Adverse events using shorter MDR-TB regimens: outcomes from Port Moresby, Papua New Guinea

Abstract

Evidence increasingly indicates that standardised, shorter regimens (SR) for multidrug-resistant TB (MDR-TB) is effective in treating this global disease, but there is little published data on associated adverse events. We report outcomes from a cohort treated with the SR in Port Moresby, Papua New Guinea (PNG). Among 26 patients treated with a TB SR from September 2017 to September 2018, 10 (39%) were successful treatments, 12 (46%) were failures, 2 died, and 2 were lost to follow-up. Of those whose treatment failed, most (n = 10) changed their regimen due to adverse events, including seven from ototoxicity, suggesting this SR may not be suited to all patients in PNG and similar settings.

Drug resistance is a major obstacle to TB control. Only 55% of multidrug-resistant TB (MDR-TB) treatment was successful in 2015, with nearly 21% of loss to follow-up (LTFU).¹ Long treatment durations, polypharmacy, painful daily intramuscular injections, and significant side effects (including ototoxicity) are considerable burdens. Since 2016, evolving research has compelled the WHO and other bodies to urge the replacement of longer regimens with shorter, easier to take, better-tolerated, all-oral treatment regimens.^2–5

However, most research on these short regimens (SR) fails to systematically screen for adverse events (AEs), making our knowledge of SR patient outcomes incomplete.^6–9 Papua New Guinea (PNG) has the highest burden of TB in the Western Pacific Region, and around 26% of its retreatment cases are suspected of MDR-TB. In support of the National Department of Health in TB management, the Médecins Sans Frontières (MSF) began using the SR at Gerehu Hospital in Port Moresby, PNG, in September 2017. We report treatment outcomes and AE profiles in this population.

ASPECT OF INTEREST

SR patients were aged ⩾15 years with bacteriologically confirmed pulmonary TB, with rifampicin resistance detected (in sputum) using Xpert® MTB/RIF (Cepheid, Sunnyvale, CA, USA). Pregnant patients, those with previous exposure to second-line drugs for >30 days, extrapulmonary TB, and known resistance to fluoroquinolones or aminoglycosides were excluded. Culture testing was performed at the PNG Central Public Health Laboratory, Port Moresby, National Capital District, PNG, and line-probe assays and phenotypic drug susceptibility testing (DST) at the Queensland Mycobacterium Reference Laboratory, Brisbane, QLD, Australia.

The SR comprised 6 months of moxifloxacin, kanamycin, clofazimine, prothionamide, isoniazid, pyrazinamide and ethambutol, followed by 5 months of moxifloxacin, clofazimine, pyrazinamide and ethambutol dosed per WHO guidelines.⁷ Treatment was directly observed and patients asked about side effects daily. Clinical reviews were conducted at Weeks 0, 1, 2 and 4, and then monthly thereafter. Baseline tests included urinary human chorionic gonadotropin, hepatitis B surface antigen, hepatitis C antibody, HIV antibody and haemoglobin A1c testing. Thyroid function tests were performed at baseline and Months 3 and 6. Audiometry, electrolyte testing, liver function tests, electrocardiograms and visual testing (using Ishihara plates and the Peek visual acuity application) were performed at baseline and monthly.¹⁰ QT intervals were calculated using the Frederica formula (QTcF). Vital sign monitoring, performance status, side effect screening and physical examinations (including peripheral neuropathy screening) occurred at each clinical visit. Sputum samples for microscopy and culture were taken monthly. Chest X-rays were performed at baseline and 6-monthly thereafter. Additional investigation was performed when clinically appropriate. Treatment outcomes were classified per WHO guidelines.⁹ Treatment failure was defined as treatment that was terminated or permanently changed because of 1) failure to convert at the end of the intensive phase, 2) bacterial reversion in the continuation phase (after a negative conversion), 3) acquired resistance to fluoroquinolones or second-line injectable drugs or 4) adverse drug reactions.

AEs were graded for severity using the endTB guidelines¹⁰ and the Division of AIDS grading system.¹¹ The SR was discontinued when ototoxicity was ⩾2. Formal ethical review was waived by the MSF-France (Paris, France) Medical Director, as this was a retrospective programme analysis. Data were recorded in patient files and stored using the MSF Bahmni database before export to STATA v15 (StataCorp, College Station, TX, USA) for analysis. We used percentages for qualitative variables and medians with interquartile ranges (IQRs) for quantitative variables for the baseline descriptive analysis. Kaplan-Meier analysis was used to assess patients’ survival rates during the course of treatment.

From September 2017 to September 2018, 26 patients (female: 11, 42%; male: 15, 58%) started SR regimens. Five (19%) were HIV co-infected, and four (15%) had chronic hepatitis B. Outcomes and AEs are given in Figures 1 and 2 and the Table. Increased liver enzyme levels, hearing impairment and vomiting were the most frequent AEs experienced. Hearing impairment was the leading cause of treatment discontinuation and change to an alternative regimen.

FIGURE 1.

Outcomes of Gerehu shorter regimen cohort, Papua New Guinea, September 2018 (n = 26). Ten patients changed onto alternative regimens due to adverse events. Seven changed to all-oral regimens due to ototoxicity. Three patients failed due to persistent prolongation of the QT interval >500 msec despite correction of electrolytes and euthyroid state. Two patients changed to other regimens on DST detection of resistance to SR components; one found to have extensively drug-resistant TB (to fluoroquinolones and kanamycin), the other was resistant to prothionamide, high-dose isoniazid, ethambutol and pyrazinamide. No confirmed bacteriological failures in this cohort. Two patients died; one at Month 8 due to sepsis, secondary to community acquired pneumonia with immunosuppression due to HIV infection. One patient died at Month 2 of unknown causes. Two patients were lost to follow-up at Month 1 and 2.

FIGURE 2.

Kaplan-Meier curve of the occurrence of unfavourable outcomes. Probability of developing unfavourable final treatment outcomes (death, loss to follow-up and failure) in drug-resistant TB patients registered on short-course regimen during the study period; 14/25 patients (56%) completed 12 months of follow-up with favourable TB treatment outcomes (cure and complete).

TABLE.

Adverse events recorded for the 26 patients started on the standardised shorter regimen *

Adverse event	Grade 1	Grade 2	Grade 3	Grade 4	Comments
Long QtcF	1	1	2	2	Three patients changed to alternative regimen Seven patients were changed to an alternative regimen; two patients discontinued the intensive phase at Month 5 due to ototoxicity, and two had kanamycin reduced to 3 times/week
Ototoxicity	4	3	3	1
Hypokalaemia	3	2	1	0
Hypomagnesaemia	0	2	0	0
Acute kidney injury	3	1	0	0	Kanamycin temporarily held Eight patients had Grade 3 or 4 hepatotoxicity, necessitating temporary cessation of all treatment, and in one of these the pyrazinamide could not be reintroduced; one patient had the continuation phase discontinued at Month 4 due to Grade 3 long QT (QTcF >500 msec) and Grade 3 hepatotoxicity; levofloxacin was substituted for moxifloxacin in the last month
Hepatotoxicity	7	1	7	1
Hypothyroidism	1	2	0	0
Nausea and vomiting	9	5	0	0	These were very common and probably under documented
Arthralgia	3	1	0	0	This was very common and probably under documented
Other	5	1	0	2	Grade 4 events were both intercurrent infections

*Ten patients were changed to an alternative regimen due to adverse events. Some adverse events, such as hepatotoxicity, acute kidney injury, vomiting and arthralgia, did not necessitate a change in regimen but could have potentially deleterious effects due to treatment interruption and dose reduction.

DISCUSSION

We report high rates of toxicity (27%) in patients treated with injectable-containing SR MDR-TB regimens. Ototoxicity is a well-recognised side effect of aminoglycosides and, because of the drugs’ long half-lives, can persist long after cessation. Previous studies have found variable rates of ototoxicity in MDR-TB patients, from 10% to 50%, with higher rates when standardised hearing assessments are conducted (clinical assessments alone may miss mild and moderate hearing loss).^12–14 In our cohort, SR success rates were even lower than in other studies with similar ototoxicity rates, likely because new drugs combined with more frequent audiometry allowed us to detect hearing loss at an early stage and promptly change ototoxic patients to a bedaquiline-containing regimen.¹⁵ Our findings may have also been unique in a population of patients who may be particularly vulnerable to hearing loss due to a high prevalence of otitis media in children, possibly caused by early S. pneumoniae and H. influenzae exposure, overcrowded living conditions, and sometimes limited water and sanitation access in the country.^16–18 Less severe AEs have also been observed in PNG, and although these may not have always required a regimen change, they still resulted in prolonged or interrupted treatment, created a higher pill burden, increased LTFU or caused other life-threatening consequences.

The relevance of older TB regimens is increasingly being called into question given the improved mortality associated with new treatments such as bedaquiline; nevertheless, current SR models require multiple drugs at high doses and have underreported side effects. The increased drug side effects we found with formal monitoring may perhaps present a more complete picture of SR toxicity and has implications for a fixed short regimen. It also confirms concerns about injectable-containing regimens as a WHO-endorsed treatment option.

As this cohort study was limited by its small size, results should be interpreted and generalised with caution. They may not be applicable to other low-resource settings or even other parts of PNG.

CONCLUSION

The standardised SR regimen may not be well suited to all populations, and our study highlights one cohort where a more clinical, individualised alternative, based on drugs with less harmful side effect profiles and treatment tailored to the patient, is warranted. Injectable-containing regimens should include audiometry for routine monitoring to detect hearing loss early and stop medication quickly. Injectable-free regimens will also improve outcomes.⁶ Modifiable, rather than standardised, all-oral SRs may provide better alternative MDR-TB treatments in the future.