Rapid Review
Tuberculosis treatment and management—an update on treatment regimens, trials, new drugs, and adjunct therapies

https://doi.org/10.1016/S2213-2600(15)00063-6Get rights and content

Summary

WHO estimates that 9 million people developed active tuberculosis in 2013 and 1·5 million people died from it. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis continue to spread worldwide with an estimated 480 000 new cases in 2013. Treatment success rates of MDR and XDR tuberculosis are still low and development of new, more effective tuberculosis drugs and adjunct therapies to improve treatment outcomes are urgently needed. Although standard therapy for drug-sensitive tuberculosis is highly effective, shorter, more effective treatment regimens are needed to reduce the burden of infectious cases. We review the latest WHO guidelines and global recommendations for treatment and management of drug-sensitive and drug-resistant tuberculosis, and provide an update on new drug development, results of several phase 2 and phase 3 tuberculosis treatment trials, and other emerging adjunct therapeutic options for MDR and XDR tuberculosis. The use of fluoroquinolone-containing (moxifloxacin and gatifloxacin) regimens have failed to shorten duration of therapy, and the new tuberculosis drug pipeline is sparse. Scale-up of existing interventions with increased investments into tuberculosis health services, development of new antituberculosis drugs, adjunct therapies and vaccines, coupled with visionary political leadership, are still our best chance to change the unacceptable status quo of the tuberculosis situation worldwide and the growing problem of drug-resistant tuberculosis.

Introduction

Tuberculosis is still a global emergency.1 The WHO 2014 global tuberculosis report2 estimates that in 2013 9 million new cases of tuberculosis occurred, an increase from 8·6 million estimated in 2012. The western Pacific and southeast Asia regions had 56% of tuberculosis cases, with India (24%) and China (11%) bearing the highest burden. 25% of cases were from the WHO Africa region. An estimated 1·1 million of the 9 million new tuberculosis cases (13%) were in people with HIV. In 2013, of an estimated 1·5 million deaths attributable to tuberculosis, 510 000 were in women, 80 000 in children, and 400 000 in people with HIV. Although standard therapy for drug-sensitive tuberculosis is highly effective, shorter, more effective treatment regimens are needed to reduce the burden of infectious cases.

Key messages

  • An estimated 9 million people develop active tuberculosis and 1·5 million people die of it each year

  • Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis continue to spread relentlessly, and treatment outcomes are still poor

  • More effective treatment regimens are needed to reduce the burden of infectious cases

  • Trials have shown that fluoroquinolone-containing regimens (moxifloxacin and gatifloxacin) do not shorten the present 6-month duration of therapy

  • Apart from two new drugs rapidly approved under licence (bedaquiline and delamanid) for use in MDR disease, the new tuberculosis drug pipeline remains sparse

  • Scale-up of existing interventions and improving tuberculosis health services is still the best option to manage and control the unacceptable status quo of tuberculosis and the growing problem of drug-resistant disease

  • WHO global guidelines and recommendations are important and provide evidence-based principles of tuberculosis care in the public and private sectors worldwide, to ensure that an accurate diagnosis is established and proven acceptable treatment regimens are used under supervision

  • With dwindling drug treatment options, the need to explore other adjunct treatment options, including host-directed therapies is growing

The number of new cases of multidrug-resistant (MDR) tuberculosis (caused by Mycobacterium tuberculosis strains resistant to at least rifampicin and isoniazid) and of extensively drug-resistant (XDR) tuberculosis (defined by resistance to rifampicin, isoniazid, plus any fluoroquinolone and at least one of the three injectable second-line tuberculosis drugs, amikacin, kanamycin, and capreomycin) continue to increase. An estimated 480 000 new cases of MDR tuberculosis occurred in 2013, making up 3·5% of the estimated 9 million people who developed tuberculosis that year.2 Of these patients, only 97 000 started treatment and 39 000 were on waiting lists, thus leaving a huge number of people untreated. Treatment success rates for MDR tuberculosis regimens are still low for both individualised and standard regimens, resulting in high death rates. MDR and XDR tuberculosis now greatly complicate patient management, particularly in resource-poor national tuberculosis programmes. The dismal treatment outcomes of MDR and XDR tuberculosis highlight the urgent need for development of new antituberculosis drugs, treatment regimens, and other adjunct treatment approaches to improve treatment outcomes.

We review the latest WHO guidelines and global recommendations for treatment and management of drug-sensitive and drug-resistant tuberculosis and provide updates from the past 2 years' literature on the drug-development pipeline, results of tuberculosis treatment trials, and adjunct host-directed therapies.

Section snippets

Treatment of drug-susceptible tuberculosis

Guidelines and recommendations for management of tuberculosis are updated regularly, including the WHO-recommended treatment regimens, approved antituberculosis drugs, and the dosage of antituberculosis drugs (table 1 and appendix). Figure 1 shows the clinical management algorithm for treatment of tuberculosis.

Present WHO recommendations3 make a clear distinction between new cases (ie, patients diagnosed with tuberculosis, who have never had tuberculosis treatment or had previously received

Standardised and individualised treatment

Strategies for the treatment of drug-resistant tuberculosis have been recently updated.5 The treatment of monodrug-resistant and polydrug-resistant tuberculosis is addressed and is largely based on the recommendations from the 2011 WHO guidelines for the programmatic management of drug-resistant tuberculosis, which underwent systematic review and analysis of the best data available.6 Table 2 summarises the stepwise approach recommended for the design of treatment regimens. Thus, tuberculosis

Implementation of WHO guidelines

Translation of WHO guidelines into optimum standards of care worldwide faces operational difficulties due to lack of adequate laboratory diagnostic services and trained personnel, difficulties in designing the treatment regimen for MDR and XDR disease on full spectrum drug-susceptibility testing, poor availability of second-line tuberculosis drugs, and patient adherence and follow-up issues. The essence of tuberculosis treatment is early case detection, initiation of appropriate therapy, and

Drug interactions

Tuberculosis is the most common cause of death in HIV-positive patients.1, 13 The widespread rollout and clinical efficacy of antiretroviral drugs has led to substantial reduction in mortality and has contributed to the reduction in the incidence of opportunistic infections.13 The co-administration of tuberculosis drugs with antiretroviral drugs needs to be carefully monitored. There are well known pharmacological interactions (table 3), and drug–drug interactions are associated with an

Treatment of latent tuberculosis infection in high-risk groups

Latent M tuberculosis infection (LTBI) is defined as a state of persistent immune response to stimulation by M tuberculosis antigens without evidence of any clinical manifestations of active tuberculosis.25 Individuals with LTBI usually have no signs or symptoms of tuberculosis but are at risk of developing active tuberculosis disease when they are immunosuppressed from any cause. Prevention of LTBI from developing into active tuberculosis is important in some risk groups. Systematic testing

New drugs

Figure 2 shows the present tuberculosis drug developmental pipeline. For the first time in more than 50 years, two new tuberculosis drugs, delamanid and bedaquiline,28, 29, 30, 31, 32 have been approved by the US and European regulatory authorities and are now recommended by WHO for use as part of combination therapy for MDR tuberculosis. In 2013, the European Medicines Agency (EMA) approved conditional marketing authorisation for use of delamanid in adults with MDR tuberculosis as an addition

Other clinical presentations of tuberculosis

Apart from drug-resistant tuberculosis, there are several other clinical presentations of tuberculosis that are associated with difficulties of diagnosis and poor treatment outcomes, and for which new treatment regimens and adjunct therapeutic interventions are needed to improve management outcomes. These presentations include tuberculosis-associated immune reconstitution inflammatory syndrome, miliary tuberculosis, tuberculosis meningitis, CNS tuberculomas, spinal and bone tuberculosis,

Where next?

Tuberculosis differs from most other bacterial infectious diseases in human beings by requiring therapy that lasts for at least 6 months for drug-sensitive tuberculosis and 20 months for drug-resistant tuberculosis, often complicated by adverse drug events and pharmacokinetic interactions with other drugs. Poor treatment outcomes for MDR and XDR tuberculosis are dependent on several variables, such as genetic background, nutritional status, extent of inflammatory and immune response and

Host-directed therapies

With the restrictions of MDR tuberculosis therapy, increasing MDR and XDR cases worldwide and drug treatment options running out, attention has focused on adjunct host-directed therapy (using repurposed drugs and immunotherapy) approaches to treatment of MDR and XDR tuberculosis.65, 66, 67, 68, 69, 70, 71 An effective immune system is crucial to eradicate or contain M tuberculosis infection as LTBI. In cases of active tuberculosis, M tuberculosis replication is sometimes associated with excess,

Conclusion

Present WHO global guidelines and recommendations are important and provide evidence-based principles of tuberculosis care in the public and private sectors worldwide, and ensure that an accurate diagnosis is established and proven acceptable treatment regimens are used under supervision. With the failure of fluoroquinolones to shorten duration of chemotherapy, very sparse pipeline of new tuberculosis drug development, and dwindling drug treatment options for MDR tuberculosis, new drug

Search strategy and selection criteria

We searched publications in English language in PubMed, the Cochrane Library, Embase, and Google Scholar for the period Jan 31, 2000, to Jan 31, 2015, to obtain background information. Since this is a rapid update review of recent progress, we focused on publications from Jan 1, 2013, to Jan 31, 2015). The search terms used were “tuberculosis”, “Mycobacterium tuberculosis”, “TB”, combined with the terms “drugs”, “new drugs”, “treatment”, “regimens”, “treatment regimens”, “trials”, “clinical

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