Update on Tuberculosis

Based on a Lancet Seminar on Tuberculosis, March 2011.

1. The incidence of tuberculosis in the world is increasing. There were 9.4 million people newly diagnosed with tuberculosis in 2009.

2. The prevalence of tuberculosis in a community is directly related to overcrowding and poverty.

3. The increase in incidence of tuberculosis is largely related to the ongoing HIV epidemic. Diabetes, the use of immunosuppressive drugs like corticosteroids and tumour necrosis factor antagonists, and drug resistance are also reasons for this increase in number of tuberculosis infection.

4. In terms of absolute numbers, the five countries with the most number of tuberculosis cases in the world are: India, China, South Africa, Nigeria and Indonesia.

5. HIV associated tuberculosis is extremely common in South Africa and South East Asia.

6. In terms of absolute numbers, the countries with the most number of drug resistant tuberculosis are India, China, countries in eastern Europe, South Africa and Bangladesh.

7. Drug resistant tuberculosis is of two types: Multidrug resistant TB (MDR) and Extensively drug resistant TB (XDR). MDR tuberculosis is caused by M.tuberculosis that is resistant to INH and Rifampicin. XDR tuberculosis is caused by M. tuberculosis that has, in addition, resistance to any fluoroquinolone and to any one of the three injectable aminoglycosides (amikacin, capreomycin, kanamycin).

8. Latent tuberculosis is a clinical disorder in which a person is infected with M. tuberculosis but whose immune system prevents replication of the bacterium and hence the person has no symptoms and signs. It is estimated that there are about 2 billion people in the world today with latent tuberculosis.

9. Tissues infected with tuberculosis bacilli typically show granulomas on histology. Granulomas however are absent or poorly formed in people infected with HIV.

10. Examination of sputum for acid fast bacilli and chest radiology are usually the tests done for diagnosis of tuberculosis. These techniques are often unsatisfactory and not available at the point where the patient first meets the doctor in low income and middle income countries.

11. Automated liquid culture systems are now the gold standard for the diagnosis of active tuberculosis.

12. Serological tests for tuberculosis are of little diagnostic value.

13. The tuberculin skin test can detect patients infected with M. tuberculosis but cannot distinguish between infection caused by M. tuberculosis and other mycobacteria.

14. The gold standard now to detect people exposed to M. tuberculosis is the Interferon Gamma Release Assay.

15. Tuberculosis most commonly affects the lungs because of the high oxygen content there. However it can affect any organ.

16. Treatment recommendations are:
a. All new patients with pulmonary tuberculosis should receive 6 months of Rifampicin and INH; four drugs are used for the first two months, and Rifampicin (R) and INH (H) are continued for the remaining four months. The optimal dosing frequency is daily but, where supervised treatment is possible, the continuation phase of RH can be given thrice weekly.
b. Ideally drug susceptibility tests should be done for all patients at the start of treatment. Where this is not possible, drug susceptibility tests should be done for those patients who have previously been treated for tuberculosis.

17. MDR tuberculosis requires prolonged treatment. At least 18 months after culture conversion. Treatment is costly but successful outcomes can be achieved in two thirds of cases.

18. XDR tuberculosis responds poorly to treatment.

19. HIV infected patients with tuberculosis should receive co-trimoxazole prophylaxis and antiretroviral therapy. Antiretroviral therapy should be started within 2 to 8 weeks after initiating anti TB treatment. Efavirenz based antiretroviral therapy is preferred for patients receiving rifampicin based anti TB treatment.

20. The BCG vaccine is effective in protecting against childhood TB meningitis and military tuberculosis. Its efficacy against adult pulmonary tuberculosis is variable.

Student (Li Cin):
It was found that low-income and middle-income countries account for more than 80% of the active TB cases in the world. Sub-Saharan Africa is accounted for four of every five cases of HIV-associated tuberculosis because of the devastating effect of HIV on susceptibility to tuberculosis. Anyhow, evidence based showed that the addition of trimethoprim sulfamethoxazole (co-trimoxazole) prophylaxis decrease the need for hospitalisation, the morbidity and the mortality rate in HIV-1 infected patients treated for tuberculosis.

1) DL Stephen MRCP, IZ Alimuddin FRCP. The Lancet, Volume 378, Issue 9785, Pages 57 - 72, 2 July 2011.
2) Trimethoprim sulfamethoxazole decreased morbidity and mortality in HIV-1 infected patients with tuberculosis. Evid Based Med 2000;5:55 doi:10.1136/ebm.5.2.55

A study from Oxford journal showed that Trimethoprim sulfamethoxazole (TMP-SMX) prophylaxis for opportunistic infections in HIV protects against development of bacterial resistance to other classes of antibiotics. This drug may directly protect against infection with drug-susceptible bacterial pathogens, and also, indirectly protect the individual from exposing to a condition which can be a risk factor for developing infection with drug resistant bacteria.
TMP-SMX was shown to reduce mortality caused by pneumocystis jiroveci pneumonia (PJP), toxoplasmosis and other infections. There were two major clinical trials in West Africa found that this drug reduces mortality in HIV and TB coinfected adults and the benefit was attributed to the protection against bacterial infections and malaria since PJP and toxoplasmosis are uncommon in this population.
As a conclusion, TMP-SMX prophylaxis should therefore be added to the routine care of HIV-positive TB patients. However, I am not able to find the evidence of the usefulness of prescribing TMP-SMX to only TB positive patients. More carefully designed studies are needed to answer the question conclusively.

LS Euphemia , Ian V.D. Weller, GH James et al. Does Trimethoprim-Sulfamethoxazole Prophylaxis for HIV Induce Bacterial Resistance to Other Antibiotic Classes?:Results of a Systematic Review Clin Infect Dis. (2011) 52 (9): 1184-1194.
Grimwade K et al. Effectiveness of cotrimoxazole prophylaxis on mortality in adults with tuberculosis in rural South Africa. AIDS 19:163–168, 2005.

Student (Yong Geng Yi):
It is a threat to people all over the world that the emergence and spread of Multiple Drug Resistance -TB (MDR-TB) to the common anti TB drug such as isoniazid and rifampicin. People who acquired MDR tuberculosis need prolong treatment. However, does anti-TB drug effective in preventing TB in those who are at risk/exposed to MDR-TB? Cochrane systemic review found no randomized controlled trials that have assessed the effectiveness of treatments of latent tuberculosis infection in people exposed to MDR-TB. The advantages and disadvantages of treatment of latent tuberculosis infection for people who are in contact with multiple drug resistance TB are still unclear. So, the drug treatment should only be implemented when there is an established well-designed randomized controlled trial to support the benefits of treatment.

Just to clarify: The definition of the 'latent' MDR tuberculosis infection is that of people who have had significant exposure to MDR-TB + new tuberculin skin test reactions >15 mm BUT no clinical manifestation of TB.

the inclusion criteria for the study design was:
Design: An initial questionnaire presented three scenarios describing persons with significant exposure to MDR-TB and with new tuberculin skin test reactions >15 mm (except one anergic patient) without evidence of disease.

Passannante MR, Gallagher CT, Reichman LB (1994). "Preventive therapy for contacts of multidrug-resistant tuberculosis: a Delphi survey". Chest 106 (2): 431–434. Available at:
URL:http://chestjournal.chestpubs.org/content/106/2/431

Moderator: ….a "latent" state is possible even with drug resistant bacilli. From the link in the CHEST Journal that you provided, I understand that if we suspect the latent TB state to be caused by MDR TB bacilli, we should treat with Pyrazinamide and a Quinolone for 6 months to 12 months, depending on the HIV status of the person.

Student (LKL):
Latent tuberculosis (TB) is tuberculosis infection without clinical manifestations and it is particularly important in HIV infected person as 30% of them eventually developing active TB and TB is one of the AIDS defining illnesses. Is there an effective treatment available for treating latent TB in HIV infected person?

In an intervention review from the Cohcrane library, the review stated that treatment with isoniazid monotherapy reduces the risk of developing active TB in persons infected with both HIV and latent TB, usually prescribed for 6 to 12 months. It was also stated that short-course multi-drug regimens were much more likely to require discontinuation of treatment due to adverse effects. This suggests that monotherapy is more effective than multidrug regime. Overall, it does show that TB preventive therapy reduces the incidence of active TB in HIV infected persons. But, what are the best drug regimes for them?
Currently, no clinical trials are available for best drug regime for latent TB in HIV infected person. Hence, further trials should be done to assess best treatment regime for people with HIV, and especially the best regimen in combination with HIV drugs. The optimal duration of preventive therapy and long term side effects need to be evaluated as well.

Reference: Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD000171. DOI: 10.1002/14651858.CD000171.pub3.

Moderator: You might find some useful information from this trial in NEJM that looked at treatment options for those with HIV and latent tuberculosis.

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