Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

BackgroundIncomplete 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 findingsWe 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.ConclusionTB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives...

BackgroundTuberculosis is a leading cause of death worldwide, yet the determinants of death are not well understood. We sought to determine risk factors for mortality during treatment of drug-susceptible pulmonary tuberculosis under program settings.MethodsRetrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001.ResultsOf 565 patients meeting eligibility criteria, 37 (6.6%) died during the study period. Of 37 deaths, 12 (32.4%) had tuberculosis listed as a contributing factor. In multivariate analysis controlling for follow-up time, four characteristics were independently associated with mortality: HIV co-infection (HR = 2.57, p = 0.02), older age at tuberculosis diagnosis (HR = 1.52 per 10 years, p = 0.001); initial sputum smear positive for acid fast bacilli (HR = 3.07, p = 0.004); and experiencing an interruption in tuberculosis therapy (HR = 3.15, p = 0.002). The association between treatment interruption and risk of death was due to non-adherence during the intensive phase of treatment (HR = 3.20, p = 0.001). The median duration of treatment interruption did not differ significantly in either intensive or continuation phases between those who died and survived (23 versus 18 days, and 37 versus 29 days, respectively). No deaths were directly attributed to adverse drug reactions.ConclusionsIn addition to advanced age, HIV and characteristics of advanced tuberculosis, experiencing an interruption in anti-tuberculosis therapy, primarily due to non-adherence, was also independently associated with increased risk of death. Improving adherence early during treatment for tuberculosis may both improve tuberculosis outcomes as well as decrease mortality.

Clinicians may need to screen for child daily controller-medication management and include even young children when educating families on the use of asthma medications and other key asthma-management tasks.

DST for ethambutol, pyrazinamide, and second-line tuberculosis drugs appears to provide clinically useful information to guide selection of treatment regimens for MDR and XDR tuberculosis.

Background Risk factors and treatment outcomes under program conditions for isoniazid (INH) mono-resistant tuberculosis have not been well described. Methods Medical charts were retrospectively reviewed for all culture-confirmed, INH mono-resistant tuberculosis cases (N=137) reported to the San Francisco Tuberculosis Control Section between 1993 and 2005 and compared to a time-matched sample of drug susceptible cases (N=274). Results In multivariate analysis, only history of treatment for latent (OR 3.1, 95% CI 1.5–6.4, p=0.003) and active (OR 2.7, 95% CI 1.4–5, p=0.002) tuberculosis were significantly associated with INH mono-resistant tuberculosis. Of the 119 patients who completed treatment, 49 (41%) completed a 6-month treatment regimen. Treatment was extended to between 7 and 12 months in 53 (45%) patients and to greater than 12 months in 17 (14%) patients. Treatment was most commonly extended when pyrazinamide was not given for the recommended 6-month duration (N=35, 29%). Despite variation in treatment regimens, the combined endpoint of treatment failure or relapse was uncommon in INH mono-resistant cases and not significantly different than for drug susceptible cases (1.7% vs. 2.2%, p=0.73). Conclusions A history of latent or active tuberculosis treatment was associated with subsequent INH mono-resistance. Treatment outcomes for INH mono-resistant cases were excellent and no different than for drug susceptible cases. However, new short course regimens are needed since a low proportion of patients completed the 6-month ATS/CDC/IDSA-recommended treatment regimen, primarily due to pyrazinamide intolerance.

In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention’s Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy.