ABSTRACT
Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second 'Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective, we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.
Subject(s)
Rifampin , Tuberculosis, Multidrug-Resistant , Adult , Antitubercular Agents/therapeutic use , Child , Clinical Protocols , Humans , Rifampin/therapeutic use , Time Factors , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Multidrug-Resistant/drug therapyABSTRACT
Worldwide uptake of new drugs in the treatment of rifampicin-resistant tuberculosis (RR-TB) has been extremely low. In June 2018, ahead of the release of the updated WHO guidelines for the management of RR-TB, South Africa announced that bedaquiline (BDQ) would be provided to virtually all RR-TB patients on shorter or longer regimens. South Africa has been the global leader in accessing BDQ for patients with RR-TB, who now represent 60% of the global BDQ cohort. The use of BDQ within a shorter modified regimen has generated the programmatic data underpinning the most recent change in WHO guidelines endorsing a shorter, injectable-free regimen. Progressive policies on access to new drugs have resulted in improved favourable outcomes and a reduction in mortality among RR-TB patients in South Africa. This supported global policy change. The strategies underpinning these bold actions include close collaboration between the South African National TB Programme and partners, introduction of new TB diagnostic tools in closely monitored conditions and the use of locally generated programmatic evidence to inform country policy changes. In this paper, we summarise a decade´s work that led to the bold decision to use a modified, short, injectable-free regimen with BDQ and linezolid under carefully monitored programmatic conditions.
Subject(s)
Antitubercular Agents , Tuberculosis, Multidrug-Resistant , Antitubercular Agents/therapeutic use , Cohort Studies , Humans , Linezolid , South Africa/epidemiology , Tuberculosis, Multidrug-Resistant/drug therapyABSTRACT
SUMMARY
Multidrug-resistant (MDR) and extensively drug-resistant tuberculosis (XDR-TB) are global concerns, with stagnant treatment success rates of roughly 54% and 30%, respectively. Despite adverse events associated with several DR-TB drugs, newly developed drugs and shorter regimens are bringing hope; recent concern has focused on drugs that prolong the corrected QT interval (QTc). QTc prolongation is a risk factor for torsades de pointe (TdP), a potentially lethal cardiac arrhythmia. While QTc prolongation is used in research as a surrogate marker for drug safety, the correlation between QTc and TdP is not perfect and depends on additional risk factors. The electrocardiogram (ECG) monitoring that has been recommended when new drugs are used has created alarm among clinicians and National Tuberculosis Programmes (NTPs). ECG monitoring is often challenging in high-burden settings where treatment alternatives are limited. According to a review of studies, the prevalence of sudden death directly attributable to TdP by QTc-prolonging DR-TB drugs is likely less than 1%. The risk of death from an ineffective MDR-TB/XDR-TB regimen thus far exceeds the risk of death from arrhythmia. In patients with QTc prolongation who develop cardiac events, other significant risk factors in addition to the drugs themselves are nearly always present. Clinicians and NTPs should be aware of and manage all possible circumstances that may trigger an arrhythmia (hypopotassaemia and human immunodeficiency virus infection are probably the most frequent in DR-TB patients). We present the limited but growing evidence on QTc prolongation and DR-TB management and propose a clinical approach to achieve an optimal balance between access to life-saving drugs and patient safety.ABSTRACT
BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB) has a poor treatment success rate and high mortality. Multidrug-resistant TB (MDR-TB) has worse outcomes when there is added resistance to second-line injectable drugs (pre-XDR-TBSLID) or fluoroquinolones (pre-XDR-TBFQ). OBJECTIVES: Treatment outcomes in patients with pre-XDR-TB and XDR-TB in a high HIV prevalence area were compared. METHODS: A retrospective medical record review was conducted of patients with pulmonary pre-XDR-TB and XDR-TB managed from 2008 to 2010 at Sizwe Tropical Disease Hospital, Johannesburg, South Africa. Standardised MDR-TB treatment was instituted and was subsequently individualised when further second-line susceptibility results became available. RESULTS: Of 86 patients studied, 95% were sputum smear-positive at baseline, 73% had sputum culture conversion, and 65% were human immunodeficiency virus (HIV) infected, with a median CD4 count of 201 cells/mm³. Of 53 patients with XDR-TB, 26 with pre-XDR-TBFQ and 7 with pre-XDR-TBSLID, respectively 13%, 12% and 29% were cured, 21%, 23% and 57% had a favourable outcome, and 26%, 23% and 14% died. Clofazimine (P < 0.001) and linezolid (P = 0.044) impacted on favourable outcomes. CONCLUSION: Patients with pre-XDR-TBFQ did not have better outcomes than those with XDR-TB. In countries with standardised regimens for resistant TB, patients with pre-XDR-TBFQ may need to receive XDR-TB treatment.
Subject(s)
Antitubercular Agents/therapeutic use , Extensively Drug-Resistant Tuberculosis/drug therapy , HIV Infections/epidemiology , Adolescent , Adult , Clofazimine/therapeutic use , Extensively Drug-Resistant Tuberculosis/complications , Extensively Drug-Resistant Tuberculosis/epidemiology , Female , Fluoroquinolones/therapeutic use , HIV Infections/complications , Humans , Linezolid/therapeutic use , Male , Microbial Sensitivity Tests , Middle Aged , Retrospective Studies , South Africa/epidemiology , Sputum/microbiology , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: South Africa has a large burden of extensively drug-resistant tuberculosis (XDR-TB); only 15% of XDR-TB patients have successful outcomes. OBJECTIVE: To describe the safety and effectiveness of bedaquiline (BDQ) in the South African BDQ Clinical Access Programme. DESIGN: An interim cohort analysis. RESULTS: Of the first 91 patients enrolled between March 2013 and July 2014 (with follow-up until August 2014), 54 (59%) were human immunodeficiency virus (HIV) infected. The median CD4 count was 239 cells/µl, and all patients were on antiretroviral therapy (ART) at initiation of BDQ; 33 had XDR-TB, 41 were pre-XDR-TB with fluoroquinolone resistance and 17 were pre-XDR-TB with resistance to an injectable. Of the 91 patients, 58 (64%) had completed 24 weeks of BDQ, 28 were still on BDQ, 3 were lost to follow-up, 1 had died and 1 had BDQ withdrawn following atrial fibrillation. Of the 63 patients with 6 months follow-up, 48 (76%) had either culture-converted or remained culture-negative after initiation of BDQ. QTcF was monitored monthly and exceeded 500 ms in three participants; this resolved in all three. CONCLUSION: Interim safety and culture conversion outcomes for patients accessing BDQ in South Africa, including HIV-infected patients on ART and patients with pre-XDR- and XDR-TB, suggest that BDQ may be both efficacious and safe.
