No action is without its side effects: Adverse drug reactions and missed doses of antituberculosis therapy, a scoping review.

AIMS: A key reason for the failure of antituberculosis (anti-TB) treatment is missed doses (instances where medication is not taken). Adverse drug reactions (ADRs) are 1 cause of missed doses, but the global evidence, their relative contribution to missed doses vs. other causes, the patterns of missed doses due to ADRs and the specific ADRs associated with missed doses have not been appraised. We sought to address these questions through a scoping review. METHODS: MEDLINE, Embase and Web of Science were searched on 3 November 2021 using terms around active TB, missed doses and treatment challenges. Studies reporting both ADR and missed dose data were examined (PROSPERO: CRD42022295209). RESULTS: Searches identified 108 eligible studies: 88/108 (81%) studies associated ADRs with an increase in missed doses; 33/61 (54%) studies documenting the reasons for missed doses gave ADRs as a primary reason. No studies examined patterns of missed doses due to ADRs; 41/108 (38%) studies examined associations between 68 types of ADR (across 15 organ systems) and missed doses. Nuance around ADR-missed doses relations regarding drug susceptibility testing profile and whether the missed doses originated from the patient, healthcare professionals, or both were found. CONCLUSION: There is extensive evidence that ADRs are a key driver for missed doses of anti-TB treatment. Some papers examined specific ADRs and none evaluated the patterns of missed doses due to ADRs, demonstrating a knowledge deficit. Knowing why doses both are and are not missed is essential in providing targeted interventions to improve treatment outcomes.

"It is not easy": Experiences of people living with HIV and tuberculosis on Tuberculosis treatment in Uganda.

Background: Completion of tuberculosis (TB) treatment presents several challenges to patients, including long treatment duration, medication adverse-effects and heavy pill burden. WHO emphasize the need for patient-centered TB care, but such approaches require understanding of patient experiences and perceptions. Methods: In 2020, we nested a qualitative study within a clinical trial that recruited 128 HIV-TB co-infected adults in Kampala receiving rifampicin-based TB treatment, alongside anti-retroviral therapy. A purposively selected sub-sample of 46 trial participants contributed to nine gender segregated focus group discussions. Of these, 12 also participated in in-depth interviews. Sessions were recorded, transcribed verbatim and translated from local languages into English. Thematic analysis focused on drug adverse-effects, use of self-prescribed medications and barriers to treatment adherence. Results: Patients seemed more concerned about adverse effects that clinicians sometimes overlook such as change in urine color. Those who remembered pre-treatment counselling advice were disinclined to manage adverse-effects by self-prescription. Difficulty in accessing a medical practitioner was reported as a reason for self-medication. Obstacles to adherence included stigma (especially from visible adverse-effects like "red urine"), difficulties with pill size and number, discomfort with formulation and medication adverse effects. Conclusion: Tailored pre-treatment counselling, improved access to clinical services, and simpler drug administration will deliver more patient-centered care.

Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin.

BACKGROUND: Higher doses of rifampicin may improve treatment outcomes and reduce the duration of tuberculosis (TB) therapy. However, drug-drug interactions with antiretroviral therapy (ART) and safety in people with human immunodeficiency virus (HIV) have not been evaluated. METHODS: This was a randomized, open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily-dose rifampicin. ART treatment-naive patients were randomized to dolutegravir- or efavirenz-based ART. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. HIV viral load was measured at week 24. RESULTS: Among 128 patients randomized, the median CD4 count was 191 cells/mm3. The geometric mean ratio (GMR) for trough dolutegravir concentrations on higher- vs standard-dose rifampicin was 0.57 (95% confidence interval [CI], .34-.97; P = .039) and the GMR for mid-dose efavirenz was 0.63 (95% CI, .38-1.07; P = .083). There was no significant difference in attainment of targets for dolutegravir trough or efavirenz mid-dose concentrations between rifampicin doses. The incidence of HIV treatment failure at week 24 was similar between rifampicin doses (14.9% vs 14.0%, P = .901), as was the incidence of drug-related grade 3-4 adverse events (9.8% vs 6%). At week 8, fewer patients remained sputum culture positive on higher-dose rifampicin (18.6% vs 37.0%, P = .063). CONCLUSIONS: Compared with standard-dose rifampicin, high-dose rifampicin reduced dolutegravir and efavirenz exposures, but HIV suppression was similar across treatment arms. Higher-dose rifampicin was well tolerated among people with HIV and associated with a trend toward faster sputum culture conversion. CLINICAL TRIALS REGISTRATION: NCT03982277.