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Factors associated with mortality among HIV-infected patients in the era of highly active antiretroviral therapy in southern India
International Journal of Infectious Diseases (2010) 14, e127—e131
http://intl.elsevierhealth.com/journals/ijid
Factors associated with mortality among HIV-infected patients in the era of highly active antiretroviral therapy in southern India N. Kumarasamy a,*, Kartik K. Venkatesh b, Bella Devaleenol a, S. Poongulali a, Tokugha Yephthomi a, A. Pradeep a, Suneeta Saghayam a, Timothy Flanigan b, Kenneth H. Mayer b, Suniti Solomon a a b
YRG Centre for AIDS Research and Education, Voluntary Health Services, Taramani, Chennai 600113, India Division of Infectious Diseases, Miriam Hospital, Brown University Medical School, Providence, Rhode Island, USA
Received 31 July 2008; accepted 31 March 2009 Corresponding Editor: William Cameron, Ottawa, Canada
KEYWORDS India; HIV; AIDS; Opportunistic infection; HAART; Mortality
Summary Objective: To describe the causes of mortality among the HIV-infected in southern India in the era of highly active antiretroviral therapy (HAART). Methods: Analyses of this patient cohort were conducted using the YRG Centre for AIDS Research and Education HIV Natural History Observational Database. Causes of death were then individually confirmed by patient chart review. Results: Sixty-nine deaths occurred within the inpatient unit; 25% were female and the median age of the 69 patients was 34 years. Over half of the patients (55%) died within three months of initiating HAART. At the time of enrollment into clinical care, the median CD4 cell count was 64 cells/ml (interquartile range (IQR) 37—134). At the time of initiating HAART, the median CD4 cell count was 58 cells/ml (IQR 31—67) for patients who died within 3 months of initiating HAART and 110 cells/ml (IQR 77—189) for patients who died more than 3 months after initiating HAART. Close to three-fourths of patients (70%) died from an AIDS-defining illness (ADI). The major ADI causes of death included Pneumocystis jiroveci pneumonia (22%), extrapulmonary tuberculosis (19%), CNS toxoplasmosis (12%), and pulmonary tuberculosis (10%). A tenth of patients died from cerebrovascular infarcts. Three patients (4%) died from non-Hodgkin lymphoma. Conclusions: AIDS-related events continue to be the major source of mortality among the HIVinfected in southern India in the era of HAART. This mortality pattern justifies increased proactive efforts to identify HIV-infected patients and initiate HAART earlier, before patients present to care with advanced immunodeficiency. # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +91 44 22542929; fax: +91 44 22542939. E-mail address: [email protected] (N. Kumarasamy). 1201-9712/$36.00 # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.03.034
e128
Introduction Studies conducted in the developed world in the era of highly active antiretroviral therapy (HAART) have repeatedly documented that AIDS-related events are no longer the major causes of death.1—5 However the mortality pattern may vary in resource-limited settings where patients often present to clinical care with advanced immunodeficiency and where opportunistic infections, primarily tuberculosis, are rampant.6—9 Despite the fact that generic antiretroviral therapy (ART) is effective in resource-limited settings,10 investigating the emerging causes of death in the era of HAART can allow clinicians to preemptively manage the clinical complications of HIV-infected patients. Earlier studies have documented the changing natural history of HIV disease in the pre- and post-HAART eras in southern India.11,12 However, data remain limited on the causes of death among HIV-infected Indians, particularly in the HAART era.13,14 The current study was undertaken to determine the causes of death among the HIV-infected in southern India who had initiated HAART. The findings of the current study are timely in assessing whether the causes of mortality among HIV-infected patients in resource-limited settings have changed as an increasing number of HIVinfected patients gain access to HAART.
Methods
N. Kumarasamy et al. whose cause of death was assigned as cerebrovascular infarct underwent computed tomography (CT).
Definitions The 1993 Centers for Disease Control and Prevention (CDC) case definitions were used with definitive diagnostic methods for cryptosporidiosis, cryptococcosis, and Mycobacterium tuberculosis, and presumptive diagnostic methods for Pneumocystis jiroveci pneumonia (PCP), cytomegalovirus retinitis, and toxoplasmosis.17 The most recent National Institutes of Health (NIH) definitions of AIDS-associated AEs were employed for diagnosis.18 The primary cause of death was confirmed through patient chart review conducted by a staff physician.
Statistical analysis Descriptive statistics were calculated with mean and standard deviation for variables that were normally distributed; the median and interquartile range (IQR) were calculated for variables influenced by extreme variables. To compare proportions, Chi-square statistics and independent t-tests were used. Survival analysis after initiating HAART was conducted using the Kaplan—Meier method. All statistical analyses were performed using SPSS software (version 13.0; SPSS, Chicago, IL, USA). A p-value less than 0.05 was considered statistically significant.
Setting
Results The YRG Center for AIDS Research and Education (YRG CARE) in Chennai is a large non-profit medical and research institution. Since 1996, it has provided comprehensive care for over 12 000 HIV-infected individuals. All patients are treated according to World Health Organization (WHO) treatment guidelines.15 Co-trimoxazole prophylaxis was initiated for all patients as per WHO guidelines.16 Patients were advised to initiate antiretroviral therapy when CD4 counts reached <200 cells/ml or when CD4 counts ranged between 200 and 350 cells/ml with an AIDS-defining illness (ADI). Nevirapine (NVP)-based regimens, which are the least expensive and most widely available, were used in first-line therapies. Patients were seen every 3 months or as clinically indicated. CD4 monitoring was done every 3 to 6 months.
Patients Patients who were older than 18 years of age, attending the YRG CARE clinic between February 1996 and January 2008, and ART-naı¨ve before initiation of HAARTwere included in the analysis. Data were collected under the approval of YRG CARE’s free-standing institutional review board. Analyses used the YRG CARE HIV Natural History Observational Database.11,12 This database is updated daily by research nurses who are trained to use a validated prospective data collection instrument, which includes demographics; clinical assessments, current treatment regimens, and adverse events (AEs); laboratory data, including hemoglobin, liver and renal function tests, CD4 cell counts, and plasma viral load (PVL); and genotypic testing, if available. All patients
Between February 1996 and January 2008, 4848 ART-naı¨ve adult patients (>18 years of age) initiated HAART at YRG CARE. The median CD4 cell count at the time of initiating HAART was 142 cells/ml (IQR 65—261); the median time from enrollment to initiating HAART was 27 days (IQR 4—237). Among HAART initiated patients, 155 (3%) consequently died, and of these, 69 died within the inpatient unit. Only these 69 patients are included in the subsequent analyses. Twenty-five percent were female; the median age of all 69 patients was 34 years. Almost all participants (>95%) had acquired HIV infection through heterosexual transmission. The most common HAART regimens included: lamivudine (3TC) + stavudine (d4T) + nevirapine (NVP) (36%), 3TC + d4T + efavirenz (EFV) (33%), and 3TC + NVP + zidovudine (AZT) (6%). Over half (55%) of the patients died within 3 months of initiating HAART, 10% of patients died at between 3 and 6 months of initiating HAART, and 35% of patients died more than 6 months after initiating HAART (Table 1). At the time of enrollment into clinical care, the median CD4 cell count was 64 cells/ml (IQR 37—134) and the median hemoglobin was 9.7 g/dl (IQR 7.8—11.1). The most common opportunistic infections at enrollment were pulmonary tuberculosis (14%) and PCP (6%). At the time of initiating HAART, the median CD4 cell count was 58 cells/ml (IQR 31— 67) for patients who died within 3 months of initiating HAART and 110 cells/ml (IQR 77—189) for patients who died more than 3 months after initiating HAART; this difference was not statistically significant ( p = 0.07). The most common incident opportunistic infection after initiating HAART was pulmonary tuberculosis (6%). The most common AEs to therapy
Deaths among HIV-infected South Indians
e129
Table 1 Demographic and clinical characteristics of patients at enrollment to care and at initiation of highly active antiretroviral therapy (HAART) (N = 69) Characteristic
Median (IQR) or %
Men Women Age, years
75% 25% 34 (29—39)
At enrollment to care CD4 cell count, cells/ml Hemoglobin, g/dl Opportunistic infections Pulmonary tuberculosis Extrapulmonary tuberculosis Tuberculous meningitis Cryptococcal meningitis Pneumocystis pneumonia Toxoplasmosis Progressive multifocal leukoencephalopathy Hepatitis B virus Hepatitis C virus Anemia Non-Hodgkin lymphoma Median duration on HAART (months)
death compared to patients who died within 3 months of initiating HAART (138 cells/ml vs. 59 cells/ml; p = 0.04). Patients who died more than 3 months after initiating HAART and patients who died within 3 months of initiating HAART did not experience statistically significant differences in median duration of hospitalization at the time of death nor in the incidence of opportunistic infections.
Discussion 64 (37—134) 9.7 (7.8—11.1) 14% 1% 1% 1% 6% 1% 1% 3% 3% 4% 1% 5.35
CD4 cell count at the time of initiating HAART, cells/ml Died <3 months 58 (31—67) Died >3 months 110 (77—189) After initiating HAART Incident infections Pulmonary tuberculosis Toxoplasmosis Cryptococcal meningitis Pneumocystis jiroveci pneumonia Extrapulmonary tuberculosis Adverse events to therapy Anemia Nausea Diarrhea Hepatitis/hepatotoxicity Immune reconstitution syndrome
17% 14% 12% 4% 3%
Died after initiating HAART 0—3 months of initiating HAART 3—6 months of initiating HAART >6 months of initiating HAART
55% 10% 35%
6% 3% 1% 3% 3%
IQR, interquartile range.
included anemia (17%), nausea (14%), and diarrhea (12%). The median duration on HAART was 5 months (Table 1). Table 2 outlines the reasons for death, median time of treatment prior to death, and median CD4 at the time of initiating HAART and at the time of death for the 69 patients. The major ADI causes of death included PCP (22%), extrapulmonary tuberculosis (19%), CNS toxoplasmosis (12%), and pulmonary tuberculosis (10%). A tenth of patients died from cerebrovascular infarcts. Three patients (4%) died from nonHodgkin lymphoma. Patients who died more than 3 months after initiating HAART had significantly higher CD4 cell counts at the time of
The present study documents that in the era of HAART in southern India, AIDS-related illnesses (70%) continue to be the major source of patient mortality. The high frequency of death due to ADIs, particularly tuberculosis, can be attributed to a low median CD4 cell count at the time of initiating ART. A study among West African HIV patients similarly documented a high mortality soon after initiating HAART and the leading role of mycobacterial infections as a cause of death.7 Many of the patients in the current study also had low hemoglobin levels after initiating HAART, confirming the strong relationship between anemia and death.19,20 The findings of the current study contrast with recent studies conducted in developed countries, in which improvements in HIV treatment have led to proportionately fewer deaths from ‘typical’ HIV-related illnesses and increasing deaths attributable to cardiac disease, trauma, and liver disease.1,3,21,22 We documented a high frequency of bacterial and fungal infections in the time period before the immune restorative effects of HAART, with Mycobacterium tuberculosis and PCP accounting for half of all patient deaths (see Figure 1). A recent study from Brazil identified tuberculosis as the leading cause of death (9%), which was responsible for more than twice as many deaths as PCP (5%).6 A retrospective analysis among HIV-infected patients in the USA found that PCP was the major cause of death in the era of HAART, which was attributed to the fact that more than 50% of patients who died were not receiving HAART.23 Timely prophylaxis and effective treatment of opportunistic infections must be an integral part of any antiretroviral treatment program, especially in resource-limited settings where opportunistic infections are rampant. The current analyses were limited to inpatient causes of death. Though three-fourths of patients who died were men, three-fourths of all patients who initiated HAART were also men. Prior studies at our center have documented that men tend to present to care with advanced immunodeficiency, and women are diagnosed earlier due to screening of partners (symptomatic men) or as part of antenatal testing.11,12 Though we documented the number of deaths occurring outside of the clinic, the definitive causes of death could not be obtained at the time of death and hence these cases were excluded from this analysis. Discernment of the precise causes of death is always a challenge. Routine autopsies are not performed at our institution; however, we undertook a thorough analysis of all available clinical and laboratory data to confirm the cause of death. The findings of the present study suggest that despite the wider introduction of HAART in resource-limited settings, mortality continues to occur due to advanced immunodeficiency soon after starting therapy. A study comparing mortality patterns between high- and low-income countries
e130
N. Kumarasamy et al.
Table 2 Causes of death and median CD4 cell count at the time of initiating highly active antiretroviral therapy (HAART) and at the time of death (N = 69) Reason for death
HIV-associated conditions Mycobacterium tuberculosis Pulmonary Meningitis Abdominal Other extrapulmonary Pneumocystis jiroveci pneumonia CNS toxoplasmosis Cryptococcal meningitis Cryptosporidial diarrhea Viral encephalitis Bacterial meningitis Progressive multifocal leukoencephalopathy Cerebrovascular infarct (neurological complication) Bacteremia
Frequency (%)
Median patient days of treatment (IQR)
Median CD4 at time of initiating HAART (IQR), cells/ml
Median CD4 at time of death (IQR), cells/ml
10 6 9 4 22 12 6 3 1 1 1
115 22 107 50 8 134 388 388 18 25 22
31 (19—62) 167 (115—218) 64 (51—111) 95 (78—338) 52 (44—130) 63(54—93) 39 (23—91) 323 (313—385) 7 NA a 17
29 (22—70) 130 (53—277) 95 (80—108) 74 (63—84) 50 (22—65) 92 (61—129) 24 (18—35) 235 (216—300) NA a NA a 17
10
187 (16—307)
142 (84—162)
96 (61—233)
(23—233) (16—26) (42—354) (36—158) (3—64) (61—310) (3—999) (57—703)
2
655
176
86
HIV co-infections Hepatitis B Hepatitis C
1 1
88 6
26 62
56 NA a
Malignancies Non-Hodgkin lymphoma Lung cancer
4 1
115 (38—213) 108
65 (46—85) 79
50 (38—106) 790
Other non-HIV conditions Cardiac complications Viral myocarditis
3 1
136 (115—199) 3
91 (60—123) 65
162 (158—166) NA a
a
CD4 cell count at the time of initiating HAART and/or at the time of death was not available.
found that despite similar virological and immunological responses at both settings, patients in low-income countries started therapy with considerably more advanced immunodeficiency.9 Increasingly HIV-infected patients are gaining access to life-saving antiretrovirals across the developing world, however greater efforts must be made via proactive voluntary counseling and testing to identify HIV-infected patients and to then consequently initiate HAART among
patients meeting treatment criteria in order to minimize a still too high AIDS-associated mortality. Initiating patients on ART is never a medical emergency, but providing prompt early treatment for opportunistic infections can avert patient deaths. With the expanded provision of ART, it is possible that tuberculosis screening, prevention, and treatment can be combined with the provision of HIV care.24,25 A related question is whether HAART should be initiated earlier than current guidelines for the purpose of optimizing survival.26 Randomized trials are needed among HIV-infected patients with advanced immunodeficiency who may also have a high possibility of undetected opportunistic infections to examine if empirical anti-tuberculosis therapy and treatment for other common opportunistic infections will be beneficial along with the provision of HAART.
Acknowledgements
Figure 1 HAART.
Kaplan—Meier survival estimate after initiating
The authors are grateful to Ms Rasmi and Ms Glory, research nurses; Mr S. Anand, data manager; Mr Gurunathan and Mr Siva, data entry operators; and all the clinical staff at the YRG Centre for AIDS Research and Education, VHS, Chennai, India, for their facilitation of the study. We thank M. Deepak for the statistical assistance. The authors would like to thank Brown University’s AIDS International Research and Training
Deaths among HIV-infected South Indians Program of the Fogarty International Center at the National Institutes of Health (NIH), USA (grant No. D43TW00237) and ACTG-ICTU/NIH-Chennai site grant (U01 AI 069432) for supporting this study. Conflict of interest: No conflict of interest to declare.
References 1. Palella FJ, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. HIV Outpatient Study Investigators. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006;43:27—34. 2. Bonnet F, Morlat P, Che ˆne G, Mercie ´ P, Neau D, Chossat I, et al. Groupe d’Epide ´miologie Clinique du SIDA en Aquitaine (GECSA). Causes of death among HIV-infected patients in the era of highly active antiretroviral therapy, Bordeaux, France, 1998—1999. HIV Med 2002;3:195—9. 3. Yang C, Huang YF, Hsiao CF, Yeh YL, Liou HR, Hung CC, et al. Trends of mortality and causes of death among HIV-infected patients in Taiwan, 1984—2005. HIV Med 2008;9:535—43. 4. Krentz H, Kliewer G, Gill MJ. Changing mortality rates and causes of death for HIV-infected individuals living in Southern Alberta, Canada from 1984 to 2003. HIV Med 2005;6:99—106. 5. Sackoff J, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med 2006;145:397—406. 6. Saraceni V, King BS, Cavalcante SC, Golub JE, Lauria LM, Moulton LH, et al. Tuberculosis as primary cause of death among AIDS cases in Rio de Janeiro, Brazil. Int J Tuberc Lung Dis 2008;12:769—72. 7. Etard J, Ndiaye I, Thierry-Mieg M, Gue `ye NF, Gue `ye PM, Lanie `ce I, et al. Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study. AIDS 2007;20:1181—9. 8. Casseb J, Fonseca LA, Veiga AP, de Almeida A, Bueno A, Ferez AC, et al. AIDS incidence and mortality in a hospital-based cohort of HIV-1-seropositive patients receiving highly active antiretroviral therapy in Sa ˜o Paulo, Brazil. AIDS Patient Care STDS 2003;17: 447—52. 9. Braitstein P, Brinkhof MW, Dabis F, Schechter M, Boulle A, Miotti P, et al. Antiretroviral Therapy in Lower Income Countries (ARTLINC) Collaboration; ART Cohort Collaboration (ART-CC) groups. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and highincome countries. Lancet 2006;367:817—24. 10. Kumarasamy N, Solomon S, Chaguturu SK, Mahajan AP, Flanigan TP, Balakrishnan P, et al. The safety, tolerability, and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India. AIDS 2003;17:2265—71. 11. Kumarasamy N, Solomon S, Flanigan TP, Hemalatha R, Thyagarajan SP, Mayer KH. Natural history of human immunodeficiency virus disease in southern India. Clin Infect Dis 2003;36:79—85. 12. Kumarasamy N, Solomon S, Chaguturu SK, Cecelia AJ, Vallabhaneni S, Flanigan TP, et al. The changing natural history of HIV disease: before and after the introduction of generic antiretroviral therapy in southern India. Clin Infect Dis 2005;41:1525—8. 13. Sobhani R, Basavaraj A, Gupta A, Bhave AS, Kadam DB, Sangle SA, et al. Mortality and clinical characteristics of hospitalized adult patients with HIV in Pune, India. Indian J Med Res 2007;162: 116—21.
e131 14. Teja V, Sudha T, Lakshmi V. Causes and pattern of mortality in HIV-infected, hospitalized patients in a tertiary care hospital: a fourteen year study. Indian J Med Sci 2007;61:555—61. 15. World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach 2006 revision. Geneva: WHO; 2006. Available at: http://www.who.int/hiv/pub/arv/adult/en/index.html (accessed May 2009). 16. World Health Organization. Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents, and adults in resource-limited settings: recommendations for a public health approach. Available at: http://www.who.int/hiv/ pub/guidelines/ctx/en/index.html (accessed May 2009). 17. Centers for Disease Control and Prevention. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871. htm (accessed May 2009). 18. Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK, CDC, National Institutes of Health, Infectious Diseases Society of America. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep 2004;53(RR15):1—112. 19. Semba R, Shah N, Klein RS, Mayer KH, Schuman P, Gardner LI, et al. Human Immunodeficiency Virus Epidemiology Research Study Group. Highly active antiretroviral therapy associated with improved anemia among HIV-infected women. AIDS Patient Care STDS 2001;15:473—80. 20. Semba R, Shah N, Klein RS, Mayer KH, Schuman P, Vlahov D, Human Immunodeficiency Virus Epidemiology Research Study Group. Prevalence and cumulative incidence of and risk factors for anemia in a multicenter cohort study of human immunodeficiency virus-infected and -uninfected women. Clin Infect Dis 2002;34:260—6. 21. Valdez H, Chowdhry TK, Asaad R, Woolley IJ, Davis T, Davidson R, et al. Changing spectrum of mortality due to human immunodeficiency virus: analysis of 260 deaths during 1995—1999. Clin Infect Dis 2001;32:1487—93. 22. Crum N, Riffenburgh RH, Wegner S, Agan BK, Tasker SA, Spooner KM, et al. Triservice AIDS Clinical Consortium. Comparisons of causes of death and mortality rates among HIV-infected persons: analysis of the pre-, early, and late HAART (highly active antiretroviral therapy) eras. J Acquir Immune Defic Syndr 2006;41: 194—200. 23. Jain M, Skiest DJ, Cloud JW, Jain CL, Burns D, Berggren RE. Changes in mortality related to human immunodeficiency virus infection: comparative analysis of inpatient deaths in 1995 and in 1999-2000. Clin Infect Dis 2003;36:1030—8. 24. Havlir D, Getahun H, Sanne I, Nunn P. Opportunities and challenges for HIV care in overlapping HIV and TB epidemics. JAMA 2008;300:423—30. 25. Golub J, Saraceni V, Cavalcante SC, Pacheco AG, Moulton LH, King BS, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS 2007;21:1441—8. 26. Wang C, Vlahov D, Galai N, Bareta J, Strathdee SA, Nelson KE, et al. Mortality in HIV-seropositive versus -seronegative persons in the era of highly active antiretroviral therapy: implications for when to initiate therapy. J Infect Dis 2004;190:1046—54.
http://intl.elsevierhealth.com/journals/ijid
Factors associated with mortality among HIV-infected patients in the era of highly active antiretroviral therapy in southern India N. Kumarasamy a,*, Kartik K. Venkatesh b, Bella Devaleenol a, S. Poongulali a, Tokugha Yephthomi a, A. Pradeep a, Suneeta Saghayam a, Timothy Flanigan b, Kenneth H. Mayer b, Suniti Solomon a a b
YRG Centre for AIDS Research and Education, Voluntary Health Services, Taramani, Chennai 600113, India Division of Infectious Diseases, Miriam Hospital, Brown University Medical School, Providence, Rhode Island, USA
Received 31 July 2008; accepted 31 March 2009 Corresponding Editor: William Cameron, Ottawa, Canada
KEYWORDS India; HIV; AIDS; Opportunistic infection; HAART; Mortality
Summary Objective: To describe the causes of mortality among the HIV-infected in southern India in the era of highly active antiretroviral therapy (HAART). Methods: Analyses of this patient cohort were conducted using the YRG Centre for AIDS Research and Education HIV Natural History Observational Database. Causes of death were then individually confirmed by patient chart review. Results: Sixty-nine deaths occurred within the inpatient unit; 25% were female and the median age of the 69 patients was 34 years. Over half of the patients (55%) died within three months of initiating HAART. At the time of enrollment into clinical care, the median CD4 cell count was 64 cells/ml (interquartile range (IQR) 37—134). At the time of initiating HAART, the median CD4 cell count was 58 cells/ml (IQR 31—67) for patients who died within 3 months of initiating HAART and 110 cells/ml (IQR 77—189) for patients who died more than 3 months after initiating HAART. Close to three-fourths of patients (70%) died from an AIDS-defining illness (ADI). The major ADI causes of death included Pneumocystis jiroveci pneumonia (22%), extrapulmonary tuberculosis (19%), CNS toxoplasmosis (12%), and pulmonary tuberculosis (10%). A tenth of patients died from cerebrovascular infarcts. Three patients (4%) died from non-Hodgkin lymphoma. Conclusions: AIDS-related events continue to be the major source of mortality among the HIVinfected in southern India in the era of HAART. This mortality pattern justifies increased proactive efforts to identify HIV-infected patients and initiate HAART earlier, before patients present to care with advanced immunodeficiency. # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +91 44 22542929; fax: +91 44 22542939. E-mail address: [email protected] (N. Kumarasamy). 1201-9712/$36.00 # 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.03.034
e128
Introduction Studies conducted in the developed world in the era of highly active antiretroviral therapy (HAART) have repeatedly documented that AIDS-related events are no longer the major causes of death.1—5 However the mortality pattern may vary in resource-limited settings where patients often present to clinical care with advanced immunodeficiency and where opportunistic infections, primarily tuberculosis, are rampant.6—9 Despite the fact that generic antiretroviral therapy (ART) is effective in resource-limited settings,10 investigating the emerging causes of death in the era of HAART can allow clinicians to preemptively manage the clinical complications of HIV-infected patients. Earlier studies have documented the changing natural history of HIV disease in the pre- and post-HAART eras in southern India.11,12 However, data remain limited on the causes of death among HIV-infected Indians, particularly in the HAART era.13,14 The current study was undertaken to determine the causes of death among the HIV-infected in southern India who had initiated HAART. The findings of the current study are timely in assessing whether the causes of mortality among HIV-infected patients in resource-limited settings have changed as an increasing number of HIVinfected patients gain access to HAART.
Methods
N. Kumarasamy et al. whose cause of death was assigned as cerebrovascular infarct underwent computed tomography (CT).
Definitions The 1993 Centers for Disease Control and Prevention (CDC) case definitions were used with definitive diagnostic methods for cryptosporidiosis, cryptococcosis, and Mycobacterium tuberculosis, and presumptive diagnostic methods for Pneumocystis jiroveci pneumonia (PCP), cytomegalovirus retinitis, and toxoplasmosis.17 The most recent National Institutes of Health (NIH) definitions of AIDS-associated AEs were employed for diagnosis.18 The primary cause of death was confirmed through patient chart review conducted by a staff physician.
Statistical analysis Descriptive statistics were calculated with mean and standard deviation for variables that were normally distributed; the median and interquartile range (IQR) were calculated for variables influenced by extreme variables. To compare proportions, Chi-square statistics and independent t-tests were used. Survival analysis after initiating HAART was conducted using the Kaplan—Meier method. All statistical analyses were performed using SPSS software (version 13.0; SPSS, Chicago, IL, USA). A p-value less than 0.05 was considered statistically significant.
Setting
Results The YRG Center for AIDS Research and Education (YRG CARE) in Chennai is a large non-profit medical and research institution. Since 1996, it has provided comprehensive care for over 12 000 HIV-infected individuals. All patients are treated according to World Health Organization (WHO) treatment guidelines.15 Co-trimoxazole prophylaxis was initiated for all patients as per WHO guidelines.16 Patients were advised to initiate antiretroviral therapy when CD4 counts reached <200 cells/ml or when CD4 counts ranged between 200 and 350 cells/ml with an AIDS-defining illness (ADI). Nevirapine (NVP)-based regimens, which are the least expensive and most widely available, were used in first-line therapies. Patients were seen every 3 months or as clinically indicated. CD4 monitoring was done every 3 to 6 months.
Patients Patients who were older than 18 years of age, attending the YRG CARE clinic between February 1996 and January 2008, and ART-naı¨ve before initiation of HAARTwere included in the analysis. Data were collected under the approval of YRG CARE’s free-standing institutional review board. Analyses used the YRG CARE HIV Natural History Observational Database.11,12 This database is updated daily by research nurses who are trained to use a validated prospective data collection instrument, which includes demographics; clinical assessments, current treatment regimens, and adverse events (AEs); laboratory data, including hemoglobin, liver and renal function tests, CD4 cell counts, and plasma viral load (PVL); and genotypic testing, if available. All patients
Between February 1996 and January 2008, 4848 ART-naı¨ve adult patients (>18 years of age) initiated HAART at YRG CARE. The median CD4 cell count at the time of initiating HAART was 142 cells/ml (IQR 65—261); the median time from enrollment to initiating HAART was 27 days (IQR 4—237). Among HAART initiated patients, 155 (3%) consequently died, and of these, 69 died within the inpatient unit. Only these 69 patients are included in the subsequent analyses. Twenty-five percent were female; the median age of all 69 patients was 34 years. Almost all participants (>95%) had acquired HIV infection through heterosexual transmission. The most common HAART regimens included: lamivudine (3TC) + stavudine (d4T) + nevirapine (NVP) (36%), 3TC + d4T + efavirenz (EFV) (33%), and 3TC + NVP + zidovudine (AZT) (6%). Over half (55%) of the patients died within 3 months of initiating HAART, 10% of patients died at between 3 and 6 months of initiating HAART, and 35% of patients died more than 6 months after initiating HAART (Table 1). At the time of enrollment into clinical care, the median CD4 cell count was 64 cells/ml (IQR 37—134) and the median hemoglobin was 9.7 g/dl (IQR 7.8—11.1). The most common opportunistic infections at enrollment were pulmonary tuberculosis (14%) and PCP (6%). At the time of initiating HAART, the median CD4 cell count was 58 cells/ml (IQR 31— 67) for patients who died within 3 months of initiating HAART and 110 cells/ml (IQR 77—189) for patients who died more than 3 months after initiating HAART; this difference was not statistically significant ( p = 0.07). The most common incident opportunistic infection after initiating HAART was pulmonary tuberculosis (6%). The most common AEs to therapy
Deaths among HIV-infected South Indians
e129
Table 1 Demographic and clinical characteristics of patients at enrollment to care and at initiation of highly active antiretroviral therapy (HAART) (N = 69) Characteristic
Median (IQR) or %
Men Women Age, years
75% 25% 34 (29—39)
At enrollment to care CD4 cell count, cells/ml Hemoglobin, g/dl Opportunistic infections Pulmonary tuberculosis Extrapulmonary tuberculosis Tuberculous meningitis Cryptococcal meningitis Pneumocystis pneumonia Toxoplasmosis Progressive multifocal leukoencephalopathy Hepatitis B virus Hepatitis C virus Anemia Non-Hodgkin lymphoma Median duration on HAART (months)
death compared to patients who died within 3 months of initiating HAART (138 cells/ml vs. 59 cells/ml; p = 0.04). Patients who died more than 3 months after initiating HAART and patients who died within 3 months of initiating HAART did not experience statistically significant differences in median duration of hospitalization at the time of death nor in the incidence of opportunistic infections.
Discussion 64 (37—134) 9.7 (7.8—11.1) 14% 1% 1% 1% 6% 1% 1% 3% 3% 4% 1% 5.35
CD4 cell count at the time of initiating HAART, cells/ml Died <3 months 58 (31—67) Died >3 months 110 (77—189) After initiating HAART Incident infections Pulmonary tuberculosis Toxoplasmosis Cryptococcal meningitis Pneumocystis jiroveci pneumonia Extrapulmonary tuberculosis Adverse events to therapy Anemia Nausea Diarrhea Hepatitis/hepatotoxicity Immune reconstitution syndrome
17% 14% 12% 4% 3%
Died after initiating HAART 0—3 months of initiating HAART 3—6 months of initiating HAART >6 months of initiating HAART
55% 10% 35%
6% 3% 1% 3% 3%
IQR, interquartile range.
included anemia (17%), nausea (14%), and diarrhea (12%). The median duration on HAART was 5 months (Table 1). Table 2 outlines the reasons for death, median time of treatment prior to death, and median CD4 at the time of initiating HAART and at the time of death for the 69 patients. The major ADI causes of death included PCP (22%), extrapulmonary tuberculosis (19%), CNS toxoplasmosis (12%), and pulmonary tuberculosis (10%). A tenth of patients died from cerebrovascular infarcts. Three patients (4%) died from nonHodgkin lymphoma. Patients who died more than 3 months after initiating HAART had significantly higher CD4 cell counts at the time of
The present study documents that in the era of HAART in southern India, AIDS-related illnesses (70%) continue to be the major source of patient mortality. The high frequency of death due to ADIs, particularly tuberculosis, can be attributed to a low median CD4 cell count at the time of initiating ART. A study among West African HIV patients similarly documented a high mortality soon after initiating HAART and the leading role of mycobacterial infections as a cause of death.7 Many of the patients in the current study also had low hemoglobin levels after initiating HAART, confirming the strong relationship between anemia and death.19,20 The findings of the current study contrast with recent studies conducted in developed countries, in which improvements in HIV treatment have led to proportionately fewer deaths from ‘typical’ HIV-related illnesses and increasing deaths attributable to cardiac disease, trauma, and liver disease.1,3,21,22 We documented a high frequency of bacterial and fungal infections in the time period before the immune restorative effects of HAART, with Mycobacterium tuberculosis and PCP accounting for half of all patient deaths (see Figure 1). A recent study from Brazil identified tuberculosis as the leading cause of death (9%), which was responsible for more than twice as many deaths as PCP (5%).6 A retrospective analysis among HIV-infected patients in the USA found that PCP was the major cause of death in the era of HAART, which was attributed to the fact that more than 50% of patients who died were not receiving HAART.23 Timely prophylaxis and effective treatment of opportunistic infections must be an integral part of any antiretroviral treatment program, especially in resource-limited settings where opportunistic infections are rampant. The current analyses were limited to inpatient causes of death. Though three-fourths of patients who died were men, three-fourths of all patients who initiated HAART were also men. Prior studies at our center have documented that men tend to present to care with advanced immunodeficiency, and women are diagnosed earlier due to screening of partners (symptomatic men) or as part of antenatal testing.11,12 Though we documented the number of deaths occurring outside of the clinic, the definitive causes of death could not be obtained at the time of death and hence these cases were excluded from this analysis. Discernment of the precise causes of death is always a challenge. Routine autopsies are not performed at our institution; however, we undertook a thorough analysis of all available clinical and laboratory data to confirm the cause of death. The findings of the present study suggest that despite the wider introduction of HAART in resource-limited settings, mortality continues to occur due to advanced immunodeficiency soon after starting therapy. A study comparing mortality patterns between high- and low-income countries
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N. Kumarasamy et al.
Table 2 Causes of death and median CD4 cell count at the time of initiating highly active antiretroviral therapy (HAART) and at the time of death (N = 69) Reason for death
HIV-associated conditions Mycobacterium tuberculosis Pulmonary Meningitis Abdominal Other extrapulmonary Pneumocystis jiroveci pneumonia CNS toxoplasmosis Cryptococcal meningitis Cryptosporidial diarrhea Viral encephalitis Bacterial meningitis Progressive multifocal leukoencephalopathy Cerebrovascular infarct (neurological complication) Bacteremia
Frequency (%)
Median patient days of treatment (IQR)
Median CD4 at time of initiating HAART (IQR), cells/ml
Median CD4 at time of death (IQR), cells/ml
10 6 9 4 22 12 6 3 1 1 1
115 22 107 50 8 134 388 388 18 25 22
31 (19—62) 167 (115—218) 64 (51—111) 95 (78—338) 52 (44—130) 63(54—93) 39 (23—91) 323 (313—385) 7 NA a 17
29 (22—70) 130 (53—277) 95 (80—108) 74 (63—84) 50 (22—65) 92 (61—129) 24 (18—35) 235 (216—300) NA a NA a 17
10
187 (16—307)
142 (84—162)
96 (61—233)
(23—233) (16—26) (42—354) (36—158) (3—64) (61—310) (3—999) (57—703)
2
655
176
86
HIV co-infections Hepatitis B Hepatitis C
1 1
88 6
26 62
56 NA a
Malignancies Non-Hodgkin lymphoma Lung cancer
4 1
115 (38—213) 108
65 (46—85) 79
50 (38—106) 790
Other non-HIV conditions Cardiac complications Viral myocarditis
3 1
136 (115—199) 3
91 (60—123) 65
162 (158—166) NA a
a
CD4 cell count at the time of initiating HAART and/or at the time of death was not available.
found that despite similar virological and immunological responses at both settings, patients in low-income countries started therapy with considerably more advanced immunodeficiency.9 Increasingly HIV-infected patients are gaining access to life-saving antiretrovirals across the developing world, however greater efforts must be made via proactive voluntary counseling and testing to identify HIV-infected patients and to then consequently initiate HAART among
patients meeting treatment criteria in order to minimize a still too high AIDS-associated mortality. Initiating patients on ART is never a medical emergency, but providing prompt early treatment for opportunistic infections can avert patient deaths. With the expanded provision of ART, it is possible that tuberculosis screening, prevention, and treatment can be combined with the provision of HIV care.24,25 A related question is whether HAART should be initiated earlier than current guidelines for the purpose of optimizing survival.26 Randomized trials are needed among HIV-infected patients with advanced immunodeficiency who may also have a high possibility of undetected opportunistic infections to examine if empirical anti-tuberculosis therapy and treatment for other common opportunistic infections will be beneficial along with the provision of HAART.
Acknowledgements
Figure 1 HAART.
Kaplan—Meier survival estimate after initiating
The authors are grateful to Ms Rasmi and Ms Glory, research nurses; Mr S. Anand, data manager; Mr Gurunathan and Mr Siva, data entry operators; and all the clinical staff at the YRG Centre for AIDS Research and Education, VHS, Chennai, India, for their facilitation of the study. We thank M. Deepak for the statistical assistance. The authors would like to thank Brown University’s AIDS International Research and Training
Deaths among HIV-infected South Indians Program of the Fogarty International Center at the National Institutes of Health (NIH), USA (grant No. D43TW00237) and ACTG-ICTU/NIH-Chennai site grant (U01 AI 069432) for supporting this study. Conflict of interest: No conflict of interest to declare.
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