Optimizing the Safety of Multidrug-resistant Tuberculosis Therapy in Namibia Evans L. Sagwa Sagwa, EL Optimizing the Safety of Multidrug-resistant Tuberculosis Therapy in Namibia Thesis Utrecht University -with ref.- with summary in Dutch Copyright © 2017 EL Sagwa. All rights reserved. The research presented in this PhD thesis was conducted under the umbrella of the Utrecht World Health Organization (WHO) Collaborating Centre for Pharmaceutical Policy and Regulation, which is based at the Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht Uni- versity, The Netherlands. The Collaborating Centre aims to develop new methods for independent pharmaceutical policy research, evidence-based policy analysis and conceptual innovation in the area of policy making and evaluation in general. ISBN: 978-94-92683-40-3 Layout and printed by: Optima Grafische Communicatie, Rotterdam, the Netherlands Optimizing the Safety of Multidrug-resistant Tuberculosis Therapy in Namibia Verbeteren van de veiligheid van de behandeling van multiresistente tuberculose in Namibië (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 24 augustus 2017 des middags te 12.45 uur door Evans Luvaha Sagwa geboren op 17 november 1972 te Kakamega, Kenia Promotor: Prof.dr. H.G.M. Leufkens Copromotor: Dr. A.K. Mantel-Teeuwisse A Quote by Donna Flagg: When the Cure Is Worse Than the Disease “Not only are the folks popping these pills not happy, but they now suffer from new problems that are caused by the drugs themselves”. http://www.huffingtonpost.com/donna-flagg/one-pill-away_b_777796.html [Blog posted on 11/04/2010] About the cover photo This photo shows some dried up trees at Deadvlei in the Namib Desert, which is inhos- pitable to human life. Tuberculosis disease could be as old as the Namibia Desert, yet humankind hasn’t been able to fully conquer it. If left untreated, TB deprives you of your full life potential and drains the vitality out of you, like the way the harshness of the Namib Desert drains life out of the trees depicted in the cover photo. However, looking above is the beautiful blue sky where rain and sunshine that sustain life, come from, symbolizing the hope and promise that TB treatment offers to patients. Photo courtesy of https://pixabay.com/en/tree-desert-namibia-dead-vlei-64311/ TABLE OF CONTENTS Chapter 1 General introduction 9 Chapter 2 An overview of adverse events during drug-resistant tuberculosis 25 treatment 2.1 The burden of adverse events during treatment of drug-resistant 27 tuberculosis in Namibia 2.2 Adverse events during treatment of drug-resistant tuberculosis: 43 a comparison between patients with or without human immunodeficiency virus co-infection 2.3 Occurrence and clinical management of moderate-to-severe 63 adverse events during drug-resistant tuberculosis treatment: a retrospective cohort study 2.4 Adverse Events and Patients’ Perceived Health-Related Quality of 79 Life at the End of Multidrug-Resistant Tuberculosis Treatment in Namibia Chapter 3 Otological safety of aminoglycosides used in drug-resistant 97 tuberculosis treatment 3.1 Differences in VigiBase® reporting of aminoglycoside and 99 capreomycin-suspected ototoxicity during tuberculosis treatment 3.2 Comparing amikacin and kanamycin-induced hearing loss in 113 multidrug-resistant tuberculosis treatment under programmatic conditions in a Namibian retrospective cohort 3.3 Comparing renal insufficiency among patients treated with 129 standard kanamycin-based anti-tuberculosis regimens or concomitantly with tenofovir-based HIV regimens Chapter 4 General discussion 143 Summary 173 Samenvatting 181 Addendum Acknowledgements 189 List of co-authors 195 List of publications 201 About the author 205 CHAPTER 1 General introduction General introduction The re-emergence of Tuberculosis: a global concern Reading current medical news and updates from journalists and the medical scientific community paints a gory and worrisome picture about the state of the tuberculosis Chapter 1 (TB) epidemic across the world. [1] The news point towards a grim resurgence of the TB epidemic. [2–5] This epidemic is raging havoc primarily in low and middle income countries, while in high income countries; TB is rearing its ugly ahead again, wanting to attack once more in a more vicious form; a form that is resistant to the current anti-TB drugs. [1,6] In many low and middle income countries especially in sub-Saharan Africa, weak health systems have been contributory to this problem. [7] Are we, therefore, losing the opportunity of eliminating TB from the face of the earth? Why is it taking mankind so long to eradicate TB? These are some of the questions that are most likely to reverberate in one’s mind while reviewing updates on the global TB epidemiology, from the year 2007 to date. A preeminent concern that is evident from these reports is the spectre of multidrug-resistant tuberculosis (MDR-TB). Box 1: Quote by the Global TB Alliance [8] “Today’s TB treatments take too long to cure, are too complicated to administer, and can be toxic. Many people have negative interactions between commonly used antiretrovirals and TB treatment. People with TB must take drugs from 6 months to 2 years or longer—or risk developing more difficult to treat drug-resistant TB. Today, treatment for drug-resistant TB can take up to two years, and is so complex, expensive, and toxic that many patients are unable to access treatment. Further, the cost of curing MDR-TB can be staggering — literally thousands of times as expensive as that of regular treatment in some regions — posing a significant challenge to governments, health systems, and other payers. Of those who do, almost half will die.” Multidrug-resistant tuberculosis, therefore, can no longer be ignored, especially in developing countries, where the MDR-TB burden is highest. [9] Unlike drug-sensitive Mycobacterium tuberculosis, the treatment of MDR-TB takes a long time; is complex, and is frequently associated with the occurrence of a range of adverse drug reactions. [10–15] Some of these adverse drug reactions, such as ototoxicity, nephrotoxicity and hepatotoxicity, could severely diminish a person’s health-related quality of life (HRQoL). [16–19] Besides, the global treatment success rates for MDR-TB have gener- ally been poor, at around 48%, due to several factors, including patients’ difficulties with adhering to their prescribed MDR-TB treatment regimens. [20,21] The occurrence of severe or serious treatment-related adverse events, along with other disease-related sequelae, may impair patients’ ability to perform activities of daily life during or after MDR-TB treatment. [19,22] This calls for the routine monitoring, clinical assessment and management of adverse events among patients undergoing MDR-TB treatment, so Page 11 CHAPTER 1 that their overall HRQoL can be preserved and the MDR-TB treatment success rates en- hanced. [19] The treatment of MDR-TB and other forms of tuberculosis drug-resistance is even more complicated in patients who are also on concomitant antiretroviral (ARV) treatment for HIV [23] because of the overwhelming pill burden, medication adher- ence challenges, the possibility of drug-drug interactions; and the potential additive or overlapping adverse reactions of the anti-TB and ARV medicines. [24] In addition, children pose a unique challenge because of the lack of appropriate pharmaceutical dosage forms for this patient category [25,26] and the inability or difficulty of younger children to adequately describe the symptoms of the adverse events they may be experiencing. [27] mDr-Tb paThology, epiDemiology anD TreaTmenT Tuberculosis is an ancient infectious disease caused by the Mycobaterium tuberculosis bacillus. [28] In a newly diagnosed patient who has never been treated before for TB, the bacterium is often susceptible to the current World Health Organization (WHO)- recommended first-line drugs (isoniazid, rifampicin, ethambutol, pyrazinamide and streptomycin). [29] However, when the M. tuberculosis is resistant to both isoniazid and rifampicin, it is then termed as MDR-TB. [29] The leading cause of MDR-TB is the failure of patients to adhere to the first-line treatment of drug-susceptible TB. [30,31] Further, if a patient who is diagnosed with MDR-TB fails to correctly take his or her second-line medicines, the patient may develop extensively (XDR) or totally resistant strains of Mycobacterium tuberculosis. [4,32] XDR-TB involves resistance to isoniazid and rifam- picin; resistance to any of the fluoroquinolones (such as levofloxacin or moxifloxacin) and to at least one of the three injectable second-line drugs (amikacin, capreomycin or kanamycin). [33] Some experts have coined the term “programmatically incurable TB”, to describe strains of M. tuberculosis that are resistant to almost all the older anti-TB drugs. [34] Multidrug-resistant tuberculosis continues to disproportionately ravage populations living in low and middle income countries of the world. [35] In sub-Saharan Africa, MDR-TB is mainly prevalent in the countries with a high TB burden, such as Namibia, Botswana, Central African Republic, Chad, Congo, Ghana, Guinea-Bissau, Liberia, and Swaziland. [36] Namibia is a southern African country with a population of about 2.4 million