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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

YRG Centre for AIDS Research and Education, Voluntary Health Services, Taramani, Chennai 600113, India

b

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

International Journal of Infectious Diseases (2010) 14, e127—e131

http://intl.elsevierhealth.com/journals/ijid 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 indivi-dually 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 cerebro-vascular infarcts. Three patients (4%) died from non-Hodgkin lymphoma.

Conclusions: AIDS-related events continue to be the major source of mortality among the HIV-infected 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:kumarasamy@yrgcare.org(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

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Introduction

Studies conducted in the developed world in the era of highly active antiretroviral therapy (HAART) have repeatedly docu-mented that AIDS-related events are no longer the major causes of death.1—5However 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 ram-pant.6—9Despite the fact that generic antiretroviral therapy (ART) is effective in resource-limited settings,10investigating 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 HIV-infected patients gain access to HAART.

Methods

Setting

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.16Patients 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 Data-base.11,12This database is updated daily by research nurses who are trained to use a validated prospective data collec-tion 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

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 Pneu-mocystis jiroveci pneumonia (PCP), cytomegalovirus retini-tis, and toxoplasmosis.17The 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 stan-dard deviation for variables that were normally distributed; the median and interquartile range (IQR) were calculated for variables influenced by extreme variables. To compare pro-portions, 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.

Results

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 inci-dent opportunistic infection after initiating HAART was pul-monary tuberculosis (6%). The most common AEs to therapy

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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%), extra-pulmonary 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.

Patients who died more than 3 months after initiating HAART had significantly higher CD4 cell counts at the time of

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

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.7Many 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 improve-ments 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.1,3,21,22We documented a high frequency of bacterial and fungal infections in the time period before the immune restorative effects of HAART, with Mycobacterium tubercu-losis 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%).6A 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, espe-cially in resource-limited settings where opportunistic infec-tions 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 immunodefi-ciency soon after starting therapy. A study comparing mor-tality patterns between high- and low-income countries

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 75%

Women 25%

Age, years 34 (29—39)

At enrollment to care

CD4 cell count, cells/ml 64 (37—134)

Hemoglobin, g/dl 9.7 (7.8—11.1) Opportunistic infections Pulmonary tuberculosis 14% Extrapulmonary tuberculosis 1% Tuberculous meningitis 1% Cryptococcal meningitis 1% Pneumocystis pneumonia 6% Toxoplasmosis 1% Progressive multifocal leukoencephalopathy 1% Hepatitis B virus 3% Hepatitis C virus 3% Anemia 4% Non-Hodgkin lymphoma 1%

Median duration on HAART (months) 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 6%

Toxoplasmosis 3%

Cryptococcal meningitis 1%

Pneumocystis jiroveci pneumonia 3% Extrapulmonary tuberculosis 3% Adverse events to therapy

Anemia 17%

Nausea 14%

Diarrhea 12%

Hepatitis/hepatotoxicity 4%

Immune reconstitution syndrome 3% Died after initiating HAART

0—3 months of initiating HAART 55% 3—6 months of initiating HAART 10% >6 months of initiating HAART 35%

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found that despite similar virological and immunological responses at both settings, patients in low-income countries started therapy with considerably more advanced immuno-deficiency.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 infec-tions 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

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

Figure 1 Kaplan—Meier survival estimate after initiating HAART.

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 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 HIV-associated conditions Mycobacterium tuberculosis Pulmonary 10 115 (23—233) 31 (19—62) 29 (22—70) Meningitis 6 22 (16—26) 167 (115—218) 130 (53—277) Abdominal 9 107 (42—354) 64 (51—111) 95 (80—108) Other extrapulmonary 4 50 (36—158) 95 (78—338) 74 (63—84)

Pneumocystis jiroveci pneumonia 22 8 (3—64) 52 (44—130) 50 (22—65)

CNS toxoplasmosis 12 134 (61—310) 63(54—93) 92 (61—129) Cryptococcal meningitis 6 388 (3—999) 39 (23—91) 24 (18—35) Cryptosporidial diarrhea 3 388 (57—703) 323 (313—385) 235 (216—300) Viral encephalitis 1 18 7 NAa Bacterial meningitis 1 25 NAa NAa Progressive multifocal leukoencephalopathy 1 22 17 17 Cerebrovascular infarct (neurological complication) 10 187 (16—307) 142 (84—162) 96 (61—233) Bacteremia 2 655 176 86 HIV co-infections Hepatitis B 1 88 26 56 Hepatitis C 1 6 62 NAa Malignancies Non-Hodgkin lymphoma 4 115 (38—213) 65 (46—85) 50 (38—106) Lung cancer 1 108 79 790

Other non-HIV conditions

Cardiac complications 3 136 (115—199) 91 (60—123) 162 (158—166)

Viral myocarditis 1 3 65 NAa

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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 sup-porting this study.

Conflict of interest: No conflict of interest to declare.

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