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. Author manuscript; available in PMC: 2018 May 12.
Published in final edited form as: J Int Assoc Provid AIDS Care. 2017 Apr 12;16(5):475–480. doi: 10.1177/2325957417702485

The Epidemiology of IRIS in Southern India: An Observational Cohort Study

Nisha Thambuchetty 1, Kayur Mehta 2, Karthika Arumugam 3, Umadevi G Shekarappa 4, Jyothi Idiculla 5, Anita Shet 6
PMCID: PMC5949067  EMSID: EMS77637  PMID: 28399724

Abstract

Immune reconstitution inflammatory syndrome (IRIS) is an uncommon but dynamic phenomenon seen among patients initiating antiretroviral therapy (ART). We aimed to describe incidence, risk factors, clinical spectrum, and outcomes among ART-naive patients experiencing IRIS in southern India. Among 599 eligible patients monitored prospectively between 2012 and 2014, there were 59.3% males, with mean age 36.6 ± 7.8 years. Immune reconstitution inflammatory syndrome incidence rate was 51.3 per 100 person-years (95% confidence interval: 44.5-59.2). One-third (31.4%) experienced at least 1 IRIS event, at a median of 27 days since ART initiation. Mucocutaneous infections and candidiasis were common IRIS events, followed by tuberculosis. Significant risk factors included age >40 years, body mass index <18.5 kg/m2, CD4 count <100 cells/mm3, viral load >10 000 copies/mL, hemoglobin <1 g/dL, and erythrocyte sedimentation rate >50 mm/h. Immune reconstitution inflammatory syndrome–related morality was 1.3% (8 of 599); 3 patients died of complicated diarrhea. These findings highlight the current spectrum of IRIS in South India and underscore the importance of heightened vigilance for anemia and treatment of diarrhea and candidiasis during ART initiation.

Keywords: HIV, AIDS, IRIS, candidiasis, anemia

Introduction

With the advent of combination antiretroviral therapy (ART), a substantial reduction in the occurrence of opportunistic events and mortality in patients with HIV has been observed. The beneficial effects of ART arise from gradual restoration of pathogen-specific immune responses mediated by suppressed viral replication and increased CD4 count.1,2 However, one challenge that is often faced during the first half year after ART initiation, particularly in individuals with advanced immunosuppression, is immune reconstitution inflammatory syndrome (IRIS), which can increase morbidity and sometimes mortality.3 Immune reconstitution inflammatory syndrome is a common phenomenon that occurs in a subgroup of HIV-infected patients who, after the initiation of ART, experience a clinical deterioration with unusual or florid inflammatory features due to a rapid restoration of the inflammatory response associated with immune recovery.4 This phenomenon has been described under various descriptions such as “paradoxical reaction,” “immune restoration disease,” “highly active antiretroviral therapy attacks,” “immune reconstitution syndrome,” and mostly commonly, “IRIS.”5–7 Immune reconstitution inflammatory syndrome is generally a consequence of exaggerated activation of the immune system against persistent antigen (paradoxical IRIS) or viable pathogens (unmasking IRIS).8,9 Immune reconstitution inflammatory syndrome has been described for multiple infectious and noninfectious diseases, tumors, and autoimmune conditions but most commonly tuberculosis (TB), Cryptococcus, Kaposi sarcoma, and herpes zoster.10 The epidemiology of IRIS described in different populations has overlapping risk factors, with the most frequently described being high viral load and low CD4 count.10 The proportion of patients starting ART who develop IRIS is variable, with estimates ranging from less than 10% to more than 50%.10–12

A vast majority of available literature on IRIS is from high-income countries.13,14 Declining ART costs, generic production of ART, and expansion of national programs to combat HIV have now resulted in a large number of infected patients in low- and middle-income countries also being able to access ART. With increasing coprevalence of opportunistic infections and access to ART in Indian settings, we conducted this observational cohort study to describe the epidemiology of IRIS, including incidence, clinical spectrum, risk factors, and clinical outcomes, among ART-naive patients in India initiating ART.

Methods

Patients were recruited prospectively from the Infectious Diseases Clinic at St John’s Medical College Hospital, a tertiary care medical facility in Bangalore, Karnataka, India. Patients included were ART-naive adults who were deemed eligible for ART initiation according to the existing 2013 national guidelines to start ART, that is, CD4 count <350 cells/mm3 or World Health Organization (WHO) clinical stage 3 or 4.15 Those patients who developed hypersensitivity to ART, were currently pregnant, or refused to consent to the study were excluded from the study. Following informed consent, patients were enrolled in the study and monitored at initiation of ART and then at intervals of 2, 4, 8, and 12 weeks and then every 3 months for the first 6 months after ART initiation. At the initial visit, patients were counseled to call the clinic if they experienced any symptoms and were seen at the clinic between study visits if necessary. The ART regimen consisted of a triple combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) that included zidovudine ([ZDV] or tenofovir [TDF]) plus lamivudine (3TC) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz (EFV) or nevirapine (NVP), per the existing national guidelines.15 The CD4 count and viral load tests along with a complete blood count, liver function tests, lipid profile, renal function tests, and urine analysis were performed at the baseline visit prior to ART initiation and 6 months after ART initiation. At each visit, the patients were seen by a physician and monitored clinically; additional blood tests were done only if clinically indicated.

Immune reconstitution inflammatory syndrome was defined as a medical event that fulfilled the following criteria: (1) HIV-related clinical events such as WHO stage 2, 3, or 4 conditions, (2) the event occurred during the first 7 to 180 days after initiating ART, and (3) an evidence of immune reconstitution as measured by a CD4 count rise of 25 cells/mm3 or viral load decline by 0.5 log10 copies within 6 months of ART initiation.13 During the study, an individual was defined as having active TB if he or she had symptoms of TB plus radiologic or microbiological evidence suggestive of TB.8

Incidence rate and risk of events, time to event, and outcomes were calculated for the IRIS and non-IRIS clinical events. Univariate and multivariate analyses of IRIS predictors included patient characteristics such as age, sex, nutritional status, ART regimen, CD4 count, and HIV-1 RNA viral load. Body mass index (BMI) <18.5 kg/m2, CD4 count <100 cells/mm3, and HIV-1 RNA viral load >10 000 copies/mL were included as continuous variables in the model. Appropriately, parametric or nonparametric tests were used to find the factors that were uniquely associated (P < .05) with the IRIS event. Those significant factors were included in the multivariate model to find the true risk factors of the event.

Ethical Considerations

Ethical clearance was obtained from the institutional ethical review board of St John’s Medical College Hospital (IERB/1/682/2010), and written informed consent was taken from all participants. All patients were given standard clinical care and counseling per the national guidelines.15

Results

Between March 2012 and September 2014, a total of 627 eligible patients were initiated on ART at our clinic. Among them, 18 declined consent at study initiation, whereas 5 withdrew consent within a month, citing lack of time to answer extra questions related to the study. Two patients died prior to ART initiation, and 3 were transferred to a clinic in a different district. The remaining 599 patients were enrolled in the study and monitored for the first 6 months following the initiation of ART. Study visits were missed by 6 patients, although all patients were seen at 6 months. There were 32 (5.3%) individuals who were diagnosed with TB and were taking anti-TB medications at the time of ART initiation. In addition, there were 18 (3%) individuals who were previously diagnosed with pulmonary and extra pulmonary TB within the past 2 years and who had received anti-TB treatment during the period prior to ART initiation. The baseline characteristics of the patients enrolled in the study are mentioned in Table 1. The mean age of the participants was 36.6 ± 7.8 years, and males constituted 59.3%. At baseline, prior to ART initiation, the mean CD4 count was 210 ± 89 cells/mm3 and mean log viral load was 5.39 ± 0.82 copies/mL. Antiretroviral therapy regimens were dispensed according to national guidelines, and the preferred first-line ART regimens changed from predominantly ZDV-based to TDF-based regimen in December 201316; 50.6% (303 of 599) were on ZDV-based regimen, and 8.0% (48/599) on stavudine (d4T)-based regimen, and 41.4% (248 of 599) were on TDF-based regimen. The NNRTI component was NVP in 63.9% (383 of 599) and EFV in 36.2% (217 of 599) of the cases.

Table 1.

Baseline Characteristics of Patients with IRIS.

Parameters IRIS, n = 188 Non-IRIS, n = 411 Bivariate
 Multivariate
OR (95% CI) P Value OR (95% CI) P Value
Age
    ≥40 years   72 (37.1) 122 (62.9) 1.47 (1.02-2.11)   .04a 1.40 (0.96-2.04)   .08
    <40 years 116 (28.6) 289 (71.4)
Sex
    Male 115 (33.5) 228 (66.5) 1.26 (0.89-1.80) .19 –   –
    Female   73 (28.5) 183 (71.5)
CD4 count
    <100 cells/mm3   63 (45.3)   76 (54.7) 2.22 (1.50-3.29)       <.001a 1.71 (1.12-2.60)     .01a
    ≥100 cells/mm3 125 (27.2) 335 (72.8)
VL, copies/mL
    >10 000 151 (34.0) 293 (66.0) 1.64 (1.08-2.50)   .02a 1.22 (0.78-1.91) .4
    ≤10 000   37 (23.9) 118 (76.1)
Anemia
    Hb < 11 g/dL   72 (43.6)   93 (56.4) 2.12 (1.46-3.08)       <.001a 1.68 (1.11-2.55)     .02a
    Hb ≥ 11 g/dL 116 (26.7) 318 (73.3)
BMI
    ≥18.5 kg/m2   70 (37.0) 119 (63.0) 1.46 (1.01-2.10)   .04a 1.20 (0.81-1.77) .4
    ≥18.5 kg/m2 118 (28.8) 292 (71.2)
ESR
    ≥50 mm/h 101 (39.8) 153 (60.2) 1.97 (1.39-2.80)       <.001a 1.34 (0.90-2.00) .2
    <50 mm/h   86 (25.1) 257 (74.9)
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Abbreviations: BMI, body mass index; CI, confidence interval; ESR, erythrocyte sedimentation rate; IRIS, immune reconstitution inflammatory syndrome; OR, odds ratio; VL, viral load.

a

Statistically significant.

Over a period of 6 months, the proportion of patients who experienced at least 1 IRIS event was 31.4% (188 of 599). The observed incidence rate of IRIS in this setting was 51.3 per 100 person-years (95% confidence interval [CI]: 44.5-59.2), and the median duration from ART initiation to the development of IRIS was 27 days, where 50% of the occurrences were within 14 to 58 days (Figure 1). The most common manifestation was candidiasis, which occurred in 28.2% of patients (53 of 188), with over three-quarter of these events occurring within the first 3 weeks (Table 2). Among those patients who developed candidiasis IRIS, 6 individuals had a prior history of oral candidiasis and had either initiated or completed antifungal treatment prior to ART initiation; these events (11.3%, 6 of 53) were considered as “paradoxical candidiasis IRIS events.” Four of all total candidiasis IRIS events were esophageal candidiasis, whereas the remaining 49 events were oral candidiasis. Pulmonary TB occurred in 5.9% (11 of 188) patients, whereas tuberculous lymphadenitis (11.7%), abdominal TB (4.7%), and tuberculous meningitis (2.1%) were also noted. Overall, TB caused 23.9% (45 of 188) of all IRIS events. Of these, 8 took place among those already on anti-TB therapy and 3 were among those who had a history of TB in the past 2 years; these were termed “paradoxical” IRIS (24.4%, 11 of 45). The remaining TB-IRIS events (75.6%, 34/45) were termed as “unmasking” IRIS as there was no evidence of the infection prior to starting ART. Diarrhea was a notable manifestation occurring in 8.5% (16 of 188) of patients. There were 3 cases of cryptococcal meningitis (1.6%) that occurred in patients between the fourth and sixth week after ART initiation; these were all classified as “ART-associated cryptococcal IRIS” as there was no evidence of cryptococcosis prior to starting ART.9 Other IRIS manifestations included pneumocystis pneumonia (2.7%) and bacterial pneumonia (1.1%). Immune reconstitution folliculitis presenting as a papular or pustular eruption resembling impetigo occurred in 15.9% (30 of 188) of patients, and viral mucocutaneous IRIS (genital herpes and warts) was seen among 5.9% (11 of 188) patients. Oral mucocutaneous herpes simplex was seen in 4.3%; herpes zoster was a manifestation in 5.9% of patients. Thus, a total of 33.0% (62 of 188) of all IRIS events consisted of relatively minor skin manifestations.

Figure 1.

Figure 1

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Kaplan-Meier curve with cumulative cases of immune reconstitution inflammatory syndrome (IRIS), diagnosed among antiretroviral therapy (ART)-naive patients with HIV, initiating ART.

Table 2.

Frequency of Manifestations of IRIS Events, with Time to Event.

IRIS Eventa, n = 188 Frequencya Percentage Time to IRIS Event (Days), Median (q1-q3)
Candidiasis 53 (11—paradoxical candidiasis IRIS) 28.2   21 (14-37)
Skin infections 30 16.0     58 (28-112)
Diarrhea 16   8.5     45 (24-115)
Tuberculous lymphadenitis 22 (5—paradoxical IRIS) 11.7   14 (13-30)
Pulmonary tuberculosis 11 (6—paradoxical IRIS)   5.9   16 (14-28)
Abdominal tuberculosis 8   4.3   23 (15-32)
Tuberculous meningitis 4   2.1   52 (33-68)
Cryptococcal meningitis 3   1.6   14 (13-57)
Pneumocystis pneumonia 5   2.7 26 (9-28)
Mucocutaneous lesions 11   5.9   29 (13-85)
Herpes zoster 11   5.9   28 (24-50)
Herpes simplex 8   4.3     25 (17-110)
Pneumonia 2   1.1     87 (25-148)
Conjunctivitis 2   1.1   58 (56-60)
CMV gastrointestinal infection 2 1.1   17 (16-18)
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Abbreviations: ART, antiretroviral therapy; CMV, cytomegalovirus; IRIS, immune reconstitution inflammatory syndrome.

a

All IRIS events were considered as ART-associated or “unmasking” IRIS, except those indicated in parentheses.

Most of the IRIS events (58.5%) occurred within the first 4 weeks of ART initiation, and 81.4% of the events took place within the first 3 months. The first month after starting ART was eventful for the occurrence of a majority of candidiasis-related IRIS (77%), pulmonary TB (64%), and tuberculous lymphadenitis (73%). All of the pneumocystis pneumonia and cryptococcal meningitis events took place within the first 8 weeks of ART. Among the 599 patients who were initiated on ART, 17 died within the first 6 months of ART initiation (overall mortality 2.8%). Of the 17 deaths, IRIS was associated with 8 deaths, thus resulting in IRIS-related mortality of 1.3% in the first 6 months. The causes of death in these patients were severe diarrhea leading to dehydration and acute renal failure (n = 3), disseminated TB (n = 2), cryptococcal meningitis (n = 2), and tubercular meningitis (n = 1). Of all IRIS events, 4.3% (8 of 188) resulted in death.

On univariate analysis, significant baseline parameters for increased risk of IRIS were age ≥40 years, BMI <18.5 kg/m2, CD4 count <100 cells/mm3, viral load >10 000 copies/mL, hemoglobin <11 g/dL, and erythrocyte sedimentation rate ≥50 mm/h (Table 1). There was no change in IRIS incidence or pattern with different drug regimens. On multivariate logistic regression analysis, we found that IRIS was independently associated with CD4 count <100 cells/mm3 (odds ratio [OR]: 1.70; 95% CI: 1.12-2.59) and Hb <11 g/dL (OR: 1.68; 95% CI: 1.11-2.55).

Discussion

Our study showed IRIS as a prominent manifestation among individuals initiated on the first-line ART. Tuberculosis was earlier shown to be the most common form of IRIS described for a North Indian population,16 whereas recent studies done in South India by Kumarasamy et al17 and Kumar et al11 mentioned that mucocutaneous candidiasis was the most common form of IRIS, and our study reports similar findings from Bangalore. A third of IRIS-related events consisted of minor mucocutaneous manifestations. Although IRIS-related mortality was low, the finding of diarrhea as a cause of IRIS-related death warrants attention as diarrhea is potentially preventable and easily treatable if diagnosed early.

Immune reconstitution inflammatory syndrome can be seen as a condition in which the immune system improves after introduction of ART, but the rising reconstitution is exaggerated due to lack of homeostatic regulation.4 The most important risk factors for IRIS are a low baseline CD4 count, an excellent virological response, an increased antigenic burden of an opportunistic infection, and early initiation of ART after an opportunistic infection.13 The immunopathological process underlying IRIS is not fully understood, but data from clinicopathological and immunological studies suggest that IRIS results from exaggerated and dysregulated cellular immune responses that depend on the associated pathogen.18,19 It is postulated that Th1 (granulomatous inflammation) and possibly Th17 (suppurative inflammation) responses are seen in mycobacteria, fungi, and protozoans infections, and CD8 T-cell responses mounted against viruses.18 While the reported incidence of IRIS has varied considerably, it is important to note that the occurrence of IRIS events and their clinical outcomes in a given setting are dependent upon the relative incidence of various opportunistic infections and the access to quality health care. The infectious pathogens most frequently implicated in this syndrome are mycobacteria, varicella zoster, herpes viruses, and cytomegalovirus (CMV).20 Given the global distribution of TB, TB-IRIS is one of the common forms of IRIS worldwide.14 However, a recent trend being noted is a shift in the clinical spectrum of IRIS, which was reported in developed nations, and is now becoming apparent in resource-limited settings as well.16,17,21 Mucocutaneous IRIS, especially candidiasis, is being observed as an important condition in IRIS,4,17,22,23 and this observation was also noticed in our cohort, with over a quarter of the patients with IRIS presenting with mucosal candidiasis.

The overall mortality in IRIS is reported to be between 0% and 15%, with variability attributed to geography, associated opportunistic infections, baseline morbidity, and degree of immunosuppression.14 According to WHO estimates, the mortality rates during the first year of ART are high (7%-16%), declining progressively with advancing years following the initiation of ART.24 Recent studies on mortality have shown a decreasing trend in IRIS-related deaths.14,17 We report an IRIS-related mortality rate of 1.3%. Strict adherence to evidence-based guidelines for ART initiation, robust pre-ART screening for infections, and vigorous review and follow-up of suspected IRIS might be possible reasons for this low rate of IRIS-related mortality observed in our cohort.

Tuberculosis is the most important AIDS-related opportunistic infection globally and is the leading cause of HIV/AIDS-related mortality. The TB-IRIS is one of the common forms of IRIS, given the global distribution of the infection.24 The initiation of antitubercular treatment in a patient with HIV and TB coinfection results in clinical improvement. The subsequent introduction of ART is accompanied by recurrence or exacerbation of TB symptoms with new or worsening clinical signs of TB that often have a marked inflammatory component constituting the TB-IRIS spectrum. Both paradoxical and unmasking type of TB-IRIS have a wide range of clinical features, often involving multiple organ systems, which reflects widespread dissemination of Mycobacterium tuberculosis among those with profound immunosuppression.25 Risk factors identified for the development of TB-IRIS include a low CD4 count prior to ART and a shorter interval between starting TB treatment and ART.26,27 Numerous studies done previously in resource-limited settings on the association of TB-IRIS, as well as our findings showing that two-thirds of the TB-IRIS events were “unmasking” TB infections, emphasize the need for early recognition and treatment of TB in those with newly diagnosed HIV.17,25 Strategies such as intense pre-ART TB case finding and delaying ART initiation for a minimum of 2 weeks during stabilization of antitubercular treatment have probably led to the overall decrease in both morbidity and mortality due to TB-IRIS.

Anemia has been previously described more commonly as a complication of ART as opposed to a risk factor for IRIS.28 In our study, we found that when adjusted for covariates using multiple logistic regression, CD4 count and low hemoglobin (<11 g/dL) were found to be significant risk factors for the subsequent development of IRIS. This is similar to the risk factors described by Kumar et al17 and also a study done in 2012 in South Africa, which is also a resource-limited and TB-burdened setting, described by Haddow et al,23 showing mild anemia as a risk factor for IRIS in their population. The prevalence of anemia in HIV/AIDS population has been estimated to be between 63% and 95%.29 In this setting of a highly anemic population and vulnerable to anemia population, hemoglobin levels should be routinely screened, especially in newly diagnosed patients with HIV; and awareness of anemia as a risk factor for IRIS could potentially reduce its incidence and associated morbidity.

Another interesting observation from our study is the relatively high incidence of diarrhea-related IRIS events. More than a third of all deaths (3 of 8) due to IRIS were attributed to diarrhea and subsequent dehydration. A wide spectrum of infectious organisms including viruses such as CMV, rotavirus, adenovirus, and astrovirus; bacteria including Escherichia coli, Salmonella species, Shigella species, Clostridium difficile, Campylobacter jejuni, and Mycobacterium avium complex and parasites such as Entamoeba histolytica and Giardia lamblia; and opportunists like Microsporidia, Cyclospora, Isospora belli, and Cryptosporidium parvum is known to cause diarrhea, sometimes associated with chronicity in HIV-positive patients. This high incidence of diarrhea in our settings could possibly be attributed to the lack of easy access to potable water and poor hygienic practices. These findings call for further emphasis on good hygienic practices during counseling, which has proven to be an effective tool in the prevention of potential infections that could present as IRIS.

The larger interpretation of this study needs to consider certain potential limitations. As this is a single-center study, the results may not be immediately generalizable to the rest of the population. Also, in many instances, the diagnostic procedures in the months preceding ART initiation were limited, and opportunistic infections may not have been identified.

In conclusion, our findings suggest that IRIS still plays a considerable role in morbidity among patients initiating ART in India. Although IRIS-related mortality is low, better measures to recognize and treat anemia, diarrhea, and candidiasis during the early days of ART initiation, as well as intense case finding of TB and treatment initiation prior to ART will further help in reducing IRIS and associated mortality among naive patients initiating ART in our settings.

Acknowledgments

The authors thank the staff at the ART Center, St John’s Medical College Hospital, for their excellent teamwork and patient care. The authors acknowledge the National AIDS Control Organisation (NACO), Government of India, and the Karnataka AIDS Prevention Society (KSAPS) for providing support for these patients. The authors are ever grateful to the study patients for participating in this study. The authors acknowledge partial support from the Wellcome Trust/Department of Biotechnology India Alliance Senior Fellowship (IA/S/13/2/501017) awarded to AS.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was partially supported by Wellcome Trust/Department of Biotechnology India Alliance Senior Fellowship (IA/S/13/2/501017).

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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