More on MDR

I wish I was at the International AIDS Soceity Conference in Australia this week. They have a special HIV-TB track, where I could submerge myself in the alarming world of HIV-TB coinfection research. I've been thinking about MDR and XDR tuberculosis a lot lately, and actually worrying about it. This is quite unusual for me--I not a big worrier when it comes to things like germs or terrorism or death or other things that normal people worry about.

For those who need something else to keep them up at night, might I suggest a review of the HIV-TB coinfection literature? For lay readers, I recommend an article I stumbled on in the Yale Alumni Magazine . For doctors and scientific-types (that means you dad), the Nature Medicine March 2007 Focus (vol 13, no. 3) is loaded with good stuff.

For those who are too tired to click a link, I am copying John Bartlett's literature review of Neel Gandhi's XDR-TB 2006 Lancet paper below [Gandhi NR; Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa; Lancet 2006;368:1575].

The purpose was to assess the prevalence and consequences of multidrug-resistant tuberculosis (MDRTB) and extensively drug-resistant tuberculosis (XDRTB) in KwaZulu Natal, South Africa.

Methods: The authors increased surveillance for MDRTB with sputum cultures and drug susceptibility testing in patients with suspected tuberculosis. The analysis included genotyping of resistant strains and susceptibility testing for first and second line drugs.

Results: Sputum cultures for TB were done on 1,539 patients; this showed 542 (35%) were positive; of these, 221 (40%) were MDRTB and 53 (24%) of the MDRTB were XMDRTB. These results are summarized in the following table:

Total tested 1539
Culture pos 542
MDR M. tuberculosis 221
XDR M. tuberculosis 53
No prior treatment 26 (55%)
HIV pos/no tested 44/44 (100%)
Hospitalized < 2 years 35 (66%)
Mortality 52 (98%)
Median time to death 16 days
Genotype KZN 39/46


Analysis of the 53 cases involving XMDRTB showed only about 50% had received prior therapy for tuberculosis, 2/3 had been hospitalized within the prior two years, and all 44 who had HIV serology were positive. Of particular note was the observation that 52 of the 53 died and the median time to death among these patients from the time of the sputum sample was a median of 16 days.

Genotyping indicated 39 of 46 strains were in the KZN family.

Conclusion: The authors conclude that this study shows the presence and potential serious consequences of XDRTB in resource-limited areas with high rates of HIV, and they emphasize the need for "urgent local and international intervention".

This is an extremely disturbing report that was presented by Dr. Gandhi at the 2006 International AIDS Conference in Toronto; in this report he finished by warning that this strain of TB could undo all of the achievements to date in the international effort to treat and control the HIV epidemic in the developing world. KwaZulu Natal is a rural province in South Africa in which about 80% of patients with active TB have HIV co-infection; mortality rates in those with co-infection are reported as high as 40%/year despite treatment for TB. The authors of the present study note that the rate of MDRTB was only 1.7% when surveyed in 2000-02, but had increased to 9% in 2003-06. XDRTB is defined as MDR (resistance to INH and rifampin) plus resistance to at least three of the six second-line drugs. In the US, these account for about 4% of the MDR strains and up to 15-19% in reports from Korea and Latvia (MMWR 2006;55:301). This susceptibility pattern renders these strains virtually untreatable (Hopewell PC Lancet Infect Dis 2006;6:710). The authors of the report summarized above emphasize four needs:

There needs to be better surveillance to determine the full extent of MDR and XDR tuberculosis in the areas with high prevalence rates of HIV.
Treatment programs need to be strengthened to improve the rates of treatment including access to second line drugs. Infection control practices, especially those within health care settings, need to be enhanced with inclusion of protection of health care workers. There needs to be simpler and more aggressive testing to detect TB and drug resistance in resource-limited areas.

In a more recent editorial comment by Mario Raviglione and Ian Smith (N Engl J Med 2007;356:656) call attention to the unique features of this epidemic that emphasizes the important points noted above. This includes the fact that most of the patients in KwaZulu-Natal province had never been treated, most had been hospitalized suggesting nosocomial acquisition, and all who were tested had HIV infection. XDRTB has been reported in at least 17 countries. Their conclusion is that the "global threat of XDRTB has great significance for the public health field" and "its very existence is a reflection of weakness in tuberculosis management".