This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >/=18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy. These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel. This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.

Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

Antimicrobial agents are some of the most widely, and often injudiciously, used therapeutic drugs worldwide. Important considerations when prescribing antimicrobial therapy include obtaining an accurate diagnosis of infection; understanding the difference between empiric and definitive therapy; identifying opportunities to switch to narrow-spectrum, cost-effective oral agents for the shortest duration necessary; understanding drug characteristics that are peculiar to antimicrobial agents (such as pharmacodynamics and efficacy at the site of infection); accounting for host characteristics that influence antimicrobial activity; and in turn, recognizing the adverse effects of antimicrobial agents on the host. It is also important to understand the importance of antimicrobial stewardship, to know when to consult infectious disease specialists for guidance, and to be able to identify situations when antimicrobial therapy is not needed. By following these general principles, all practicing physicians should be able to use antimicrobial agents in a responsible manner that benefits both the individual patient and the community.

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General Principles of Antimicrobial Therapy

In patients with HIV-1 infection who are starting combination antiretroviral therapy (ART), the incidence of immune reconstitution inflammatory syndrome (IRIS) is not well defined. We did a meta-analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infections, and examined the relation between occurrence and the degree of immunodeficiency. Systematic review identified 54 cohort studies of 13 103 patients starting ART, of whom 1699 developed IRIS. We calculated pooled cumulative incidences with 95% credibility intervals (CrI) by Bayesian methods and did a random-effects metaregression to analyse the relation between CD4 cell count and incidence of IRIS. In patients with previously diagnosed AIDS-defining illnesses, IRIS developed in 37.7% (95% CrI 26.6-49.4) of those with cytomegalovirus retinitis, 19.5% (6.7-44.8) of those with cryptococcal meningitis, 15.7% (9.7-24.5) of those with tuberculosis, 16.7% (2.3-50.7) of those with progressive multifocal leukoencephalopathy, and 6.4% (1.2-24.7) of those with Kaposi's sarcoma, and 12.2% (6.8-19.6) of those with herpes zoster. 16.1% (11.1-22.9) of unselected patients starting ART developed any type of IRIS. 4.5% (2.1-8.6) of patients with any type of IRIS died, 3.2% (0.7-9.2) of those with tuberculosis-associated IRIS died, and 20.8% (5.0-52.7) of those with cryptococcal meningitis died. Metaregression analyses showed that the risk of IRIS is associated with CD4 cell count at the start of ART, with a high risk in patients with fewer than 50 cells per microL. Occurrence of IRIS might therefore be reduced by initiation of ART before immunodeficiency becomes advanced.

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Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis.

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.

Immune restoration disease after antiretroviral therapy.

Background: There is little systematic information regarding the immune reconstitution inflammatory syndrome (IRIS). Objective: To determine the incidence, risk factors, and long-term outcome of IRIS in HIV-infected patients receiving highly active antiretroviral therapy (HAART) who were coinfected with one of three common opportunistic pathogens. Design: A retrospective cohort identified through a city-wide prospective surveillance program. Methods: A retrospective chart review was performed for 180 HIV-infected patients who received HAART and were coinfected with Mycobacterium tuberculosis, Mycobacterium avium complex, or Cryptococcus neoformans between 1997 and 2000. Medical records were reviewed for baseline demographics, receipt and type of HAART, response to antiretroviral therapy, development of IRIS, and long-term outcome. Results: In this cohort, 31.7% of patients who received HAART developed IRIS. Patients with IRIS were more likely to have initiated HAART nearer to the time of diagnosis of their opportunistic infection (P < 0.001), to have been antiretroviral naive at time of diagnosis of their opportunistic infection (P < 0.001), and to have a more rapid initial fall in HIV-1 RNA level in response to HAART (P < 0.001). Conclusions: IRIS is common among HIV-infected persons coinfected with M. tuberculosis, M. avium complex, or C. neoformans. Antiretroviral drug-naive patients who start HAART in close proximity to the diagnosis of an opportunistic infection and have a rapid decline in HIV-1 RNA level should be monitored for development of this disorder.

Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy

Background: To determine if infectious disease events in HIV-infected patients treated with highly active antiretroviral therapy (HAART) are a consequence of the restoration of pathogen-specific immune responses, a single-centre retrospective study of all HIV-infected patients commencing HAART prior to 1 July 1997 was undertaken to determine the incidence, characteristics and time of onset of disease episodes in HAART responders (decrease in plasma HIV RNA of > 1 log10 copies/mL).

Methods: Baseline and post-therapy changes in CD4 T-cell counts and HIV RNA were compared in patients with and without disease and delayed-type hypersensitivity responses to mycobacterial antigens were measured in selected patients.

Results: Thirty-three of 132 HAART responders (25%) exhibited one or more disease episodes after HAART, related to a pre-existent or subclinical infection by an opportunistic pathogen. Disease episodes were most often related to infections by mycobacteria or herpesviruses but hepatitis C virus (HCV), molluscum contagiosum virus and human papilloma virus were also implicated. They were most common in patients with a baseline CD4 T-cell count of < 50/uL and occurred most often during the first 2 months of therapy and when CD4 T-cell counts were increasing. Mycobacteria- and HCV-related diseases were associated with restoration of pathogen-specific immune responses.

Conclusions: We conclude that improved immune function in immunodeficient patients treated with HAART may restore pathogen-specific immune responses and cause inflammation in tissues infected by those pathogens.

M-L. Tay-Kearney

Papers

Immune restoration disease after the treatment of immunodeficient HIV‐infected patients with highly active antiretroviral therapy