Immune Restoration Disease After Antiretroviral Therapy

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


AIDS. 2004;18(12) 

In This Article


The increasing use of HAART in developing countries and late presentation of HIV patients in some developed countries[148] will inevitably result in a large number of severely immunodeficient patients being given HAART. There will therefore be many patients at-risk of developing IRD. Although some IRD are short-lived or cause minor clinical problems, others may result in significant morbidity and sometimes death. Infectious IRD of the central nervous system is of particular concern because it may result in permanent neurological disability or death.[6,93,96,102,104]

Strategies should therefore be devised to prevent IRD. In patients about to commence a new HAART regimen, these might include identification of patients with risk-factors for infectious IRD (see Fig. 1) so that subclinical infection by opportunistic pathogens can be excluded, or measures taken to reduce pathogen load in patients with an opportunistic infection. However, the potential benefits of delaying HAART to prevent IRD in patients receiving treatment for an opportunistic infection might be outweighed by the risk of developing another opportunistic infection if HAART is delayed. This issue should be examined in prospective clinical studies.

The development of new therapeutic approaches for IRD requires a better understanding of pathogenic mechanisms. It has become clear that infectious IRD has two patterns of presentation. Early IRD presents during the first 3 months of HAART and appears to result from an immune response against viable opportunistic pathogens, which are often present as a subclinical infection. An exception may be VZV IRD, which sometimes presents later than 3 months because VZV infection reactivates infrequently.[6] Late IRD presents month to years after commencing HAART and appears to result from an immune response against the antigens of non-viable opportunistic pathogens. Cryptococcal lymphadenitis and CMV IRU are good examples of this. Anti-microbial therapy is unlikely to be effective. Late IRD would appear to be different to the opportunistic infections, such as localized MAC infection,[149,150] that occur infrequently in patients who had nadir CD4 T-cell counts of < 50 × 106 cells/l and cease prophylaxis because their CD4 T-cell count has increased on HAART. This type of disease is characterized by isolation of viable pathogens and is probably the result of an immune defect that has not been corrected by HAART, which might include deficiency of type 1 cytokines.[151]

Finally, it has become clear that the immunopathological response to different pathogens has different pathogenic mechanisms. Mycobacterial and fungal IRD appear to be the result of a DTH response whereas IRD associated with viruses, such as herpes viruses and JCV, appear to result from a CD8 T-cell response. The association of mycobacterial and herpes virus IRD with polymorphisms in the genes encoding different cytokines[120] provides further evidence of different types of immune response. The long-term effect of these immunopathological responses is unclear. The increase in plasma bioavailable IL-6 in patients with CMV retinitis IRD persists for at least 4 years,[87] which may partly explain the elevation of plasma IL-6 levels in patients with a previous history of IRD.[152] Mycobacterial IRD may also increase the plasma IL-6 level[153] but the effect is transient. The immunological and metabolic consequences of increased IL-6 production deserve further attention as it might contribute to persistent immune activation in patients with well-controlled HIV replication on HAART[154] or to the pathogenesis of type 2 diabetes,[155] which is increasingly being recognized as a long-term complication of HAART.[156]


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