INT J TUBERC LUNG DIS 17(2):178–185 © 2013 The Union http://dx.doi.org/10.5588/ijtld.12.0314
Anti-tuberculosis treatment outcomes in HIV-infected adults exposed to isoniazid preventive therapy in Botswana T. Sibanda,* Z. Tedla,* S. Nyirenda,* T. Agizew,* M. Marape,† A. G. Miranda,‡ H. Reuter,§ J. L. Johnson,¶ T. Samandari*# * Centers for Disease Control and Prevention (CDC) Botswana, Gaborone and Francistown, † Botswana Baylor Children’s Clinical Centre of Excellence, Gaborone, Botswana; ‡ Division of Global HIV/AIDS, CDC, Atlanta, Georgia, USA; § University of Stellenbosch, Cape Town, South Africa; ¶ Division of Infectious Diseases, University Hospitals Case Medical Center, Cleveland, Ohio, # Division of Tuberculosis Elimination, CDC, Atlanta, Georgia, USA SUMMARY SETTING:
Eight public health clinics in Gaborone and Francistown, Botswana. O B J E C T I V E S : To describe the characteristics and outcomes of incident tuberculosis (TB) cases in human immunodeficiency virus (HIV) infected adults exposed to isoniazid preventive therapy (IPT) with access to antiretroviral and anti-tuberculosis treatment. D E S I G N : In 1995 HIV-infected adults, TB disease was excluded before commencing IPT. During and after receipt of 6 or 36 months of IPT, symptomatic participants were evaluated using chest radiographs, sputum microscopy, cultures and drug susceptibility testing (DST). Incident TB cases received ⩾6 months of anti-tuberculosis treatment. R E S U LT S : Seventy-five incident TB cases were identified among 619 symptomatic participants. The median dura-
tion of IPT in these cases was 6 months (range 1–35), and the median time to initiation of anti-tuberculosis treatment was 12 months after IPT cessation. Antiretroviral therapy (ART) was initiated before anti-tuberculosis treatment in 37 cases. Culture was positive in 43/58 (74%) TB cultures. DST was available for 38 cases, of which six (16%) were resistant to isoniazid (INH); 67/ 75 (89%) cases, including four with INH-monoresistant TB, completed anti-tuberculosis treatment or were cured. C O N C L U S I O N S : With prompt initiation of anti-tuberculosis treatment and access to ART, excellent outcomes were achieved in a public health setting in HIV-infected adults who developed TB disease. K E Y W O R D S : tuberculosis; HIV infection; antiretroviral therapy; tuberculosis drug resistance; cohort study
TUBERCULOSIS (TB) remains a principal cause of morbidity and mortality for persons living with the human immunodeficiency virus (PLWH) in countries where TB is endemic. The Joint United Nations Programme on HIV/AIDS estimated that in 2010, of the 1.8 million deaths among PLWH, 360 000 (20%) were caused by TB.1 The African Region accounted for 82% of TB cases among PLWH in the same year.2 Antiretroviral therapy (ART) reduces the risk of TB disease in PLWH; if PLWH develop TB disease, ART reduces the risk of death when co-administered with antituberculosis treatment.3–5 However, the risk of TB remains high in PLWH receiving ART.6 There is therefore a critical need to implement adjunctive therapies for the prevention of TB in this vulnerable population.7 Isoniazid preventive therapy (IPT) has been shown to prevent TB in PLWH with positive tuberculin skin test (TST) results.8 However, program implementation in many countries has lagged due to concerns
about effectively excluding prevalent TB prior to IPT initiation, difficulties in diagnosing TB in PLWH, and treatment outcomes among emergent TB cases, particularly those resistant to isoniazid (INH).9–12 We prospectively followed a cohort of 1995 PLWH in Botswana who had TB disease excluded at baseline and who were enrolled in a 3-year IPT clinical trial conducted in government clinics.13 In previous publications, we reported that among 2732 asymptomatic potential participants screened for this trial, 43 (1.6%) had active TB disease, and that from the perspective of Botswana health care it was not costeffective to implement chest radiograph (CXR) screening for all IPT candidates.14,15 In this paper, we describe the characteristics of TB disease in incident cases during and after IPT receipt among trial participants and their response to anti-tuberculosis treatment, sometimes combined with ART.
Correspondence to: Taraz Samandari, Division of Tuberculosis Elimination, CDC, 1600 Clifton Road NE, Mailstop E45, Atlanta, GA 30333, USA. Tel: (+267) 392 2400 x 471. Fax: (+267) 393 0429. e-mail:
[email protected], samandarit@ bw.cdc.gov Article submitted 26 April 2012. Final version accepted 23 August 2012. [A version in French of this article is available from the Editorial Office in Paris and from the Union website www.theunion.org]
TB after INH prophylaxis
METHODS Study participants The enrolment process is described in detail elsewhere.13 Briefly, between 2004 and 2006, PLWH aged ⩾18 years seen at eight government clinics providing ART and IPT were invited to participate in the trial. Subjects were excluded if they had any signs or symptoms of TB disease, i.e., cough, weight loss, night sweats, other acute illnesses, anti-tuberculosis treatment within the past 3 years or abnormal CXR without a previous history of TB or pneumonia. Persons with any CD4+ lymphocyte count and regardless of TST status were eligible for enrollment. According to the protocol, half of the participants were to receive 6 months of IPT and half were to receive 36 months of IPT. Because the study participants were invited to remain under observation until 30 June 2011, additional TB cases were identified after the 54 cases reported during the 36 months of the clinical trial.13 Tuberculosis-related procedures After enrollment, participants were seen every 1– 3 months and asked about symptoms of TB, including cough of any duration, fever, night sweats, shortness of breath, chest pain, weight loss or lymphadenopathy. If they had any of these symptoms, attempts were made to obtain sputum specimens and, in those with lymphadenopathy, fine-needle aspirates. A trial of antibiotic therapy was used if respiratory symptoms developed, if all sputum smears were acid-fast bacilli (AFB) negative and if TB was not strongly suspected. Antibiotics used included amoxicillin, trimethoprim sulfamethoxazole, erythromycin and doxycycline. Due to the large number of participants enrolled, initial evaluations of symptomatic individuals were frequently conducted by local clinicians rather than study physicians. Once received from patients, sputum specimens were kept in cool boxes, transported to the local laboratory’s refrigerator and then shipped by land to a reference laboratory in Johannesburg within 1–2 days. The typical time from sample receipt to sputum processing by the reference laboratory was 24–36 h. Sputum specimens were stained with auramine-O and examined by fluorescent microscopy, and if found to be positive they were confirmed as AFB using the Ziehl-Neelsen method. Sputum samples were inoculated into Mycobacterial Growth Indicator Tubes (MGIT™ 960, BD, Sparks, MD, USA). If culture became positive within 6 weeks, Mycobacterium tuberculosis was speciated and drug susceptibility testing (DST) was conducted with the MGIT system using a subculture at concentrations of respectively 0.1 μg/ml, 1.0 μg/ml, 5.0 μg/ml and 1.0 μg/ml for INH (H), rifampin (R, RMP), ethambutol (E, EMB) and streptomycin (S, SM). DST for pyrazinamide (Z, PZA) was not performed. Tissue specimens were treated
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with hematoxylin and eosin stains and examined for AFB. TB cases were defined as participants with clinical presentations consistent with TB, who also responded to anti-tuberculosis treatment and were categorized as follows: definite TB if ⩾1 culture was positive for M. tuberculosis or ⩾2 sputum smears were AFBpositive; probable TB if one sputum smear or one biopsy specimen was AFB-positive; and possible TB if smears and cultures were negative. Antiretroviral therapy and anti-tuberculosis treatment Efavirenz- or nevirapine-based ART was offered if a participant met World Health Organization (WHO) clinical staging criteria or had a CD4+ count 4 months (continuation phase range 5–16); 1% (1/73) received 4HREZ/2HR; 1% (1/73) received standard 6-month treatment twice consecutively; 1% (1/73) received 12HRE; and 4% (3/73) received various other regimens for drug-resistant TB (Table 3). Treatment outcomes Of the 75 cases, 67 (89%) achieved treatment success per WHO criteria; one of these relapsed, then completed treatment again and was free of TB for the subsequent 31 months of follow-up. Of the remaining eight patients, two defaulted from anti-tuberculosis treatment and then were cured or completed treatment with reinstitution of anti-tuberculosis treatment, three failed 2HREZ/4HR due to multidrug-resistant TB (MDR-TB) and completed treatment for MDRTB, one withdrew from the trial before treatment completion and two died before treatment initiation. * Numbers before the letters indicate the duration in months of the phase of treatment.
TB after INH prophylaxis
Table 2 Summary of characteristics, treatment and outcomes of incident TB cases among HIV-infected adults exposed to IPT, Botswana, 2005–2011 (n = 75) n/N (%) or median [IQR] Characteristic Culture positive or ⩾2 smear-positive ‘definite’ TB 44/75 (59) One smear positive ‘probable’ TB 11/75 (15) Smear and culture negative ‘possible’ TB 20/75 (27) Sputum smear positive (number/total attempted) 24/70 (34) Culture positive (number/total attempted) 43/58 (74) TB culture positive with drug susceptibility testing 38/43 (88) TB culture susceptible to HRES 31/38 (82) Any TB culture resistant to H 6/38 (16) Any TB culture resistant to R 3/38 (8) MDR-TB (resistant to H and R) 2/38 (5) Extra-pulmonary TB* 27/75 (36) IPT prior to anti-tuberculosis treatment initiation, months 5.8 [5.0–6.1]† IPT at the time of TB diagnosis 15/75 (20) Months after stopping IPT when anti-tuberculosis treatment was initiated 12.0 [6.5–27.5]‡ CD4+ cell count at time closest to anti-tuberculosis treatment, cells/mm3 208 [129–380] Delay in anti-tuberculosis treatment initiation, months§ 1 [0.3–1.6] Treatment Anti-tuberculosis treatment regimen 2HREZ/4HR 50/73 (68) 6REZ-containing regimens 7/73 (10) ART initiated prior to completion of anti-tuberculosis treatment 37/75 (49) ART initiated after anti-tuberculosis treatment 8/75 (11) ART initiated before anti-tuberculosis treatment was begun or completed 52/75 (69) Outcomes of anti-tuberculosis treatment Treatment success with first round of treatment¶ 67/73 (92) Default after initiation of treatment 2/73 (3) Withdrew after initiation of treatment 1/73 (1) Treatment failure after initiation of treatment# 3/73 (4) Relapse after completion of treatment 1/73 (1) Follow-up after treatment, months** 31 [18–39] * Twelve TB cases had both pulmonary and extra-pulmonary TB. † Range: 1–35 months. ‡ Range: 0–44 months. § Defined as the delay in the initiation of anti-tuberculosis treatment from the time of presentation to the clinic with symptoms. Range: 0–12 months. ¶ Denominator excludes two TB cases who died and had not initiated antituberculosis treatment. Treatment success included 55 treatment completions and 12 cures. # Three treatment failures occurred in the three cases with RMP-resistant TB but they all completed 24–32 months of anti-tuberculosis treatment for MDRTB, received ART and were alive 0–24 months after completion of treatment. ** Excludes the two TB cases who died and one case who withdrew. Range: 0–55 months. TB = tuberculosis; IPT = isoniazid preventive therapy; HIV = human immunodeficiency virus; IQR = interquartile range; H = isoniazid; R, RMP = rifampin; E = ethambutol; S = streptomycin; Z = pyrazinamide; MDR-TB = multidrugresistant TB.
Considering the entire period of observation, 99% (72/73) of the TB cases who initiated anti-tuberculosis treatment eventually achieved treatment success. Four TB cases resistant to INH but susceptible to RMP, EMB and SM, were cured or completed treatment without relapse during a follow-up period of 35–51 months. All four received RMP, PZA and EMB for 6 months; three of these cases also received INH
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for 2–6 months. The two TB cases who died did not initiate anti-tuberculosis treatment but multiple cultures obtained during their illness yielded positive results for drug-susceptible TB post mortem. One case had non-specific symptoms, including cognitive impairment over an 8-month period and purulent inguinal lymphadenopathy. The patient’s refusal to be examined and difficulties convincing her family to permit an examination or obtain a CXR contributed to the delay in diagnosing TB. Two swabs of inguinal discharge were collected and became culture-positive after her death. The second case died after a 4-month period of symptoms, including cough, weight loss, a normal CXR, response to antibiotics and negative sputum smears. Two sputum cultures and one blood culture turned positive after her death when she developed acute renal failure shortly after initiating tenofovir-containing ART. ART was begun before initiation of anti-tuberculosis treatment in 37 TB cases (median 15 months before treatment, range 0–56); seven of these cases initiated ART while TB symptoms were being evaluated, but prior to the initiation of anti-tuberculosis treatment, and two of these cases met the criteria for unmasking immune reconstitution disease, did not require additional interventions and had an excellent clinical outcomes.17 ART was initiated after anti-tuberculosis treatment initiation in 23 others (median 3 months, range 1–23).
DISCUSSION During prospective monitoring of 1995 HIV-infected adults, we diagnosed 75 incident cases of TB disease among participants who had received IPT for up to 3 years. Two thirds had AFB-negative sputum smears; a fifth of those who had a CXR performed had no radiographic abnormality, and 16% had no cough. Among those who had specimens cultured, three quarters grew M. tuberculosis. These observations highlight the difficulties of TB diagnosis in PLWH and the importance of culturing specimens. Despite such challenges for the HIV-infected adults in this study— all of whom received IPT and were treated for TB and HIV in a public health setting—outcomes were comparable or superior to reports of clinical trials and cohort studies of anti-tuberculosis treatment for presumably IPT-naïve PLWH.18 Few studies have examined TB outcomes in PLWH exposed to IPT. One such study was conducted in a large prospective study among South African miners exposed to IPT, of whom ~86% were HIV coinfected.19 Limited to those with known outcomes and who did not default from anti-tuberculosis treatment, we observed a superior initial treatment success among participants initiating anti-tuberculosis treatment (67/70, 96%) compared to an imputed 85% (64/75) observed in the South African study.
Symptoms
C, W, P C, W, F, N C, W, F, P C, F, P C, P C, W, F, P, N C, W, F, P, N C, W, N C, F, N C C, F C, F, N C C, W, F C, W, P, N C, W, F, N C, P C, W, F, N C, F C, W C C, F, P, N C, W, P C, W, P C, W, F, N C, P, N C, F, P, N C, W, F, N C, P, N C, F, N C, F, P W, F, N, L C, W, F, N C, P, N C, W C C, P W, L, P C, F, P, N C
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
No No No Yes No Yes Yes No No No Yes Yes No No No No No No Yes No Yes Yes Yes Yes Yes No No Yes Yes Yes No No Yes Yes Yes Yes Yes No No No
5 6 2 6 35 25 26 10 6 6 6 6 6 6 10 6 5 3 9 6 2 6 30 6 6 11 5 6 6 16 35 6 24 6 6 6 5 6 6 35
32 36 10 12 11 1 0 8 35 36 11 27 42 10 6 26 15 27 0 15 0 8 0 7 13 9 26 7 1 0 5 10 0 5 9 17 0 42 37 5
Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite Definite
PTB Both EPTB PTB PTB Both Both PTB PTB PTB PTB PTB PTB PTB PTB PTB PTB PTB PTB PTB PTB PTB PTB EPTB Both PTB PTB PTB PTB PTB Both EPTB PTB PTB PTB PTB PTB EPTB Both PTB
Incidence Receiving IPT of TB INH at duration, after IPT, TB TB diagnosis months months category location Infiltrate Infiltrate, hilar adenopathy Pericardial effusion NA Normal Infiltrate, hilar adenopathy Infiltrate, hilar adenopathy Infiltrate, cavity Infiltrate, cavity Normal Normal Infiltrate Normal NA Infiltrate, fibrosis Infiltrate Infiltrate, effusion Infiltrate, nodules, cavity Infiltrate, hilar adenopathy Cavity, fibrosis Other Infiltrate Other Effusion Effusion Infiltrate Infiltrate, cavity Normal Normal Other Infiltrate, hilar adenopathy Normal Infiltrate, cavity Cavity Infiltrate, cavity Infiltrate, cavity Normal NA Normal Nodules
CXR 125 375 298 341 307 43 135 95 256 515 722 434 233 4 77 33 188 130 141 215 160 502 76 289 350 120 629 380 802 602 263 108 482 543 356 475 387 114 9 416
0.7 0.5 0.0 1.1 5.5 1.0 1.2 0.3 0.0 1.2 2.1 1.6 1.3 0.4 0.0 0.0 2.9 0.5 1.7 0.3 1.2 0.3 1.2 1.0 2.1 1.5 1.2 1.0 1.0 2.3 0.1 0.1 0.0 2.2 0.1 1.5 3.9 — — 1.6
CD4+ count closest ATT to TB delay, diagnosis months*
— — 2HREZ/4HR
¶
2HREZ/4REZ 6HREZ 6HREZ 6REZ
§
‡
2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 12HRE 2HREZ/4HR repeat 2HREZ/6HR 2HREZ/7HR 2HREZ/9HR 2HREZ/4HR
ATT regimen
−26.7
12.2 −34.6
1.4 −13.6 8.0 8.2
−1.3
−32.5 7.9 −15.1 −3.1 −31.0 −16.3 −5.7 −0.4 −13.8 2.9 −12.6 6.7 −7.3 7.6 22.1
−31.4 −27.9 3.4 −16.1 −4.3 −1.0 2.6 −16.2 −14.9
ART TB culture initiation drug in relation susceptibility to ATT tests, initiation,† HRE-S months SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S SSS-S Contaminated RRR-R RRS-R RSS-S RSS-S RSS-S RSS-S SRS-R SSS-S SSS-S NA
Detailed line list of TB cases diagnosed prospectively in an IPT clinical trial among HIV-infected adults, Botswana, 2005–2011
TB case
Table 3
13
26 20 47 41 13 27 36 38 18 1 39 23 17 12 46 26 36 26 45 35 46 48 31 37 31 40 31 45 46 40 4 13 35 51 38 36 25
(continued )
Treatment completion Treatment completion Cured Treatment completion Cured Cured Cured Defaulted Cured Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Defaulted Cured Treatment completion Treatment completion Treatment completion Treatment failure Treatment failure Cured Cured Treatment completion Cured Tx failure Died Died Treatment completion
Post ATT follow-up, Treatment outcome months
182 The International Journal of Tuberculosis and Lung Disease
C C C, W, F, P, N C, W, F, P, N C, W, F C, W, F, P W, L C, W, F, P, N, L L L W, L L L W C, P, L C, W, P Other C, P W, F, N C, W, F, P, N C, W, F, L C, W, F, P, N C, W, F, L C, W, F, P, N C, F, P C, F, N C, W C, W, F W, F, P, N C, F, P C, W, F, P C, W, F C, W, F, P C, W, F, N C, W, F, N
41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
No Yes No Yes Yes No No No No No No No Yes No No Yes No No No No No No Yes No Yes No No No No Yes Yes Yes Yes Yes No
3 6 2 13 6 5 5 2 2 3 6 1 6 0 10 6 6 5 5 17 2 6 35 2 26 6 6 3 6 5 4 6 6 6 5
44 28 26 0 28 35 22 40 12 43 33 24 17 38 9 0 31 28 15 20 23 25 3 20 0 33 9 40 7 0 0 23 8 12 9
Definite Definite Definite Definite Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Probable Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible Possible
PTB EPTB PTB PTB Both Both Both Both EPTB EPTB EPTB EPTB EPTB EPTB EPTB PTB EPTB PTB PTB Both Both EPTB PTB PTB PTB PTB EPTB PTB PTB PTB PTB PTB PTB PTB PTB
Infiltrate Hilar adenopathy Infiltrate, cavity Infiltrate, cavity Infiltrate, hilar adenopathy Infiltrate, hilar adenopathy Infiltrate, hilar adenopathy Infiltrate, cavity, fibrosis NA Normal Normal NA Normal NA Normal Infiltrate, nodules NA Infiltrate, fibrosis Infiltrate Infiltrate, effusion Infiltrate, hilar adenopathy Hilar adenopathy Infiltrate, fibrosis Infiltrate, cavity Infiltrate, cavity Other Infiltrate, effusion Other Infiltrate Infiltrate, cavity Infiltrate Infiltrate Infiltrate, effusion Infiltrate, nodules Infiltrate, cavity
CXR 186 492 187 140 129 171 265 113 236 240 129 442 392 378 94 196 804 179 172 28 208 69 211 192 465 282 524 156 89 40 426 131 181 152 50
2.2 2.2 0.0 0.7 5.4 0.5 1.7 0.5 12.0 0.5 2.8 0.3 5.1 1.0 0.1 0.4 1.9 1.4 0.3 0.3 0.2 0.8 10.0 0.3 0.9 0.0 0.0 0.7 0.2 0.3 1.2 0.9 6.8 1.8 1.2
CD4+ count closest ATT to TB delay, diagnosis months*
2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 6HREZ 2HREZ/10HR 2HREZ/16HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/4HR 2HREZ/5HR 2HREZ/6HR 4HREZ/2HR 6HREZ 6HREZ 6HREZ
#
2HREZ/4HR 2HREZ/4HR 2HREZ/7HR
ATT regimen NA NA NA No growth NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 1.0 −4.8 −1.7 3.2 2.8 −4.9 2.3 −12.1
1.1
1.3 −5.9 22.7
−19.1 −35.9
−0.7 −6.0 −56.3
−43.9 −0.9 14.9 −20.3
−26.1 1.9 2.5 5.3 18.6 −36.9
−45.6
ART TB culture initiation drug in relation susceptibility to ATT tests, initiation,† HRE-S months Cured Treatment completion Cured Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Withdrew Cured Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion Treatment completion
38 19 7 24 18 31 6 17 38 15 39 48 58 21 32 39 43
9 14 34 31 34 18 32 17 35 13 17 28 30 19 44 56 19
Post ATT follow-up, Treatment outcome months
* Time from first presentation to clinic until anti-tuberculosis treatment was initiated. †ART initiation in relation to date of diagnosis and not anti-tuberculosis treatment initiation. ‡ Received AMK, CFX, ETH, PZA and EMB for 19 months; died 4 months after completion. § Received AMK, CFX, ETH, CS and PZA for 24 months. ¶ Received AMK, CFX, INH, EMB and PZA for 29 months. # Relapsed 6 months after 2HREZ/7HR but achieved cure after a second course of 2HREZ/4HR. TB = tuberculosis; IPT = isoniazid preventive therapy; HIV = human immunodeficiency virus; INH = isoniazid; CXR = chest radiography; ATT = anti-tuberculosis treatment; HRES = order of susceptibility test results (isoniazid, rifampin, ethambutol, streptomycin); ART = antiretroviral therapy; C = cough; W = weight loss; P = chest pain; PTB = pulmonary TB; H = isoniazid; R = rifampin; E, EMB = ethambutol; Z, PZA = pyrazinamide; F = fever; N = nocturnal sweats; EPTB = extra-pulmonary TB; L = lymphadenopathy; NA = not available; AMK = amikacin; CFX = ciprofloxacin; ETH = ethionamide; CS = cycloserine.
Symptoms
TB case
Incidence Receiving IPT of TB INH at duration, after IPT, TB TB diagnosis months months category location
Table 3 (Continued )
TB after INH prophylaxis
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The International Journal of Tuberculosis and Lung Disease
The median CD4+ lymphocyte count in TB patients from both studies was similar: 196 cells/mm3 vs. 208 cells/mm3. ART use at the time of TB diagnosis was higher among our cases (49% vs. 24%); however, the following may be additional reasons why we observed a higher success rate: all participants were likely to have benefited from regular reminders about reporting TB symptoms to study nurses, selection criteria at enrollment may have improved outcomes as enrollees were likely in better health than persons excluded by trial criteria despite no minimum CD4+ cell count criterion, or they may have benefited from their association through participation in the clinical trial.20 A national anti-tuberculosis drug resistance survey in Botswana conducted between 2007 and 2008 found that 8–10% of TB patients had any INH resistance.21 As IPT eradicates INH-susceptible but not INH-resistant latent TB infection, an increased proportion of INH-resistant TB would be expected to emerge from a cohort receiving IPT compared to individuals never exposed to IPT.13,22,23 Compared with our published results from the clinical trial, the present analysis—which adds nine more cases with DST data—demonstrated a slightly lower proportion of INH-resistant TB cases (17% vs. 16%), below the expected proportion of 18%.13 There is more treatment failure in INH-monoresistant cases of TB who receive standard short-course therapy but, with 6-month REZ treatment, outcomes are no different than for fully drug-susceptible TB.12,24,25 In the case of our four INH-monoresistant cases, outcomes were excellent with the use of 6-month REZ-containing regimens. Untreated TB disease in PLWH is lethal, and rapidly so in those with advanced HIV disease.26 Prompt diagnosis of TB and initiation of anti-tuberculosis treatment is thus critical to avoid adverse outcomes in HIV-infected TB patients. Imputation from the results of a meta-analysis of PLWH receiving ⩾6 months of RMP-based anti-tuberculosis treatment for TB disease demonstrated 3.2% treatment failure, 11.5% relapse and 12.3% death rates.18 Most of the patients included in this meta-analysis did not receive ART. Death is reduced with the integrated provision of ART and anti-tuberculosis treatment for PLWH with CD4+ counts
