Severe Immune Reconstitution Inflammatory Syndrome Research Articles

Comparison of IL-6, IL-10, and TNFα levels between PLWHIV with and without Kaposi Sarcoma and healthy controls.

Kaposi sarcoma (KS) is an angioproliferative disease caused by human herpesvirus 8 (HHV-8) and is mediated by cytokines in an immunodeficient environment. This study aimed to compare IL-6, IL-10, and TNFα levels among AIDS patients with disseminated KS (DKS), treatment naïve patients living with HIV (PLWHIV) without DKS, and healthy controls. Secondary outcomes were to compare cytokines levels in patients with DKS and unfavorable outcomes, as well as an analysis of the behavior of cytokines over time. This cohort study was performed at two centers in Mexico City. Three groups were included. Group 1: HIV+ treatment naïve with DKS, Group 2: HIV+ treatment naïve without KS, and Group 3: HIV negative, healthy controls. Plasmatic IL-6, IL-10, and TNFα levels were measured at baseline and over time in Groups 1 and 2. Seventy-six patients were included: 39 (52%) in Group 1, 17 (22%) in Group 2, and 20 (26%) in Group 3. The median baseline IL-6, IL-10, and TNFα levels were significantly higher in group 1. In group 1, baseline IL-6 was higher in patients who died than in survivors (14.4 vs 5.8 pg/mL p=0.048). Patients with severe immune reconstitution inflammatory syndrome due to KS (S-IRIS-KS) had higher IL-6 values than those without it (14.4 vs 5.8 pg/mL p=0.004). In the repeated-measures model in group 1, IL-10 levels were higher in patients who died (p<0.001) and developed IRIS-KS (p=0.01). IL-6, IL-10, and TNF α levels were markedly higher in patients with DKS. IL-6 and IL-10 levels were higher in patients with unfavorable outcomes.

Clinical Worsening in an Adolescent With Pleural Tuberculosis

A 17-year-old previously healthy female presented with unilateral chest pain and dyspnea. Chest radiographs demonstrated a unilateral pleural effusion and pneumonia. Pleural fluid bacterial cultures were negative; acid-fast cultures grew Mycobacterium tuberculosis. Two months after starting appropriate therapy, she had a recrudescence of symptoms and reaccumulation of the pleural fluid. Her tuberculosis antibiotic regimen was expanded, the effusion drained, and systemic corticosteroids initiated, resulting in rapid clinical improvement. Cultures of the second pleural fluid collection were negative. Her clinical deterioration was due to immune reconstitution inflammatory syndrome (IRIS). IRIS can be seen within the first several months of starting tuberculosis therapy and can result in paradoxical worsening of symptoms or radiographic findings in adolescents who are on the appropriate therapy. IRIS is a diagnosis of exclusion after drug resistance and medication malabsorption, intolerance, and nonadherence are excluded. Therapy includes nonsteroidal anti-inflammatory agents for milder reactions and systemic corticosteroids for more severe IRIS cases.

Severe Mycobacterial Immune Reconstitution Inflammatory Syndrome (IRIS) in Advanced Human Immunodeficiency Virus (HIV) Has Features of Hemophagocytic Lymphohistiocytosis and Requires Prolonged Immune Suppression.

People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART). Severe mycobacterial IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We evaluated the pathophysiologic similarities between mycobacterial IRIS and HLH to identify clinical and immune predictors of mycobacterial IRIS severity. HLH criteria were applied to a longitudinal cohort of 80 patients with HIV (CD4 <100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell subsets were assessed at baseline and IRIS-equivalent time points. HLH-IRIS patients required corticosteroids more frequently (OR: 21.5; 95%CI: 5.6-114.8) and for longer duration (21.2; 95%CI: 10.7-31.7 weeks) than those not meeting HLH criteria. Utilizing decision tree analyses, hemoglobin <9.2 g/dL was the best predictor of HLH-IRIS before ART, whereas ferritin, CXCL9 and sCD25 were most diagnostic for HLH at IRIS onset. At the IRIS timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T cells along with greater production of IFNγ-IL-18 axis biomarkers compared with both IRIS and non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients. Severe mycobacterial IRIS and HLH have an overlapping pathogenesis involving IFNγ and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS [FIRIS]). Hemoglobin, ferritin, CXCL9, and sCD25 identify high-risk patients and may improve risk stratification and therapeutic strategies for mycobacterial IRIS.

Progressive multifocal leukoencephalopathy or immune reconstitution inflammatory syndrome after fingolimod cessation? A case report

BackgroundFingolimod is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML); however, its discontinuation may cause severe immune reconstitution inflammatory syndrome (IRIS). As both of these conditions (especially fingolimod induced PML) are rarely described in medical case reports distinguishing between PML-IRIS and MS-IRIS may be diagnostically challenging.Case presentationWe report a patient with severe clinical decline (Expanded Disability Status Scale (EDSS) increasing from 3.5 to 7.5) and multiple, large, contrast-enhancing lesions on brain magnetic resonance imaging (MRI) a few months after fingolimod withdrawal. The diagnostic possibilities included IRIS due to fingolimod withdrawal versus PML-IRIS. The JC virus (JCV) antibody index was positive (2.56); however, cerebrospinal fluid (CSF) JCV real-time polymerase chain reaction (JCV-PCR) was negative and brain biopsy was not performed. After a long course of aggressive treatment (several pulsed methylprednisolone infusions, plasmapheresis, intravenous dexamethasone, oral mirtazapine) the patient gradually recovered (EDSS 2.5) and MRI lesions decreased.ConclusionsThis case report demonstrates the importance of monitoring patients carefully after the discontinuation of fingolimod for PML-IRIS and rebound MS with IRIS as these conditions may manifest similarly.

Pathologic Findings of Chronic PML-IRIS in a Patient with Prolonged PML Survival Following Natalizumab Treatment.

Immune reconstitution inflammatory syndrome (IRIS) is a common complication during treatment for natalizumab-associated progressive multifocal leukoencephalopathy (PML). Although severe IRIS can result in acute worsening of disability and is associated with poor prognosis, effective immune reconstitution may account for the high survival rate of this cohort of PML patients. We present pathological evidence of chronic IRIS 3.5 years after diagnosis with natalizumab-associated PML. Our case showed that the IRIS initially developed after plasma exchange therapy and resolved clinically and radiologically following a combination treatment with corticosteroids, maraviroc, and cidofovir. Autopsy 3.5 years later revealed evidence of grey-white matter junction demyelinating lesions characteristic of PML and perivascular leukocyte infiltrates predominated by CD8+ T-lymphocytes, and polymerase chain reaction analysis demonstrated the presence of JC viral DNA in this tissue, indicative of persistent PML-IRIS. While clinical symptoms of PML-IRIS typically stabilize within 6 months, our case report suggests that prolonged low-grade inflammation may persist in some patients. Better assays are needed to determine the prevalence of prolonged low-grade IRIS among PML survivors.

Rescue of severe brain and cervical cord IRIS by restarting natalizumab in a pregnant MS patient

Natalizumab inhibits lymphocyte trafficking across the blood–brain barrier, reducing relapse rates by up to 70% in patients with relapsing-remitting multiple sclerosis (RRMS). Discontinuation of the drug, usually due to pregnancy or risk of progressive multifocal leukoencephalopathy (PML), can trigger the return of disease activity or, occasionally, a fulminant immune reconstitution inflammatory syndrome (IRIS) as lymphocytes re-enter the CNS.1–3 Acknowledgment: The authors thank the patient and her family for their assistance with this report.

Immune-reconstitution Inflammatory Syndrome in Multiple Sclerosis Patients Treated With Natalizumab: A Series of 4 Cases

PurposeNatalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Progressive multifocal leukoencephalopathy (PML) is a rare complication of NTZ treatment. In patients developing PML, NTZ cessation causes a reconstruction of cellular immunity, a rapid transition of cells through the blood-brain barrier, and significant inflammation in the central nervous system, leading to immune-reconstitution inflammatory syndrome (IRIS), with potentially poor outcomes. The occurrence of this syndrome is accelerated by plasmapheresis, the standard treatment for NTZ-PML, due to enhanced clearance of NTZ and thus rapid reconstitution of cellular immunity. IRIS can also occur after cessation of NTZ in the absence of PML. MethodsWe describe 4 patients who developed IRIS after NTZ cessation. FindingsFor the first patient, treatment was switched to fingolimod to avoid risk of developing PML. Despite plasmapheresis, corticosteroids, and other therapies, the outcome in this patient was fatal. For the 3 other patients, PML was detected early on magnetic resonance imaging, and IRIS after NTZ cessation was managed with a favorable outcome; 1 of these patients was managed without plasmapheresis or corticosteroid treatment. ImplicationsThese cases demonstrate the need to consider and manage therapeutic strategies relative to the individual patient’s risk for PML or IRIS. NTZ cessation to avoid PML risk can lead to severe IRIS without PML. On the other hand, if PML develops and is detected early, plasmapheresis may not be considered necessary and IRIS may be limited, with a favorable outcome. These 2 scenarios should be considered when managing NTZ MS patients.

Treatment with adalimumab for severe immune reconstitution inflammatory syndrome in an HIV-infected patient presenting with cryptococcal meningitis

Treatment with adalimumab for severe immune reconstitution inflammatory syndrome in an HIV-infected patient presenting with cryptococcal meningitis

Dramatic Improvement of Severe Cryptococcosis-Induced Immune Reconstitution Syndrome With Adalimumab in a Renal Transplant Recipient

In solid organ transplant recipients, immune reconstitution inflammatory syndrome (IRIS) is a rare complication of cryptococcosis, which may require steroids in its most severe forms. Here, we report the case of a renal transplant recipient who developed severe cryptococcal meningitis-associated IRIS 1 week after immunosuppression reduction. High-dose steroids failed to improve the disease. Finally, a recombinant human monoclonal tumor necrosis factor-α (TNF-α) antagonist, adalimumab, was prescribed, and the patient rapidly experienced dramatic neurological improvement. No IRIS relapse occurred within 14 months following adalimumab discontinuation.

Partial Recovery After Severe Immune Reconstitution Inflammatory Syndrome in a Multiple Sclerosis Patient with Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a rare and severe complication of natalizumab therapy in patients with multiple sclerosis and it may be accompanied by immune reconstitution inflammatory syndrome (IRIS). Here, we describe a case of abnormally severe IRIS, which occurred 2 months after natalizumab-associated PML in a 38-year-old woman affected by multiple sclerosis. The patient was John Cunningham virus-positive and was treated for 21 months when she developed PML. The subsequent IRIS diffusely afflicted the brain, producing edema and signs of intracranial hypertension, with a clinically severe form compromising the state of consciousness, requiring intensive care and high-dosage steroid treatment. Nevertheless, she survived and partially recovered. There is still difficulty in differentiating PML progression from IRIS onset and there is not a clear description in the literature about different clinical forms of IRIS, prognostic factors and guidelines to properly treat this complication in order to reduce the residual disability of the patient surviving this treatment complication.

Unusual natalizumab-associated progressive multifocal leukoencephalopathy starting in the brainstem

we report on a 45-year-old German patient with relapsingremitting (RR) multiple sclerosis (MS) who was started on natalizumab (NAT) therapy in November 2007, because of ongoing disease activity despite interferon therapy. She had never been treated with immunosuppressants before. After she tested positive for anti-JCV (John Cunningham Virus)antibodies for the first time, she decided to discontinue NAT treatment in July 2011 (after 49 NAT infusions). At this time point, as well as during NAT therapy, she was clinically stable (EDSS 3.5). Six weeks later in August 2011, she developed new brainstem symptoms, with left facial and trigeminal nerve palsy, double vision and mild dysphagia. On magnetic resonance imaging (MRI), a large brainstem-midbrain lesion was seen (Fig. 1D). The symptoms were initially interpreted as MS relapse and treated with corticosteroids. After transient improvement, she deteriorated again and was seen for the first time at our hospital. Progressive multifocal leukoencephalopathy (PML) was diagnosed in September 2011 after detection of JCV DNA (31 c/ml in CSF, 5 c/ml in serum; EDSS 7.0). Subsequently, she developed severe immune reconstitution inflammatory syndrome (IRIS), deteriorated clinically (EDSS 9.5), and had to be transferred to the intensive care unit (ICU) for several weeks. Finally, she stabilized after repeated courses of high-dose iv glucocorticosteroids (GC) and iv immunoglobulins (IVIgG, 5 days a 0.4 g/kg body weight), as well as concomitant therapy with mefloquine and mirtazapine. Six months later, she had improved, but still showed severe ataxia and brainstem symptoms (EDSS 6.0). Retrospective analysis of all available MRI scans identified a small new-initially asymptomatic-T2 brainstem lesion as the first MRI manifestation of this patient’s PML in November 2010, which slowly progressed over 41 weeks until clinical PML presentation (Fig. 1A–D). Several aspects in this report are unusual: (1) brainstem PML is rare and has been reported in association with NAT therapy in MS patients only once so far [1]; (2) the longlasting pre-symptomatic phase of 41 weeks and clinical manifestation of PML only 6 weeks after NAT was discontinued; and (3) clinical improvement after combined therapy with GC and IVIgG. In this patient, a new, asymptomatic, non-contrast-enhancing T2 lesion appeared in the brainstem in November 2010 (Fig. 1B). Notably, before the MRI lesion was rated as important, the patient decided to stop NAT therapy in July 2011 due to fear of PML. At this time and during NAT treatment, the lesion was completely asymptomatic. The patient developed new brainstem symptoms only 6 weeks after discontinuation of NAT and showed a large brainstem-midbrain lesion on MRI at that time. Detailed retrospective MRI analysis identified that this large lesion had progressed over time from the small brainstem lesion 41 weeks before. NATassociated PML with a pre-symptomatic course up to 24 weeks has been reported, but not in the brainstem so far [2]. More recently, Yousry and colleagues [3] identified common MRI patterns of NAT-associated PML, which help in the early diagnosis of PML. Except for the unusual initial localization in the brainstem and size (\ 3 cm), all J. Havla (&) R. Hohlfeld T. Kumpfel Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, Medical Campus Grosshadern, Marchioninistr. 15, 81377 Munich, Germany e-mail: joachim.havla@med.lmu.de

Therapeutic Plasma Exchange for Progressive Multifocal Leukoencephalopathy Related to Multiple Sclerosis Therapy with Natalizumab

Abstract 4386 Background:Progressive multifocal leukoencephalopathy (PML) associated with natalizumab in multiple sclerosis (MS) treatment is a complication for which therapeutic plasma exchange (TPE) has been used. We describe such a case treated with TPE. Case Report:A 54 year old woman with a past medical history of relapsing-remitting MS presented with recent onset ataxia and bilateral upper and lower extremity weakness and right hand dysmetria. Two weeks prior to presentation, she completed 57 treatments with natalizumab, a monoclonal antibody against cellular adhesion molecule α4-integrin that blocks lymphocytes from crossing the blood-brain barrier. Brain MRI showed new non-enhancing lesions in the right cerebellum and anterior left temporal lobe. Natalizumab was discontinued and investigation revealed high serum and CSF titers of JC virus DNA indicative of PML. The patient underwent a total of 3 TPE’s (1 every other day) with 3L of 5% albumin solution (1.4 plasma volume [PV]) used as replacement each TPE. After TPE, the patient initially showed improvement of neurological function and was transferred to inpatient acute rehabilitation. However, 4 days later she suffered a seizure and developed slurred speech. MRI showed that the cerebellar lesion had extended into the pons. The patient also developed dysphagia requiring nasogastric tube feeding and poorly-localized pain requiring pain management. She was treated with steroids for possible Immune Reconstitution Inflammatory Syndrome (IRIS) and discharged to hospice care for rehabilitation and pain management. The patient’s condition continued to deteriorate and she died shortly after being arriving at hospice. Conclusion:Natalizumab selectively immune suppresses the CNS putting patients at risk for PML and TPE with or without immunadsorption, can rapidly reverse the immune suppression by clearing natalizumab. Although we did not measure natalizumab concentrations in our patient, 1 report showed that a series of 3 TPE’s (1.5 PV) significantly decreased natalizumab levels while another showed that 3–5 TPE’s (1–1.5 PV) was effective. The effect of reducing natalizumab is to exchange the problem of a typically fatal opportunistic infection for the problem of an aggressive potentially injurious immune response to that virus. IRIS itself requires intense management to prevent brain injury or death and while there is no set standard of care, steroids are typically used. According to the manufacturer’s global monitoring system, the majority of natalizumab induced PML cases are treated with TPE which typically induces IRIS within days to weeks. The most recent mortality rate for all PML cases related to this drug is 22%, significantly lower than that seen with AIDS or in the oncology setting. Although our patient initially improved after TPE, the proximity of the PML to her brainstem, with or without IRIS, made her particularly vulnerable. Whether TPE may lead to more severe IRIS, as suggested by one report, requires further study. Nevertheless, given the severe consequences of PML itself, we would recommend TPE for natalizumab -induced PML. Disclosures:No relevant conflicts of interest to declare.

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus-specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy ((1)H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. (1)H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery.

1 Introduction

1 Introduction

The immune reconstitution inflammatory syndrome and antiretroviral therapy

Although generally mild, severe immune reconstitution inflammatory syndrome may complicate antiretroviral therapy, and it may be difficult to differentiate from treatment failure or toxicity. This article looks at diagnostic and therapeutic challenges of severe infectious manifestations of immune reconstitution inflammatory syndrome.

Treatment of HIV‐related tuberculosis—unresolved issues

Abstract: Tuberculosis (TB) is one of the most common opportunistic infections among persons with HIV infection. However, there are uncertainties about both TB and HIV treatment regimens among patients with advanced immunodeficiency. On the TB treatment side, there are lingering concerns about whether patients with advanced immunodeficiency should have a more intensive regimen for TB treatment (longer duration, more frequent [daily] dosing and/or post‐treatment isoniazid). The use of antiretroviral therapy among patients with TB and AIDS dramatically decreases the risk of death and other opportunistic infections. However, use of antiretroviral therapy during TB treatment is complicated by the need to coordinate the activities of the TB control program and the HIV care clinic, overlapping side‐effect profiles of anti‐TB and antiretroviral drugs, drug–drug interactions between the rifamycins and many antiretroviral drugs, and the occurrence of immune reconstitution inflammatory syndrome events. The combination of rifampin‐based TB treatment and efavirenz‐based antiretroviral therapy is clearly the best option for cotreatment of these two infections. However, there are a number of uncertainties about the optimal antiretroviral therapy if efavirenz cannot be used (because of intolerance, drug resistance, pregnancy or lack of an appropriate formulation in children). The competing risks of AIDS events and severe immune reconstitution inflammatory syndrome events raise uncertainties about the optimal timing of antiretroviral therapy during TB treatment. Despite all of these complexities, the treatment of HIV‐related TB can be remarkably successful. I review these unresolved questions in the treatment of HIV‐related TB and suggest studies to help resolve them.

First UK report of successful treatment of Mycobacterium simiae and immune reconstitution inflammatory syndrome in an HIV-seropositive patient

Non-tuberculous mycobacteria (NTM) such as Mycobacterium avium intracellulare are commonly encountered by HIV physicians and management strategies are well established. Experience of other NTM is, however, limited. As HIV epidemiology...

Prevalence And Characteristics Of Human Immunodeficiency Virus Associated Kaposi Sarcoma

Skin manifestations are frequently associated with the Human Immunodeficiency Virus (HIV) infection. Kaposi's Sarcoma (KS) is one of the most common cancers seen in people with HIV, and is an AIDS defining illness. The incidence of HIV associated Kaposi's Sarcoma has decreased since the advent of antiretroviral drugs in developed countries. This is not the case with Cameroon people present with generalized and aggressive KS. This study reviews the characteristics and prevalence of KS and the impact of antiretroviral drugs in a treatment center in YaoundE, Cameroon. The prevalence of KS among HIV infected patients was found to be 10.0%. Both sexes were equally affected unlike in endemic KS which is more common in males. Most patients had generalized disease, and death occurred within six months of diagnosis. These cases were associated with low CD4 cell count, anemia and low platelet counts. Patients with less extensive lesions, had tumor regression ranging from partial to total when Highly Active Antiretroviral Therapy was administered. Early diagnosis and antiretroviral therapy will decrease morbidity, mortality and severe Immune Reconstitution Inflammatory syndrome (IRIS) common in patients with aggressive HIV associated KS.

Response to “Optimum Time to Initiate Antiretroviral Therapy in Patients With HIV-Associated Tuberculosis

In Reply: We thank Drs. Lawn and Wood for their interest in our article. To determine probability estimates for our decision analysis, we used all published data. We did not exclude data from developing world settings, but data from such settings were simply not available for most probability estimates at the time of the analysis. We agree that data from resource-poor settings should be used to assess the optimal timing of antiretroviral therapy (ART) initiation among HIV-infected patients with tuberculosis (TB) in such settings. This is supported by the following points. The event rates that were most important in our decision analysis were mortality associated with HIV, immune reconstitution inflammatory syndrome (IRIS), and drug toxicity; treatment failure or relapse was also important.1 In the South African setting of Drs. Lawn and Wood, the HIV-associated mortality rate among patients with TB receiving ART is substantially higher than the rate used in our decision analysis, which was from a study conducted in North America.2 In addition, however, Lawn and Wood have recently reported on 19 TB/HIV-infected patients at their site who developed IRIS while receiving anti-TB therapy and ART, of whom 2 (10.5%) died.3 Of note, more than 75% of the 160 patients who received concomitant anti-TB therapy and ART started ART more than 2 months after initiating anti-TB therapy. There could have been even more severe IRIS cases had more patients initiated ART within 2 months of anti-TB therapy. It is also important to note that this IRIS-related mortality rate contrasts with a recent review of all reported TB-related IRIS cases (most of which were from developed countries), in which there were no deaths.4 An IRIS-related mortality rate of 10.5% would exceed the threshold value from our analysis (4.6%), and therefore favor deferred ART initiation. With the higher HIV-associated mortality rate at their clinic, however, the threshold value for IRIS-associated mortality would almost certainly be higher than 4.6%. This example demonstrates the need to address the issue of optimal timing of ART initiation in HIV-infected patients with TB using data entirely from a developing world setting. A randomized clinical trial would be the best way to address this issue, but as Lawn and Wood mention, the appropriate clinical trials have been slow to enroll. Therefore, a formal decision analysis with data from the developing world would be beneficial to confirm that early ART initiation is indeed preferred in this setting. We have recently shown that the conclusions of decision analyses pertaining to infectious disease topics usually correspond with the results of subsequent clinical studies that address the same scientific question.5 This provides support for the validity of decision analysis in guiding clinical decision making. It should be noted that for any future decision analysis on this topic, sufficient data are necessary for variables that are important but for which current data are limited, including HIV-related mortality, drug toxicity and associated mortality, and TB failure and relapse-all for persons who initiate ART within 2 months of anti-TB therapy versus those who initiate after 2 to 6 months of therapy. Joshua T. Schiffer, MD*† Timothy R. Sterling, MD‡§ *Division of Infectious Diseases Department of Medicine University of Washington Seattle, WA †Department of Medicine Johns Hopkins University Baltimore, MD ‡Division of Infectious Diseases Department of Medicine Vanderbilt University Medical Center Nashville, TN §Center for Health Services Research Department of Medicine Vanderbilt University Medical Center Nashville, TN

Timing of Antiretroviral Therapy Initiation in Tuberculosis Patients With AIDS

In HIV-infected tuberculosis patients with <200 CD4 lymphocytes/mm, highly active antiretroviral therapy (HAART) improves survival but can be complicated by immune reconstitution inflammatory syndrome (IRIS) and drug toxicity. We conducted a decision analysis in hypothetical cohorts of 1000 patients in which HAART was initiated during the first 2 months of tuberculosis therapy (early) or during months 2 through 6 of tuberculosis therapy (deferred) or was withheld until after tuberculosis therapy (no HAART). Outcomes assessed were 1-year mortality and the combined outcome of 1-year mortality, new AIDS-defining illness, severe IRIS, and severe drug toxicity. There were 33, 48, and 147 deaths and 497, 501, and 501 combined outcome events in the early HAART, deferred HAART, and no-HAART groups, respectively; most events were drug toxicity in the early and deferred groups and HIV-related mortality or AIDS-defining illness in the no-HAART group. In a 2-way sensitivity analysis of mortality, early HAART was favored, even with the highest reported rates of IRIS (70%) and severe drug toxicity (56%). Deferred HAART was favored over early HAART only if the IRIS-related mortality rate in the early group exceeded 4.6%. These results support early initiation of HAART in patients with AIDS, except when IRIS-related mortality rates are high.