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Search date July 2005 Lilia Ziganshina and Paul Garner

Infectious diseases

QUESTIONS What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing tuberculosis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 What are the effects of different drug regimens in people with newly diagnosed pulmonary tuberculosis without HIV infection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4 What are the effects of different drug regimens in people with multidrug resistant tuberculosis without HIV infection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 What are the effects of low level laser therapy in people with tuberculosis without HIV infection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Which interventions improve adherence to treatment in people with tuberculosis without HIV infection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8 Which interventions improve reattendance for Mantoux test reading in people who have had tuberculosis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13 INTERVENTIONS PREVENTING TUBERCULOSIS IN HIGH-RISK PEOPLE WITHOUT HIV INFECTION Trade off between benefits and harms Isoniazid. . . . . . . . . . . . . . . . . . . . . . . . .3 Rifampicin plus isoniazid New . . . . . . . . .3 DRUGS FOR PULMONARY TB IN PEOPLE WITHOUT HIV Beneficial Shorter course chemotherapy (6 month regimen as good as longer courses) . . . .4 Likely to be beneficial Adding pyrazinamide in chemotherapy regimens for 6 months . . . . . . . . . . . .4 Adding rifampicin to isoniazid (more effective than isoniazid alone) . . . . . . . . . . . . . .5 Unknown effectiveness Intermittent chemotherapy for 6 months . . . . . . . . . . . . . . . . . . . . . . . . . . . ...0 Regimens containing quinolones . . . . . . . .6 Unlikely to be beneficial Ethambutol in place of rifampicin in continuation phase New . . . . . . . . . . .6 Likely to be ineffective or harmful Chemotherapy for less than 6 months. . . . .7 DIFFERENT REGIMENS FOR DRUG RESISTANT TB Unknown effectiveness Comparative benefits of different regimens in multidrug resistant tuberculosis . . . . . . .7 LOW LEVEL LASER THERAPY FOR PULMONARY TB IN PEOPLE WITHOUT HIV Unknown effectiveness Low level laser therapy . . . . . . . . . . . . . . .8 IMPROVING ADHERENCE TO TREATMENT Likely to be beneficial Cash incentives . . . . . . . . . . . . . . . . . . . .8 Defaulter actions . . . . . . . . . . . . . . . . . . .9 Health education by a nurse . . . . . . . . . . .9 Unknown effectiveness Community health advisors . . . . . . . . . . .12 Direct observation treatment versus self administered treatment . . . . . . . . . . . .10 Health education by a doctor or peer educator . . . . . . . . . . . . . . . . . . . . . .11 Prompts to adhere to treatment . . . . . . . .12 Sanctions for non-adherence. . . . . . . . . .12 Staff training . . . . . . . . . . . . . . . . . . . . .12 Support mechanisms for directly observed treatment New . . . . . . . . . . . . . . . . .10 IMPROVING SCREENING ATTENDANCE Unknown effectiveness Prompts and contracts to improve reattendance for Mantoux test reading . .13 Covered elsewhere in Clinical Evidence See preventing tuberculosis under HIV infection, p 01 See glossary

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Clin Evid 2006;15:12.

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Tuberculosis
Key Messages About a third of the worlds population have latent tuberculosis. Over 14 million people in 2004 had active tuberculosis. Approximately 1.7 million people died from the infection. Over 80% of new cases diagnosed in 2004 were in people in Africa, South-East Asia and Western Pacific regions. Most people who inhale Mycobacterium tuberculosis clear the infection and become skin test positive. Active infection is more likely in people with social factors such as poverty, overcrowding, homelessness and inadequate health care, or with reduced immune function such as with HIV infection. Some people develop latent infection persistent bacterial presence but asymptomatic and not infectious. Drug treatments can reduce the risk of active tuberculosis in people at high risk of infection. Prophylactic isoniazid for 6 months can reduce the risk of tuberculosis infection in high risk people without HIV, but increases the risk of hepatotoxicity. Rifampicin plus isoniazid for 3 months, or isoniazid for 6-12 months, are equally effective at reducing active infection rates in people with latent tuberculosis. Treatment requires chemotherapy with combination regimens. Adding rifampicin to isoniazid is more effective than isoniazid treatment alone, and more effective than ethambutol plus isoniazid regimens. Regimens including pyrazinamide improve short term sputum clearance, but long term effects are unclear. Quinolones such as ciprofloxacin have not been shown to improve outcomes compared to ethambutol, isoniazid and pyrazinamide regimens but the evidence is sparse. The optimal length of treatment seems to be six months but evidence is not robust. Relapse rates are the same after 6 months treatment compared with longer regimens. Intermittent chemotherapy, taken 2-3 times a week, may be as effective as daily treatment for 6 or more months but the evidence is weak. Current practice in multidrug resistant tuberculosis is to use at least three drugs to which the particular strain is sensitive. Adherence to antituberculous treatment can be increased by using incentives, intensive input and education from health workers.
DEFINITION INCIDENCE/ PREVALENCE Tuberculosis is caused by Mycobacterium tuberculosis and can affect many organs. Specific symptoms relate to site of infection and are generally accompanied by fever, sweats, and weight loss. The Mycobacterium tuberculosis organism kills more people than any other infectious agent. The number of cases of tuberculosis was stable or falling in five of six World Health Organization (WHO) regions in 2004, but growing at 0.6% per year globally.1 Incidence is rising in Africa where the tuberculosis epidemic is still driven by the spread of the human immunodeficiency virus (HIV). According to WHO data, there were 8.9 million new cases of tuberculosis worldwide in 2004 (140/100 000 population), of which 3.9 million (62/100 000) were smear positive and 741 000 were in adults infected with HIV. There were 14.6 million prevalent cases (229/100 000), of which 6.1 million were smear positive (95/100 000). More than 80% of all people newly diagnosed with tuberculosis in 2004 were in the African, South-East Asia and Western Pacific regions.1 About a third of the worlds population have latent tuberculosis (see aetiology).2 Aetiology: The chief route of infection is by inhalation of airborne bacteria released by people with active respiratory tuberculosis by cough, sneeze, or speech. Inhaled mycobacteria reach the lung and grow slowly over several weeks. The immune system of most healthy exposed people (8090%) kills the bacteria and they are removed from the body with only a positive skin test left as a marker of exposure. In a small proportion of people infected, a defensive barrier is built round the infection but the tuberculosis bacteria are not killed and lie dormant.2 This is known as latent tuberculosis, where
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AETIOLOGY/ RISK FACTORS

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the person is asymptomatic and is not infectious. In the rest of those infected, active tuberculosis develops immediately. Risk factors: Social factors include poverty, overcrowding, homelessness, and inadequate health services. Medical factors include HIV and immunosuppression. PROGNOSIS Prognosis varies widely and depends on treatment.3 An estimated 1.7 million people (27/100 000) died from tuberculosis in 2004, including those co-infected with HIV (248 000).1

Infectious diseases

AIMS OF To cure tuberculosis; eliminate risk of relapse; reduce infectivity; avoid emergence of drug resistance; INTERVENTION and prevent death. OUTCOMES METHODS M tuberculosis in sputum (smear examination and culture), symptoms, weight, cure, relapse rates, attendance, completion of treatment. Clinical Evidence search and appraisal July 2005. Key words: tuberculosis, pulmonary, isoniazid, pyrazinamide, rifampicin, ethambutol, fluoroquinolones. The authors also performed a search of The Cochrane Library, Issue 1, 2006. We included all Cochrane systematic reviews and studies that were randomised or used alternate allocation, and had at least 1 year of follow up after completion of treatment.

QUESTION

What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing tuberculosis? ISONIAZID

OPTION

One systematic review, in people without HIV infection at high risk of tuberculosis, found that isoniazid prophylaxis for 612 months reduced the risk of active tuberculosis or extrapulmonary tuberculosis compared with placebo. It also found that a short 6 month course was as effective as a 12 month course. One large RCT found that treatment with isoniazid increased the risk of hepatotoxicity compared with placebo. Benefits: Isoniazid versus placebo: We found one systematic review (search date 2003; 11 RCTs, 73 375 people).4 The review compared 612 month courses of isoniazid versus placebo in HIV negative people at increased risk of developing tuberculosis (people with previous pulmonary tuberculosis or positive skin tests; people with recent or remote contact with an active case of pulmonary tuberculosis; or people living in an area with a high incidence and prevalence of disease). It found that, over not less than 2 years of follow up ( 10 years), isoniazid significantly reduced the risk of active tuberculosis (defined as symptoms, positive microscopy or culture, or change in chest x-ray) or extrapulmonary tuberculosis compared with placebo (AR for active tuberculosis; 11 RCTs: 239/40 262 [0.6%] with isoniazid v 557/33 113 [1.7%] with placebo; RR 0.40, 95% CI 0.31 to 0.52; AR for extrapulmonary tuberculosis; 4 RCTs: 9/22 379 [0.04%] with isoniazid v 28/22 257 [1.3%] with placebo; RR 0.34, 95% CI 0.16 to 0.71). The review found no significant difference in active tuberculosis or extrapulmonary tuberculosis between a 6 month and a 12 month course of isoniazid (AR for active tuberculosis; 1 RCT: 34/6965 [0.5%] with 6 months of isoniazid v 24/6919 [0.3%] with 12 months of isoniazid; RR 1.41, 95% CI 0.84 to 2.37). Isoniazid did not significantly reduce deaths from tuberculosis compared with placebo (2 RCTs: 3/16 318 [0.02%] with isoniazid v 10/9396 [0.1%]; RR 0.29, 95% CI 0.07 to 1.18). Isoniazid versus placebo: The review found that hepatotoxicity was significantly more common in people receiving isoniazid compared with placebo (AR for hepatitis; 1 RCT: 77/13 884 [0.6%] with isoniazid v 7/6990 [0.1%] with placebo; RR 5.54, 95% CI 2.56 to 12.00).4 Other reported adverse effects of isoniazid include mild and transient headache, nausea, and dizziness. Even in the isoniazid group, the absolute risk of hepatotoxicity was small (0.6%).4 RIFAMPICIN PLUS ISONIAZID New

Harms:

Comment: OPTION

One RCT found that, in people with latent tuberculosis infection, rifampicin plus isoniazid for 3 months and isoniazid alone for 612 months led to similar reductions in rates of active tuberculosis over 13 years. Rates of adverse effects requiring withdrawal (hepatotoxicity, rash, gastrointestinal intolerance) were similar between groups.
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Tuberculosis
Benefits: Rifampicin plus isoniazid versus isoniazid alone: We found one systematic review (search date 2005), which identified one RCT (196 adults from Spain with latent tuberculosis infection determined by positive skin test without HIV) comparing rifampicin plus isoniazid daily for 3 months versus isoniazid daily for 612 months.5 The mean duration of follow up varied from 13 to 37 months. The RCT found no significant difference between groups in the proportion of people who developed culture confirmed active tuberculosis (1/972 [0.1%] with rifampicin plus isoniazid v 0/98 [0%] with isoniazid; ARR +1%; 95% CI 2% to +4%). Results from this trial were supported by a meta-analysis of trials including people with HIV. The RCT did not assess mortality. The review found no significant difference in mortality between rifampicin plus isoniazid and isoniazid alone in people with HIV (3 RCTs: 67/707 [9%] with rifampicin plus isoniazid v 71/683 [10%] with isoniazid alone; ARR 1%; 95% CI, 4% to +2%). Rifampicin plus isoniazid versus isoniazid alone: The review found similar rates of adverse effects (hepatotoxicity, rash, gastrointestinal intolerance) requiring withdrawal from treatment between rifampicin plus isoniazid for 3 months and isoniazid alone for 612 months (10% with rifampicin plus isoniazid v 13% with isoniazid alone; CI and absolute numbers not reported).5 None.

Harms:

Comment:

QUESTION

What are the effects of different drug regimens in people with newly diagnosed pulmonary tuberculosis without HIV infection? SHORTER (6 MONTHS) VERSUS LONGER (89 MONTHS) CHEMOTHERAPY REGIMENS

OPTION

Two RCTs found no significant difference in relapse rates between 6 month and longer course chemotherapy regimens. Benefits: We found two RCTs (1295 people with untreated, culture/smear positive pulmonary tuberculosis), which compared 6 versus 89 months of chemotherapy.6,7 Participants were followed up for at least 1 year after treatment was completed. The trials were performed in the UK and in east and central Africa, and used different combinations of isoniazid, rifampicin, ethambutol, streptomycin, and pyrazinamide for initial (first 2 months) and continuation (47 months) treatment. Both RCTs found no significant difference in relapse rates between 6 month and longer course chemotherapy regimens (P > 0.1). The first RCT (851 people) found no significant difference in relapse rate between 6 and 8 months continuation with isoniazid alone (9% with isoniazid alone for 6 months v 3% with isoniazid alone for 8 months; P > 0.1).6 The second RCT (444 people) compared a 6 month regimen (isoniazid plus rifampicin supplemented in initial 2 months with ethambutol plus pyrazinamide or with streptomycin plus pyrazinamide) versus a 9 month regimen (isoniazid plus rifampicin supplemented in initial 2 months with ethambutol).7 It found similar relapse rates between 6 and 9 months treatment (4/127 [3%] with ethambutol v 2/119 [2%] with streptomycin; significance assessment not reported). In the first RCT possible adverse reactions were reported in 24/851 people (3%), with six requiring modification of treatment.6 Two people in the trial developed jaundice, one of whom died. The second RCT gave no information on adverse effects.7 None. PYRAZINAMIDE IN CHEMOTHERAPY REGIMENS FOR 6 MONTHS

Harms:

Comment: OPTION

Three RCTs found that chemotherapy regimens containing pyrazinamide improved sputum clearance in the first 2 months compared with other regimens, but found limited evidence about effects on relapse rates. 4
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Benefits: We found three RCTs that compared chemotherapy regimens with or without pyrazinamide for initial and continuation treatment.79 The first RCT (444 people) found that sputum conversion was faster with regimens containing pyrazinamide at 2 months (AR for negative cultures: 77% with pyrazinamide v 64% without pyrazinamide; P < 0.01).7 The second RCT (833 people) compared four different 6 month regimens and found that bacterial relapse was significantly higher for those not receiving pyrazinamide in the 12 months after chemotherapy (8/625 [1.3%] with pyrazinamide v 12/160 [7.5%] without pyrazinamide; P < 0.001).8 The third RCT (497 people) compared ongoing pyrazinamide versus no treatment.9 It found that relapse at 18 months was more likely in those not receiving pyrazinamide, but the difference was not significant (3% with pyrazinamide v 1% with no pyrazinamide; P = 0.49). The first RCT found that adding pyrazinamide did not increase the risk of hepatitis (4% with pyrazinamide v 4% without pyrazinamide).7 However, mild adverse effects were more common, including arthralgia, skin rashes, flu-like symptoms, mild gastrointestinal disturbance, vestibular disturbance, peripheral neuropathy, and confusion. Arthralgia was the most common adverse effect, reported in about 1% of people on pyrazinamide, but was mild and never required modification to treatment.7,8 None. RIFAMPICIN IN CONTINUATION PHASE OF CHEMOTHERAPY REGIMENS FOR 6 MONTHS OR LONGER

Infectious diseases

Harms:

Comment: OPTION

One large RCT found that a 6 month regimen of rifampicin plus isoniazid reduced relapse rate compared with isoniazid alone. Benefits: We found one RCT (851 people) which compared four daily chemotherapy regimens (three 6 months and one 8 months in duration).6 All four treatment arms had the same initial 2 month phase of streptomycin, isoniazid, rifampicin, and pyrazinamide. The continuation phases of the 6 month regimens were as follows: isoniazid plus rifampicin; isoniazid plus pyrazinamide; or isoniazid alone. The continuation phase of the 8 month regimen was isoniazid alone. It found that bacteriological relapse was significantly reduced with isoniazid plus rifampicin compared with isoniazid alone at 6 months (2% with rifampicin plus isoniazid v 9% with isoniazid alone; P < 0.01). In the RCT possible adverse reactions were reported in 24/851 people (3%), with six requiring modification of treatment.6 Two people in the trial developed jaundice, one of whom died. None. INTERMITTENT CHEMOTHERAPY FOR 6 MONTHS OR OVER

Harms:

Comment: OPTION

Two RCTs, one identified by a systematic review, in people with newly diagnosed tuberculosis found no significant difference in cure rates between daily and two or three times weekly short course chemotherapy regimens. However, the RCTs may have lacked power to detect a clinically important difference. Benefits: We found one systematic review (search date 2003)10 and one additional RCT.11 The review identified one RCT (399 people) that compared three times weekly versus daily chemotherapy for 6 months in people with newly diagnosed pulmonary tuberculosis.10 It found no significant difference in bacteriological cure rates (defined as negative sputum culture: 99.9% with 3 times weekly v 100% with daily) or relapse rates (5/186 [2.7%] with 3 times weekly v 1/192 [0.5%] with daily; RR 4.0, 95% CI 0.7 to 24.1) between three times weekly and daily chemotherapy 1 month after treatment was completed. The additional RCT (206 children with all forms of intrathoracic tuberculosis, tuberculosis confirmed in 4%, probable in 94%, and suspected in 2%) compared twice weekly versus daily chemotherapy.11 It found no significant difference in cure rates between the two regimens (85/89 [95%] people with twice weekly v 114/117 [97%] people with daily; RR 0.98, 95% CI 0.84 to 1.02). 5

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Tuberculosis
Harms: Comment: It has been documented that drug resistance is associated with previous treatment, but this was not found in the RCTs.10,11 The RCTs had low event rates and were too small to detect a clinically important effect difference between the dosing regimens. At least 12 cohort studies have found cure rates of 80100% with three times weekly regimens taken over 69 months.10 REGIMENS CONTAINING QUINOLONES

OPTION

One systematic review found that ciprofloxacin was less effective in reducing relapse rates than standard first line drugs (ethambutol, rifampicin, pyrazinamide) in people with tuberculosis with or without HIV. Other quinolones have not been adequately evaluated. Benefits: We found one systematic review (search date 2005, 10 RCTs, 1178 people with bacterially confirmed pulmonary tuberculosis with or without HIV infection) assessing fluoroquinolones (mainly ciprofloxacin) substituted for or added to standard drug regimens (ethambutol, rifampicin, pyrazinamide).12 The review did not report data for most outcomes separately for people with or without HIV. The review found no significant difference between ciprofloxacin and standard drugs in cure at 8 weeks (2 RCTs: 33/39 [85%] with ciprofloxacin v 36/41 [88%] with standard drugs; RR 0.89, 95% CI 0.55 to 1.43) or treatment failure at 12 months (3 RCTs: 9/163 [5%] with ciprofloxacin v 4/195 [2%] with standard drugs; RR 2.14, 95% CI 0.71 to 6.42) in people with tuberculosis with or without HIV. It found that ciprofloxacin significantly increased relapse rates over the duration of the trials (unspecified) compared with standard drug regimens (3 RCTs: 10/191 [5.0%] with ciprofloxacin v 1/193 [0.5%] with ethambutol plus pyrazinamide or rifampicin; RR 7.17, 95% CI 1.33 to 38.58) and increased the time to sputum culture conversion (1 RCT, 168 people: WMD 0.50 months, 95% CI 0.18 months to 0.82 months), although this was confined to HIV positive participants. It found no significant increase in time to sputum culture conversion in HIV negative participants (1 RCT, 101 people: WMD +0.20 months, 95% CI 0.10 months to +0.50 months). Adding levofloxacin to basic regimens in drug resistant areas had no beneficial effect at 8 weeks (1 RCT, cure: 59/75 [79%] with adding levofloxacin v 36/87 [42%] with no levofloxacin, RR 1.28, 95% CI 0.93 to 1.76). There was also no significant difference in cure at 2 weeks between levofloxacin and ofloxacin added to basic regimens (59/75 [79%] with adding levofloxacin v 56/69 [81%] with adding ofloxacin; RR 0.97, 95% CI 0.82 to 1.14). The review found no significant difference in cure (42/92 [46%] with sparfloxacin v 19/92 [21%] with ofloxacin; RR 2.10, 95% CI 0.77 to 5.71) or treatment failure (7/71 [10%] with sparfloxacin v 12/78 [15%] with ofloxacin; RR 0.61, 95% CI 0.26 to 1.47) between sparfloxacin and ofloxacin added to standard drug regimens. Adverse effects, which were mild and responsive to symptomatic treatment, were similar between people taking quinolone regimens and standard drug regimens (3 RCTs, 376 people, total number of adverse effects: RR 1.00, 95% CI 0.71 to 1.40). Serious adverse effects with quinolones substituted into regimen were also similar between regimens (4 RCTs, 407 people: RR 0.84, 95% CI 0.40 to 1.74). There was no significant difference in total number of adverse effects between levofloxacin and ofloxacin (1 RCT: 11/65 [17%] with levofloxacin v 13/69 [19%] with ofloxacin; RR 0.78, 95% CI 0.37 to 1.62). There was also no significant difference in total number of adverse effects between sparfloxacin and ofloxacin (3 RCTs: 23/123 [19%] with sparfloxacin v 24/130 [18%] with ofloxacin; RR 0.98, 95% CI 0.59 to 1.64).12 Quinolones are potentially important, and some of the newer quinolones have greater in vitro activity against Mycobacteria tuberculosis than ciprofloxacin; larger trials are awaited. ETHAMBUTOL IN PLACE OF RIFAMPICIN IN CONTINUATION PHASE IN CHEMOTHERAPY REGIMENS FOR 6 MONTHS OR LONGER

Harms:

Comment:

OPTION

New

One multicentre RCT comparing 8 months chemotherapy regimens found that ethambutol plus isoniazid in the continuation phase was less effective than rifampicin plus isoniazid in reducing bacteriological failures and relapse rates at 12 months. 6
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Benefits: One RCT (1355 people from 8 centres in Africa and Asia with newly diagnosed pulmonary tuberculosis, 10% with HIV infection) compared three short course regimens.13 One group received initial 2 months of ethambutol plus isoniazid plus rifampicin plus pyrazinamide daily, followed by ethambutol plus isoniazid daily in a 6 month continuation phase. A second group received the same initial 2 months treatment followed daily rifampicin plus isoniazid in a 4 month continuation phase. A third group received the same treatments as the first but were given initial drugs three times weekly. The RCT found that the regimen containing ethambutol in the continuation phase was significantly less effective than the regimen containing rifampicin in reducing the proportion of people with unfavourable status defined as bacteriological failure or relapse at 12 months after treatment (14% with ethambutol v 5% with rifampicin; adjusted OR 2.25, 95%CI 1.22 to 4.15). Possible adverse effects were reported in 28/1355 (2.07%) people requiring modification or interruption of treatment for 7 days or longer.13 There were no deaths attributable to adverse effects. None. CHEMOTHERAPY FOR LESS THAN 6 MONTHS

Infectious diseases

Harms:

Comment: OPTION

One systematic review found limited evidence that 3 month chemotherapy regimens were less effective in reducing relapse rates than 12 month regimens. Benefits: We found one systematic review (search date 2004, 7 RCTs, 4100 people with newly diagnosed pulmonary tuberculosis), which compared a variety of shorter (minimum 2 months) and longer (maximum 12 months) drug regimens.14 The RCTs included people in India, Hong Kong, Singapore, and Germany. The review found that a 3 month regimen significantly increased relapse rates compared with a 12 month regimen (5 RCTs: 71/1290 [5.5%] with 3 months v 39/1298 [3.0%] with 12 months; RR 3.03, 95% CI 2.08 to 4.40). However, one RCT found that people given a 2 month regimen were significantly less likely to change or discontinue drugs than those given a 12 month regimen (6/299 [2.0%] with 2 months v 17/299 [5.7%] with 12 months; RR 0.35; 95% CI 0.14 to 0.88). The review14 found similar rates of adverse effects or toxicity requiring interruption, alteration, or complete cessation of treatment with both shorter and longer regimens with the exception of one RCT15 in which significantly fewer participants changed or discontinued treatment in the 2 month regimen than in the 12 month regimen, but numbers were small (6/299 [2%] with 2 months v 17/299 [6%] with 12 months; RR 0.35, 95% CI 0.14 to 0.88). The treatments were given under optimal conditions. In clinical practice adherence is likely to be lower, and so relapse rates associated with the shorter regimens are likely to be higher than those in clinical trials. What are the effects of different drug regimens in people with multidrug resistant tuberculosis without HIV infection? COMPARATIVE BENEFITS OF DIFFERENT REGIMENS IN MULTIDRUG RESISTANT TUBERCULOSIS

Harms:

Comment:

QUESTION

OPTION

We found no systematic review and no RCTs comparing different drug regimens for multidrug resistant tuberculosis. Benefits: Harms: We found no systematic review or RCTs comparing different regimens in people with multidrug resistant tuberculosis. We found no RCTs. 7

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Tuberculosis
Comment: Clinical guide: Current clinical practice in people with multidrug resistant tuberculosis is to include at least three drugs to which the particular strain of tuberculosis is sensitive, using as many bactericidal agents as possible. People are observed directly and managed by a specialised clinician. What are the effects of low level laser therapy in people with tuberculosis without HIV infection? LASER THERAPY

QUESTION

OPTION

One systematic review provided insufficient evidence to assess effects of low level laser therapy in people with tuberculosis. Benefits: Harms: Comment: Low level laser therapy: We found one systematic review (search date 2001, no RCTs; see comment below) and no subsequent RCTs.16 Low level laser therapy: The systematic review did not provide reliable data on harms.16 The systematic review found 29 observational studies, mainly from Russia and India.16 It found no reliable evidence for a beneficial effect of low level laser therapy in people with tuberculosis, although a range of positive effects was reported. Which interventions improve adherence to treatment in people with tuberculosis without HIV infection? CASH INCENTIVES

QUESTION

OPTION

One systematic review found that cash incentives improved attendance among people living in deprived circumstances compared with usual care. One subsequent RCT found that cash incentives improved treatment completion in intravenous drug users. A second subsequent RCT found no significant difference in treatment completion between immediate and deferred cash incentives. A third subsequent RCT found no significant difference in treatment completion between cash payment and non-cash payment (fast food or grocery coupon, phone cards, or bus tokens). Benefits: Cash incentives versus no cash incentive: We found one systematic review (search date 2000, 2 RCTs conducted in the USA)17 and two subsequent RCTs.19,20 The first RCT (244 homeless men) identified by the review found that a cash incentive ($5 [1992 US$]) significantly improved attendance at the first appointment compared with usual care (RR 1.6, 95% CI 1.3 to 2.0).17 The second RCT (248 migrants; 205 followed up) identified by the review found that a cash incentive ($10 [1985 US$]) combined with health education significantly improved attendance in people on tuberculosis preventive therapy compared with usual care, but did not improve attendance in individuals being treated for clinical disease (preventive therapy: RR 2.4, 95% CI 1.5 to 3.7; treatment: RR 1.07, 95% CI 0.97 to 1.19).17 The first subsequent RCT (163 drug users with positive tuberculin skin test) compared three groups: direct observation at a participant chosen site plus a cash incentive ($5 [19941997 US$]) per visit; direct observation at a designated site plus $5 a visit; and direct observation at a participant chosen site without a cash incentive.19 It found that both groups given cash incentives were significantly more likely to complete treatment compared with the group given no cash incentive (AR for treatment completion: 28/53 [53%] with chosen site plus cash v 2/55 [4%] with no cash incentive; OR 29.7, 95% CI 6.5 to 134.5; 33/55 [60%] with designated site plus cash v 2/55 [4%] with no cash incentive; OR 39.7, 95% CI 8.7 to 134.5). The second subsequent RCT (119 homeless adults with a positive tuberculin skin test treated under direct observation at a tuberculosis clinic) compared cash payment ($5 [19961997 US$]) versus non-cash payment (fast food or grocery coupon, phone cards, or bus tokens worth $5).20 It found no significant difference in treatment completion rates between treatment groups (58/65 [90%] with cash payment v 44/54 [82%] with non-cash payment; P = 0.23). Immediate versus deferred cash
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incentive: We found one RCT (300 intravenous drug users with latent tuberculosis), which compared three interventions: treatment with direct observation (see benefits of direct observation treatment, p 11) by a nurse; treatment with self administration plus peer counselling and education; and routine care.21 Participants in each group were further randomised to receive either an immediate or a deferred cash incentive ($10 [19951997 US$]). The immediate payment was given at the end of each month when people completed a routine assessment for adherence and drug toxicity. The deferred payment was given either after the 6 month treatment period or when the person withdrew from the study. The RCT found no difference in treatment completion between immediate versus deferred payments (125/150 [83%] with immediate payment v 112/150 [75%] with deferred payment; P = 0.09). Harms: Comment: Cash incentives: The review17 and RCTs1921 did not assess adverse effects. Cash incentives sometimes represent transport reimbursement costs. True cash payments for attending clinic are likely to be impractical with the large number of people with tuberculosis in developing countries. DEFAULTER ACTIONS

Infectious diseases

OPTION

One systematic review found that intensive action (repeated home visits and reminder letters) improved completion of treatment compared with routine action (single reminder letter and home visit) for defaulters. Benefits: We found one systematic review (search date 2000, 2 RCTs conducted in India).17 The first included RCT (170 people randomised; 150 followed up) found that up to four home visits to defaulters significantly improved completion of treatment compared with the routine policy of a reminder letter followed by one home visit (RR 1.32, 95% CI 1.02 to 1.71). The second included RCT (200 people) found that up to two reminder letters significantly improved completion of treatment (RR 1.21, 95% CI 1.05 to 1.39), even in people who were illiterate. The review gave no information on adverse effects.17 None. HEALTH EDUCATION BY A NURSE

Harms: Comment: OPTION

One RCT found that health education by a nurse improved treatment completion compared with an educational leaflet alone. One RCT in drug users found no significant effect of 510 minutes of health education by a clinic nurse compared with no targeted health education on attendance rates for scheduled follow up. Benefits: We found one systematic review (search date 2000, 2 RCTs conducted in the USA).17 The first RCT (1004 people) identified by the review17 compared four methods of health education: telephoning by a nurse; visiting by a nurse; consultation by a clinic doctor; and provision of an educational leaflet.23 It found that nurse telephone call and nurse visit both significantly increased treatment completion compared with the leaflet alone (75/80 [94%] with nurse telephone call v 55/77 [71%] with leaflet; RR 1.30, 95% CI 1.18 to 1.37; 75/79 [95%] with nurse visit v 55/77 [71%] with leaflet; RR 1.33, 95% CI 1.20 to 1.38 [see also benefits of Health Education by a doctor or peer educator, p 11]). The second RCT identified by the review (403 drug users) found that 510 minutes of health education by a clinic nurse had no significant effect on whether people kept a scheduled appointment compared with no targeted health education (RR 1.04, 95% CI 0.70 to 1.54).24 The review gave no information on adverse effects.17 Education is often part of a package of care that includes prompts and incentives, which makes it difficult to evaluate the independent effects of education. 9

Harms: Comment:

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OPTION SUPPORT MECHANISMS FOR DIRECTLY OBSERVED TREATMENT New

RCTs found no significant difference in non-compliance direction observation at different sites (participant chosen v designated) or direct observation and direct observation done by different people (health professionals v family members). Benefits: Participant chosen site versus designated site: We found one systematic review (search date 2002),17 which identified one RCT (163 drug users with positive tuberculin skin test).19 The RCT found no significant difference in treatment completion rate between direct observation at a participant chosen site compared with direct observation at a designated site, with or without cash incentives (see also benefits of cash incentives, p 8) at 12 months (RR 0.88, 95% CI 0.63 to 1.23).18 Clinic based support versus family member support: We found one RCT (173 adults with tuberculosis) comparing family based direct observation treatment versus direct observation treatment through clinics.28 It found no significant difference in non-compliance between treatment groups (22/87 [26%] with family based direct observation v 19/86 [22%] with direct observation through clinics; RR 1.04, 95% CI 0.88 to 1.23). Only 50/87 (58%) of those assigned to family based direct observation actually received treatment; in 22 this was because they had no family to administer the treatment, eight refused family supervision, and seven had other reasons not to comply with the group to which they had been assigned. Community-based health workers support versus family member support: We found one RCT (1353 adults and children with smear positive or negative pulmonary tuberculosis or extrapulmonary tuberculosis or relapse of previously treated tuberculosis in a rural African district with high prevalence of HIV) comparing direct observation treatment supported by community health workers during participants daily visits to a diagnostic centre versus direct observation treatment supported by a family member.26 It found no significant difference in cure and completion rates between groups (453/664 [68%] with community health worker support v 440/662 [66%] with family member support; ARR +2%, 95% CI 3% to +7%, P = 0.52). The difference in cure and completion rates approached significance in a subgroup analysis of newly sputum smear positive people (214/290 [74%] with community health worker support v 197/296 [66%] with family member support; ARR 7%, 95% CI 0% to 15%, P = 0.06). Community based health worker support versus health facility support: We found one RCT (587 adults and children > 5 years of age with newly diagnosed smear positive or negative pulmonary or extrapulmonary tuberculosis in an urban African district) compared direct observation treatment (guardians including family members, close relatives, or former tuberculosis patients).27 This was supported by community based health workers who made home visits; plus two weekly clinic visits compared with direct observation treatment by going to the health facility daily for 2 months (the initial intensive phase). During the 6 month continuation phase all participants took self administered treatment. The RCT found no significant difference in cure or treatment completion rates at 78 months between groups (221/260 [85%] with community based health worker support v 271/327 [83%] with health facility support; OR 1.17, 95% CI 0.75 to 1.83). Subgroup analysis in smear positive or smear negative participants also found no significant difference between groups. Potential harms include reduced cooperation between patient and doctor, removal of individual responsibility, detriment to long term sustainability of antituberculosis programmes, and increased burden on health services to the detriment of care for other diseases. None of these has been adequately investigated in RCTs. Numerous observational studies have evaluated interventions described as direct observation treatment, but all were packages of interventions that included specific investment in antituberculosis programmes, such as strengthened drug supplies; improved microscopy services; and numerous incentives, sanctions, and other co-interventions that were likely to influence adherence.28,29 DIRECT OBSERVATION TREATMENT VERSUS SELF ADMINISTERED TREATMENT

Harms:

Comment:

OPTION

One systematic review provided insufficient evidence to compare direct observation of treatment versus self treatment for improving cure rates in people with tuberculosis. 10
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Benefits: We found one systematic review (search date 2002, 6 RCTs, 1910 people with positive smear tests with or without HIV)25 and one subsequent RCT26 that compared direct observation of people as they took their drugs (by a health professional, lay health worker, or family member) versus self administered treatment. Treatment for all studies was for 6 months, and cure was measured at the end of treatment (4 RCTs) or at 12 months (1 RCT). The review found no significant difference in cure between any direct observation treatment compared with self treatment (4 RCTs: 587/914 [64%] with direct observation treatment v 432/689 [63%] with self treatment; RR 1.06, 95% CI 0.98 to 1.14). When analysed by the person observing the treatment, there was no significant difference in cure and treatment completion rates combined between self administered treatment and treatment observed by a health professional, lay health worker, or family member. However, one large RCT (836 people) identified by the review, which allowed participants to choose their therapy observer, found that direct observation therapy significantly improved both cure rates (RR 1.13, 95% CI 1.04 to 1.24) and cure plus treatment completion rates combined (RR 1.11, 95% CI 1.03 to 1.18), compared with self administration. Allocation concealment in the RCT was inadequate, raising the possibility of selection bias. Furthermore, participants receiving direct observation therapy also received twice weekly home visits by health workers as part of the monitoring process, which included tablet counting and urine testing for rifampicin. These co-interventions may have contributed to better adherence rates. Another RCT identified by the review (300 intravenous drug users with latent tuberculosis)25 compared three interventions: treatment with direct observation by a nurse; treatment with self administration plus peer counselling and education; and routine care.21 It was not included in the meta-analysis performed by the review. Participants in each group were further randomised to receive either an immediate or a deferred cash incentive ($10 [19951997 US$]) (see benefits of immediate versus deferred cash incentives, p 8). The RCT found no significant difference between any direct observation therapy, with or without cash incentives, compared with self administration alone at 6 months (direct observation v self administration alone; RR 1.02, 95% CI 0.89 to 1.18).21 Potential harms include reduced cooperation between patient and doctor, removal of individual responsibility, detriment to long term sustainability of antituberculosis programmes, and increased burden on health services to the detriment of care for other diseases. None of these has been adequately investigated in RCTs. Numerous observational studies have evaluated interventions described as direct observed treatment, but all were packages of interventions that included specific investment in antituberculosis programmes, such as strengthened drug supplies; improved microscopy services; and numerous incentives, sanctions, and other cointerventions that were likely to influence adherence.2830 HEALTH EDUCATION BY A DOCTOR OR PEER EDUCATOR

Infectious diseases

Harms:

Comment:

OPTION

One RCT found no significant difference in treatment completion between consultation by the clinic doctor and the education leaflet alone. One RCT found no significant difference in completion rates between adherence coaching by peer educators plus usual care, self esteem counselling by college students plus usual care, and usual care alone. Benefits: We found one systematic review (search date 2000, 1 RCT conducted in the USA)17 and one subsequent RCT.22 The RCT (1004 people) identified by the review17 compared four methods of health education: telephoning by a nurse; visiting by a nurse; consultation by a clinic doctor; and provision of an educational leaflet.23 It found no significant difference in treatment completion between consultation by the clinic doctor and the education leaflet alone (64/82 [78%] with consultation v 55/77 [71%] with leaflet; RR 1.09, 95% CI 0.89 to 1.23 [see also benefits of health education by a nurse, p 9]).23 The subsequent RCT (286 adolescents with latent tuberculosis) compared adherence coaching by peer educators plus usual care, self esteem counselling by peer educators plus usual care, and usual care alone.22 It found no significant difference in completion rates among treatment groups (51.1% with adherence coaching plus usual care v 41.8% with self esteem counselling plus usual care v 37.5% with usual care; P value not reported). 11

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Harms: Comment: The review17 and subsequent RCT gave no information on adverse effects.22 Education is often part of a package of care that includes prompts and incentives, which makes it difficult to evaluate the independent effects of education. COMMUNITY HEALTH ADVISORS

OPTION

One RCT found that consultation with peer health advisors recruited from the community significantly increased the rate of attendance for treatment compared with no consultation. Benefits: We found one systematic review (search date 2000, 1 RCT).17 The RCT (200 homeless people) identified by the review found that consultation with peer health advisors recruited from the community significantly increased the rate of attendance for diagnostic follow up compared with no consultation (62/83 [75%] with consultation v 42/79 [53%] with no consultation; RR 1.4, 95% CI 1.1 to 1.8). The review gave no information on adverse effects. None. PROMPTS TO ADHERE TO TREATMENTS

Harms: Comment: OPTION

One systematic review identified no RCTs about the effects of prompts on adherence to treatment in people with tuberculosis. Benefits: Harms: Comment: OPTION We found one systematic review (search date 2000), which found no RCTs of prompts to return for treatment.17 We found no RCTs. None. SANCTIONS FOR NON-ADHERENCE

One systematic review identified no RCTs on the effect of sanctions in people with tuberculosis. Benefits: Harms: Comment: We found one systematic review (search date 2000), which identified no RCTs of sanctions.17 The use of sanctions may be ethically dubious. In New York (USA), incarcerating people who did not comply with treatment was thought to increase compliance with the Department of Healths community tuberculosis treatment programme.31 STAFF TRAINING

OPTION

Two RCTs provided insufficient evidence to assess the effects of staff training on adherence to treatment. Benefits: We found one systematic review17 (search date 2000, 1 poorly randomised RCT18) and one subsequent RCT32 comparing intensive staff supervision versus routine supervision. The RCT (1300 people with newly detected tuberculosis from 7 health centres) compared intensive staff supervision versus routine supervision at centres in Korea performing tuberculosis extension activities.18 The trial used cluster randomisation, but the unit of analysis was the individual, thus weakening its results.18 Centres were paired and randomised, and supervision was carried out by senior doctors. The RCT found that higher completion rates were achieved with intensive supervision (RR 1.2; CI not estimated because of cluster design).18 The subsequent RCT (1200 adults aged > 14 years with smear positive pulmonary tuberculosis in nurse managed ambulatory primary care clinics in South Africa) compared adding staff training to direct observation treatment versus direct observation treatment alone.32 Staff training consisted of an 18
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hour experimental participatory in service programme for clinic staff delivered by nurse facilitators and focusing on patient centredness, critical reflection of practice, and quality improvement. The RCT found no significant difference in cure and treatment completion rates between staff training and no staff training, although rates were higher in the staff training group (treatment completion: ARR 4.8%, 95% CI 5.5% to +15.2%; bacteriological cure rates: ARR 10.4%, 95% CI 1.2% to +22.0%). Harms: Comment: QUESTION The RCTs gave no information on adverse effects.17,32 None. Which interventions improve reattendance for Mantoux test reading in people who have had tuberculosis? PROMPTS AND CONTRACTS TO IMPROVE REATTENDANCE FOR MANTOUX TEST READING

Infectious diseases

OPTION

One RCT in healthy people found that telephone prompts to return for Mantoux test reading slightly increased the number of people who reattended compared with no prompts, but the difference was not significant. One RCT found that healthy people were more likely to reattend for Mantoux test reading after providing either a verbal or written commitment compared with no such commitment. Benefits: Prompts: We found one systematic review (search date 2000), which identified one RCT (701 healthy people) comparing an automatic telephone message prompt to return for Mantoux reading versus no prompt. It found that people were slightly more likely to return for testing after prompting, but the difference was not significant (93% with prompting v 88% with no prompting; RR 1.05, 95% CI 1.00 to 1.10).17 Contracts: We found no systematic review. One RCT (2053 healthy students in the USA) found that reattendance for Mantoux reading was significantly improved both by verbal and written commitments compared with no commitment (reattendance with verbal commitment: RR 1.10, 95% CI 1.03 to 1.18; reattendance with written commitment: RR 1.12, 95% CI 1.05 to 1.19).30 The review and RCTs did not assess adverse effects.17,30 None.

Harms: Comment:

GLOSSARY
Defaulter actions Actions taken by health workers when people fail to attend for treatment of their tuberculosis. Direct observation Tuberculosis patients whose therapy was directly observed by a trained, regularly supervised individual according to national programme guidelines for treatment (WHO definition).

Substantive changes
Intermittent short course chemotherapy Evidence reassessed; recategorised as Unknown effectiveness. Regimens containing quinolones One systematic review added;12 categorisation unchanged (unknown effectiveness). New option added on support mechanisms for directly observed treatment; categorised as unknown effectiveness. Direct observation treatment versus self administered treatment One RCT added;25 categorisation unchanged (unknown effectiveness). Community health advisors Evidence reassessed; recategorised as Unknown effectiveness. Staff training One RCT added;31 categorisation unchanged (unknown effectiveness).

REFERENCES
1. Global tuberculosis control: surveillance, planning, financing. WHO report 2006. Geneva, World Health Organization (WHO/HTM/TB/2006.362). 2. NICE Clinical Guideline 33. Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. March 2006. Developed by the National Collaborating Centre for Chronic Conditions Royal College of Physicians. Available online at ww.nice.org.uk (last accessed 11 July 2006).

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3. Enarson D, Rouillon A. Epidemiological basis of tuberculosis control. In: Davis PD, ed. Clinical tuberculosis. 2nd ed. London: Chapman and Hall Medical, 1998. 4. Smieja MJ, Marchetti CA, Cook DJ, et al. Isoniazid for preventing tuberculosis in non-HIV infected persons. In: The Cochrane Library, Issue 1, 2006. Chichester UK, John Wiley & Sons Ltd. Search date 2003; primary sources Cochrane Infectious Diseases Group specialised trials register, Cochrane Central Register of Controlled Trials, Science Citation Index, Cumulated Index Medicus, Medline, Embase and referenced lists of articles. 5. Ena J, Valls V. Short-course therapy with rifampin plus isoniazid, compared with standard therapy with isoniazid, for latent tuberculosis infection: a meta-analysis. Clin Infect Dis 2005;40:670676. 6. East and Central African/British Medical Research Council Fifth Collaborative Study. Controlled clinical trial of 4 short-course regimens of chemotherapy (three 6-month and one 8-month) for pulmonary tuberculosis. Tubercle 1983;64:153166. 7. British Thoracic Society. A controlled trial of 6 months chemotherapy in pulmonary tuberculosis, final report: results during the 36 months after the end of chemotherapy and beyond. Br J Dis Chest 1984;78:330336. 8. Hong Kong Chest Service/British Medical Research Council. Controlled trial of four thrice weekly regimens and a daily regimen given for 6 months for pulmonary tuberculosis. Lancet 1981;1:171174. 9. Farga V, Valenzuela P , Valenzuela MT, et al. Short-term chemotherapy of tuberculosis with 5-month regimens with and without pyrazinamide in the second phase (TA-82). Rev Med Chil 1986;114:701705. [In Spanish] 10. Mwandumba HC, Squire SB. Fully intermittent dosing with drugs for tuberculosis in adults. In: The Cochrane Library, Issue 1, 2006. Chichester, UK: John Wiley & Sons Ltd. Search date 2001; primary sources Cochrane Infectious Diseases Group Trials Register, Cochrane Controlled Trials Register, Medline, Embase, reference lists of article, and researchers contacted for unpublished trials. 11. Naude JMTW, Donald PR, Huseey GD, et al. Twice weekly vs. daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis 2000;19:405410. 12. Ziganshina LE, Vizel AA, Squire SB. Fluoroquinolones for treating tuberculosis. In: The Cochrane Library, Issue 1, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2005, primary sources Cochrane Infectious Diseases Group Specialized Register, The Cochrane Library, Medline, Embase, Lilacs, Science Citation Index, and Russian database and hand searches of reference lists of all identified studies and contact with researchers. 13. Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of chemotherapy for treatment of newly diagnosed pulmonary tuberculosis: international multicentre randomised trial. Lancet 2004;364:12441251. 14. Gelband H. Regimens of less than six months treatment for TB. In: The Cochrane Library, Issue 1, 2006. Oxford: Update Software. Search date 1999; primary sources Medline, Cochrane Parasitic Diseases Trials Register, contact with researchers, and hand searches of reference lists. 15. Hong Kong Chest Service, Tuberculosis Research Centre, Madras, India, British Medical Research Council. Sputum-smear-negative pulmonary tuberculosis: controlled trial of 3-month and 2-month regimens od chemotherapy. Lancet 1979;i:13611363. 16. Vlassov VV, Pechatnikov LM, MacLehose HG. Low level laser therapy for treating tuberculosis. In: The Cochrane Library, Issue 1, 2006. Chichester, UK: John Wiley & Sons Ltd. Search date 2001; primary sources Cochrane Infectious Diseases Group Register, Embase, Cinahl, Pedro, Science Citation Index, National Centre for Science Information at the Indian Institute of Science, Central Medical Library and Google. 17. Volmink J, Garner P . Interventions for prompting adherence to tubercular treatment. In: The Cochrane Library, Issue 1, 2006. Chichester UK: John Wiley & Sons Ltd. Search date 2000, primary sources Medline, Embase, Cochrane Controlled Trials Register 1998, Issue 3, Cochrane Collaboration Effective Professional Practice (CCEPP) Trials Registry, LILACS, hand searches of journals and reference lists, and contact with authors. 18. Jin BW, Kim SC, Mori T, et al. The impact of intensified supervisory activities on tuberculosis treatment. Tuber Lung Dis 1993;74:267272. 19. Malotte CK, Hollingshead JR, Larro M. Incentives vs. outreach workers for latent tuberculosis treatment in drug users. Am J Prev Med 2001;20:103107. 20. Tulsky JP , Hahn JA, Long HL, et al. Can the poor adhere? Incentives for adherence to TB prevention in homeless adults. Int J Tuberc Lung Dis 2004;8:8391. 21. Chaisson R, Barnes GL, Hackman JR, et al. A randomized, controlled trial of interventions to improve adherence to isoniazid therapy to prevent tuberculosis in injection drug users. Am J Med 2001;110:610615. 22. Hovell MF, Sipan CL, Blumberg EJ, et al. Increasing Latino adolescents adherence to treatment for latent tuberculosis infection: a controlled trial. Adolesc Health 2003;93:18711877. 23. Sanmarti L, Megias JA, Gomez MN, et al. Evaluation of the efficacy of health education on the compliance with antituberculosis chemoprophylaxis in school children: a randomized clinical trial. Tuber Lung Dis 1993;74:2831. [Erratum in: Tuber Lung Dis 1993;74:217] 24. Malotte CK, Rhodes F, Mais KE. Tuberculosis screening and compliance with return for skin test reading among active drug users. Am J Public Health 1998;88:792796. 25. Volmink J, Garner P . Directly observed therapy for treating tuberculosis. In: The Cochrane Library, Issue 1, 2006. Chichester, UK: John Wiley & Sons Ltd. Search date 2002; primary sources, Cochrane Library, Medline, Embase, Lilacs, hand searches of reference lists, and contact with experts in the field and relevant organisations. 26. Wright J, Walley J, Philip A, et al. Direct observation of treatment for tuberculosis: a randomized controlled trial of community health workers versus family members. Trop Med Int Health 2004;9:559565. 27. Wandwalo E, Kapalata N, Egwaga S, et al. Effectiveness of community-based directly observed treatment for tuberculosis in an urban setting in Tanzania: a randomised controlled trial. Int J Tuberc Lung Dis 2004;8:12481254. 28. Macintyre CR, Goebel K, Brown GV, et al. A randomised controlled clinical trial of the efficacy of family-based direct observation of anti-tuberculosis treatment in an urban, developed-country setting. Int J Tuberc Lung Dis 2003;7:848854. 29. Volmink J, Matchaba P , Garner P . Directly observed therapy and treatment adherence. Lancet 2000;355:13451350. Search date 1999; primary sources Medline, Embase, Cochrane Controlled Trials Register, and hand searches of reference lists. 30. Wurtele SK, Galanos AN, Roberts MC. Increasing return compliance in a tuberculosis detection drive. J Behav Med 1980;3:311318. 31. Fujiwara PI, Larkin C, Frieden TR. Directly observed therapy in New York history, implementation, results and challenges. Tuberculosis 1997;18:135148. 32. Lewin S, Dick J, Zwarenstein M, et al. Staff training and ambulatory tuberculosis treatment outcomes: a cluster randomized controlled trial in South Africa. Bull World Health Organ 2005;83:250259.

Lilia Ziganshina Professor Department of Clinical Pharmacology and Pharmacotherapy Kazan State Medical Academy Kazan Russia Paul Garner

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Professor Liverpool School of Tropical Medicine Liverpool UK
Competing interests: None declared. We would like to acknowledge the previous contributors of this chapter, including Alison Holmes.

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