Immune Restoration Disease After Antiretroviral Therapy

Martyn A. French; Patricia Price; Shelley F. Stone


AIDS. 2004;18(12) 

In This Article

Abstract and Introduction

Suppression of HIV replication by highly active antiretroviral therapy (HAART) often restores protective pathogen-specific immune responses, but in some patients the restored immune response is immunopathological and causes disease [immune restoration disease (IRD)]. Infections by mycobacteria, cryptococci, herpesviruses, hepatitis B and C virus, and JC virus are the most common pathogens associated with infectious IRD. Sarcoid IRD and autoimmune IRD occur less commonly. Infectious IRD presenting during the first 3 months of therapy appears to reflect an immune response against an active (often quiescent) infection by opportunistic pathogens whereas late IRD may result from an immune response against the antigens of non-viable pathogens. Data on the immunopathogenesis of IRD is limited but it suggests that immunopathogenic mechanisms are determined by the pathogen. For example, mycobacterial IRD is associated with delayed-type hypersensitivity responses to mycobacterial antigens whereas there is evidence of a CD8 T-cell response in herpesvirus IRD. Furthermore, the association of different cytokine gene polymorphisms with mycobacterial or herpesvirus IRD provides evidence of different pathogenic mechanisms as well as indicating a genetic susceptibility to IRD. Differentiation of IRD from an opportunistic infection is important because IRD indicates a successful, albeit undesirable, effect of HAART. It is also important to differentiate IRD from drug toxicity to avoid unnecessary cessation of HAART. The management of IRD often requires the use of anti-microbial and/or anti-inflammatory therapy. Investigation of strategies to prevent IRD is a priority, particularly in developing countries, and requires the development of risk assessment methods and diagnostic criteria.

Treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy (HAART) partially corrects the immune defects caused by chronic HIV infection. It was apparent that this included restoration of protective pathogen-specific immune responses shortly after the introduction of HAART because opportunistic infections were reported to resolve.[1] This has resulted in a sharp decline in the prevalence of opportunistic infections in HIV patients.[2] Furthermore, studies of the effect of HAART on cytomegalovirus (CMV) viraemia and CMV-specific CD4 T-cell responses[3,4] have provided direct evidence that HAART enhances protective pathogen-specific immune responses.

Suppression of HIV viraemia by antiretroviral therapy is accompanied by atypical 'opportunistic infections' or other inflammatory diseases in some patients. When these conditions were first reported, there was uncertainty about whether they were a consequence of the restoration of an immune response against opportunistic pathogens, or opportunistic infections resulting from residual defects of cell-mediated immunity.[5,6,7,8,9] Subsequently, there has been acceptance that they are a consequence of immune reconstitution in patients who experience a virological response to HAART. These conditions have previously been reviewed,[10,11,12,13,14,15] although there has been a divergence of opinion about nomenclature and there continues to be uncertainty about pathogenic mechanisms and management. Here, we argue that atypical 'opportunistic infections' after commencing HAART are the consequence of restoring an immune response against the antigens of opportunistic pathogens that is immunopathological rather than protective. These conditions are therefore considered to be immune restoration disease (IRD) rather than immunodeficiency disease.

Sarcoid-like disease and autoimmune diseases are observed less frequently in patients responding to HAART and also appear to have an immunological basis. These conditions will also be considered as IRD. However, there is a need to differentiate the different types of IRD and we will consider them under the headings of infectious IRD, sarcoid IRD and autoimmune IRD.

As the use of HAART increases around the world, physicians managing patients with HIV infection will encounter increasing numbers of patients with IRD. Management of these conditions is often problematic, in particular their differentiation from opportunistic infections or drug toxicity. It is therefore important to understand the immunopathogenesis of IRD so that diagnostic criteria and prevention and treatment strategies can be developed.


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