Successful treatment of XDR-TB patient in Tanzania: report of the first XDR-TB patient

Introduction

Extensively drug-resistant tuberculosis (XDR-TB) is defined as TB resistant to any fluoroquinolone, and at least one of the three second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to multidrug resistance. ¹ The disease has recently become a matter of public health importance as the prevalence continues to rise despite raised awareness and preventive measures put in place. In 2017, the World Health Organization (WHO) reported 160,684 cases of multi-drug resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) notified in 2017, among whom an estimated 8.5% had XDR-TB. ¹

Tanzania is one of 30 high-burden TB countries globally with a documented increasing trend of detected drug-resistant TB cases. ¹ In 2017, its incidence was estimated at 29 per million population. ² It accounts for 0.9% of all new TB patients seen and 4.7% of previously treated TB cases; among notified pulmonary TB patients in 2017, some 640 have been duly recorded. ¹

The treatment for drug-resistant TB is very complicated and expensive, and requires a prolonged duration of treatment, which has higher rates of toxicity. ² Following WHO approval of bedaquiline, Tanzania started its use in 2015. We report the first XDR-TB patient and describe both his management approach and outcome.

Case report

A 31-year-old man, HIV-negative, was initially diagnosed with pulmonary TB in 2008 and initiated on treatment, but was lost to follow-up after two months. In 2011, he was recommenced on a retreatment regime consisting of streptomycin and oral first-line medications according to WHO 2010 recommendations, ³ being incarcerated in prison at the time in South Africa. He returned to Tanzania in 2013. At this time was still smear-positive; testing with GeneXpert confirmed that he was resistant to rifampicin. He was then started on a standard MDR-TB treatment regimen comprising kanamycin, pyrazinamide, levofloxacin, ethambutol and cycloserine while awaiting baseline culture results (Table 1).

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Table 1.

Drug susceptibility results at the time of MDR-TB diagnosis.

Drug tested	Status
Rifampicin	Resistant
Isoniazid	Resistant
Streptomycin	Resistant
Ofloxacin	Sensitive
Kanamycin	Sensitive
Ethambutol	Sensitive

During follow-up, he attained culture conversion by the second month, but culture tested positive on the fifth month of MDR-TB treatment. In the sixth month, culture was negative, but a chest radiogram showed perihilar opacities and in the subsequent two months, both cultures were positive. The drug susceptibilities using MGIT at this time are summarized in Table 2. A diagnosis of XDR-TB based on the DST results in Table 2 was made.

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Table 2.

Drug susceptibility results during MDR-TB follow-up at month 8.

Drug tested	Status
Amikacin	Resistant
Kanamycin	Resistant
Ofloxacin	Resistant
Moxifloxacin	Resistant
Levofloxacin	Sensitive

Our patient was started in October 2014 on capreomycin 1G once daily (o.d. × 5/week), levofloxacin-1G, isoniazid 600 mg, clofazimine 300 mg, cycloserine 500 mg, pyrazinamide 1.5 G, para-aminosalicylic acid (PAS) 8 G and vitamin B6 200 mg once daily. This treatment was a salvage plan while waiting for bedaquiline and linezolid to be introduced once available.

The chest radiograph at this stage showed increased hilar opacification. Despite radiological improvement, he remained smear positive after one month. However, the next month, he reverted to being culture-negative; in the subsequent month, as well as three and six months later, cultures were again positive. Unfortunately, cultures for other months were not available.

In November 2015, bedaquiline at 400 mg o.d. was eventually introduced for two weeks and subsequently at 200 mg o.d. (×3/week) for 22 weeks, as well as linezolid 600 mg, ethambutol 1.2 G, levofloxacin 1 G, PAS 8 G and amoxicillin-clavulanic acid 2.6 G daily for 18 months.

Culture became negative one month following the introduction of this new medication and remained so till the end of the treatment period, except for one result in March 2016 which was later disregarded as it was presumed to be a laboratory error due to contamination. The chest radiograph at one year of treatment showed signs of healing with an increase in fibrotic changes especially in the left upper lung.

He completed treatment in July 2017, thus having undergone 30 months of medications (12 months on a salvage regime plus 18 months on the strengthened regime with bedaquiline and linezolid, both having been given for six months).

He was declared cured as >11 sputum cultures were negative over the final 18 months. He did not develop any severe adverse drug reaction, despite close monitoring. He remained stable, progressing normally with his daily activities. Monthly follow-up for two years confirmed his weight as remaining stable and all cultures negative.

A written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review from the Editor-in-Chief of this journal.

Discussion

In this report, we document the first case of XDR-TB in Tanzania. The patient had interrupted treatment, a documented risk for developing drug resistance. South Africa, where he was incarcerated, has a higher burden of MDR-/XDR-TB than Tanzania. ⁴ His first drug sensitivity test was sensitive to fluoroquinolones and second-line injectables which makes the possibility of initial infection with a drug-resistant TB strain unlikely. However, he had a history of poor adherence to treatment and therefore was susceptible of acquiring drug-resistant TB.

Ours is the first patient to use bedaquiline in Tanzania. The case report highlights some of the challenges of managing MDR-TB and the very costly long duration of treatment necessary. Fortunately, there were no severe adverse events which could have further complicated his management.

Addition of bedaquiline and linezolid after 12 months of initial salvage regimen led to quick sputum conversion in our patient. A similar experience was had in Singapore. ⁵ Bedaquiline appears to be associated with more rapid sputum conversion and higher cure rates than many other medications for drug-resistant TB. Similarly, good treatment outcomes were achieved in Kyrgyzstan and Mali. ⁶

Treatment for XDR-TB is often, however, associated with poor outcomes including treatment failure and mortality, worse than with MDR-TB.^7,8 It seems that later generation quinolones improve treatment outcomes, even in those with resistance to quinolones.^9,10

Nutritional support was given to our patient throughout his treatment; this may improve chances of treatment success by 50%.^11,12 As has been shown to improve the odds of treatment success by 69% in one meta-analysis, ¹³ directly observed therapy was the approach used in the management of our patient.

The major concern with drug-resistant TB treatment is adverse drug reactions, usually resulting in at least one adverse event. ¹⁴