Global Health Interventions: A Review of the Evidence Background Methodology • Glossary

Tuberculosis

Infectious Diseases

Other Health Conditions

Key Findings

See a detailed Key Findings table for estimated risk reduction and strength of evidence.

TB Disease Logic Model Thumbnail

See a detailed disease logic model to better understand disease acquisition, progression, and opportunities for intervention.

Toolbox

Overview: Tuberculosis

Background

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. It most commonly affects the lungs (pulmonary TB). It is transmitted from person to person, via droplets from the throat and lungs of individuals with active pulmonary TB. In otherwise healthy individuals, TB infection is often asymptomatic (known as latent disease). The symptoms of active TB of the lung are coughing, sometimes with sputum or blood, chest pains, weakness, weight loss, fever and night sweats. Tuberculosis is curable with antimicrobial drugs, typically using a six-month course of treatment. Multi-drug resistant (MDR) TB requires 2nd line therapy that takes longer, is more expensive, and has more side effects. Extremely drug resistant TB (XDR-TB), which fails even 2nd line therapy, has been reported in 58 countries.[1]

Epidemiology

  • There were 9.4 million new cases of TB in 2008. This is an increase from 9.3 million in 2007; small drops in incidence rates were outweighed by population increases.[2]
  • Per capita TB incidence peaked in 2004 at 142 per 100,000.[3]
  • Most new cases in 2008 occurred in Asia (55%) and Africa (30%). India and China account for an estimated 35% of cases.[2]
  • In 2008, the countries with the highest prevalence were India (2.0 million cases), China (1.3 million), Indonesia (530,000), Nigeria (460,000), and South Africa (460,000).[2]
  • There were 289,000 new cases and 500,000 prevalent cases of multi-drug resistant TB in 2007.[3]
  • In 2008 there were 1.4 million new TB cases in HIV+ persons, of which 78% were in Africa and 13% in Southeast Asia.[2]
  • There were 1.8 million TB deaths in 2008: 1.3 million among HIV-uninfected and 500,000 among HIV+ persons.[2]
  • Prevalence and mortality rates appear to be falling in all six WHO regions.[3]

The intervention assessments below summarize the information presented in the "Key Findings" table.

Prevention: What Works?

Prevention interventions can be divided into three categories: a vaccine, antimicrobials in general, and antimicrobials for HIV+ persons.

  • BCG vaccine: BCG vaccine is estimated to reduce TB mortality by 68-77% and morbidity by 52-69%, with weak strength of evidence. Using the vaccine during infancy reduces disease by an estimated 74% (strength of evidence = 3; not shown in table). Another vaccine, Mycobacterium vaccae shows promise in preventing TB in selected high risk populations (PPD strong positive, type 2 diabetes mellitus, and aged persons with clinically cured pulmonary TB) and induces immune response in HIV+ persons.[4]
  •  Antimicrobials: The mainstay drug for TB prevention is isoniazid (INH). In HIV uninfected persons, INH reduces progression to active TB by an estimated 60-66% (very strong evidence). INH may reduce mortality by more than half, though a negative effect cannot be ruled out due to statistical uncertainty. A 12-month course of INH reduces the incidence of active TB by 29-76% as compared with a standard 6-month regimen (moderately strong evidence). INH preventive therapy may increase the risk of INH-resistant TB by 45%.
  • Antimicrobials for HIV+ persons: INH is also effective for many HIV-infected persons. For individuals with a positive PPD skin test (indicating TB exposure and enough immune function to mount a response), INH reduces mortality by 21-27% and disease by 60-68% (moderately strong evidence). It may not work if there is a negative PPD. INH appears to help HIV+ children, with reductions of 54% and 72% for mortality and disease (however, weak evidence). Cotrimoxazole (bactrim in the U.S.) is an inexpensive drug which protects against multiple opportunistic infections, reducing TB mortality by 20-43% (moderate strength of evidence) and perhaps disease by one quarter. The effects of antiretroviral therapy (ART) on TB incidence are considerable,[5] but not reviewed here.

Treatment: What Works?

Multiple interventions are available to slow the progression of latent to active TB, and to reduce mortality and morbidity. Systematic reviews assess a myriad of specific clinical options. We present evidence on those issues most relevant to broad program design, divided into: antimicrobials for uncomplicated cases, antimicrobials for HIV+ persons, managing MDR-TB, other drug therapies, nutritional supplements, and adherence enhancement.

  • Antimicrobials for uncomplicated cases: The standard treatment for TB is isoniazid, rifampicin, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampicin for four months. Regimens of six months reduce failure rates by 55-84% versus regimens of less than six months, especially 2-3 months (moderately strong evidence). The net gain from these differences may be modest.[6] Exceeding 6 months appears to add no benefit, from limited evidence (not in table).[7] Compared with rifampicin, a standard TB medication, rifapentine (less frequent dosing, more expensive) has comparable effect on disease and 37-51% lower bacteriological relapse (weak evidence). Rifabutin (also relatively expensive) is less effective than rifampicin. Regimens with pyrazinamide appear to improve outcomes (bacteriological cure) better than those without (weak evidence), however with higher liver toxicity and other adverse events than INH.
  • Antimicrobials for HIV+ persons: INH alone reduces the progression to active TB by 33% (very strong evidence) and may also reduce deaths and progression to AIDS (listed in the “Other Indicators” column). INH + rifampicin reduces mortality by 31% and active TB incidence by 59% (moderate strength of evidence). INH alone appears to be as effective as rifampicin + pyrazinimide for both mortality and disease, with 36% lower lack of drug adherence (strong evidence). 
  • Managing MDR-TB. MDR (multi-drug resistant) TB is a growing and vexing challenge, requiring multi-drug regimens. Longer therapy has an estimated 15% better cure rate (weak evidence). Individualized drug choice appears less effective than standard therapy (weak evidence). Adding a fluoroquinolone to regimens appears to reduce mortality by 70% and treatment failure by 55% (weak evidence). Surgery appears to lower treatment failure by 48% (moderately strong evidence).
  • Other drug therapies. Immuno-therapy aims to enhance immune response to reduce the incidence and/or severity of illness (Weber 1997).[8] Unfortunately, strong evidence indicates that there is no benefit from this therapy TB. Corticosteroids for TB meningitis reduce mortality by 10-27% (moderately strong evidence). Clinical management of TB complications, including drug choice, is generally beyond the scope of this review.
  • Nutritional supplements. Vitamin D and Zinc with micronutrients both appear to improve outcomes when combined with treatment of active TB. Vitamin D reduces treatment failures by 22-100% (moderate strength of evidence) and has uncertain effect on mortality. Zinc plus micronutrients appears to reduce mortality by 71% (weak evidence). All other nutritional supplements for which we found data (zinc alone, vitamins A and E, and multivitamins) lack statistically significant evidence of benefit.
  • Adherence enhancement. Medication adherence is a critical challenge for long treatment regimens, especially for latent (asymptomatic) infection. Varied adherence interventions have shown mixed results. Patient “tracers” via home visits or letters reduce rates of treatment failure by 55-72% (moderately strong evidence). Fixed-dose drug combination pills showed an 11% reduced risk of failure compared with the same drugs administered separately, with an unclear improvement in adherence (weak evidence).

    Directly observed therapy (DOT) is recommended as a key strategy by WHO. However, the evidence we found suggests no significant effect of most DOT on TB cure and treatment completion rates (moderately strong evidence). A recent RCT (not in table) found that a particular DOT model (reinforced counseling and supervision, decentralization, and patient choice of DOT supporter) decreased failures by 15%;[9] we are assessing the DOT literature to determine if this model consistently performs well.

    Finally, TB reminder phone calls, especially paired with education, appear to reduce non-adherence by more than 80% (moderately strong evidence), with no evidence on clinical outcomes.
  • Other (not in table). While XDR-TB is resistant to both first- and second-line drugs, seriously limiting its treatment options, it can be treated in some cases. However, meta-analysis of currently available data has not yet been conducted due to inconsistent definitions and methodologies across studies.[10] Therefore, treatment of XDR-TB is not included at this time.

Summary/Future Directions

Prevention. BCG vaccine appears to provide long-term protection against TB, especially when given in infancy. Isoniazid (INH) for 6 months reduces active TB by 60%; 12-month regimens add benefit. However, INH may increase the risk of INH-resistant TB. In HIV+ children and HIV+ adults who are PPD+, INH reduces mortality and active disease. Cotrimoxazole also appears to reduce mortality.

Treatment. A wide variety of interventions reduce the lethal or morbid effects of TB. Standard treatment is multi-drug, for 6 months. Longer treatments further reduce disease outcomes by more than half. Alternative medications, e.g., refipentine, may allow less frequent dosing. For HIV+ persons, INH alone and in combination works well. MDR (multi-drug resistant) TB benefits from longer therapy, use of a fluoroquinolone, and surgery in appropriate cases. To enhance adherence, reminder home visits and letters appear to reduce treatment failures, and phone calls appear to improve adherence. Directly observed therapy (DOT) has unclear benefit, though particular program features may foster efficacy.

According to WHO, the global incidence of TB is falling very slowly, yet all regions of the world are on track to meet the “Stop TB Partnership” targets of halving TB prevalence and deaths by 2015 compared with 1990 levels.[11] Progress is threatened by the rising incidence of multi-drug resistant TB. Since the cost of diagnosing and treating these cases is high, responding effectively will require additional funding, potentially 60 times more than available funds in 2009.[12] A number of anti-TB agents are being studied, many under the aegis of the Global Alliance for TB Drug Development, and some have entered clinical trials of the treatment of MDR TB.[7] Although more individuals with TB have access to high-quality treatment as well as to related interventions such as anti-retroviral therapy, much remains to be done in order to consolidate and accelerate progress. An estimated 90% of patients with MDR-TB are not being diagnosed and treated according to international guidelines; and most HIV+ TB-infected persons do not know their HIV status or are not yet accessing ART.

References

1. WHO. Health topics: Tuberculosis. Available from: http://www.who.int/topics/tuberculosis/en/.

2. WHO. Global tuberculosis control: a short update to the 2009 report. 2009. Publication no.WHO/HTM/TB/2009.426. Available from: http://www.who.int/tb/publications/global_report/2009/update/en/index.html

3. WHO. Global tuberculosis control - epidemiology, strategy, financing: WHO report 2009. Publication no. WHO/HTM/TB/2009.411. Available from: http://www.who.int/tb/publications/global_report/2009/en/index.html

4. Yang XY, et al. Mycobacterium vaccae vaccine to prevent tuberculosis in high risk people: a meta-analysis. J Infect. 2010 May; 60(5):320-30.

5. Lawn S. The challenge of the HIV-associated tuberculosis epidemic in sub-Saharan Africa: will antiretroviral therapy help? SACEMA Quarterly, Update on Epidemiology, South African Centre for Epidemiological Modelling and Analysis. 2 June, 2010. Available from: http://www.sacemaquarterly.com/hiv-treatment/the-challenge-of-the-hiv-associated-tuberculosis-epidemic-in-sub-saharan-africa-will-antiretroviral-therapy-help.html.

6. Gelband H. Regimens of less than six months for treating tuberculosis. Cochrane Database of Systematic Reviews. 1999, Issue 4. Art. No.: CD001362. DOI: 10.1002/14651858.CD001362.

7. Ziganshina LE, Garner P. Tuberculosis (HIV-negative people). Clin Evid (Online). 2009 Apr 14;2009. pii: 0904.

8. de Bruyn G, Garner P. Mycobacterium vaccae immunotherapy for treating tuberculosis. Cochrane Database of Systematic Reviews 2003, Issue 1.

9. Thiam S, et al. Effectiveness of a strategy to improve adherence to Tuberculosis treatment in a resource-poor setting: A cluster randomized controlled trial. JAMA. 2007; 297(4):380-386 (doi:10.1001/jama.297.4.380).

10. Sotgiu et al. Epidemiology and clinical management of XDR-TB: a systematic review by TBNET. Eur Respir J 2009; 33: 871–881 DOI: 10.1183/09031936.0016800.

11. WHO. MDG 6: combat HIV/AIDS, malaria and other diseases. 2011. Available from: http://www.who.int/topics/millennium_development_goals/diseases/en/index.html.

12. Donald, P. R. and P. D. van Helden (2009). The global burden of tuberculosis—combating drug resistance in difficult times. N Engl J Med 360(23): 2393-2395.

-- Updated June 2011