To the Editor:
People infected with Mycobacterium tuberculosis and HIV are much more likely to develop active tuberculosis (TB) than people with M. tuberculosis but without HIV . Patients infected with multidrug-resistant (MDR)-TB (defined as resistance to at least rifampicin and isoniazid, the two most powerful anti-TB drugs) require longer, more expensive treatment regimens than drug-susceptible TB, with poorer treatment success , . Therefore, MDR-TB poses a major challenge to the control of TB, with an estimated global disease incidence in 2012 of ∼450 000 cases (95% CI 300 000–600 000) . Although HIV is a powerful risk factor for all forms of TB and institutional outbreaks of MDR-TB among people living with HIV have been reported , population-level data on the association between HIV infection and MDR-TB are limited.
We explored the relationship between HIV infection and MDR-TB disease using data reported by member states to the World Health Organization (WHO) within the context of the Global Project on Anti-TB Drug Resistance Surveillance. The data were aggregated numbers of cases reported from either drug resistance surveys or continuous surveillance systems. Such surveys are epidemiological studies designed to measure drug resistance among a representative sample of notified pulmonary TB patients. Continuous surveillance is based on routine drug susceptibility testing of all bacteriologically confirmed TB patients. Subnational level data that were not representative of the entire country were excluded from the analysis, except for the Russian Federation and Ukraine, which are high MDR-TB burden countries for which high quality national level data were not available. The data included in the analysis met the criteria for data quality and national representativeness provided in detail elsewhere , . The laboratory methods used for diagnosis were endorsed by WHO.
For each country, the relationship between HIV infection and MDR-TB disease was investigated by logistic regression to calculate odds ratios and 95% confidence intervals, using Stata (version 12; StataCorp, College Station, TX, USA). For countries with data from multiple years, robust standard errors accounted for within-country time dependencies. In order to minimise bias, data for a given year were excluded if ≤25% of reported TB patients had a documented HIV test result. 41 countries, accounting for 25% of the estimated global MDR-TB burden in 2012, met the inclusion criteria for ≥1 year. Most were high-income countries and/or in the European Region. Only four countries were in the African region, which accounted for 75% of the global number of HIV-positive TB cases in 2012 . Of these 41 countries, odds ratios could be calculated for 24 countries; the other 17 countries reported no HIV-positive MDR-TB cases (table 1). Complete HIV and MDR-TB data were available for 104 781 TB patients from 1997–2012.
For 11 of the 24 countries for which the analysis was performed, HIV-positive TB patients had a significantly higher odds (p<0.05) of MDR-TB disease than HIV-negative TB patients (table 1). Seven of these countries were in eastern Europe and central Asia: Estonia, Kazakhstan, Latvia, the Republic of Moldova, the Russian Federation, the Ukraine and Uzbekistan. For almost all of these 11 countries, the prevalence of MDR-TB among newly diagnosed TB cases (table 1) was higher than the estimated global average of 3.6% (95% CI 2.1–5.1%) in 2012 . Although the odds ratio was highest in Kuwait, only low numbers of HIV-positive cases were reported. HIV-positive TB patients in the USA had a lower odds of MDR-TB disease than HIV-negative patients.
As data were included if ≥75% of reported TB patients had a documented HIV test, the possibility of bias due to missing data cannot be ruled out. Although a positive association between HIV infection and MDR-TB disease was demonstrated in less than half of the countries, a recent systematic review and meta-analysis found an odds of MDR-TB in HIV-positive patients that was 1.24 times (95% CI 1.04–1.43) higher than in HIV-negative patients . A subgroup analysis showed that this association was stronger for primary MDR-TB disease than acquired MDR-TB disease, which supports previous findings . However, most of these studies were from institutional settings, where outbreaks are known to occur more commonly in HIV-positive patients . At the population level, a detailed analysis of surveillance data from the Republic of Moldova showed that, even after adjustment for potential confounders, a positive association HIV and MDR-TB existed .
Among those 11 countries with a positive association between HIV infection and MDR-TB disease, there was wide variation in the estimated prevalence of HIV among incident TB cases in 2012 (table 1) . Given that the analysis was performed using aggregated rather than individual patient data, there are likely to be risk factors common to HIV-positive and MDR-TB patients that could not be explored in our analysis, such as shared behaviours or population characteristics. Further investigation is needed for specific high risk groups, such as prisoners or people living in congregate settings, miners, or injecting drug users. Additionally, the relationship between HIV and MDR-TB probably depends on the epidemiological setting. In the USA, where a negative association was observed between HIV infection and MDR-TB disease, investigation into the demographics of these patients is required in order to identify potential confounders. However, a cross-sectional study in eight states did not demonstrate a significant association between HIV infection and MDR-TB disease . HIV has been shown to be an independent risk factor for drug resistance acquired during treatment in California .
Data were only available for three countries listed among both the 27 high MDR-TB burden countries and 41 high TB/HIV burden countries: Nigeria, the Russian Federation and the Ukraine. In order to better understand the relationship between HIV infection and MDR-TB, more high quality data are needed from other high burden countries. This includes the Democratic Republic of Congo, Ethiopia, Myanmar, South Africa and Vietnam. In these five countries, the percentage of estimated cases of MDR-TB that were detected and notified in 2012 ranged from just 2.2% to 30% and the percentage of TB patients with a known HIV status in 2012 ranged from 13 to 66%, excluding South Africa . This is probably a reflection of low levels of testing for MDR-TB and HIV among TB patients as well as underreporting. Priorities in these countries should include integrated TB and HIV services and programmes, with universal access to HIV testing and routine and prompt TB drug susceptibility testing for patients suspected to have MDR-TB. This must be underpinned by greater awareness of healthcare workers, increased laboratory capacity, and improved data management and reporting . The roll-out of rapid diagnostic tests and the use of MDR-TB treatment models that include community-based care could rapidly increase MDR-TB case notification and enrolment on second-line treatment, ultimately limiting spread . Development of region- and country-specific comprehensive responses, including research for better diagnosis, treatment and scale-up of quality services, is essential .
All authors are staff members of WHO. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO.
Conflict of interest: None declared.
This article is one of a selection of articles published as ERJ Open papers, as part of an initiative agreed between the European Respiratory Society and the World Health Organization.
- Received December 13, 2013.
- Accepted January 25, 2014.
- © ERS 2014
ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 3.0.