Management of IRIS

Purpose and Development of This Guideline

Reviewed and updated: James C. M. Brust, MD, April 2021
Original publication: June 2017; Steven M. Fine, MD, PhD, lead author
Writing group: Joseph P. McGowan, MD, FACP, FIDSA; Steven M. Fine, MD, PhD; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD, FACP, AAHIVS; Rona M. Vail, MD; Lyn C. Stevens, MS, NP, ACRN; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD
Committee: Medical Care Criteria Committee

Purpose

This guideline was developed by the New York State Department of Health (NYSDOH) AIDS Institute (AI) for primary care providers and other practitioners who manage immune reconstitution inflammatory syndrome (IRIS) in patients with HIV. The guideline aims to achieve the following goals:

• Raise awareness among healthcare providers about IRIS, including its clinical presentation.
• Provide treatment recommendations for IRIS.
• Encourage clinicians to seek the assistance of an experienced HIV care provider when managing IRIS.
• Emphasize that antiretroviral therapy (ART) should not be interrupted in patients with IRIS except in life-threatening cases.

The NYSDOH AI is publishing this guideline at a critical time: 1) Initiation of ART is now recommended for all patients diagnosed with HIV; 2) Identifying and linking patients with HIV infection to care and treatment that achieves optimal virologic suppression are crucial to the success of New York State’s Ending the Epidemic initiative; and 3) The ability of primary care providers and other clinicians in New York State to manage IRIS is key to the successful treatment of patients with HIV.

Although ART dramatically reduces HIV-associated mortality and improves patient outcomes, initiation of or a change in ART introduces the potential for IRIS. This early complication is seen most often within the first 8 weeks of therapy in patients with advanced HIV disease. Mild IRIS resolves over time in most patients, and symptomatic treatment is often sufficient. Severe IRIS may threaten a patient’s functional status or cause permanent disability or death. But interrupting combination ART in a patient with IRIS may lead to acquisition of new opportunistic infections, recurrence of IRIS when therapy is later restarted, and possible HIV-drug resistance.

This guideline, therefore, addresses management of IRIS to avoid ART interruption except in life-threatening cases. Key recommendations cover the following:

• Timing of ART initiation relative to timing of treatment for opportunistic infections
• When to consult an experienced HIV care provider
• Diagnosis of IRIS
• Management and treatment of mild and severe IRIS

Development of This Guideline

This guideline was developed by the NYSDOH AI Clinical Guidelines Program, which is a collaborative effort between the NYSDOH AI Office of the Medical Director and the Johns Hopkins University School of Medicine, Division of Infectious Diseases.

Established in 1986, the goal of the Clinical Guidelines Program is to develop and disseminate evidence-based, state-of- the-art clinical practice guidelines to improve the quality of care provided to people with HIV, hepatitis C virus, and sexually transmitted infections and to improve drug user health and LGBT health throughout the State of New York.

NYSDOH AI guidelines are developed by committees of clinical experts through a consensus-driven process.

The NYSDOH Medical Care Criteria Committee (MCCC) was charged with developing evidence-based clinical recommendations for primary care clinicians in New York State who manage IRIS in patients with HIV. The resulting recommendations are based on an extensive review of the medical literature and reflect consensus among the MCCC panel of experts. Each recommendation is rated for strength and for quality of the evidence (see below). If recommendations are based on expert opinion, the rationale for the opinion is included.

Guideline Committee and Development

April 2021

NYSDOH AIDS Institute Medical Care Criteria Committee (MCCC) 

The New York State Department of Health (NYSDOH) AIDS Institute (AI) protects and promotes the health of NYS’s diverse population through disease surveillance and the provision of quality services for prevention, health care, and psychosocial support for those affected by HIV/AIDS, sexually transmitted diseases, viral hepatitis, and related health concerns. In addition, the NYSDOH AI promotes the health of LGBT populations, substance users, and the sexual health of all New Yorkers. This guideline is an update of the IRIS guideline published in June 2017.

Committee makeup: Members of the Medical Care Criteria Committee (MCCC) (see Box A1: MCCC Leaders, Members, and IRIS Guideline Reviewers) were appointed by the NYSDOH AI to ensure representation of clinical practice in all major regions of the state, relevant medical disciplines and sub-specialties, key NYS agencies, community stakeholders, and patient advocates. Individuals confirmed as Committee members are required to disclose any potential conflicts of interest; disclosures are reviewed and approved by the NYSDOH AIDS Institute Office of the Medical Director (see Funding and Financial Disclosure of Potential Conflicts of Interest, below).

Committee role: Committee members actively participate in guideline development, including evidence review, drafting of recommendations and text, manuscript review, consensus approval of all recommendations, and rating of recommendations.

Committee leadership: Working with the lead author, the MCCC Writing Group of Committee leaders reviewed and refined the manuscript, facilitated consensus approval of all recommendations, and addressed feedback from external peer and consumer reviewers.

Johns Hopkins University (JHU) editorial role: The JHU editorial team coordinated, guided, and documented all Committee activities, and edited the guideline material for clarity, flow, and style.

MCCC Writing Group for IRIS at the time of guideline review and update (all Committee members and reviewers are listed in Box A1, below)

• Joseph P, McGowan, MD, FACP, FIDSA, Chair
• Steven M. Fine, MD, PhD, Vice-Chair
• Samuel T. Merrick, MD, Chair Emeritus
• Charles J. Gonzalez, MD, AIDS Institute Medical Director
• Lyn C. Stevens, MS, NP, ACRN, AIDS Institute Deputy Medical Director
• Christopher J. Hoffmann, MD, MPH, JHU Principal Investigator

JHU Editorial and Program Management Team

• Mary Beth Hansen, MA, Project Director
• Johanna Gribble, MA, Medical Editor
• Jen Ham, MPH, Medical Editor
• Rachel Lastra, Medical Editor
• Jesse Ciekot, Program Coordinator

Funding and Disclosure of Potential Conflicts of Interest

Funding: New York State funds supported development of the Management of Immune Reconstitution Inflammatory Syndrome (IRIS) guideline through a grant awarded to the Johns Hopkins University School of Medicine, Division of Infectious Diseases, from the New York State Department of Health AIDS Institute.

Conflicts of interest: All active MCCC members, invited consultants and coauthors, peer reviewers, and program staff are required to disclose financial relationships with commercial entities, including gifts that may be actual conflicts of interest or may be perceived as conflicts. These individuals must disclose financial relationships annually, for themselves, their partners/spouses, and their organization/institution. On their annual disclosures, MCCC members are asked to report for the previous 12 months and the upcoming 12 months. No conflicts of interest are reported for the 2021 edition of the guideline.

Management of COIs: All reported financial relationships with commercial entities are reviewed by the NYSDOH AI guidelines program to assess the potential for undue influence on guideline recommendations made by the Committee. For the Committee members reporting conflicts, it was determined that the potential for the exertion of undue influence on recommendations was exceedingly low to non-existent.

All guideline recommendations received consensus approval of the full MCCC, and the final review and approval of the recommendations was performed by the Committee Chair, and the NYSDOH AI Medical Director and Deputy Medical Director, none of whom reported conflicts of interest.

External peer reviewers were also required to submit conflict of interest/financial disclosure information, which were similarly screened. Neither peer reviewer reported conflicts.

Recommendation Development and Ratings Process

The clinical recommendations presented in this guideline were developed by consensus based on a synthesis of the current evidence collected through review of current published peer-reviewed literature. If no data were available, the recommendations are based on expert opinion, and this status is indicated in the rating and in the text.

The Writing Group met via monthly teleconferences over approximately 24 months to finalize the guideline and reach consensus on recommendations and rationale. Once consensus among the Writing Group members was reached, the guideline was reviewed by the full MCCC, and consensus was reached on all recommendations. These deliberations were conducted by teleconference; MCCC members were invited to submit comments in writing as well. Committee review discussions were recorded, and recordings were reviewed carefully to ensure that all decisions and changes were captured and integrated into the manuscript.

Members of the Writing Group then individually reviewed the evidence for each recommendation and assigned a two-part rating (see below). The individual ratings were compiled into a report distributed to all raters, and conference call discussions were held to deliberate ratings for which consensus was needed. Once all raters agreed on the interpretation of evidence and ratings for all recommendations, the guideline was sent to the NYSDOH AI for review and approval.

External Review

Two external peer reviewers recognized for their experience and expertise in HIV primary care were identified by program leaders (see Box A1). These individuals submitted a financial disclosure statement for the purpose of identifying potential conflicts of interest before participating as peer reviewers; neither disclosed financial relationships with commercial entities in the 12 months prior or the 12 months following submission of the disclosure.

Peer reviewers were asked to review the guideline for accuracy, balance, clarity, and practicality of the recommendations for primary care providers. The Planning Group addressed peer review feedback; any conflicting opinions were resolved by the Committee chairs. Members of NYSDOH AI Community Advisory Committee also reviewed and commented on the guideline.

Guideline Updates

Members of the MCCC will monitor developments in management of IRIS in an ongoing, structured manner to maintain guideline currency. Once the guideline is published on the program website: www.hivguidelines.org, any updates will be made to the HTML document as needed.

Notification of newly published studies will be automated, and the Planning Group will review new data at least every 6 months. Newly published data that provide support for existing recommendations will be cited in the text, and the studies will be added to the reference list(s).

If newly published data prompt a revision to recommendations or rationale, the Planning Group will propose appropriate edits and determine whether the changes warrant review and approval by the entire MCCC. If MCCC review is required, a conference call will be convened for that purpose. Deletion of existing recommendations, addition of any new recommendations, and/or substantive changes to existing recommendations will prompt MCCC review and consensus.

The full guideline will be reviewed and updated on the 4th anniversary of original publication to prepare for publication of an updated guideline on or before the 5th anniversary of original publication.

Manifestations of IRIS

Reviewed and updated: James C. M. Brust, MD, April 2021

The goal of antiretroviral therapy (ART) in individuals with HIV is immune reconstitution, which may also produce the manifestation of immune reconstitution inflammatory syndrome (IRIS). IRIS, which is also known as immune restoration disease, refers to a disease- or pathogen-specific inflammatory response that may be triggered after ART initiation in treatment-naive patients, after re-initiation of ART, or after a change to a more effective ART regimen in patients who fail to achieve viral suppression. After a patient starts ART, IRIS may manifest as a worsening of previously diagnosed disease, termed paradoxical IRIS, or as the appearance of a previously undiagnosed disease, termed unmasking IRIS.

Terminology

• IRIS: An undesirable disease- or pathogen-specific inflammatory response that may be triggered by ART-associated immune system recovery.
• Immune restoration disease: Another name for IRIS.
• Paradoxical IRIS: Refers to the worsening of a previously diagnosed disease after ART initiation.
• Unmasking IRIS: Refers to the appearance of a previously undiagnosed disease following ART initiation.

IRIS is usually accompanied by an increase in CD4 count and/or a rapid decrease in viral load. Although most cases of IRIS occur in patients who have low CD4 counts and high viral loads at the time of ART initiation, IRIS can occur at any CD4 count [Breton, et al. 2004; Shelburne, et al. 2005a; Shelburne, et al. 2005b; Müller, et al. 2010; Novak, et al. 2012]. It usually presents within the first 4 to 8 weeks after ART initiation but has occurred many weeks later and in sequestered sites, such as bone [McComsey, et al. 2012].

Development and Pathogenesis of IRIS

IRIS often presents within the first 4 to 8 weeks after initiation of or a change in ART as mild to moderate disease or symptoms; life-threatening cases are rare [Müller, et al. 2010]. Although most cases of IRIS occur in patients who, at the time of ART initiation, have a low CD4 count, particularly below 50 cells/mm³, and a high viral load (>100,000 copies/mL) [Breton, et al. 2004; Shelburne, et al. 2005a; Shelburne, et al. 2005b; Müller, et al. 2010; Novak, et al. 2012], specific changes in these markers are not required for the diagnosis of IRIS. For example, IRIS may occur without a significant increase in the absolute CD4 count, suggesting that measurements obtained from the peripheral blood may not reflect the number of CD4 cells present at the site of an opportunistic infection (OI) [Haddow, et al. 2010b]. Some studies have found a higher incidence of IRIS in patients treated with regimens containing integrase strand transfer inhibitors. This may be related to the rapid drop in viral load seen in patients treated with these agents [Dutertre, et al. 2017; Psichogiou, et al. 2017; Wijting, et al. 2019].

Although understanding of the pathogenesis of IRIS, including the inflammatory role of T-regulatory cells and cytokine imbalances [Shankar, et al. 2008; Boulware, et al. 2010; Haddow, et al. 2010a], remains largely speculative, inflammatory reactions to many pathogens have been described, including mycobacteria, fungi, viruses, and bacteria (see Table 2: Major and Minor Presentations of IRIS). IRIS that involves worsening symptoms of some malignancies, including Kaposi’s sarcoma (KS) [Feller, et al. 2008], and autoimmune phenomena, such as sarcoid [Foulon, et al. 2004], also have been documented. IRIS may be more severe in patients with a higher burden of an OI organism, suggesting that antigen load may play a role in pathogenesis [Shelburne, et al. 2005a].

Paradoxical IRIS

“Paradoxical IRIS” describes the worsening of previously diagnosed disease after ART is initiated. Epidemiologic data regarding paradoxical IRIS are variable and depend largely on the CD4 count and the prevalence and types of OI present at the time of ART initiation. A review and meta-analysis of 54 cohort studies from 22 countries that included 13,903 patients initiating ART found that, overall, 13% of patients developed IRIS [Müller, et al. 2010]. In 22 studies (41%) that reported participants’ CD4 counts at the start of therapy, CD4 counts were low overall, with a median of 57 cells/mm³ (range, 17 to 174 cells/mm³), and occurrences of IRIS were significantly higher among patients with CD4 counts <50 cells/mm³. Though rates of IRIS were highest in patients with cytomegalovirus (CMV) retinitis (37.7%), it was also observed in patients with cryptococcal meningitis (19.5%), progressive multifocal leukoencephalopathy (16.7%), tuberculosis (TB) (15.7%), herpes zoster (12.2%), and KS (6.4%). As noted in the analysis, the higher occurrences of IRIS associated with CMV retinitis, in particular, were not surprising because this condition most often occurs at CD4 counts <50 cells/mm³. Significant heterogeneity between studies was also noted, in part, because of non-standardized diagnostic criteria and difficulty in distinguishing IRIS from the progression of OIs.

In the United States, the prospective AIDS Clinical Trials Group study A5164 reported IRIS in 7.6% of patients [Grant, et al. 2010], and another large multisite U.S. prospective cohort reported an occurrence of 10.6% [Novak, et al. 2012].

However, concurrent steroid treatment in some individuals and the studies’ inclusion of low numbers of patients with the OIs that are most commonly associated with IRIS may obscure the true incidence. Retrospective studies have reported a higher occurrence, with IRIS reported in 63% of patients with a history of CMV retinitis [Karavellas, et al. 1999] and in 30% to 34% of those with previously diagnosed cryptococcal infection [Shelburne, et al. 2005a; Shelburne, et al. 2005b]. Other retrospective studies have reported IRIS in 30% and 31% of patients with TB and Mycobacterium avium complex (MAC), respectively [Shelburne, et al. 2005b]. However, the studies were conducted in the era before early treatment, when ART was more often initiated in patients with low CD4 counts, and, as retrospective studies, are more likely to overestimate the incidence of IRIS.

Unmasking IRIS

“Unmasking IRIS” describes the appearance of previously undiagnosed disease after ART is initiated. Data on unmasking IRIS are limited primarily to case reports. A re-analysis of cohort data from 6 European countries and the United States found a significantly increased risk of MAC-IRIS up to 3 months after ART initiation. A slight but statistically nonsignificant increase of IRIS-associated TB, CMV retinitis, herpes simplex virus, KS, and non-Hodgkin lymphoma was reported among patients without HIV who had a median CD4 count of 279 cells/mm³ at the time of ART initiation. The epidemiologic patterns for MAC and TB were most consistent with unmasking IRIS [Lodi, et al. 2014]. In a French study of 47 patients taking ART at the time of TB diagnosis, 11 patients were diagnosed with unmasking TB-IRIS; identified risk factors for unmasking TB-IRIS included African origin, higher baseline RNA, and a strong response to ART [Valin, et al. 2010].

Mortality

IRIS is associated with an increased risk of death, with a reported overall mortality rate of 4.5% [Müller, et al. 2010; Novak, et al. 2012]. However, mortality rates depend on the associated OI, access to treatment, diagnostic criteria, degree of immunosuppression, and geography. In general, the highest mortality rates (13% to 75%) have been reported among patients with IRIS affecting the central nervous system [Müller, et al. 2010; Bahr, et al. 2013].

References

Bahr N, Boulware DR, Marais S, et al. Central nervous system immune reconstitution inflammatory syndrome. Curr Infect Dis Rep 2013;15(6):583-593. [PMID: 24173584]

Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med 2010;7(12):e1000384. [PMID: 21253011]

Breton G, Duval X, Estellat C, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004;39(11):1709-1712. [PMID: 15578375] 

Dutertre M, Cuzin L, Demonchy E, et al. Initiation of antiretroviral therapy containing integrase inhibitors increases the risk of IRIS requiring hospitalization. J Acquir Immune Defic Syndr 2017;76(1):e23-e26. [PMID: 28418992] 

Feller L, Anagnostopoulos C, Wood NH, et al. Human immunodeficiency virus-associated Kaposi sarcoma as an immune reconstitution inflammatory syndrome: a literature review and case report. J Periodontol 2008;79(2):362-368. [PMID: 18251652] 

Foulon G, Wislez M, Naccache JM, et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004;38(3):418-425. [PMID: 14727215] 

Grant PM, Komarow L, Andersen J, et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS One 2010;5(7):e11416. [PMID: 20617176] 

Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010a;10(11):791-802. [PMID: 21029993] 

Haddow LJ, Moosa MY, Easterbrook PJ. Validation of a published case definition for tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010b;24(1):103-108. [PMID: 19926965]

Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 1999;179(3):697-700. [PMID: 9952380] 

Lodi S, del Amo J, Moreno S, et al. Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries. AIDS 2014;28(16):2461-2473. [PMID: 25265230]

McComsey GA, Kitch D, Daar ES, et al. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir. AIDS 2012;26(11):1371-1385. [PMID: 22546988] 

Müller M, Wandel S, Colebunders R, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis 2010;10(4):251-261. [PMID: 20334848] 

Novak RM, Richardson JT, Buchacz K, et al. Immune reconstitution inflammatory syndrome: incidence and implications for mortality. AIDS 2012;26(6):721-730. [PMID: 22233655] 

Psichogiou M, Basoulis D, Tsikala-Vafea M, et al. Integrase strand transfer inhibitors and the emergence of immune reconstitution inflammatory syndrome (IRIS). Curr HIV Res 2017;15(6):405-410. [PMID: 29173177]

Shankar EM, Vignesh R, Velu V, et al. Does CD4+CD25+foxp3+ cell (Treg) and IL-10 profile determine susceptibility to immune reconstitution inflammatory syndrome (IRIS) in HIV disease? J Inflamm (Lond) 2008;5:2. [PMID: 18282273] 

Shelburne SA, Darcourt J, White AC, Jr., et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005a;40(7):1049-1052. [PMID: 15825000]

Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005b;19(4):399-406. [PMID: 15750393] 

Valin N, Pacanowski J, Denoeud L, et al. Risk factors for ‘unmasking immune reconstitution inflammatory syndrome’ presentation of tuberculosis following combination antiretroviral therapy initiation in HIV-infected patients. AIDS 2010;24(10):1519-1525. [PMID: 20549841]

Wijting IEA, Wit F, Rokx C, et al. Immune reconstitution inflammatory syndrome in HIV infected late presenters starting integrase inhibitor containing antiretroviral therapy. EClinicalMedicine 2019;17:100210. [PMID: 31891143] 

Timing of ART Initiation in Patients with Recent OIs and Prevention of IRIS

Reviewed and updated: James C. M. Brust, MD, April 2021

Initiating ART

Because ART is key to the recovery of immune function, the benefits of early ART initiation outweigh the risks of IRIS under most circumstances [Grant, et al. 2010; Lodi, et al. 2014]. Clinicians should strongly recommend that patients being treated for any of the following active infections initiate ART within 2 weeks of starting OI treatment or as soon as the patient is clinically stable on OI therapy and the potential for drug-drug interactions has been minimized:

• Cryptosporidiosis
• Microsporidiosis
• Progressive multifocal leukoencephalopathy
• Kaposi’s sarcoma (KS)
• Pneumocystis jiroveci pneumonia—formerly known as Pneumocystis carinii
• HBV infection
• HCV infection
• Any other serious bacterial infection

The optimal timing for ART initiation is not well established for other OIs, including TB meningitis, extrapulmonary TB, CMV retinitis, and cryptococcal meningitis, as described below. Clinicians should consult with a care provider experienced in the management of ART in patients with these infections.

Prevention of complications associated with IRIS involves careful monitoring, particularly in patients with low CD4 counts and past or current history of co-infections. After initiating ART in patients at the highest risk for IRIS, including those with CD4 counts <100 cells/mm³ or known concomitant OIs, clinicians should be vigilant for signs and symptoms of IRIS, which are described in more detail in the Presentation and Diagnosis of IRIS section of this guideline. These patients should be counseled about the risk of developing IRIS at the time of ART initiation. To promote trust in the treatment plan and adherence to ART, patients should be informed that starting ART could lead to an initial worsening of OI symptoms or the appearance of a previously undiagnosed OI (e.g., herpes zoster).

References

Grant PM, Komarow L, Andersen J, et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS One 2010;5(7):e11416. [PMID: 20617176] 

Lodi S, del Amo J, Moreno S, et al. Opportunistic infections and AIDS malignancies early after initiating combination antiretroviral therapy in high-income countries. AIDS 2014;28(16):2461-2473. [PMID: 25265230]

Pulmonary TB

Reviewed and updated: James C. M. Brust, MD, April 2021

IRIS has been described in 8% to 51% of patients with HIV and TB after initiation of ART [Meintjes, et al. 2008; Haddow, et al. 2010; Narendran, et al. 2013] with a reported overall mortality rate of 2% [Namale, et al. 2015]. In determining the timing of ART initiation in patients with HIV/TB co-infection, the risk of TB-IRIS and the overlapping toxicity, potential drug-drug interactions, and adherence challenges of multidrug therapy for HIV and TB warrant careful consideration.

Several studies have assessed the optimal timing of ART initiation during treatment for pulmonary TB [Abdool Karim, et al. 2010; Blanc, et al. 2011; Havlir, et al. 2011; Manosuthi, et al. 2012; Sinha, et al. 2012; Mfinanga, et al. 2014; Amogne, et al. 2015]. Results of a recent meta-analysis comparing ART initiation at 1 to 4 weeks after starting TB treatment with ART initiation at 8 to 12 weeks after starting TB treatment indicate that early ART reduced overall mortality. However, the decrease was statistically significant only in the subgroup of patients with CD4 counts <50 cells/mm³. Early ART doubled the incidence of TB-IRIS irrespective of CD4 count. The authors concluded that although early ART improves survival for patients with low CD4 counts, not enough evidence is available to support or refute a survival benefit from early ART in patients with pulmonary TB who have CD4 counts >50 cells/mm³. Further studies are needed to more definitively determine the CD4 count threshold below which the mortality benefit supports early initiation of ART [Uthman, et al. 2015].

Two trials compared ART initiation during TB treatment with deferral until after completion of TB treatment. The SAPIT trial (n = 642) in South Africa [Abdool Karim, et al. 2010], which evaluated patients with smear-positive TB, was stopped early because the mortality rate in the group that initiated ART during TB treatment was 56% lower than in the deferred group. The survival benefit of initiating ART before completing TB treatment was observed in all ranges of CD4 counts but was highest in patients with CD4 counts <50 cells/mm³. Although the incidence of IRIS was much higher in patients who initiated ART early, it was mostly mild and was outweighed by the other benefits of early treatment. The subsequent TB- HAART trial (n = 1,675), conducted in South Africa, Tanzania, Uganda, and Zambia [Mfinanga, et al. 2014], compared initiation of ART after 2 weeks of TB treatment with ART initiation deferred until after completion of 6 months of TB treatment in patients with CD4 counts >220 cells/mm³. More grade 3 and 4 adverse events were reported among those with early ART initiation, with no difference in mortality or IRIS incidence between early and deferred ART.

Although early ART increases the risk of TB-associated IRIS, this risk should be weighed against the survival benefit of early HIV treatment given a patient’s CD4 count. The benefits of early ART initiation in patients with active TB and very low CD4 counts (<50 cells/mm³) likely outweigh the risks for morbidity associated with TB-IRIS [Lawn, et al. 2007; Battegay, et al. 2008]. To decrease the risk of IRIS, initiation of ART may be safely delayed up to 12 weeks after starting TB therapy in patients with CD4 counts of ≥50 cells/mm³. Careful monitoring for IRIS, and timely treatment if it occurs, may significantly reduce morbidity associated with TB-IRIS; it may also ensure that other risks associated with severe immunosuppression (CD4 counts <50 cells/mm³) are managed effectively with ART.

A study of 240 patients enrolled in the PredART trial demonstrated that prednisone initiated around the time of ART initiation reduced the risk of IRIS in patients receiving TB treatment [Meintjes, et al. 2018]. ART-naive adults with HIV infection, CD4 counts <100 cells/mm³, who were on confirmed treatment for TB were randomized to receive either 40 mg per day of prednisone for 2 weeks followed by 20 mg per day of prednisone for 2 weeks or placebo. The prednisone and ART were initiated on the same day and were initiated within 30 days of the start of TB treatment. Use of corticosteroids was allowed to treat IRIS if it developed. Patients with rifampin resistance, central nervous system (CNS) TB, KS, HBVsAg+, or poor adherence were excluded from the study. In patients receiving prednisone, TB-IRIS was reduced by 30% (47% vs 33%; RR 0.7, p 0.03) and subsequent use of corticosteroids to treat IRIS was reduced by 53% (28% vs 13%; RR 0.47). Grade 3 adverse events were reduced from 45% to 28% (p 0.01), and fewer hospitalizations occurred in patients who received prednisone. The prednisone was well tolerated, and there were no additional infections or malignancies in patients receiving prednisone compared with those receiving placebo.

References

Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;362(8):697-706. [PMID: 20181971]

Amogne W, Aderaye G, Habtewold A, et al. Efficacy and safety of antiretroviral therapy initiated one week after tuberculosis therapy in patients with CD4 counts < 200 cells/μL: TB-HAART Study, a randomized clinical trial. PLoS One 2015;10(5):e0122587. [PMID: 25966339] 

Battegay M, Fehr J, Flückiger U, et al. Antiretroviral therapy of late presenters with advanced HIV disease. J Antimicrob Chemother 2008;62(1):41-44. [PMID: 18408235] 

Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365(16):1471-1481. [PMID: 22010913]

Haddow LJ, Moosa MY, Easterbrook PJ. Validation of a published case definition for tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24(1):103-108. [PMID: 19926965]

Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365(16):1482-1491. [PMID: 22010914]

Lawn SD, Myer L, Bekker LG, et al. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS 2007;21(3):335-341. [PMID: 17255740] 

Manosuthi W, Mankatitham W, Lueangniyomkul A, et al. Time to initiate antiretroviral therapy between 4 weeks and 12 weeks of tuberculosis treatment in HIV-infected patients: results from the TIME study. J Acquir Immune Defic Syndr 2012;60(4):377-383. [PMID: 22592586]

Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8(8):516-523. [PMID: 18652998] 

Meintjes G, Stek C, Blumenthal L, et al. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS. N Engl J Med 2018;379(20):1915-1925. [PMID: 30428290]

Mfinanga SG, Kirenga BJ, Chanda DM, et al. Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial. Lancet Infect Dis 2014;14(7):563-571. [PMID: 24810491]

Namale PE, Abdullahi LH, Fine S, et al. Paradoxical TB-IRIS in HIV-infected adults: a systematic review and meta-analysis. Future Microbiol 2015;10(6):1077-1099. [PMID: 26059627]

Narendran G, Andrade BB, Porter BO, et al. Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) in HIV patients with culture confirmed pulmonary tuberculosis in India and the potential role of IL-6 in prediction. PLoS One 2013;8(5):e63541. [PMID: 23691062]

Sinha S, Shekhar RC, Singh G, et al. Early versus delayed initiation of antiretroviral therapy for Indian HIV-Infected individuals with tuberculosis on antituberculosis treatment. BMC Infect Dis 2012;12:168. [PMID: 22846195] 

Uthman OA, Okwundu C, Gbenga K, et al. Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: a systematic review and meta-analysis. Ann Intern Med 2015;163(1):32-39. [PMID: 26148280]

TB Meningitis and Extrapulmonary TB

Reviewed and updated: James C. M. Brust, MD, April 2021

Compared with non-CNS-related diseases, IRIS-associated TB meningitis has a higher mortality rate [Marais, et al. 2013]. The optimal timing of ART initiation in patients treated for TB meningitis or extrapulmonary TB remains unclear. In a randomized controlled trial, initiation of ART within 7 days was not associated with increased survival for patients with TB meningitis compared with delaying treatment for 2 months. Although the incidence of severe (grade 3 and 4) adverse events was similar in the 2 groups, early initiation of ART was associated with a higher incidence of the most severe (grade 4) adverse events [Török, et al. 2011]. A 2- to 9-fold increased risk of development of IRIS has been described for patients with extrapulmonary TB after ART initiation [Namale, et al. 2015]; however, insufficient data are available to guide timing of ART initiation.

References

Marais S, Meintjes G, Pepper DJ, et al. Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome. Clin Infect Dis 2013;56(3):450-460. [PMID: 23097584]

Namale PE, Abdullahi LH, Fine S, et al. Paradoxical TB-IRIS in HIV-infected adults: a systematic review and meta-analysis. Future Microbiol 2015;10(6):1077-1099. [PMID: 26059627]

Török ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)–associated tuberculous meningitis. Clin Infect Dis 2011;52(11):1374-1383. [PMID: 21596680]

Cryptococcal Meningitis

Reviewed and updated: James C. M. Brust, MD, April 2021

With rapid immune reconstitution in patients with cryptococcal meningitis, there is a risk of increased inflammatory response in the meninges that can lead to paradoxical worsening of the symptoms and, sometimes, death. Paradoxical IRIS was noted in 6% to 45% of patients with cryptococcal meningitis following ART initiation [Longley, et al. 2013]. Most cases occurred within the first 1 to 2 months, but some occurred 6 to 9 months later. The presentation of cryptococcal IRIS may mimic aseptic meningitis and can be difficult to distinguish from progression of cryptococcal disease associated with treatment failure [Bicanic, et al. 2009; Boulware, et al. 2010; Haddow, et al. 2010].

The optimal timing of ART initiation in patients with cryptococcal meningitis is controversial, with inconclusive study results among the 4 trials conducted to date. In 2 studies (each with fewer than 40 participants with cryptococcal meningitis), initiation of ART within 2 weeks of diagnosis was observed to be safe but without significant improvement in survival [Zolopa, et al. 2009; Bisson, et al. 2013]. In contrast, 2 clinical trials were stopped early because of a high mortality rate in the early ART arm [Makadzange, et al. 2010; Boulware, et al. 2014]. In a study from Zimbabwe of 54 patients with cryptococcal meningitis, administration of ART within 72 hours of diagnosis resulted in higher mortality than when ART was deferred for 10 or more weeks [Makadzange, et al. 2010]. The more recent and larger COAT trial involving 177 ART-naive patients with HIV and cryptococcal meningitis in Uganda and South Africa was also stopped early because of a 15% higher mortality in the group randomized to ART initiation within 2 weeks compared with delaying treatment by at least 5 weeks [Boulware, et al. 2014]. However, interpretation of results is limited because neither trial included flucytosine in the cryptococcal treatment regimen [Scriven, et al. 2015].

Until further studies are available to definitively determine the optimal time for ART initiation for patients with cryptococcal meningitis, treatment should be delayed for at least 2 weeks (after completion of antifungal therapy induction phase) and possibly for up to 10 weeks (after completion of both induction and consolidation phases of antifungal therapy), particularly in those with increased intracranial pressure or low cerebral spinal fluid white blood cell counts. If ART is started before 10 weeks, clinicians should be vigilant for signs and symptoms of IRIS and aggressively manage any complications. The optimal timing for initiation of ART for other forms of cryptococcosis is also unclear; it is recommended to delay ART initiation for at least 2 weeks after starting antifungal therapy [Clinical Info HIV.gov 2019].

References

Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009;51(2):130-134. [PMID: 19365271]

Bisson GP, Molefi M, Bellamy S, et al. Early versus delayed antiretroviral therapy and cerebrospinal fluid fungal clearance in adults with HIV and cryptococcal meningitis. Clin Infect Dis 2013;56(8):1165-1173. [PMID: 23362285] 

Boulware DR, Bonham SC, Meya DB, et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis 2010;202(6):962-970. [PMID: 20677939]

Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014;370(26):2487-2498. [PMID: 24963568]

Clinical Info HIV.gov. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV: Cryptococcosis. 2019 Jun 26. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/cryptococcosis?view=full [accessed 2021 Mar 8]

Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010;10(11):791-802. [PMID: 21029993] 

Longley N, Harrison TS, Jarvis JN. Cryptococcal immune reconstitution inflammatory syndrome. Curr Opin Infect Dis 2013;26(1):26-34. [PMID: 23242412] 

Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis 2010;50(11):1532-1538. [PMID: 20415574] 

Scriven JE, Rhein J, Hullsiek KH, et al. Early ART after cryptococcal meningitis is associated with cerebrospinal fluid pleocytosis and macrophage activation in a multisite randomized trial. J Infect Dis 2015;212(5):769-778. [PMID: 25651842] 

Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009;4(5):e5575. [PMID: 19440326] 

CMV Retinitis

Reviewed and updated: James C. M. Brust, MD, April 2021

Immediate initiation of ART is not recommended based on the results of a controlled study that reported a lower prevalence and severity of immune recovery uveitis in patients with deferred initiation of ART [Ortega-Larrocea, et al. 2005]. The optimal timing for initiation of ART in patients treated for CMV retinitis has not been definitively established. The overall incidence of CMV-IRIS has declined to an estimated 2.7 to 3.6 per 100 person-years in recent years [Jabs, et al. 2010; Jabs, et al. 2015], and the risk of IRIS should be weighed against the risk of developing other OIs due to delay in ART initiation.

To avoid the possible devastating effects of CMV-IRIS, ART should not be started immediately in patients with known or strongly suspected CMV. All patients with HIV who have CD4 counts <100 cells/mm³ who do not have known or strongly suspected CMV should be screened for signs of CMV by dilated ophthalmologic examination as soon as possible after initiation of ART. If signs of CMV are seen on dilated exam, clinicians should consult with an experienced HIV care provider to determine if ART must be temporarily paused. In mild cases, it may be appropriate to continue ART while treating the CMV, but such patients must be followed closely by an ophthalmologist with experience in managing CMV retinitis.

Even if receiving treatment, patients with a history of CMV retinitis should receive a dilated ophthalmologic examination every 3 months for the first year after initiation of ART and immediately if there is a change in visual acuity or development of floaters. Cases of CMV-IRIS myelopathy that respond to steroids have been reported, as have cases of CMV-IRIS colitis [Acosta, et al. 2008; von Both, et al. 2008]. (See DHHS > Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV > Cytomegalovirus Disease for more information.)

References

Acosta RD, Mays BC, Wong RK. Electronic clinical challenges and images in GI. CMV colitis with immune reconstitution syndrome. Gastroenterology 2008;134(2):e1-2. [PMID: 18242197] 

Jabs DA, Ahuja A, Van Natta M, et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: five-year outcomes. Ophthalmology 2010;117(11):2152-2161.e2151-2152. [PMID: 20673591] 

Jabs DA, Ahuja A, Van Natta ML, et al. Long-term outcomes of cytomegalovirus retinitis in the era of modern antiretroviral therapy: Results from a United States cohort. Ophthalmology 2015;122(7):1452-1463. [PMID: 25892019] 

Ortega-Larrocea G, Espinosa E, Reyes-Terán G. Lower incidence and severity of cytomegalovirus-associated immune recovery uveitis in HIV-infected patients with delayed highly active antiretroviral therapy. AIDS 2005;19(7):735-738. [PMID: 15821403] 

von Both U, Laffer R, Grube C, et al. Acute cytomegalovirus colitis presenting during primary HIV infection: an unusual case of an immune reconstitution inflammatory syndrome. Clin Infect Dis 2008;46(4):e38-40. [PMID: 18199043] 

Presentation and Diagnosis of IRIS

Reviewed and updated: James C. M. Brust, MD, April 2021

Table 2, below, describes major and minor clinical presentations of IRIS. Proposed case definitions do not provide clear consensus on the many manifestations of IRIS [French, et al. 2004; Robertson, et al. 2006; Shelburne, et al. 2006; Meintjes, et al. 2008; Bicanic, et al. 2009; Haddow, et al. 2010a; Haddow, et al. 2010b]. Common features are clinical deterioration after ART initiation and localized tissue inflammation, with or without a systemic inflammatory response [Walker, et al. 2015], but the presentation of IRIS varies depending on the underlying opportunistic infection (OI) or illness. The majority of IRIS cases occur within 4 to 8 weeks after initiation of or a change in ART [Breton, et al. 2004; Shelburne, et al. 2005a; Novak, et al. 2012]. However, cases have been reported as early as 3 days or as late as several months, or, rarely, several years, after ART initiation [Rambeloarisoa, et al. 2002; Lortholary, et al. 2005; Shelburne, et al. 2005b; Haddow, et al. 2010b; Valin, et al. 2010; Novak, et al. 2012; Letang, et al. 2013]. Late manifestations of IRIS (>7 months) may be atypical, such as osteomyelitis resulting from Mycobacterium avium complex [Aberg, et al. 2002].

A definitive diagnostic test is not available for IRIS; therefore, diagnosis is based largely on clinical judgment, which may be challenged by the broad array of IRIS signs and symptoms and the presence of multiple OIs. A rise in CD4 count is often present in IRIS cases but is not a required criterion for diagnosis [Robertson, et al. 2006; Meintjes, et al. 2008; Haddow, et al. 2010a; Haddow, et al. 2010b; Walker, et al. 2015]; therefore, absence of an increase in absolute CD4 count should not exclude the possibility of IRIS during a paradoxical response to treatment of an OI.

In patients who were responding favorably to OI treatment prior to ART initiation, but who worsen after, the differential diagnosis includes OI treatment toxicity, OI drug resistance, poor OI treatment adherence, or development of a new OI. Development of a new OI after ART initiation of ART may be attributable to unmasking IRIS or to the effects of persistent immune compromise [Walker, et al. 2015].

References

Aberg JA, Chin-Hong PV, McCutchan A, et al. Localized osteomyelitis due to Mycobacterium avium complex in patients with Human Immunodeficiency Virus receiving highly active antiretroviral therapy. Clin Infect Dis 2002;35(1):E8-e13. [PMID: 12060894] 

Anderson AM, Mosunjac MB, Palmore MP, et al. Development of fatal acute liver failure in HIV-HBV coinfected patients. World J Gastroenterol 2010;16(32):4107-4111. [PMID: 20731028] 

Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009;51(2):130-134. [PMID: 19365271] 

Bowen LN, Smith B, Reich D, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nat Rev Neurol 2016;12(11):662-674. [PMID: 27786246] 

Bower M, Nelson M, Young AM, et al. Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. J Clin Oncol 2005;23(22):5224-5228. [PMID: 16051964] 

Breton G, Duval X, Estellat C, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis 2004;39(11):1709-1712. [PMID: 15578375] 

Crane M, Oliver B, Matthews G, et al. Immunopathogenesis of hepatic flare in HIV/hepatitis B virus (HBV)-coinfected individuals after the initiation of HBV-active antiretroviral therapy. J Infect Dis 2009;199(7):974-981. [PMID: 19231993] 

Drake A, Mijch A, Sasadeusz J. Immune reconstitution hepatitis in HIV and hepatitis B coinfection, despite lamivudine therapy as part of HAART. Clin Infect Dis 2004;39(1):129-132. [PMID: 15206064] 

Foulon G, Wislez M, Naccache JM, et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004;38(3):418-425. [PMID: 14727215] 

French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004;18(12):1615-1627. [PMID: 15280772] 

Gray F, Bazille C, Adle-Biassette H, et al. Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol 2005;11 Suppl 3:16-22. [PMID: 16540449] 

Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010a;10(11):791-802. [PMID: 21029993] 

Haddow LJ, Moosa MY, Easterbrook PJ. Validation of a published case definition for tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010b;24(1):103-108. [PMID: 19926965] 

Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 2008;46(11):1694-1701. [PMID: 18433339] 

Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 1999;179(3):697-700. [PMID: 9952380] 

Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS 2005;19(6):593-601. [PMID: 15802978] 

Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005a;5(6):361-373. [PMID: 15919622]

Lawn SD, Bekker LG, Myer L, et al. Cryptococcocal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme. AIDS 2005b;19(17):2050-2052. [PMID: 16260920]

Lawn SD, Wood R. Hepatic involvement with tuberculosis-associated immune reconstitution disease. AIDS 2007;21(17):2362-2363. [PMID: 18090294]

Leidner RS, Aboulafia DM. Recrudescent Kaposi’s sarcoma after initiation of HAART: a manifestation of immune reconstitution syndrome. AIDS Patient Care STDS 2005;19(10):635-644. [PMID: 16232048] 

Letang E, Lewis JJ, Bower M, et al. Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK. AIDS 2013;27(10):1603-1613. [PMID: 23462220] 

Lortholary O, Fontanet A, Mémain N, et al. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005;19(10):1043-1049. [PMID: 15958835] 

Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8(8):516-523. [PMID: 18652998] 

Meintjes G, Rangaka MX, Maartens G, et al. Novel relationship between tuberculosis immune reconstitution inflammatory syndrome and antitubercular drug resistance. Clin Infect Dis 2009;48(5):667-676. [PMID: 19191655] 

Novak RM, Richardson JT, Buchacz K, et al. Immune reconstitution inflammatory syndrome: incidence and implications for mortality. AIDS 2012;26(6):721-730. [PMID: 22233655]

Odongo FC. Fatal disseminated Kaposi’s sarcoma due to immune reconstitution inflammatory syndrome following HAART initiation. Case Rep Infect Dis 2013;2013:546578. [PMID: 23936695] 

Perrella O, Sbreglia C, De Sena R, et al. Immune reconstitution: bad or good factor in hepatitis B virus and HIV co-infection? AIDS 2006;20(5):790-791. [PMID: 16514319]

Rambeloarisoa J, Batisse D, Thiebaut JB, et al. Intramedullary abscess resulting from disseminated cryptococcosis despite immune restoration in a patient with AIDS. J Infect 2002;44(3):185-188. [PMID: 12099747]

Rasul S, Delapenha R, Farhat F, et al. Graves’ disease as a manifestation of immune reconstitution in HIV-infected individuals after initiation of highly active antiretroviral therapy. AIDS Res Treat 2011;2011:743597. [PMID: 21804938] 

Robertson J, Meier M, Wall J, et al. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 2006;42(11):1639-1646. [PMID: 16652323] 

Safdar A, Rubocki RJ, Horvath JA, et al. Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 2002;35(10):1250-1257. [PMID: 12410486] https://pubmed.ncbi.nlm.nih.gov/12410486

Shelburne SA, Darcourt J, White AC, Jr., et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005a;40(7):1049-1052. [PMID: 15825000] 

Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 2006;57(2):167-170. [PMID: 16354748] 

Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005b;19(4):399-406. [PMID: 15750393] 

Stover KR, Molitorisz S, Swiatlo E, et al. A fatal case of kaposi sarcoma due to immune reconstitution inflammatory syndrome. Am J Med Sci 2012;343(5):421-425. [PMID: 22227511]

Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009;72(17):1458-1464. [PMID: 19129505] 

Valin N, Pacanowski J, Denoeud L, et al. Risk factors for ‘unmasking immune reconstitution inflammatory syndrome’ presentation of tuberculosis following combination antiretroviral therapy initiation in HIV-infected patients. AIDS 2010;24(10):1519-1525. [PMID: 20549841] 

Volkow P, Cesarman-Maus G, Garciadiego-Fossas P, et al. Clinical characteristics, predictors of immune reconstitution inflammatory syndrome and long-term prognosis in patients with Kaposi sarcoma. AIDS Res Ther 2017;14(1):30. [PMID: 28558783] 

Walker NF, Scriven J, Meintjes G, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients. HIV AIDS (Auckl) 2015;7:49-64. [PMID: 25709503] 

Management and Treatment of IRIS

Reviewed and updated: James C. M. Brust, MD, April 2021

Whenever IRIS is suspected, initial efforts should focus on diagnosing and treating the underlying OI. IRIS resolves over time in most patients, and if not severe, symptomatic treatment is often sufficient.

Mild IRIS

When minor IRIS presentations occur, clinicians can reassure patients that symptoms are an indication of immune reconstitution rather than progression of HIV disease and will resolve with standard treatment. In addition to standard therapy for the underlying OI to reduce pathogen load, the following treatments may alleviate inflammation in patients with mild IRIS:

• Nonsteroidal anti-inflammatory agents for discomfort associated with mild inflammation or fevers
• Drainage of abscesses
• Excision of inflamed and painful lymph nodes
• Inhaled steroids for bronchospasm or cough associated with mild pulmonary inflammation

Severe IRIS

Severe IRIS may threaten a patient’s functional status or may cause permanent disability. Examples of this are a decline in pulmonary capacity from TB or Mycobacterium avium complex (MAC) infection, neurologic complications from cryptococcal infection, or vision loss from CMV retinitis infection.

Corticosteroid therapy to suppress inflammatory response is the most commonly used intervention in cases of severe IRIS. Studies to determine the effectiveness of corticosteroid treatment are limited. A randomized, placebo-controlled trial demonstrated benefits of corticosteroids for paradoxical TB-IRIS [Meintjes, et al. 2010], and a study of patients with MAC-IRIS (n = 9) demonstrated clinical response to prednisone [Phillips, et al. 2005]. No trials have compared different dosing regimens of corticosteroids, but this Committee recommends 1 to 2 mg/kg prednisone, or the equivalent, for 1 to 2 weeks, followed by a period of tapering dose that is individualized. If a flare of symptoms occurs during or at the end of the steroid taper, the dose may be increased and the taper slowed, and the patient should be assessed for possible disease progression due to failure of treatment.

The risks of corticosteroid therapy should be weighed against the severity of the IRIS manifestations and the potential benefits, particularly given the high prevalence of type 2 diabetes, hypertension, and mental health disorders among patients with HIV. Risks of corticosteroid therapy include the following:

• Hyperglycemia
• Hypertension
• Mental status changes
• Avascular necrosis
• Worsening of an existing infection
• Predisposition to a new infection

Except in the most severe cases, ART should not be interrupted in patients with IRIS. Discontinuation of ART can be considered in life-threatening cases in which corticosteroids did not result in improvement, usually associated with central nervous system (CNS)-IRIS. Risks of stopping combination ART include acquisition of new OIs and recurrence of IRIS when therapy is later restarted. HIV drug resistance may also be a theoretical concern. The decision to stop ART should be made in consultation with an experienced HIV care provider if possible.

In cases of cryptococcal-IRIS with worsening meningitis symptoms, including cranial nerve defects, hearing, or vision changes, therapeutic lumbar puncture can be used to lower intracranial pressure. Corticosteroids are not recommended for treatment of cryptococcal meningitis in patients with HIV. A trial of treatment of HIV-associated cryptococcal meningitis with dexamethasone was stopped because of the high incidence of adverse events and disability observed in the treatment arm compared with placebo [Beardsley, et al. 2016].

Corticosteroids are associated with increased risk of development of new KS or worsening of pre-existing disease among patients with HIV [Gill, et al. 1989; Elliott, et al. 2004; Volkow, et al. 2008]. Treatment of CMV vitritis with intraocular steroids has been described [Schrier, et al. 2006] but has not been useful in uveitis.

There are limited case reports of improvement in clinical symptoms following treatment with thalidomide and other immunomodulators (pentoxifylline, chloroquine, TNF-a inhibitors, leukotriene antagonists) in patients with severe disease [Hardwick, et al. 2006; Marais, et al. 2009; Brunel, et al. 2012; Meintjes, et al. 2012; Fourcade, et al. 2014]. However, data are insufficient to recommend the use of these alternative therapies.

The CCR5 inhibitor maraviroc has been used for treatment of progressive multifocal leukoencephalopathy-associated IRIS because direct treatment for JC virus is not available to lower the pathogen burden and treatment with corticosteroids may dampen the immune response. However, case reports indicate mixed success [Martin-Blondel, et al. 2009; Giacomini, et al. 2014; Rodríguez, et al. 2014], and a recent randomized, placebo-controlled trial found that maraviroc was not effective for prevention of IRIS in patients starting ART with CD4 count <100 cells/mm³ and HIV RNA >1,000 copies/mL [Sierra-Madero, et al. 2014].

For further OI-specific guidance on management of IRIS, see DHHS > Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV [McComsey, et al. 2012].

References

Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 2016;374(6):542-554. [PMID: 26863355]

Brunel AS, Reynes J, Tuaillon E, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012;26(16):2110-2112. [PMID: 22874513] 

Elliott AM, Luzze H, Quigley MA, et al. A randomized, double-blind, placebo-controlled trial of the use of prednisolone as an adjunct to treatment in HIV-1-associated pleural tuberculosis. J Infect Dis 2004;190(5):869-878. [PMID: 15295690] 

Fourcade C, Mauboussin JM, Lechiche C, et al. Thalidomide in the treatment of immune reconstitution inflammatory syndrome in HIV patients with neurological tuberculosis. AIDS Patient Care STDS 2014;28(11):567-569. [PMID: 25285462] 

Giacomini PS, Rozenberg A, Metz I, et al. Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. N Engl J Med 2014;370(5):486-488. [PMID: 24476450]

Gill PS, Loureiro C, Bernstein-Singer M, et al. Clinical effect of glucocorticoids on Kaposi sarcoma related to the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989;110(11):937-940. [PMID: 2719427] 

Hardwick C, White D, Morris E, et al. Montelukast in the treatment of HIV associated immune reconstitution disease. Sex Transm Infect 2006;82(6):513-514. [PMID: 17151039] 

Marais S, Wilkinson RJ, Pepper DJ, et al. Management of patients with the immune reconstitution inflammatory syndrome. Curr HIV/AIDS Rep 2009;6(3):162-171. [PMID: 19589302]

Martin-Blondel G, Cuzin L, Delobel P, et al. Is maraviroc beneficial in paradoxical progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome management? AIDS 2009;23(18):2545-2546. [PMID: 19907215] 

McComsey GA, Kitch D, Daar ES, et al. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir. AIDS 2012;26(11):1371-1385. [PMID: 22546988] 

Meintjes G, Scriven J, Marais S. Management of the immune reconstitution inflammatory syndrome. Curr HIV/AIDS Rep 2012;9(3):238-250. [PMID: 22752438] 

Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24(15):2381-2390. [PMID: 20808204] 

Phillips P, Bonner S, Gataric N, et al. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis 2005;41(10):1483-1497. [PMID: 16231262] 

Rodríguez M, Silva-Sánchez FA, Luna-Rivero C, et al. Maraviroc failed to control progressive multifocal leukoencephalopathy-associated IRIS in a patient with advanced HIV infection. Case Rep Med 2014;2014:381480. [PMID: 25587282] 

Schrier RD, Song MK, Smith IL, et al. Intraocular viral and immune pathogenesis of immune recovery uveitis in patients with healed cytomegalovirus retinitis. Retina 2006;26(2):165-169. [PMID: 16467672] 

Sierra-Madero JG, Ellenberg SS, Rassool MS, et al. Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial. Lancet HIV 2014;1(2):e60-67. [PMID: 26423989] 

Volkow P, Cornejo P, Zinser JW, et al. Life-threatening exacerbation of Kaposi’s sarcoma after prednisone treatment for immune reconstitution inflammatory syndrome. AIDS 2008;22(5):663-665. [PMID: 18317012] 

All Recommendations

Reviewed and updated: James C. M. Brust, MD, April 2021

Updates to This Guideline

April 2021

• Citations and references have been updated throughout the guideline.
• New key point added to Timing of ART Initiation in Patients with Recent OIs and Prevention of IRIS section:
  • Clinicians should strongly recommend that patients being treated for infections other than TB meningitis, cryptococcal disease, and CMV retinitis initiate ART within 2 weeks of starting OI treatment or as soon as the patient is clinically stable on OI therapy and the potential for drug-drug interactions has been minimized.
• Recommendations for initiation of ART in patients with CMV retinitis have been updated. 
• New recommendation added to Management and Treatment of Iris section:
  • Clinicians should not use prednisone to prevent IRIS in patients with low CD4 counts who do not have active TB. (A3)