Predictors of antiretroviral treatment associated tuberculosis in Ethiopia: a nested case control study Nebiyu Mesfin, MD

INTRODUCTION Even though antiretroviral treatment (ART) has decreased the incidence of HIV associated TB by 80%, TB remains the most common cause of morbidity in adults receiving ART ¥,£,‡ TB occurring after initiation of ART in resource poor settings can be due to undiagnosed clinical TB or subclinical TB becoming apparent after ART initiation (unmasking).§ ¥Seyler et al, Antivir Ther 2003; 8:385-393 £Badri et al, Lancet 2002; 359: 2059–64. ‡Clinical Epidemiology 2011; 3: 21-29 §Bonnet et al, AIDS 2006; 20: 1275–79.

INTRODUCTION Cont’d... Unmasking TB immune reconstitution inflammatory syndrome (TB IRIS) defines a subset of patients with ART associated TB who develop rapidly progressive signs and symptoms of TB after initiation of ART* *Colebunders et al, Lancet Infect Dis. 2008 Aug; 8(8):516-23.

METHODS A nested case control study was conducted in October, 2009 Study population: Adults (> 14 years) with HIV infection who developed active TB in the first six months of ART initiation Controls were those who didn’t develop active TB Data were collected using a structured and pre-tested questionnaire. Cox proportions hazards analysis was done to determine predictors of ART associated TB.

RESULTS A total of 357 patients (119 cases and 238 controls) participated in the study. After six months of follow up, cumulative incidence of ART associated TB was 5.2% (123/2,355). Forty (33.6%) cases were lost to follow up after they developed ART associated TB out of whom 11(9.2%) died. Fifty one (21.4%) controls interrupted ART out of whom 11(4.6%) died

RESULTS Cont’d... Figure 1. Occurrence probability of ART associated TB with in the first six months after starting antiretroviral treatment (ART) in Jimma, Ethiopia.

RESULT Cont’d... Independent predictors were: A CD4 lymphocyte count increase > 0.5/µl/day [AHR=19.80, 95%CI: 9.52: 41.12, P<0.001], A base-line CD4 lymphocyte count <200 cells/µL [AHR=9.59, 95%CI: 2.36: 39.04, P=0.002], WHO clinical stage 3 or 4 [AHR=3.04, 95%CI: 1.62: 5.69, P<0.001], Night sweats during ART initiation [AHR=1.53, 95%CI: 1.06: 2.21, P<0.001] and High ART adherence [AHR=1.30, 95%CI: 1.13: 1.50, P<0.001] were independent predictors of ART associated TB

RESULTS Cont’d... Table 1. Predictors of developing TB after ART initiating versus controls not developing TB at Jimma University Hospital Cox proportions hazards analysis Characteristics Univariate HR, (95% CI) p-value Adjusted HR, Age (per year) 0.99 (0.97-1.02) 0.63 - Males vs Females) 1.68 (1.17-2.42) 0.005 Not married vs others 1.27 (0.87-1.87) 0.21 Not employed 1.39 (0.97-1.99) 0.07 Level of education 0.92(0.74-114) 0.45 Pre ART TB presence 2.14 (1.49-3.09) <0.001 INH during ART initiation 1.31 (0.66-2.60) 0.43 Cough during ART initiation 0.51 (0.32-.82) Fever during ART initiation 2.44 (1.70-3.52) Weight loss during ART initiation 1.10 (0.74-1.63) 0.65 Night sweat during ART initiation 2.61 (1.82-3.74) 1.53 (1.06-2.21) Pre-ART tuberculosis duration 2.79 (1.49-5.19) 0.353 High ART adherence* 1.49 (1.29-1.72) 1.30(1.13-1.50) Baseline CD4 count < 200/µl 16.17(3.99-65.42) 9.59(2.36-39.04) 0.002 WHO stage 3 or 4 4.14 (2.23-7.71) 3.04 (1.62-5.69) 0.001 CD4 increase > 1.0/µl/day 6.57 (4.53-9.53) NA CD4 increase > 0.5/µl/day 29.19(14.19-60.06) 19.80(9.52-41.12) HR, hazard rates; CI, confidence intervals; ART, antiretroviral therapy; INH, Isoniazide; *When ≥ 95% of ART is taken (i.e. of 30 doses ≤ 2 doses are missed or of 60 doses <3 doses are missed).

RESULT Cont’d... Figure 2. ROC curve exploring CD4 change cut off point for predicting ART associated TB in HIV infected adults starting antiretroviral treatment (ART) in Jimma, Ethiopia

Conclusion During routine care of persons with HIV infection TB remains under diagnosed and treatment adherence of HIV/TB co-infected patients remains far from ideal HIV infected adults with a low CD4 lymphocyte count (< 200 cells/µL), night sweats for more than two weeks, or in WHO clinical stage 3 or 4 at ART initiation should be cautiously followed for the development of ART associated TB.

Conclusion Good ART adherence and a good immunological response during ART was associated with ART associated TB probably because of IRIS unmasking TB Finally, we recommend ART initiation earlier at CD4 lymphocyte count of 350 cells /µL as proposed by the new WHO guidelines.

Acknowledgment We would like to thank Jimma University for funding this research. We are also grateful for all the staffs of Jimma University Hospital ART clinic and the medical team of Jimma University Hospital for taking care of the patients. Nebiyu Mesfin*1,4, Amare Deribew2, 3, Alemeshet Yami4, Theodros Solomon5, Jean Pierre Van geertruyden3, Robert Colebunders3, 6 1Department of Internal Medicine, Hawassa University, Hawassa, Ethiopia; 2Department of Epidemiology, Jimma University, Jimma, Ethiopia; 3Department of Epidemiology and Social Medicine, University of Antwerp, Antwerp, Belgium; 4Department of Internal Medicine, Jimma University, Jimma, Ethiopia; 5Institute of Virology, Hannover Medical School, Hannover, Germany; 6Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium;

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