Exclusion of Clofazimine is a Barrier to Access
‘Tuberculosis (TB) is a public health crisis despite being curable, and claims approximately 4 000 lives globally every day,’ noted Dr Nirupa Misra who graduated with a PhD in Pharmacy.
Supervised by Professors Panjasaram Naidoo and Nesri Padayatchi, Misra conducted a two-phase study focusing on access and evaluating dose-weight interactions on outcomes. She found that the fact that Clofazimine (CFZ) is not registered in South Africa and is not included in the country’s Standard Treatment Guidelines (STGs) or the Essential Medicines List (EML) is a barrier to access.
‘Despite huge investments in programmatic management, humankind seems to be losing the battle against this deadly bacterium with low treatment success rates reported globally. This has resulted in the emergence of drug resistant tuberculosis (DRTB) which is more difficult to treat than drug sensitive TB,’ she said.
‘Historically the treatment journey for DRTB has been long (18–20 months) with a daily injection and a handful of oral medicine. Overlapping side effects, mainly permanent hearing loss caused by the injectable and difficult treatment journey, contributes to poor outcomes with high loss to follow up and death rates.
‘The medicine pipeline has been stagnant for years and recent registration of Bedaquiline and Delaminid and repurposing of Clofazimine hold promise of improved outcomes. Medicine must be available and accessible and used at a dose that is effective and safe in order to reduce further resistance,’ explained Misra.
Given that the optimal dose of CFZ that is safe and effective in the South African population is unknown. Misra’s study sought to fill this gap.
Whilst CFZ was being used as an unregistered product, she implemented a stock management system, distributing CFZ to all initiating sites in KwaZulu-Natal whilst ensuring that informed consent and progress reports were completed and submitted to the regulatory authorities. She assisted with quantification and forecasting of CFZ needs for the province.
An article on barriers to access was published in Ponte, an internationally recognised peer-reviewed journal. Misra also motivated for the inclusion of CFZ in STG and EML as part of the National TB Control Programme Committee.
CFZ is now registered in South Africa and included in guidelines; however, a gap still remains on the optimal dose of CFZ that is safe and effective.
Guidelines published in 2011 recommended weight-based dosing of CFZ at high doses for long periods of time despite a lack of evidence on safety and efficacy. The new guidelines upgrade CFZ from a group 5 medicine classified as medicine with unknown safety and efficacy to a core medicine to treat DRTB together with BDQ in a short course, all oral treatment regimen at a dose of 100mg daily. Misra said this recommendation appears to be based on low quality evidence and may be due to concerns of overlapping cardiotoxicity of CFZ and Bedaquiline.
Her study found that dose-weight interaction plays a role in the odds of a successful outcome. Patients >50kg prescribed 100mg CFZ were 60% less likely to have a successful outcome compared to those <50kg receiving 100mg. Patients <50kg who received >200mg were 40% less likely to have a successful treatment outcome (and were found to have a higher risk of adverse events) than patients <50kg receiving 100mg. Weight based dosing in patients <50kg and >50kg must be considered to achieve optimal treatment outcomes and reduce adverse events.
‘The recommended dose needs to be reviewed in light of the evidence provided. Active drug safety monitoring must be implemented as a package of care,’ she said.
Words: Nombuso Dlamini