamin B12 level correlates significantly to AITD. The concentration of vitamin B12 should therefore be determined in patients with autoimmune thyroiditis as a diagnostic test with high sensitivity and good specificity.

Cost-effectiveness of bedaquiline, pretomanid and linezolid for treatment of extensively drug-resistant tuberculosis in South Africa, Georgia and the Philippines.

OBJECTIVES: Patients with highly resistant tuberculosis have few treatment options. Bedaquiline, pretomanid and linezolid regimen (BPaL) is a new regimen shown to have favourable outcomes after six months. We present an economic evaluation of introducing BPaL against the extensively drug-resistant tuberculosis (XDR-TB) standard of care in three epidemiological settings. DESIGN: Cost-effectiveness analysis using Markov cohort model. SETTING: South Africa, Georgia and the Philippines. PARTICIPANTS: XDR-TB and multidrug-resistant tuberculosis (MDR-TB) failure and treatment intolerant patients. INTERVENTIONS: BPaL regimen. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Incremental cost per disability-adjusted life years averted by using BPaL against standard of care at the Global Drug Facility list price. (2) The potential maximum price at which the BPaL regimen could become cost neutral. RESULTS: BPaL for XDR-TB is likely to be cost saving in all study settings when pretomanid is priced at the Global Drug Facility list price. The magnitude of these savings depends on the prevalence of XDR-TB in the country and can amount, over 5 years, to approximately US$ 3 million in South Africa, US$ 200 000 and US$ 60 000 in Georgia and the Philippines, respectively. In South Africa, related future costs of antiretroviral treatment (ART) due to survival of more patients following treatment with BPaL reduced the magnitude of expected savings to approximately US$ 1 million. Overall, when BPaL is introduced to a wider population, including MDR-TB treatment failure and treatment intolerant, we observe increased savings and clinical benefits. The potential threshold price at which the probability of the introduction of BPaL becoming cost neutral begins to increase is higher in Georgia and the Philippines (US$ 3650 and US$ 3800, respectively) compared with South Africa (US$ 500) including ART costs. CONCLUSIONS: Our results estimate that BPaL can be a cost-saving addition to the local TB programmes in varied programmatic settings.

Incidence rate and time to serious adverse events among rifampicin resistant tuberculosis patients in Georgia treated with new and repurposed anti-tuberculosis drugs, 2016-2018.

Considering the complexity of second-line anti-tuberculosis (TB) treatment regimens, the management of drug-resistant TB (DR-TB) in Georgia remains a major challenge. Since the introduction of new and repurposed anti-TB medications, the implementation of active TB Drug Safety Monitoring (aDSM) was a critical program component to help establish safety and manage all treatment related Serious Adverse Events (SAEs). In our study, we aimed to describe the occurrence, characteristics and timing of SAE among patients with Rifampicin Resistant and Multi-Drug Resistant TB (RR/MDR-TB) receiving new and/or repurposed anti-TB medications (bedaquiline, delamanid, linezolid, clofazimine, imipenem) during the period of 2016-2018 in Georgia and identify predictors of SAE. The data were obtained from the medical charts, electronic database and standardized aDSM reports During 2016-2018 period in total 970 people with RR/MDR-TB were notified in Georgia and 388 of them received new and/or repurposed TB drugs as part of their treatment regimen and all were included into the study. The results showed a total of 73 SAEs registered among 49 (12.6%) patients receiving new and/or repurposed drugs. The overall SAE incidence rate per 100 person-months was 1.16. The severity of the majority of the SAEs (46.6%) was grade III and 21.9% were grade IV. The most common SAE reported was hepatotoxicity, with an incidence of 0.26 per 100 person-month (n=16, 21.9%) followed by cardiotoxicity with an incidence of 0.16 per 100 person-month (n=10, 13.7%). Median time to SAE occurrence was 183 days (IQR 84 - 334) after treatment initiation. Resistance profile was the only predictor associated with occurrence of a SAEs. There was increased hazard of SAEs among patients with XDR-TB (adjusted HR=2.18, 95% CI: 1.12-4.23). Our findings on SAEs among patients treated with new or repurposed anti-TB drugs are echoing the findings available in the literature. They highlight the need for close monitoring of patients and underlines the importance of the aDSM during the whole treatment. Safety profile of the medications and combinations used are yet to be established and larger datasets comprised of patients receiving same treatment regimens need to be utilized.

Treatment Outcomes Among Pediatric Patients With Highly Drug-Resistant Tuberculosis: The Role of New and Repurposed Second-Line Tuberculosis Drugs.

BACKGROUND: Among pediatric patients with multidrug-resistant tuberculosis (MDR-TB), limited data exist regarding treatment outcomes in the context of the new and repurposed second-line TB drugs (SLDs). We aimed to describe the treatment outcomes among pediatric MDR-TB patients receiving new and repurposed SLDs including the proportion who achieved favorable outcomes. METHODS: We conducted a retrospective cohort study among pediatric patients (age ≤18 years) treated for MDR-TB in the country of Georgia from 2009 to 2016. A "new and repurposed" SLD regimen was defined as a regimen that included linezolid, bedaquiline, and/or delamanid. Favorable treatment outcome was defined by treatment completion or documented microbial "cure" status at the end of treatment. We assessed the association between the use of the new and repurposed SLDs with MDR-TB treatment outcomes using bivariate analyses and log-binomial regression. RESULTS: There were 124 pediatric MDR-TB patients (median age: 13.7; interquartile range: 4.6-16.0) initiating treatment; 119 (96.0%) had a treatment outcome recorded and were included in our analyses. Eighteen (15.1%) patients received new and repurposed SLDs from 2015 or later. After adjusting for potential confounders, the proportion achieving favorable MDR-TB treatment outcomes was higher among patients treated with SLD regimens that included new and/or repurposed drugs when compared with those treated without (adjusted risk ratio: 1.17; 95% confidence interval: 0.51-2.72). CONCLUSIONS: We observed a high proportion of favorable treatment outcomes among pediatric patients with MDR-TB receiving the new and repurposed SLDs. Further studies to evaluate the efficacy and children's tolerability of the new and repurposed SLDs are still warranted.

Long-term Follow-up Reveals High Posttreatment Mortality Rate Among Patients With Extensively Drug-Resistant Tuberculosis in the Country of Georgia.

BACKGROUND: Given very limited data, we assessed the long-term outcomes among patients with extensively drug-resistant (XDR) tuberculosis (TB). METHODS: A retrospective population-based cohort study was performed in patients with XDR-TB diagnosed during 2011-2013 in the country of Georgia. Data were abstracted from the National TB Program, medical charts, interviews, and the national Georgian death registry. RESULTS: Among 111 patients starting treatment for XDR-TB, 59 (53.2%) had newly diagnosed tuberculosis, and 3 (2.9%) had human immunodeficiency virus (HIV) coinfection. The median length of follow-up from diagnosis of XDR-TB to death or the end of study was 53.9 months (interquartile range, 27.2-66.3 months). End-of-treatment outcomes were available for 106 patients; 35 (33.0%) had a favorable outcome, and 71 (67.0%) had an unfavorable outcome, including death in 16 (15.1%). An additional 20 patients died after cessation of initial treatment, increasing the overall mortality rate to 34.0%. In multivariable analysis, an unfavorable initial end-of-treatment outcome was associated with posttreatment death (adjusted odds ratio, 14.41; 95% confidence interval, 1.78-117.13). CONCLUSIONS: The overall mortality rate and specifically the posttreatment mortality rate were high among patients with XDR-TB. Patients with an unfavorable end-of-treatment outcome had an increased risk of death during follow-up. Our findings highlight the need for improved adherence, better-tolerated and shorter therapies, and enhanced posttreatment surveillance among patients treated for XDR-TB.

High-dose vitamin D3 in adults with pulmonary tuberculosis: a double-blind randomized controlled trial.

BACKGROUND: Tuberculosis, including multidrug-resistant tuberculosis (MDR-TB), is a major global health problem. Individuals with tuberculosis disease commonly exhibit vitamin D deficiency, which may adversely affect immunity and the response to therapy. OBJECTIVE: We determined whether adjunctive high-dose vitamin D3 supplementation improves outcomes in individuals with pulmonary tuberculosis disease. DESIGN: The study was a double-blind, randomized, placebo-controlled, intent-to-treat trial in 199 individuals with pulmonary tuberculosis disease in Tbilisi, Georgia. Subjects were randomly assigned to receive oral vitamin D3 [50,000 IUs (1.25 mg) thrice weekly for 8 wk and 50,000 IU every other week for 8 wk] or a placebo concomitant with standard first-line antituberculosis drugs. The primary outcome was the time for the conversion of a Mycobacterium tuberculosis (Mtb) sputum culture to negative. RESULTS: Baseline characteristics between groups were similar. Most subjects (74%) were vitamin D deficient (plasma 25-hydroxyvitamin D [25(OH)D] concentration <50 nmol/L). With vitamin D3, plasma 25(OH)D concentrations peaked at ∼250 nmol/L by 8 wk and decreased to ∼125 nmol/L at week 16. Adverse events and plasma calcium concentrations were similar between groups. In 192 subjects with culture-confirmed tuberculosis, an adjusted efficacy analysis showed similar median culture-conversion times between vitamin D3 and placebo groups [29 and 27 d, respectively; HR: 0.86; 95% CI: 0.63, 1.18; P = 0.33). Eight-week culture-conversion rates were also similar (84.0% and 82.1% for vitamin D3 and placebo, respectively; P = 0.99). CONCLUSION: A high-dose vitamin D3 regimen safely corrected vitamin D deficiency but did not improve the rate of sputum Mtb clearance over 16 wk in this pulmonary tuberculosis cohort. This trial was registered at clinicaltrials.gov at NCT00918086.

Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis.

BACKGROUND: The country of Georgia has a high prevalence of tuberculosis (TB) and hepatitis C virus (HCV) infection. PURPOSE: To determine whether HCV co-infection increases the risk of incident drug-induced hepatitis among patients on first-line anti-TB drug therapy. METHODS: Prospective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase [ALT] activity) were obtained at baseline and monthly during treatment. RESULTS: Among 326 study patients with culture-confirmed TB, 68 (21%) were HCV co-infected, 14 (4.3%) had chronic hepatitis B virus (HBV) infection (hepatitis B virus surface antigen positive [HBsAg+]), and 6 (1.8%) were HIV co-infected. Overall, 19% of TB patients developed mild to moderate incident hepatotoxicity. In multi-variable analysis, HCV co-infection (adjusted Hazards Ratio [aHR]=3.2, 95% CI=1.6-6.5) was found to be an independent risk factor for incident anti-TB drug-induced hepatotoxicity. Survival analysis showed that HCV co-infected patients developed hepatitis more quickly compared to HCV seronegative patients with TB. CONCLUSION: A high prevalence of HCV co-infection was found among patients with TB in Georgia. Drug-induced hepatotoxicity was significantly associated with HCV co-infection but severe drug-induced hepatotoxicity (WHO grade III or IV) was rare.