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Incidence and predictors of tuberculosis among adult people living with human immunodeficiency virus at the University of Gondar Referral Hospital, Northwest Ethiopia
© Addis Alene et al.; licensee BioMed Central Ltd. 2013
Received: 15 August 2012
Accepted: 20 June 2013
Published: 28 June 2013
Tuberculosis (TB) is the leading killer of people living with HIV (PLHIV). Many of these deaths occur in developing countries. This study aimed at determining the incidence and predictors of tuberculosis among PLHIV.
A five year retrospective follow up study was conducted among adult PLHIV. The Cox proportional hazards model was used to identify predictors.
A total of 470 patients were followed and produced 1724.13 Person-Years (PY) of observation, and 136 new TB cases occurred during the follow up period. The overall incidence density of TB was 7.88 per 100 PY. It was high (95.9/100PY) in the first year of enrolment. The cumulative proportion of TB- free survivals was 79% and 67% at the end of the first and fifth years, respectively. Baseline WHO clinical stage III (AHR = 2.88, 95% CI = 1.53-5.43), WHO clinical stage IV (AHR = 3.82, 95% CI = 1.86-7.85), CD4 count <50 cell/ul (AHR = 2.13, 95% CI = 1.28-3.53) and ambulatory or bed ridden functional status (AHR = 1.64, 95%CI = 1.13-2.38) were predictors of time to TB occurrence.
TB incidence rate among PLHIV, especially in the first year of enrollment was high. Advanced WHO clinical stage, limited functional status, and low CD4 count (<50 cell cell/ul) were found to be the independent predictors of TB occurrence. Early care seeking and initiation of HAART to improve the CD4 count and functional status are important to reduce the risk of TB infection.
TB is a major public health problem and the most frequently diagnosed opportunistic infection among PLHIV worldwide [1, 2]. It is still the leading killer of PLHIV causing one in four deaths mostly in developing countries . Worldwide, about 11.1 million adults most of whom live in Sub-Saharan Africa are co-infected .
The main reason for the resurgence of TB in Africa is not the deterioration of control programs; it is rather the link between TB and HIV/AIDS in addition to the lack of adequate economic and human resources. People with a latent infection of mycobacterium tuberculosis (MTB), which accounts for about one-third of the inhabitants of Sub-Saharan Africa, are at a greater risk of developing active TB if they are also immunologically weakened by concurrent HIV infection . In HIV infected individuals, the presence of TB increases the occurrence of other opportunistic infections and HIV replication that lead to an increased viral load which in turn results in a more rapid progression of HIV disease. One third of all PLHIV worldwide are latently infected with MTB, making them 21–34 times more likely to develop active TB than people who are HIV negative [5–7]. Late TB diagnosis contributes to increased death rates among PLHIV . The management of a TB and HIV co-infected individual is challenging because of pill burden , increased drug adverse effects , drug interaction  and the immune reconstitution inflammatory syndrome (IRIS) .
In Ethiopia, TB/HIV co-infected individuals have a greater risk of common mental disorders, low quality of life, and poor physical health than HIV infected individuals without active TB [12, 13]. In recent years, great efforts have been made to integrate TB diagnosis and treatment with HIV care in order to prevent, diagnose and treat TB among PLHIV. This needs an adequate understanding of the situation through additional research in the study area where TB incidence rate and associated factors are not yet studied. This study, therefore, aimed at determining the incidence and predictors of TB among PLHIV who attended ART care at Gondar University Referral Hospital.
Study design and setting
A five-year institution based retrospective follow up study was conducted at the University of Gondar Referral Hospital, a teaching hospital in Gondar town, northwest Ethiopia. The hospital serves more than five million people of North Gondar and neighboring zones. The HIV care service in this hospital was initiated in 2005 with three clinics: The Adult Anti-Retroviral Therapy (ART) Clinic, Pediatric ART Clinic, and VCT Clinic. Currently, more than 7,000 patients are in active follow-up, of which over 3,888 have been initiated on highly active antiretroviral treatment (HAART). The hospital uses standardized monitoring and evaluation tools, and the data collection and management processes are well controlled and supported by electronic data back-up and processing. Patient data, including socio-demographic characteristics, like age, sex, residence, family size, level of education, occupation, marital status, substance use, and disclosure status are recorded on enrollment in the HIV Program. The patient database also includes information on WHO clinical stage, CD4 counts, Haemoglobin level (Hgb), and HAART.
The treatment is given based on the national HAART guidelines of the Ethiopian Federal Ministry of Health which consists of daily cotrimoxazole prophylaxis for patients in clinical stage 2, 3 or 4 ( irrespective of CD4 count) or CD4 <350 irrespective of WHO clinical stage. After ruling out active TB, isoniazid prophylaxis is considered in order to protect the PLHIV from developing TB disease. HAART is initiated when the CD4 count < 200 cells/mm3 at any WHO clinical stage or WHO clinical stage 4 (no matter what the CD4 count) or WHO clinical stage 3 (if the CD4 count < 350 cells/mm3). First-line HAART consists of two non-nucleoside reverse transcriptase inhibitor stavudine (d4T) or zidovudine (AZT) in combination with lamivudine (3TC) plus a non-nucleoside reverse transcriptase inhibitor in standard doses (nevirapine (NVP) or efavirenz (EFV)). The choice of HAART combination is up to decision of the physician and the availability of the drug at the time of initiation.
Definitions of tuberculosis
TB is diagnosed using microscopic examinations of sputum smears, chest radiology, and fine-needle aspiration of lymphadenopathy and cytology with very high clinical grounds. No mycobacterial culture facilities are available in the hospital. When patients are diagnosed with active TB, the treatment is given according to the National TB Program recommendations with a standard 8 month regimen with an 8 week, 4 drug (isoniazid, rifampicin, ethambutol and pyrazinamide) intensive phase and a subsequent 6 month, 2 drug (isoniazid, ethambutol) continuation phase. Incident TB, which is defined in this study, as an event, during follow-up was ascertained retrospectively when the patient is diagnosed for TB and starts anti TB treatment. PLHIV who were not diagnosed for TB until the end of the follow up period were considered as censored.
Inclusion and exclusion criteria
All PLHIV aged 15 years and above and were newly enrolled into the adult chronic HIV care clinic at the University of Gondar Referral Hospital from September 11, 2006 to August 31, 2007, were included in the study and followed for five years, until February 29, 2012. This period was selected in order to have the nearest five year follow up study period. In this period the facility started full implementation of standardized formats, documentation, and a recording system in a regular manner. A total of 529 PLHIV were registered during the period out of whom 59 patients were excluded due to missing charts or incomplete baseline and follow-up data.
All available information on patient records was checked and an appropriate data extraction format was prepared. Then, data were extracted from patients’ charts by four nurses who had ART training and experience in HIV care.
Data were cleaned and entered into a computer using EPI info version 3.5.3 statistical software and exported to the Statistical Package for Social Science (SPSS) version 20 for analysis. Summary statistics and Incidence Density Rate (IDR) were calculated. To calculate TB incidence among PLHIV, the total duration of follow-up for the whole cohort in PY was used. The duration of follow-up for PLHIV who did not develop TB was calculated from the time of enrolment in the HIV Care Program until the last visit. For these people, the total duration of follow-up was considered TB-free. For PLWH who developed TB, the TB-free follow-up was calculated from the time of enrolment in the HIV Care Program until the development of TB. Subsequently, the number of TB cases within the cohort was divided by the TB-free follow-up duration and reported per 100 PY.
As this study has considered time-to-event data, the survival analysis technique was carried out, Cox proportional hazards model was fitted, and a life table was used to estimate cumulative probabilities. The Kaplan-Meier curve (an intuitive graphical presentation which describes survivorship of the study population) was used to estimate the median duration of TB occurrence. The Log rank test was used to compare survival curves between different categories of explanatory variables. Bivariate and multivariate Cox proportional hazard models were used to identify the predictors of TB occurrence. Variables with p value < 0.2 in the bivariate analysis were entered into the multivariate proportional hazard model. Hazard Ratios (HR) with 95% confidence intervals were computed and statistical significance was accepted at the 5% level (p < 0.05). The necessary assumptions for Cox proportional hazard model were checked using the Schoenfield residuals test.
Ethical clearance was obtained from the institutional review board of the Institute of Public Health, the University of Gondar. Letter of permission was obtained from the Chief Executive Officer of the hospital. The department head of the HIV care clinics gave the consent for extracting data from records. Patient names and identification numbers were not extracted so as to ensure confidentiality of patient information.
Baseline socio demographic and clinical characteristics of PLHIV on chronic HIV care at University of Gondar Referral Hospital, September 2006 to February, 2012
Level of Educational
ART eligibility criteria
WHO clinical stage
Regimen change during follow up
2 nd line
Reason for switch first regimen
Past TB treatment history
WHO clinical stage
Tuberculosis incidence density rate stratified by socio-demographic and clinical characteristics of PLHIV on chronic HIV care at University of Gondar Referral Hospital, September 2006 to February, 2012
Past TB treatment history
WHO clinical stage
Year of follow up
Tuberculosis incidence density
Predictors of time to TB occurrence
HIV positive people are 20 times at higher risk of developing TB as compared to HIV negative people in countries with a generalized HIV epidemic . TB is also the most common cause of death among PLHIV . In this study, the overall incidence of TB was 7.89 per 100 PY. It was similar with that of studies done in Ethiopia and many other Sub Sahara African countries with reported incidences ranging from 5.4 to 11 per 100 PY [15–18]. But, this finding is higher than that of studies done in Brazil and Taiwan which were 3.8% and 4.01/100 PY, respectively. This could be explained by the fact that unlike these two countries, Ethiopia is one of the high TB burden countries . Studies also revealed that in very high burden countries the incidence of TB among individuals on HAART was high .
The highest incidence of TB was observed in the first year of enrolment. This observation was in line with the evidence of declining TB incidence after enrolment and HAART initiation reported in cohorts of HIV-infected persons in Sub-Saharan Africa  and Ethiopia . The Peak TB incidence shortly after enrollment may have several explanations. Firstly, it may represent the progression of a subclinical disease that remained undetected during enrollment and a rapid progression of either a newly reactivated disease or an exogenous infection. Secondly, immune reconstitution inflammatory syndrome (IRIS) may have been responsible for some of these cases. TB is the most frequently reported IRIS associated infection . Though the available data did not permit making this distinction, it was known that IRIS occurred in the early initiation of HAART .
The result of this study showed that large numbers of patients started HAART within the first year of follow up which led to the development of IRIS. The finding also showed a significant decrease in TB incidence in the subsequent years of follow up. These indirectly indicated that the reduction in TB incidence following the introduction of HAART can be particularly linked with HAART induced prevention. A study done at Arba Minch Hospital, Ethiopia, showed that TB incidences were 3.7 and 11.1 per 100 PY in the ART and Pre ART groups, respectively . Other findings [17, 24, 25], revealed that HAART reduces the risk of TB in line with our study. Thirdly, the other possible reason for increased TB- free survival within the duration of enrolment could be the result of progressive increase in CD4 cell count which builds the immune system and may decrease the viral load over time. Although TB risk has decreased with time following enrolment, it was still significantly higher than that of the general population of Ethiopia, even after 5 years of follow up. In this study, the incidence of TB at the end of the follow up period was 1.6 per 100 PY, which was four fold higher than the overall TB rate in Ethiopia which was approximately 0.38/PY . This might be due to the synergy between TB and HIV co-infection.
Cox regression analysis of predictors of tuberculosis among PLHIV cohorts on chronic HIV car at University of Gondar referral Hospital from September 2006 to February, 2012
AHR, (95% CI)
WHO clinical stage
CD4 cell count
The main limitation of our study was the retrospective nature of the cohort. The study participants whose charts were lost were not included in the study, perhaps undermining the result if the charts excluded were related to TB.
Incidence of TB was high among people living with HIV, especially in the first year of enrollment in chronic HIV care. WHO clinical stage III and IV, ambulatory or bed ridden functional status, and low CD4 count (<50 cell/ul) were found to be independent predictors of TB-free survival time. Therefore, it is important to give special attention to PLHIV in diagnosing, preventing and treating TB early. TB/HIV collaborative long term surveillance programs should be strengthened at chronic HIV care clinics with early initiation of HAART as recommended in the national guideline.
The authors would like to thank the University of Gondar for financial support that made this study possible. They would also like to thank the data collectors for their tolerance and collaboration during the work.
- Corbett E, Marston B, Churchyard G, Cock KD: Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet. 2006, 367: 926-937. 10.1016/S0140-6736(06)68383-9.View ArticlePubMedGoogle Scholar
- Reid A, Scano F, Getahun H, Williams B, Dye C, Nunn P: Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration. Lancet Infect Dis. 2006, 6: 483-495. 10.1016/S1473-3099(06)70549-7.View ArticlePubMedGoogle Scholar
- WHO: Priority research questions for TB/HIV in HIV-prevalent and resource-limited settings. 2010, Geneva, SwitzerlandGoogle Scholar
- FMOH: Tuberculosis, Leprosy, and TB/HIV prevention and control programme manual. 2008, Addis Abeba, Ethiopia, 71-74. Fourth editionGoogle Scholar
- Jamison T, Feachem G, Makgoba W, Bos R, Baingana K, Hofman J: Disease and Mortality in Sub-Saharan Africa. 2006, Washington: World Bank, secondGoogle Scholar
- Anthony F, Dan L, Eugene B, Dennis K, Stephen H, Larry J, Loscalzo J: Harrison’s Principles of internal medicine vol. one Seventeenth edn. 2008, McGraw-Hill Companies: United States of AmericaGoogle Scholar
- Kent M, Yin S: Controlling Infectious Diseases, vol. 1. 2006, Washington: Mary Mederios KentGoogle Scholar
- Burman W, Weis S, Vernon A: Frequency, severity and duration of immunereconstitution events in HIV-related tuberculosis. Int J Tuberc Lung Dis. 2007, 11: 1282-1289.PubMedGoogle Scholar
- Lorent N, Sebatunzi O, Mukeshimana G, Ende JV, Clerinx J: Incidence and risk factors of serious adverse events during antituberculous treatment in Rwanda: a prospective cohort study. J Acquir Immune Defic Syndr. 2011, 58 (1): 32-37. 10.1097/QAI.0b013e3182255dc2.View ArticleGoogle Scholar
- Breen R, Smith C, Bettinson H: Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax Aug. 2004, 59 (8): 704-707. 10.1136/thx.2003.019224.View ArticleGoogle Scholar
- Havlir D, Kendall M, Ive P, Kumwenda J, Swindells S, Qasba S: Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis. N Engl J Med. 2011, 365: 482-491.View ArticleGoogle Scholar
- Deribew A, Tesfaye M, Hailmichael Y, Negussu N, Daba S, Wogi A, Belachew T, Apers L, Colebunders R: Tuberculosis and HIV co-infection: its impact on quality of life. Health Qual Life Outcomes. 2009, 7: 105-10.1186/1477-7525-7-105. 2009View ArticlePubMedPubMed CentralGoogle Scholar
- Deribew A, Tesfaye M, Hailmichael Y, Apers L, Abebe G, Duchateau L, Colebunders R: Common mental disorders in TB/HIV co-infected patients in Ethiopia. BMC Infect Dis. 2010, 10: 201-10.1186/1471-2334-10-201.View ArticlePubMedPubMed CentralGoogle Scholar
- World Health Organization (WHO): WHO Global TB Report, Ethiopian tuberculosis profile. 2009, Addis Abeba, Ethiopia: WHO EthiopiaGoogle Scholar
- Ngowi B, Mfinanga S, Bruun J, Morkve O: Pulmonary tuberculosis among people living with HIV/AIDS attending care and treatment in rural northern Tanzania. BMC Publ Health. 2008, 8: 341-10.1186/1471-2458-8-341.View ArticleGoogle Scholar
- Iliyasu Z, Babashani M: Prevalence and Predictors of Tuberculosis Coinfection among HIV-Seropositive Patients Attending the Aminu Kano Teaching Hospital, Northern Nigeria. J Epidemiol. 2009, 19 (2): 81-87. 10.2188/jea.JE20080026.View ArticlePubMedPubMed CentralGoogle Scholar
- Assefa D, Melaku Z, Gadissa T, Negash A, Hinderaker S, Harries A: Intensified tuberculosis case finding among people living with the human immunodeficiency virus in a hospital clinic in Ethiopia. Int J Tuberc Lung Dis. 2011, 15 (3): 411-413.PubMedGoogle Scholar
- Marianne A, Sande B, Maarten F, Loeffa S, Bennett R: Incidence of tuberculosis and survival after its diagnosis in patients infected with HIV-1 and HIV-2. Lippincott Williams & Wilkins. 2004, 18: 3-4.Google Scholar
- Bonnet M, Pinoges L, Varaine F, Oberhauser B, O’Brien D, Kebede Y: Tuberculosis after HAART initiation in HIV-positive patients from five countries with a high tuberculosis burden. AIDS. 2006, 20 (9): 1275-1279. 10.1097/01.aids.0000232235.26630.ee.View ArticlePubMedGoogle Scholar
- Brinkhof M, Egger M, Boulle A: Tuberculosis after initiation of antiretroviral therapy in low-income and high-income countries. Clin nfect Dis. 2007, 45: 1518-1521.View ArticleGoogle Scholar
- Stephen D, Wilkinson R, Lipman M, Wood R: Immune Reconstitution and “Unmasking” of Tuberculosis during Antiretroviral Therapy. Am J Respir Crit Care Med. 2008, 177 (7): 680-10.1164/rccm.200709-1311PP.View ArticleGoogle Scholar
- Stephen D, Wilkinson RJ, Marc C, Robin W, Respir J, et al: Pulmonary Perspective Immune Reconstitution and “Unmasking” of Tuberculosis during Antiretroviral Therapy. Respir Crit Care Med. 2008, 177: 680-685. 10.1164/rccm.200709-1311PP.View ArticleGoogle Scholar
- Jerene D, Næss A, Lindtjørn B: Antiretroviral therapy at a district hospital in Ethiopia prevents death and tuberculosis in a cohort of HIV patients. AIDS Res Ther. 2006, 3: 10-10.1186/1742-6405-3-10.View ArticlePubMedPubMed CentralGoogle Scholar
- Tseng S-H, Jiang D, Hoi H-S: Short Report: Impact of HAART Therapy on Co-Infection of Tuberculosis and HIV Cases for 9 Years in Taiwan. AmJTrop Med Hyg. 2009, 80 (4): 675-677.Google Scholar
- Golub JE, Saraceni V, Cavalcante SC, Pacheco AG, Moulton LH, King BS: The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS. 2007, 21 (11): 1441-1448. 10.1097/QAD.0b013e328216f441.View ArticlePubMedPubMed CentralGoogle Scholar
- Sterling T, Lau B, Zhang J, Aimee F, Bosch R, Brooks J: Risk Factors for Tuberculosis After Highly ActiveAntiretroviral Therapy Initiation in the United States and Canada: Implications for Tuberculosis Screening. Infect Dis Soc Am. 2011, 204: 896-898.Google Scholar
- Seyler C, Toure S, Messou E, Bonard D, Gabillard D, Anglaret X: Risk factors for active tuberculosis after antiretroviral treatment initiation in Abidjan. Am J Respir Crit Care Med. 2005, 172: 123-127. 10.1164/rccm.200410-1342OC.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/13/292/prepub
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