What Is Immune Restoration Inflammatory Syndrome Resulting From Highly Active Antiretroviral Therapy (HAART)?

John R. Roberts, MSN, RNCS, ANP


February 06, 2001


Could you explain the immune restoration inflammatory syndrome that sometimes results from treatment with highly active antiretroviral therapy (HAART)?

Response from John R. Roberts, MSN, RNCS, ANP

Highly active antiretroviral therapy (HAART) has given clinicians the ability to suppress viral levels to very low levels, currently less than 50 copies per mL of blood. In the presence of full (or even partial) suppression of viral replication, we have seen recovery of the immune system as clinically measured by the CD4+ or T-helper cell count. This viral suppression has been accompanied by the recovery of immune system function as evidenced by the ability of persons living with HIV/AIDS to discontinue prophylaxis for common opportunistic pathogens without an increase in the incidence of those infections.

Discontinuation of Pneumocystis carinii pneumonia (PCP) prophylactic treatment in HIV/AIDS patients is a prime example. The degree and completeness of recovery of immune function in these patients is influenced by various factors, including a person's age and genetic makeup, the duration of HIV infection, the baseline CD4+ cell count, and the baseline viral load, as well as the effectiveness and durability of the antiretroviral treatment.[1,2,3]

There can be instances of a condition termed immune restoration inflammatory syndrome, or immunorestitution disease, in which the recovering immune system responds exuberantly to a previously existing infectious process. This condition may present in response to mycobacterial infection, in which cervical and mediastinal adenitis may develop as the immune system responds to the presence of Mycobacterium avium (MAC) infection. This response has been seen within the first 3 months on HAART, and represents an improvement in immune system function.[4,5]

A patient on effective HAART (as evidenced by a decrease in HIV viral load, with or without CD4+ cell count rise) who develops fever and/or tissue inflammation presents a diagnostic challenge. Possibilities include:

  • Infection with an opportunistic pathogen that occurs because specific responses of the immune system have not been recovered;

  • Inflammation that occurs because of the restoration of previously impaired immune function;

  • An adverse reaction to HAART.

The diagnostic challenge increases when a specific causative agent cannot be identified. Withdrawal of effective therapy would potentially reduce future therapeutic options. Certain pre-existing subclinical infections, hepatitis B and C virus, cytomegalovirus, and mycobacterial infections have been associated with the return of specific immune responses. Clinical investigation is under way to determine useful approaches to measure this response and to look for pretreatment antimicrobial strategies based on other clinical markers. For now, a general approach to treatment is to presumptively begin antimicrobial therapy, adding anti-inflammatory agents such as corticosteroids to combat organ dysfunction and pain as necessary. Symptom-specific palliative care measures may also be attempted. Discontinuation of HAART, even temporarily, should be reserved as a last resort.


While it may seem that individuals deteriorate on HAART (unrelated to the medication adverse effects), the overall experience has been one of improved immune function. As evidenced by the declining AIDS death rate, treatment with HAART serves to prolong the time before the occurrence of AIDS-defining conditions, or serious illness leading to AIDS-related deaths. Despite the improved response, prevention of HIV infection remains an urgent priority. While the rate of new infections in the United States remains at a stable, constant rate, the rate of new infections in most of the developing world is increasing.[7]


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