Since its introduction, antiretroviral therapy (ART) has led to significant declines in the incidence of AIDS-associated opportunistic illness (OI) mediated through adequate immune reconstitution [1,2]. However, some patients initiating ART experience clinical deterioration and unique reactions to opportunistic pathogens during immune recovery . These symptoms are the result of an inflammatory response or ‘dysregulation’ of the immune system to a variety of subclinical OI and residual OI antigens [3–8]. When clinical deterioration occurs during immune recovery and is associated with the host inflammatory response to pathogens, the clinical presentation has been termed the immune reconstitution inflammatory syndrome (IRIS) .
To date, studies report 17–32% of patients initiating ART will develop IRIS [3,10–12]. Previous studies have been limited by their retrospective nature, variations in OIs investigated, differences in case definitions, and differences in study populations. Importantly, few have estimated the incidence of IRIS and its impact on ART care in sub-Saharan Africa where the burden of OIs, such as tuberculosis, is high.
In addition, the retrospective nature of previous studies has limited our insight into the immunopathogenesis of the syndrome. While some studies cite significant quantitative differences in CD4 profiles or HIV RNA levels at baseline or over the course of therapy between IRIS and non-IRIS subjects [3,10–13], others have observed only trends or no significant differences between groups [7,14].
We conducted a prospective study in an HIV-infected cohort in South Africa to determine IRIS incidence during the first 6 months following the initiation of ART, to characterize its clinical manifestations, and to identify baseline risk factors. We also performed a nested case–control study to further our understanding of the immunopathogenesis of the syndrome.
All adult patients (> 18 years) participated in the prospective surveillance cohort if they were ART-naive (except for single dose nevirapine for prevention of mother-to-child transmission) at the time they initiated therapy at the Johannesburg Hospital adult or maternal HIV clinics between 6 January 2006 and 7 July 2006. Treatment initiation was in accordance with the South African National Antiretroviral Treatment Guidelines , which define ART initiation criteria as CD4 cell count ≤ 200 cells/μl or WHO stage IV AIDS-defining illness irrespective of CD4 cell count. Enrollment into the nested case–control study required participation in the prospective surveillance cohort, a pretreatment CD4 cell count and HIV RNA level, and willingness to provide written informed consent for an additional blood draw and sample storage. Cases required signs and symptoms of IRIS (see case definition). The study protocol was reviewed and approved by all participating institutional review boards.
Data collection and participant evaluation
As part of the National ART Program, patients received scheduled clinical assessments at regular intervals. These included at least one pretreatment assessment, one treatment commencement assessment, and regularly scheduled assessments at weeks 2, 4, 8 and every 3 months thereafter. Inpatient and outpatient records of the patients who met the inclusion criteria were reviewed to collect data relevant to the time of baseline assessment and during 6 months of follow-up. Demographic characteristics, HIV treatment history, previous and incident opportunistic infections, and antimicrobial use were extracted and systematically entered into the study database. Microbiology results, CD4 cell counts, HIV RNA levels, and any other relevant laboratory data were abstracted from electronic medical records.
For possible IRIS cases identified from the surveillance cohort, additional clinical data collection and an additional blood draw occurred at the time of enrollment into the nested case–control study. Since immunological response to ART varies with duration of treatment, eligible control subjects were matched with cases on time since ART initiation within ± 2 weeks using risk set sampling techniques in a 1: 1 ratio.
Immune reconstitution inflammatory syndrome case definition
No gold standard definition for IRIS exists. In general, IRIS is defined as a paradoxical clinical worsening due to a subclinical opportunistic pathogen (‘unmasking’ IRIS) or previously known treated (completed or ongoing) opportunistic pathogen (‘paradoxical’ IRIS) in the setting of an adequate response to ART [16–18]. For the ‘unmasking’ form of IRIS, a new localized infection was required from a focal inflammatory process (suppurative lymph node, pulmonary infiltrate, positive cerebrospinal fluid culture, etc.) in a patient who, prior to ART, exhibited no signs or symptoms of disease and in whom adequate OI screening and clinical assessment had been performed [i.e. negative pre-ART sputum acid-fast bacillus tests in the case of ‘unmasking’ pulmonary tuberculosis (TB)]. For organisms for which cultures or diagnostic studies were available (i.e. TB, cryptococcus) demonstration of the organism or a pathological process characteristic of the organism (i.e. caseous necrosis, granulomatous inflammation) were required. For the ‘paradoxical’ form of IRIS, a patient required the diagnosis and treatment initiation of an OI prior to ART initiation with a positive clinical response. Following ART, the patient experienced a new inflammatory process (worsening lymphadenopathy or suppuration, expansion of Kaposi's lesions, recurrence of meningeal signs and symptoms) at the original or new site of infection accompanied by systemic symptoms (fever, loss of weight, elevated white blood cell count). For all cases, no other identifiable pathogen could be present after thorough diagnostic evaluation.
IRIS cases were classified according to a priori definitions of suspect, probable, or confirmed cases. Suspect cases consisted of cases for which no objective evidence of immune system reconstitution exists; probable cases had immunological evidence of immune reconstitution at 6 month follow-up; and confirmed cases were those with evidence for adequate immune reconstitution at the time of IRIS. Suspect cases were defined as patients who exhibited symptoms consistent with an infectious or inflammatory condition while on ART which could not be explained by the expected clinical course of a previously recognized infectious agent or by side effects of therapy. Probable IRIS was defined in a patient: (1) who met criteria for suspect IRIS, and (2) whose treatment led to a ≥ 1 log10 drop in HIV RNA 6 months post-ART, or (3) whose CD4 cell count 6 months post-ART was equal to or above the pretreatment baseline value. Confirmed IRIS was defined in a patient: (1) who met criteria for suspect IRIS, and (2) whose treatment resulted in a ≥ 1 log10 drop in HIV RNA at time of IRIS diagnosis.
Exclusion criteria for the diagnosis of IRIS were: (1) primary virologic failure (< 1 log10 drop in HIV RNA over the 6 month ART treatment course); (2) progression of HIV/AIDS (continued drop in CD4 cell count or primary virologic failure with the development of an OI or malignancy > 3 months after initiation of ART); (3) documented noncompliance with ART regimen by ART counselors; or (4) known diagnosis of multidrug-resistant TB (MDR TB) (in the setting of suspected TB-IRIS).
For all IRIS cases, the agreement of two primary investigators (D.M.M., W.D.F.V., or C.F.) was required following review of clinical information and examination of the patient.
Patient follow-up (person-time at risk) began at date of ART initiation for patients who had at least one documented clinical assessment after ART initiation. Patients were censored at the earliest occurrence of death, loss to follow-up, or 6 month clinical evaluation. As only one individual experienced two IRIS events and in order to preserve statistical power, patients were censored at the time of their first IRIS event. Incidence rates for IRIS cases were calculated by dividing the number of IRIS events by person-time at risk and expressed as number of IRIS cases per 100 person-years. For nested case–control data, demographic and clinical characteristics were contrasted by IRIS status using chi-squared or Fisher's exact test for categorical variables, and Student's t-test or Wilcoxon rank-sum test for continuous variables.
In order to identify baseline predictors of IRIS among cohort participants, multivariable analyses were performed using Cox proportional hazards modeling. Variables of interest included baseline age, weight, hemoglobin, CD4 cell count, viral load, number of previous OIs and HIV-related illnesses prior to ART initiation, and an OI diagnosis and treatment within 30 days of ART initiation. CD4 cell count was continuous and expressed in 50 cells/μl increments. We first fitted a full model containing the variables of interest. We then removed factors which did not independently predict IRIS based on an a priori alpha of 0.05 using a hierarchical backwards elimination procedure to arrive at our final predictive model. Validity of the proportional hazards assumption was assessed for each variable entered into the model. All analyses were performed using STATA version 8.2 (College Station, Texas, USA).
Cohort patient characteristics
Between 6 January 2006 and 7 July 2007, 546 patients initiated ART at the Johannesburg Hospital adult HIV clinic. Of these, 123 (22.5%) were ineligible for inclusion in the observational cohort, mainly because they were not ARV naive at presentation (102/123, 82.9%) (Fig. 1). The 423 patients eligible for the cohort analyses contributed 180.8 person-years (p-y) of follow-up during the study period, with a median of 182 days of follow-up [interquartile range (IQR), 181–182]. During the observational period, 26 (6.1%) patients elected to transfer their care to another HIV treatment facility after a median follow-up of 115 days (IQR, 95–123). 52 (12.3%) patients were lost to follow-up after a median of 60 days (IQR, 32–87) and eight (1.9%) patients died during the study period.
Patients were predominately female (69.7%), young (median age 34 years), single (68.3%), and almost exclusively of black race (99%) (Table 1). One-fifth (21.9%) of the cohort were pregnant females. Substance abuse and pre-existing comorbid illnesses, such as hypertension and diabetes, were uncommon. The majority (63.3%) had a history of one or more illnesses prior to ART initiation. Sixty-two of 423 (14.7%) patients had a history of TB therapy and 85 of 423 (20.1%) were receiving TB treatment at ART initiation. The majority of patients (76.8%) were initiated on stavudine, lamivudine, and efavirenz.
Immune reconstitution inflammatory syndrome incidence and clinical outcomes
Among the 423 cohort patients initiated on ART, there were 44 (10.4%) cases of IRIS, corresponding to an overall incidence rate of 25.1 IRIS cases/100 p-y of ART. Of the 44 IRIS cases, 22 were confirmed cases, 21 were probable and one was a suspect IRIS case.
Clinical details and outcomes for confirmed and probable/suspect cases are presented in Tables 2 and 3. The median onset of IRIS was 48 days (IQR, 29–99), with 33 of 44 (75%) cases occurring within 90 days of ART. Of the 44 cases, infectious etiologies included TB (18/44, 41%), cryptococcal meningitis (3/44, 6.8%), herpes simplex infection (4/44, 9.1%), varicella zoster infection (6/44, 13.6%), molluscum contagiosum (3/44, 6.8%), and Kaposi's sarcoma (2/44, 4.5%). Dermatological manifestations including abscess formation and suppurative folliculitis were common, accounting for eight (18.2%) cases. Of the 44 cases, 35 (79.5%) were new presentations, and nine (20.5%) were due to exacerbations or recurrent episodes of previously documented infections. Unmasking infections primarily involved TB (16/18 cases), cryptococcal meningitis (3/3 cases), varicella zoster virus (6/6 cases), and suppurative dermatological manifestations (6/8 cases). Exacerbations or recurrent (paradoxical) infectious episodes primarily involved molluscum contagiosum (2/3 cases) and herpes simplex infection (3/4 cases).
Of the 44 IRIS cases, there were only three deaths, two of which were directly attributable to IRIS. These two deaths included a case of severe cryptococcal meningitis and a case of disseminated TB with obstructive jaundice and liver failure. The majority (93.2%) of patients with IRIS continued on ART without interruption and only four (9.1%) required the use of systemic anti-inflammatory medications to ameliorate symptoms of IRIS. Twelve of 44 (27.3%) patients required hospitalization related to their IRIS event.
Nested case–control study
Of the 44 IRIS cases, 22 were enrolled in the nested case–control study. Reasons for failure to include cases were prisoner status (n = 2), patient refusal (n = 3), missing baseline or follow-up CD4 cell count or viral load (n = 4), and failure to enroll patient within 2 weeks of IRIS identification (n = 13). Even though, in comparison with the source population, controls were older, more likely to have had treatment for prevention of mother-to-child transmission, to be employed, to have been diagnosed recently, and to be married, controls were representative of the source population as these differences were not statistically significant, with the exception of age and proportion of pregnant females (Table 1).
At baseline, cases had lower median CD4 and CD8 cell counts than controls (79 versus 142 cells/μl, and 578 versus 875 cells/μl, respectively; P = 0.02) (Table 4). The CD4 cell count remained significantly lower in cases than controls at time of IRIS (or time of enrollment for controls) (183 versus 263 cells/μl, respectively; P = 0.05). At 6 months follow-up, cases still tended to have lower CD4 cell counts (161 versus 277 cells/μl, respectively; P = 0.10). Cases and controls showed no differences in absolute changes in CD4 cell count (56 versus 115 cells/μl, respectively; P = 0.19) or percentage change of absolute CD4 cell counts (77 versus 85%, respectively; P = 0.86) between ART initiation and time of IRIS (or time of enrollment for controls). The majority of patients achieved rapid viral suppression with undetectable HIV RNA levels in 73% of cases and 86% of controls (P = 0.46) at time of IRIS (or time of enrollment for controls). The majority (88.6%) of patients had undetectable HIV RNA levels at 24 weeks with no differences in HIV RNA levels or proportion with undetectable levels between groups (P = 0.26 and 0.99, respectively).
Independent predictors of immune reconstitution inflammatory syndrome
In multivariate Cox proportional hazard analyses, only baseline CD4 cell count remained an independent predictor of IRIS. A high CD4 cell count was protective of developing IRIS (hazard ratio, 0.72; 95% confidence interval, 0.52–0.98) for every 50 cells/μl increase in baseline CD4 cell count. Kaplan–Meier estimates for the probability of remaining IRIS free by baseline CD4 cell count are presented in Fig. 2.
In this first prospective IRIS study in sub-Saharan Africa, 44 of 423 (10.4%) of patients developed IRIS, corresponding to an incidence rate of 25.1 IRIS cases/100 p-y among ART-naive patients initiating ART. The majority of cases occurred within 90 days of initiating ART, which is consistent with other published studies [11,12]. In comparison with controls, IRIS cases demonstrated significantly lower CD4 cell counts both at baseline and at the time of IRIS. Cases and controls demonstrated no significant differences in HIV RNA levels at baseline, the time of IRIS, or after 6 months of follow-up.
The incidence of IRIS observed in this South African cohort was lower than those reported in retrospective cohorts. In similar cohorts where all forms of IRIS were examined, estimates suggest 17–25% of patients initiating ART will develop one or more manifestation of the syndrome [3,10,11]. Studies focusing on disease-specific forms of IRIS, such as TB-IRIS, have also varied, with estimates ranging from 11–45% [7,14,19–21]. These wide estimates reflect different study populations, case definitions, and efforts to identify a clinical syndrome retrospectively with the risk of substantial recall bias. The incidence rate of 25.1 IRIS cases/100 p-y of ART reported in this cohort reflects the prospective application of strict case definitions and thus represents a more accurate estimate of the true IRIS incidence in a population of patients with baseline CD4 cell counts < 200 cells/μl initiating ART.
Consistent with previous literature , the majority of IRIS cases observed in this cohort were due to TB. Of the 44 cases of IRIS, the majority were new, or ‘unmasking’, presentations of the syndrome, with only 20.5% of the IRIS cases manifesting as the ‘paradoxical’ form. This observation differs from a similar developed world cohort, where each form represented 50% of cases . Although possibly attributable to a higher underlying OI burden in this developing world setting, this ratio of new to ‘paradoxical’ IRIS cases occurred despite the tertiary care setting and thorough diagnostic evaluations performed in the majority of patients prior to ART initiation. In contrast to other series [13,22], the use of steroids was infrequent and ART was safely continued in the majority (93.2%) of patients. Although one-quarter of patients required hospitalization due to a new diagnosis of an IRIS-related OI disease, most presentations were of low morbidity and were treated on an outpatient basis.
The present study is also the first case–control study, with specimens collected at the time of IRIS identification, in an effort to determine the immunopathogenesis of the syndrome. The nested case–control study revealed significant differences in CD4 cell counts in comparison with matched controls. This observation was consistent with previous observations of lower baseline CD4 cell counts in patients who subsequently develop IRIS [3,10] and lower median CD4 cell counts at IRIS . These differences were noted despite similar OI history, TB status at ART initiation, and hemoglobin levels between cases and controls. Furthermore, all patients were initiated on ART on an ambulatory outpatient basis, and only two IRIS cases were identified and recruited as inpatients. Thus, this difference existed despite similar markers of health status between groups. Although the trend of lower CD4 cell counts in IRIS subjects continued to persist to 24 weeks, it failed to reach significance (P = 0.10). In fact, median absolute CD4 cell counts and percentage increase in absolute CD4 cell counts at 24 weeks were similar to those observed at IRIS diagnosis/control enrollment. Given that the majority of IRIS cases occurred within 90 days of ART initiation, this suggests an increase in CD4 cells soon after initiation of ART, which may be due to redistribution of CD4+ lymphocytes from peripheral tissues . The 24 week observation period may have been insufficient to discern any differences between groups in their ability to increase naive CD4+ populations, which would generate further increases in absolute CD4+ cell counts.
Although we noted a higher absolute CD8 cell count at IRIS, we failed to observe differences in CD8 cell percentages [11,13]. Importantly, in contrast to previous studies , we did not detect any significant differences in baseline or changes in HIV RNA levels, with the majority of patients achieving undetectable HIV RNA levels at IRIS and at 24 weeks of follow-up. Taken together, these observations suggest quantitative differences in baseline CD4 cell counts may, in part, contribute to the pathogenesis of the disease rather than the rapidity of viral load suppression. Alternatively, a low CD4 cell count may be a marker of subclinical infection with an IRIS-related organism and high underlying antigen load, resulting in a greater risk for developing the syndrome. Previous studies [3,11] have also failed to note an association between IRIS risk and the magnitude of increase in CD4 cell count. Instead, recent data in TB-IRIS patients suggest IRIS may, in part, be due to prompt restoration of antigen-specific responses to mycobacterial antigens [24,25] rather than simply an increase in absolute cell counts. Whether additional factors, such as underlying antigenic OI burden, T cell phenotypic expression, or host response to inflammatory mediators, contribute to the syndrome remains largely unknown.
To evaluate whether a low baseline CD4 cell count was independently predictive or simply a marker for overall disease progression, multivariate analyses with a number of clinical and immunological predictors were performed. Consistent with differences observed in the nested case–control study, only baseline CD4 cell count was predictive of IRIS in multivariate analyses. In contrast to previous studies [7,12,14], diagnosis and treatment of a new OI within 30 days of ART initiation was not predictive of IRIS. These previous studies focused primarily on TB-IRIS, however, and may have identified an association between the occurrence of a specific OI and its ability to precipitate TB-IRIS.
Overall mortality after ART initiation in this cohort was low (1.9%), but in agreement with post-ART mortality rates reported in similar South African cohorts [26,27]. IRIS-attributable mortality was also relatively low (2/44 cases or 4.5%). One IRIS-associated death was due to refractory cryptococcal meningitis and profound systemic inflammation and illustrates the potential mortality associated with this syndrome. This case required multiple lumbar punctures for elevated cerebrospinal fluid pressures despite appropriate antifungal therapy, corticosteroids, and documented HIV RNA suppression.
The present study was limited by several factors. As with any open cohort, this study was subject to varying follow-up time. In order to accurately assign right censoring times and to arrive at unbiased incidence estimates, disposition was determined by active case finding by clinic personnel and the use of clinic and pharmacy appointment dates. We attempted to minimize subjective diagnoses of IRIS through the use of strict case definitions and the requirement of agreement between two investigators after all data was reviewed. Recruitment of patients into the nested case–control study was dependent upon prompt recognition of IRIS, which was not always possible in this setting. The small sample size recruited into the nested case–control study may have limited our ability to detect significant differences in other immunovirological parameters, such as HIV RNA levels. We also lacked the ability to obtain additional immunologic data at baseline for all patients initiating ART. Lastly, controls differed by age and pregnancy status, but these variables are unlikely to have influenced results.
In conclusion, IRIS occurs as a result of restored immunity to a variety of opportunistic pathogens and their antigens. As demonstrated in this study, the clinical manifestations are diverse, necessitating a high clinical suspicion for its occurrence. The syndrome may impact on the rollout of ART as it affects 10% of ART-naive patients initiating ART in sub-Saharan Africa. IRIS usually occurs within the first 90 days of ART, mainly affects patients with lower baseline CD4 cell counts (< 100 cells/μl), and most frequently presents as TB or dermatological manifestations. Hospitalization and increased resources may be required for up to one-quarter of patients with IRIS, but the majority of patients recover without significant intervention and ART may be safely continued in most cases.
We wish to thank all of the patients who agreed to participate in this study. We thank the Johannesburg Hospital Area 556 clinical and support staff and members of the Reproductive Health & HIV Research Unit (RHRU) (Mercia Tellie, Mmabatho Mqhayi, and Sibongile Motloung) who made this study possible. We wish to thank the laboratories of Wendy Stevens and Debbie Glencross. We are indebted to Joseph J. Eron, MD and Sonia Napravnik, PhD for their help in preparation of the manuscript for publication.
Sponsorship: the University of North Carolina at Chapel Hill, Center for AIDS Research, National Institutes of Health (NIH) funded program P30 AI50410; and the University of North Carolina, General Clinical Research Center, NIH funded program RR00046; NIH funded ICOHRTA program D71 TW06906; PEPFAR Agreement No. 674-A-00-05-00004-00.
No authors have any conflict of interest to disclose regarding the work presented in this manuscript.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
HIV; immune reconstitution inflammatory syndrome; incidence; IRIS; opportunistic infections; risk factors; sub-Saharan Africa