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Review

Preventive Therapy for Contacts of Drug-Resistant Tuberculosis

by
Yousra Kherabi
1,2,*,
Simone Tunesi
3,
Alexander Kay
4 and
Lorenzo Guglielmetti
1,5
1
Centre d’Immunologie et des Maladies Infectieuses, Sorbonne Université, INSERM, U1135, Cimi-Paris, Équipe 2, 75013 Paris, France
2
Department of Infectious Diseases, Hôpital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, 75018 Paris, France
3
Department of Infectious Diseases, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy
4
Global Tuberculosis Program, Baylor College of Medicine, Houston, TX 77030, USA
5
Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Laboratoire de Bactériologie-Hygiène, Hôpital Pitié-Salpêtrière, APHP Sorbonne Université, 75013 Paris, France
*
Author to whom correspondence should be addressed.
Pathogens 2022, 11(10), 1189; https://doi.org/10.3390/pathogens11101189
Submission received: 19 September 2022 / Revised: 12 October 2022 / Accepted: 14 October 2022 / Published: 15 October 2022
(This article belongs to the Special Issue Mycobacterium tuberculosis Infection: Policy Gaps and Research Breakthroughs)
Review Reports Versions Notes

Abstract

:
Preventing the progression of a drug-resistant tuberculosis (DR-TB) infection to disease is an important pillar of the DR-TB elimination strategy. International guidelines have recently proposed fluoroquinolones for tuberculosis preventive therapy (TPT) in DR-TB contacts, although the available evidence is low quality. The pooled data from small observational studies suggest that a fluoroquinolone-based TPT is safe, effective and cost-effective as a preventive treatment in DR-TB contacts. Three clinical trials are currently ongoing to generate higher quality evidence on the efficacy of levofloxacin and delamanid as a DR-TB preventive therapy. Additional evidence is also needed, regarding TPT treatment in fluoroquinolone-resistant-TB contacts, patient and health care worker perceptions on DR-TB preventive therapy for contacts, and the service delivery models to increase DR-TPT access. This state-of-the-art review presents the current literature on TPT for contacts of DR-TB cases, focusing on the available evidence and international guidelines.

1. Introduction

Rifampin-resistant tuberculosis (RR-TB) and multidrug-resistant tuberculosis (MDR-TB), defined as TB resistant to both rifampin and isoniazid, are a global public health issue [1]. In 2019, there were 465,000 incident cases of RR/MDR-TB. The estimated global treatment success rate for RR/MDR-TB is low, around 59% in 2018 [2]. Hence, preventive actions, such as developing effective vaccines and implementing tuberculosis preventive therapy (TPT), are essential to reduce the cases of drug-resistant TB (DR-TB) and achieve the goals of the End TB Strategy, set by the World Health Organization (WHO) [3].
A TB infection occurs when Mycobacterium tuberculosis is inhaled without causing clinical signs. Once this happens, a TB infection can be cleared by the innate immune system and remain silent—what we define as a latent tuberculosis infection (LTBI)—or evolve into active TB disease [4]. Active TB is typically associated with the development of clinical and/or radiological changes. A person with active pulmonary TB disease can transmit M. tuberculosis. It has been recently estimated that about a quarter of the global population is infected with TB; the rate of infected populations varies considerably across the WHO regions [5]. The reservoir of potential TB cases must be managed in order to control the TB pandemic; this is also true for DR-TB cases, which are linked most frequently with the direct transmission of DR-TB strains, rather than with an acquired drug resistance [6,7,8].
Preventing the progression of a DR-TB infection to disease is thus a major component of the strategy leading to TB elimination [9,10]. Timely screening and treatment of close contacts of patients with DR-TB is a major priority, as 90% of active cases among MDR-TB contacts occurs within the first two years after the exposure [11,12]. This is particularly true for young children and people living with HIV, who have a higher risk of infection with M. tuberculosis and a rapid progression towards TB disease [13,14]. Despite the need for DR-TB prevention strategies, global TPT coverage remains insufficient. Between 2018 and 2020, only 29% of children under 5 years and 1.6% of other household contacts—of drug-susceptible and DR-TB cases—eligible for TPT, received it [2]. In addition, the proportion of DR-TB household contacts receiving TPT is presumed to be substantially lower than this overall proportion.
Moreover, the COVID-19 pandemic led to a concerning decrease in DR-TB diagnosis, treatment and contact tracing, resulting in a potential increase in the transmission [2]. The consequences of the pandemic on DR-TB epidemiology are still not fully known, but they underscore the need for a stronger global policy on DR-TB preventive therapy.
The objective of this article is to provide an up-to-date review of the literature on the preventive therapy for contacts of DR-TB cases, focusing on the available evidence, ongoing clinical trials and existing guidelines.

2. Published Evidence on the Preventive Therapy for DR-TB Contacts

Contacts of DR-TB Cases

Household contacts of a patient with active pulmonary TB are at high risk for a TB infection and disease as they have a prolonged exposure to the index cases [15,16]. A meta-analysis published by Shah and colleagues, showed that 47% (95% confidence interval (95% CI), 30–61%) of the DR-TB patients’ household contacts are infected [12]. The prevalence of a TB infection and disease is particularly high among children who are household contacts and exposed to RR-TB, reaching up to 57% in an observational study published by Kim and colleagues [17]. These transmission rates are even higher between mother and children in the household.
Household contact evaluations entail actively detecting and treating contacts with LTBI, who would benefit from TPT. Although considerable that differences exist between countries, this strategy is generally well-established in low-incidence TB settings. Conversely, in high-burden, low-resources settings, a less expensive “passive” contact management strategy is the rule [18]. The programmatic surveillance of the DR-TB patients’ contacts without TPT administration, is useful to detect active TB disease at an early stage but it does not curb the risk of developing active TB disease [19]. In a modelling study published by Dodd and colleagues, the active household contact management in rifampicin-susceptible tuberculosis, required more effort to prevent each death, compared to the RR/MDR-TB contact management [20]. This finding suggests that active DR-TB household contact management should be considered a high priority in the global fight against tuberculosis.

3. Preventive Therapy: Effectiveness, Safety and Cost-Effectiveness

Multiple TPT regimens are available for drug-susceptible TB. The World Health Organization’s recommended regimens rely on single drugs (6–9 months of daily isoniazid or 4 months of daily rifampin), or multiple medications (3 months of daily isoniazid and rifampin, 3 months of weekly isoniazid and rifapentine and 1 month of daily isoniazid and rifapentine). These regimens, according to the TB pharmacologic principles, are unlikely to provide effective TPT for a MDR-TB infection [5]. However, a prospective study led in Peru by Huang and colleagues has shown some efficacy of TPT with isoniazid, even in contacts of MDR-TB cases [21]. Isoniazid monotherapy is also used as a control in a randomized, controlled trial for TPT of MDR-TB contacts (PHOENIx trial, NCT03568383). While other evidence suggests that isoniazid provides insufficient protection following an infection with MDR-TB, these recent data suggest that isoniazid may need to be re-evaluated in this context.
Several regimens have been tested as DR-TB preventive therapy, using one, two or three drugs thought to be effective against the source case, including isoniazid, pyrazinamide, ethambutol, fluoroquinolones and/or ethionamide. The strong evidence-based policies for TPT of DR-TB contacts are lacking because the current published data primarily consists of small cohort studies. No randomized, controlled trial data is available to date. The results of the main studies analyzing the effectiveness of DR-TB preventive therapy, which were published at the time of writing (September 2022), are described in Table 1. Although the highest proportion of studies are from South Africa, in which the co-prevalence of DR-TB and HIV is high, the largest studies are from Pakistan and Peru. All studies reported here include a pediatric population. The fluroquinolone-based regimens, either a fluoroquinolone monotherapy or fluoroquinolone with a companion drug, e.g., ethambutol or ethionamide, are the most commonly evaluated. The most frequently reported primary outcome is an incidence of active TB disease, and the completion rates are reported in most of studies. Unfortunately, the safety data is not always explicitly detailed.
In 2017, Marks and colleagues published a meta-analysis pooling of the data of the available observational studies on DR-TB preventive therapy [22]. They estimated a statistically significant reduction in TB incidences among the treated, compared to the untreated contacts. In a negative binomial model, they found a 90% (very wide CI, 9–99%) risk reduction of developing active TB. In this meta-analysis, the most effective regimen seemed to include fluoroquinolone combined with ethionamide. Recently, Malik and colleagues published a large cohort study evaluating TPT with a fluoroquinolone-based, 2-drug regimen, in Pakistan [23]. High-risk household contacts of all ages began a 6-month standardized course of preventive therapy with levofloxacin or moxifloxacin, associated with either ethambutol or ethionamide, regardless of the drug susceptibility pattern of the strain harboured by the source case. The control group was an historical cohort of untreated contacts from previous published studies. Overall, 172 adults and children contacts of fluoroquinolone-susceptible DR-TB patients were included. In this cohort, the fluoroquinolone-based therapy reduced the risk for TB disease in high-risk contacts exposed to DR-TB by 65% within 2 years after the diagnosis of a DR-TB in the index patient.
An important factor to consider while evaluating TPT effectiveness is the treatment completion. The extended duration of the therapy, the excessive pill burden and medication related adverse events can contribute to the patient’s decision making surrounding the TPT initiation and completion. In the aforementioned meta-analysis, the overall treatment completion rate was of 68% (95% CI, 64–71%), of all treatment regimens taken into account.
A major reason for the treatment discontinuation, is the toxicity associated with TPT. In a small prospective cohort study performed in the United States of America, Adler-Shohet and colleagues followed, prospectively, 31 children with a suspected MDR-LTBI, for 2 years [28]. Twenty-six children received a 9-month regimen of levofloxacin and pyrazinamide. All of the treated children experienced adverse events, and 42% of them stopped treatment. The severity of the adverse events was not specified in the article, but the most frequent were arthralgia, myalgia, abdominal pain, and elevated hepatic enzymes. Another study evaluating levofloxacin and pyrazinamide as TPTs for a presumptive MDR-LTBI in adults reported similar results, namely that all participants experienced at least one adverse effect, and all discontinued the treatment [34]. In the meta-analysis by Marks et al., regimens containing pyrazinamide seemed to have the highest rate of adverse events (average, 66%) and most of those resulted in the discontinuation of the TPT (average, 51%; 95% CI, 44–59%) [22]. Fluoroquinolones and pyrazinamide should not be used together for TPT. While fluoroquinolone–based regimens (without pyrazinamide) have shown a high percentage (33%) of adverse events, they rarely lead to TPT discontinuation (2%; 95% CI, 1–4%), suggesting a lower severity [22]. While some concerns regarding the safety of fluoroquinolones remain, particularly in the pediatric population, there is now extensive evidence for their safety, including in children [35].
Moreover, the fear of enhancing the emergence of drug resistance has been cited by physicians as an obstacle to TPT prescription [36]. Though this concern has been repeatedly proven to be unfounded for isoniazid regimens in drug-susceptible TB prevention, some authors argue that the absence of an observed elevation in the risk of DR-TB among those receiving TPT, in small studies, does not imply that the selective pressure imposed by a community-wide TPT will not be substantial, especially in the context of DR-TB contacts [37,38].
Overall, the existing data suggest that TPT for a DR-TB exposure and infection is both effective and safe. In a modelling study, Dodd and colleagues assessed the cost-effectiveness of screening child household contacts of RR/MDR-TB patients and compared the TPT regimens given to the groups who were at high risk of developing the tuberculosis disease [20]. The results indicated that TPT given to children younger than 15 years is likely to be cost-effective for preventing new TB cases and reducing TB-associated mortality in most countries. Moreover, a regimen with levofloxacin was more cost-effective than a delamanid-based TPT. Other modelling studies came to similar conclusions regarding the TPT of a MDR-LTBI: Holland and colleagues found that the association of fluoroquinolone with ethambutol was cost-effective, while Fox and colleagues’ model found that fluoroquinolone monotherapy was cost-saving [39,40]. In the aforementioned meta-analysis, the MDR-LTBI preventive therapy was cost-saving, compared to no treatment [22]. The most cost-effective regimen was fluoroquinolone associated with ethambutol, followed by fluoroquinolone alone, and the association of pyrazinamide with ethambutol. In the specific population of young contacts, in patients with comorbidities or in high tuberculosis burden settings, a monotherapy with fluoroquinolone became more cost-effective.

4. Available Guidelines on Preventive Therapy for DR-TB Contacts

The recommendations from available international guidelines are summarized in Table 2. Although based on the low-level evidence coming from the observational studies, the guidelines generally agree on the need to treat the contacts of MDR-TB patients. A daily levofloxacin-based treatment is the most commonly recommended regimen for both adults and children. The WHO guidelines recommend a fluoroquinolone-based regimen (with or without a companion drug e.g., ethionamide and/or ethambutol), when tolerated. However, the role of companion drugs in TPT regimens is not clear yet, as their use is linked with the increased risk of side effects and early treatment interruption [5]. The European Centre for Disease Prevention and Control (ECDC) guidelines, while still recommending TPT as a first option, underline the lack of strong evidence both in favour and against the pharmacological treatment and allow the strict observation for the onset of the symptoms among contacts [41]. Doctors Without Borders (MSF) guidelines recommend assessing the indication for treatment according to each case, evaluating the resistance patterns of the source case, the risk of progression, the intensity of exposure and the risk of side effects during treatment [42]. If eligibility is established, a six-months standard levofloxacin treatment is recommended. Similarly, the joint American Thoracic Society, the U.S. Centres for Disease Control and Prevention, the European Respiratory Society, and the Infectious Diseases Society of America (ATS/CDC/ERS/IDSA) guidelines recommend to use a daily levofloxacin monotherapy for 6 to 12 months [43]. The use of other drugs, such as pyrazinamide, is not advised due to the frequent discontinuation for toxicity. Overall, all guidelines underline the need for research on TPT in drug-resistant TB contacts, considering the scarcity of the randomized trials and the weakness of the existing evidence in favour of or against TPT in this field.

5. Trial Landscape

In recent years, the need to increase the evidence on the efficacy of DR-TB preventive therapy has been satisfied by the launch of three randomized prospective trials, whose primary endpoints are the description of incidence of active TB among patients receiving experimental treatment vs. patients receiving a placebo or standard-of-care treatment (Table 3).
The V-QUIN MDR-TB trial is a placebo-controlled, double-blind trial aiming to assess the role of levofloxacin in TPT for adult household contacts of MDR-TB patients (ACTRN12616000215426) [44]. The population of the trial, performed in Vietnam, included patients aged >15 years who were in contact with confirmed MDR-TB cases, during the prior three months and had a positive tuberculin skin test (TST). The patients were randomized into two groups, one receiving a daily dose of 750 mg of levofloxacin, the other receiving a placebo. The study follow-up was up to 30 months after the start of the treatment. The total expected sample size was 3344 participants. The recruitment for the V-QUIN MDR-TB trial has been recently completed.
The TB-CHAMP (Tuberculosis child multidrug-resistant preventive therapy, ISRCTN92634082) Phase III, cluster randomised controlled trial differs from the V-QUIN MDR TB trial, primarily for the inclusion criteria [45]. This study, set in South Africa, recruits only children aged <5 years who have been in contact with confirmed MDR-TB cases. The focus on children was justified by the lack of evidence in this population, the need to assess the pediatric safety of a fluoroquinolone-based treatment and the increased risk of progression to the active disease in children. The children were randomized into two treatment groups, receiving either 15–20 mg/kg/day of levofloxacin or a placebo, for 24 weeks. The participants were followed up for 18 months after treatment. Aiming to include 1556 patients, recruitment started in 2017 and it is still ongoing.
PHOENIx (Protecting Households On Exposure to Newly diagnosed Index Multidrug-Resistant Tuberculosis Patients) is an ACTG/IMPAACT collaborative phase III, open-label, multicentre, international trial (NCT03568383). The aim is to evaluate the efficacy and safety of delamanid for TPT in high-risk household contacts of MDR-TB. The patients from 12 countries (Botswana, Brazil, Haiti, India, Kenya, Peru, Philippines, South Africa, Tanzania, Thailand, Uganda, Zimbabwe) are separated into two groups, one receiving 26 weeks of delamanid, while the others receive 26 weeks of isoniazid. The patients are followed up for 96 weeks post-randomization. The total recruitment is still ongoing, aiming for a total sample size of 5610 participants.
The results of these three clinical trials are pending. Further research should also focus on individualised treatment strategies, based on the strain of the index case, particularly in the settings with high background rates of a fluoroquinolone resistance [46]. Moreover, recent studies on mouse models have demonstrated the promising potential of short-term regimens, based on newly approved drugs, such as bedaquiline, which should be evaluated as a possible candidate in DR-TB preventive therapy [47].

6. Conclusions

High-quality data on the management of TPT in contacts of DR-TB patients are lacking. Three major randomized controlled clinical trials are undergoing and may shed light on the optimal approach to a DR-TB prevention. While waiting for the results of these promising clinical trials, the pooled data of the observational studies show that fluoroquinolone-based TPT regimens are safe, effective and cost-effective in DR-TB contacts. Indeed, all major guidelines recommend TPT for contacts of RR/MDR-TB patients, mostly with fluoroquinolone or with the combination of fluoroquinolone and another drug. Yet, major challenges are still to be faced. First, there are no approved recommendations for TPT for patients in contact with pre-XDR or XDR cases. There is thus an urgent need to evaluate the TPT regimens that do not include fluoroquinolones, in particular those based on new drugs, such as delamanid—with the ongoing PHOENIx trial- and bedaquiline. Second, the TPT treatment completion is also a major concern. All ongoing clinical trials are testing 6-month regimens, which may be perceived as too long for symptom-free contacts and entail a high pill burden, especially for patients who are already treated for another medical condition, such as HIV. Studies on shorter regimens are needed, building on the recent breakthroughs in TPT for a drug-susceptible LTBI. Third, safety concerns can also be a barrier to TPT implementation. Framing a pharmacovigilance network, offering a standardized follow-up for contacts starting TPT and providing counselling for both contacts and physicians, may increase the global uptake of TPT. Finally, individualised treatment strategies, based on the strain of the index case, should be considered for the exposed household contacts of DR-TB patients.

Author Contributions

Conceptualization, Y.K. and L.G.; methodology, Y.K., S.T., A.K. and L.G.; validation, Y.K., S.T., A.K. and L.G.; investigation, Y.K., S.T., A.K. and L.G.; writing—original draft preparation, Y.K. and S.T.; writing—review and editing, Y.K., S.T., A.K. and L.G.; supervision, A.K. and L.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Meeting Report of the WHO Expert Consultation on the Definition of Extensively Drug-Resistant Tuberculosis. Available online: https://www.who.int/publications-detail-redirect/meeting-report-of-the-who-expert-consultation-on-the-definition-of-extensively-drug-resistant-tuberculosis (accessed on 17 May 2021).
  2. Global Tuberculosis Report 2021. Available online: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2021 (accessed on 7 November 2021).
  3. Fu, H.; Lewnard, J.A.; Frost, I.; Laxminarayan, R.; Arinaminpathy, N. Modelling the Global Burden of Drug-Resistant Tuberculosis Avertable by a Post-Exposure Vaccine. Nat. Commun. 2021, 12, 424. [Google Scholar] [CrossRef] [PubMed]
  4. Kendall, E.A.; Shrestha, S.; Dowdy, D.W. The Epidemiological Importance of Subclinical Tuberculosis. A Critical Reappraisal. Am. J. Respir. Crit. Care Med. 2021, 203, 168–174. [Google Scholar] [CrossRef] [PubMed]
  5. WHO Consolidated Guidelines on Tuberculosis. Module 1: Prevention—Tuberculosis Preventive Treatment; World Health Organization: Geneva, Switzerland, 2020; Available online: Https://Apps.Who.Int/Iris/Bitstream/Handle/10665/331170/9789240001503-Eng.Pdf (accessed on 12 August 2022).
  6. Andrews, J.R.; Gandhi, N.R.; Moodley, P.; Shah, N.S.; Bohlken, L.; Moll, A.P.; Pillay, M.; Friedland, G.; Sturm, A.W. Tugela Ferry Care and Research Collaboration Exogenous Reinfection as a Cause of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis in Rural South Africa. J. Infect. Dis. 2008, 198, 1582–1589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Ershova, J.V.; Volchenkov, G.V.; Kaminski, D.A.; Somova, T.R.; Kuznetsova, T.A.; Kaunetis, N.V.; Cegielski, J.P.; Kurbatova, E.V. Epidemiology of Primary Multidrug-Resistant Tuberculosis, Vladimir Region, Russia. Emerg. Infect. Dis. 2015, 21, 2048–2051. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Yang, C.; Luo, T.; Shen, X.; Wu, J.; Gan, M.; Xu, P.; Wu, Z.; Lin, S.; Tian, J.; Liu, Q.; et al. Transmission of Multidrug-Resistant Mycobacterium Tuberculosis in Shanghai, China: A Retrospective Observational Study Using Whole-Genome Sequencing and Epidemiological Investigation. Lancet Infect. Dis. 2017, 17, 275–284. [Google Scholar] [CrossRef] [Green Version]
  9. Das, P.; Horton, R. Tuberculosis–Getting to Zero. Lancet 2015, 386, 2231–2232. [Google Scholar] [CrossRef]
  10. Rangaka, M.X.; Cavalcante, S.C.; Marais, B.J.; Thim, S.; Martinson, N.A.; Swaminathan, S.; Chaisson, R.E. Controlling the Seedbeds of Tuberculosis: Diagnosis and Treatment of Tuberculosis Infection. Lancet 2015, 386, 2344–2353. [Google Scholar] [CrossRef] [Green Version]
  11. Seddon, J.A.; Fred, D.; Amanullah, F.; Schaaf, H.S.; Starke, J.R.; Keshavjee, S.; Burzynski, J.; Furin, J.J.; Swaminathan, S.; Becerra, M.C. Post-Exposure Management of Multidrugresistant Tuberculosis Contacts: Evidence-Based Recommendations; Policy Brief No. 1; Harvard Medical School Center for Global Health Delivery–Dubai: Dubai, United Arab Emirates, 2015; Available online: Http://Sentinel-Project.Org/Wp-Content/Uploads/2015/11/Harvard-Policy-Brief_revised-10Nov2015.Pdf (accessed on 12 August 2022).
  12. Shah, N.S.; Yuen, C.M.; Heo, M.; Tolman, A.W.; Becerra, M.C. Yield of Contact Investigations in Households of Patients With Drug-Resistant Tuberculosis: Systematic Review and Meta-Analysis. Clin. Infect. Dis. 2014, 58, 381–391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. McShane, H. Co-Infection with HIV and TB: Double Trouble. Int. J. STD AIDS 2005, 16, 95–100; quiz 101. [Google Scholar] [CrossRef] [PubMed]
  14. Marais, B.J.; Gie, R.P.; Schaaf, H.S.; Hesseling, A.C.; Obihara, C.C.; Starke, J.J.; Enarson, D.A.; Donald, P.R.; Beyers, N. The Natural History of Childhood Intra-Thoracic Tuberculosis: A Critical Review of Literature from the Pre-Chemotherapy Era. Int. J. Tuberc. Lung Dis. 2004, 8, 392–402. [Google Scholar] [PubMed]
  15. Sepkowitz, K.A. How Contagious Is Tuberculosis? Clin. Infect. Dis. 1996, 23, 954–962. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Andrews, R.H.; Devadatta, S.; Fox, W.; Radhakrishna, S.; Ramakrishnan, C.V.; Velu, S. Prevalence of Tuberculosis among Close Family Contacts of Tuberculous Patients in South India, and Influence of Segregation of the Patient on Early Attack Rate. Bull. World Health Organ. 1960, 23, 463–510. [Google Scholar] [PubMed]
  17. Kim, S.; Wu, X.; Hughes, M.D.; Upton, C.; Narunsky, K.; Mendoza-Ticona, A.; Khajenoori, S.; Gonzales, P.; Badal-Faesen, S.; Shenje, J.; et al. High Prevalence of Tuberculosis Infection and Disease in Child Household Contacts of Adults With Rifampin-Resistant Tuberculosis. Pediatr. Infect. Dis. J. 2022, 41, e194. [Google Scholar] [CrossRef] [PubMed]
  18. Malik, A.A.; Fuad, J.; Abbass, W.; Ikhlaque, S.; Fareeda, G.; Siddiqui, M.R.; Khan, A.J.; Keshavjee, S.; Becerra, M.C.; Hussain, H. Preventive Treatment of Drug-Resistant TB in a Rural Setting. Int. J. Tuberc. Lung Dis. 2021, 25, 231–233. [Google Scholar] [CrossRef] [PubMed]
  19. Malik, A.A.; Becerra, M.C.; Hussain, H. Ringing the Alarm Bell: Time to Scale up Drug-Resistant Tuberculosis Preventive Treatment. EClinicalMedicine 2021, 34, 100821. [Google Scholar] [CrossRef]
  20. Dodd, P.J.; Mafirakureva, N.; Seddon, J.A.; McQuaid, C.F. The Global Impact of Household Contact Management for Children on Multidrug-Resistant and Rifampicin-Resistant Tuberculosis Cases, Deaths, and Health-System Costs in 2019: A Modelling Study. Lancet Glob. Health 2022, 10, e1034–e1044. [Google Scholar] [CrossRef]
  21. Huang, C.-C.; Becerra, M.C.; Calderon, R.; Contreras, C.; Galea, J.; Grandjean, L.; Lecca, L.; Yataco, R.; Zhang, Z.; Murray, M. Isoniazid Preventive Therapy in Contacts of Multidrug-Resistant Tuberculosis. Am. J. Respir. Crit. Care Med. 2020, 202, 1159–1168. [Google Scholar] [CrossRef] [PubMed]
  22. Marks, S.M.; Mase, S.R.; Morris, S.B. Systematic Review, Meta-Analysis, and Cost-Effectiveness of Treatment of Latent Tuberculosis to Reduce Progression to Multidrug-Resistant Tuberculosis. Clin. Infect. Dis. 2017, 64, 1670–1677. [Google Scholar] [CrossRef] [Green Version]
  23. Malik, A.A.; Gandhi, N.R.; Lash, T.L.; Cranmer, L.M.; Omer, S.B.; Ahmed, J.F.; Siddiqui, S.; Amanullah, F.; Khan, A.J.; Keshavjee, S.; et al. Effectiveness of Preventive Therapy for Persons Exposed at Home to Drug-Resistant Tuberculosis, Karachi, Pakistan. Emerg. Infect. Dis. 2021, 27, 805–812. [Google Scholar] [CrossRef]
  24. Gureva, T.; Turkova, A.; Yablokova, E.; Smirnova, P.; Sveshnikova, O.; Zolotaya, O.; Nikishova, E.; Heldal, E.; Hinderaker, S.; Seddon, J.A.; et al. Fluoroquinolone Preventive Therapy for Children Exposed to MDR-TB. Int. J. Tuberc. Lung Dis. 2022, 26, 171–173. [Google Scholar] [CrossRef] [PubMed]
  25. Malik, A.A.; Fuad, J.; Siddiqui, S.; Amanullah, F.; Jaswal, M.; Barry, Z.; Jabeen, F.; Fatima, R.; Yuen, C.M.; Salahuddin, N.; et al. Tuberculosis Preventive Therapy for Individuals Exposed to Drug-Resistant Tuberculosis: Feasibility and Safety of a Community-Based Delivery of Fluoroquinolone-Containing Preventive Regimen. Clin. Infect. Dis. 2020, 70, 1958–1965. [Google Scholar] [CrossRef] [PubMed]
  26. Malik, A.A.; Becerra, M.C.; Lash, T.L.; Cranmer, L.M.; Omer, S.B.; Fuad, J.; Siddiqui, S.; Amanullah, F.; Jaswal, M.; Salahuddin, N.; et al. Risk Factors for Adverse Events in Household Contacts Prescribed Preventive Treatment for Drug-Resistant Tuberculosis Exposure. Clin. Infect. Dis. 2021, 72, 1709–1715. [Google Scholar] [CrossRef]
  27. Huang, W.; Chiu, N.-C.; Chi, H.; Huang, F.-Y.; Huang, C.-Y. Inoculation Age of Bacillus Calmette-Guérin Tokyo-172 Strain and Vaccine-Related Adverse Reactions in Taiwan Birth Cohort of 2012–2017. Clin. Infect. Dis. 2021, 73, e1554–e1559. [Google Scholar] [CrossRef]
  28. Adler-Shohet, F.C.; Low, J.; Carson, M.; Girma, H.; Singh, J. Management of Latent Tuberculosis Infection in Child Contacts of Multidrug-Resistant Tuberculosis. Pediatr. Infect. Dis. J. 2014, 33, 664–666. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Bamrah, S.; Brostrom, R.; Dorina, F.; Setik, L.; Song, R.; Kawamura, L.M.; Heetderks, A.; Mase, S. Treatment for LTBI in Contacts of MDR-TB Patients, Federated States of Micronesia, 2009–2012. Int. J. Tuberc. Lung Dis. 2014, 18, 912–918. [Google Scholar] [CrossRef] [Green Version]
  30. Garcia-Prats, A.J.; Zimri, K.; Mramba, Z.; Schaaf, H.S.; Hesseling, A.C. Children Exposed to Multidrug-Resistant Tuberculosis at a Home-Based Day Care Centre: A Contact Investigation. Int. J. Tuberc. Lung Dis. 2014, 18, 1292–1298. [Google Scholar] [CrossRef] [PubMed]
  31. Seddon, J.A.; Hesseling, A.C.; Finlayson, H.; Fielding, K.; Cox, H.; Hughes, J.; Godfrey-Faussett, P.; Schaaf, H.S. Preventive Therapy for Child Contacts of Multidrug-Resistant Tuberculosis: A Prospective Cohort Study. Clin. Infect. Dis. 2013, 57, 1676–1684. [Google Scholar] [CrossRef] [PubMed]
  32. Denholm, J.T.; Leslie, D.E.; Jenkin, G.A.; Darby, J.; Johnson, P.D.R.; Graham, S.M.; Brown, G.V.; Sievers, A.; Globan, M.; Brown, L.K.; et al. Long-Term Follow-up of Contacts Exposed to Multidrug-Resistant Tuberculosis in Victoria, Australia, 1995–2010. Int. J. Tuberc. Lung Dis. 2012, 16, 1320–1325. [Google Scholar] [CrossRef]
  33. Schaaf, H.S.; Gie, R.P.; Kennedy, M.; Beyers, N.; Hesseling, P.B.; Donald, P.R. Evaluation of Young Children in Contact with Adult Multidrug-Resistant Pulmonary Tuberculosis: A 30-Month Follow-Up. Pediatrics 2002, 109, 765–771. [Google Scholar] [CrossRef] [Green Version]
  34. Papastavros, T.; Dolovich, L.R.; Holbrook, A.; Whitehead, L.; Loeb, M. Adverse Events Associated with Pyrazinamide and Levofloxacin in the Treatment of Latent Multidrug-Resistant Tuberculosis. CMAJ 2002, 167, 131–136. [Google Scholar] [PubMed]
  35. Goldman, J.A.; Kearns, G.L. Fluoroquinolone Use in Paediatrics: Focus on Safety and Place in Therapy; World Health Organization: Geneva, Switzerland, 2011; pp. 1–13. [Google Scholar]
  36. Kalema, N.; Semeere, A.; Banturaki, G.; Kyamugabwa, A.; Ssozi, S.; Ggita, J.; Kabajaasi, O.; Kambugu, A.; Kigozi, J.; Muganzi, A.; et al. Gaps in TB Preventive Therapy for Persons Initiating Antiretroviral Therapy in Uganda: An Explanatory Sequential Cascade Analysis. Int. J. Tuberc. Lung Dis. 2021, 25, 388–394. [Google Scholar] [CrossRef] [PubMed]
  37. Balcells, M.E.; Thomas, S.L.; Godfrey-Faussett, P.; Grant, A.D. Isoniazid Preventive Therapy and Risk for Resistant Tuberculosis. Emerg. Infect. Dis. 2006, 12, 744–751. [Google Scholar] [CrossRef] [PubMed]
  38. Mills, H.L.; Cohen, T.; Colijn, C. Community-Wide Isoniazid Preventive Therapy Drives Drug-Resistant Tuberculosis: A Model-Based Analysis. Sci. Transl. Med. 2013, 5, 180ra49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Holland, D.P.; Sanders, G.D.; Hamilton, C.D.; Stout, J.E. Strategies for Treating Latent Multiple-Drug Resistant Tuberculosis: A Decision Analysis. PLoS ONE 2012, 7, e30194. [Google Scholar] [CrossRef]
  40. Fox, G.J.; Oxlade, O.; Menzies, D. Fluoroquinolone Therapy for the Prevention of Multidrug-Resistant Tuberculosis in Contacts. A Cost-Effectiveness Analysis. Am. J. Respir. Crit. Care Med. 2015, 192, 229–237. [Google Scholar] [CrossRef]
  41. European Centre for Disease Prevention and Control. Management of Contacts of MDR TB and XDR TB Patients; ECDC: Stockholm, Sweden, 2012. [Google Scholar]
  42. Médecins Sans Frontières and Partners in Health. Tuberculosis. Practical Guide for Clinicians, Nurses, Laboratory Technicians and Medical Auxiliaries; Médecins Sans Frontières and Partners in Health: Paris, France, 2022. [Google Scholar]
  43. Nahid, P.; Mase, S.R.; Migliori, G.B.; Sotgiu, G.; Bothamley, G.H.; Brozek, J.L.; Cattamanchi, A.; Cegielski, J.P.; Chen, L.; Daley, C.L.; et al. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. 2019, 200, e93–e142. [Google Scholar] [CrossRef]
  44. Fox, G.J.; Nguyen, C.B.; Nguyen, T.A.; Tran, P.T.; Marais, B.J.; Graham, S.M.; Nguyen, B.H.; Velen, K.; Dowdy, D.W.; Mason, P.; et al. Levofloxacin versus Placebo for the Treatment of Latent Tuberculosis among Contacts of Patients with Multidrug-Resistant Tuberculosis (the VQUIN MDR Trial): A Protocol for a Randomised Controlled Trial. BMJ Open 2020, 10, e033945. [Google Scholar] [CrossRef] [Green Version]
  45. Seddon, J.A.; Garcia-Prats, A.J.; Purchase, S.E.; Osman, M.; Demers, A.-M.; Hoddinott, G.; Crook, A.M.; Owen-Powell, E.; Thomason, M.J.; Turkova, A.; et al. Levofloxacin versus Placebo for the Prevention of Tuberculosis Disease in Child Contacts of Multidrug-Resistant Tuberculosis: Study Protocol for a Phase III Cluster Randomised Controlled Trial (TB-CHAMP). Trials 2018, 19, 693. [Google Scholar] [CrossRef] [Green Version]
  46. Khan, U.; Guglielmetti, L. Evidence and Ethical Considerations for the Treatment of Contacts Exposed to Drug-Resistant TB. Int. J. Tuberc. Lung Dis. 2022, 26, 900–901. [Google Scholar] [CrossRef]
  47. Kaushik, A.; Ammerman, N.C.; Tasneen, R.; Lachau-Durand, S.; Andries, K.; Nuermberger, E. Efficacy of Long-Acting Bedaquiline Regimens in a Mouse Model of Tuberculosis Preventive Therapy. Am. J. Respir. Crit. Care Med. 2022, 205, 570–579. [Google Scholar] [CrossRef]
Table
Table 1. Characteristics of the main studies assessing the tuberculosis preventive therapy effectiveness in drug-resistant tuberculosis contacts.
Table 1. Characteristics of the main studies assessing the tuberculosis preventive therapy effectiveness in drug-resistant tuberculosis contacts.
StudyCountry Study DesignDR-TB Contacts IncludedAdults/
Children		Evidence of a TB Infection (LTBI)Compared TPT (Months/Drug)Primary EndpointGrade 3 or 4 Adverse EventsCompletion Rate
Gureva et al., 2022
[24]		RussiaProspective cohort study 72Children ≤ 18 years-oldLTBI was diagnosed in 51 children, some children were treated without any evidence of a LTBI.9 Mfx
OR
9 Ofx
OR
No treatment		Incidence of TB disease:
0/58 (0%) with TPT
1/14 (7%) without TPT		None90%
Malik et al., 2020–2021
[23,25,26]		PakistanProspective cohort study800Adults & childrenLTBI was diagnosed in six subjects, some subjects were treated without any evidence of a LTBI.6 Lfx + E
OR
6 LFx + Eth
OR
6 Mfx + E
OR
6 MFx+ Eth		Overall effectiveness on TB incidence compared to the historical control cohorts: 65% (95% CI 13–86)None70%
Huang et al., 2020
[27]		PeruProspective cohort study652Children ≤ 19 years-oldLTBI status was assessed in all subjects, the proportion of subjects included with a proven LTBI is not reported.6–9 H
No specific DR-TB contact control group		Incidence of TB disease
26/652 (4%) with TPT		NRNR
Adler-Shohet et al.,
2014
[28]		United States of AmericaRetrospec-tive cohort study31ChildrenAll of the children included in the study had a proven LTBI.Lfx + ZIncidence of TB disease:
0/26 (0%) with TPT
0/5 (0%) without TPT		NR58%
Bamrah et al.,
2014
[29]		Federated States of MicronesiaProspective cohort study119Adults & childrenAll of the subjects included in the study had a proven LTBI.12 Lfx
12 Lfx + E
12 LFx + Eth
12 Mfx
12 MFx + E
No treatment		Incidence of TB disease:
0/104 (0%) with TPT
3/15 (20%) without TPT		None83–100%
Garcia-Prats et al.,
2014
[30]		South AfricaRetrospec-tive cohort study24Children ≤ 15 years-oldLTBI was diagnosed in eight subjects, some subjects were treated without any evidence of a LTBI.6 H + E + OfxIncidence of TB disease:
0/24 (0%) with TPT		None88%
Seddon et al.,
2013
[31]		South AfricaProspective cohort study186Children ≤ 5 years-old
HIV-positive children ≤ 15 years-old		LTBI was diagnosed in 73 children, some children were treated without any evidence of a LTBI.6 HE + OfxIncidence of TB disease:
6/186 (3%) with TPT		7/186 (4%)76%
Denholm et al.,
2012
[32]		AustraliaRetrospec-tive cohort study49Adults & childrenAll of the subjects included in the analysis had a proven LTBI.6–9 Mfx +/− E
6 Cfx +/− Z
6 RZE
9 HZ
6–9 RZ
No treatment		Incidence of TB disease:
0/11 (0%) with TPT
2/38 (5%) without TPT		None82%
Schaaf et al.,
2002
[33]		South AfricaProspective cohort study105Children ≤ 5 years-oldLTBI was diagnosed in 70 children, some children were treated without any evidence of a LTBI.6 HZ + Eth
6 HZE
6 HE + Eth
6 E + Eth
6 HZE + Eth
6 ZE + Eth
6 HZ + Eth		Incidence of TB disease:
2/41 (5%) with TPT
13/64 (20%) without TPT		NRNR
Abbreviations. DR-TB, drug-resistant tuberculosis (i.e., rifampicin-resistant or multidrug-resistant tuberculosis); LTBI, latent tuberculosis infection; TPT, tuberculosis preventive therapy; Mfx, moxifloxacin; Ofx, ofloxacin; Lfx, levofloxacin; E, ethambutol; Eth, ethionamide; H, isoniazid; Cfx, ciprofloxacin; Z, pyrazinamide; R, rifampicin; TB, tuberculosis; 95% CI, 95% confidence interval and NR, not reported.
Table
Table 2. Available guidelines on the preventive therapy for DR-TB contacts.
Table 2. Available guidelines on the preventive therapy for DR-TB contacts.
SourceYear of PublicationPopulation AddressedRecommendation to TreatWatchful Observation ApproachDrugAncillary DrugsTreatment Duration
WHO2020GeneralYesConsider LfxE, Eth6 months
ECDC2012GeneralYesConsiderLfxNo6 months
ATS/CDC/
ERS/IDSA		2019GeneralYesNot recommendedLfxNo6–12 months
MSF2022PediatricYesConsiderLfxNo6 months
Abbreviations: WHO, World Health Organisation; ECDC, European Centre for Disease Prevention and Control; ATS, American Thoracic Society; CDC, U.S. Centers for Disease Control and Prevention; ERS, European Respiratory Society; IDSA, Infectious Diseases Society of America; MSF, Doctors Without Borders; Lfx, levofloxacin, E, ethambutol and Eth, ethionamide.
Table
Table 3. Trial landscape on preventive therapy for DR-TB contacts.
Table 3. Trial landscape on preventive therapy for DR-TB contacts.
StudyStatusPopulation TypeStructureDuration of TreatmentCountryTotal Population Size (N)Duration of Follow-Up
V-QUINEnrolment completedAdults > 15 yearsLfx vs. Placebo6 monthsVietnam334430 months
TB-CHAMPEnrolment ongoingChildren < 5 yearsLfx vs. Placebo6 monthsSouth Africa155624 weeks
PHOENIxEnrolment ongoingAdults > 15 yearsDlm vs. H6 monthsInternational561026 weeks
Abbreviations: Lfx, levofloxacin; Dlm, delamanid and H, isoniazid.
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Kherabi, Y.; Tunesi, S.; Kay, A.; Guglielmetti, L. Preventive Therapy for Contacts of Drug-Resistant Tuberculosis. Pathogens 2022, 11, 1189. https://doi.org/10.3390/pathogens11101189

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Kherabi Y, Tunesi S, Kay A, Guglielmetti L. Preventive Therapy for Contacts of Drug-Resistant Tuberculosis. Pathogens. 2022; 11(10):1189. https://doi.org/10.3390/pathogens11101189

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Kherabi, Yousra, Simone Tunesi, Alexander Kay, and Lorenzo Guglielmetti. 2022. "Preventive Therapy for Contacts of Drug-Resistant Tuberculosis" Pathogens 11, no. 10: 1189. https://doi.org/10.3390/pathogens11101189

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