Summary of findings
Description of the condition
Tuberculosis (TB) continues to be a common cause of death worldwide. Between 8.5 to 9.2 million new cases of TB, and 1.1 to 1.6 million TB deaths were estimated to have occurred worldwide in 2010. Most of these new cases occurred in South-East Asia and the Western Pacific (59%), and in Africa (26%) (WHO 2011a). In 2011, there were an estimated 8.7 million new cases of TB, 13% of whom were co-infected with human immunodeficiency virus (HIV); 1.4 million people died from TB, including almost one million deaths among HIV-negative individuals, of which 300,000 were in HIV-negative women (WHO 2012). Only 5.8 million of the new cases were notified, and 80% of the estimated 8.7 million cases were from the 22 countries with a high TB burden. China and India accounted for 40% and a further 24% were from Africa, which has the highest rates of cases and deaths per capita, and the highest number of people with TB and HIV co-infection (WHO 2012).
TB is caused by Mycobacterium tuberculosis (though the M. tuberculosis complex includes four other TB-causing mycobacteria: M. bovis, M. africanum, M. canetti, and M. microti). An estimated two billion people (about a third of the world's population) are infected with M. tuberculosis, but only 5% to 10% of them manifest clinically active TB disease (Lin 2010; WHO 2010a). In the remainder of those infected, immune responses completely eradicate the infection in ˜10%; while the immune response only succeeds in containment of the infection in ˜90%. Some M. tuberculosis bacilli evade the microbicidal mechanisms of immune cells and remain dormant and undetected, except by immunological tests, in granulomas in the lungs that are the immunological and physical barriers erected by the infected person's immune reaction to contain the infection (Barry 2009; Lin 2010; Ahmad 2011). This sub-clinical infection, with the potential for re-activation to develop active TB, is called latent TB infection (LTBI).
As opposed to active TB disease, people with LTBI are clinically asymptomatic, and have normal chest radiographs. The tuberculin skin test (TST) and interferon-gamma release assays (IGRA) are widely used to identify people with LTBI; however, both tests are associated with false positive and false negative results in different circumstances. While IGRAs have the potential to facilitate risk stratification of people with LTBI in low TB-transmission settings (Corbiere 2012), there is no gold standard test currently available for the diagnosis of LTBI in countries with a high TB burden, in immunocompromised individuals such as with those with HIV infection, and in young children; neither do these tests accurately predict progression to active TB disease, nor accurately monitor the response to preventive treatment (Pai 2008; Dyrhol-Riise, 2010; Cattamanchi 2011; Diel 2011; Machingaidze 2011; Pai 2011; Sester 2011; Rangaka 2012; Zwerling 2012).
Reactivation of LTBI
People with LTBI can develop active TB disease (reactivation of LTBI) when bacterial multiplication exceeds the immune responses mounted to control bacterial growth (Barry 2009; Lin 2010; Ahmad 2011; Zuniga 2012). The lifetime risk of developing active TB in people with LTBI is about 10%, and in about 50%, progression to active TB occurs within the first two years following M. tuberculosis infection (Frieden 2003). This risk of progression is much higher in certain high-risk groups including HIV-positive people, and in others on immunosuppression, or with diseases that suppress immunity. Also at moderately high risk are young children (below five years) who are close contacts of people with pulmonary TB, those with diabetes mellitus, silicosis, and with severe malnutrition (Jasmer 2002a; Barboza 2008; Lobue 2010). Incarcerated prisoners are also at risk of developing TB due to the high prevalence and incidence of TB among prisoners; overcrowding; and other factors that increase the spread of TB among prisoners, including those without HIV (TBCTA 2009). Health care workers, particularly those working in certain locations and roles, are also at higher risk of developing LTBI (and active TB), than the normal population (Pai 2005; Joshi 2006; Baussano 2011; Christopher 2011).
Description of the intervention
The risk of progression to active TB could be reduced by the treatment of people with LTBI. Although the same drugs are used for the treatment of active TB as are used for the treatment of LTBI, the principles of treatment of LTBI differ from that of active TB. People with active TB require treatment with a combination of drugs for a long duration and treatment with a single drug is not recommended to treat active TB due to the risk of developing resistance. The current internationally recommended regimen for the treatment of active TB is a combination of four drugs: isoniazid (INH), rifampicin, pyrazinamide, and ethambutol for the first two months; followed by two drugs: INH and rifampicin for the next four months (WHO 2007; WHO 2010b; CDC 2011; NICE 2011). In contrast, standard therapy for people with LTBI, with much lower mycobacterial loads, is a single drug (monotherapy) or a combination of two or more drugs (combination chemotherapy) for shorter durations (Jasmer 2002a).
INH prophylaxis in LTBI
Currently, INH monotherapy for six to nine months is recommended for the prevention of active TB in people at high risk of active TB (ATS/CDC 2003; WHO 2007; WHO 2010b; NICE 2011; WHO 2012). A Cochrane systematic review reported that INH-monotherapy decreases the risk of active TB by about 60% (95% CI 42% to 69%) in HIV-negative people at high risk of active TB followed up for two years (Smieja 1999). While six- and 12-month courses of INH were associated with similar reductions in the risk of active TB, the risk of hepatotoxicity (liver damage) was marginally higher in people treated with INH for 12 months. Though all-cause mortality was not reduced, TB-related deaths were reduced by treatment with INH (Smieja 1999). Nine months of INH is considered optimal for chemoprophylaxis, and with good adherence, nine months of INH is 90% protective against active TB; though for practical considerations, many programmes recommend the shorter six-month course (Lobue 2010). The benefits of INH prophylaxis are most apparent in those with LTBI who are HIV-negative; the protective efficacy is greater in those who are HIV-positive when the TST is positive (WHO 2010b). However, the long treatment duration and the fear of liver damage (CDC 2010) result in fewer than 50% to 60% completing the prescribed course of INH treatment, particularly the nine-month course, outside of clinical trials (LoBue 2003; Marais 2006; Horsburgh 2009).
Alternative INH and non-INH monotherapy or combination chemotherapy regimens
The efficacy of monotherapy with other antituberculous drugs for a shorter duration, such as rifampicin (from the family of rifamycin compounds) for three to four months; or a combination of antituberculous drugs (rifampicin plus INH for three months, rifampicin plus pyrazinamide for two to three months) have been demonstrated against placebo (Akolo 2010), and compared to six to 12 months of INH (Ena 2005; Gao 2006) in systematic reviews and meta-analyses of studies done mostly in HIV-positive people. Many believe these shorter alternative regimens would enhance acceptance and adherence to treatment in people with LTBI (Cook 2006; Lardizabal 2006; van Zyl 2006; Lobue 2010).
Another promising alternative in preventing active TB in those with LTBI is rifapentine, a cyclopentyl-substituted rifamycin that is as effective as rifampicin, but whose serum half-life is five times that of rifampicin, thus permitting weekly dosing. Intermittent rifapentine was effective and safe in the treatment of active TB, when combined with INH once weekly during the continuation phase of treatment in HIV-negative patients with active TB (Benator 2002; Bock 2002).
A Phase II randomized controlled trial (RCT) of weekly rifapentine 900 mg with INH 900 mg for three months versus daily rifampicin plus pyrazinamide for two months showed similar efficacy in preventing active TB in household contacts of people with pulmonary TB in Brazil, but had to be stopped early due to unanticipated liver toxicity in the rifampicin plus pyrazinamide arm (Schechter 2006).
Once weekly INH (900 mg) plus rifapentine (900 mg) for 12 weeks administered by directly-observed treatment (DOT) was equally effective in preventing TB over a median follow-up duration of approximately four years, as was twice-weekly, INH (900 mg) and rifampicin (600 mg) by DOT, and daily self-supervised INH (300 mg daily), taken for six months or for up to six years in trials of HIV-positive, TST–reactive participants from Brazil, Canada, Spain, and the US, aged ≥18 years who were not receiving antiretroviral treatment. Treatment completion was greater in the two rifamycin-containing regimens than the INH regimens. Grade 3 (severe) or Grade 4 (potentially life-threatening) adverse effects were more common in those randomized to INH for six years (Martinson 2011).
The efficacy of intermittent rifapentine plus INH prophylaxis has not been demonstrated in HIV-positive people with LTBI from high burden countries in Africa, in China, and in India. The effects of rifapentine compared to INH monotherapy in HIV-negative adults and children with LTBI are also uncertain.
Potential for adverse events with alternative regimens
Notwithstanding the potential advantage of enhanced adherence, the alternative drug regimens for the treatment of LTBI are also associated with a risk of adverse effects, including hepatotoxicity, peripheral neuropathy, hypersensitivity reactions, and increased uric acid levels (McElroy 2005; Andrade 2011). Among these, hepatotoxicity is the most common treatment-limiting adverse effect, and all three drugs commonly used for the treatment of LTBI – INH, rifampicin, and pyrazinamide – have the potential to cause hepatotoxicity. The earlier recommended combination of rifampicin plus pyrazinamide given daily or twice weekly for two months is not currently recommended in HIV-negative adults with LTBI due to empirical evidence (Gao 2006) and surveillance data, indicating high rates of severe liver injury with the combination (ATS/CDC 2003), although children and HIV-positive adults appear to tolerate this short-duration combination treatment better.
Concerns about drug resistance
Another concern, apart from hepatotoxicity, is the potential emergence of drug-resistant TB with INH monotherapy or combination short-course chemotherapy for LTBI.
The use of INH or rifampicin monotherapy for the treatment of LTBI could potentially promote the emergence of multiple-drug resistant TB (MDR-TB), defined as combined resistance to at least rifampicin and INH; and even extensively drug-resistant TB (XDR-TB), defined as MDR-TB strains additionally resistant to a ﬂuoroquinolone and at least one of the second-line injectable agent such as kanamycin, amikacin, or capreomycin (WHO 2008).
In a systematic review of 13 studies including over 18,000 people treated with INH monotherapy and nearly 18,000 controls, the pooled relative risk for the development of INH-resistant TB was not significantly increased (RR 1.45, 95% CI 0.85 to 2.47); and the risk was similar in studies of HIV-positive and HIV-negative people (Balcells 2006). However, many of the included studies were limited by the incomplete testing of isolates.
On the other hand, the use of combination chemotherapy for the treatment of LTBI could prevent, at least theoretically, the development of drug-resistant TB; but the risk of drug-resistant TB following treatment with regimens other than the conventional INH monotherapy is also currently unknown. Acquired rifamycin resistance has been documented in HIV-seropositive adults who fail or relapse after treatment with intermittent regimens combining INH with rifampicin, rifapentine, or rifabutin (CDC 2002); but the true extent of resistance, systematically ascertained from cohort studies or from RCTs, in HIV-negative people with LTBI is lacking. While contacts of people with INH-resistant TB can be effectively treated with rifampicin, there is currently insufficient evidence of moderate or high quality from RCTs on the optimal management of contacts of people with MDR-TB or XDR-TB (WHO 2011b; van der Werf 2012).
How the intervention might work
The potential advantages of alternative rifampicin-containing regimens over the standard six or nine months of INH prophylaxis in people with LTBI that need to be empirically demonstrated are:
- increased acceptance and treatment completion rates in people with LTBI due to the shorter duration of treatment;
- potentially reduced incidence of adverse events with non-INH containing regimens, particularly liver damage, leading to less need for intense monitoring and reduced costs associated with monitoring or in the management of adverse events;
- equivalent efficacy as with six and nine months of INH;
- possibly superior effectiveness, due to increased treatment completion rates compared to the six and nine month INH courses;
- increased prescription of the alternative prophylactic regimens by physicians due to less perceived risks with treatment and more favourable risk/benefit assessments by physicians (and by people with LTBI);
- reduced incidence of drug resistance due to increased treatment completion rates;
- reduced resource costs and overall cost savings from the societal and payers' perspectives, in high and in low TB burden countries
- reduction in deaths in people with LTBI
Why it is important to do this review
Since the risk of progression to active TB is far greater in HIV-positive than in HIV-negative people (Ahmad 2011; WHO 2011c), LTBI preventive treatment in HIV-negative people is less of a priority, particularly in resource-constrained settings. TB in people with HIV is more likely to be due to new infections (re-infection), particularly in high-transmission settings, rather than reactivation of LTBI (Houben 2011). Reactivation of LTBI is the major concern in HIV-negative people, and most of the active TB cases in low TB incidence countries, and in high TB incidence countries outside Africa such as China and India, arise from this pool of HIV-negative individuals with LTBI. In addition, in countries with a high TB incidence, the duration of protection with LTBI treatment may be reduced due to the increased incidence of re-infection, even in HIV-negative people (Nardell 2011).
An updated Cochrane Review concluded that while alternative regimens to INH for LTBI in HIV-positive people were as effective, they were less well tolerated (Akolo 2010). However, HIV-positive people differ from HIV-negative people in the frequency of co-morbid conditions (infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) and are often on concomitant medications that also increase the risk for adverse events, particularly liver toxicity (Gordin 2004). Current international guidelines (WHO 2010b; CDC 2011; NICE 2011) differ in their recommendations for LTBI preventive treatment in HIV-negative people. TB is common, and effective and well-tolerated preventive therapy is an important policy issue. A reliable summary across all relevant trials of alternative regimens with differing effect profiles compared to INH in HIV-negative people will help inform policies to control the global transmission of TB.
To compare the effects of rifampicin monotherapy or rifamycin-combination therapy versus INH monotherapy for preventing active TB in HIV-negative people at risk of developing active TB.
Criteria for considering studies for this review
Types of studies
RCTs that randomized individuals or clusters of individuals. Quasi-RCTs (where allocation to intervention arms could be predicted) were excluded.
Types of participants
HIV-negative people at risk of developing active TB and without active TB at the time of enrolment.
While people with LTBI can be stratified by levels of risk of developing active TB (TBCTA 2009; Lobue 2010), we included all trials of HIV-negative people diagnosed to have LTBI, irrespective of risk stratification. We also included trials of children at risk for active TB (eg asymptomatic children of patients with pulmonary TB).
We excluded trials including primarily HIV-positive people.
Types of interventions
Treatment with rifampicin or rifamycin-containing drug combinations (any dose or duration).
INH monotherapy for six to 12 months.
Types of outcome measures
Rates of active TB.
Ideally this should have been based on mycobacterial diagnosis (smear or culture); histological diagnosis; or as a defined clinical syndrome with typical symptoms, consistent and independently assessed chest X-ray, and a documented response to anti-TB treatment (ATS 1990). We included data for active TB from trials that used a combination of clinical, mycobacterial, and radiological criteria even if the procedures used did not satisfy all ATS 1990 criteria. Where criteria used were not clear, we attempted to obtain information from trial authors, failing which we documented the criteria used, but did not exclude the trial.
- TB-related deaths
- All-cause death
- Incidence of drug-resistant TB including MDR-TB and XDR-TB
- Adherence to treatment (as defined by the study authors)
- Serious adverse events (as defined by the study authors based on clinical as well as laboratory criteria)
- Drug-related deaths
- Hepatotoxicity (severity based on classifications such as those of Blumberg 2003, or as described in the trial report)
- Adverse events requiring treatment discontinuation
- Other adverse events (including skin rash, nausea or vomiting, diarrhoea, epigastric pain, fatigue or malaise, dizziness, headache, fever or chills, arthralgia, peripheral neuropathy, anorexia/weight loss, insomnia, pruritis, and dysmenorrhoea)
Search methods for identification of studies
We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and ongoing).
On 5 December 2012 we updated searches conducted in November 2008, January 2011, November 2011, and May 2012 of the Cochrane Infectious Diseases Group (CIDG) Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (Issue 11, 2012); MEDLINE; EMBASE; and LILACS using the terms detailed in Appendix 1. The search was conducted by Vittoria Lutje, the Trials Search Coordinator of the CIDG.
Additionally, in order to identify relevant trials from journals that may not be indexed in these databases, we searched the web-site of the Indian Medlars Center (IndMED; http://indmed.nic.in/) and the South Asian Database of Controlled Clinical Trials (http://www.cochrane-sadcct.org/ ) using 'tuberculosis' and 'isoniazid' as search terms.
We searched the following conference proceedings of the American Thoracic Society based on availability (http://www.thoracic.org/journals/pats/index.php):
- ATS International Conference, San Diego, May 2009
- ATS International Conference, New Orleans, May 2010
- ATS International Conference, Denver, Colorado, May 2011
We also searched the conferences proceedings of the International Union against Tuberculosis and Lung Disease (http://www.theunion.org/index.php/en/conferences):
- 1st Conference of The Union South-East Asia Region, New Delhi, India, September 2008
- 5th Conference of The Union Europe Region, Dubrovnik, Croatia, May 2009
- 13th Conference of The Union Latin American Region, San Salvador, El Salvador, March 2010
- 18th Union Conference for the African Region, Abuja, Nigeria, March 2011
- 3rd Conference of The Union Asia-Pacific Region, Hong Kong, China, July 2011
- 42nd Union World Conference on Lung Health, Lille, France, October 2011
We searched the metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/) and the WHO International Trials Clinical Registry Platform's Search Portal (http://apps.who.int/trialsearch/) for ongoing or completed but unpublished trials.
Searching other resources
We contacted researchers in the field to identify additional studies that were eligible for inclusion. We also contacted relevant organizations, including the World Health Organization (WHO), the Prevention of Tuberculosis Trials Consortium (TBTC), and the Global Partnership to Stop TB, for unpublished and ongoing trials.
We also checked the reference lists of all studies identified by the above methods.
Data collection and analysis
Selection of studies
Three authors (SKS, TK, and AS) independently screened all citations and abstracts identified by the search strategy to identify potentially eligible studies. We obtained full text articles of potentially eligible studies. We assessed the articles for inclusion using a pre-designed eligibility form based on the inclusion criteria. We checked for multiple publications of the same data and selected one reference as the primary reference and listed the others as subsidiary references. We contacted the trial authors for clarification if eligibility was unclear. We resolved any differences in opinion with the fourth author (PT). We documented the reason for excluding studies. The fourth author (PT) independently checked the table of excluded studies to confirm the accuracy of the stated reasons for exclusion. We responded to peer referee and editorial suggestions on inclusion and exclusion of studies.
Data extraction and management
Two authors (SKS and TK) independently extracted data using a pre-tested data extraction sheet. For all included trials, we extracted information on the number of participants randomized and number for which outcomes were measured. We extracted the number of events and the number of participants in each treatment arm for dichotomous outcomes.
We resolved any discrepancies in the extracted data by discussion and, if required, referred to PT. PT independently checked all extracted data and extracted additional data. We attempted to contact the contact author or senior author for further details when data were not clear or not presented in the publication.
Assessment of risk of bias in included studies
Three authors (SKS, TK, and PT) independently assessed the risk of bias in the included trials. We attempted to contact the trial authors if details were missing or unclear in the publications. We resolved disagreements through consensus and in one instance by consulting an editor of the CIDG. We assessed each of the included trials for the risk of bias on six domains: sequence generation; allocation concealment; blinding; incomplete outcome data; selective outcome reporting; and other biases. For each of these components, we assigned a judgement regarding the risk of bias as yes, no, or unclear (Higgins 2011). We recorded our judgements and justifications in risk of bias tables accompanying the characteristics of each included study and summarized the findings in a risk of bias summary figure.
Measures of treatment effect
TK and PT independently entered data and this was checked by all authors. We compared dichotomous outcomes using the risk ratio (RR) and we presented all results with their 95% confidence interval (CI) values.
Unit of analysis issues
If studies employ cluster randomizations (such as randomization by family, household, or institution), pooling of clustered data may pose problems if the reported analyses have not accounted for the clustering effect. Failing to account for intra-class correlation in clustered studies, leads to a unit of analysis error (Divine 1992) whereby P values are spuriously low and, CI values unduly narrow. When results had been adjusted for clustering, we attempted to extracted the point estimate and the 95% CI. If results had not adjusted for clustering, or were otherwise not usable, we attempted to account for clustering using methods described in the Cochrane Handbook, Chapter 16.3.4 and 16.3.5 (Higgins 2011b). When this was not possible (eg cluster sizes or number of clusters were not reported, loss of clusters were large, or the number of missing clusters were unknown), we extracted the data as for the individually randomized trials and used it in a sensitivity analysis.
Dealing with missing data
We attempted to obtain missing data from study authors. We conducted an intention-to-treat analysis in trials with no loss to follow-up and completed case analysis for trials with incomplete follow-up. We made no assumptions about those lost to follow-up but utilised this information in assessing risk of attrition bias due to incomplete outcome data reporting and in grading the overall quality of evidence for each outcome.
Assessment of heterogeneity
We assessed heterogeneity between the trials by examining forest plots for inconsistency in the direction or magnitude of the effect estimates, with non-overlapping CIs. We used the Chi
In general, we interpreted an I
Assessment of reporting biases
We would have evaluated the possibility of publication bias by the use of funnel plots, had there been 10 or more trials in a meta-analysis.
We synthesised comparable data using the Mantel-Haenszel method to derive pooled, weighted risk ratios in fixed-effect meta-analyses. We used the random-effects model for data synthesis when heterogeneity was identified as significant (see above) and could not be explained by subgroup analyses (see below). If I
Subgroup analysis and investigation of heterogeneity
When data were available, we explored potential sources of heterogeneity in the following subgroup analyses for the primary outcome measure: participant age (children < 18 years versus adults); presence of underlying systemic or pulmonary diseases (eg silicosis or chronic renal failure on haemodialysis); and treatment duration.
Where there were sufficient data, we undertook sensitivity analyses to investigate the robustness of the results to the exclusion of trials at high risk of bias.
Summarising and interpreting results
We used the GRADE approach to interpret findings (Schunemann 2008) and used GRADE Profiler (GRADE 2004) to import data from Review Manager (RevMan) to create 'Summary of findings' tables for each comparison included in this review. These tables provide information concerning the overall quality of the evidence from the trials, the magnitude of effect of the interventions examined, and the sum of available data on the primary outcome and selected secondary outcomes. The outcomes selected for inclusion in these tables that were rated important or critically important to clinical decision-making were: development of active TB; adherence; treatment-limiting adverse events; and hepatotoxicity. This summary was used to guide our conclusions and recommendations.
Description of studies
Results of the search
We retrieved 615 reports by our searches performed between November 2008 to December 2012. After we removed duplicates and excluded irrelevant reports, we identified 72 potentially relevant records and we obtained full text reports. We selected 10 RCTs for inclusion and we have shown the selection process in Figure 1.
|Figure 1. Study flow diagram.|
The 10 RCTs (detailed in 17 reports) that met the inclusion criteria for this review are described in the Characteristics of included studies table. Salient features summarized below.
Participants, interventions, and comparisons
The 10 included trials randomized 10,717 participants to four sets of interventions. Eight trials randomized individuals, one trial (Tortajada 2005) randomized households (by index case), and one trial (Sterling 2011) randomized households as well as individuals.
1. Rifampicin monotherapy versus INH monotherapy
Five trials randomized 1781 participants to rifampicin (N = 891) given daily for three months (HKCS 1992) or for four months (Magdorf 1994; Menzies 2004; Menzies 2008; Chan 2012) versus INH monotherapy (N = 890) given daily for six months (HKCS 1992; Magdorf 1994; Chan 2012) or for nine months (Menzies 2004; Menzies 2008).
HKCS 1992 was a four-armed trial (rifampicin versus INH versus INH plus rifampicin versus placebo) conducted in 589 adult Chinese males with exposure to silica dust or with silicosis attending a special pneumoconiosis clinic in Hong Kong, who had no history of treatment for TB, and who had active TB ruled out by clinical assessment, three sputum smears and culture for M. tuberculosis. At inclusion, 94% of participants had a TST reaction of ≥ 10 mm. Participants were followed up for two to five years. Of the 159 people randomized to placebo only (data not used in quantitative synthesis in this review), 36 (23%) developed active TB over five years' follow-up; an indication of the high risk that those with silicosis and LTBI in this trial had of progression to TB.
Magdorf 1994 was a three-armed trial (rifampicin versus INH versus rifampicin plus pyrazinamide) conducted in Germany that randomized 150 boys and girls less than 18 years of age with a normal chest radiograph and who were TST convertors within the previous 24 months. Participants were followed up for two years.
Menzies 2004 randomized adult males and females with a positive TST who were referred for LTBI treatment by physicians to a university-associated respiratory clinic in Quebec, Canada, and who were not contacts of people with INH resistance, allergic to rifampicin, or taking drugs likely to interact with rifampicin. Of the 116 people randomized, 110 had a TST reaction of ≥ 10 mm. Participants were followed up until treatment completion (four months in the rifampicin arm and nine months in the INH arm).
Menzies 2008 included adult male and female participants from nine university affiliated hospitals in Brazil (1), Canada (7), Saudi Arabia (1), with similar inclusion and exclusion criteria, study design, aims, and duration of follow-up as in Menzies 2004. Of the 847 randomized participants, 804 had a TST reaction of ≥ 10 mm. Both these trial reports did not mention methods used to rule out those with active TB at inclusion.
Chan 2012 recruited consenting adult male prisoners in Taipei, Taiwan who were TST-positive and Quantiferon Gold Positive, and had no evidence of active TB, HIV infection, or liver disease. They were randomized to receive INH daily for six months or rifampicin daily for four months. The primary outcomes were safety and adherence as assessed at the end of treatment in each group. Patients were followed up for three years for efficacy and though data for this secondary outcome was not published in the trial report, Dr. Chan kindly provided us data on the development of active TB in those followed up.
The HIV status of participants were not reported in two trials (HKCS 1992; Magdorf 1994). In Menzies 2004 and Menzies 2008, randomization was stratified by the risk of developing active TB, with HIV infection considered a high risk factor; however, the former did not report the inclusion of any participant with HIV infection. Menzies 2008 enrolled six HIV-positive participants (1%) to rifampicin and seven (2%) to INH.
2. Rifampicin plus INH versus INH
Two trials randomized 536 people to receive a combination of rifampicin plus INH (N = 265) given daily for three months versus daily INH (N = 271) for six months (HKCS 1992) or for nine months (Martinez Alfaro 1998).
HKCS 1992 (described above) had one trial arm where 167 of the 589 randomized participants in this four-armed trial took rifampicin and INH daily for three months.
Martinez Alfaro 1998 was conducted at a general hospital in the Albacete province in Spain and randomized 196 people of all ages and both genders. The detailed inclusion and exclusion criteria are described in Characteristics of included studies The duration of follow-up was 19 ± 11 months in the INH plus rifampicin arm and 16 ± 10 months in the INH arm. Those randomized to INH were all adults.
3. Rifampicin plus pyrazinamide versus INH
Four trials (Magdorf 1994; Leung 2003; Sanchez-Arcilla 2004; Tortajada 2005) that randomized 661 participants evaluated rifampicin and pyrazinamide (N = 347) given daily for two months or to INH daily (N = 384) for six months.
Magdorf 1994 (described above) randomized 150 children who were TST convertors in the previous two years to three interventions where 50 children in one arm were given rifampicin plus pyrazinamide daily for two months.
Leung 2003 recruited 77 Chinese adults (mostly males) with clinical and radiological evidence of silicosis attending the pneumoconiosis clinic of the department of health in Hong Kong, China, with a TST reaction of ≥ 10 mm. The report followed participants to treatment completion but the senior author of the report provided us with unpublished data on follow-up to five years.
Neither trial specified HIV-infection as an exclusion criterion, nor did they report if any participant was tested for HIV infection or were HIV-positive.
Sanchez-Arcilla 2004 randomized 172 homeless adult men and women recruited from government-run and charitable shelters in Madrid, Spain, with a TST reaction > 5 mm. Apart from a positive TST in all, 105 (61%) had at least one risk factor for LTBI. One participant in each arm was HIV-positive. The duration of follow-up was six months in the INH arm, and two months in those given rifampicin plus pyrazinamide.
Tortajada 2005 randomized 352 adults and children older than one year who were contacts of an infectious person with TB, was TST-positive, and met criteria for treatment of LTBI. None were HIV-positive. The trial was stopped prematurely after an interim evaluation due to unexpectedly high rates of liver toxicity. Duration of follow-up was unclear, and was likely to have to have been unequal for all participants due to the premature termination while recruitment had not been completed,
4. Rifapentine plus INH once a week (DOT) for three months versus daily INH daily (self administered) for nine months
Sterling 2011 is the primary publication of an ongoing trial, PREVENT-TB, (NCT00023452) that is due to be completed in 2013. This open-label, randomized, non-inferiority trial, compared three months of DOT once-weekly with rifapentine (900 mg) plus INH (900 mg) (combination-therapy group) with nine months of self-administered daily INH (300 mg) (INH-only group) in 7799 people at high risk for TB who fulfilled eligibility criteria (of 8053 initially randomized) from 26 centres in four countries: USA (21), Canada (3), Brazil (1), Spain (1). Children over two years of age were eligible but the proportions of children among those randomized was unclear. One hundred participants (2.7%) in the INH only arm and 105 (2.6%) in the combination arm were HIV-positive. The primary end point was confirmed TB, and the non-inferiority margin was 0.75%. Participants were followed up for 33 months after enrolment.
This trial used a combination of cluster and individual randomization; close contacts of the first eligible person in a household were randomized by household, and other high-risk participants who were not part of a household were randomized individually. The number of participants randomized in clusters were 1345 of 3986 (33.7%) in the combination-therapy arm and 1050 of 3745 (28%) in the INH-only arm.
Three trials (Sanchez-Arcilla 2004; Menzies 2008; Sterling 2011) did not report data separately for HIV- positive and HIV-negative participants, but we do not feel that the small proportions of HIV-positive individuals (2% in total) included in the three trials biased our analyses.
Five trials reported on the development of active TB (HKCS 1992; Magdorf 1994; Leung 2003; Tortajada 2005; Sterling 2011). Of these, Magdorf 1994 did not report the definition used for the diagnosis of active TB. HKCS 1992 followed up participants with silicosis with bacteriological and radiological evaluations for active TB over two to five years after completion of treatment. The other trial in people with silicosis (Leung 2003,) followed up participants for active TB with sputum and radiological examinations up to treatment completion, but we were provided unpublished data on the yearly evaluations for up to five years of follow-up (courtesy of Dr Leung). Tortajada 2005 did not provide criteria used for the diagnosis of active TB and had unequal ascertainment periods due to premature termination of the trial. The average duration of follow-up was also not reported in the trial. Sterling 2011 supplemented active follow-up of participants in US and Canada with passive follow-up of national US and Canadian TB databases. Chan 2012 provided unpublished data on follow-up by active case finding (clinical, X-ray; sputum culture) for three years. It was unclear if all trials used procedures that strictly adhered to ATS 1990 criteria
Of the remaining four trials, Martinez Alfaro 1998 evaluated efficacy by evaluating the diameter of induration produced by the TST following the course of treatment and at follow-up time points; we did not use this data in quantitative synthesis in this review. Efficacy was not a stated objective of Menzies 2004; Menzies 2008; and Sanchez-Arcilla 2004.
Of the secondary outcomes for this review some reported TB-related deaths and non-TB deaths, while Sterling 2011 provided data for all-cause deaths. HKCS 1992; Leung 2003; and Sterling 2011 reported the development of drug resistant TB including MDR-TB; none of the trials reported XDR-TB.
All the trials reported on adherence to treatment. All trials reported adverse events and serious adverse events, and treatment-limiting adverse events. The definitions used and methods to ascertain these outcomes differed and are described in Appendix 2.
Tortajada 2005 reported adjusted odds ratios and 95% CI that were adjusted for clustering, but we were not able to use these adjusted estimates since RRs were the effect measures used in this review. We were unable to use methods described in Chapter 16.3.4 and 16.3.5 of the Cochrane Handbook (Higgins 2011b) to extract reported data to adjust for clustering and compute adjusted RRs, since the number of clusters were not reported. Even if we had approximated this information from the data provided, the number of missing clusters were also not known, due to the premature termination of the trial and the unequal follow-up periods of participants. Imputing data from cluster randomized trials in such circumstances are more prone to error than when data are missing in cluster randomized trials at random or are co-variate dependant (Ma 2011), We therefore extracted data as for individual RCTs. The outcomes of hepatotoxicity, and other adverse events are less likely to be significantly correlated within individuals in clusters, while a cluster effect is more likely for outcomes such as development of active TB and adherence. None of the included participants developed TB in this trial. For adherence, we assessed the impact on the pooled effect estimates in sensitivity analyses of the inclusion and exclusion of the adherence data from this trial that were not adjusted for a cluster effect.
We excluded 50 reports pertaining to 47 studies. Two were not interventional studies; seven were not RCTs; and three were quasi-RCTs. Thirty-eight reports pertaining to 36 RCTs did not fulfil the inclusion criteria of our review (see Characteristics of excluded studies for further details).
The three ongoing trials aim to recruit over 6920 participants randomized to rifampicin given daily for four months versus INH for nine months and anticipate completing recruitment in 2013 (NCT01398618), 2014 (ISRCTN53253537), and 2016 (NCT00931736). Further details are provided under Characteristics of ongoing studies.
Studies awaiting classification
One RCT (White 2012) registered retrospectively (NCT00128206) was conducted among adult prisoners in San Francisco City and Country Jail diagnosed with LTBI at jail entry. The trial evaluated INH 900 mg DOT given twice weekly for nine months with daily rifampicin 600 mg. Of 364 randomized, only 29% (107) completed therapy (26% (47 of 184) of INH participants and 33% (60 of 180) of rifampicin participants. In addition to very high attrition and the non-standard administration of INH and rifampicin in this trial, compared to the other included trials of INH versus rifampicin there were discrepancies regarding primary and secondary outcomes, and the estimated sample size within the registration document and between the registration document and the trial publication. Drug toxicity, adherence, cost-effectiveness, reasons for non-completion, and efficacy are outcomes listed in the trials registration document, but data for cost effectiveness and efficacy are not available in the trial publication or in the results posted in the trials registry. In addition, 178 of those recruited were transferred or deported from prison (nearly 50%) and were classified as non-adherent, raising serious doubts as to the validity of the data on adherence. We shall decide on inclusion of the results of this trial in future updates of this review once clarifications are received from trial authors.
Risk of bias in included studies
The assessments regarding the risk of bias for all included studies are depicted in Figure 2; assessments for included trial are available in the "Risk of Bias" tables accompanying each study's characteristics and are summarised in Figure 3.
|Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
|Figure 3. Forest plot of comparison: 1 Rifampicin versus INH, outcome: 1.3 Adherence.|
Six of the included studies were judged to be free of the risk of bias for sequence generation and allocation concealment (HKCS 1992; Leung 2003; Menzies 2004; Menzies 2008; Sterling 2011; Chan 2012). Tortajada 2005 was judged free of bias for sequence generation but at high risk of selection bias due to inadequate allocation concealment. Three trials (Magdorf 1994; Martinez Alfaro 1998; Sanchez-Arcilla 2004) provided inadequate details to assess adequacy of allocation concealment and were judged unclear with regard to the risk of selection bias.
Efficacy outcomes: active TB, drug-resistant TB, and adherence
We judged seven of the included trials to be free of the risk of performance and detection bias with regard to efficacy outcomes. We judged one open-label trial (Martinez Alfaro 1998) as not free of the risk of bias with respect to self-reported adherence, and use of post-treatment TST diameter as a proxy indicator of active TB. The latter, apart from doubtful validity as an indicator of active TB after chemoprophylaxis, is at risk of bias due to knowledge of treatment allocation. Sanchez-Arcilla 2004 was also judged to be at high risk of detection bias for adherence due to selective supervision of only those with features of liver disease. Tortajada 2005 was judged unclear for detection bias.
Adverse events: hepatotoxicity, serious adverse events, and treatment-limiting adverse events
Three trials (Magdorf 1994; Chan 2012; and Tortajada 2005) were judged unclear. We judged four other open-labelled trials (Menzies 2004; Sanchez-Arcilla 2004; Menzies 2008; Sterling 2011) as at high risk of detection bias in ascertaining serious adverse events.
Incomplete outcome data
Martinez Alfaro 1998 did not report treatment allocation of the one participant who developed active TB. It is also unclear whether all patients were evaluated for active TB using standard clinical methods; the proxy measure reported was not used in this review. Sanchez-Arcilla 2004 was also judged at high risk of attrition bias due to high differential drop-out rates in the two intervention arms. Tortajada 2005 was judged unclear for risk of attrition bias due to the premature termination due to hepatotoxicity and the resultant loss of an unknown number of clusters.
Other potential sources of bias
It was unclear whether the randomization procedures in Sterling 2011, which used a combination of cluster and individual randomization, led to biased efficacy estimates since analysis did not account for a cluster effect. However, a sensitivity analysis in the report that excluded those randomized in clusters did not alter effect estimates.
We judged Tortajada 2005 as unclear for other potential sources of bias due to the loss of clusters resulting from those that were not adjusted for clustering, and detail the methods used to deal with potential biases under outcomes in the description of Included studies. All the other trials appeared free of other potential sources of bias.
Effects of interventions
See: Summary of findings for the main comparison Rifampicin compared to isoniazid for preventing active TB in HIV-negative people; Summary of findings 2 Rifampicin plus isoniazid compared to isoniazid for preventing active TB in HIV-negative people; Summary of findings 3 Rifampicin plus pyrazinamide compared to isoniazid in preventing active TB in HIV-negative people; Summary of findings 4 Rifapentine plus isoniazid weekly compared to isoniazid daily for preventing active TB in HIV-negative people at risk of TB infection
1. Rifampicin versus INH
Five trials provided data for this comparison. See Summary of findings for the main comparison for details of relative and absolute effects of the interventions linked to the overall quality of evidence for critically important and important outcomes.
Three trials evaluated the development of TB but only one trial including adult Chinese men with silicosis and LTBI (HKCS 1992) reported that active TB developed over five years follow-up. The other two trials did not detect active TB over three years' follow-up in prisoners with LTBI (Chan 2012), or over two years' follow-up in children and adolescents at risk (Magdorf 1994). Rifampicin 600 mg/day given for three months did not differ significantly from INH 300 mg/day given for six months in proportions developing active TB (one trial, 332 participants, Analysis 1.1: subgroup 1.1.1). The cumulative percentage of active TB in those participants in this trial (HKCS 1992) evaluated over five years among those who completed their treatment without known interruption (rifampicin 142/165; INH 123/167) also did not differ significantly (rifampicin 10%, INH 14%).
One arm of the four-arm HKCS 1992 trial randomized 159 participants to matching placebo for rifampicin and INH (not included in the quantitative synthesis in this review). Of the 159 participants randomized to placebo 36 (23%) developed active TB, compared to 12% in the rifampicin arm and 15% in the INH arm.The cumulative percentage of those developing active TB over the five years among 133 participants on placebo who completed their treatment without interruption was 27%.
The use of rifampicin in these trials was not reported to be associated with the emergence of rifampicin resistance, though only HKCS 1992 specifically reported on follow-up to monitor drug resistance. In this trial, two of 34 participants who developed active TB were found to be INH-resistant, and none were rifampicin-resistant ( Analysis 1.2).
In four trials comparing three to four months of rifampicin versus six to nine months of INH in adults (Chan 2012; HKCS 1992; Menzies 2004; Menzies 2008), those allocated to rifampicin were more likely to be adherent (RR 1.19, 95% CI 1.10 to 1.30; four trials, 1668 participants, Analysis 1.3: subgroup 1.3.1; Figure 3). There was a trend towards better compliance with rifampicin in the trials with INH given for nine months compared to INH given for six months but the results were not consistent (I
Adherence did not significantly differ between rifampicin given for four months compared to INH given for six months in the small trial (Magdorf 1994) that recruited only children (one trial, 100 participants, Analysis 1.3; subgroup 1.3.2; Figure 3).
Rifampicin reduced the risk ofserious adverse events by 64% compared to INH in adults (RR 0.36, 95% CI 0.17 to 0.77; two trials, 956 participants, Analysis 1.4).
The point estimate for treatment-limiting adverse events from the four trials that provided data for this outcome also favoured rifampicin but the 95% CI did not rule out random error (RR 0.48, 95% CI 0.23 to 1.00; four trials, 1674 participants; Analysis 1.5). The results were inconsistent (I
Rifampicin also consistently reduced the risk of severe hepatotoxicity by 88% in the four trials in adults (best estimate of relative risk reduction: 95%; worst estimate: 70% relative risk reduction) compared to INH (RR 0.12, 95% CI 0.05 to 0.30; four trials, 1674 participants, Analysis 1.6; Figure 4). The trial with the greatest relative risk reduction for hepatotoxicity was Chan 2012, where the higher frequency of HCV infection in those given INH for 6 months, is likely to have contributed to the differential risk of hepatotoxicity. Only one child on rifampicin was detected to have developed liver toxicity in Magdorf 1994 (one trial, 100 children, Analysis 1.6: subgroup 1.6.2),
|Figure 4. Forest plot of comparison: 1 Rifampicin versus INH, outcome: 1.6 Hepatotoxicity.|
No significant differences in event rates were reported for other adverse events includinggastrointestinal intolerance (three trials, 1535 participants, Analysis 1.7), rash (two trials, 1213 participants, Analysis 1.8), haematological adverse events (one trial, 840 participants, Analysis 1.9), and for any adverse event (one trial, 322 participants, Analysis 1.10).
No data were reported on all cause mortality, deaths due to TB, or due to either drug.
2. Rifampicin plus INH versus INH alone
Only one four-arm trial in silicosis patients reported this outcome (HKCS 1992). As with the comparison between rifampicin alone versus INH alone, the addition of INH 300 mg/day to rifampicin 600 mg/day for three months did not significantly reduce the risk of developing active TB when compared to INH 300 mg/ day given for six months (one trial, 328 participants, Analysis 2.1). However, analyses comparing the effects of INH plus rifampicin versus the placebo arm in the trial did reveal (as with rifampicin alone) significant reductions in the cumulative risk of active TB over five years of follow-up in 123/161 adults with silicosis who completed treatment with INH plus rifampicin with no known interruptions (16%) versus those who completed uninterrupted treatment with placebo (27%).
Only HKCS 1992 reported data for this outcome and none of the adult men with silicosis given rifampicin plus INH or INH alone developed active TB with rifampicin-resistant mycobacteria. In the arm given rifampicin plus INH, two people had INH-resistant TB, while five of those given INH alone had INH-resistant TB. No instance of rifampicin resistance was detected ( Analysis 2.2).
In pooled data from HKCS 1992 and Martinez Alfaro 1998, adherence did not significantly differ in those given rifampicin plus INH for three months versus INH for six months or nine months (two trials, 524 participants, Analysis 2.3). Though there was a trend toward better adherence with rifampicin plus INH for three months in Martinez Alfaro 1998, where nine months of INH was used ( Analysis 2.3: subgroup 2.3.2) the lower limit of the 95% CI included no difference and the test for subgroup differences did not exclude random error (P = 0.3).
INH added to rifampicin for three months did not significantly differ from INH given alone for six to nine months in the proportions developing serious adverse events (one trial, 196 participants, Analysis 2.4), treatment-limiting adverse events (two trials, 536 participants, Analysis 2.5); hepatotoxicity (two trials, 536 participants, Analysis 2.6); gastrointestinal intolerance (two trials, 510 participants, Analysis 2.7); or any adverse event (one trial, 314 participants, Analysis 2.8).
No deaths were reported in these trials.
3. Rifampicin plus pyrazinamide versus INH
Three trials reported this outcome. Tortajada 2005 did not detect any participant with TB during this trial that was stopped early for harms; hence comparative efficacy could not evaluated. The proportions who developed active TB over two to five years' follow-up in adults with silicosis (Leung 2003) and in children (Magdorf 1994) did not significantly differ in those given rifampicin plus pyrazinamide compared to those given INH alone (two trials, 176 participants, Analysis 3.1).
The pooled data from four trials did not reveal significant differences in adherence to rifampicin plus pyrazinamide or to INH (four trials, 700 participants, Analysis 3.3; Figure 5). Tests for subgroup differences between trials in adults and children were not statistically significant (P = 0.56), but the results of the trials in adults ( Analysis 3.3: subgroup 3.3.1) were not consistent in the direction of effects (I
|Figure 5. Forest plot of comparison: 3 Rifampicin plus pyrazinamide versus INH, outcome: 3.3 Adherence.|
In sensitivity analysis, removal of the data for adherence from Sanchez-Arcilla 2004 from the pooled estimates resulted in consistent results (I
None of the included trials reported serious adverse events.
Treatment-limiting adverse events were significantly more frequent with rifampicin plus pyrazinamide than with INH (19% versus 5%; RR 3.61, 95% CI 1.82 to 7.19; two trials, 368 participants, Analysis 3.4).
Hepatotoxicity was not detected in Magdorf 1994 in 100 children randomized to rifampicin plus pyrazinamide or to INH, and comparative safety could not be evaluated. The three trials in adults reported hepatotoxicity significantly more frequently in those randomized to rifampicin plus pyrazinamide than to INH (11% versus 2%; RR 4.59, 95% CI 2.14 to 9.85; four trials, 540 participants, Analysis 3.5, Figure 6). This is likely to be an underestimate since in Sanchez-Arcilla 2004, hepatotoxicity was reported only for people who completed the trial among those randomized; and overall attrition was high (35%), with no data available about those lost to follow-up.
|Figure 6. Forest plot of comparison: 3 Rifampicin plus pyrazinamide versus INH, outcome: 3.5 Hepatotoxicity.|
At least one adverse event was reported significantly more frequently in Tortajada 2005 in people on rifampicin and pyrazinamide than in those on INH (RR 1.71, 95% CI 1.24 to 2.35; one trial, 292 participants; Analysis 3.6).
Gastrointestinal intolerance were significantly more frequent with the combination than with INH (RR 2.19, 95% CI 1.37 to 3.49; two trials, 368 participants; Analysis 3.7)
Nodeaths were reported in these trials.
4. Rifapentine plus INH once a week (DOT) for three months versus daily INH daily (self administered) for nine months
This trial that was designed to demonstrate the non-inferiority of 12 doses of rifapentine plus INH DOT given weekly over three months compared to 270 doses of daily, self-administered INH over nine months. TB developed in seven of 3986 people (0.2%) in the combination treatment arm versus 15 of 3745 people (0.4%) in the INH arm over 33 months of follow-up after enrolment (one trial, 7731 participants, Analysis 4.1). Of those who took 100% of treatment doses, TB developed in five of 3376 subjects (0.1%) in the combination-therapy arm versus six of 2792 (0.2%) in the INH-only arm.
The combination-therapy was consistently non-inferior to the INH-only regimen in the primary analysis where the upper limit of the 95% CI of the difference was set at < 0.75%, and in sensitivity analysis when this was reduced to < 0.50%.
In this trial, close contacts of the first eligible person in a household were randomized by household, and other high-risk participants who were not part of a household were randomized individually. The risk of developing TB was similar when the results included only the first person randomized in a household, in sensitivity analysis done to adjust for the effects of clustering. The results were also similar after 24 months of follow-up after the last treatment. TB incidence rates did not differ disproportionately between the study sites in the US, Canada, Brazil, or Spain.
Sterling 2011 reported no significant difference between interventions in all cause mortality (31/3986 (0.7%) versus 39/3745 (1%)) during therapy or within 60 days of treatment (one trial, 7731 participants, Analysis 4.2). None of these deaths were attributed to TB or to any of the study medications.
One of the seven people who developed active TB (M. bovis on culture) in the combination treatment arm was HIV-positive with a CD4+ count of 271 per cubic mm at enrolment and completed treatment after many interruptions. The isolate was found to be rifapentine resistant. Of the 15 people in the INH alone arm who developed active TB, two had INH-resistant M. tuberculosis strains ( Analysis 4.3).
Adherence rates were significantly greater in those given the combination treatment by DOT (82%) compared to self-administered INH (69%) (RR 1.19, 95% CI 1.16 to 1.22; one trial, 7731 participants, Analysis 4.4).
The combination treatment was associated with significantly fewer severe adverse events (1.6%) than INH alone (2.8%) (RR 0.55, 95% CI 0.44 to 0.74; one trial, 7799 participants, Analysis 4.5).
However, more people receiving the combination treatment had treatment-limiting adverse events that led to permanent discontinuation (4.9%) compared to those on INH alone (3.7%) (RR 1.32, 95% CI 1.07 to 1.64; one trial, 7731 participants, Analysis 4.6).
The rifapentine combination was also associated with more frequent symptoms that were considered possible hypersensitivity reactions (3.8%) than with INH alone (0.5%) (RR 8.32, 95% CI 5.05 to 13.71; one trial, 7799 participants, Analysis 4.7). Six of the 152 people with possible hypersensitivity reactions had hypotensive episodes.
The combination resulted in significantly fewer instances of severe hepatoxicity (0.4%) than with INH given for nine months (2.7%) (RR 0.16, 95% CI 0.10 to 0.27; one trial, 7799 participants; Analysis 4.8).
The interventions did not significantly differ in producing a rash (one trial, 7799 participants, Analysis 4.9).
Of the 7799 subjects who received at least one dose of a study drug, 1062 (13.6%) had one adverse event, and 194 (2.5%) had more than one adverse event. Overall, there was a small but statistically significant excess in the proportions on INH alone (17.6%) who reported any adverse event than on the rifapentine plus INH combination (14.7%) (RR 0.84, 95% CI 0.76 to 0.93; one trial, 7799 participants, Analysis 4.10).
This review includes 10 trials that randomized 10,717 participants, mostly HIV-negative adults and children (2% HIV-positive), who were followed up for two to five years. INH was compared to rifampicin or to a rifamycin-containing regimen in four sets of comparisons.
Summary of main results
Rifampicin versus INH
Four months of rifampicin and the standard INH treatment of six or nine months may not differ in preventing progression to active TB in HIV-negative people with LTBI. Rifampicin probably increases adherence and treatment completion compared to INH in adults. It is uncertain if treatment-limiting adverse events are any different, but rifampicin probably results in significantly less hepatotoxicity in adults (0.2% to 1.5%) than INH (5%). No instances of rifampicin resistance were observed in 40 people who developed active TB while on rifampicin. However, more evidence for its efficacy in adults and in children, particularly from high TB burden countries, would be required before it is considered as an routine alternative to, or replacement for, standard INH prophylaxis in people with LTBI.
Rifampicin plus INH versus INH alone
No benefit in preventing progression to active TB, increasing adherence, or reducing the frequency of treatment-limiting adverse events and hepatotoxicity was detected when INH was added to rifampicin for three months compared to treatment with INH alone for six to nine months. This indicates that rifampicin plus INH combination treatment may not be a better alternative to INH alone (or rifampicin alone) for people with LTBI.
Rifampicin plus pyrazinamide versus INH
Rifampicin plus pyrazinamide for two months may not differ from INH for six months in preventing active TB in HIV-negative people with LTBI, or in treatment completion compared to INH in spite of the shorter treatment duration. This drug combination also probably increases the risk of hepatotoxicity in adults, and increases the incidence of treatment-limiting adverse events; These attributes are not consistent with those required of a public health intervention for preventing active TB in people with LTBI.
Rifapentine plus INH weekly for three months (DOT) versus daily INH for three months (self-administered)
Twelve doses of rifapentine plus INH administered weekly by DOT over three months is probably an effective and safer alternative to INH given for nine months in HIV-negative people at risk, though more data on the safety of the combination in adults (particularly the risk of hepatotoxicity in women), as well as in children are needed. One case of rifapentine resistance was observed in an HIV-positive individual who had low CD4 counts, though none were observed in HIV-negative people who developed active TB. The effects of this intermittent regimen in high TB burden countries in Africa, in China, and in India also need to be evaluated before its widespread use outside low TB burden countries can be envisaged.
Overall completeness and applicability of evidence
We believe that we have identified all RCTs relevant to this review's objectives. The most important outcome when considering alternatives to INH is the development of active TB; yet, data for this outcome was reported only in three trial publications. Intermittent (twice weekly) rifampicin (600 mg) DOT in INH-resistant or intolerant cases, or when nine months of INH is not feasible; and rifabutin (300g) when rifampicin is contraindicated or not tolerated, are recommended by some guidelines (CDC 2000; NYC 2005). Another option proposed is self-administered INH plus rifapentine given daily for one month that was proven beneficial in the murine model (Zhang 2009), and postulated to be more cost effective than three months of weekly rifapentine plus INH, given by DOT or self-administered; and nine months of daily INH (Holland 2011). We did not find any RCTs comparing intermittent rifampicin, or rifabutin, or self-administered INH plus daily rifapentine, with standard INH prophylaxis in HIV-negative people with LTBI.
While reactivation of LTBI can occur any time in a person's lifetime, the risk is the highest in the early years after infection, particularly in children. The duration of follow-up in the included trials ranged from two years in the trial in children to three to five years in the trials in adults. Since these trials were conducted in low to moderate TB transmission settings, and in largely HIV-negative populations, the risk of re-infection as opposed to reactivation is likely to have been low.
However, for the same reasons, the results from these trials may not yield the same effect estimates in high TB burden countries in Africa and Asia (particularly China and India) where re-infection rates would be higher and co-morbid conditions that impair effectiveness such as nutritional and micronutrient deficiencies, are higher. These trials were also conducted in high- and middle-income countries where health systems arrangements and the delivery of care, such as the availability of resources to provide DOT effectively, may differ from those in low-income countries where treatment of active TB is a priority. There was also some variability in these trials regarding the diagnosis of LTBI, and the definitions used to diagnose active TB and in determining the incidence of hepatotoxicity. The data for children is from only one trial with a total sample size of 100. While the relative advantage in treatment completion and safety with the shorter rifampicin regimen over INH is likely to be seen even in low-income countries, these issues may limit the applicability of the evidence to resource-constrained countries with a high TB burden.
The trials included in the review excluded pregnant and lactating women, malnourished children, and children below two years of age, and this review does not provide evidence for the efficacy and safety of rifampicin in these vulnerable groups to inform clinical practice or policy. Similarly, data are insufficient to confirm or refute the efficacy and safety of rifapentine in young children below 12 years.
Ensuring adherence to shorter regimens for LTBI
Direct observation of short courses of rifampicin or 12 doses of weekly rifapentine plus INH is mandatory in order to ensure compliance with all doses, and is a factor that is critical to its efficacy. Several factors influence the acceptance of DOT in enhancing adherence and thereby cure in TB, including social and economic factors, the acceptance of the DOT provider, the location of treatment provision, the benefits provided, and the flexibility of the DOT service to individual needs (Noyes 2007; Volmink 2007). It is uncertain whether low-income, high TB burden countries can divert scarce resources from treating active TB to treating large numbers of asymptomatic people with LTBI.
Resource use and resource costs
Another factor that would influence the uptake of shorter rifampicin regimens over the standard nine months of INH in guidelines and policy is resource use and resource costs. While this review did not directly address economic outcomes, two of the trials in this review (Menzies 2008; Sterling 2011) provided additional information in supplementary reports on costs that would have a bearing on the uptake of these regimens in guidelines and in policy decisions.
A prospective examination of direct costs for scheduled and unscheduled visits from the perspective of the health care system in the high- and middle-income settings in the Menzies 2008 trial assumed the efficacy of rifampicin for four months and INH for nine months to be equivalent at 90% in the base case analysis, and sensitivity analyses to estimate the incremental cost-effectiveness ratio varied the efficacy of four months of rifampicin to as little as 60%. Four months of rifampicin was deemed to be cost saving while preventing more cases of TB reactivation, if its efficacy was 75% or greater. The difference in costs was primarily due to the greater number of scheduled clinic visits in the nine-month INH regimen, and also due to the greater number of unscheduled visits due to toxicity. All costs were in Canadian dollars in 2007, but rifampicin remained cost saving when costs where compared between centres in Canda and between centres in Canada and Brazil (Aspler 2010). Another decision analysis based on the same data concluded that four months of rifampicin was cost saving and more effective in preventing reactivation of TB at an efficacy threshold of 69% for rifampicin (Esfahani 2009). While other analyses have arrived at similar conclusions that four months of rifampicin is cost saving compared to nine months of INH (Holland 2009; Ziakas 2009), local cost variations for drugs and for monitoring, and variations in monitoring schedules, can alter these cost determinations. However, cost estimates based on actual efficacy estimates of the two regimens are currently unavailable, except from the limited data from one early trial in men with silicosis (HKCS 1992).
Rifapentine is more expensive than INH and the added costs incurred with direct observation of the combination suggest that rifapentine plus INH may not be cost effective. A formal cost-effectiveness analysis of Sterling 2011 is underway. However, a previous cost-effectiveness analysis using a computerized Markov model to estimate societal costs, concluded that rifapentine plus INH is cost saving for extremely high-risk patients and is cost-effective for lower-risk patients (Holland 2009). A subsequent re-analysis of cost-effectiveness also confirmed the cost-effectiveness of weekly rifapentine plus INH for three months versus nine months of INH (Holland 2011). However, the actual experience with this combination in real world settings outside a clinical trial, and careful monitoring for adverse events such as hypersensitivity reactions, hepatotoxicity, and other adverse events that may emerge when used widely in clinical practice, will inform decisions regarding cost-effectiveness of this intervention. Rifapentine is currently unavailable in many parts of the world, though the Centers for Disease Control (CDC) have recommended the use of the 12-dose weekly rifapentine and INH combination with DOT as an alternative regimen for treating LTBI (CDC 2011).
Additional barriers to the uptake of four months of rifampicin in treating LTBI is the fear of inadvertent treatment of active TB leading to the development of rifampicin resistance (Stout 2010), or the emergence of rifampicin resistance if rifampicin were to be more widely used for treating LTBI. While the trials in this review did not reveal that anyone given rifampicin developed resistance, rifampicin resistance does occasionally occur in the context of LTBI prophylaxis particularly in immuno-compromised people (Ridzon 2005); thus, careful selection of people with LTBI for rifampicin prophylaxis would be necessary. Ensuring compliance would also be important if four months of rifampicin were to become standard treatment for LTBI, as interrupted courses of treatment would increase the potential for the emergence of widespread resistance to rifampicin. If this were to occur, then any potential cost savings with four months of rifampicin would be rapidly offset by the costs of treating rifampicin resistance (Stout 2010).
However, given the growing prevalence of resistance to INH (WHO 2004), it is estimated that active case detection and treatment of LTBI with a non-INH regimen would lead to substantial health benefits (Khan 2002). The shorter duration of treatment with four months of rifampicin; comparable efficacy with INH; less frequent and less toxic adverse events with rifampicin; greater preference expressed among diverse populations for the shorter regimen; and their willingness to complete treatment even in the face of adverse events; greater feasibility to supervise the shorter course; and greater incremental cost-effectiveness (particularly in populations with high INH resistance) are potential reasons advanced to consider four months of rifampicin as standard treatment for LTBI prophylaxis (Reichman 2004).
Quality of the evidence
The assessments of the overall quality of the evidence were made using the GRADE approach (Schunemann 2008). The GRADE approach considers ‘quality’ to be a judgment of the extent to which we can be confident that the estimates of effect are correct. 'Quality’ is graded for each pre-selected outcome on five domains. Evidence from randomized controlled studies is initially graded as high and downgraded by one or two levels on each domain after full consideration of: any limitations in the design of the studies, the directness (or applicability) of the evidence, the consistency and precision of the results, and the possibility of publication bias. This results in an assessment of the quality of a body of evidence ashigh, moderate, low, orvery low. A GRADE quality level of 'high' reflects confidence that the true effect lies close to that of the estimate of the effect for an outcome. A judgement of 'moderate' quality indicates that the true effect is likely to be close to the estimate of the effect, but acknowledges the possibility that it is substantially different. 'Low' and 'very low' quality evidence limit our confidence in the effect estimate (Balshem 2011).
These judgements for pre-selected patient-important outcomes for each comparison in this review are presented in the 'Summary of findings' tables.
The evidence for the efficacy of shortened prophylactic regimens of rifampicin versus INH in LTBI was downgraded for indirectness since the results of the sole trial with useable data was conducted in adults with silicosis in Hong Kong over 20 years ago, and may not readily generalise to other settings today. We also downgraded the quality of evidence for imprecision, since the single trial that provided effect estimates was underpowered to rule out clinically important differences. We judged the resulting imprecision in the effect estimate, indicating appreciable benefit with both interventions, to be very serious and downgraded the evidence by two levels, following guidance in Guyatt 2011. The overall quality of the evidence for treatment limiting adverse events was also downgraded to 'very low' due to serious study limitations, inconsistency and imprecision. Evidence graded as 'moderate' quality for adherence and for hepatotoxicity suggests reasonable confidence in the estimates of better adherence and less frequent liver toxicity with rifampicin monotherapy compared to INH ( Summary of findings for the main comparison).
The overall quality of evidence for all outcomes in the comparison of rifampicin plus INH versus INH alone was graded 'low' to 'very low' for similar reasons, except for adherence where 'high quality' evidence indicates confidence in the estimates that adherence was not significantly different with the two treatment regimens ( Summary of findings 2). The overall quality of the evidence indicating no significant difference with rifampicin plus pyrazinamide versus INH for preventing active TB and for adherence was graded 'low' or 'very low'; but the evidence for safety outcomes was graded 'moderate to high quality' ( Summary of findings 3).
The evidence that a shortened course of weekly rifapentine plus INH is non-inferior to nine months of INH in preventing active TB was judged to be of moderate quality; the main factor limiting full confidence in this estimate was the uncertainty in generalising this result from settings with low to moderate TB incidence (North America, Europe and Brazil), to settings with higher TB incidence (Africa and Asia), and the limited data available to date regarding the effects of the weekly combination treatment in children ( Summary of findings 4).
Potential biases in the review process
We used standard methods described in the Cochrane handbook for systematic reviews of interventions (Higgins 2011a), and complied with the Cochrane Collaboration's methodological standards for the conduct of new reviews of interventions (MECIR 2011).
Agreements and disagreements with other studies or reviews
Rifampicin versus INH
The results of Ziakas 2009, a meta-analysis of data from four studies (3336 participants), concluded that four months of treatment with rifampicin was associated with about half the non-completion rate of nine months of INH treatment and 12% the risk of hepatotoxicity. Although two of the included studies were retrospective comparisons, these results are in agreement with the results from our review.
Guidance for treatment of LTBI in the UK (NICE 2011) recommends either six months of INH or three months of rifampicin and INH for adults and children not known to have HIV infection. Four months of rifampicin finds no place as an alternative in these guidelines. NICE 2011 does recommend six months of rifampicin for contacts, aged 35 or younger, of people with INH-resistant TB. In contrast, the rifampicin plus INH combination finds no place in the CDC guidelines, though four months of rifampicin does (CDC 2011).This review found that the liver toxicity of the combination of rifampicin plus INH was around 5% and similar to that seen with INH; and there was no advantage with the combination over INH alone in treatment completion rates. Rifampicin alone for four months has better adherence and less hepatotoxicity than INH, though there is insufficient high quality evidence regarding efficacy as yet.
Rifampicin plus INH versus INH
Four trials with 1601 participants comparing rifampicin plus INH to INH monotherapy were included in a systematic review (Akolo 2010). Among HIV-positive people, the efficacy of INH plus rifampicin was similar to that of INH monotherapy, while the treatment-limiting adverse events were significantly greater with the combination than with placebo, but not significantly different compared to INH. The effects of rifampicin plus INH on active TB and treatment-limiting adverse events among HIV-negative people in our review were similar to that observed among HIV-positive people in Akolo 2010. Another systematic review by Ena 2005 included trials comparing rifampicin plus INH with INH monotherapy irrespective of the HIV status of the participants. Ena 2005 included the two RCTs on HIV-negative people included in the present review, and three of the four RCTs included in Akolo 2010. The results in Ena 2005 on the effects of rifampicin plus INH on active TB and treatment-limiting adverse events were similar, compared to INH monotherapy, and were also concordant with the results of our review. However, the conclusions we draw with regard to its continued use for LTBI prophylaxis are based on the higher risk of hepatotoxicity with the combination that are similar to the risk with INH and greater than the risk with rifampicin alone.
Rifampicin plus pyrazinamide versus INH
The results of this review are in broad agreement with that of the systematic review and meta-analysis by Gao 2006 on the efficacy of rifampicin plus pyrazinamide for the prevention of active TB that included both HIV-negative as well as HIV-positive people. Notwithstanding differences in trial selection, the conclusions in Gao 2006 that rifampicin plus pyrazinamide was associated with a significantly higher risk of severe hepatotoxicity and severe adverse events among HIV-negative people, are in agreement with the conclusions in this review.
The Cochrane Review on the prevention of TB among HIV-positive people (Akolo 2010) reported that rifampicin plus pyrazinamide was similar in efficacy to INH monotherapy in preventing active TB (five trials including 3409 participants), with a 37% lower risk of treatment-limiting adverse events in the INH arms (five trials including 3409 participants). The effects of rifampicin plus pyrazinamide on active TB and treatment-limiting adverse events among HIV-negative people in our review are similar to that observed among HIV-positive people in Akolo 2010.
Weekly rifapentine plus INH
Based on the results of Sterling 2011 (and guided by the results of Schechter 2006 and Martinson 2011), rifapentine plus INH given as 12 weekly doses with DOT is now recommenced by the CDC as an alternative treatment regimen to standard INH in preventing active TB in otherwise healthy HIV-negative people above 12 years of age with LTBI, and in HIV-positive people who are not on antiretroviral agents (CDC 2011). The combination is also recommended for people who are less likely to complete a six or nine-month course of INH, where 12 supervised weekly doses may confer practical advantages, such as people in correctional facilities, in shelters, or recent immigrants who may have a high prevalence of LTBI infection. Expert opinion from the CDC panel recommends the use of the combination on a case by case basis for people not represented in the PREVENT-TB trial, including those with risk factors such as diabetes. The current CDC recommendations for children above two years and below 12 years continues to be nine months of INH, and is likely to remain so till the PREVENT-TB trial completes recruitment and reports the results in the remaining children.
No data from low-income, high TB burden countries are available for weekly rifapentine plus INH and this reduced our confidence in extrapolating the otherwise high quality evidence from this trial to settings where DOT may not be feasible, or practical, given resource constraints; and where reinfection rates are likely to be higher than in the low-transmission settings that Sterling 2011 was conducted in. The experience with rifapentine is limited and the potential for adverse events, hepatotoxicity, and the possibility of rifapentine resistance will require careful monitoring with more widespread use.
Implications for practice
On current evidence shortened prophylactic regimens containing rifampicin or weekly, directly observed rifapentine plus INH appear no different to INH monotherapy given for six months to nine months for preventing active TB in people at risk. Rifampicin for four months and weekly directly-observed rifapentine plus INH for three months may have additional advantages of higher treatment completion and improved safety. However, the weekly rifapentine plus INH combination has not been evaluated against INH in low-income, high TB burden countries. Shorter regimens of rifampicin with INH may confer no additional benefits compared to longer INH treatment regimens. Rifampicin combined with pyrazinamide increases the risk of liver toxicity in adults.
Implications for research
A number of trials are ongoing that will provide data to clarify many of the issues raised in this review.
Three ongoing trials evaluating the efficacy of rifampicin (four months) compared to INH (nine months) in preventing active TB among adults and children with LTBI will provide data to add to the evidence from this review to inform guidance in countries on considering four months of rifampicin as an alternative to INH. NCT00931736 will include 5720 adults with LTBI from low-income, high TB transmission countries in Africa and Asia, and will also provide prospective data for estimating incremental cost-effectiveness of rifampicin over INH, based on actual efficacy estimates of the two regimens. NCT01398618 is being conducted in 300 adults in Taiwan. ISRCTN53253537 is recruiting 900 children with LTBI from high-income countries as well as high burden, low income countries in Africa and Asia. Efficacy, safety, tolerability, and the emergence of drug resistance are the outcomes sought and the results of this trial will add to the sparse data from the sole trial in this review of four months of rifampicin versus nine months of INH in children.
The rifapentine plus INH trial (PREVENT-TB; Sterling 2011) is ongoing (NCT00023452) and on completion will provide additional date on its efficacy, safety, and tolerability in approximately 454 additional young children to complement the currently insufficient evidence for children with this combination. An ongoing, open-label, three-armed, RCT in the US (NCT01582711) is examining 12 weekly doses of rifapentine 900 mg plus INH 900 mg DOT over three months versus self-administered rifapentine plus INH 12-dose regimen, or self-administered rifapentine plus INH 12 doses with weekly mobile phone short messaging system (SMS) reminders, in 1000 adults .
We did not find on-going trials evaluating adherence to preventive rifampicin-containing treatments for LTBI from low- and middle-income, high TB incidence countries. We also did not find any ongoing trials comparing intermittent rifampicin, or rifabutin, or self-administered INH plus daily rifapentine, with standard INH prophylaxis in HIV-negative people with LTBI.
In addition, pharmacovigilance for adverse events and resistance to rifamycins is also required as these regimens become more widely used. Further trials and implementation research exploring approaches for active case finding and to enhance adherence will help provide evidence to inform approaches to optimise TB control programmes.
We are grateful for technical support from the editorial base of the CIDG (Caroline Hercod, Vittoria Lutje, Anne-Marie Stephani, Sarah Donegan, Reive Robb, Dave Sinclair, and Paul Garner) and to the referees of the protocol of this review, Henry Mwandumba and Mical Paul. We are also grateful to OFLOTUB Co-ordinator, Christian Lienhardt and WHO Stop TB Department Coordinator, Haileyesus Getahun from WHO, Geneva for helpful comments and information about potential studies. We sincerely thank Dr. CC Leung for unpublished follow-up data; and Dr Sterling and Dr. Chan for clarifications regarding their trial methods and additional data.
We are also grateful to Danielle Cohen, Justin T Denholm, and Tonya Esterhuizen for incisive refereeing and helpful suggestions; to Thambu David Sudarsanam for editorial support; and to Paul Garner and Dave Sinclair for editorial revisions and suggestion that considerably helped to improve the quality of the final version of this review.
This review is an output of protocol development and review completion workshops organized by the Prof. BV Moses & Indian Council of Medical Research (ICMR) Centre for Advanced Research and Training in Evidence-Informed Healthcare that hosts the South Asian Cochrane Network & Centre at the Christian Medical College, Vellore. This review is also a funded output of the Effective Health Care Research Consortium, a project funded by UKaid: Department for International Development (DFID) for the benefit of developing countries, of which the South Asian Cochrane Centre is a programme partner. The views expressed herein are not necessarily those of DFID or the ICMR.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. Search methods: detailed search strategies
Appendix 2. Outcomes reported and definitions used in included studies
Contributions of authors
SKS conceived the review and wrote the protocol for this review. All authors helped draft the protocol. PT updated the background section of the protocol during review completion. SKS, TK, and AS screened studies for inclusion. PT checked excluded studies. SKS, TK, and PT assessed trials for risk of bias. TK and PT extracted and entered data. All authors checked entered data. TK wrote the draft of the review and drafted the summary of findings tables. PT revised the summary of findings tables and wrote the final version of the review. All authors contributed to revising the review in accordance with referees' comments and editorial suggestions, and approved the final version.
Declarations of interest
None of the authors declare financial or academic conflicts of interest.
Sources of support
- All India Institute of Medical Sciences, New Delhi, India.Employment for Surendra K. Sharma
- Indian Council of Medical Research, New Delhi, India.Employment for Anju Sharma
- Council of Scientific and Industrial Research, New Delhi, India.Funding for Tamilarasu Kadhiravan as a Senior Research Associate under the Scientists' Pool Scheme during the initial period of this review.
- Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry (Pondicherry), India.Employment for Tamilarasu Kadhiravan during the subsequent period of this review
- Christian Medical College, Vellore, India.Employment for Prathap Tharyan; logistic support for the Prof. BV Moses & Indian Council for Medical Research (ICMR) Centre for Evidence-Informed Healthcare that hosts the South Asian Cochrane Centre
- UKaid: Department for International Development, UK.Funding for the Effective Health Care Research Consortium via the International Health Group, Liverpool School of Tropical Medicine (Paul Garner)
- Indian Council for Medical Research, India.Funding for the Prof. BV Moses & ICMR Centre for Advanced Research and Training in Evidence-Informed Healthcare (Prathap Tharyan)
Differences between protocol and review
The title of the review was changed from "Isoniazid mono-therapy versus other mono-therapies or combination chemotherapy for preventing active tuberculosis in HIV-negative persons" to "Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB)" to more accurately describe the focus of the review.
The background section was updated since the publication of the protocol to include more recent information relevant to understanding LTBI, and recent advances in the conceptual understanding of re-activation of LTBI. 'Risk of bias' tables and 'Summary of findings' tables were introduced as standard for Cochrane reviews after this protocol was published. We generated 'Risk of bias' for the included studies in this review using the methods described in Higgins 2011. We used GRADE profiler (GRADE 2004) and interpreted the evidence for each important and critically important outcome for the comparisons in the included trials using the GRADE approach (Schunemann 2008) to create 'Summary of findings' tables for each comparison. We selected outcomes to include in these tables though discussion, and before evaluating the search results.
We clarified in the methods section our approach to dealing with unit of analysis issues arising from cluster randomized trials that were not described in the protocol. These methods were based on advice provided in Higgins 2011b.
To respond to referees' comments, we restructured the background section to provide more clarity; made explicit that quasi-RCTs would be excluded under "Types of studies" and also provided additional information on the interpretation of I
Medical Subject Headings (MeSH)
*HIV Seronegativity; Antibiotics, Antitubercular [*therapeutic use]; Directly Observed Therapy; Drug Administration Schedule; Isoniazid [therapeutic use]; Latent Tuberculosis [*drug therapy]; Randomized Controlled Trials as Topic; Rifabutin [*therapeutic use]; Rifampin [*analogs & derivatives; *therapeutic use]; Tuberculosis, Pulmonary [*prevention & control]
MeSH check words
Adult; Child; Humans
* Indicates the major publication for the study