Opportunistic infections and immune reconstitution inflammatory syndrome in HIV-1-infected adults in the combined antiretroviral therapy era: a comprehensive review

Abstract

Despite the availability of effective combined antiretroviral treatment, many patients still present with advanced HIV infection, often accompanied by an AIDS-defining disease. A subgroup of patients starting antiretroviral treatment under these clinical conditions may experience paradoxical worsening of their disease as a result of an exaggerated immune response towards an active (but also subclinical) infectious agent, despite an appropriate virological and immunological response to the treatment. This clinical condition, known as immune reconstitution inflammatory syndrome, may cause significant morbidity and even mortality if it is not promptly recognized and treated. This review updates current knowledge about the incidence, diagnostic criteria, risk factors, clinical manifestations, and management of opportunistic infections and immune reconstitution inflammatory syndrome in the combined antiretroviral treatment era.

Keywords:

• AIDS-defining diseases
• combined antiretroviral therapy
• immune reconstitution inflammatory syndrome
• IRIS definition
• IRIS incidence
• IRIS management
• IRIS treatment
• Kaposi sarcoma
• opportunistic infections
• TB

Financial & competing interests disclosure

This work was partially supported by the Fundación Máximo Soriano Jiménez (Barcelona, Spain), the ‘Red Temática Cooperativa de Grupos de Investigación en Sida del Fondo de Investigación Sanitaria (FIS) and grant ISCIII-RETIC RD06/006 from the Instituto de Salud Carlos III, Madrid (Spain). In 2011, JM Miró received an INT10/219 Research Intensification Grant (I3SNS & PRICS programs) from the Instituto de Salud Carlos III, Madrid (Spain) and the Departament de Salut de la Generalitat de Catalunya, Barcelona (Spain). No additional external funding was received for this study. The funders had no role in the preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Immune reconstitution inflammatory syndrome (IRIS) is defined as a worsening of clinical condition in patients starting combined antiretroviral therapy (cART) as a result of an immune response to an active (but also subclinical) opportunistic agent, despite a correct virological response to cART.

• The most recognized risk factors for the development of paradoxical IRIS are a very low CD4⁺ T-cell count (<100 or <50, depending on the study, or a percentage lower than 10%), disseminated infection with/without (out) a high count of the causative pathogen and earlier initiation of cART after starting antimicrobial treatment.

• The incidence of IRIS varies considerably according to the study, depending on clinical context (e.g., developing vs western countries), enrollment form, IRIS definition used, median CD4⁺ T-cell count, among other factors.

• The ‘classical’ model of pathogenesis of IRIS basically involves three factors: antigen load; degree of pathogen-specific immune response recovery after the start of HAART; and host genetic susceptibility. However, in contrast with this view involving pathogen-specific immunity, in more recent years, the innate immune system has become the subject of increasing interest in explaining the pathogenesis of IRIS.

• Pathogenic pathways triggering IRIS seem to be slightly different for bacteria and fungi on the one hand and viruses on the other hand.

• Clinical presentation of IRIS is generally characterized by sustained fever and the deterioration of the patient’s general condition (e.g., weight loss, malaise, fatigue) soon after the initiation of cART. Apart from systemic involvement, IRIS can affect specific organs depending on the pathogens involved.

• In general terms, antiretroviral treatment should be started soon (2–4 weeks) after the commencement of specific treatment for opportunistic infections. In the case of cryptococcal and tubercular meningitis, given the available data, cART should probably be started after 4 weeks, although more controlled data are urgently needed.

• Corticoids are generally used in the management of TB-IRIS, although their use might be detrimental in other forms of IRIS. Other treatment strategies are under investigation.

• The possibility of interrupting cART should be considered only in life-threatening cases.

Notes

cART: Combined antiretroviral treatment; IRIS: Immune reconstitution inflammatory syndrome; OIs: Opportunistic infections.

^†Case definitions for specific OIs are discussed in the corresponding paragraph.

cART: Combined antiretroviral treatment; IRIS: Immune reconstitution inflammatory syndrome; OIs: Opportunistic infections.

Adapted from Meintjes et al. [15].