Adherence interventions and outcomes of tuberculosis treatment: A systematic review and meta-analysis of trials and observational studies

Abstract

Background: Incomplete adherence to tuberculosis (TB) treatment increases the risk of delayed culture conversion with continued transmission in the community, as well as treatment failure, relapse, and development or amplification of drug resistance. We conducted a systematic review and meta-analysis of adherence interventions, including directly observed therapy (DOT), to determine which approaches lead to improved TB treatment outcomes.

Methods and findings: We systematically reviewed Medline as well as the references of published review articles for relevant studies of adherence to multidrug treatment of both drug-susceptible and drug-resistant TB through February 3, 2018. We included randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies (CSs) with an internal or external control group that evaluated any adherence intervention and conducted a meta-analysis of their impact on TB treatment outcomes. Our search identified 7,729 articles, of which 129 met the inclusion criteria for quantitative analysis. Seven adherence categories were identified, including DOT offered by different providers and at various locations, reminders and tracers, incentives and enablers, patient education, digital technologies (short message services [SMSs] via mobile phones and video-observed therapy [VOT]), staff education, and combinations of these interventions. When compared with DOT alone, self-administered therapy (SAT) was associated with lower rates of treatment success (CS: risk ratio [RR] 0.81, 95% CI 0.73-0.89; RCT: RR 0.94, 95% CI 0.89-0.98), adherence (CS: RR 0.83, 95% CI 0.75-0.93), and sputum smear conversion (RCT: RR 0.92, 95% CI 0.87-0.98) as well as higher rates of development of drug resistance (CS: RR 4.19, 95% CI 2.34-7.49). When compared to DOT provided by healthcare providers, DOT provided by family members was associated with a lower rate of adherence (CS: RR 0.86, 95% CI 0.79-0.94). DOT delivery in the community versus at the clinic was associated with a higher rate of treatment success (CS: RR 1.08, 95% CI 1.01-1.15) and sputum conversion at the end of two months (CS: RR 1.05, 95% CI 1.02-1.08) as well as lower rates of treatment failure (CS: RR 0.56, 95% CI 0.33-0.95) and loss to follow-up (CS: RR 0.63, 95% CI 0.40-0.98). Medication monitors improved adherence and treatment success and VOT was comparable with DOT. SMS reminders led to a higher treatment completion rate in one RCT and were associated with higher rates of cure and sputum conversion when used in combination with medication monitors. TB treatment outcomes improved when patient education, healthcare provider education, incentives and enablers, psychological interventions, reminders and tracers, or mobile digital technologies were employed. Our findings are limited by the heterogeneity of the included studies and lack of standardized research methodology on adherence interventions.

Conclusion: TB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives and enablers, psychological interventions, reminders and tracers, and digital health technologies. Trained healthcare providers as well as community delivery provides patient-centered DOT options that both enhance adherence and improve treatment outcomes as compared to unsupervised, SAT alone.

Fig 1. PRISMA summary.

TB, tuberculosis.

Fig 2

(A) SAT compared with DOT on TB treatment outcomes. (B) Impact of any DOT provided by lay providers, family members, or healthcare workers on TB treatment outcomes. * = significant heterogeneity in the meta-analysis as determined by I² statistic. 1 = depicted is the rate of adherence in one study defined as completing >90% of treatment doses by pill counting in one CS and based on six positive INH urine tests done at random in one RCT. Conversion = sputum conversion to negative at the end of two months (CS) and three months (RCT). N = number of studies included within the meta-analysis. Resistance = development of drug resistance. CS, cohort study; DOT, directly observed therapy; HCW, healthcare worker; INH, isoniazid; LTFU, loss to follow-up; RCT, randomized controlled trial; RR, risk ratio; SAT, self-administered therapy; TB, tuberculosis.

Fig 3. Funnel plot of cohort studies comparing treatment success rates in patients undergoing SAT versus DOT. No funnel plot of RCTs has been included as there were fewer than 10 RCTs.

DOT, directly observed therapy; RCT, randomized controlled trial; RR, risk ratio; SAT, self-administered therapy; SE, standard error.

Fig 4. Meta-analysis of treatment success rates in patients undergoing SAT versus DOT.

DOT, directly observed therapy; M-H, Mantel-Haenszel; SAT, self-administered therapy.

Fig 5. Forest plot of adherence rates in studies comparing patients undergoing SAT versus DOT.

CHW, community health worker; DOT, directly observed therapy; INH, isoniazid; M-H, Mantel-Haenszel; SAT, self-administered therapy.

Fig 6. Meta-analysis of rates of sputum conversion in patients undergoing SAT versus DOT.

DOT, directly observed therapy; M-H, Mantel-Haenszel; RCT, randomized controlled trial; SAT, self-administered therapy.

Fig 7. Meta-analysis of treatment success rates in HIV/TB patients undergoing SAT versus DOT.

DOT, directly observed therapy; M-H, Mantel-Haenszel; SAT, self-administered therapy; TB, tuberculosis.

Fig 8. Meta-analysis of treatment success rates in patients receiving DOT by different types of providers.

DOT, directly observed therapy; HCW, healthcare worker; M-H, Mantel-Haenszel.

Fig 9. Comparison of adherence rates in patients receiving DOT by a family member versus HCW.

DOT, directly observed therapy; HCW, healthcare worker; M-H, Mantel-Haenszel.

Fig 10

(A) Impact of DOT provided at home, in the community, or in clinic on TB treatment outcomes. (B) Impact of patient education and counseling interventions on TB treatment outcomes. * = significant heterogeneity in the meta-analysis, as determined by I² statistic. 1 = adherence defined as the proportion of patients that took >75% of prescribed doses in one CS and the proportion of patients attending all appointments in one RCT. Conversion = sputum conversion to negative at the end of two months. N = number of studies included within the meta-analysis. Composite outcome reported by one study defined as combined failure, default, death, or transfer out. CS, cohort study; DOT, directly observed therapy; LTFU, loss to follow-up; RCT, randomized controlled trial; RR, risk ratio; TB, tuberculosis; UO, unfavorable outcome.

Fig 11. Meta-analysis of treatment success rates in patients receiving DOT in various locations.

DOT, directly observed therapy; HCW, healthcare worker; M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 12. Adherence rates in patients receiving DOT at various locations.

DOT, directly observed therapy; M-H, Mantel-Haenszel.

Fig 13. Meta-analysis of sputum conversion rates at two months in patients receiving DOT at various locations.

DOT, directly observed therapy; M-H, Mantel-Haenszel.

Fig 14. Meta-analysis of treatment success rates in patients receiving patient education and counseling interventions in addition to standard care versus standard care alone.

M-H, Mantel-Haenszel.

Fig 15. Adherence rates in patients receiving patient education and counseling interventions in addition to standard care versus standard care alone.

M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 16

(A) Impact of incentives and enablers on TB treatment outcomes. (B) Impact of reminders and tracers on TB treatment outcomes. * = significant heterogeneity in the meta-analysis as determined by I² statistic. 1 = adherence defined as the proportion of patients who presented for all drug collections in the first six months of treatment. Conversion = sputum conversion at the end of two months. Resistance = development of drug resistance. N = number of studies included within the meta-analysis. LTFU, loss to follow-up; RCT, randomized controlled trial; RR, risk ratio; TB, tuberculosis.

Fig 17. Meta-analysis of treatment success rates in patients receiving incentives and enablers in addition to standard care versus standard care alone.

M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 18

(A) Meta-analysis of treatment success rates in patients receiving reminders/tracers in addition to standard care versus standard care alone. (B) Sensitivity analysis: removing the heaviest weighted study (Bronner 2012) in which control and intervention cohorts had different pre-intervention success rates. M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 19. Adherence rates in patients receiving reminders/tracers in addition to standard care versus standard care alone.

M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 20. Meta-analysis of rates of sputum conversion at two months in patients receiving reminders/tracers in addition to standard care versus standard care alone.

M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 21

(A) Impact of staff education on TB treatment outcomes. (B) Impact of using psychological interventions, such as mental health counseling and support groups, on TB treatment outcomes. * = significant heterogeneity in the meta-analysis, as determined by I² statistic. N = number of studies included within the meta-analysis. CS, cohort study; LTFU, loss to follow-up; RCT, randomized controlled trial; RR, risk ratio; TB, tuberculosis.

Fig 22. Meta-analysis of the impact of staff education on treatment success rates.

M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 23

(A) Impact of digital technologies on TB treatment outcomes. (B) Impact of combining different types of adherence interventions on TB treatment outcomes. * = significant heterogeneity in the meta-analysis, as determined by I² statistic. 1 = defined as proportion of patients taking >90% of pills. Conversion = sputum conversion at the end of two months. N = number of studies included within the meta-analysis. Poor adherence = percentage of patient-months in which >20% of doses were missed. CS, cohort study; DOT, directly observed therapy; LTFU, loss to follow-up; RCT, randomized controlled trial; RR, risk ratio; TB, tuberculosis; VOT, video-observed therapy.

Fig 24. Meta-analysis of treatment success rates in patients receiving phone reminders in addition to standard care versus standard care alone.

M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 25. Rates of sputum conversion at two months in patients receiving phone reminders in addition to standard care versus standard care alone.

M-H, Mantel-Haenszel; RCT, randomized controlled trial.

Fig 26. Meta-analysis of treatment success rates in patients receiving combination adherence interventions (enhanced DOT) in addition to standard care versus standard care alone.

DOT, directly observed therapy; M-H, Mantel-Haenszel; RCT, randomized controlled trial; SAT, self-administered therapy.

Fig 27. Adherence rates in patients receiving combination adherence interventions (enhanced DOT or enhanced SAT) in addition to standard care versus standard care alone.

DOT, directly observed therapy; M-H, Mantel-Haenszel; RCT, randomized controlled trial; SAT, self-administered therapy.