Treatment of Multi-Drug-Resistant Tuberculosis with Second-Line All-Oral Drugs in Ghana: Incidence of Adverse Events.

Technical Summary: Treatment of Multi-Drug-Resistant Tuberculosis with Second-Line All-Oral Drugs in Ghana

Problem Statement
The management of multidrug-resistant tuberculosis (MDR-TB) remains a critical public health challenge, particularly in resource-limited settings like Ghana. While the World Health Organization (WHO) has transitioned from injectable-based regimens to all-oral regimens (incorporating drugs such as bedaquiline, linezolid, and fluoroquinolones) to improve tolerability and outcomes, there is a scarcity of peer-reviewed data regarding the incidence and determinants of adverse events (AEs) associated with these new regimens in Ghana. The toxicity of second-line drugs poses significant risks, potentially leading to treatment interruptions, reduced efficacy, and poor patient outcomes. This study addresses the knowledge gap by investigating the incidence, types, severity, and predictors of adverse events among MDR-TB patients treated with second-line all-oral drugs in Ghana.

Methodology
The research employed a retrospective cohort study design, analyzing medical records of MDR-TB patients treated between 2020 and August 2024.

• Study Sites: Data were extracted from three major MDR-TB treatment centers (Directly Observed Therapy clinics): Greater Accra Regional Hospital, Eastern Regional Hospital, and Kumasi South Hospital.
• Population: The initial review included 402 patients. After excluding 18 patients due to transfer to other centers, voluntary herbal treatment, or missing data, the final analysis comprised 384 patients. Inclusion criteria required bacteriological confirmation of rifampicin and/or isoniazid resistance via GeneXpert and treatment exclusively with second-line all-oral regimens.
• Data Collection: A customized Kobo Collect tool was used to extract demographics, baseline clinical characteristics, treatment regimens, and adverse events. Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 2.1), categorizing events as "not severe" (Grades 1–2) or "severe" (Grade 3+).
• Analysis: Descriptive statistics summarized patient characteristics and AE frequencies. Associations between independent variables (age, sex, comorbidities) and adverse events were analyzed using multivariate Poisson regression to calculate Adjusted Risk Ratios (aRR). Statistical significance was set at p < 0.05.

Key Results

• Demographics: The cohort had a mean age of 45 years (SD=15), with 65.8% male. The majority of patients were aged 25–64 years. Approximately 25% of patients presented with comorbidities, with HIV co-infection being the most prevalent (19.5%).
• Adverse Event Incidence: Half of the patients (50.52%) experienced at least one adverse event. The most frequently reported AEs were diarrhea (14.0%), dizziness (13.7%), and vomiting (12.3%).
• Severity and Trends: The majority of adverse events were mild to moderate. Severe events, such as leukopenia (3.1%) and acute kidney injury (0.6%), were rare (<5%). Gastrointestinal symptoms (vomiting, nausea) showed a significant decline over the treatment course (e.g., vomiting dropped from 12.5% in months 1–3 to ~2% in months 7–9), suggesting patient adaptation or improved management. However, neurological and gastrointestinal symptoms like dizziness and headache persisted at moderate levels throughout the treatment period.
• Risk Factors: Multivariate analysis identified two significant predictors of adverse events:
  • Comorbidities: Patients with comorbid conditions (e.g., diabetes, hypertension, HIV) were approximately 2.6 times more likely to experience adverse events compared to those without (aRR = 2.65, 95% CI: 1.58–4.43, p < 0.001).
  • Age: Contrary to general expectations, patients aged 65 years and older had a 56% lower risk of adverse events compared to younger patients (aRR = 0.44, 95% CI: 0.25–0.79, p = 0.005).
  • Sex: Sex was not a statistically significant predictor after adjustment (aRR = 1.03, p = 0.86).
• Treatment Outcomes: The study reported a successful treatment outcome rate (cured + treatment completed) of 74.9%. Unsuccessful outcomes (death, failure, default) accounted for 25.1%.

Significance and Claims
The authors posit that this study provides essential evidence for optimizing MDR-TB management in Ghana. The findings confirm that while all-oral regimens are generally well-tolerated with a high success rate, adverse events remain a common occurrence, particularly gastrointestinal and neurological symptoms.

The paper claims that the identification of comorbidities as a primary risk factor underscores the necessity for integrated care models that manage TB alongside chronic conditions like HIV and diabetes. Furthermore, the observation that older patients experienced fewer adverse events challenges assumptions about age-related vulnerability in this context, potentially indicating better adherence or closer monitoring in this demographic.

Ultimately, the study concludes that continuous monitoring and proactive management of adverse events are critical to maintaining treatment adherence and improving outcomes. The authors assert that these findings support the continued adoption of all-oral regimens in Ghana while highlighting the need for targeted interventions for patients with comorbidities to minimize complications and align with global TB elimination goals.