Descriptive Analysis
Between 2000 and 2016, 2,477 cases of MDR-TB were reported in RJ, with 208 cases excluded: 8 non-residents in RJ, 11 undergoing treatment, 3 unknown results, 11 changes in diagnosis and 175 drug-susceptibility testings not indicating resistance to, at least, rifampicin and isoniazid. Of the total of 2,269 cases, 1999 (88.1%) had a negative result for HIV, 156 (6.9%) positive and 114 (5.0%) unknown. There were 1466 (64.6%) male patients. Table 1 describes the sociodemographic and clinical variables relating to MDR-TB patients with HIV positive, negative, and unknown results.
Overall, the median age was 38 (IQR 28-49) years, whereas among HIV positive patients, the median was 37 (IQR 30-45). HIV positive cases also stand out for having 14.7% of cases with extrapulmonary or pulmonary/extrapulmonary MDR-TB, while in the HIV negative and unknown group they had, respectively, 1.3% and 2.6%. In addition, HIV positive patients had a higher percentage of comorbidities (14.1% [excluding diabetes]) than patients with negative and unknown HIV (11.9% and 11.4%). The groups with negative and unknown HIV had more cases with diabetes, 9.8% and 14.9%, respectively, than the group with HIV positive, which had 3.2%. Among the 22 HIV positive patients with comorbidities, the most prevalent types were viral hepatitis, mental disorder, neoplasia, and depression.
Unemployment was frequent within the groups, with 307 cases (15.4%) within HIV negative cases, 42 (26.9%) within HIV positive and 24 (27.0%) within unknown HIV. The use of illicit drugs was reported in 30 (19.2%) HIV positive patients, a higher percentage than among HIV negative and unknown patients, 6.9% and 10.5% respectively.
Among the 156 HIV positive patients, 137 (87.8%) already had a diagnosis of HIV when they started MDR-TB treatment, 117 (75%) had a CD4 record, and 88 (56.4%) had a CD8 record available. The median of CD4 was 311 cells/mm3 (IQR 141-497), while the median of CD8 was 840.5 cells/mm3 (IQR 520.5-1204.5). HIV viral load was available in 65 (41.6%) records, with a median of 8166 copies/ml (IQR 903-37,000). As for ART, 85 (66.4%) had a treatment record during the treatment of MDR-TB.
Table 1. Demographic and clinical characteristics of 2,269 MDR-TB patients by HIV status
Characteristics
|
HIV negative
(%)
N=1999
|
HIV positive
(%)
N=156
|
HIV unknown (%)
N=114
|
p-value*
|
Sex
Female
Male
Age Range
0 - 24
25 - 44
45 - 64
≥65
Ethnical group
Caucasian
Afro-Brazilian
Unknown
Years of study
None
1 a 3
4 a 7
8 a 11
≥12
Ignored
Site of disease
Extrapulmonary
Pulmonary
Both
Other factors
Diabetes
Alcohol abuse
Illicit Drug use
Smoking
Unemployed
Comorbidities†
Chest radiography (n=2189)
Cavitation
Bilateral
Drug Resistance type
Primary
Acquired
Previous MDR-TB treatment
No
Yes
Outcomes
Cured/Treatment completed
Lost to follow up
Died
Failed
|
670 (34.8)
1304 (65.2)
316 (15.8)
975 (48.7)
635 (31.7)
74 (3.7)
730 (36.5)
1198 (60.0)
71 (3.5)
95 (4.7)
379 (19.0)
771 (38.6)
437 (21.9)
153 (7.6)
164 (8.2)
9 (0.5)
1974 (98.7)
16 (0.8)
197 (9.8)
243 (12.2)
138 (6.9)
170 (8.5)
307 (15.4)
237 (11.9)
1586 (82.0)
1478 (76.4)
298 (14.9)
1701 (85.1)
1550 (77.5)
449 (22.5)
1126 (56.3)
368 (18.4)
295 (14.8)
210 (10.5)
|
61 (39.1)
95 (60.9)
11 (7.1)
104 (66.7)
40 (25.6)
1 (0.6)
44 (28.2)
106 (68.0)
6 (3.8)
13 (8.3)
31 (19.9)
65 (41.7)
24 (15.4)
7 (4.5)
16 (10.2)
10 (6.4)
133 (85.3)
13 (8.3)
5 (3.2)
14 (9.0)
30 (19.2)
10 (6.4)
42 (26.9)
22 (14.1)
99 (68.3)
108 (74.5)
22 (14.1)
134 (85.9)
118 (75.6)
38 (24.3)
74 (47.4)
38 (24.4)
36 (23.1)
8 (5.1)
|
47 (41.2)
67 (58.8)
18 (15.8)
47 (41.2)
41 (36.0)
8 (7.0)
42 (36.8)
68 (59.6)
4 (3.5)
5 (4.4)
20 (17.5)
43 (37.7)
30 (26.3)
6 (5.3)
10 (8.8)
1 (0.9)
111 (97.4)
2 (1.7)
17 (14.9)
16 (14.0)
12 (10.5)
12 (10.5)
24 (27.0)
13 (11.4)
87 (78.4)
62 (56.4)
14 (12.3)
100 (87.7)
76 (66.7)
38 (33.3)
64 (56.1)
27 (23.7)
16 (14.0)
7 (6.1)
|
0.226
<0.001
0.155
0.296
<0.001
0.004
0.399
<0.001
0.477
<0.001
0.695
<0.001
<0.001
0.725
0.026
0.098
0.084
0.019
0.037
|
TB: tuberculosis; MDR-TB: multidrug-resistant TB; XDR-TB: extensively drug-resistant TB;
HIV: human immunodeficiency virus.
*Comparison between HIV negative, positive and unknown.
† Except Diabetes and HIV.
In general, 1,005 (44.3%) patients had unfavorable outcomes, being more frequent among HIV positive patients (52.6%) than in HIV negative cases (43.7%), and in HIV unknown (43.9%). The most frequent variable associated with unfavorable treatment was lost to follow up, which occurred in 38 (24.4%) cases with HIV positive, and in 395 (18.4%) with HIV negative. Death affected 36 (23.1%) of HIV positive cases, and 295 (14.8%) of HIV negative. Failure was twice as high among HIV negative patients (10.5%) as among HIV positive patients (5.1%).
Drug resistance and treatment outcomes
Upon analysis of treatment outcomes by HIV status and drug resistance (see Table 2), MDR or XDR-TB, it was observed that MDR-TB patients, regardless of HIV serological status, have more therapeutic success. The success among XDR-TB HIV negative/unknown cases was only 20.8%, while, in the same period, there was no case of therapeutic success among XDR-TB HIV positive cases. Death was more frequent in HIV positive, especially in XDR-TB patients, while failure was practically the same among XDR-TB groups, but it was lower among MDR-TB HIV positive (2.8%) than among MDR-TB HIV negative cases (8.5%).
Table 2: Treatment outcomes among 2,269 patients with MDR-TB and XDR-TB by HIV status
Outcomes
|
HIV Negative/Unknown
|
HIV Positive
|
MDR
(n= 1983)
|
XDR
(n= 130)
|
p-value*
|
MDR
(n= 145)
|
XDR
(n=11)
|
p-value*
|
Cure/treatment completed
Lost to follow up
Died
Failed
|
1163 (58.6)
379 (19.1)
273 (13.8)
168 (8.5)
|
27 (20.8)
16 (12.3)
38 (29.2)
49 (37.7)
|
<0.001
0.054
<0.001
<0.001
|
74 (51.0)
35 (24.1)
32 (22.1)
4 (2.8)
|
0 (0.0)
3 (27.3)
4 (36.4)
4 (36.4)
|
0.001
0.815
0.278
<0.001
|
TB: tuberculosis; MDR-TB: multidrug-resistant TB; XDR-TB: extensively drug-resistant TB;
HIV: human immunodeficiency virus.
*Comparison between MDR/XDR-TB.
Among HIV positive patients who did not undergo ART, half died within the first 180 days after starting treatment for MDR-TB, while among those who did ART, the time span was 510 days. These patients were treated with a median of 5 drugs. The most common initial regimens included amikacin (65%), streptomycin (28%), ethambutol (92%), clofazimine (25%), terizidone (95.5%), pyrazinamide (55%), ofloxacin (47%) and levofloxacin (44%).
Factors associated with treatment outcomes in MDR-TB patients with HIV coinfection in the bivariate model
Bivariate analyses of the factors associated with unsuccess, loss to follow up, death and failure for HIV-positive MDR-TB patients are displayed in table 3. Unsuccess was more likely among illicit drug users (HR 1.64, 95% CI 1.01-2.70), the unemployment (HR 1.73, 95% CI 1.08-2.75), and patients with previous MDR-TB treatment (HR 1.97, 95% CI 1.22-3.19). Six-month culture conversion (HR 0.50, 95% CI 0.29-0.87) and receiving ART (HR 0.61, 95% CI 0.39-0.95) were protective factors for unsuccess. The loss to follow up was associated with the use of illicit drugs (HR 3.59, 95% CI 1.87-6.90), alcohol abuse (HR 2.30, 95% CI 1.05-5.05), and being unemployed (HR 2.08, 95% CI 1.07-4.01). Risk factors for treatment failure were previous MDR-TB treatment (HR 5.13, 95% CI 1.23-21.41), and being XDR-TB (HR 6.47, 95% CI 1.49-28.0), while ART (HR 0.16, 95% CI 0.03-0.80) was a protective factor. For death, six-month culture conversion (HR 0.19, 95% CI 0.05-0.63) and ART (HR 0.37, 95% CI 0.18-0.73) were protective factors.
Table 3. Bivariate analysis: Predictors of unsuccessful, default and death among 156 MDR-TB HIV positive patients
Predictors
|
Unsuccess
|
Loss to follow up
|
Death
|
Failure
|
HR (95% CI) p-value
|
HR (95% CI) p-value
|
HR (95% CI) p-value
|
HR (95% CI) p-value
|
Sex
Female
Male
<40 years
No
Yes
Years of schooling
≥ 8
< 8
Afro-Brazilian
No
Yes
Diabetes
No
Yes
Comorbidities
No
Yes
Illicit drug use
No
Yes
Alcohol abuse
No
Yes
Smoking
No
Yes
Unemployed
No
Yes
Six-month culture conversion
No
Yes
Treatment regimen
Individualized
Standardized
Drug Resistance type
Primary
Acquired
Chest radiography
No cavitation
Cavitation
Unilateral
Bilateral
Previous MDR-TB Treatment
No
Yes
Categories of drug resistance
MDR-TB
XDR-TB
ART
No
Yes
|
1.0
0.89 (0.57–1.39) 0.621
1.0
1.35 (1.07-3.52) 0.186
1.0
1.16 (0.63-2.13) 0.619
1.0
1.22 (0.73-2.01) 0.438
1.0
0.26 (0.03-1.91) 0.188
1.0
1.12 (0.60-2.07) 0.717
1.0
1.64 (1.01-2.70) 0.048
1.0
1.26 (0.67-2.37) 0.468
1.0
1.12 (0.48-2.58) 0.788
1.0
1.73 (1.08-2.75) 0.020
1.0
0.50 (0.29-0.87) 0.015
1.0
1.05 (0.66-1.67) 0.823
1.0
1.34 (0.67-2.70) 0.400
1.0
1.09 (0.67-1.75) 0.719
1.0
1.17 (0.68-2.05) 0.558
1.0
1.97 (1.22-3.19) 0.005
1.0
1.60 (0.83-3.08) 0.156
1.0
0.61 (0.39-0.95) 0.029
|
1.0
0.84 (0.44-1.62) 0.622
1.0
1.66 (0.86-3.29) 0.127
1.0
1.10 (0.47-2.53) 0.819
1.0
1.39 (0.66-2.96) 0.381
___
1.0
1.39 (0.61-3.17) 0.431
1.0
3.59 (1.87-6.90) <0.001
1.0
2.30 (1.05-5.05) 0.037
1.0
1.90 (0.74-4.89) 0.182
1.0
2.08 (1.07-4.01) 0.029
1.0
0.92 (0.46-1.83) 0.820
1.0
1.31 (0.64-2.66) 0.446
1.0
1.52 (0.54-4.31) 0.424
1.0
1.53 (0.72-3.27) 0.264
1.0
0.91 (0.44-1.90) 0.815
1.0
1.75 (0.87-3.51) 0.110
1.0
1.10 (0.34-3.61) 0.864
1.0
1.04 (0.52-2.07) 0.909
|
1.0
1.05 (0.53-2.10) 0.875
1.0
2.16 (0.83-5.59) 0.112
1.0
1.19 (0.45-3.16) 0.717
1.0
0.91 (0.44-1.89) 0.811
1.0
0.63 (0.08-4.68) 0.656
1.0
1.09 (0.42-2.84) 0.849
1.0
0.40 (0.12-1.36) 0.142
1.0
0.42 (0.10-1.81) 0.251
1.0
0.45 (0.06-3.31) 0.434
1.0
1.28 (0.61-2.70) 0.498
1.0
0.19 (0.05-0.63) 0.007
1.0
1.24 (0.60-2.55) 0.551
1.0
1.22 (0.42-3.49) 0.705
1.0
0.89 (0.44-1.80) 0.755
1.0
1.21 (0.52-2.80) 0.652
1.0
1.73 (0.81-3.67) 0.154
1.0
1.24 (0.43-3.61) 0.683
1.0
0.37 (0.18-0.73) 0.004
|
1.0
0.62 (0.15-2.50) 0.508
1.0
2.78 (0.34-22.6) 0.339
1.0
1.64 (0.19-13.7) 0.646
1.0
3.66 (0.44-30.0) 0.227
___
-----
1.0
1.79 (0.35-8.99) 0.476
1.0
1.91 (0.22-16.08) 0.548
___
1.0
1.87 (0.44-7.86) 0.390
1.0
0.25 (0.03-2.05) 0.198
1.0
0.18 (0.03-0.91) 0.038
1.0
1.30 (0.16-10.63) 0.803
1.0
0.86 (0.20-3.62) 0.841
___
1.0
5.13 (1.23-21.41) 0.025
1.0
6.47 (1.49-28.0) 0.013
1.0
0.16 (0.03-0.80) 0.026
|
TB: tuberculosis; MDR-TB: multidrug-resistant TB; XDR-TB: extensively drug-resistant TB
HR: hazard rates; CI: confidence interval
HIV: human immunodeficiency virus
ART: antiretroviral therapy
† Except Diabetes and HIV
The multivariate model: Factors associated with treatment outcomes in MDR-TB patients with HIV coinfection
In the final model, having previous MDR-TB was associated with unsuccess (HR 1.91 CI 95% 1.18-3.09 p = 0.008), and death (HR 2.99 CI 95% 1.22-7.31 p = 0.016). Use of illicit drugs was associated with unsuccess (HR 1.63 CI 95% 0.98-2.71 p = 0.055) and had three times more risk of loss to follow up (HR 3.25 CI 95% 1.67-6.31 p = 0.001). Being XDR-TB had six times more risk than MDR-TB for failure (HR 6.11 CI 95% 1.41-26.32 p = 0.015). Six-month culture conversion was a protective factor for unsuccess (HR 0.46 CI95% 0.26-0.80 p = 0.007) and death (HR 0.30 CI95% 0.08-1.03 p = 0.056), while ART was a protective factor for unsuccess (HR 0.58 CI95% 0.37-0.91), death (HR 0.38 CI95% 0.16-0.92 p = 0.034), and failure (HR 0.15 CI 95% 0.03-0.78 p = 0.024) (Table 4).
Table 4. Multivariate analysis: Predictors of unsuccessful, default and death among 157 patients with HIV positive.
Predictors
|
Unsuccess
|
Loss to follow up
|
Death
|
Failure
|
HR (95% CI) p-value
|
HR (95% CI) p-value
|
HR (95% CI) p-value
|
HR (95% CI) p-value
|
Illicit drug use
No
Yes
Six-month culture conversion
No
Yes
Previous MDR-TB Treatment
No
Yes
Categories of drug resistance
MDR-TB
XDR-TB
ART
No
Yes
|
1.0
1.83 (1.10-3.04) 0.019
1.0
0.49 (0.28-0.85) 0.012
1.0
1.81 (1.11-2.95) 0.016
1.0
0.58 (0.37-0.91) 0.018
|
1.0
3.25 (1.67-6.31) 0.001
|
1.0
0.29 (0.85-0.99) 0.050
1.0
3.14 (1.26-7.77) 0.013
1.0
0.38 (0.15-0.93) 0.035
|
1.0
6.11 (1.41-26.32) 0.015
1.0
0.15 (0.03-0.78) 0.024
|
TB: tuberculosis; MDR-TB: multidrug-resistant TB; XDR-TB: extensively drug-resistant TB;
HR: hazard rates; CI: confidence interval
HIV: human immunodeficiency virus.
ART: antiretroviral therapy