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    Culture results of patients initiated on multidrug-resistant tuberculosis treatment based on Xpert MTB/RIF results and clinical approach.

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    Cumulative adverse events experienced during the follow-up period.

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Treatment Outcomes and Adverse Events from a Standardized Multidrug-Resistant Tuberculosis Regimen in a Rural Setting in Angola

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  • 1 Tropical Medicine and International Health Unit Vall d’Hebron-Drassanes PROSICS Barcelona, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain;
  • | 2 Hospital Nossa Senhora da Paz, Cubal, Angola;
  • | 3 Microbiology Department, Vall d’Hebron University Hospital, PROSICS Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain;
  • | 4 Support Research Unit, Territorial Health Management of Central Catalonia, Catalonia, Spain

Treatment for multidrug-resistant tuberculosis (MDR TB) is associated with adverse events (AE). Patients treated with an MDR TB regimen in Hospital Nossa Senhora da Paz, Cubal, Angola, were prospectively enrolled from May 2013 to July 2015. Baseline characteristics, AE, and clinical and microbiological outcomes were recorded. A total of 216 patients were treated with an MDR TB regimen and 179 (82.9%) patients developed at least one AE. The most common AE were elevation of liver enzymes (46.8% of patients), elevated creatinine (44.4% of patients), and ototoxicity (40.7% of patients). Previous TB treatment was associated with the occurrence of AE (OR 4.89, 95% CI: 2.09–11.46, P < 0.001) and months on treatment was associated to severe AE (OR 1.11 95% CI: 1.04–1.18, P = 0.001). Successful treatment was achieved in 117 (54.2%) patients. Incidence of AE was associated with an unsuccessful outcome (OR 1.23, 95% CI: 1.09–1.40, P = 0.001). Patients treated with MDR TB treatment frequently experience AE, and these are related with previous TB treatment and duration of treatment. Given the high percentage of patients experiencing AE and the low treatment success rates, more effective and less toxic drugs to treat MDR TB are urgently needed.

INTRODUCTION

Tuberculosis (TB) continues to be one of the top 10 causes of death worldwide and the emergence of resistance to TB drugs represents a persistent threat in TB control. Globally in 2017, an estimated 4% of new cases and 19% of previously treated cases had multidrug-resistance (MDR). Highly toxic, suboptimal effective drugs used for long durations contribute to higher proportion of unfavorable outcomes in MDR TB compared with susceptible TB.1

Republic of Angola is one of the 14 countries listed in the three TB high-burden country lists.1 A recent study in this setting observed a proportion of MDR TB of 71% in previously treated patients and 8% in new patients, reflecting one of the highest prevalence worldwide.2 Until 2013, access to second-line drugs was only available in a single clinic in Luanda. In May 2013, hospital Nossa Senhora da Paz (HNSP), a reference center of TB located in Cubal, southwest Angola, started to provide MDR TB treatment.

WHO recommends an 18–20-month fully oral regimens including fluoroquinolones (levofloxacin or moxifloxacin), bedaquiline, and linezolid because of adverse events (AEs) associated with the injectable.34 In eligible patients who were not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a standardized, shorter MDR TB regimen may be offered.4 However, access to some of the drugs used in these new regimens is challenging in some settings with high burdens of MDR TB,5 and some national TB programs have not yet incorporated the short regimen to their guidelines. Consequently, the knowledge of the most frequent AE and the factors associated with unfavorable clinical outcomes related to a 20-month standardized MDR treatment are crucial in poor-resource settings, where access to new drugs is still difficult.

The objectives of this study were to describe the clinical characteristics, AEs, treatment outcomes, and factors associated with AE and unfavorable outcomes in a cohort of MDR TB patients treated with second-line drugs.

METHODS

Study area, study design, participants, and ethics.

This prospective cohort study was conducted in HNSP, in Cubal, southwest Angola, from May 2013 to July 2015. The study was approved by the Vall d’Hebron Research Institute Ethics Committee, Angolan National Tuberculosis Program (PNLT), and the University of Katyavala Bwila Ethics Committee. Written informed consent was required to be included in the study. In patients < 16 years, the parents or legal guardians signed the consent form. All patients who were started on an MDR TB treatment regimen were consecutively enrolled in the study. Criteria for initiating MDR TB treatment were 1) confirmed rifampin (RIF) resistance by Xpert MTB/RIF (Cepheid, Sunnyvale, CA) (incorporated in May 2014 as part of the TB diagnosis in the context of a clinical research),6 2) suspected MDR TB in patients with a positive acid-fast bacilli (AFB) sputum with a history of failure after at least two previous TB treatments, and 3) contacts of MDR TB–confirmed cases with clinical and radiography signs, suggestive of active TB and in whom it was not possible to obtain a sputum sample.

Data collection.

Sociodemographic characteristics, clinical symptoms, duration of illness, and history of previous treatment were recorded. Malnutrition was defined as BMI < 18.5 in patients older than 18 years, BMI-for-age < −2 SD in children between 5 and 18 years, and weight-per-age < −2 SD for children younger than 5 years.7,8 All patients were offered an HIV test. Chest X-rays were interpreted by the physician in charge of the patient’s care.

Sputum collection.

From each patient, three sputum samples from three different days were collected. The samples were examined through direct smear microscopy for the presence of AFB. All patients provided an additional sputum sample that was stored at −80° and were periodically transported to the Microbiology Department of Vall d’Hebron University Hospital in Barcelona, Spain, for culture and determination of drug susceptibility.2 Patients who were included in the clinical research mentioned previously provided one more sputum sample after a smear-positive result used to perform the Xpert MTB/RIF.

Follow-up and AE monitoring.

A daily follow-up while inpatient, a weekly follow-up during the first 2 months, and a monthly follow-up thereafter was performed by a team of physicians and nurses. If any symptoms suggesting AE or TB worsening developed, patients were instructed to contact the team before the scheduled appointment. Directly observed therapy was performed in all patients by a nurse during the first 8 months and by a relative afterward. A complete blood count, levels of serum creatinine, and serum transaminases were performed monthly. Sputum samples were collected every month. The following AEs were assessed at each clinic appointment: ototoxicity, peripheral neuropathy, psychiatric disorders, gastrointestinal symptoms, dermatological disorders, nephrotoxicity, and hepatotoxicity. Nephrotoxicity was defined as any value of serum creatinine above 1.2 mg/dL and hepatotoxicity as any elevation of transaminases above 1.5 times the upper limit of normal (ULN). Diagnosis of clinical AEs was based on self-reported data using a standardized questionnaire form (Supplemental Appendix 1). Severity of adverse drug event was defined according the WHO Toxicity Grading Scale for Determining the Severity of AE in mild, moderate, severe, and life-threatening (Supplemental Appendix 1).9

Treatment.

All patients included in this study received a standardized regimen for MDR TB containing ethambutol (EMB), isoniazid (INH), ethionamide (Eto), cycloserine (Cs), ofloxacin (Ofx), and a second-line injectable drug (kanamycin, capreomycin, or amikacin depending on the available drug from the PNLT) for 8 months, followed by 12 months of EMB, INH, Eto, Cs, and Ofx. Until August 2015, there were no available alternative agents to replace in case of intolerance. From August 2015, para-aminosalicylic acid sodium (PAS) was added to the regimen in case the offending drug was withdrawn. Patients with a concomitant diagnosis of HIV initiated treatment with tenofovir, emtricitabine, and efavirenz according to Angolan HIV guidelines.10 Treatment outcomes were based on WHO classifications.11 Because it was not possible to perform follow-up cultures, we based treatment outcomes in smear results. A successful outcome included patients meeting the definition of cure or treatment complete. Two different definitions were used for unsuccessful outcome; a first one including patients lost to follow-up, patients who died, and patients who experience treatment failure and a second one including patients who died and patients who experience treatment failure.

Data analysis.

Descriptive statistics are presented as number (percent) and median (interquartile range, IQR) or mean (SD) depending on variable normality. We used chi-squared tests or Fisher’s exact tests to compare categorical variables and t-tests or Mann–Whitney tests to compare continuous variables. To palliate the problem of lower proportion of AE in patients with shorter treatment durations, a variable called AE incidence was created. It was defined as the rate of AE per 20 months of treatment (considering as if all patients would have been followed for 20 months, experiencing the same rate of AE per month during missing follow-up period than during treatment follow-up period). Demographics, comorbidities, previous TB treatment, and months on treatment were considered as possible risk factors for developing an AE. Demographics, grading of basal AFB, comorbidities, previous TB treatment, AFB status at 2 months of treatment, incidence of AE, and resistance to second-line drugs were considered as factors that could be associated with an unsuccessful treatment outcome. Three models were developed using a multivariate analysis, including AE (at least one AE yes or not as dichotomous variable), severe AE (at least one severe or life-threatening AE yes or not as dichotomous variable), and treatment outcomes (successful and unsuccessful treatment outcome as dichotomous variable) as dependent variables. Variables with a P-value < 0.20 in the univariate analysis and variables considered a priori to be clinically important, were included in the multivariate logistic regression analysis. We performed two analyses to assess treatment outcomes; one of them in all patients and a second one restricted to patients with a confirmed RIF resistance TB based on either culture or Xpert TB/RIF. For treatment outcomes, we performed two different analyses considering the two different definitions used for unsuccessful outcomes previously mentioned. A two-sided P-value < 0.05 was considered statistically significant for all analyses. All analyses were performed using SPSS statistical software (IBM SPSS version 23, Armonk, NY).

RESULTS

From May 2013 to May 2015, 216 patients were treated with an MDR TB regimen. Twelve patients were younger than 15 years, with a median (IQR) age of 9.0 (2–11.5) years. Thirteen (6%) of them were HIV coinfected, with a median (IQR) CD4 of 383 (154–509). Mycobacterium tuberculosis was isolated in 101 patients, and MDR TB was confirmed in 92 (91.1%) of them (See Figure 1). No cases of extensively drug-resistant TB were detected. Baseline characteristics of patients treated with MDR TB treatment are summarized in Table 1.

Figure 1.
Figure 1.

Culture results of patients initiated on multidrug-resistant tuberculosis treatment based on Xpert MTB/RIF results and clinical approach.

Citation: The American Journal of Tropical Medicine and Hygiene 101, 3; 10.4269/ajtmh.19-0175

Table 1

Baseline characteristics of patients treated with MDR regimen

N = 216, N (%)
Gender, male124 (57.4)
Age, median (IQR)30.0 (24.2–38.0)
City of origin
 Cubal83 (38.4)
 < 50 km from Cubal*16 (7.4)
 > 50 km from Cubal†117 (54.2)
HIV infection13 (6.0)
Previous TB treatment182 (84.3)
Clinical signs
 Cough208 (96.3)
 Fever165 (76.4)
 Hemoptysis43 (19.9)
Malnutrition141/192 (73.4)
Duration of illness months, mean (SD)24.8 (24.2)
Radiological findings
 Cavity any size61/185 (28.2)
 Cavity ≥ 5 cm50/185 (23.1)
 Cavity < 5 cm11/185 (5.9)
 Lung infiltrates111/185 (51.4)
 Pleural thickening20/185 (9.3)
 Miliar TB2/185 (0.9)
 Pleural effusion10/185 (4.6)
Hb (mg/dL), mean (DE)10.3 (2.4)
Indication for treatment
 RIF resistance detected by Xpert128 (59.3)
 Presumptive MDR TB88 (41.7)
Culture results125 (57.9%)
MTB isolated in sputum101/125 (80.8)
Susceptibility to antibiotics
 Resistance to one drug5/101
  RIF only2/101
  INH only3/101
 First-line polydrug resistance
  INH + STM + PZA3/101
  INH + STM + EMB1/101
 Confirmed MDR92/101 (91.1%)
  Any second-line resistance21/100 (21%)
   Am + Cm2/92
   Am + Eto1/92
   Cm6/92
   Cm + Eto2/92
   Eto7/92
   Eto + Mxf + Ofx1/92
   Eto + Ofx1/92
   Ofx1/92

* Includes the cities of Caimbambo and Ganda.

† Includes the cities of Benguela, Lobito, Bahia Farta, Chongoroi and Catumbela.

Am = amikacin; BMI = body mass index; Cm = capreomycin; EMB = ethambutol; Eto = ethionamide; INH = isoniazid; MDR = multidrug resistance; Mfx = moxifloxacin; MTB = Mycobacterium tuberculosis; Ofx = ofloxacin; PZA = pyrazinamide; RIF = rifampin; STM = streptomycin; TB = tuberculosis.

Adverse events.

One hundred and seventy-nine (82.9%) patients developed at least one AE; and two patients committed suicide during the treatment (both on cycloserine treatment). All AEs were initially managed symptomatically. Dose adjustment for at least one drug was required in 42/216 (19.4%) patients, temporary interruption of at least one antibiotic in 12/216 (5.6%), and termination of at least one antibiotic in 42/216 (19.4%). All patients received an aminoglycoside for at least 5 months. Adverse events persisted in 58/179 (32.4%) patients after completion of treatment; hearing loss persisted in 38/179 (21.2%) patients, polyneuropathy in 8/179 (4.5%), and both polyneuropathy and hearing loss in 12 (6.7%) patients. Fifty-four (25%) patients experienced at least a severe or life-threatening AE; 13/216 (9.9%) with severe ototoxicity, 5/216 (2.3%) with severe peripheral neuropathy, 18/216 (8.3%) with severe or life-threatening psychiatric disorders, 2 (1%) with severe nephrotoxicity, 2/216 (1%) with convulsions, 1/216 (0.5%) with a severe dermatological reaction, and 8 (3.7%) experienced several severe AE (one with severe ototoxicity, polyneuropathy, and psicosis; four with both ototoxicity and polyneuropathy; one with ototoxicity, polyneuropathy, and vomits; one with ototoxicity and nephrotoxicity; and one with polyneuropathy and psychosis). Details on severity, management and evolution of AE are shown in Table 2. Cumulative AEs experienced during the follow-up period are shown in Figure 2. Cumulative AEs stratified by previous treatment is shown in Supplemental Figures 1 and 2. We observed that previous TB treatment was associated with both at least one AE and severe AE (OR 4.89, 95% CI: 2.09–11.46, P < 0.001 and OR 9.99, 95% CI: 2.47–40.34, P = 0.002, respectively) and months on treatment was associated with severe AE (OR 1.11 95% CI: 1.04–1.18, P = 0.001). This information is summarized in Table 3. When we analyzed the most common AE separately, we observed that both previous TB treatment and months on treatment were associated with ototoxicity (OR 3.88, 95% CI: 1.46–10.31, P = 0.007 and OR 1.08, 95% CI: 1.03–1.12, P = 0.001), hepatotoxicity (OR 2.82, 95% CI: 1.20–6.60, P = 0.017 and OR 1.08, 95% CI: 1.03–1.23, P < 0.001), and nephrotoxicity (OR 3.86. 95% CI: 1.52–9.85, P = 0.005 and OR 1.10, 95% CI: 1.05–1.15, P < 0.001). Months on treatment and age were associated with polyneuropathy (OR 1.08, 95% CI: 1.03–1.13, P = 0.002) and (OR 1.04, 95% CI: 1.01–1.07, P = 0.020) (Table 4).

Table 2

Patients who developed AE associated with MDR TB regimen

HepatitisNephrotoxicityOtotoxicityPeripheral neuropathyPsychiatric disordersGI disordersDermatological disordersArthralgiasGynecomastia/impotenceConvulsions
N (%)101 (46.8)96 (44.4)88 (40.7)69 (31.9)46 (21.3)50 (23.1)25 (11.6)13 (6.0)12 (5.6)2 (1.0)
Median (IQR) months until development of AE3 (2–5)4 (2–7)4 (2–6)5 (2–7.7)6 (3.7–11)1.5 (1–6)6 (2–13)4 (2.5–6)7.5 (3.25–9)3 (3–3)
Mild, N (%)66 (65.3)42 (43.7)17 (19.3)22 (31.9)3 (6.5)24 (48)15 (60)12 (92.3)12 (100)0
Moderate, N (%)33 (32.7)51 (53.1)49 (55.7)35 (39.8)23 (50)23 (46)9 (36)1 (7.7)00
Severe, N (%)2 (2.0)3 (3.1)22 (25)12 (17.4)12 (26.1)3 (6.0)1 (4)002 (100)
Life-threatening, N (%)00008 (17.4)00000
Additional medication000
 Pyridoxine58 (84%)46 (100%)
 Anxiolytics12 (26.1%)
 Antipsychotics1 (2.2%)
 Antiemetics34 (68%)
 Anti-acids5 (10%)
 Antiepileptics1 (1.4%)
 NSAID2 (15.4%)2 (100%)
 Topic steroids3 (12%)(100%)
Dose reduction of antibiotics required31*320300000
Withdrawal of antibiotics required110105‡37§00021
Evolution of AEs
 Resolved, N (%)86 (85.1)71 (73.9)14 (15.9)45 (65.2)28 (60.9)50 (100)013 (100)02 (100)
 Stable1 (9.9)5 (5.2)56 (63.6)12 (17.4)1 (2.2)015 (60)012 (100)0
 Worsening01 (1)18 (20.4)8 (11.6)1 (2.2)010 (40)000
 No follow-up14 (13.9)19 (19.8)04 (5.8)14 (30.4)00000
 Death00002 (2.9)00000
Drugs more probably implicatedINH, EtoSLISLIINH, eto, CsCsEto, INHOfloINH, ofloEtoEto, Cs

AE = adverse effect, Cs = cycloserine; Eto = ethionamide; GI = gastrointestinal, INH = isoniazid; IQR = interquartile range; NSAID = non-steroidal anti-inflammatory; Oflo = ofloxacin; SLI = second-line injectable.

* Aminoglycoside (AG) was stopped in all three patients who developed severe nephrotoxicity. Of 51 patients who developed moderate nephrotoxicity, seven required withdrawal of the AG, 27 required dose reduction of the AG, 11 raised their creatinine after the eighth month of treatment, and six were lost to follow-up (FU).

Of two patients who developed severe hepatotoxicity, one patient was lost to FU and no treatment adjustment could be done; isoniazid was stopped in the other patient.

‡ Isoniazid was stopped in two patients, Cs was stopped in the other two patients, and all antibiotics were stopped in one patient.

§ Cycloserine was stopped in 30 patients, and all the antibiotics were stopped in seven patients because of psychiatric disorders. Cycloserine was replaced by PAS in 17 patients.

Figure 2.
Figure 2.

Cumulative adverse events experienced during the follow-up period.

Citation: The American Journal of Tropical Medicine and Hygiene 101, 3; 10.4269/ajtmh.19-0175

Table 3

Comparison of demographic and clinical characteristics in patients with and without any AEs

AEs vs. no AEsSevere AEs vs. no AEs
Adverse effects, N = 179Severe AEs, N = 53No adverse effects, N = 37Univariate analysis, OR (95% CI)P-valueMultivariate analysis, OR (95% CI)P-valueUnivariate analysis, OR (95% CI)P-valueMultivariate analysis, OR (95% CI)P-value
Gender, male107 (59.8%)28 (52.8%)17 (45.9%)1.75 (0.86–3.56)0.1242.02 (0.95–4.30)0.0681.32 (0.57–3.06)0.521
Age (years), median (IQR)930 (25–37)33 (27.5–39.5)30 (23.5–41.5)0.99 (0.96–1.02)0.9930.98 (0.95–1.01)0.2561.02 (0.98–1.05)0.3791.03 (0.99–1.07)0.146
Malnutrition120 (73.6%)39 (81.3%)21 (72.4%)1.06 (0.44–2.58)0.4961.65 (0.55–4.91)0.367
HIV coinfection10 (5.6%)3 (5.7%)3 (8.1%)0.67 (0.17–2.57)0.5590.68 (0.13–3.57)0.649
Baseline Hb, media (SD)10.7 (2.4)10.2 (2.7)10.0 (2.0)1.14 (0.87–1.48)0.3351.04 (0.78–1.39)0.780
Previous TB treatment158 (88.8%)49 (92.5%)24 (64.9%)4.28 (1.88–9.71)0.0014.89 (2.09–11.46)< 0.0016.63 (1.95–22.53)0.0029.99 (2.47–40.34)0.002
Total months on treatment, median (IQR)20 (12–20)17 (8.5–20)5 (1–19.5)0.98 (0.94–1.02)0.2631.09 (1.03–1.15)0.0031.11 (1.04–1.18)0.001

AEs = adverse events; Hb = hemoglobin; IQR = interquartile range, TB = tuberculosis.

Table 4

Comparison of demographic and clinical characteristics in patients with and without specific adverse events

Ototoxicity (N = 88)No ototoxicity (N = 128)Univariate modelMultivariate model
OtotoxicityOR (95% CI)P-valueOR (95% CI)P-value
Gender, male58 (65.9%)66 (51.6%)1.82 (1.04–3.18)0.0371.88 (1.00–3.32)0.051
Age (years), median (IQR)30 (27–39)29 (24–37)1.03 (1.00–1.05)0.0411.02 (0.99–1.05)0.101
Malnutrition58 (73.4%)83 (73.5%)0.99 (0.99–1.91)0.996
HIV coinfection6 (6.8%)7 (5.5%)1.26 (0.41–3.90)0.683
Previous TB treatment82 (93.2%)100 (78.1%)3.83 (1.51–9.69)0.0053.88 (1.46–10.31)0.007
Months on treatment, median (IQR)20 (16–20)18 (6.25–20)1.07 (1.03–1.12)0.0011.08 (1.03–1.12)0.001
PolyneuropathyPolyneuropathy (N = 69)No polyneuropathy (N = 147)OR (95% CI)P-valueOR (95% CI)P-value
Gender, male41 (59.4%)83 (56.5%)1.13 (0.63–2.02)0.682
Age (years), median (IQR)33 (27–39)29 (24–37)1.03 (1.01–1.06)0.0131.04 (1.01–1.07)0.011
Malnutrition48 (71.6%)93 (74.4%)0.87 (0.45–1.69)0.680
HIV coinfection4 (5.9%)9 (6.1%)0.94 (0.28–3.18)0.925
Previous TB treatment63 (91.3%)119 (81%)2.47 (0.97–6.28)0.0572.23 (0.84–5.93)0.109
Months on treatment, median (IQR)20 (16–21)18 (8–20)1.07 (1.02–1.12)0.0031.08 (1.03–1.13)0.002
PsychiatricPsychiatric disorders (N = 46)No psychiatric disorders (N = 170)OR (95% CI)P-valueOR (95% CI)P-value
Gender, male29 (63%)95 (55.9%)1.35 (0.69–2.63)0.384
Age (years), median (IQR)29.5 (25.7–37)30 (24–39)1.00 (0.97–1.03)0.899
Malnutrition30 (76.9%)111 (72.5%)1.26 (0.55–2.88)0.581
HIV coinfection2 (4.3%)11 (6.5%)1.52 (0.32–7.12)0.594
Previous TB treatment41 (89.1%)141 (82.9%)1.69 (0.61–4.63)0.311
Months on treatment, median (IQR)19 (9-20)19 (8.7–20.2)1.00 (0.96–1.05)0.89
HepatotoxicityHepatotoxicity (N = 101)No hepatotoxicity (N = 115)OR (95% CI)P-valueOR (95% CI)P-value
Sex, male63 (62.4%)61 (53%)1.47 (0.85–2.53)0.1671.70 (0.94–3.06)0.076
Age (years), median (IQR)30 (24–36.5)30 (25–39)0.98 (0.96–1.01)0.9840.98 (0.95–1.00)0.081
Malnutrition68 (70.1%)73 (76.8%)0.71 (0.37–0.35)0.291
HIV coinfection4 (4%)9 (7.8%)0.49 (0.14–1.63)0.242
Previous TB treatment91 (90.1%)91 (79.1%)2.40 (1.09–5.30)0.0302.82 (1.20–6.60)0.017
Months on treatment, median (IQR)20 (14.5–21)18 (5–20)1.08 (1.03–1.12)< 0.0011.08 (1.03–1.23)< 0.001
NephrotoxicityNephrotoxicity (N = 96)No nephrotoxicity (N = 119)OR (95% CI)P-valueOR (95% CI)P-value
Gender, male60 (62.5%)64 (53.8%)1.43 (0.83–2.48)0.1991.45 (0.79–2.64)0.230
Age (years), median (IQR)30 (25–38.5)30 (24–38)1.02 (0.99–1.04)0.2021.01 (0.99–1.04)0.321
Malnutrition70 (76.1%)71 (71.7%)1.25 (0.66–2.40)0.493
HIV coinfection5 (5.2%)8 (6.7%)0.76 (0.24–2.41)0.644
Previous TB treatment89 (92.7%)92 (77.3%)3.73 (1.55–9.00)0.0033.86 (1.52–9.85)0.005
Months on treatment, median (IQR)20 (17.2–20.7)16 (6–20)1.10 (1.05–1.15)< 0.0011.10 (1.05–1.15)< 0.001

IQR = interquartile range; TB = tuberculosis.

Treatment outcomes.

Information about treatment outcomes is summarized in Table 5. We observed that the incidence of AE was associated with an unsuccessful outcome in both the first analysis (patients lost to follow-up, patients who died, and patients who experience treatment failure considered as unsuccessful treatment) (1.23, 95% CI: 1.09–1.40, P = 0.001) and in the second analysis (patients who died and patients who experience treatment failure considered as unsuccessful outcome) (OR 1.33, 95% CI: 1.09–1.61, P = 0.004). Malnutrition was associated with unsuccessful outcome in the second analysis (4.73, 95% CI: 1.04–21.5, P = 0.044). This information is shown in Table 6. Variables associated with unsuccessful outcomes restricted to patients whose sputum samples showed MTB RIF resistance is shown in Supplemental Table 1.

Table 5

Treatment outcomes based on WHO definition (modified by smear) stratified by confirmed and non–confirmed cases

All patients who started an MDR TB regimen, N = 216Patients with confirmed RIF resistance (either culture or Xpert MTB/RIF), N = 147
Cured69 (31.9%)42 (28.6%)
Treatment completed48 (22.2%)37 (25.2%)
Lost to follow-up57 (26.4%)41 (27.9%)
Treatment failure4 (1.8%)3 (2%)
Death38 (18.3%)24 (16.3%)
Definitions used for the first analysis*
Successful treatment117/216 (54.2%)79/147 (53.7%)
Unsuccessful treatment99/216 (45.8%)68/147 (46.2%)
Definitions used for the second analysis†
Successful treatment117/168 (69.6%)79/106 (74.5%)
Unsuccessful treatment42/168 (25%)27/106 (25.6%)

MDR TB = multidrug-resistant tuberculosis; RIF = rifampin.

* First analysis: Considering unsuccessful outcome as patients lost to follow-up, patients who died, and patients who experienced treatment failure.

† Second analysis: Excluding patients lost to follow-up and considering unsuccessful outcome as patients who died and patients who experienced treatment failure.

Table 6

Patient characteristics and their associations with unsuccessful treatment outcome

Including patients lost to FUExcluding patients lost to FU
Successful outcome N = 117Unsuccessful outcome*, N = 99Unsuccessful outcome†, N = 42Univariate analysis, OR (95% CI)P-valueMultivariate analysis, OR (95% CI)P-valueUnivariate analysis, OR (95% CI)P-valueMultivariate analysis, OR (95% CI)P-value
Gender, male65 (55.6%)59 (56.9%)23 (54.8%)1.18 (0.69–2.03)0.5500.93 (0.48–1.97)0.929
Age, median (IQR)29 (24–37)30 (25–39)32 (25.7–39.5)1.01 (0.98-1.03)0.5451.02 (0.99–1.05)0.221
City of origin16 (38.1%)
Cubal44 (37.6%)39 (39.4%)3 (7.1%)1.08 (0.62–1.87)0.7881.02 (0.49–2.11)0.955
< 50 km from Cubal10 (8.5%)6 (6.1%)23 (54.8%)0.69 (0.24–1.97)0.4890.82 (0.21–3.15)0.776
> 50 km from Cubal63 (53.8%)54 (54.5%)17 (43.6%)1.03 (0.60–1.76)0.9181.04 (0.51–2.11)0.919
AFB > 3+37 (34.3%)29 (35.8%)2 (4.8%)1.07 (0.58–1.96)0.8261.48 (0.70–3.13)0.302
HIV6 (5.1%)7 (7.1%)31 (93.9%)1.41 (0.56–4.33)0.5510.92 (0.18–4.77)0.926
Malnutrition75 (67.6%)66 (81.5%)37 (88.1%)2.11 (1.06–4.20)0.0331.73 (0.84–3.57)0.1367.44 (1.69–32.82)0.0084.73 (1.04–21.50)0.044
Previous TB treatment99 (84.6%)83 (83.8%)11 (30.6%)0.94 (0.45–1.96)0.8761.34 (0.47–3.88)0.583
Cavities > 5 cm29 (26.9%)21 (27.3%)10 (50%)1.02 (0.53–1.97)0.9491.20 (0.52–2.74)0.668
Positive AFB 2 months42 (40%)25 (39.7%)4 (18.2%)0.99 (0.52–1.87)0.9681.50 (0.57–3.92)0.408
Resistance to second-line drugs13 (25.5%)8 (16.3%)0.57 (0.21–1.23)0.2640.65 (0.19–2.27)0.500
AE incidence 20 months, mean (SD)‡2.56 (1.49)5.72 (8.13)6.91 (3.98)1.22 (1.09–1.37)0.0011.23 (1.09–1.40)0.0011.30 (1.10–1.53)0.0021.33 (1.09–1.61)0.004

AFB = Acid-fast bacilli.

* Unsuccessful outcomes, including patients lost to follow-up, patients who died, and patients who experience treatment failure.

† Unsuccessful outcomes, including patients who died, and patients who experience treatment failure.

‡ Adverse events (AEs) incidence: Rate of AEs per 20 months of treatment (considering as if all patients would have been followed-up for 20 months, experiencing the same rate of AE per month during missing follow-up period than during treatment follow-up period). For example: If a patient was lost to follow-up after a period of 3 months, and he/she experienced three AEs, then the rate of AEs per month would be 1, and the rate of AEs per 20 months would be 20.

DISCUSSION

Similarly to the 2018 Global TB report and recent studies, we observed that 53.8% of patients experienced treatment success.1,12 Adverse events were common, and 25% of patients experienced a severe AE. Moreover, AE persisted in 32.4% patients after completion of treatment.

Recent studies reporting data of TB in Angola have observed a high proportion of MDR TB2,6; however, access to MDR TB diagnosis is not available for all TB patients in Angola, and it leads physicians to empirically start a second-line regimen in patients with high risk of MDR TB. In fact, 41.5% of our patients were started empirically on MDR TB treatment. Despite the potential harms of empirical TB treatment, benefits including prevention of transmission and mortality and morbidity reduction make that empirical treatment is often used in high-burden settings.13,14

We observed that 82.9% of patients developed at least one AE, and AEs were associated with previous TB treatment. Moreover, severe AEs were associated with both previous TB treatment and months of treatment. Overall, AEs in patients treated for MDR TB are common, although frequency differs depending on the type of drugs used, the duration of the regimen, and other clinical characteristics such as HIV coinfection, and previous TB history.1520 The association between previous TB treatment and AE has been previously described in the literature.21 It is possible that patients previously treated with TB drugs had experienced some persistent AE that predisposes the development of subsequent AEs. This has been well described with the use of aminoglycosides.22 Because a regimen containing streptomycin (category 2 treatment) was used in some of the previously treated patients, it may explain the association between previous TB treatment and ototoxicity. On the other side, we are not able to ensure if some of the AEs were already present before starting treatment because this information was not collected. Treatment duration has been also related to AEs,23 and it is one of the reasons why shorter regimens have been proposed during the last years. However, shorter regimens currently recommended contain aminoglycosides, so may also be ototoxic. Therefore, shorter regimens without aminoglycosides are needed.

The percentage of patients developing both hepatotoxicity and nephrotoxicity in our study are higher compared with other cohorts of patients, probably because of different definitions (any elevation of transaminases above 1.5 times the ULN versus five times the ULN and any value of serum creatinine above 1.2 mg/dL versus a rise of serum creatinine of 0.5 mg/dL from baseline, respectively).2426 Peripheral neuropathy and psychiatric disorders were more commonly observed than those reported from other cohorts of MDR TB patients and like those reported from cohorts of HIV-infected patients.27,28 A possible explanation is that pyridoxine was not free provided by our program, so we cannot ensure that all patients received it. It is also possible that these AEs are underreported in studies that did not actively search for those. Cycloserine was stopped in 13.4% of patients who developed psychiatric symptoms, in contrast to previous studies in which psychiatric symptoms has been successfully managed without compromising MDR regimen.29

We observed a high proportion of patients lost to follow-up compared with other cohorts of MDR TB patients.18 This may be due to several factors; many patients included in our study live far from the hospital; moreover, the proportion of AEs observed was also high, and AEs have been previously associated with lost to FU.30 By contrast, the proportion of treatment failure was low, similar to that in other cohorts of MDR TB patients from Africa.18 This low proportion of treatment failure may be due to the recent introduction of second-line treatment, with scarce prevalence of resistances to second-line drugs. Moreover, this number might be underestimated because cultures were not done during follow-up. We observed that incidence of AE was a risk factor for an unsuccessful outcome. It has been previously observed that the most common reason for stopping the treatment is AE.30 It is easily understandable that either the patient or the physician decides to discontinue the treatment if an AE is not well controlled, and consequently, it is more unlikely to achieve a successful outcome.

Shorter regimens reporting treatment success rates > 80% have become available to treat MDR TB31,32; however, recent data have reported high proportions of resistance to some of the drugs of the regimen and controversies about the global implementation of these regimen have recently arise.33,34 In fact, in our study, 20/92 (21.7%) MDR TB–infected patients had resistance to at least 1 second-line drug included in the short regimen recommended by WHO. Moreover, access to second-line drug susceptibility testing is required to use the short regimen, and this is not the case in Angola. Consequently, although short regimens may help improve clinical outcomes of patients with MDR TB, it must be accompanied by improvements in laboratory capacity. New WHO recommendations recently published prioritize the use of all oral regimens not containing the use of injectables.4 The high proportion of ototoxicity related to aminoglycosides found in our study would support the use of these regimens. However, as mentioned earlier, access to some of the drugs that should be included in these regimens such as bedaquiline is very challenging in many countries.5

Our study has several limitations. First, diagnosis of MDR TB was not based on culture results in all patients and criteria of cure were based on smear microscopy rather than culture. These limitations reflect the reality of TB diagnosis and management in many poor-resource settings. Second, definition of AE was based on self-reported data; so, we may underestimate the real incidence of some AEs. Third, some of the common AEs related to MDR TB regimen such as hypothyroidism were not reported because of the absence of laboratory material, so we may underestimate the overall incidence of AE. Furthermore, we do not have data of some underlying medical conditions that may be associated with AE.

Patients treated with a long standardized MDR TB treatment frequently experience AE, and these are related with previous TB treatment and duration of treatment. Only the incidence of AE was associated with an unsuccessful treatment outcome. The adequate management of AE is critical to treat MDR TB patients.

Supplementary Material

Acknowledgment:

We acknowledge all of the collaboration from Hospital Nossa Senhora da Paz.

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Author Notes

Address correspondence to María Luisa Aznar, Infectious Disease Department, Vall d’Hebron University Hospital, Passeig Vall d’Hebron 119–129, Barcelona 08035, Spain. E-mail: maznarru@gmail.com

Financial support: We are grateful for the financial support received from the Probitas Foundation, which not only made it possible to purchase the equipment and reagents to launch the Xpert study, but to also strengthen the capacity of the laboratory and local staff.

Authors’ addresses: María Luisa Aznar, Cristina Bocanegra, and Israel Molina, PROSICS Barcelona and Medicine Department, Tropical Medicine and International Health Unit, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain, E-mails: maznarru@gmail.com, cristinabocanegra@gmail.com, and israelmolina@ymail.com. María Milagros Moreno, Eva Gil Olivas, Arlete Nindia Eugénio, Adriano Zacarias, Domingos Katimba, Estevao Gabriel, and Maria Teresa López García, Hospital Nossa Senhora da Paz, Cubal, Angola, E-mails: milamor14@yahoo.es, evagilolivas1982@gmail.com, arletenindacubal@yahoo.com, adrianozacarias1967@yahoo.com, domingoskatimba1977@yahoo.com, estevaogabriel1968@yahoo.com, and materloga2@yahoo.es. Ariadna Rando Segura, Mateu Espasa, Elena Sulleiro, Tomas Pumarola, and María Teresa Tórtola, Microbiology Department, Vall d’Hebron University Hospital, PROSICS Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain, E-mails: ariadnarando@gmail.com, mespasa@vhebron.net, esulleir@vhebron.net, tpumarola@vhebron.net, and ttortola@vhebron.net. Jacobo Mendioroz, Support Research Unit, Territorial Health Management of Central Catalonia, Catalonia, Spain, E-mail: jmendioroz.cc.ics@gencat.cat.

These authors were contributed equally to this work.

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