Table.

Descriptive Analysis of Included Studies

Author, Year (Country)	Design (NOS score), Sample Size, Age	Study Purpose	Diagnostic Methods of HL	Absolute risk of HL	HIV Prev.	ART Status	Type of AGs (%)	Major Findings
Harris et al.13 2012 (South Africa)	Prospective cohort (8) N= 153 Adults [range=14–70y]	To document the incidence of ototoxicity in MDR-TB patients with and without HIV, and develop clinical guidelines relating to ototoxicity in such patients	Audiometric HL by PTA + Tympanometry + otoscopy	87/153 (57%)	86/153 (56%)	86/86 (100%)	AMK(1), KM (94), SM(4), CPM(1)	57% developed high frequency HL within 3m. Of those who developed HL, 69% were HIV positive and 31% were HIV negative.
Seddon et al.30 2012 (South Africa)	Prospective cohort (8) N=93 (Confirmed MDR-TB n= 50) Children [IQR=20–110m]	To determine the extent of hearing loss in children treated for MDR-TB	Audiometric HL by PTA Audiometric HL by DPOAE + Tympanometry + otoscopy	23/93 (24%)	28/93 (30%)	20/28 (71%)	AMK(88), SM(10), CPM(1)	64% had audiometric HL and had progression of HL after finishing the injectable drug.
Brust et al.31 2013 (South Africa)	Retrospective cohort (7) N=89 Adults [IQR= 29–41y]	To examine the frequency and severity of AEs in patients with MDR-TB and HIV coinfection treated at an integrated MDR-TB/HIV home-based treatment program	Composite HL (audiometric + clinician-identified HL)	31/89 (34%)	76/89 (84%)	66/76 (87%)	KM (100)	34% developed HL during treatment. 69% had some degree of HL; 11% had severe HL; and 10% patients required dose reductions of kanamycin for HL.
			Audiometric HL by PTA	24/35 (69%)
Sagwa et al.32 2013 (Namibia)	Retrospective cohort (6) N=57 No age restriction [range= 11–55y]	To compare the absolute risks and risk factors for commonly observed adverse events (occurring in >20 % of patients) during DR-TB treatment in HIV-infected and HIV-uninfected patients.	Self-reported HL	13/57 (23%)	31/57 (54%)	13/31 (42%)	AMK(36), KM(51), SM(5), CPM(7)	23 % developed HL during treatment. The absolute risk of HL was 8/31 (26 %) in HIV-coinfected and 5/26 (19 %) in HIV-uninfected group.
Modongo et al.33 2014 (Botswana)	Retrospective cohort (7) N=437 Adults [IQR= 31–49y]	To determine the effect of amikacin on treatment outcomes and development of hearing loss in MDR-TB patients	Composite HL (audiometric + clinician-identified HL)	270/437 (62%)	288/437 (66%)	267/288 (93%)	AMK(100)	HIV infection was not associated with increased risk of HL (aOR= 1.32, 95% CI: 0.83–2.12). The most important HL risk factors were treatment duration in month (aOR 1.98, 95% CI 1.86–2.12) and dosage per mg/kg/month (aOR 1.15, 95% CI 1.04–1.28).
			Audiometric HL by PTA	147/437 (34%)
			Clinician-identified HL	123/437 (28%)
Modongo et al.34 2015 (Botswana)	Retrospective cohort (6) N=28 Adult [mean(SD)= 44y(18)]	To identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among MDR pulmonary TB patients	Composite HL (audiometric + clinician-identified HL)	11/28 (39%)	12/28 (43%)	12/12 (100%)	AMK(100)	A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days·mg·h/liter, while that of 20% occurred at 120,000 days·mg·h/liter.
			Audiometric HL by PTA	7/28 (25%)
Sagwa et al.35 2015 (Namibia)	Retrospective cohort (7) N=353 No age restriction [mean (SD)= 35.69y (9.56) in Am; 36.47y (11.57) in Km group]	To compare the cumulative incidence of hearing loss among patients treated for MDR-TB with amikacin or kanamycin-based regimens, and to identify the most-at-risk patients, based on the real-life clinical practice experiences	Audiometric HL by PTA	206/353 (58%)	164/353 (46%)	132/164 (80%)	AMK(14), KM(86)	Patients received Am had a higher risk of developing more severe HL than those used Km (aOR= 4.0, 95% CI 1.5–10.8). HIV coinfection (OR= 3.4, 95% CI 1.1–10.6), male sex (OR= 4.5, 95% CI 1.5–13.4) and lower baseline body weight (40–59 kg, OR= 2.8, 95% CI 1.1–6.8) were associated with increased risk of HL.
Kelly et al.24 2016 (South Africa)	Retrospective cohort + cross-sectional (5) N=121 Adults [range=17–63y]	To describe concordance between patient report and clinician documentation of ADR from MDR-TB treatment	Self-reported HL	39/121 (32%)	90/121 (74%)	79/90 (88%)	N/S	Among ADRs from MDR-TB treatment, the highest degree of concordance was found between patient-reported and audiometric HL (kappa= 0.23).
			Audiometric HL by PTA	32/121 (26%)

NOS=Newcastle-Ottawa Quality Assessment Scale; HIV=human immunodeficiency virus; ART=antiretroviral therapy; AG=aminoglycoside; MDR-TB=multidrug-resistant tuberculosis; PTA=pure tone audiometry; AMK=amikacin; KM=kanamycin; SM=streptomycin; CPM=capreomycin; IQR=interquartile range; DPOAE=distortion product otoacoustic emissions; AE=adverse effect; DR-TB=drug-resistant tuberculosis; aOR=adjusted OR; CI=confidence interval; SD=standard deviation; AUC=area under the curve; OR=odds ratio; ADR=adverse drug reaction.