The scale of the divergence is striking. In 2021, MDR-TB carried the heaviest absolute burden among the resistant forms, with an age-standardized incidence rate of 5.4161 per 100,000 population and an age-standardized death rate of 1.2791 per 100,000. Yet the most explosive relative growth belonged to HIV/AIDS-XDR-TB, tuberculosis that is resistant to isoniazid and rifampicin plus a fluoroquinolone and a second-line injectable drug, occurring in people with HIV. Death cases in that category rose from just 9.78 in 1993 to 840 in 2021, an 84.89-fold increase, with the age-standardized death rate climbing at an estimated annual percentage change (EAPC) of 10. By contrast, MDR-TB deaths grew 5.65-fold over the same span, from 16,062.84 to 106,817.98 cases, with an EAPC in the death rate of just 1.18, a confidence interval that touched zero. XDR-TB alone showed a 29.67-fold rise in deaths, and HIV/AIDS-MDR-TB a 23.96-fold rise, underscoring how resistance and immune suppression compound each other.

The study’s definitions matter for interpreting these numbers. The GBD 2021 framework used the pre-2021 World Health Organization classification, under which MDR-TB denotes resistance to the two most effective first-line drugs, isoniazid and rifampicin, without resistance to fluoroquinolones or second-line injectables such as amikacin, kanamycin, or capreomycin. XDR-TB adds resistance to any fluoroquinolone and any second-line injectable drug. The HIV-associated categories apply the same resistance profiles among HIV-positive individuals. Because WHO revised the XDR-TB definition in January 2021 to include resistance to bedaquiline or linezolid and introduced the intermediate pre-XDR-TB category, the estimates may understate the burden under current surveillance criteria, a limitation the authors flag explicitly.

Geographically, the burden follows a socioeconomic gradient with an unexpected twist. Deaths from MDR-TB in 2021 were concentrated in the low-middle Socio-Demographic Index (SDI) region, which recorded 51,909.62 deaths, roughly 48.6 percent of the global total. The age-standardized death rate fell steadily as development rose, from 5.0894 per 100,000 in the low SDI region to just 0.0234 in the high SDI region. Death rates are still climbing in the low and low-middle SDI regions, with EAPCs of 3.61 and 4.8 respectively, while the middle, high-middle, and high SDI regions have seen declines. But when the researchers examined the proportion of disease burden attributable to resistant tuberculosis relative to all tuberculosis, the high-middle SDI region stood out with the highest ratios over three decades. MDR-TB accounted for as much as 20.6 percent of deaths there, compared with only 7 percent in the high SDI region, and the high-middle SDI region also recorded the peak number of HIV/AIDS-XDR-TB deaths in 2021, at 285.87, about one-third of the global total.

At the regional level, most of the world’s 21 GBD regions saw increases, but a handful bucked the trend. High-income North America, East Asia, the Caribbean, and Western Europe recorded declines. High-income North America showed the sharpest drops in HIV/AIDS-MDR-TB, with EAPCs of −9.24 for incidence and −10.74 for death rates, and its 2021 MDR-TB counts had fallen by more than 60 percent for incidence and 80 percent for deaths relative to baseline. The authors attribute this to early screening, effective treatment, vaccination, and stronger public health infrastructure. Conversely, Oceania and South Asia experienced the most pronounced increases in age-standardized rates across the resistant forms.

Country-level patterns reinforce the regional divide. India recorded the highest national death counts in 2021 for both MDR-TB and XDR-TB, at 53,333.12 and 2,815.29 respectively, accounting for roughly half and one-third of global deaths from those diseases, with rates still rising. The steepest increases in death rates occurred in Lesotho for MDR-TB (EAPC 12.6), Papua New Guinea for XDR-TB (19.84), and Pakistan for both HIV-associated categories (46.09 and 50.9). China presents a contrasting story: despite substantial case numbers, its age-standardized rates are comparatively low and declining, with an MDR-TB death rate of 0.1469 per 100,000 and an EAPC of −10.03, a trajectory the researchers link to social protection measures and an increasingly mature tuberculosis control system. Slovenia showed the most significant overall declines, with MDR-TB co-prevalence reported at or below 1 percent.

Sex and age patterns add further nuance. Men carried a higher burden than women in 2021 for MDR-TB, XDR-TB, and HIV/AIDS-XDR-TB, consistent with evidence that tuberculosis spreads through social networks in which men predominate, and with higher rates of smoking and alcohol use among men. However, women’s rates increased faster over the study period, suggesting the gender gap will narrow. For HIV/AIDS-MDR-TB, women already bore the higher burden in 2021, with an age-standardized incidence rate of 0.5886 per 100,000 versus 0.5223 for men, and the authors attribute this to women’s heightened vulnerability to HIV acquisition through unsafe sex, intimate partner violence, and inadequate sexual and reproductive health services. By age, the burden of MDR-TB and XDR-TB grew most sharply in the 15 to 49 group, though in 2021 the highest rates fell on those aged 75 and older, whose MDR-TB death rate of 7.102 per 100,000 was roughly 70 times that of children aged 5 to 14. The HIV-associated categories showed their largest increases in the 5 to 14 group, where HIV/AIDS-MDR-TB deaths rose 103.26-fold, though the authors caution that small case numbers and modeling uncertainty warrant careful interpretation of these pediatric estimates.

The risk factor analysis reveals where prevention could intervene. Globally, the leading contributors to MDR-TB and XDR-TB deaths were smoking, high fasting plasma glucose, high alcohol use, and high body mass index. Smoking and alcohol use were most prominent in the high-middle SDI region, contributing 30.5 percent and 21.8 percent of MDR-TB deaths respectively, and 33.4 percent and 23.6 percent of XDR-TB deaths. Sex differences were marked: for women, high fasting plasma glucose and high body mass index were the primary contributors, with high BMI overtaking alcohol and smoking as the second leading contributor among women over the study period, a shift the authors connect to rising obesity, obesity-related immune dysfunction, and the compounding effect of diabetes on tuberculosis susceptibility. For HIV-associated disease, the attributable factors were unsafe sex, drug use, and intimate partner violence, which act mainly as upstream drivers of HIV infection rather than direct causes of resistant tuberculosis mortality.

The authors are careful to frame the analysis within its limits. GBD estimates rely heavily on statistical modeling, particularly in countries with sparse primary data, and the underlying surveillance captures resistance to bedaquiline and linezolid poorly, if at all. The database also lacks treatment regimen, adherence, and health-system variables, so the programmatic drivers of drug resistance could not be assessed, and the risk factor attribution should be read as complementary rather than a full causal account. Even so, the central message is unambiguous: over three decades, the burden of every category of drug-resistant tuberculosis has grown, the HIV-associated extensively resistant form has grown fastest of all, and the high-middle SDI region now carries a disproportionate share of the problem. The authors argue that tailored strategies, from tobacco and alcohol control to bidirectional screening for metabolic risk, pre-migration screening in high-mobility settings, and rapid diagnostics paired with shorter, less toxic regimens, will be essential to bend these curves and to meet the WHO’s End TB Strategy targets.

Subject of Research: Epidemiology of drug-resistant tuberculosis

Article Title: The burden of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis and its attributable risk factors in 204 countries and territories, 1990–2021

Article References: Wang, H., Lv, S., Yao, P., & Cen, J. (2026). The burden of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis and its attributable risk factors in 204 countries and territories, 1990–2021. Frontiers in Public Health, 14, Article 1960895. https://doi.org/10.3389/fpubh.2026.1960895

Image Credits: AI Generated

DOI: 10.3389/fpubh.2026.1960895

Keywords: tuberculosis, MDR-TB, XDR-TB, Global Burden of Disease, HIV/AIDS, antimicrobial resistance, epidemiology, public health, burden, multidrug-resistant, extensively, drug-resistant