Abstract
Introduction
About one third of the world's population has immunological evidence of previous exposure to Mycobacterium tuberculosis. In 2013, an estimated 9.0 million people developed tuberculosis (TB) and 1.5 million died from the disease.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of directly observed treatment (DOT) versus self-administered treatment (SAT) in people with tuberculosis without HIV infection? What are the effects of support mechanisms for DOT in people with tuberculosis without HIV infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).
Results
At this update, searching of electronic databases retrieved 189 studies. After deduplication and removal of conference abstracts, 104 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 86 studies and the further review of 18 full publications. Of the 18 full articles evaluated, three systematic reviews and one RCT were added at this update. We performed a GRADE evaluation for 12 PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for 13 interventions based on information relating to the effectiveness and safety of directly observed treatment and support mechanisms for directly observed treatment.
Key Points
In 2013, an estimated 9.0 million people developed TB and 1.5 million died from the disease.
Most people who inhale Mycobacterium tuberculosis contain the infection and become skin-test positive.
Some people develop latent infection: persistent bacterial presence that is asymptomatic and not infectious.
About one third of the world’s population has immunological evidence of previous exposure to M tuberculosis.
Drug treatments can reduce the risk of active tuberculosis in people at high risk of infection.
Active infection is more likely in people affected by social factors (such as poverty, drug misuse, overcrowding, imprisonment, homelessness, and inadequate health care) or with reduced immune function (such as with HIV infection).
Social factors associated with active infection have been associated with reduced adherence to anti-tuberculous treatment.
Directly observed treatment (DOT) has been developed to ensure adherence to treatment in patients treated for M tuberculosis infection. It involves the engagement of an appointed agent (health worker, community volunteer, family member) who directly monitors people swallowing their antituberculous drugs.
DOT does not seem to increase cure rates compared with self-administered treatment. However, it may increase treatment compliance.
We don't know how different types of support mechanisms for DOT compare with each other.
Clinical context
General background
To improve adherence to anti-tuberculous treatment, in 1995 the World Health Organization (WHO) introduced directly observed treatment, short course (DOTS). In 2005, implementation of DOTS had been undertaken by 187 countries, with 4.9 million patients with tuberculosis managed by this strategy. This overview looks at directly observed treatment (DOT) and the effects of support mechanisms for DOT in people with tuberculosis without HIV infection.
Focus of the review
This overview provides a representation of the evidence base regarding effectiveness of DOT compared to self-administered treatment, as well as of the support mechanisms that have been investigated to enhance the effectiveness of DOT. Treatment success in tuberculosis relies on adherence. New support mechanisms to DOT (such as mobile phone reminders) emerge and require systematic evaluation of effects.
Comments on evidence
Five RCTs investigated the effectiveness of DOT versus self-administered treatment and provided moderate-quality evidence. Eight RCTs provided low-quality evidence regarding measures to support DOT, including choice of site, financial incentives, use of healthcare workers, complex interventions, mobile phone reminders, and food incentives.
Search and appraisal summary
The update literature search for this review was carried out from the date of the last search, June 2010, to June 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 189 studies. After deduplication and removal of conference abstracts, 104 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 86 studies and the further review of 18 full publications. Of the 18 full articles evaluated, three systematic reviews and one RCT were added at this update.
Additional information
We did not reveal trials (except for one) or subgroup analyses in people at a very high risk or with a proven record of non-adherence, such as homeless people, those with drug addictions, or prisoners. Effects of DOT and support mechanisms in these groups are not known.
About this condition
Definition
Tuberculosis (TB) 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. This review focuses on TB in people who do not have HIV. For TB in people with HIV, see our separate review on TB in people with HIV.
Incidence/ Prevalence
The M tuberculosis organism kills more people than any other infectious agent. The global incidence of TB per capita peaked around 2003 and seems to have stabilised or begun to decline. Incidence per 100,000 population is approximately stable in the European Region and is falling in all of the five other WHO regions. It is also falling in all nine subregions, with the possible exception of African countries with low HIV prevalence (Africa — low HIV). The downward trend was fastest in the Latin America and Caribbean subregion (–3.4% per year, 2001–2006). Globally, the slow decline in incidence per capita is more than offset by population growth. This means that the number of new cases was still increasing between 2005 and 2006, from 9.1 to 9.2 million (an increase of 0.6%). The increases in numbers of new cases were in the African, Eastern Mediterranean, European, and South-East Asian Regions.
Aetiology/ Risk factors
The chief route of infection is through inhalation of airborne bacteria released by people with active respiratory TB by cough, sneeze, or speech. Inhaled mycobacteria reach the lung, and grow slowly over several weeks. The immune systems of most healthy exposed people (80%–90%) contain the bacteria, with only a positive skin test left as a marker of exposure. In a proportion of people infected, a defensive barrier is built around the infection, but the TB bacteria are not killed and lie dormant. This is known as latent TB, where the person is asymptomatic and not infectious. In the rest of those infected, active TB develops either immediately or after reactivation of the dormant bacteria. Risk factors Social factors include poverty, overcrowding, homelessness, and inadequate health services. Medical factors include HIV infection and immunosuppression.
Prognosis
Prognosis varies widely and depends on treatment. In 2013, an estimated 9.0 million people developed TB and 1.5 million died from the disease. Cure rates in TB depend on adherence to treatment. Poor adherence to antituberculous treatment may lead to treatment failure and relapse and to drug resistance; prolonged and expensive therapy of drug-resistant TB is less likely to be successful than the treatment of drug-susceptible TB. Measures to improve adherence include: directly observed treatment, short course (DOTS) (staff motivation and supervision, reminder systems and late patient tracers in the diagnosis and management of tuberculosis, education and counselling for promoting adherence to the treatment of active tuberculosis); incentives and reimbursements (money or cash in kind to reimburse expenses of attending services or to improve the attractiveness of visiting the service); contracts (written or verbal agreements to return for an appointment or course of treatment); and peer assistance (people from the same social group helping someone with tuberculosis return to the health service by prompting or accompanying them). The cure rate among cases registered under DOTS worldwide was 77.6%, and a further 7.1% completed treatment (no laboratory confirmation of cure), giving a reported overall treatment success rate of 84.7% — very close to the 85% target. This means that 49% of the smear-positive cases estimated to have occurred in 2005 were treated successfully by DOTS programmes. Recurrence after successful treatment ranged from 0% to 14% in one systematic review (search date 2006), which identified RCT and observational studies assessing recurrence after successful treatment; little is known about the long-term efficacy of this strategy.
Aims of intervention
To improve adherence to treatment in people with tuberculosis without HIV infection, with minimal adverse effects.
Outcomes
Mortality; cure rates/treatment failure rates; relapse rates, measured by M tuberculosis in sputum (smear examination and culture), symptoms or weight; treatment compliance, including completion of treatment; adverse effects.
Methods
Search strategy BMJ Clinical Evidence search and appraisal June 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to June 2014, Embase 1980 to June 2014, The Cochrane Database of Systematic Reviews, 2014, issue 6 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this overview were systematic reviews and RCTs published in English, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics, such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Tuberculosis (HIV-negative people): improving adherence.
| Important outcomes | Cure rate, Cure rates, Mortality, Relapse rates, Treatment compliance | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of directly observed treatment (DOT) versus self-administered treatment (SAT) in people with tuberculosis without HIV infection? | |||||||||
| 5 (2135) | Cure rates | Directly observed treatment versus self-administered treatment | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for potential heterogeneity among RCTs in terms of implementation of DOT |
| 1 (574) | Relapse rates | Directly observed treatment versus self-administered treatment | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for potential heterogeneity among RCTs in terms of implementation of DOT |
| 4 (1706) | Treatment compliance | Directly observed treatment versus self-administered treatment | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for potential heterogeneity among RCTs in terms of implementation of DOT and for variation in definition of 'defaulting' across trials included in the analysis |
| What are the effects of support mechanisms for DOT in people with tuberculosis without HIV infection? | |||||||||
| 1 (108) | Treatment compliance | Participant-chosen site versus designated site | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for restricted population (drug users) |
| 1 (108) | Treatment compliance | Participant-chosen site plus financial incentive versus participant-chosen site alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for restricted population (drug users) |
| 2 (1109) | Cure rates | Clinic-based support versus home-based (with family-member or community health-volunteer support) | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for cluster randomised trial; directness point deducted for composite outcome in 1 RCT |
| 2 (2223) | Cure rates | Community-based health worker support versus family member support | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for cluster randomised trial; directness point deducted for composite outcome (cure or completion of treatment) |
| 2 (1628) | Cure rates | Complex support interventions versus usual treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological flaws (cluster randomised trial and incomplete reporting in 1 RCT); directness point deducted for lack of clarity about intervention in 1 RCT |
| 2 (1618) | Treatment compliance | Complex support interventions versus usual treatment | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for methodological flaws (cluster randomised trial and incomplete reporting in 1 RCT); directness point deducted for lack of clarity about intervention in 1 RCT |
| 1 (98) | Cure rates | Mobile phone reminders versus usual treatment | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (270) | Cure rates | Food incentives versus usual treatment (nutritional advice) | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for different regimes for different arms (clinic attendance); directness point deducted for external events (conflict), which may have affected overall results and generalisability |
| 1 (270) | Treatment compliance | Food incentives versus usual treatment (nutritional advice) | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for different regimes for different arms (clinic attendance); directness point deducted for external events (conflict), which may have affected overall results and generalisability |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
See question on the effects of anti-tuberculosis prophylaxis in people with HIV infection, in review on HIV: prevention of opportunistic infections.
See also review on Tuberculosis in people with HIV
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Professor Liliya Eugenevna Ziganshina, Kazan Federal University, Kazan, Russia.
Michael Eisenhut, Luton & Dunstable University Hospital NHS Foundation Trust, Luton, UK.
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