Treatment outcomes in HIV/tuberculosis co-infected patients with CD4 cell counts < 200 cells/mm 3 and 200 cells/mm 3

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1 Original Article Vol. 29 No. 2 Treatment outcomes in HIV/TB co-infection:- Rattanamaneekorn S & Sungkanuparph S. 5 Treatment outcomes in HIV/tuberculosis co-infected patients with CD4 cell counts < 200 cells/mm and 200 cells/mm Sumeth Rattanamaneekorn, M.D. Somnuek Sungkanuparph, M.D. ABSTRACT Background: The early initiation of highly active antiretroviral therapy (ART) during tuberculosis (TB) treatment has improved survival of HIV/TB co-infected patients. The optimal timing for initiation of ART in HIV/TB co-infected patients in Thailand remains debatable. The National AIDS Program (NAP) currently defers the implement of early ART initiation at CD4 < 50 cells/mm and ART is deferred in some HIV/TB co-infected patients who had CD4 200 cells/mm. There is limited data on the survival and treatment outcomes of HIV/TB co-infected patients with CD4 200 cells/mm. Methods: A retrospective cohort study was conducted among patients with HIV/TB co-infection who were diagnosed TB between January 2005 and December 2010 at Ramathibodi Hospital, Mahidol University. Patients were categorized into two groups according to CD4 cell count at diagnosis of TB; low CD4 group (CD4 < 200 cells/mm ) and high CD4 group (CD4 200 cells/mm ). Treatment outcomes were compared between the two groups. Results: A total of 97 patients with HIV/TB co-infection were studied. The mean ± SD age was 7.4 ± 8. years, and 64 (66%) patients were male. Of all, 4.%, 28.9%, and 27.8% had pulmonary, extrapulmonary, and disseminated TB, respectively. Seventy-four (76.%) patients were in low CD4 group. Patients were followed up for a median (IQR) duration of 6. ( ) months after diagnosis of TB. The majority of patients (68.0%) had received standard short course TB regimen. Median (IQR) duration of TB treatment was 9.8 (8.-1.7) months. Regarding TB treatment, 92 (94.8%) were cured; 4 (4.1%) had relapsed TB, and 1 (1%) had treatment failure. Regarding ART, 89 (91.8%) had received ART within 12 months of TB diagnosis; this rate is significantly higher in low CD4 group (95.9% vs. 78.%, p=0.017). Among patients who had received ART, 90.8% had achieved undetectable HIV RNA at one year of ART; this rate was not different between low and high CD4 groups (91.5% vs. 88.2%, p=0.650). Median (IQR) CD4 change from TB diagnosis to 6 and 12 months of ART was 122 (48-170) and 17 ( ) cells/mm, respectively. Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. Reprint request: Somnuek Sungkanuparph, M.D., Professor of Medicine, Division of Infectious Diseases, Department of Medicine, Ramathibodi Hospital, 270 Rama 6 Road, Bangkok 10400, Thailand. somnuek.sun@mahidol.ac.th Keywords: HIV, AIDS, tuberculosis, antiretroviral therapy, CD4 5

2 54 J INFECT DIS ANTIMICROB AGENTS May-August 2012 Median change of CD4 was not different between the two groups, neither at 6 or 12 months (p=0.05 and p=0.465, respectively). For patients who did not receive ART, median CD4 had declined, at one year, 10 cells/mm in low CD4 group and 21 cells/mm in high CD4 group. There were no patient deaths in either group. Conclusion: In the era that ART is widely accessible, survival and treatment outcomes of both TB and HIV are good. HIV/TB co-infected patients with CD4 200 cells/mm have a significant lower rate of ART initiation in one year. Although TB and HIV treatment outcomes are similar between low and high CD4 groups in this study, defer ART in this population in the larger study shows higher mortality rate. ART should be scaled up in HIV/TB co-infected patients regardless CD4 cell count levels. (J Infect Dis Antimicrob Agents 2011;29:5-66.) INTRODUCTION Tuberculosis (TB) is one of the most important opportunistic infections (OIs) affecting human immunodeficiency virus (HIV)-infected patients worldwide particularly in developing countries. Both TB and HIV disease are closely intertwined, and the number of patients with HIV/TB co-infection continues to grow rapidly. World Health Organization (WHO) has estimated that there were approximately 9.4 million cases of TB in Of these, 1.2 million cases were among HIV-infected patients. HIV/TB co-infected patients have been shown to have a higher mortality rate than those without TB, regardless of CD4 cell count. 2 Prior to the era of antiretroviral therapy (ART), TB caused substantial mortality in patients with advanced HIV infection. Introduction of ART has significantly reduced mortality and morbidity of HIV/ TB co-infected patients. Although the effective therapies exist for both HIV and TB, concomitant administration is difficult due to the risks and benefits of either early or delayed initiation of ART. 4 These concerns include overlapping drug toxicities, drug-drug interactions between anti-tb drugs and antiretroviral drugs, high pill burden and immune reconstitution inflammatory syndrome (IRIS). These adverse events can potentially affect adherence, which has been shown to be essential for the successful treatment of HIV disease. However, delaying ART until after the completion of TB treatment in co-infected persons may increase the risk of AIDS progression and death. 5,6 Therefore, there has been significant interest recently in determining the optimal timing of ART initiation relative to TB treatment in the setting of HIVassociated TB. The optimal timing for initiation of ART in HIV/ TB co-infected remains debatable. WHO guidelines recommend all HIV-infected patients with active TB should receive ART as soon as TB treatment is tolerated, irrespective of CD4 cell counts. 7 In the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) study, an open label, randomized controlled trial conducted in a large clinic in Durban, South Africa showed that the initiation of ART during TB therapy, in patients with confirmed TB and HIV co-infection, significantly reduced the mortality rate. 8 Among patients with CD4 cell counts of less than 200 cells/mm, the mortality rate was significant lower in the initiation of ART during TB therapy group than in the initiation of ART when completing TB treatment group. Although the number of deaths was small in the subgroup of patients who had CD4 cell counts between

3 Vol. 29 No. 2 Treatment outcomes in HIV/TB co-infection:- Rattanamaneekorn S & Sungkanuparph S and 500 cells/mm, there was a trend toward lower mortality in the initiation of ART during TB therapy. Thai national guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2010 recommends to initiate ART in HIV-infected patients with AIDS-defining illness or with CD4 cell counts < 50 cells/mm. 9 However, the National AIDS Program (NAP) currently defers the implement of this early ART initiation at CD4 <50 cells/mm. Although TB is an AIDS defining illness, it can occur in patients with any level of immune deficiency in endemic area of TB and HAART is deferred in some HIV/TB co-infected patients who had CD4 200 cells/mm. There is limited data on the treatment outcomes of HIV/TB co-infected patients with CD4 200 cells/mm. This study was aimed to determine the treatment outcomes in HIV/ TB co-infected patients and to compare the treatment outcomes between patients with CD4 cell counts < 200 cells/mm and 200 cells/mm. METHODS The study design was a retrospective cohort study involving patients with HIV/TB co-infection who were diagnosed TB between January 2005 and December 2010 at Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Ethic approval for the study was obtained from Ramathibodi Hospital ethics committee. Inclusion criteria were as follows: (1) documented HIV infection in patients aged 18 years old, (2) diagnosis of active TB by clinical features, pulmonary infiltrates on chest radiography, positive acid fast stain and/or positive culture for Mycobacterium tuberculosis, () received antituberculous therapy, and (4) received ART at or after the diagnosis of TB. Patients were excluded if they were (1) on ART prior to TB diagnosis and (2) non-compliance with ART. Patients were categorized into two groups according to CD4 cell count at the diagnosis of TB: low CD4 55 group (CD4 < 200 cells/mm ) and high CD4 group (CD4 200 cells/mm ). Variables including gender, age, presence of underlying disease, previous opportunistic infections, type of TB (pulmonary, extra-pulmonary and disseminated), CD4 cell count and HIV RNA at baseline, at 6 and 12 months after initiation of ART, type of ART regimen, the duration from TB treatment to initiation of ART, and other related clinical and laboratory data were reviewed and collected from medical records. The primary objective of this study was to determine the treatment outcomes of TB and HIV in the HIV/TB co-infected patients and compare between patients with CD4 < 200 cells/mm and 200 cells/ mm. The secondary objectives were (1) to determine the difference of CD4 cell count change between those who received ART and those who did not receive ART, (2) to determine the adverse effects and the occurrence of the immune reconstitution inflammatory syndrome, () to determine the predicting factors for undetectable HIV RNA after 1 year of ART, and (4) to determine the predicting factors for CD4 change 200 cells/mm after 1 year of ART. All analyses were performed using SPSS version Mean values (± standard deviation, SD) or median values with interquartile range (IQR), and frequencies (%) were used to describe patients characteristics for continuous and categorical data, respectively. Chisquare test or Fischer exact test was used to compare categorical variables between the two groups where appropriate. Student s t-test was performed to assess the difference of mean between the two groups. Mann- Whitney U test was used to compare the median between the two groups, when the variables were not normally distributed. Logistic regression analysis was used to determine the predicting factors of undetectable HIV RNA and CD4 change 200 cells/mm after 1

4 56 J INFECT DIS ANTIMICROB AGENTS May-August 2012 year of ART. Kaplan-Meier analysis was used to determine the median time to CD4 change 200 cells/ mm after 1 year of ART and log-rank test was used to compare between the two groups. A P value at < 0.05 was considered statistically significant. RESULTS Patient characteristics A total of 97 patients were studied. The mean ± SD age was 7.4 ± 8. years, and 64 (66%) patients were male. Risk of HIV infection as heterosexual, homosexual, and intravenous drug use were 96.9%, 1.0%, and 2.1%, respectively. Of all, 4.%, 28.9%, and 27.8% had pulmonary, extrapulmonary, and disseminated TB, respectively. Eleven (11.%) patients had susceptibility test for M. tuberculosis and 2 patients had drug-resistance TB at baseline. Thirty-three (2.8%) patients had previous major opportunistic infections including Pneumocystis jiroveci pneumonia (16 patients, 16.5%), cryptococcal infection (5 patients, 5.2%) and toxoplasmosis (2 patients, 2.1%). Of 82 patients who were tested for HBsAg, 9 (11.0%) had HBV co-infection. Of the 70 patients who were tested for anti-hcv antibody, 1 (1.4%) had HCV co-infection. Of 97 patients, 74 (76.%) patients were in low CD4 group and 2 (2.7%) patients were in high CD4 group. Table 1 shows the clinical characteristics of the study patients. Treatment outcomes of TB Median (IQR) time between the diagnosis of HIV infection to the diagnosis of TB was 14 (1-58) days. The majority of patients 66 (68.0%) had received standard short course TB regimen. Median (IQR) duration of TB treatment was 9.8 (8.-1.7) months. Of 97 patients, 92 (94.8%) were cured; 4 (4.1%) had relapsed TB and 1 (1%) had TB treatment failure. Patients were followed up for a median (IQR) duration of 6. ( ) months after the diagnosis of TB. Table 2 shows the TB treatment outcomes of the study patients. In Kaplan-Meier analysis, Figure 1 shows proportion of patients free from TB relapse. At 6 months after diagnosis of TB, there was less than 5% of patients with TB relapse. Treatment outcomes of HIV Regarding ART, 89 (91.8%) patients had received ART within 12 months of TB diagnosis. Proportion of patients receiving ART in low CD4 group is significantly higher than high CD4 group (95.9% vs. 78.%, p=0.017). Median (IQR) duration from the diagnosis of TB to initiation of ART was.0 ( ) months. This duration in low CD4 group is significantly shorter than high CD4 group (2.8 vs..6, p=0.005). Median (IQR) baseline CD4 cell count at TB diagnosis was 79 (8-186) cells/mm. Median (IQR) baseline HIV RNA was 8,19 (< ,890) copies/ml. The most common ART regimen used was nonnucleoside reverse transcriptase inhibitor (NNRTI)- based regimen such as efavirenz (EFV) and nevirapine (NVP)-based regimens. Among patients who had received ART, 90.8% had achieved undetectable HIV RNA at one year of ART; this rate was not different between low CD4 and high CD4 group (91.5% vs. 88.2%, p=0.650). Median (IQR) CD4 change from TB diagnosis to 6 and 12 months of ART was 122 (48-170) and 17 ( ) cells/mm, respectively. Median change of CD4 was not different between the low CD4 and high CD4 groups, neither at 6 or 12 months (p=0.05 and p=0.465, respectively). For patients who did not

5 Vol. 29 No. 2 Treatment outcomes in HIV/TB co-infection:- Rattanamaneekorn S & Sungkanuparph S. 57 Table 1. Baseline characteristics of HIV/TB co-infected patients with CD4 cell counts < 200 cells/mm and 200 cells/mm. CD4 cell CD4counts cell counts (cells/mm ) Characteristics All < 200 > 200 ( n = 97) ( n = 74) (n = 2) P value Age, years, mean + SD Sex, number (%) M ale 64 (66) 5 (71.6) 11 (47.8) F emale (4) 21 (28.4) 12 (52.2) Underlying disease, number (%) D iabetes mellitus (.1) (4.1) H ypertension 7 (7.2) 7 (9.5) C hronic kidney disease 1 (1) 0.27 D yslipidemia 15 (15.5) 14 (18.9) O ther underlying disease 10 (10.) 9 (12.) 0.44 A lcohol, number (%) 29 (29.9) 24 (2.4) 5 (21.7) 0.47 S moking, number (%) 28 (28.9) 2 (1.1) 5 (21.7) HIV exposure, number (%) H omosexual 1 (1) 1 (1.4) H eterosexual 94 (96.9) 71 (95.9) 2 (100) H omosexual + IVDU H eterosexual + IVDU 2 (2.1) 2 (2.7) Prior opportunistic infections, number (%) P CP 16 (16.5) 15 (20.) C ryptococcosis 5 (5.2) 5 (6.8) 0.5 T oxoplasmosis 2 (2.1) 2 (2.7) C andidiasis 21 (21.6) 16 (21.6) 5 (21.7) O ther OIs 0 (0.9) 24 (2.4) 6 (26.1) Hepatitis co-infection, number (%) H BV (n = 82) 9 (11) 7 (11.7) 2 (9.1) H CV (n = 70) 1 (1.4) 1 (1.9) IVDU=intravenous drug user, OIs=opportunistic infections, PCP=Pneumocystis jiroveci pneumonia, HBV=hepatitis B virus, HCV=hepatitis C virus 57

6 58 J INFECT DIS ANTIMICROB AGENTS May-August 2012 Table 1. Baseline characteristics of HIV/TB co-infected patients with CD4 cell counts < 200 cells/mm and 200 cells/mm. (continued) CD4 cell CD4 counts cell counts (cells/mm ) Characteristics TB diagnosis with, number (%) All < 200 > 200 ( n = 97) ( n = 74) (n = 2) P value S putum AFB (n = 62) 15 (24.2) 11 (22.4) 4 (0.8) O ther AFB (n = 42) 16 (8.1) 1 (48.1) (20) S putum culture for TB (n = 8) 18 (47.4) 12 (42.9) 6 (60) P CR TB (n = 7) 1 (14.) 1 (25) H emoculture for TB (n = 9) 5 (12.8) 5 (14.7) TB diagnosis with, number (%) S putum AFB (n = 62) 15 (24.2) 11 (22.4) 4 (0.8) O ther AFB (n = 42) 16 (8.1) 1 (48.1) (20) S putum culture for TB (n = 8) 18 (47.4) 12 (42.9) 6 (60) P CR TB (n = 7) 1 (14.) 1 (25) H emoculture for TB (n = 9) 5 (12.8) 5 (14.7) Type of TB, number (%) P ulmonary 42 (4.) 4 (50.0) 8 (4.8) E xtra-pulmonary 28 (28.9) 18 (24.) 10 (4.5) D isseminated 27 (27.8) 22 (29.7) 5 (21.7) H istory of previous TB, number (%) 2 (2.1) 2 (8.7) D rug resistance TB, number (%) (n = 11) 2 (18.2) 1 (14.) 1 (25) CD4 at TB diagnosis, cells/mm, median (IQR) 79 (8-186) 58 (29-95) 25 (246-64) <0.001 H emoglobin, g/dl, median (IQR) (n = 96) 10. ( ) 9.9 ( ) 11.9 ( ) Blood chemistries, median (IQR) A ST, μ/ L (n = 91) 42 (27-68) 44.5 (28-71) 29 (22-48) A LT, μ/l (n = 92) 49 (1-80) 56 (5-80) 5 (28-61) 0.08 A LP, μ/l (n = 89) 116 (80-202) 18 (86-250) 89 (60-115) C reatinine, mg/dl (n = 71) 0.9 ( ) 1.0 ( ) 0.9 ( ) 0.65 AFB=acid fast bacilli, PCR=polymerase chain reaction,ast=aspartate aminotransferase, ALT=alanine aminotransferase, ALP=alkaline phosphatase

7 Vol. 29 No. 2 Treatment outcomes in HIV/TB co-infection:- Rattanamaneekorn S & Sungkanuparph S. 59 Table 2. Treatment outcomes of TB in HIV/TB co-infected patients with CD4 cell counts < 200 cells/mm and 200 cells/mm. CD4 cell CD4counts cell counts (cells/mm ) Variables All < 200 > 200 ( n = 97) ( n = 74) (n = 2) P value Time from HIV diagnosis to TB diagnosis, days, median (IQR) 14 (1-58) 12 (4-6) 22 (0-65) 0.77 Antituberculous regimen, number (%) IRZE + 4 IR 66 (68.0) 48 (64.9) 18 (78.) O ther regimens 1 (2.0) 26 (5.1) 5 (21.7) Blood chemistries during TB treatment, median (IQR) A ST (n = 79) 0 (2-42) 6 (25-44) 25 (18-0) A LT (n = 88) 42 (4-59) 45 (5-66) 6 (2-42) A LP (n = 62) 96 (8-125) 10 (84-12) 85 (67-94) D uration TB treatment, months, median (IQR) 9.8 (8.-1.7) 9.8 (8.-1.8) 9.8 (8.-1.5) 0.70 Follow-up time after diagnosis of TB, median (IQR) months, 6. ( ) 65. ( ) 56.0 ( ) TB outcome, number (%) C ured 92 (94.8) 71 (95.9) 21 (91.) R elapsed 4 (4.1) (4.1) F ailure 1 (1) I=isoniazid, R=rifampicin, Z=pyrazinamide, E=ethambutol, AST=aspartate aminotransferase, ALT=alanine aminotransferase, ALP=alkaline phosphatase receive ART, median HIV RNA had increased 720,219 copies/ml in low CD4 group and,658 copies/ml in high CD4 group at one-year follow-up period. Median CD4 cell count had declined 10 cells/mm in low CD4 group and 21 cells/mm in high CD4 group at one-year follow-up period. In Kaplan-Meier analysis, Figure 2 shows proportion of patient with CD4 change 200 cells/mm after 1 year of ART. At 15-month follow-up time after diagnosis of TB (or 1 year of ART), 69.6% of patients had probability to achieve CD4 change 200 cells/ 59 mm. Median time to achieve CD4 change 200 cells/ mm after 1 year of ART was 14. months [95% confidence interval (CI) ]. Predicting factors for undetectable HIV RNA after 1 year of ART From univariate analysis, female gender, presence of underlying disease, history of opportunistic infections, disseminated TB, CD4 cell count 200 cells/mm, and duration diagnosis from TB diagnosis to ART initiation were not significant predicting factors

8 60 J INFECT DIS ANTIMICROB AGENTS May-August Proportion of patient free from TB relapse Follow-up time after diagnosis of TB (months) Figure 1. Kaplan-Meier analysis of TB relapse among HIV/TB co-infected patients who were initiated ART. Proportion of patient with CD4 change 200 cells/mm after 1 year of ART Follow-up time after diagnosis of TB (months) Figure 2. Kaplan-Meier analysis of CD4 change 200 cells/mm after 1 year of ART among HIV/TB co-infected patients. for achieving undetectable HIV RNA at 1 year (Table 4). Predicting factors for CD4 change 200 cells/ mm after 1 year of ART From univariate analysis, age, female gender, presence of underlying disease, history of opportunistic infections, disseminated TB, CD4 cell count 200 cells/ mm, and duration from TB diagnosis to ART initiation were not significant predicting factors for CD4 change 200 cells/mm at 1 year. When we categorized patients into two groups according to gender, the Kaplan-Meier analysis shows that the median time to achieve CD4 change 200

9 Vol. 29 No. 2 Treatment outcomes in HIV/TB co-infection:- Rattanamaneekorn S & Sungkanuparph S. 61 Table. Treatment outcomes of HIV in HIV/TB co-infected patients with CD4 cell counts < 200 cells/mm and 200 cells/ mm. CD4 C cell counts (cells/mm ) ) Variables All < 200 > 200 ( n = 97) ( n = 74) (n = 2) P value R eceiving ART, number (%) 89 (91.8) 71 (95.9) 18 (78.) Virological and immunological outcomes R eceiving ART patients (n = 89) Time from TB to ART initiation, months, median.0 ( ) 2.8 (1.9-.6).6 ( ) (IQR) CD4 at ART initiation, cells/mm, median (IQR) 67 (2-151) 56 (24-90) 251 (197-1) <0.001 (n = 88) HIV RNA at ART initiation, copies/ml, median 8,19 9,854 8, (IQR) (n = 95) (<50-271,890) (<50-27,472) ( ,000) ART regimen, number (%) N evirapine-based (7.1) 26 (6.6) 7 (8.9) E favirenz-based 52 (58.4) 41 (57.7) 11 (61.1) P I-based 4 (4.5) 4 (5.6) Undetectable HIV RNA at 1 year, number (%) 69 (90.8) 54 (91.5) 15 (88.2) (n = 76) CD4 at 6 months, cells/mm, median (IQR) 218 (11-292) 17 ( ) 25 (242-97) <0.001 (n = 84) CD4 at 1 year, cells/mm, median (IQR) 254 ( ) 221 (164-7) 446 (21-568) <0.001 (n = 6) CD4 change from baseline to 6 months, (48-170) 15 (52-18) 6 ( ) 0.05 cells/mm, median (IQR) (n = 84) CD4 change from baseline to 1 year, cells/mm, 17 ( ) 17 ( ) 205 ( ) median (IQR) (n = 6) Hemoglobin within 1 year, g/dl, median (IQR) 12.7 ( ) 12.5 ( ) 12.8 ( ) (n = 64) Creatinine within 1 year, mg/dl, median (IQR) 0.9 ( ) 0.9 ( ) 0.9 ( ) (n = 64) PI=protease inhibitor 61

10 62 J INFECT DIS ANTIMICROB AGENTS May-August 2012 Table. Treatment outcomes of HIV in HIV/TB co-infected patients with CD4 cell counts < 200 cells/mm and 200 cells/ mm. (continued) CD4 cell CD4 counts cell counts (cells/mm ) Variables Not receiving ART patients (n = 8) All < 200 > 200 ( n = 97) ( n = 74) (n = 2) P value HIV RNA within 1 yr after TB diagnosis, 418, ,219, median (IQR) (n = 5) (, ,219) (418,000-1,022,48) (, ,000) CD4 at 6 months after TB diagnosis, cells/mm, median (IQR) (n = ) CD4 at 1 year after TB diagnosis 12 months, 46 (10-59) - 46 (10-59) - 42 ( ) 6 45 ( ) 0.14 cells/mm, median (IQR) (n = 6) CD4 change from TB diagnosis to 6 months, - 28 ( ) -28 ( ) cells/mm, median (IQR) (n = ) CD4 change from TB diagnosis to 1 year, -52 (-12-24) ( ) 0.80 cells/mm, median (IQR) (n = 6) Other outcomes H ospitalization, number (%) 10 (10.) 9 ( 12.2) 0.44 L oss to follow-up, number (%) 5 (5.2) 4 (5.4) Death, number (%) Adverse events R ash, number (%) 8 (8.2) 8 (10.8) 0(0) I RIS, number (%) 6 (6.2) 4 (5.4) 2(8.7) S teroid in IRIS (n = 6) 2 (.) 1 (25) 1 (50) D rug-drug interaction, number (%) (.1) 2 (2.7) IRIS=immune reconstitution inflammatory syndrome cells/mm at 1 year of ART was 14.5 months [95% CI) ] in male and 1.1 months [95% CI ] in female (log rank test, p=0.158, Figure ). When we categorized patients into two groups according to the presence of history of opportunistic infections, the Kaplan-Meier analysis shows that the median time to achieve CD4 change 200 cells/mm at 1 year of ART was 1.6 months in patients without history of opportunistic infections and 14.5 months in patients with history of opportunistic infections (log rank test, p=0.201, Figure 4). When we categorized patients into two groups according to CD4 cell count at diagnosis of TB: low CD4 group (CD4 < 200 cells/mm ) and high CD4 group (CD4 200 cells/mm ), the Kaplan-Meier analysis

11 Vol. 29 No. 2 Treatment outcomes in HIV/TB co-infection:- Rattanamaneekorn S & Sungkanuparph S. 6 Table 4. Predicting factors for undetectable HIV RNA at 1 year of ART by univariate analysis. Factors Odds ratio 95% confidence interval P value Age (years) Female gender Presence of underlying disease History of opportunistic infection Disseminated TB C D4 cell count > 200 cells/m m Duration from TB diagnosis to ART initiation (months) Table 5. Predicting factors for achieving CD4 change 200 cells/mm at 1 year of ART by univariate analysis. Factors Odds ratio 95% confidence interval P value Age (years) Female gender Presence of underlying disease History of opportunistic infection Disseminated TB C D4 cell count > 200 cells/m m Duration from TB diagnosis to ART initiation (months) shows that the median time to achieve CD4 change 200 cells/mm at 1 year of ART was 14. months [95% confidence interval (CI) ] in low CD4 group and 14.4 months [95% CI ] in high CD4 group (log rank test, p=0.98, Figure 5). Adverse Events During the follow-up period, adverse drug reactions from the use of antituberculous regimen and ART were found in some patients. Skin rash from antituberculous drugs was observed in 8 (8.2%) patients. Drug-drug interaction was found in (.1%) patients. IRIS was observed in 6 (6.2%) patients (Table ). There were no differences of these events between 6 patients with baseline CD4 cell counts < 200 cells/mm and 200 cells/mm. There were no patient deaths in either group. DISCUSSION In the era that ART is widely accessible, multiple studies demonstrate the impact of ART on the survival and treatment outcomes among HIV-infected patients with successful immune restoration and reductions in morbidity and mortality.,8,10-1 The results from the present study have shown that most patients with HIV/ TB co-infection presented with very low CD4 cell counts and about three-fourths of patients had CD4 cell counts < 200 cells/mm. TB treatment outcomes and virological

12 64 J INFECT DIS ANTIMICROB AGENTS May-August 2012 Proportion of patient with CD4 change 200 cells/mm after 1 year of ART Sex male female Follow-up time after diagnosis of TB (months) Figure. Kaplan-Meier analysis of CD4 change 200 cells/mm at 1 year of ART compared between genders of HIV/TB co-infected patients. Proportion of patient with CD4 change 200 cells/mm after 1 year of ART Ols no history of Ols no history of Ols Follow-up time after diagnosis of TB (months) Figure 4. Kaplan-Meier analysis of CD4 change 200 cells/mm at 1 year of ART compared between HIV/TB co-infected patients with and without history of opportunistic infections.

13 Vol. 29 No. 2 Treatment outcomes in HIV/TB co-infection:- Rattanamaneekorn S & Sungkanuparph S. 65 Proportion of patient with CD4 change 200 cells/mm after 1 year of ART Group CD4 < 200 cells/mm CD4 200 cells/mm Follow-up time after diagnosis of TB (months) Figure 5. Kaplan-Meier analysis of CD4 change 200 cells/mm at 1 year of ART compared between HIV/TB co-infected patients with baseline CD4 < 200 cells/mm and 200 cells/mm. and immunological responses of ART were good in both low and high CD4 groups. However, HIV/TB co-infected patients with CD4 200 cells/mm had a significantly lower rate of ART initiation in one year. The findings of multiple retrospective and prospective studies provide evidence that initiation of ART in patients with HIV/TB co-infection, regardless of CD4 cell counts, significantly reduced morbidity and mortality This warrants the need of scaling up of ART in HIV/TB co-infected patients with CD4 cell counts 200 cells/mm. The limitations of the present study included the nature of a retrospective study, small sample size specifically in the group of high CD4 cell count ( 200 cells/mm ) and the follow-up HIV RNA assay was not routinely performed in study patients, secondary to the limited resources. However, this study provides useful information of both TB and HIV treatment outcomes in the real-life setting with various 65 baseline CD4 cell counts. In conclusion, this study has demonstrated the beneficial treatment outcomes of ART in patients coinfected with HIV and TB in all CD4 cell count levels. Rate of ART initiation in HIV/TB co-infected patients with CD4 cell counts 200 cells/mm is lower than patients with CD4 cell counts < 200 cells/mm. Deferral ART in this population in the larger study has shown the higher mortality rate. Therefore, ART should be commenced in HIV/TB co-infected patients regardless CD4 cell count levels. References 1. WHO global tuberculosis control report Summary. Cent Eur J Public Health 2010;18: Lopez-Gatell H, Cole SR, Hessol NA, et al. Effect of tuberculosis on the survival of women infected with human immunodeficiency virus. Am J Epidemiol 2007;165:

14 66 J INFECT DIS ANTIMICROB AGENTS May-August Manosuthi W, Chottanapand S, Thongyen S, Chaovavanich A, Sungkanuparph S. Survival rate and risk factors of mortality among HIV/tuberculosis-coinfected patients with and without antiretroviral therapy. J Acquir Immune Defic Syndr 2006;4: Dean GL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16: Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009;4:e Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programmes in sub-saharan Africa. AIDS 2008;22: World Health Organization. Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents [Internet]. Geneva: WHO; 2009 [cited 2012 Feb 29]. Available from: rapid_advice_art.pdf 8. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;62: Sungkanuparph S, Techasathit W, Utaipiboon C, et al. The Adults and Adolescents Committee of the Thai National HIV Guidelines Working Group. Thai national guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents Asian Biomed 2010;4: Wong KH, Chan KC, Lee SS. Delayed progression to death and to AIDS in a Hong Kong cohort of patients with advanced HIV type 1 disease during the era of highly active antiretroviral therapy. Clin Infect Dis 2004;9: Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998;8: Hung CC, Chen MY, Hsiao CF, Hsieh SM, Sheng WH, Chang SC. Improved outcomes of HIV-1-infected adults with tuberculosis in the era of highly active antiretroviral therapy. AIDS 200;17: Tabarsi P, Saber-Tehrani AS, Baghaei P, et al. Early initiation of antiretroviral therapy results in decreased morbidity and mortality among patients with TB and HIV. J Int AIDS Soc 2009;12: Sanguanwongse N, Cain KP, Suriya P, et al. Antiretroviral therapy for HIV-infected tuberculosis patients saves lives but needs to be used more frequently in Thailand. J Acquir Immune Defic Syndr 2008;48: Velasco M, Castilla V, Sanz J, et al. Effect of simultaneous use of highly active antiretroviral therapy on survival of HIV patients with tuberculosis. J Acquir Immune Defic Syndr 2009;50: Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)--associated tuberculous meningitis. Clin Infect Dis 2011;52: Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;65: