Introduction of new drugs and drug regimens for the management of drug-resistant tuberculosis in south africa: policy framework

Objectives

This framework aims to improve survival, treatment success and quality of life for people with drug-resistant tuberculosis (DR-TB) in South Africa by expanding equitable access to safer and more effective new or repurposed medicines and individualised regimens. It responds to poor multidrug-resistant tuberculosis (MDR-TB) outcomes, toxicity from older standardised regimens, tuberculosis and HIV co-infection, and the risks of treatment failure, further resistance and preventable harm.[1][2][3][4]

• Provide immediate, patient-centred treatment for rifampicin-resistant tuberculosis, using standardised regimens for eligible new patients and individualised regimens where prior second-line exposure, resistance, intolerance or complex clinical circumstances require this.[4][5]
• Introduce and scale up bedaquiline, linezolid, delamanid and other newer or repurposed medicines, alongside potentially shorter regimens, while maintaining appropriate selection, safety oversight and access to quality-assured products.[6][3]
• Construct regimens with as many tolerated medicines likely to be effective as possible, including at least four for pre-extensively drug-resistant or extensively drug-resistant tuberculosis where feasible.[5][7]
• Prevent acquired resistance by avoiding inadequate regimens, unsupported interruptions, failure to identify existing resistance and addition of a single medicine to a failing regimen.[4][5][8]
• Protect patients through active pharmacovigilance, adverse-drug-reaction management, monitoring for cardiac, renal, hepatic, neuropsychiatric and hearing toxicity, and surveillance for emerging resistance to new medicines.[2][9][10][11]
• Strengthen clinician and healthcare-worker capacity in DR-TB diagnosis, treatment, adverse-event management, clinical case management, monitoring, evaluation, recording and reporting.[12][13]

Implementation

Implementation combines national policy oversight with phased decentralisation to designated sites, provincial coverage and district delivery. The National Department of Health and National Tuberculosis Programme lead the framework, while provincial health departments, district and facility teams, clinicians, pharmacies, laboratories, civil-society and non-governmental partners, academic institutions, patients and technical experts contribute to delivery, training, review and support.[3][14][12][15]

• Phase introduction through pre-implementation access programmes before regulatory approval, post-approval use at designated sites, provincial expansion and subsequent district coverage.[3][14]
• Develop SMART scale-up plans for each medicine or drug group, covering staffing, equipment, laboratory support, adherence, supply chains, pharmacovigilance, standard operating procedures, model of care, referral arrangements and budget implications.[15]
• Ensure uninterrupted availability of quality-assured medicines, including affordable generic linezolid where available, and recognise that the source does not provide a quantified programme budget or monetary allocation.[2][3]
• Train nurses, doctors, pharmacists, counsellors, managers and public- and private-sector healthcare workers before medicine roll-out; provide refresher training after staff changes and continuing support through face-to-face sessions, webcasts and electronic learning.[12][13][15]
• Establish provincial DR-TB Clinical Advisory Committees and clinical sub-committees to review difficult individual cases, advise on individualised regimens, treatment extensions, medico-legal and ethical matters, and potential treatment termination.[16][12]
• Use clinical advisory review for complex bedaquiline prescribing, including selected patients with limited effective regimen options, treatment beyond six months, pregnancy, younger age or significant contraindications.[17][18]
• Deliver bedaquiline through trained and mentored sites, use an optimised background regimen rather than adding it alone to failing treatment, and manage HIV co-infection by avoiding efavirenz where it could reduce bedaquiline exposure.[19][8][10]
• Maintain facility-level data capture in EDRweb, the national DR-TB monitoring system; validate and verify information across district, provincial and national levels; preserve treatment histories during transfers; and assign data custodianship to the National Department of Health.[20]
• Classify treatment outcomes as cured, completed, died, failed, lost to follow-up or not evaluated, using culture conversion and bacteriological results to assess treatment response and outcomes.[21]
• Record adverse drug reactions in EDRweb and report serious events to the Medicines Control Council, National Pharmacovigilance Centre, relevant manufacturer and provincial advisory structures as applicable; review national and provincial reports quarterly.[9][22][23]
• Monitor electrocardiographic QT intervals for regimens containing bedaquiline, clofazimine or moxifloxacin, undertake bedaquiline resistance testing through national and referral laboratories, and escalate concerning minimum inhibitory concentration results for urgent clinical review, enhanced surveillance and infection control.[24][10][11]
• Monitor hearing before and during injectable treatment where possible, prioritise people at greatest ototoxicity risk when resources are limited, continue follow-up after treatment, and refer hearing-loss cases for audiology and rehabilitation where available.[25][26][27]
• Update the framework as clinical studies, programme experience, pharmacovigilance findings and further evidence become available, recognising that several clinical and operational questions remain unresolved.[1][6]

Monitoring & Evaluation

Monitoring and accountability combine programme-level data systems, clinical audit, pharmacovigilance, laboratory surveillance and structured advisory review to support safe scale-up of new and repurposed treatments for drug-resistant tuberculosis (DR-TB). National oversight is paired with implementation at provincial, district and facility levels, using the Electronic Drug-Resistant Tuberculosis Register (EDRweb) as the principal platform for routine data capture, reporting and review.[6][3][15][20]

• Establish monitoring and evaluation for new drugs and regimens, including active pharmacovigilance, adverse-event reporting and surveillance for emerging drug resistance.[2][6][11]
• Capture facility-level DR-TB data daily where EDRweb is available, enter paper-register data into EDRweb at least weekly, and apply validation, verification and quality checks as data move through district, provincial and national levels.[20]
• Submit quarterly reports by the last Friday of the month after each quarter, subject to annual deadlines issued by the RIMES Directorate of the tuberculosis cluster.[20]
• Assign data capturers responsibility for complete, accurate and timely records; retain National Department of Health custodianship of data where partners support data capture or cleaning.[20]
• Record patient transfers at the initiating facility, assign subsequent data entry and outcomes to the receiving site, and merge records to preserve the treatment history.[20]
• Identify duplicate or erroneous patient records through facility data capturers, confirm deletions through data managers and notify affected facilities.[21]

Clinical outcome monitoring relies on bacteriological testing, culture conversion, regimen response and treatment-outcome classification. Rifampicin-resistant tuberculosis outcomes are classified as cured, completed, died, failed, lost to follow-up or not evaluated; culture conversion requires two negative cultures at least 30 days apart, while reversion requires two positive cultures at least 30 days apart after conversion.[21]Treatment response is monitored through culture conversion, with treatment duration and regimen adaptation informed by drug-susceptibility testing, prior treatment, adverse reactions, comorbidities and tolerability.[4][5][28]

• Use culture-based drug-susceptibility testing and line probe assay results to determine whether a regimen requires individualisation and whether medicines should be included or excluded.[4][5][28]
• Define treatment failure through failure to convert, bacteriological reversion during continuation treatment, additional acquired resistance to fluoroquinolones or second-line injectable drugs, or adverse drug reactions.[21]
• Identify patients recorded as not evaluated and request outcome assessment from the treating clinician, including where a transferred patient’s outcome is unknown.[21]
• Undertake regular clinical audits led by the Drug-Resistant Tuberculosis Directorate to assess adherence to national guidance, staffing, equipment, monitoring and reporting systems, and medical files.[13]
• Match medical files with EDRweb and paper registers to verify reported patient numbers and assess facility capacity, including staffing, diagnostics, pharmacy services and DR-TB beds.[13]

Adverse drug reaction monitoring uses targeted spontaneous reporting for all rifampicin-resistant tuberculosis patients and cohort event monitoring at capacitated sentinel sites, initially focused on bedaquiline.[9]Events are classified by seriousness, causality and severity, and reports capture the reaction, onset and outcome dates, suspected medicines, treatment interruption, rechallenge and dose changes.[9][22][23]National and provincial levels review EDRweb adverse drug reaction reports quarterly.[23][29]

• Monitor renal function monthly during the intensive phase for patients receiving injectable agents associated with renal dysfunction, and use clinical and laboratory review to grade and manage toxicity.[29]
• Monitor neuropsychiatric effects through monthly medical-officer review or earlier assessment when symptoms occur.[30]
• Undertake baseline and monthly hepatic testing for patients receiving potentially hepatotoxic medicines, with repeat testing within 48 hours when aminotransferases exceed three times the upper limit of normal.[31]
• Assess hearing before or within seven days of starting ototoxic treatment where possible, continue testing during treatment, and repeat pure-tone audiometry at three and six months after treatment ends.[32]
• Prioritise patients with previous second-line drug exposure or pre-existing unilateral hearing loss when audiology resources are constrained.[27]

Bedaquiline monitoring includes baseline and scheduled electrocardiograms, with monthly testing during treatment and weekly corrected QT interval monitoring during the first month when clofazimine, moxifloxacin or specified antiretroviral combinations increase risk.[10][33][24]Minimum inhibitory concentration testing is undertaken at baseline, week 8 and week 24, with quarterly review and urgent notification to the clinician and National Clinical Advisory Committee when values rise fourfold from baseline or exceed 0.25 micrograms per millilitre.[11]During the first rollout year, designated sites submit weekly bedaquiline initiation data, and the National Department of Health Drug-Resistant Tuberculosis Directorate audits the first 500 patient records.[34]

Provincial clinical advisory committees and their clinical sub-committees provide accountability for difficult clinical, ethical and medico-legal cases, individualised regimens and treatment extensions.[16][12]Full provincial committee meetings occur monthly, decisions are recorded in minutes, and electronic case decisions require at least three clinical sub-committee members before inclusion in the subsequent monthly record.[12]Training records are maintained in EDRweb, with certificates issued to successful participants.[12]Quantitative programme-wide performance targets and a fully specified evaluation timetable are not provided in the supplied material.[2][7]

Costing & Financing

The supplied material provides limited costing information. It identifies cost and resource considerations relevant to medicine procurement, training, data systems, clinical monitoring and referral arrangements, but does not provide a total programme budget, currency-denominated allocations, expenditure estimates, quantified funding gaps or economic assumptions.[6][3][35][15][20]

• Recognise that the cost of Pfizer’s patented linezolid restricted its use in DR-TB treatment, and source a more affordable quality-assured generic linezolid through the South African National Tuberculosis Programme during 2015.[3]
• Use partner support for training and refresher courses before new tuberculosis medicines are introduced, including possible partner financial assistance for training sessions.[12][15]
• Plan and quantify scale-up resources, including electrocardiography and portable audiometry, alongside human-resource capacity, laboratory support, pharmacovigilance, supply-chain requirements and the model of care.[15]
• Address budget implications for referral arrangements through agreement between provincial clinical advisory committees and treatment-site leadership before medicine distribution.[15]
• Note that Right to Care supported the 8 December 2014 policy-framework review meeting and drafting technical assistance through a United States Agency for International Development funding cooperative agreement.[35]
• Recognise that partner-supported data-capturing arrangements are mentioned without associated monetary values.[20]

No monetary cost is specified for bedaquiline implementation, resistance surveillance, pharmacovigilance, audiometry, adverse-event monitoring or wider DR-TB treatment.[29][36][19][10][33]