LTBI screening and therapy for HIV 337Study protocol and study definitions standardised pill counts.15 The primary study outcomeAt TUH (IPT group), TST was performed at enrol- was incidence of PTB; secondary outcomes were all-ment. Positive TST reactivity was defined as skin in- cause mortality, change in CD4 counts, and HIV vi-duration ⩾5 mm at 72 h. TST indurations were mea- rological responses.sured by the ball point pen method.12 Patients withreactive TST were offered INH 300 mg/day and Statistical analysispyridoxine 50 mg/day for 9 months.13 Repeated TST Data analysis was performed using SPSS version 15was performed in patients with acquired immune- (Statistical Package for the Social Sciences Inc, Chi-deficiency syndrome (AIDS) who initially had non- cago, IL, USA). χ2 or Fisher’s exact test was used toreactive TST and subsequently had CD4 counts compare categorical data, as appropriate. Continuous>200 cells/μl on ART, and in those with reported TB variables were compared using the Mann-Whitneyexposure. TB exposure was defined as self-reported U-test. PTB incidence was calculated and comparedclose contact with active TB cases. using generalised linear models based on Poisson dis- At BIDI (non-IPT group), neither TST screening tribution. Probability of disease-free status and effectnor IPT were offered. At each site, chest radiograph of TST and IPT were analysed using the Kaplan-Meier(CXR) was performed at enrolment and annually estimate of the survival curve. All P values were two-thereafter. Patients with abnormal CXR findings sug- tailed; P < 0.05 was considered statistically significant.gestive of PTB underwent sputum collection for acid-fast bacilli (AFB) smear and culture of expectorated, RESULTSinduced or bronchoscopic specimens. PTB was de-fined as positive sputum for AFB with and without Study populationMycobacterium tuberculosis culture. Respectively 244 and 250 patients were initially Post-enrolment, participants at each site who devel- screened at TUH and BIDI (Figure 1): 44 (18%) andoped symptoms suggestive of PTB underwent CXR 50 (20%) patients were excluded at each site due to aand sputum collection for AFB and culture.14 ART diagnosis of active TB; all 94 excluded patients hadwas initiated in all patients with CD4 < 200 cells/μl CD4 < 100 cells/μl. The final study cohort includedaccording to the national guidelines for both groups.10 200 patients from each HIV clinic, with no signifi-Adherence to ART was defined as at least 75% by cant differences in age, sex or HIV clinical variables,Figure 1 Flow chart of study population, recruitment and outcomes. TUH = Thammasat University Hospital; IPT = isoniazidpreventive therapy; BIDI = Bamrasnaradura Infectious Diseases Institute; TB = tuberculosis; TST = tuberculin skin test.
338 The International Journal of Tuberculosis and Lung Diseaseexcept that patients in the IPT group were more likely vs. 11 (5.5%) cases in the non-IPT group (Table 1).to have acquired HIV from a sex partner than those in The median CD4 count most proximal to detectionthe non-IPT group (Table 1). More than 75% of the of PTB was similar for the two groups (35 vs.patients in each group had initial CD4 < 200 cells/μl. 41 cells/μl, P = 0.75). One of the 5 PTB cases fromART was initiated in each group for all patients with the IPT group (20%) and 1/11 from the non-IPTCD4 < 200 cells/μl. During follow-up, 58 (29%) par- group (9%) were asymptomatic, yet had abnormalticipants dropped out from the IPT group and 66 findings on annual CXR.(33%) dropped out from the non-IPT group. Reasons All TB isolates were pan-susceptible to first-linefor dropping out are shown in Figure 1. anti-tuberculosis drugs. There were no reported sig- nificant adverse reactions to anti-tuberculosis drugsIncidence of tuberculosis or treatment interruption. Four-year incidence of PTBHistory of TB exposure was similar for the IPT (6%) was not statistically different for the IPT and non-and non-IPT (3%) groups; no subsequent TB expo- IPT groups (0.80 vs. 1.76 cases/100 person-years [py]).sure was reported. For the IPT group, 17 (9%) par- However, the incidence of PTB was significantly higherticipants had a reactive TST (Figure 1), 14 (82%) of during the first 6 months in the non-IPT group thanwhom completed IPT. None of the 17 (100%) had in the IPT group (8.60 vs. 0 cases/100 py, respectively;subsequent TB case detection; 3 (18%) had a positive P = 0.01; actual number of cases 8 vs. 0), regardlessfollow-up TST after CD4 counts were >200 cells/μl. of initial CD4 count. Among patients with initialThe median CD4 count was 157 cells/μl for these CD4 < 200 cells/μl, the incidence of PTB during the17 IPT recipients and ART was initiated at the same first 6 months was significantly higher in the non-IPTtime as IPT in all 17 patients. than in the IPT group (9.41 vs. 0 cases/100 py; P = There were 5 (2.5%) cases of PTB in the IPT group 0.02; actual number of cases 8 vs. 0). Table 1 Baseline demographic and clinical characteristics of the study population stratified by receipt of TB preventive strategies IPT group Non-IPT group (n = 200) (n = 200) Characteristic n/N (%) n/N (%) P value Demographic Age, years, median [IQR] 35 [30–41] 35 [30–40] 0.72 Male sex 119 (60) 122 (61) 0.76 Reported mode of HIV acquisition* Sexual contact 194 (97) 182 (91) 0.01 Injection drug use 11 (6) 17 (8) 0.24 Others† 4 (2) 1 (1) 0.37 Baseline HIV data Duration of infection since diagnosis, years 0.47 >10 2 (1) 2 (1) 1–10 113 (57) 125 (62) <1 85 (42) 73 (37) CD4 count at initial visit, cells/μl, median [IQR] 97 [36–198] 91 [30–156] 0.16 HIV RNA at initial visit, log, copies/ml, median [IQR] 4.68 [4.08–5.09] 5.18 [4.83–5.58] 0.07 History of TB exposure 12 (6) 6 (3) 0.23 TB screening performed at initial visit Tuberculin skin test 200 (100) — Chest X-ray 200 (100) 200 (100) Incidence of TB during 48-month follow-up period, cases/100 py New LTBI 17 (2.71) NA — New active TB 5 (0.80) 11 (1.76) 0.13‡ TB treatment initiated during the 48-month period Active TB 1.00 Completed treatment 5/5 (100) 9/11 (82) Treatment not completed 0/5 (0) 2/11 (18) LTBI Receipt of chemoprophylaxis 17/17 (100) NA — Completed chemoprophylaxis 14/17 (82) Chemoprophylaxis not completed 3/17 (18) All-cause mortality during the 48-month period 6 (3) 5 (3) 0.76 * Patients may have more than one mode of HIV acquisition. † Includes tattooing and blood and blood product transfusion. ‡ Comparison based on Poisson distribution. TB = tuberculosis; IPT = isoniazid preventive therapy; IQR = interquartile range; HIV = human immunodeficiency virus; py = person-years; LTBI = latent TB infection; NA = not applicable.
LTBI screening and therapy for HIV 339 No PTB occurred in patients with CD4 ⩾ 200 cells/μl during the study period. After 6 months, the an-nual incidence of PTB in the IPT and non-IPT groupswas not significantly different (respectively 0 vs. 0 case/100 py in the second 6 months of Year 1; 0.64 vs.0.61 case/100 py in Year 2; 1.34 vs. 0 cases/100 py inYear 3; and 1.41 vs. 1.49 cases/100 py in Year 4). Noextra-pulmonary TB cases were detected; all-causemortality was similar (3%) for the two groups, withno cases of TB-related immune reconstitution inflam-matory syndrome.Effect of TST and IPTKaplan-Meier survival curves for the probability ofno PTB are shown in Figure 2. Using the log-ranktest, there was no significant difference in incidenceof PTB between the IPT and non-IPT groups acrossall initial CD4 categories. However, using the Bres-low test to detect the effects of short-term risks fo-cused at the beginning of observations, the IPT grouphad significantly lower incidence of PTB than thenon-IPT group (χ2 = 3.66, P = 0.04). The same anal-ysis among patients with CD4 < 50 cells/μl also dem-onstrated the early protective effect of IPT and ART(χ2 = 3.24, P = 0.05).Retention in care and HIV-related outcomesAnnual retention in care was similar for the IPT andnon-IPT groups (Table 2). All patients with initial orsubsequent CD4 < 200 cells/μl in each group receivedART (95% were prescribed a non-nucleoside reversetranscriptase inhibitor-based regimen and 5% wereprescribed a protease-inhibitor-based regimen). Ad-herence to ART was 95% for the IPT group and 92%for the non-IPT group (P = 0.27) over the 4-year pe-riod. The median CD4 cell count in the IPT and non-IPT groups was similar at each year of follow-up, aswas the proportion of participants on ART with un-detectable HIV RNA (Table 2).DISCUSSIONThe major finding from this study was that the groupthat received targeted TB treatment via initial TST-guided IPT upon entry into HIV care had a signifi-cantly lower incidence of PTB than the group with-out TST-guided IPT during the first 6 months ofobservation. This study is one of the short list of pro-spective studies to provide evidence in support of theWHO recommendations for TB preventive strategiesalong with ART among persons with HIV infection Figure 2 Kaplan-Meier disease-free survival analysis for pulmo-in developing countries.16–18 The study by Samandari nary tuberculosis between IPT and non-IPT groups, stratified by in-et al. demonstrated that 6-month and 36-month IPT itial CD4 count. A. Analysis for all patients, χ2 = 2.38, P = 0.12were more effective than placebo in reducing TB inci- for log-rank test and χ2 = 3.66, P = 0.04 for Breslow test. B. Anal-dence in HIV-infected patients in Botswana and, fur- ysis for patients with initial CD4 count < 50 cells/μl, χ2 = 2.30, P = 0.13 for log-rank test and χ2 = 3.24, P = 0.05 for Breslow test.thermore, that the 36-month regimen was superior to C. Analysis for patients with initial CD4 count 50–199 cells/μl, χ2 =the 6-month regimen.16 In South Africa, routine use 0.15, P = 0.69 for log-rank test and χ2 = 0.42, P = 0.50 for Bres-of IPT in conjunction with ART was associated with low test. TB = tuberculosis; IPT = isoniazid preventive therapy.
340 The International Journal of Tuberculosis and Lung Disease Table 2 Retention in care and HIV outcomes of the study population stratified by receipt of tuberculosis preventive strategies IPT group Non-IPT group (n = 200) (n = 200) Characteristics n/N (%) n/N (%) P value Retention in care At initial visit 200 (200) 200 (100) 1.00 At 12 months after initial visit 180 (90) 186 (93) 0.28 At 24 months after initial visit 156 (78) 164 (82) 0.32 At 36 months after initial visit 149 (75) 140 (70) 0.32 At 48 months after initial visit 142 (71) 134 (67) 0.39 CD4 count, cells/μl, median [IQR] At 12 months after initial visit 205 [141–316] 224 [152–330] 0.39 At 24 months after initial visit 325 [263–390] 330 [224–448] 0.55 At 36 months after initial visit 375 [273–461] 373 [284–472] 0.68 At 48 months after initial visit 401 [285–502] 407 [286–520] 0.41 Undetectable HIV RNA At 12 months after initial visit 158/180 (88) 166/186 (89) 0.66 At 24 months after initial visit 139/156 (89) 139/164 (85) 0.25 At 36 months after initial visit 134/149 (90) 119/140 (85) 0.20 At 48 months after initial visit 131/142 (92) 118/134 (88) 0.24 HIV = human immunodeficiency virus; IPT = isoniazid preventive therapy; IQR = interquartile range.lower mortality among HIV-infected adults and re- not a standard of care in this group. However, base-duced risk of TB among children.17,18 Detection of line characteristics and TB incidence were comparableLTBI infection, particularly in persons with ad- between the two groups and it is unlikely that TSTvanced HIV infection initiating medical care, has status in the non-IPT group was significantly differ-well-recognised challenges for patients, providers and ent from the IPT group. Second, the small sample sizeeach health care delivery system.19,20 Given that the and case detection of PTB limited our ability to iden-majority of persons initiating HIV care in this study tify differences in the incidence of PTB, particularlyhad CD4 < 200 cells/μl, our findings may serve as a among patients with CD4 ⩾ 200 cells/μl. Third, themodel to promote uptake of TST-guided IPT in other study population was from two HIV clinics at ter-resource-constrained settings. tiary care sites, and the findings may not be general- In our study, the initial detection of LTBI was co- isable to other Thai and non-Thai clinical settings.incident with the initiation of ART, and after the ini- Fourth, although we were able to demonstrate thattial 6-month observation period, the annual incidence annual CXR alone detected two asymptomatic casesof PTB was similar between the two groups. This of PTB (13%), with an estimated cost of US$7 perfinding may be explained by the less pronounced ad- test, the routine use of CXR may not be feasible inditive benefit of IPT to persons on ART over time other resource-constrained settings. Nonetheless, oth-given the potential benefits of immune restoration. ers have reported that the combination of screeningFurther analysis of incident PTB, stratified by receipt for symptoms of TB had 93% sensitivity for the de-of TST-guided IPT and categorical CD4 groupings, tection of PTB in developing countries, with evenrevealed that the magnitude of benefit for IPT might higher sensitivity when CXR was obtained.22 Our re-be restricted to persons with CD4 < 200 cells/μl. sults are particularly relevant, as global and nationalHence, our data suggest that TST-guided IPT should Thai guidelines for LTBI screening in TB-HIV-endemicbe provided for HIV-infected patients after initial en- regions continue to evolve.9,10try into medical care. In conclusion, the addition of initial TST-guided The interferon-gamma release assays (IGRAs) were IPT to routine CXR upon entry into HIV care wasrecently approved for use in the diagnosis of LTBI. associated with reduced case detection of PTB onlyHowever, a systemic review and meta-analysis sug- during the initial 6 months of HIV care among pa-gests that the performance of IGRAs is similar to tients on ART. We suggest that IPT should be targetedTST in the detection of LTBI among HIV-infected pa- at HIV-infected patients with LTBI while awaitingtients.21 Given the cost and the unavailability of the TB protective effect from ART. Early ART to im-IGRAs in most resource-constrained settings, TST re- prove immunological status and effective TB screen-mains the preferred screening test to guide IPT for ing methods remain important for TB treatment andHIV-infected populations in these settings. prevention in HIV-infected patients. There were notable limitations in this study. First,the study design was not randomised, and TST reac- Acknowledgementstivity, a major risk factor for active TB, remains un- The data from this study were presented as a late-breaker poster atknown in the non-IPT group, as case detection was the 18th Conference on Retroviruses and Opportunistic Infections
LTBI screening and therapy for HIV 3412011, Boston, MA, USA, on 1 March 2011 (poster number 888). and adolescents: the recommendations of the Thai AIDS Soci-This study was supported by the National Research University ety (TAS) 2008. J Med Assoc Thai 2008; 91: 1925–1935.Project of the Thailand Office of Higher Education Commission 11 Khawcharoenporn T, Apisarnthanarak A, Sungkanuparph S,(to AA and TK). Woeltje K F, Fraser V J. Tuberculin skin test and isoniazid Disclosure: LMM is a consultant for GlaxoSmithKline and prophylaxis among health care workers in high tuberculosison a Speakers Bureau with Robert Michael Educational Insti- prevalence areas. Int J Tuberc Lung Dis 2011; 15: 14–23.tute, LLC. 12 Pouchot J, Grasland A, Collet C, Coste J, Esdaile J M, Vince- neux P. Reliability of tuberculin skin test measurement. Ann Intern Med 1997; 126: 210–214.References 13 Khawcharoenporn T, Apisarnthanarak A, Mundy L M. Assess- 1 World Health Organization. WHO report 2010. 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LTBI screening and therapy for HIV i RÉSUMÉC O N T E X T E : Dispensaires pour le virus de l’immuno- ment différente entre les groupes IPT et non-IPT (0,80déficience humaine (VIH) dans deux centres médicaux vs. 1,76 cas/100 années-personne [py] ; P = 0,13). Toute-de soins tertiaires en Thaïlande. fois, l’incidence de la TB pulmonaire dans le groupeO B J E C T I F S : Evaluer l’efficacité d’un traitement préven- non-IPT a été significativement plus élevée au cours destif à l’isoniazide (IPT) orienté en fonction du tests cu- 6 premiers mois (8,60 vs. 0 cas/100 py ; P = 0,01), ainsitanés tuberculiniques (TST) et combiné avec un traite- que chez les patients dont les décomptes initiaux dement antirétroviral (ART) dans la prévention de la CD4 étaient < 200 cellules/μl (9,41 vs. 0 cas/100 py ;tuberculose (TB). P = 0,02). Les courbes de survie ont démontré un effetS C H É M A : Etude comparative prospective pendant 4 ans protecteur de l’IPT (χ2 = 3,66 ; P = 0,04) pour la TBdes patients dans deux dispensaires VIH ; l’une a réalisé précoce.le TST lors du recrutement et prescrit l’IPT en cas de C O N C L U S I O N S : Les avantages de l’IPT accompagné depositivité (Groupe IPT) et l’autre n’a pas exécuté le TST l’ART n’ont été évidents que pour les 6 premiers mois(Groupe non-IPT). de traitement. Ces observations suggèrent qu’un IPTR É S U LTAT S : On a inclus 200 patients dans chaque guidée par le TST pourrait être administré en routinegroupe. Les caractéristiques de départ et les taux de chez les patients infectés par le VIH dès leur premièreperte ont été similaires dans les deux groupes. L’incidence admission dans le système des soins médicaux.de la TB pulmonaire sur 4 ans n’a pas été significative- RESUMENMARCO DE REFERENCIA: Los consultorios de atención La diferencia entre los grupos en la incidencia de TBde la infección por el virus de la inmunodeficiencia hu- pulmonar en los 4 años no fue estadísticamente signifi-mana (VIH) en dos centros tailandeses de atención ter- cativa (0,80 casos/100 años-persona [py] en el grupociaria de salud. que recibió profilaxis, comparado con 1,76 casos/py enO B J E T I V O S : Evaluar la eficacia del tratamiento pre- el grupo sin profilaxis; P = 0,13). Sin embargo, la inci-ventivo con isoniazida (IPT) asociado al tratamiento dencia de TB pulmonar fue significativamente más altaantirretrovírico (ART), decidido en función del resul- durante los primeros 6 meses en el grupo que no reci-tado de la prueba cutánea de la tuberculina (TST) en la bió tratamiento preventivo (8,60 casos/100 py, contraprevención de la tuberculosis (TB). 0 casos/100 py; P = 0,01) y en los pacientes con unM É T O D O : Se llevó a cabo un estudio comparativo pro- recuento inicial de CD4 < 200 células/μl (9,41 casos/spectivo de 4 años de los pacientes de dos consultorios 100 py, contra 0 casos/100 py; P = 0,02). El análisis dede atención de la infección por el VIH; en uno de los la supervivencia puso en evidencia un efecto protectorcentros se practicó la prueba TST en el momento de la del IPT (χ2 = 3,66; P = 0,04) contra la TB temprana.inscripción y en caso de resultado positivo se administró C O N C L U S I Ó N : La ventaja que ofrece el IPT asociadoel IPT (grupo con profilaxis) y en el otro centro no se con el ART fue manifiesta solo durante los primerospracticó la prueba (grupo sin profilaxis). 6 meses de manejo. Estos resultados indican que se debeR E S U LTA D O S : Se incluyeron 200 pacientes en cada practicar la prueba TST en forma sistemática a los paci-grupo. Las características iniciales de los pacientes y las entes infectados por el VIH, tan pronto como comienzantasas de abandono fueron equivalentes en ambos grupos. su atención médica.