Profile of HIV Associated Tuberculosis at a Tertiary Institute in Setting of Free Anti-Retroviral Therapy

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1 Original Article Profile of HIV Associated Tuberculosis at a Tertiary Institute in Setting of Free Anti-Retroviral Therapy Upasna Agarwal *, Amitabh Kumar **, Digamber Behera *** Abstract Setting: With the rollout of the national program, free of cost antiretroviral therapy is available to the Indian population since 2004, resulting in sea change in outcome of HIV associated tuberculosis. Objective: To assess the presentation and outcome in patients being treated for concurrent TB and HIV. Design: Retrospective analysis of data from standardized patient records. Results: Seventy-three (29.1%) of the 251 HIV infected patients, who reported to the ART centre at LRS Institute of TB and Respiratory Diseases, New Delhi, between January 2006 and June 2007, were diagnosed with concurrent active tuberculosis. The mean CD4 count at presentation was cells/µl and 87.6% patients had CD4 counts less than 200 cells/µl. 38.4% patients had purely pulmonary tuberculosis, 39.7% had purely extra-pulmonary tuberculosis and 21.9% had both. Sputum positivity in those with pulmonary involvement was 34.1%. Immune reconstitution inflammatory syndrome was seen in 20.5% patients. 67.2% patients had a favorable outcome (cure and treatment completed). 17.8% case fatality was observed in the study period. Conclusion: Despite severe immune suppression, treatment with ATT and ART leads to an improved outcome in patients with concurrent HIV and TB. Introduction H uman immunodeficiency virus (HIV) associated tuberculosis (TB) poses an immediate and serious threat to public health. Globally, nearly 2 billion people are infected with Mycobacterium tuberculosis and about 33.2 million are estimated to be living with HIV infection. 1 India accounts for a fifth of the world s new TB cases and is a country with the highest TB burden in the world. 2 Every year 1.8 million people of the country develop tuberculosis and 370,000 people die of it. 2 India has an adult HIV prevalence of 0.36 percent and an estimated 2.5 million people are living with HIV/AIDS. 3 Twenty five to sixty five percent of people infected with HIV have been observed to have active TB of one organ or the other in different reports from India. 4 Despite the burden of HIV, the epidemiology of tuberculosis in India is being primarily driven by the TB-infected non-hiv infected pool. 2 Effective implementation of ongoing Revised National TB Control Programme (RNTCP) is expected to markedly change the number of new TB cases occurring at any level of HIV prevalence in the country. 2 The Government of India has launched the free antiretroviral therapy (ART ) program in April 2004, making ART widely available to the Indian population. Nevertheless, it still remains to be seen, how TB in HIV patients changes in terms of presentation, outcome, relapse and diagnostic modalities. This study was undertaken with the aim to assess the presentation and outcome in patients concurrently treated for TB and HIV. * Head, Department of Medicine & In charge (ART centre); ** Senior Medical Officer, ART Centre; *** Director and Senior Chest Physician, LRS Institute of Tuberculosis and Respiratory Diseases, Sri Aurobindo Marg, near Qutab Minar, New Delhi Received: ; Revised: ; Accepted: Materials and Methods This study is retrospective review of medical records of 251 adult and adolescent HIV positive patients, registered between January 2006 and June These patients accessed HIV care, at the antiretroviral therapy centre (ART centre) at LRS Institute of Tuberculosis and Respiratory Diseases, a tertiary care TB institute at New Delhi, India. All patients registered in pre ART or ART care were screened for both pulmonary TB (PTB) and extra-pulmonary TB (EPTB), with a detailed history, physical examination, chest x-ray, sputum for acid fast bacilli (AFB), ultrasonography (USG) of abdomen. Where required, pleural aspiration, ascitic tap, lumbar puncture and fine needle aspiration (FNA) were done. (Table 1) In addition, patients already diagnosed with active TB and presenting to the centre for antiretroviral therapy for a concurrent HIV infection, were also included in this study. Patients were said to be concurrently diagnosed with HIV and active tuberculosis if the two diseases were diagnosed within one month of each other. The diagnosis of tuberculosis was made by a physician, based on presence of symptoms and signs compatible with TB and/or radiological evidence of active TB; demonstration of acid fast bacilli (AFB) from a clinical specimen (sputum, FNA of lymph node, pleural fluid, ascitic fluid, cerebrospinal fluid) wherever isolated. Cases of active TB were treated with directly observed treatment, short-course (DOTS) under the RNTCP of Government of India or with daily, self administered regimens. HIV infection was diagnosed using three antigenically different rapid kits as per the national HIV testing policy. 5 CD4 cell counts were determined by flow-cytometry technique using Facs Count machine with Facscount reagents (Becton Dickinson, USA). Antiretroviral therapy (ART) was started for eligible patients and was guided by baseline and six monthly CD4 counts in accordance with the national ART guidelines. 5 JAPI OCTOBER 2009 VOL

2 Table 1: Investigations undertaken for diagnosis of TB (n=73)* Investigation Sputum smear examination for acid fast bacilli(afb) No. of patients tested positive for TB / No. of patients who underwent the test (% positive diagnostic yield) 15/67 (22.4 %) Chest roentgenography 59/73 (80.8 %) Ultrasonography (abdomen) 27/72 (37.5 %) Fine needle aspiration of peripheral lymph node(s) Pleural fluid examination Ascitic fluid examination Cerebrospinal fluid examination 6/10 (60 %) 4/10 (40 %) 9/16 (56.3 %) 0/16 2/5 (40 %) 0/5 3/3 (100%) 0/3 (0) CT scan (Chest) 8/8 (100%) CT scan (head) 3/5 (60 %) * All patients were cases of active TB (pulmonary, extra-pulmonary or both) with HIV co infection. S. No 1, 2, 3 were routinely advised in all cases. Further investigations were guided by clinical findings. Regime Stavudine/Lamivudine/ Efavirenz Zidovudine/Lamivudine/ Efavirenz Stavudine/Lamivudine/ Nevirapine Zidovudine/Lamivudine/ Nevirapine Table 2: ART regimes prescribed (Number of patients) Percentage (%) Various ART regimens prescribed are given in Table 2. Immune reconstitution syndrome was defined as paradoxical clinical deterioration temporally associated with start of antiretroviral therapy, and included new or worsening symptoms like fever, increased in size of or development of new lymphadenopathy, worsening pulmonary infiltrates, effusion, increasing neck rigidity, expanding CNS lesions, cutaneous lesions etc, not explained by a new infection or the expected course of an infection that was diagnosed previously or drug toxicity. Patient data had been recorded in a standardized patient record booklet developed by the ART centre. The data was analyzed using standard statistical software. Descriptive statistical methods were used to provide general profile of the study population. Non-parametric Mann-Whitney test was used to compare continuous variables and Chi-square test was used to compare proportions. Results Two hundred and fifty one adult patients with HIV infection were registered at the ART centre at LRS Institute of TB and Respiratory Diseases, New Delhi between January 2006 and June Seventy three patients (29.1%) were diagnosed with concurrent active tuberculosis (HIV-TB). Of these patients, 60 (82.2%) were male and 13 (17.8%) were female. The mean age of the HIV-TB patients was 33.6 years (median 34, range16-55). Majority of the patients (56.2%) were in the age group of years. Heterosexual contact was the predominant (97.3%) route of transmission of HIV infection in the study. CD4 counts: The initial CD4+ T helper cell count (CD4 count) was available for all 73 patients of HIV-TB. The mean CD4 count at presentation was cells/µl (median 92, range 6-311) (Table 3). Sixty four (87.6%) patients had an initial CD4 count of 200 cells/µl or less and 22 (30.1%) patients had an initial CD4 count less than 50 cells/µl. CD4 counts at 6 months of treatment were available for 29 patients and showed a mean of cells/µl (median 328, range ), with a mean rise of cells/µl. CD4 rise at 6 months correlated significantly to initial CD4 count (p<0.05). CD 4 counts at 12 months were available for 8 patients Fig. 1: Initial and follow up CD4 counts 686 JAPI OCTOBER 2009 VOL. 57

3 CD4 evaluation (number of patients) Mean CD4 Table 3: CD4 counts in HIV-TB. Standard deviation (SD) Standard error of mean (SEM) Minimum Maximum Initial months months months Rise at 6 months Rise at 12 months Rise at 18 months Symptoms (number of patients) Table 4: Presenting symptoms in HIV-TB Mean duration (Months) Standard deviation (SD) Standard error of mean (SEM) Median Median duration (Months) Weight loss (>10%) Fever Cough Expectoration Chest pain Breathlessness Haemoptysis Diarrohea Pain abdomen CNS symptoms Table 5: Sites involved by TB in the study population* (n=73) Site Number of patients Lungs 44 Pleura 17 Abdomen 27 Lymph node 14 CNS 3 Genito-urinary 1 Pericardial 1 * Many patients had more than one site involvement. Fig. 2: Type of TB (mean 485.5, median 482, range ) and 18 months counts were available for 3 patients (mean cells/µl), all of whom showed a notable rise (Figure 1, Table 3). Presentation: Sixty nine (94.5%) of the 73 HIV-TB patients presented with weight loss of more than ten percent. Fever was seen in 63 (86.3%) patients and the mean duration of fever was 8.7 months (Table 4). Among the symptoms, fever significantly correlated to low rise of CD4 at 6 months (p<0.05). Type of TB: Pulmonary TB in isolation was seen in 28 of the 73 (38.4%) patients. Twenty-nine (39.7%) had only extra-pulmonary tuberculosis, whereas 16 (21.9%) had both pulmonary as well as extra pulmonary tuberculosis (Figure 2, Table 5). The mean CD4 count of patients with only pulmonary TB was cells/ µl (median 82.5, range ) and was similar to those with only extra pulmonary TB (mean cells/µl, median101.00, range ). The mean CD4 was observed to be lower in the third group (mean 87.5, median 62.5, range 6-262). However, this difference in CD4 counts across the groups was not found to be statistically significant (p>0.05). Chest x-ray: Chest x-ray was done in all HIV-TB patients and was found to be abnormal in 59 (80.8%). Forty-three (58.9%) patients had parenchymal lesions, out of which 3 (7%) had cavitatory disease and 40 (93%) had non-cavitatory disease (Table 6). One patient had normal chest x-ray and the parenchymal disease was revealed on CT scan. Acid fast bacilli (AFB): Of the 73 patients of HIV-TB, initial sputum direct smear examination were available in 67 patients. Sputum was found to be positive for AFB in 15 patients out of the group of 44 patients who had a pulmonary involvement; sputum positivity in pulmonary disease was found to be 34.1%. Additionally, in four patients of disseminated tuberculosis, who were sputum negative, fine needle aspirate of lymph nodes revealed AFB. Thus, AFB could be demonstrated in a total of 19 cases. The mean CD4 count in sputum positive cases was cells/µl (median 124, range ) compared to the mean CD4 count of cells/µl (median 84, range ) in sputum negative cases (p>0.05). Culture for AFB was done only in cases JAPI OCTOBER 2009 VOL

4 of treatment failure. Table 6: Chest X-ray in HIV-TB. Chest X-ray findings (number of Percentage (%) patients) Normal 14* 19.2 Only parenchymal lesion Parenchymal with pleural lesion Parenchymal lesion with mediastinal lymph nodes Parenchymal and pleural lesion with mediastinal lymph nodes Only pleural lesion Only mediastinal lymph nodes Pleural lesion with mediastinal lymph nodes *One patient had normal CXR and the parenchymal disease was revealed on CT scan. Table 7: Side effects to ART Side effect to ART (number of patients) Percentage (%) Skin rash Nausea/vomiting Neuropathy Anaemia Psychosis CNS symptoms Others No side effect Treatment: Forty seven (64.4%) of the 73 HIV-TB patients were started on category-i antitubercular treatment containing isoniazid, rifampicin, pyrazinamide and ethambutol and 26 (35.6%) patients were started on category-ii treatment containing streptomycin, INH, rifampicin, pyrazinamide and ethambutol. Thirty four (46.6%) were given directly observed, intermittent treatment under DOTS and 39 (53.4%) were on daily, selfadministered regimens. The mean total duration of ATT given was 7.8 months (median 8, range 6-18) in this data. ATT was generally well tolerated by all the patients except 5 (6.8%), who developed transient hepatitis, which resolved to conservative management. Antiretroviral therapy was started in all the 73 patients. Seventy (95.89%) patients were on EFV containing regime. Forty eight (65.8%) patients were given ART regime containing stavudine, lamivudine, efavirenz; 22 (30.1%) were on ziduvudine, lamivudine, efavirenz; 2 (2.7%) on stavodine, lamivudine, nevirapine and 1 (1.4%) on zidovudine, lamivudine, nevirapine. Twenty four (32.9%) patients had developed side effect to ART during the course of the study period (Table 7). Previous TB: Twenty seven (36.9 %) of the 73 patients had a past history of ATT. Only 13 patients (48.1 %) gave history of completing treatment for previous tuberculosis. A mean interval of 16.9 months (median 12, range 0-96) between the present and past TB was observed in these 13 patients. Immune reconstitution inflammatory syndrome (IRIS): IRIS was seen in 15 (20.5 %) patients. Fever was the most common presentation of IRIS and was seen in eight of the 15 patients (53.4%). The mean interval between initiation of ART and IRIS was found to be 17.7 days (median 15, range 7-44). Table 8: Outcome of TB treatment Outcome of TB treatment (number of patients) Percentage (%) Cure Treatment completed Default Failure Died On treatment Outcome of tuberculosis treatment: Of the 73 HIV-TB patients, 15 (20.5%) patients were still on ATT at the time of analysis. Thirty nine (67.2%) out of the 58, had a favorable outcome which includes 4 cure and 35 treatment completed, as per the definitions of RNTCP. Four (5.5%) of the total patients on ATT, defaulted treatment and were lost to follow up. Two (2.73%) patients failed category II treatment and there was only one patient of proven multi drug resistant (MDR) tuberculosis in this data. Thirteen patients died during the study period (case fatality 17.8%) (Table 8). 61.5% of the deaths occurred within 8 weeks of starting ATT. The mean interval between start of ATT and death was 65.8 days (median 45, range 2-174). Discussion Recently, HIV estimate for India has been revised to less than half; however, most of this drop is not due to an actual decrease in HIV burden but due to availability of more reliable population based data. 6,7 Tuberculosis is the most common opportunistic infection in HIV positive persons, developing at any stage of the disease. 4 As per the 2007 WHO report, India has an estimated 10% global burden of incident TB cases arising in people with HIV. 8 In this analysis, nearly 30 percent of the 251 HIV infected patients who reported to the ART centre at the LRS Institute, New Delhi, between January 2006 and June 2007 were concomitantly diagnosed with active tuberculosis. Similar findings has been reported by other studies. 9,10 Our study reports a maximum prevalence of HIV-TB in the economically productive age group of years (56.2%). The male preponderance seen here has also been observed in earlier Indian papers. 9,11 Tuberculosis, unlike other HIV-associated opportunistic infections, may occur at relatively high levels of CD4 counts, although its frequency markedly increases in patients with more severe immunosuppression. The mean CD4 count at presentation, for patients of concurrent HIV-TB in our study was cells/µl (median 92, range 6-311). All of the patients under our care were diagnosed with HIV around the time of the diagnosis of tuberculosis. Due to unawareness of their HIV status, these patients missed the opportunity to receive antiretroviral treatment during the asymptomatic phase of HIV infection, which could have prevented the deterioration of their immune status and reduced their risk of tuberculosis. It has been seen that a high proportion of patients are unaware of their HIV status at the time of tuberculosis diagnosis, 12 leading to profound immune suppression by the time they access medical care. This may be a reflection of lack of knowledge about HIV/ AIDS as well as poor access to medical services. As many as 64 (87.6%) out of 73 patients had initial CD 4 counts less than 200 and 22 (30.1%) patients had initial CD4 counts less than 50 cells/µl, signifying advanced disease (Figure 1, Table 3). HIV-TB cases have been observed to have severe immunosuppresion at presentation, with several studies reporting CD4 counts of less than ,13,14 Comparative studies from India have also reported significantly 688 JAPI OCTOBER 2009 VOL. 57

5 lower CD4 counts in patients with HIV-TB than HIV alone. 14 Among the presenting symptoms, significant weight loss and fever was present in 94.5% and 86.3% patients respectively. Fever and weight loss are the commonest presentations of HIV-TB in several other studies as well. 11 Mycobacteremia has been implicated as an important cause of pyrexia of unknown origin in HIV infected patients. 15 Haemoptysis which is commonly seen in HIV negative pulmonary tuberculosis was present in only one patient in our study (Table 4). The proportion of purely pulmonary TB versus purely extra pulmonary TB was almost equal. 21.9% patients had both pulmonary and extrapulmonary TB (Figure 2). In immunocompetent adult patients, pulmonary TB is the most common form of TB encountered. While extra pulmonary TB accounts for only 20 per cent of cases in HIV-negative persons, it accounts for 53 to 62 per cent of cases in HIV-positive individuals. 16,17 The high proportion of disseminated disease seen in this study has also been reported by others. 9,18 We observed that the mean CD4 count in cases of pulmonary TB was similar to mean CD4 count of those with only extra pulmonary TB (117.2 cells/µl and cells/µl respectively) but was higher than the mean CD4 count seen in patients in the third group (mean 87.6), though the difference was not statistically significant (p>0.05). Investigators have seen that proportion of patients having extra-pulmonary tuberculosis increases as CD4 counts fall. 13 More of extra-pulmonary and disseminated tuberculosis is observed as immune suppression increases due to unrecognized and demonstrable mycobacteremia. 13 The sputum positivity in pulmonary involvement of 34% seen in this study was similar to that reported from India. 9 It has been seen that as immune suppression increases the smear negativity increases. 16 Thirteen (17.8%) of the total patient population had a history of completed TB treatment in the past with mean interval between the present and past TB of 16.9 months (median 12, range 0-96). Comparable findings have been reported from developed world. 10 In this analysis, more than half of the patients with a history of previous tuberculosis had not taken complete treatment. Incomplete treatment of active tuberculosis has been one of the major factors contributing to the resurgence of tuberculosis. 10 Various retrospective studies have shown that TB associated IRIS occurs in 7 45% HIV-TB patients. 19 IRIS was seen in as many as 20% patients in our study. Fever was the most common presentation of IRIS (53.3%) similar to those reported in previous studies. 19 The mean interval between start of ART and IRIS was found to be 17.7 days (median 15, range 7-44). TB associated IRIS usually occurs within two months of ART initiation 19 but we have seen it to occur as early as 7 days. This underscores the need to maintain a high level of vigilance in this period. TB accounts for a third of AIDS deaths. Earlier reports have indicated towards grim prognosis once a HIV infected patient develops tuberculosis. 18,20 Nevertheless, more than two thirds (67% ) patients in this study population had favorable outcome (cure and treatment completed) (Table 8). The notable aspect of this study was concomitant administration of ART with ATT and improved outcome is possibly due to this. Case fatality of 17.8% was observed for HIV-TB in the study period. 61.5% of the deaths occurred within 8 weeks of starting ATT. Mortality was much less later during treatment, once the patient could derive full benefits of the dual therapy. Conclusions Efficient HIV-TB collaboration should be an integral component of comprehensive HIV care. As observed in this study, nearly 30% of HIV infected patients accessing medical care had concurrent active tuberculosis and treatment of both the conditions together lead to an improved outcome. All patients seeking HIV care merit meticulous screening for tuberculosis and timely institution of appropriate treatment regimens for the dual diseases. Strengthening of linkages between the Revised National Tuberculosis Control Program (RNTCP) and National AIDS Control Program would contribute towards early case detection and early treatment of the two diseases, thereby significantly reducing the morbidity and mortality associated with them. Acknowledgements The authors acknowledge the Microbiology and Pathology departments of the Institute for their laboratory support. References 1. UNAIDS/ World Health Organization. AIDS Epidemic Update. December Geneva: UNAIDS Central TB Division. TB India 2007; RNTCP status report. New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare, Govt. of India. 2007; pp National AIDS Control Organization. Technical Report on HIV Estimation, New Delhi: National AIDS Control Organization, Ministry of Health and Family Welfare, Government of India. 2006; pp Sharma SK, Mohan A, Kadhiravan T. HIV-TB co-infection: epidemiology, diagnosis and management. Indian J Med Res 2005; 121: National AIDS Control Organization. Anti retroviral therapy guidelines for HIV infected adult and adolescents including post exposure prophylaxis. New Delhi: National AIDS Control Organization, Ministry of Health and Family Welfare, Government of India. May 2007; pp 7-8, Dandona L, Dandona R. Drop of HIV estimate for India to less than half. Lancet 2007; 370: Cohen J. India slashes estimate of HIV-infected people. Science 2007; 317: World Health Organization. WHO report 2007; Global Tuberculosis Control. Surveillance, Planning, Financing. Geneva: WHO Rajasekaran S, Mahilmaran A, Annadurai S, Kumar S, Raja K. Manifestation of tuberculosis in patients with human immunodeficiency virus. A large Indian study. Ann Thorac Med 2007; 2: Girardi E, Antonucci G, Vanacore P, et al. Tuberculosis in HIVinfected persons in the context of wide availability of highly active antiretroviral therapy. Eur Respir J 2004; 24: Swaminathan S, Sangeetha M, Arunkumar N, et al. Pulmonary tuberculosis in HIV positive individuals: preliminary report on clinical features and response to treatment. Ind J Tub 2002; 49: Sackoff J, Bernard MA, Adams L. HIV-associated tuberculosis in the era of highly active antiretroviral therapy. Int J Tuberc Lung Dis 2001; 5: Jones BE, Young SMM, Antoniskis D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993; 148: Vajpayee M, Kanswal S, Seth P, Wig N, Pandey RM. Tuberculosis infection in HIV-infected Indian patients. AIDS Patient Care STDs JAPI OCTOBER 2009 VOL

6 2004; 18: Archibald L, Dulk MO, Pallangyo KJ et al. Fatal Mycobacterium tuberculosis blood stream infections in febrile hospitalized adults in Dar es Salaam, Tanzania. Clin Infect Dis 1998; 26: Raviglione MC, Narain JP, Kochi A. HIV-associated tuberculosis in developing countries: clinical features, diagnosis and treatment. Bull World Health Organ 1992;70: Fanning A. Tuberculosis: 6. Extrapulmonary disease. CMAJ 1999; 160: Aerts D, Jobim R. The epidemiological profile of tuberculosis in southern Brazil in times of AIDS. Int J Tuberc Lung Dis 2004; 8: Murdoch DM, Venter WD, Van Rie A, Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther 2007; 4: Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999; 340: I n t e r n a t i o n a l E c h o C o u r s e & W o r k s h o p International Echo Course & Workshop will be held on 29th November (Sunday) 2009 at Hotel Jehan Numa Palace, Shamla Hills, Bhopal. Course Director: Dr. Navin C. Nanda, Birmingham Registration fees Rs.3500/- till Demand Draft in favour ISCDEE & CC Payable at Bhopal. Registration fees includes 5 Volumes of Echocardiography Update & Course Certificate. Conference Secretariat: E-5/103 Arera Colony, Bhopal-16, Mob. No.: , pmanoria@rediffmail.com. 690 JAPI OCTOBER 2009 VOL. 57