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Justification
Treatment support
Treatment support terminology in this document is used to describe an approach to supporting patients who are taking prescribed doses of TB medicines in order to help ensure adherence to treatment and maximize its efficacy. Treatment support needs to be provided in the context of people-centred care and should be based on the individual patient’s needs, acceptability and preferences. It includes aspects of support, motivation and understanding of patients without coercion. Historically, this group of interventions were labelled as “directly observed treatment” or DOT. However, with a need to emphasize the need to support people in adhering to treatment, as recommended by the WHO TB ethics guidance of 2010 and 2017 (6, 7), this legacy terminology has been replaced by “treatment support” throughout this document in order to align the language with the essence of the recommendation of the WHO TB ethics guidance.
In the systematic review that led to the recommendations on treatment adherence, “treatment support” was defined as any person observing the patient taking medications in real time. The treatment supporter does not need to be a health-care worker, but could be a friend, a relative or a lay person who works as a treatment supporter.
Treatment support may also be achieved with real-time video feed and video recording which is referred to as video-supported treatment (VST). VST was analysed separately in this review.
Adherence definitions varied across the studies. In general, however, adherence was defined as taking > 90% of medications under conditions of observation by another person.
The systematic review conducted in support of this guideline was based on synthesis of data from randomized controlled trials (8–15) and from observational studies (16–29), with preference given to the results of randomized controlled trials. Outcomes from treatment support with observation were compared with outcomes from self-administered treatment (SAT) given under standard TB practice and without any additional support. Treatment support could be given by a health-care worker, a family member or a community member and could be done at home, in the patient’s community or at a clinic. Treatment support was generally performed daily. The GDG focused preferentially on randomized controlled trial data from the systematic review. When the data from randomized controlled trials were limited or not available, observational data were examined and their results were presented. Interpretation of the associations, however, requires caution due to limitations of the observational data when the associations are confounded by different factors. In uncontrolled observational studies, for instance, patients with more severe disease or higher risk of non-adherence are likely to be assigned treatment support and the less sick or, less likely, incompliant patients are assigned SAT. The same may apply to the selection of treatment support location, treatment support provider or other interventions in cohort studies.
When treatment support alone was compared with SAT, patients who were on treatment support had better rates of treatment success, adherence and 2-month sputum conversion, and also had slightly lower rates of loss to follow-up and acquired drug resistance. However, patients on treatment support had a slightly higher relapse rate. The GDG considered that, overall, the evidence was inconsistent in showing clear advantages of treatment support alone over SAT or vice versa. However, the evidence showed that some subgroups of patients (e.g. TB patients living with HIV) with factors affecting treatment adherence are likely to benefit from treatment support more than other patients do, and that specific types of treatment support delivery (e.g. locations of treatment support or support providers) are likely to work better than others. The evidence also showed that, when patients received treatment adherence interventions (e.g. different combinations of patient education, staff education, material support, psychological support, tracers and use of medication monitor) in conjunction with treatment support or SAT, the treatment outcomes were significantly improved compared to treatment support with observation or SAT alone (see below).
Only cohort studies were available to examine treatment support and SAT in HIV-positive TB patients (30–46), and many of these studies were conducted in the pre-ART era prior to antiretroviral treatment (ART) or shortly after the introduction of this treatment for HIV-positive TB patients (42–45). As above, treatment support could have been administered by a variety of people in a variety of settings, including homes and clinics; occasionally, during initial intensive-phase treatment, the treatment support was hospital-based. A few studies provided incentives and enablers or provided treatment support only for persons considered to be at higher risk of loss to follow-up. HIV-positive TB patients on SAT had lower rates of treatment success, treatment completion and cure; they also had higher rates of mortality, treatment failure and loss to follow-up. The evidence showed that HIV-positive TB patients, as a subgroup, benefit more from treatment support than TB patients in general do and that SAT alone is not advisable in HIV-positive TB patients. Reasons such as increased rates of drug– drug interactions and more severe disease in this cohort may cause treatment support to offer a significant advantage over SAT.
Treatment support and SAT in MDR-TB patients were also examined in the systematic review. However, very limited data were available from a cohort study (32). There were higher rates of mortality and non-adherence and lower rates of treatment completion in MDR-TB patients on SAT compared with those on treatment support, although the differences were not significant.
Randomized controlled trials (10, 12–14) and observational studies (17, 18, 21, 23, 28, 31, 36, 38, 41, 42, 46) were available for examination of the effect of treatment support providers versus SAT. Providers were classed as health-care workers, lay providers or family members. The health-care worker group was varied and included personnel working at different levels of health-care systems and who had received health training. Health-care workers could be nurses, physicians or trained community health workers. Lay providers were also varied and could include teachers, community volunteers or traditional healers. Treatment support by lay providers had higher rates of treatment success and cure, and a slightly lower rate of loss to follow-up compared with SAT. However, in one cohort study there was a higher rate of treatment completion with SAT compared to treatment support with lay providers. Patients receiving treatment support from a family member had higher rates of treatment success and lower rates of loss to follow-up compared with patients using SAT. When treatment support provided by a health-care worker was compared to SAT, there were higher rates of cure and adherence and lower rates of relapse and acquisition of drug resistance with the treatment support provided by a health-care worker. However, there was a higher rate of treatment completion with SAT compared to treatment support provided by health-care workers in cohort studies.
The effect that different types of treatment support provider had on outcomes was also examined. Treatment support provided by health-care workers and treatment support provided by lay persons were compared. Only observational studies were available in the literature (18, 21, 38, 47–51). There were no significant differences although slightly higher rates of success – and lower rates of mortality, failure and loss to follow-up – were observed among patients who had received treatment support administered by a lay provider as opposed to a health-care worker.
When provision of treatment support by a family member was compared to health-care worker provision of treatment support, there were higher rates of mortality, loss to follow-up and failure, and lower rates of successful treatment, cure and treatment adherence among patients who had treatment support administered by a family member. Therefore, although treatment support by a health-care worker, trained lay provider and family member showed advantages compared to SAT, provision by trained lay providers and health-care workers are the preferred options for treatment support, with the least preferred treatment support provider being a family member.
Treatment support location
Randomized controlled trials (10, 12, 14, 28, 52–55) and observational studies (16, 23, 36, 38, 41, 42, 56–89) examined how the location of treatment support affected the treatment outcome. Locations were grouped by community- or home-based treatment support and health facility-based treatment support. Community- or home-based treatment support was defined as treatment support delivered in the community that is close to the patient’s home or workplace. In general, community- or homebased treatment support was provided close to the patients. Health facility-based treatment support was defined as treatment support delivered at a health centre, clinic or hospital, although there were some instances of community- or home-based treatment support being provided by healthcare workers. When comparing treatment support locations, community- or home-based treatment support had higher rates of treatment success, cure, treatment completion and 2-month sputum conversion. Community- or home-based treatment support also had lower rates of mortality and lower rates of unfavourable outcomes compared with health facility-based treatment support.
When comparing community/home-based treatment support or health facility-based treatment support with SAT, there were no significant differences across the outcomes in randomized controlled trials. However, cohort studies showed higher rates of treatment success and adherence, and a lower rate of loss to follow-up, with community/home-based treatment support compared with SAT.
Observational data from cohort studies also showed lower rates of treatment completion and slightly higher rates of failure and loss to follow-up in health-facility treatment support compared to SAT.
Observational data from cohort studies also showed lower rates of treatment completion and slightly higher rates of failure and loss to follow-up in health-facility treatment support compared to SAT.
Combining the evidence on treatment support provider and treatment support location, treatment support should preferably be delivered at home or in the community by a health-care worker or trained lay provider. Treatment support that is delivered at a health facility or provided by a family member, and treatment that is unsupported are not preferable options.
Video-supported treatment (VST)
For VST there were only two cohort studies from high-income countries and no data from low- and middle-income countries (90, 91). These studies compared in-person treatment support with VST done in real time. Patients given VST had no statistically significant difference in treatment completion and mortality compared to patients who had in-person treatment support.
Although there is some concern as to the indirectness of evidence for VST, given that the studies were conducted in high-income countries and there is uncertainty of evidence regarding the use of VST, the results from the two cohort studies showed that in-person treatment support was not better than VST. Treatment support has been the standard of care that many programmes aim for, even if in practice they have to resort to SAT for many patients because of lack of resources. The advantages of using VST are its potential to observe adherence to treatment from a distance – even when people travel and cannot visit or be visited by a treatment support provider. VST is also more flexible with regard to people’s schedules as it offers virtual observation at different times of the day. VST could help achieve better levels of patient interaction at a much lower cost and less inconvenience when compared with in-person treatment support. VST can be used in addition to, or may be interchangeable with, in-person treatment support or other treatment administration options. For instance, it is not expected that a patient receives VST as the sole option of supervision during the whole duration of treatment.
Furthermore, the technology required for VST (broadband Internet and smartphone availability) is becoming increasingly available in resource-constrained settings. Moreover, VST delivery options are evolving (e.g. enhanced possibility for real-time communication in addition to recorded video), and therefore evidence and best practices are likely to develop further in the coming years, especially from the ongoing randomized controlled trials. The benefits of VST may become more apparent as programmes are able to choose forms of VST that best meet their needs. In fact, VST may be particularly useful for easing the burden on the health-care system in low- and middle-income countries.
Package of combined treatment adherence interventions
Both randomized controlled trials (91–96) and observational studies (56–62, 97) examined the effects of combined treatment adherence interventions. When patients receiving combined treatment adherence interventions along with treatment support or SAT were compared to those receiving treatment support or SAT alone, the patients who received the combined treatment adherence interventions had higher rates of treatment success, treatment completion, cure and adherence, and lower rates of mortality and loss to follow-up. The mixture of types of adherence intervention was varied (Table 1). These included different combinations of patient education, staff education, material support (e.g. food, financial incentives, transport fees, bonuses for reaching treatment goals), psychological support and counselling. The treatment adherence interventions also included tracers such as home visits, use of digital health communication (e.g. SMS, telephone calls) or a medication monitor. Interventions should be selected on the basis of an assessment of individual patients’ needs, providers’ resources and conditions for implementation.
Tracers and digital health interventions rather than VST
Varied tracers were included in randomized controlled trials (98–105) and observational studies (90, 91, 106–110). These interventions included, for instance, SMS, telephone calls or automated telephone reminders. Patients who missed appointments or failed to collect their medication received reminder letters or home visits by health-care workers. Medication monitors or computer systems in the clinic were also used to aid health-care workers in tracing patients. Medication monitors can measure the time between openings of the pill box, give audio reminders, record when the pill box is opened or send SMS reminders to take medications.
There were higher rates of treatment success, treatment adherence and 2-month sputum conversion, and lower rates of mortality, loss to follow-up and drug resistance acquisition with tracers, either through home visits or mobile telephone communication (SMS or telephone call).
When mobile telephone interventions were examined separately, there were higher rates of treatment success, cure and 2-month sputum conversion and lower rates of treatment failure, loss to follow-up, poor adherence and unfavourable outcomes with mobile telephone reminders as opposed to no intervention.
Medication monitors had better rates of adherence and favourable outcomes, and combined interventions of SMS and medication monitors also showed better adherence compared to no intervention.
It should be noted, however, that only a small number of studies were available for all digital health interventions. There was only one small randomized controlled trial (99) on which these data are based. With all the digital interventions and tracers, including VST, it is important to preserve patient support and the ability of patients to interact with health-care workers. In fact, these digital interventions should be considered as tools to enable better communication with the health-care provider rather than as replacements for other adherence interventions. In practice, it is expected that SMS, telephone calls and VST may replace in-person treatment support for certain periods of time rather than for the entire duration of treatment and that they promote patient-centered approaches to care.
Mobile telephone interventions, tracers and VST may also increase health equity if the need to travel to a health clinic or to a patient’s home is reduced. However, the ability of patients to participate in these programmes depends on the patient living in an area with a good telecommunications infrastructure.
Material support for patients
The effects of material support were examined both with randomized controlled trials (69–72) and observational studies (78, 111–118). The interventions included giving meals with treatment support with observation, monthly food vouchers, food baskets, food supplements and vitamins. Food support for patients and family members is an important incentive for TB patients and also helps protect patients from the catastrophic costs associated with TB. Food may be an incentive but it may also improve the outcome biologically by reducing malnutrition and consequently improving immune function. Other material support could be in the form of financial incentives, transport subsidies, living allowance, housing incentives, or financial bonuses after reaching treatment targets.
There were higher rates of treatment success, completion and sputum conversion in patients who received material support, and lower rates of treatment failure and loss to follow-up compared with patients who did not receive material support. It is of note that all these studies were in low- and middle-income countries, so presumably these incentives were of significant value to the patients in these settings. However, the material support would also be of significant value to TB patients even in higher-income countries, especially in countries that do not have a good social welfare system, since TB is a disease of poverty
The studies in this review found that material support was usually given to the most vulnerable groups, and therefore health equity was presumably improved by this intervention. However, if these incentives are not applied equitably, health disparities may be increased. The distribution of material support is likely to depend on the country context and may have different effects both within and between countries.
Patient education or educational counselling
Analysis of the benefit of patient education included randomized controlled trials (64–67) and observational studies (75). Patients who received education or educational counselling had better rates of treatment success, treatment completion, cure and treatment adherence, and had lower rates of loss to follow-up. It should be noted in this case that “counselling” refers to educational counselling and not psychological counselling. Patient education could include oral or written education via health-care workers or pharmacists. The education could be a one-time session at discharge from the intensive phase of therapy or at each presentation for follow-up care. The educational session might include only the health-care worker and patient, or it could involve the patients’ social network and family members. It is important to make sure that education and counselling are done in a culturally appropriate manner. Additionally, specific marginalized populations may require special educational efforts.
Staff education
Staff education may include peer training, visual aids to help initiate conversations with patients, other tools to aid in decision-making and as reminders, as well as the education of laboratory staff. This intervention was examined in both randomized controlled trials (68, 69, 118) and observational studies (119). Staff education led to higher rates of treatment success and slightly lower rates of mortality and loss to follow-up. With better staff education, treatment for patients is likely to improve. Any stigma that health-care workers may hold towards patients would decrease as the health-care workers better understand TB disease and TB treatment.
Psychological support
Psychological support was varied and could include self-help groups, alcohol cessation counselling and TB clubs (56, 74, 120). Patients who had access to psychological support had higher rates of treatment completion and cure, as well as lower rates of treatment failure and loss to follow-up. However, the GDG expressed concerns about confounding in these studies due to the severity of illness in the groups receiving support. Additionally, allocation of patients to the support groups was not always randomized.
When considering these data, it should also be noted that types of psychological support are very broad and may not be adequately represented in this review. To maximize health equity, psychological support should be targeted at the most marginalized populations.
Subgroup considerations
The evidence that was reviewed did not allow for conclusions about the advantages of treatment support over SAT or vice versa for TB patients; however, in a subgroup analysis of TB patients living with HIV, treatment support showed clear benefit with significantly improved treatment outcomes. It is probable that treatment support may not be beneficial for all patients but that it is likely to have more benefit in certain subgroups of TB patients. Apart from HIV-positive TB patients, other factors or groups of patients that were more or less likely to result in treatment adherence (and therefore require treatment support) were not examined in the scope of the systematic review.
Implementation considerations
Treatment adherence interventions
As treatment support alone is not likely to be sufficient to ensure good TB treatment outcomes, additional interventions for treatment adherence need to be provided. Patient education should be provided to all patients on TB treatment. A package of the other treatment adherence interventions also needs to be offered to patients on the basis of an assessment of individual patients’ needs, providers’ resources and conditions for implementation.
With regard to telephone or video-assisted interventions, there may be reluctance to use new technology, making implementation more difficult. There may be privacy concerns regarding the security of telephone data, so encryption and other measures to safeguard privacy will need to be considered. The feasibility of implementing these types of interventions depends on telecommunications infrastructure, telephone availability and connection costs. Multiple organizations have initiated programmes such as these, so TB programmes may find it helpful to collaborate and communicate with other medical service delivery programmes that have already set up such infrastructure.
There may be reluctance on the part of implementers (e.g. national or local governments, health partners) to pay for incentives. Implementers may be more willing to pay for material support for smaller subgroups at particularly high risk (e.g. patients with MDR-TB). However, one of the components of the End TB Strategy (121) is to provide “social protection and poverty alleviation” for patients with TB. The strategy specifically calls for measures to “alleviate the burden of income loss and non-medical costs of seeking and staying in care”. Included in the suggested measures are social welfare payments, vouchers and food packages. The benefit of material support found in this review supports these components of the End TB Strategy (121).
In order to distribute the material support, a government or nongovernmental organization (NGO) infrastructure would need to be in place, including anti-fraud mechanisms (e.g. reliable unique personal identifiers) and appropriate accounting to ensure that incentives are distributed equitably and to the people who need them most. Countries should choose incentives that are the most appropriate for their situation.
Treatment administration
Community-based or home-based treatment support has more advantages than health facility-based treatment support, although family members should not be the first or only option for administering treatment support. Treatment support is better provided at home or in the community by trained lay providers or health-care workers. However, there may be challenges in providing community- or home-based treatment support by health-care workers because of the increased number of healthcare workers required and the increased costs for staff time and daily travel to the community or to a patient’s home. Treatment support provided in the community or at home by trained local lay persons is more feasible. A combination of lay provider and health-care worker for provision of community- or home-based treatment support is also an option. Community-based or home-based treatment support is more likely to be acceptable and accessible to patients than other forms of treatment support. Nevertheless, stigma may continue to be a concern with community- or homebased treatment support. Having a health-care worker coming regularly to a patient’s house may be stigmatizing, and the feeling of being “watched over” may be disempowering to patients. Other forms of treatment support (e.g. administered by an emotionally supportive relative or close friend) may be more acceptable but may still be stigmatizing.
Given complex family social dynamics, family members may not always be the best people to supervise treatment, so the suitability of such treatment adherence supervisors needs to be carefully analysed in each national or local context. If family members are already providing treatment support, careful identification and training of those persons is required. Additional supervision of local supporters or health-care workers is still needed, as family members cannot be depended on as the only option for care. Patients will continue to need social support, even if family members are providing treatment support
Assessment of potential risk factors for poor adherence must be taken into account by health-care workers at the start of a patient’s treatment in order to decide which treatment administration option should be selected for that patient. Some groups of patients who are less likely to adhere to treatment may gain more benefit from treatment support than others do. Another factor to consider when selecting options for treatment administration is that some patients with inflexible work or family responsibilities may not be able to provide treatment support. Any treatment administration option offered to a patient must also be provided in conjunction with proper medical care, including regular pick-up of TB drugs, consultations with a physician or other health-care workers when necessary, TB treatment that is free of charge, and provision to the patient of essential information on TB treatment.
Monitoring and evaluation
Programmes should attempt to measure whether the provision of incentives improves programme performance.
⁸ Treatment adherence interventions include social support such as: informational or educational support (e.g. patient education or
educational counselling), material support (e.g. food, financial incentives, transport fees) and psychological support; tracers such as
home visits or digital health communications (e.g. SMS, telephone calls); medication monitor; and staff education. The interventions
should be selected based on the assessment of the individual patient’s needs, provider’s resources and conditions for implementation.
⁹ Suitable treatment administration options include various forms of treatment support, such as video-supported treatment and regular
community or home-based treatment support.
¹⁰ Tracers refer to the communication with the patient – including via SMS, telephone (voice) calls or home visits.
¹¹ A digital medication monitor is a device that can measure the time between openings of the pill box. The medication monitor may have
audio reminders or may send an SMS to remind the patient to take the medications, along with recording when the pill box is opened.
¹² Material support can be food or financial support: meals, food baskets, food supplements, food vouchers, transport subsidies, living
allowance, housing incentives or financial bonus. This support addresses indirect costs incurred by patients or their attendants in
accessing health services and, possibly, tries to mitigate the consequences of income loss related to the disease.
¹³ Psychological support can be counselling sessions or peer-group support.
¹⁴ Staff education can be adherence education, charts or visual reminders, educational tools and desktop aids for decision-making
and reminder