Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV

Opportunistic infections (OIs), which in the context of HIV have been defined as infections that are more frequent or more severe because of HIV-mediated immunosuppression,¹ were the first clinical manifestations that alerted clinicians to the occurrence of AIDS. Pneumocystis pneumonia, toxoplasma encephalitis, cytomegalovirus retinitis, cryptococcal meningitis, tuberculosis, disseminated Mycobacterium avium complex (MAC) disease, and pneumococcal respiratory disease, as well as certain cancers such as Kaposi sarcoma and central nervous system lymphoma, have been hallmarks of AIDS. These OIs, and many more, occurred on average 7 to 10 years after infection with HIV.^2,3 Until effective antiretroviral therapy (ART) was developed, patients generally survived only 1 to 2 years after the initial manifestation of AIDS.⁴

Starting in the late 1980s, the use of chemoprophylaxis, immunization, and better strategies for managing OIs improved quality of life and lengthened survival of people with HIV.⁵ Early antiretroviral drugs and treatment strategies added further benefit.⁶ However, the most profound reduction in OI-related morbidity and mortality in people with HIV resulted from the introduction of highly effective combination ART in the mid-1990s.^7-13

Despite the availability of multiple safe, effective, and simple ART regimens that, when used widely, have led to corresponding population-level declines in the incidence of OIs,^11,14,15 the Centers for Disease Control and Prevention (CDC) estimates that more than 13% of people with HIV are unaware of their HIV infection and that 34% of Americans who are aware of their HIV infection are not effectively virally suppressed.¹⁶ As a result, OIs continue to cause preventable morbidity and mortality in the United States.

Achieving and maintaining durable viral suppression in all people with HIV, and thus preventing or substantially reducing the incidence of HIV-related OIs, remains challenging for three main reasons:

• Not all HIV infections are diagnosed, and once diagnosed many people have already experienced substantial immunosuppression. CDC estimates that in 2019, among those with diagnosed HIV, approximately 20% had a CD4 T lymphocyte (CD4) cell count <200 cells/mm³ (or <14%) at the time of diagnosis.¹⁶
• Not all people with diagnosed HIV receive timely, continuous HIV care or are prescribed ART. CDC estimates that in 2019, 81% of people with newly diagnosed HIV had been linked to care within 1 month. However, only 58% of people with HIV were adequately engaged in continuous care.¹⁶
• Not all people greater than 13 years old treated for HIV achieve durable viral suppression. CDC estimates that in 2019, only 68% of people had durable viral suppression within 6 months of HIV diagnosis.¹⁷ Causes for the suboptimal response to treatment include poor adherence, unfavorable pharmacokinetics, or unexplained biologic factors.^18,19

Thus, some people with HIV infection will continue to present with an OI as the sentinel event leading to a diagnosis of HIV infection or present with an OI as a complication of unsuccessful viral suppression.¹⁷

Durable viral suppression eliminates most but not all OIs. Tuberculosis, pneumococcal disease, and dermatomal zoster are examples of infectious diseases that occur at higher incidence in people with HIV regardless of CD4 count. The likelihood of each of these OIs occurring does vary inversely with the CD4 count, however.^20-26

Certain OIs—most notably tuberculosis and syphilis—can increase plasma viral load,^27-31 which both accelerates HIV progression and increases the risk of HIV transmission if patients are not virally suppressed by ART.

Thus, clinicians continue to need to be knowledgeable about the prevention and management of HIV-related OIs.

History of These Guidelines

In 1989, the Guidelines for Prophylaxis Against Pneumocystis carinii Pneumonia for Persons Infected with the Human Immunodeficiency Virus became the first HIV-related treatment guideline published by the U.S. government.³² This guideline was published in the Morbidity and Mortality Weekly Report (MMWR), which was the most rapid mode of publication at the time. It was followed by a guideline on prevention of MAC disease in 1993.³³ In 1995, these guidelines were expanded to include the treatment of 18 HIV-related OIs. In 2004, information about the prevention of HIV-related OIs was incorporated into the guidelines. The National Institutes of Health (NIH), the HIV Medicine Association (HIVMA), and the Infectious Diseases Society of America (IDSA) jointly co-sponsor these guidelines,^1,34,35 which have been published in peer-reviewed journals and/or the MMWR in 1997, 1999, and 2002.^35-44 Since 2009, the guidelines have been managed as a living document on the web with each chapter reviewed quarterly by the guidelines committee. Updates are published as often and as promptly as deemed appropriate by the guidelines committee.

Data regarding the use of these guidelines demonstrate that the document is a valuable reference for HIV health care providers. In 2021, there were approximately 417,000 page views of the online version of the guidelines and approximately 19,600 PDF downloads.

All guideline recommendations regarding therapy and prevention are rated in terms of the quality of supporting evidence; comments about diagnosis are not rated. These ratings allow readers to assess the relative importance of each recommendation. This document focuses on adults and adolescents; recommendations for children with HIV can be found in separate documents on the Clinicalinfo website.

These guidelines are intended for clinicians, other health care providers, patients with HIV, and policymakers in the United States. Guidelines pertinent to other regions of the world, especially resource-limited countries, may differ with respect to the spectrum of relevant OIs and the diagnostic and therapeutic options that are available to clinicians.

Snapshot of Guidelines Development Process

These guidelines were prepared by the OI Working Group under the auspices of the Office of AIDS Research Advisory Council (OARAC), an authorized Federal Advisory Committee to the U.S. Department of Health and Human Services established in 1994. Co-chairs who are selected and appointed by their respective agencies or organizations (i.e., NIH, IDSA, HIVMA) convene OI-specific working groups of clinicians and scientists with subject matter expertise in those specific OIs. The co-chairs appoint a leader for each working group.

The working groups review in real time the relevant literature published since the last review, with the help of quarterly literature searches for articles relevant to their section that are provided by guidelines support staff. The working groups propose revisions to their section as appropriate. The co-chairs, representatives from HIVMA and IDSA, and other Panel working groups with special expertise (e.g., pharmacology, pregnancy) review proposed revisions.

The co-chairs and working group leaders have a teleconference quarterly to discuss updates to sections. The co-chairs also convene a meeting each year with members of the Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV to review guidelines content and format and set an agenda for the coming year.

The names and affiliations of all contributors, as well as their financial disclosures, are provided in Appendix B: Panel Roster and Financial Disclosures.

How to Use the Information in These Guidelines

Recommendations in this report address—

1. Preventing exposure to opportunistic pathogens;
2. Preventing disease;
3. Discontinuing primary prophylaxis after immune reconstitution;
4. Treating disease;
5. When to start ART in the setting of an acute OI;
6. Monitoring for adverse effects (including immune reconstitution inflammatory syndrome);
7. Managing treatment failure;
8. Preventing disease recurrence (secondary prophylaxis or chronic maintenance therapy);
9. Discontinuing secondary prophylaxis or chronic maintenance therapy after immune reconstitution; and
10. Special considerations during pregnancy.

Recommendations are rated according to the criteria in the table below and accompanied, as needed, by explanatory text that reviews the evidence and the working group’s assessment. In this system, the letters A, B, or C signify the strength of the recommendation for or against a preventive or therapeutic measure, and the Roman numerals I, II, or III indicate the quality of the evidence supporting the recommendation.

This document also includes tables in each section pertinent to the prevention and treatment of the OI(s) in that section, as well as six summary tables at the end of the document (Tables 1–6).

References

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