Guidelines for Prevention and Treatment of Opportunistic Infections in HIVInfected Adults and Adolescents

Table of Contents What’s New in the Guidelines..........................................................................................................................i Introduction ..................................................................................................................................................A1 Pneumocystis Pneumonia .............................................................................................................................B1 Toxoplasma gondii Encephalitis...................................................................................................................C1 Cryptosporidiosis .........................................................................................................................................D1 Microsporidiosis............................................................................................................................................E1 Mycobacterium tuberculosis Infection and Disease ....................................................................................F1 Disseminated Mycobacterium avium Complex Disease .............................................................................G1 Bacterial Respiratory Disease .....................................................................................................................H1 Bacterial Enteric Infections ..........................................................................................................................I1 Bartonellosis...................................................................................................................................................J1 Syphilis ..........................................................................................................................................................K1 Mucocutaneous Candidiasis ........................................................................................................................L1 Invasive Mycoses..........................................................................................................................................M1 Introduction.......................................................................................................................................M1 Cryptococcosis ..................................................................................................................................M1 Histoplasmosis ................................................................................................................................M12 Coccidioidomycosis........................................................................................................................M19 Cytomegalovirus Disease .............................................................................................................................N1 NonCMV Herpes.........................................................................................................................................O1 Herpes Simplex Virus Disease...........................................................................................................O1 VaricellaZoster Virus Diseases .........................................................................................................O7 Human Herpesvirus8 Disease ........................................................................................................O15 Human Papillomavirus Disease ...................................................................................................................P1 Hepatitis B Virus Infection..........................................................................................................................Q1 Hepatitis C Virus Infection..........................................................................................................................R1 Progressive Multifocal LeukoencephalopathyJC Virus Infection...........................................................S1 Geographic Opportunistic Infections of Specific Consideration..............................................................T1 Malaria................................................................................................................................................T1 Penicilliosis marneffei........................................................................................................................T9 Leishmaniasis ...................................................................................................................................T15 Chagas Disease.................................................................................................................................T26 Isosporiasis (Cystoisosporiasis)........................................................................................................T34 Downloaded from https:aidsinfo.nih.govguidelines on 8172017 Guidelines for the Prevention and Treatment of Opportunistic Infections in HIVInfected Adults and Adolescents iii Tables Table 1. Prophylaxis to Prevent First Episode of Opportunistic Disease .........................................U1 Table 2. Treatment of AIDSAssociated Opportunistic Infections (Includes Recommendations for Acute Treatment and Chronic SuppressiveMaintenance Therapy)...................................................U6 Table 3. Recommended Doses of FirstLine Drugs for Treatment of Tuberculosis in Adults and Adolescents....................................................................................................................U29 Table 4. Indications for Discontinuing and Restarting Opportunistic Infection Prophylaxis in HIVInfected Adults and Adolescents...............................................................................................U30 Table 5. Significant Pharmacokinetic Interactions for Drugs Used to Treat or Prevent Opportunistic Infections ..................................................................................................................U33 Table 6. Common or Serious Adverse Reactions Associated With Drugs Used for Preventing or Treating Opportunistic Infections....................................................................................................U47 Table 7. Dosing Recommendations for Drugs Used in Treating or Preventing Opportunistic Infections Where Dosage Adjustment is Needed in Patients with Renal Insufficiency....................U52 Table 8. Summary of PreClinical and Human Data on, and Indications for, Opportunistic Infection Drugs During Pregnancy .................................................................................................U59 Figure: Immunization Schedule for Human Immunodeficiency Virus (HIV)Infected Adults.............V1 Appendix A. Recommendations to Help HIVInfected Patients Avoid Exposure to, or Infection from, Opportunistic Pathogens..................................................................................................W1 Appendix B. List of Abbreviations..............................................................................................................X1 Appendix C. Panel Roster and Financial Disclosures ...............................................................................Y1 Appendix D. Contributors............................................................................................................................Z1 Downloaded from https:aidsinfo.nih.govguidelines on 8172017 Guidelines for the Prevention and Treatment of Opportunistic Infections in HIVInfected Adults and Adolescents A1 Introduction (Last updated June 17, 2013; last reviewed July 25, 2017) NOTE: Update in Progress Prior to the widespread use of potent combination antiretroviral therapy (ART), opportunistic infections (OIs), which have been defined as infections that are more frequent or more severe because of immunosuppression in HIVinfected persons,1,2 were the principal cause of morbidity and mortality in this population. In the early 1990s, the use of chemoprophylaxis, immunization, and better strategies for managing acute OIs contributed to improved quality of life and improved survival.3 Subsequently, the widespread use of potent ART has had the most profound influence on reducing OIrelated mortality in HIVinfected persons.310 Despite the availability of ART, OIs continue to cause considerable morbidity and mortality in the United States for three main reasons: 1. Approximately 20% of HIVinfected persons in the United States are unaware of their HIV infection,11,12 and many present with an OI as the initial indicator of their disease;13 2. Some individuals are aware of their HIV infection, but do not take ART due to psychosocial or economic factors; and 3. Some patients are enrolled in HIV care and prescribed ART, but do not attain an adequate virologic and immunologic response due to inconsistent retention in care, poor adherence, unfavorable pharmacokinetics, or unexplained biologic factors.6,14,15 Recent analyses suggest that while 77% of HIVinfected persons who are retained in care and prescribed ART are virologically suppressed, only 20% to 28% of the total estimated HIVinfected population in the United States are virologically suppressed,11,16 with as few as 10% in some jurisdictions.17 Thus, while hospitalizations and deaths have decreased dramatically due to ART, OIs continue to cause substantial morbidity and mortality in HIVinfected persons.1828 Clinicians must be knowledgeable about optimal strategies for diagnosis, prevention, and treatment of OIs to provide comprehensive, high quality care for these patients. It is important to recognize that the relationship between OIs and HIV infection is bidirectional. HIV causes the immunosuppression that allows opportunistic pathogens to cause disease in HIVinfected persons. OIs, as well as other coinfections that may be common in HIVinfected persons, such as sexually transmitted infections (STIs), can adversely affect the natural history of HIV infection by causing reversible increases in circulating viral load2934 that could accelerate HIV progression and increase transmission of HIV.35 Thus, while chemoprophylaxis and vaccination directly prevent pathogenspecific morbidity and mortality, they may also contribute to reduced rate of progression of HIV disease. For instance, randomized trials have shown that chemoprophylaxis with trimethoprimsulfamethoxazole can both decrease OIrelated morbidity and improve survival. The survival benefit is likely to result, in part, from reduced progression of HIV infection.3640 In turn, the reduced progression of HIV infection would reduce the risk of subsequent OIs.

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Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

Downloaded from https://aidsinfo.nih.gov/guidelines on 8/17/2017

Visit the AIDSinfo website to access the most up-to-date guideline.

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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults

and Adolescents

Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association

of the Infectious Diseases Society of America

How to Cite the Adult and Adolescent Opportunistic Infection Guidelines:

Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents Guidelines for the

prevention and treatment of opportunistic infections in HIV-infected adults and adolescents:

recommendations from the Centers for Disease Control and Prevention, the National Institutes

of Health, and the HIV Medicine Association of the Infectious Diseases Society of America

Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf Accessed (insert date)

[include page numbers, table number, etc if applicable]

It is emphasized that concepts relevant to HIV management evolve rapidly The Panel has a

mechanism to update recommendations on a regular basis, and the most recent information is

available on the AIDSinfo website (http://aidsinfo.nih.gov)

Access AIDSinfo

mobile site

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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents i

What’s New in the Guidelines

Updates to the Guidelines for the Prevention and Treatment of Opportunistic Infections

in HIV-Infected Adults and Adolescents

The Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV Infected Adults and Adolescents document was published in an electronic format that could be easily updated as relevant changes

in prevention and treatment recommendations occur.

The editors and subject matter experts are committed to timely changes in this document because so many health care providers, patients, and policy experts rely on this source for vital clinical information.

All changes are developed by the subject matter groups listed in the document (changes in group

composition are also promptly posted) These changes are reviewed by the editors and by relevant outside reviewers before the document is altered Major revisions within the last 6 months are as follows:

August 10, 2017

1 Bacterial Enterics: This revision highlights new data from the CDC Health Advisory Network (April,

2017) indicating growing concern over fluoroquinolone resistant in Shigella isolates Fluoroquinolones should only be used to treated Shigella isolates when the MIC<0.12 ug/ml Reflex cultures of stools positive for Shigella spp by culture-independent diagnostic tests is required for antibiotic sensitivity

testing.

August 3, 2017

1 Hepatitis B Virus: This section was updated to include TAF/FTC as a treatment option for patients with

HBV/HIV coinfection Data on the virologic efficacy of TAF for the treatment of HBV in persons without HIV infection and TAF/FTC in persons with HBV/HIV coinfection are discussed.

The Panel no longer recommends adefovir or telbivudine as options for HBV/HIV coinfected patients,

as there is limited safety and efficacy data on their use in this population In addition, these agents have a higher incidence of toxicities than other recommended treatments.

July 25, 2017

1 Pneumocystis Pneumonia: Sections of the Pneumocystis guidelines have been updated to modernize

some of the language and to more closely reflect the standard of care in 2017, which includes early

cART initiation for all patients In addition, suggested criteria for stopping both primary and secondary prophylaxis in patients with HIV viral loads below detection limits and CD4 counts between 100 and 200 cells/mm3 are provided.

2 Toxoplasma gondii Encephalitis: Sections of the toxoplasmosis guidelines have been updated to

modernize some of the language and to more closely reflect the standard of care in 2017, which includes early cART initiation for all patients Greater detail is provided on management of toxoplasmosis during pregnancy In addition, suggested criteria for stopping primary prophylaxis in patients with HIV viral loads below detection limits and CD4 counts between 100 and 200 cells/mm3 are provided.

3 Table 1 , Table 2 and Table 4 : Updated to reflect the changes in the sections

July 6, 2017

1 Progressive Multifocal Leukoencephalopathy/JC Virus Infection: Evolving work on clinical PML

management has allowed some clarification about the value and use of CSF PCR DNA detection,

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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents ii

emphasizing the use of highly sensitive assays that are required to optimize sensitivity of CSF testing for JC virus and its specificity to the setting of PML Also of interest is work demonstrating increases in JC-specific IgG with the onset of PML, recognizing that mere detection of JC antibodies is not generally helpful because of the high prevalence of JC antibodies in the population A subtle but important evolution

of understanding of PML management is that immune reconstitution inflammatory syndrome (IRIS) is common, and when severe may be life-threatening in itself, leading to recommendation of corticosteroid use when it is suspected to be driving post-immune reconstitution clinical deterioration Many references were also updated in this revision to reflect the most recent reports about PML detection and treatment.

May 18, 2017

1 Tuberculosis: In this revision, the epidemiology, diagnosis, and treatment sections for latent TB

infection and TB disease were updated to include more recent statistics, diagnostic tests (e.g., IGRAs, Xpert MTB/RIF assay, LAM) and data regarding treatment (e.g., 3HP, when to start ART, new

drugs for treatment of drug-resistant TB) In addition, Table 1 , Table 2 and Table 3 were updated to include preferred and alternative treatment regimens, and drug-drug interactions with commonly used medications.

March 28, 2017

1 Malaria: The epidemiology and treatment sections were updated to include more recent statistics and

data regarding treatment Recently, Table 5 was updated to add potential drug interactions between anti-malarial medications and commonly used medications, including hepatitis C direct acting agents, antibiotics, and antifungals.

March 13, 2017

1 Table 5 has been updated with the following key modifications:

a Antiretroviral drugs are removed from this table; clinicians should refer to the Adult and Adolescent Antiretroviral Treatment Guidelines’ Drug Interaction section to review potential interactions and recommendations for when OI drugs are used concomitantly with certain antiretroviral drugs.

b Drugs used for the treatment of hepatitis C virus infection and malaria are added to this table.

2 Table 6 has been updated with the inclusion of adverse effects associated with drugs for the treatment of

hepatitis C virus infection and malaria

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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents ii

Table of Contents

What’s New in the Guidelines i Introduction A-1

Pneumocystis Pneumonia B-1 Toxoplasma gondii Encephalitis C-1

Cryptosporidiosis D-1 Microsporidiosis E-1

Mycobacterium tuberculosis Infection and Disease F-1

Disseminated Mycobacterium avium Complex Disease G-1

Bacterial Respiratory Disease H-1 Bacterial Enteric Infections I-1 Bartonellosis J-1 Syphilis K-1 Mucocutaneous Candidiasis L-1 Invasive Mycoses M-1

Introduction M-1 Cryptococcosis M-1 Histoplasmosis M-12 Coccidioidomycosis M-19

Cytomegalovirus Disease N-1 Non-CMV Herpes O-1

Herpes Simplex Virus Disease O-1 Varicella-Zoster Virus Diseases O-7 Human Herpesvirus-8 Disease O-15

Human Papillomavirus Disease P-1 Hepatitis B Virus Infection Q-1 Hepatitis C Virus Infection R-1 Progressive Multifocal Leukoencephalopathy/JC Virus Infection S-1 Geographic Opportunistic Infections of Specific Consideration T-1

Malaria T-1

Penicilliosis marneffei T-9

Leishmaniasis T-15 Chagas Disease T-26 Isosporiasis (Cystoisosporiasis) T-34

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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents iii

Tables

Table 1 Prophylaxis to Prevent First Episode of Opportunistic Disease U-1 Table 2 Treatment of AIDS-Associated Opportunistic Infections (Includes Recommendations for Acute Treatment and Chronic Suppressive/Maintenance Therapy) U-6 Table 3 Recommended Doses of First-Line Drugs for Treatment of Tuberculosis in

Adults and Adolescents U-29 Table 4 Indications for Discontinuing and Restarting Opportunistic Infection Prophylaxis in

HIV-Infected Adults and Adolescents U-30 Table 5 Significant Pharmacokinetic Interactions for Drugs Used to Treat or Prevent

Opportunistic Infections U-33 Table 6 Common or Serious Adverse Reactions Associated With Drugs Used for Preventing or Treating Opportunistic Infections U-47 Table 7 Dosing Recommendations for Drugs Used in Treating or Preventing Opportunistic

Infections Where Dosage Adjustment is Needed in Patients with Renal Insufficiency U-52 Table 8 Summary of Pre-Clinical and Human Data on, and Indications for, Opportunistic

Infection Drugs During Pregnancy U-59

Figure: Immunization Schedule for Human Immunodeficiency Virus (HIV)-Infected Adults V-1 Appendix A Recommendations to Help HIV-Infected Patients Avoid Exposure to, or

Infection from, Opportunistic Pathogens W-1 Appendix B List of Abbreviations X-1 Appendix C Panel Roster and Financial Disclosures Y-1 Appendix D Contributors Z-1

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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents A-1

Introduction (Last updated June 17, 2013; last reviewed July 25, 2017)

NOTE: Update in Progress

Prior to the widespread use of potent combination antiretroviral therapy (ART), opportunistic infections (OIs), which have been defined as infections that are more frequent or more severe because of

immunosuppression in HIV-infected persons,1,2 were the principal cause of morbidity and mortality in

this population In the early 1990s, the use of chemoprophylaxis, immunization, and better strategies for managing acute OIs contributed to improved quality of life and improved survival.3 Subsequently, the

widespread use of potent ART has had the most profound influence on reducing OI-related mortality in infected persons.3-10

HIV-Despite the availability of ART, OIs continue to cause considerable morbidity and mortality in the United States for three main reasons:

1 Approximately 20% of HIV-infected persons in the United States are unaware of their HIV infection,11,12and many present with an OI as the initial indicator of their disease;13

2 Some individuals are aware of their HIV infection, but do not take ART due to psychosocial or economic factors; and

3 Some patients are enrolled in HIV care and prescribed ART, but do not attain an adequate virologic and immunologic response due to inconsistent retention in care, poor adherence, unfavorable

pharmacokinetics, or unexplained biologic factors.6,14,15

Recent analyses suggest that while 77% of HIV-infected persons who are retained in care and prescribed ART are virologically suppressed, only 20% to 28% of the total estimated HIV-infected population in the United States are virologically suppressed,11,16 with as few as 10% in some jurisdictions.17 Thus, while

hospitalizations and deaths have decreased dramatically due to ART, OIs continue to cause substantial

morbidity and mortality in HIV-infected persons.18-28 Clinicians must be knowledgeable about optimal

strategies for diagnosis, prevention, and treatment of OIs to provide comprehensive, high quality care for these patients

It is important to recognize that the relationship between OIs and HIV infection is bi-directional HIV causes the immunosuppression that allows opportunistic pathogens to cause disease in HIV-infected persons OIs,

as well as other co-infections that may be common in HIV-infected persons, such as sexually transmitted infections (STIs), can adversely affect the natural history of HIV infection by causing reversible increases

in circulating viral load29-34 that could accelerate HIV progression and increase transmission of HIV.35 Thus, while chemoprophylaxis and vaccination directly prevent pathogen-specific morbidity and mortality, they may also contribute to reduced rate of progression of HIV disease For instance, randomized trials have shown that chemoprophylaxis with trimethoprim-sulfamethoxazole can both decrease OI-related morbidity and improve survival The survival benefit is likely to result, in part, from reduced progression of HIV

infection.36-40 In turn, the reduced progression of HIV infection would reduce the risk of subsequent 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 Public Health Service.41 This publication was followed by a guideline on prevention of Mycobacterium avium complex disease in 1993.42 In 1995 these guidelines were expanded to include the prevention of all HIV-related OIs and the Infectious Diseases Society of America (IDSA) joined as a co-sponsor.43 These

prevention guidelines were revised in 1997, 1999, and 2002 and were published in Morbidity and Mortality Weekly Report (MMWR),44-46 Clinical Infectious Diseases,47-49 The Annals of Internal Medicine,50,51 American Family Physician,52,53 and Pediatrics;54 accompanying editorials appeared in the Journal of the American

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Medical Association (JAMA)2,55 and in Topics in HIV Medicine.56

In 2004 the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the IDSA published a new guideline including recommendations for treating OIs among HIV-infected adults and adolescents.57 Companion guidelines were published for HIV-infected children.58 Revised guidelines for both prevention and treatment of OIs in HIV-infected adults and adolescents59 and HIV-exposed/infected children60 were published in 2009.

Responses to these guidelines (e.g., numbers of requests for reprints, website contacts) demonstrate that these documents are valuable references for HIV health care providers The inclusion of ratings that indicate both the strength of each recommendation and the quality of supporting evidence allows readers to assess the relative importance of each recommendation The present revision includes recommendations for prevention and treatment of OIs in HIV-infected adults and adolescents; a revision of recommendations for HIV-exposed and infected children can also be found in http://www.aidsinfo.nih.gov

These guidelines are intended for clinicians, other health care providers, HIV-infected patients, and policy makers in the United States; guidelines pertinent to other regions of the world, especially resource-limited countries, may differ with respect to the spectrum of OIs of interest and diagnostic and therapeutic capacities.

Guidelines Development Process

These guidelines were prepared by the Opportunistic Infections Working Group under the auspices of the Office of AIDS Research Advisory Council (OARAC) of the NIH Briefly, six co-editors selected and

appointed by their respective agencies (i.e., NIH, CDC, IDSA) convened working groups of clinicians and scientists with subject matter expertise in specific OIs The co-editors appointed a leader for each working group, which reviewed the literature since the last publication of these guidelines, conferred over a period

of several months, and produced draft revised recommendations Issues requiring specific attention were reviewed and discussed by the co-editors and the leaders from each working group at the annual meeting of the IDSA in Vancouver, Canada, in October 2010 After further revision, the guidelines were reviewed by patient care advocates and by primary care providers with extensive experience in the management of HIV infection The final document reflects further revision by the co-editors, the Office of AIDS Research (OAR), experts at CDC, and by the IDSA and affiliated HIV Medicine Association prior to final approval and

publication on the AIDSinfo website The names and affiliations of all contributors as well as their financial

disclosures are provided in the Panel roster and Financial Disclosure section (Appendix C) The names of the patient advocates and primary HIV care providers who reviewed the document are listed in Contributors

(Appendix D).

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Guidelines Development Process (page 1 of 2)

Goal of the

guidelines Provide guidance to HIV care practitioners on the optimal prevention and management of HIV-related opportunistic infections (OIs) for adults and adolescents in the United States

Panel members The panel is composed of six co-editors who represent the National Institutes of Health (NIH), the Centers for

Disease Control and Prevention (CDC), and the HIV Medicine Association of the Infectious Disease Society

of America (HIVMA/IDSA), plus more than 100 members who have expertise in HIV clinical care, infectious disease management, and research Co-editors are appointed by their respective agencies or organizations Panel members are selected from government, academia, and the healthcare community by the co-editors and assigned to a working group for one or more the guideline’s sections based on the member’s area of subject mater expertise Each working group is chaired by a single panel member selected by the co-chairs Members serve on the panel for a 4-year term, with an option to be reappointed for additional terms The panel co-editors also select members from the community of persons affected by HIV disease (i.e., adults living with HIV infection, advocates for persons living with HIV infection) to review the entire guidelines document The lists of the current panel members and of the patient advocates and primary HIV care providers who reviewed the document can be found in Appendices C and D, respectively

to which a panel member contributes content Financial interests include direct receipt by the panel member

of payments, gratuities, consultancies, honoraria, employment, grants, support for travel or accommodation,

or gifts from an entity having a commercial interest in that product Financial interest also includes direct compensation for membership on an advisory board, data safety monitoring board, or speakers’ bureau Compensation and support that filters through a panel member’s university or institution (e.g., grants, research funding) is not considered a conflict of interest

Users of the

guidelines HIV treatment providers

Developer Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and

Adolescents—a working group of the Office of AIDS Research Advisory Council (OARAC)

Funding source The Office of AIDS Research (OAR), NIH

Evidence

collection The recommendations in the guidelines are generally based on studies published in peer-reviewed journals On some occasions, particularly when new information may affect patient safety, unpublished data presented

at major conferences or information prepared by the U.S Food and Drug Administration or manufacturers (e.g., warnings to the public) may be used as evidence to revise the guidelines Panel members of each working group are responsible for conducting a systematic comprehensive review of the literature, for conducting updates of that review, and for bringing to their working group’s attention all relevant literature

by patient care advocates and by primary care providers with extensive experience in the management of HIV infection to assess cultural sensitivity and operational utility Finally, all material is reviewed by the co-editors, OAR, subject matter experts at CDC and the HIVMA/IDSA prior to final approval and publication

Recommendation

rating Recommendations are rated using a revised version of the previous rating system (see How to Use the Information in this Report and Rating System for Prevention and Treatment Recommendations, below) and

accompanied, as needed, by explanatory text that reviews the evidence and the working group’s assessment All proposals are discussed at teleconferences and by email and then assessed by the panel’s co-editors and reviewed by OAR, CDC, and the HIVMA/IDSA before being endorsed as official recommendations

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Guidelines Development Process (page 2 of 2)

Other guidelines These guidelines focus on prevention and treatment of HIV-related OIs for adults and adolescents A separate

guideline outlines similar recommendations for HIV-infected and exposed children These guidelines are also

available on the AIDSinfo website (http://www.aidsinfo.nih.gov)

Update plan Each work group and the co-editors meet at least every 6 months by teleconference to review data that may

warrant modification of the guidelines Updates may be prompted by approvals of new drugs, vaccines, medical devices or diagnostics, by new information regarding indications or dosing, by new safety or efficacy data, or by other information that may affect prevention and treatment of HIV-related OIs Updates that may significantly affect patient safety or treatment and that warrant rapid notification may be posted temporarily

on the AIDSinfo website (http://www.aidsinfo.nih.gov) until appropriate changes can be made in the guidelines document

Public comments After release of an update on the AIDSinfo website, the public is given a 2-week period to submit comments

to the panel These comments are reviewed, and a determination is made by the appropriate work group and the co-editors as to whether revisions are indicated The public may also submit comments to the Panel at any time at contactus@aidsinfo.nih.gov

Major Changes in Guidelines Since Last Publication

Major changes in the document include:

1) New information on when to start ART in the setting of an acute OI, including tuberculosis;

2) When to start therapy for hepatitis B and hepatitis C disease, and what drugs to use;

3) Drug interactions between drugs used to manage OIs and HIV;

4) A change in the system for rating the strength of each recommendation, and the quality of evidence supporting that recommendation (see Rating System for Prevention and Treatment Recommendations); and

5) Inclusion of pathogen-specific tables of recommended prevention and treatment options at the end of each OI section, in addition to summary tables at the end of the document

How to Use the Information in this Report

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 [IRIS]);

7) Managing treatment failure;

8) Preventing disease recurrence (“secondary prophylaxis” or chronic maintenance therapy);

9) Discontinuing secondary prophylaxis after immune reconstitution; and

10) Special considerations during pregnancy

Recommendations are rated using a revised version of the previous rating system (see Rating System for Prevention and Treatment Recommendations below) and accompanied, as needed, by explanatory text that

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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 Roman numerals

I, II, or III indicate the quality of evidence supporting the recommendation In cases where there were no data for the prevention or treatment of an OI based on studies conducted in HIV-infected populations, but data derived from HIV-uninfected persons existed that could plausibly guide management of HIV-infected patients, the recommendation is rated as a II or III but is assigned A, B, or C depending on the strength of the recommendation

Rating System for Prevention and Treatment Recommendations

Strength of Recommendation Quality of Evidence for the RecommendationA: Strong recommendation for the statement

B: Moderate recommendation for the statement

C: Optional recommendation for the statement

I: One or more randomized trials with clinical outcomes and/

or validated laboratory endpoints

II: One or more well-designed, non-randomized trials or

observational cohort studies with long-term clinical outcomes

III: Expert opinion

This document also includes tables in each OI section pertinent to the prevention and treatment of OIs, as well as eight summary tables at the end of the document ( Tables 1–8 ), a figure that includes immunization recommendations, and an appendix that summarizes recommendations pertinent to preventing exposure to opportunistic pathogens, including preventing exposure to STIs ( Appendix A ).

Special Considerations Regarding Pregnancy

No large studies have been conducted concerning the epidemiology or manifestations of HIV-associated OIs among pregnant women No data demonstrate that the spectrum of OIs differs from that among non-pregnant women with comparable CD4+ counts.

Physiologic changes during pregnancy can complicate the recognition of OIs and complicate treatment due

to changes in pharmacokinetic parameters, which may influence optimal dosing for drugs used for prevention

or treatment of OI Factors to consider include the following:61

• Increased cardiac output by 30% to 50% with concomitant increase in glomerular filtration rate and renal clearance.

• Increased plasma volume by 45% to 50% while red cell mass increases only by 20% to 30%, leading to dilutional anemia.

• Tidal volume and pulmonary blood flow increase, possibly leading to increased absorption of aerosolized medications The tidal volume increase of 30% to 40% should be considered if ventilator assistance is required.

• Placental transfer of drugs, increased renal clearance, altered gastrointestinal absorption, and metabolism

by the fetus that might affect maternal drug levels.

• Limited pharmacokinetic data are available; use usual adult doses based on current weight, monitor levels if available, and consider the need to increase doses if the patient is not responding as expected Non-invasive imaging, including imaging that may expose a patient to radiation, is an important component

of OI diagnosis Fetal risk is not increased with cumulative radiation doses below 5 rads; the majority of imaging studies result in radiation exposure to the fetus that is lower than the 5-rad recommended limit In humans, the primary risks associated with high-dose radiation exposure are growth restriction, microcephaly,

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and developmental disabilities The most vulnerable period is 8 to 15 menstrual weeks of gestation,

with minimal risk before 8 weeks and after 25 weeks The apparent threshold for development of mental retardation is 20 to 40 rads, with risk of more serious mental retardation increasing linearly with increasing exposure above this level Among children, risk for carcinogenesis might be increased approximately 1 per 1000 or less per rad of in utero radiation exposure.62 Therefore, pregnancy should not preclude usual diagnostic evaluation when an OI is suspected.63 Abdominal shielding should be used when feasible to further limit radiation exposure to the fetus Experience with use of magnetic resonance imaging (MRI) in pregnancy is limited, but no adverse fetal effects have been noted.64

Other procedures necessary for diagnosis of suspected OIs should be performed in pregnancy as indicated for non-pregnant patients A pregnant woman who is >20 weeks of gestation should not lie flat on her back but should have her right hip elevated with a wedge to displace the uterus off the great vessels and prevent supine hypotension Oxygenation should be monitored when pregnant patients are positioned such that ventilation or perfusion might be compromised.

In the United States, pregnancy is an indication to start antiretroviral therapy if the HIV-infected woman is not already on therapy A decision to defer therapy based on a current or recent OI should be made on the same basis as for non-pregnant individuals supplemented by consultation with the obstetrician regarding factors unique to each individual pregnancy

After first-trimester exposure to agents of uncertain teratogenic potential, including many of the

anti-infective agents described in this guideline, an ultrasound should be conducted every 4 to 6 weeks in the third trimester to assess fetal growth and fluid volume, with antepartum testing if growth lag or decreased fluid are noted

2 Kaplan JE, Masur H, Jaffe HW, Holmes KK Reducing the impact of opportunistic infections in patients with

HIV infection New guidelines JAMA Jul 26 1995;274(4):347-348 Available at http://www.ncbi.nlm.nih.gov/

pubmed/7609267

3 Walensky RP, Paltiel AD, Losina E, et al The survival benefits of AIDS treatment in the United States J Inf ect Dis Jul

1 2006;194(1):11-19 Available at http://www.ncbi.nlm.nih.gov/pubmed/16741877

4 Palella FJ, Jr., Delaney KM, Moorman AC, et al Declining morbidity and mortality among patients with

advanced human immunodeficiency virus infection HIV Outpatient Study Investigators N Engl J Med Mar 26

1998;338(13):853-860 Available at http://www.ncbi.nlm.nih.gov/pubmed/9516219

5 Detels R, Munoz A, McFarlane G, et al Effectiveness of potent antiretroviral therapy on time to AIDS and death in men

with known HIV infection duration Multicenter AIDS Cohort Study Investigators JAMA Nov 4

6 Jones JL, Hanson DL, Dworkin MS, et al Surveillance for AIDS-defining opportunistic illnesses, 1992-1997 MMWR

CDC surveillance summaries: Morbidity and mortality weekly report CDC surveillance summaries / Centers for Disease Control Apr 16 1999;48(2):1-22 Available at http://www.ncbi.nlm.nih.gov/pubmed/12412613

7 Mocroft A, Vella S, Benfield TL, et al Changing patterns of mortality across Europe in patients infected with

HIV-1 EuroSIDA Study Group Lancet Nov 28 1998;352(9142):1725-1730 Available at http://www.ncbi.nlm.nih.gov/pubmed/9848347

8 McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis Adult/Adolescent Spectrum of Disease Group

AIDS Sep 10 1999;13(13):1687-1695 Available at http://www.ncbi.nlm.nih.gov/pubmed/10509570

9 Miller V, Mocroft A, Reiss P, et al Relations among CD4 lymphocyte count nadir, antiretroviral therapy, and HIV-1

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disease progression: results from the EuroSIDA study Ann Intern Med Apr 6 1999;130(7):570-577 Available at http://www.ncbi.nlm.nih.gov/pubmed/10189326

10 Dore GJ, Li Y, McDonald A, Ree H, Kaldor JM, National HIVSC Impact of highly active antiretroviral therapy

on individual AIDS-defining illness incidence and survival in Australia J Acquir Immune Defic Syndr Apr 1

11 Centers for Disease C, Prevention Vital signs: HIV prevention through care and treatment—United States MMWR

Morb Mortal Wkly Rep Dec 2 2011;60(47):1618-1623 Available at http://www.ncbi.nlm.nih.gov/pubmed/22129997

12 Campsmith ML, Rhodes PH, Hall HI, Green TA Undiagnosed HIV prevalence among adults and adolescents in the

United States at the end of 2006 J Acquir Immune Defic Syndr Apr 2010;53(5):619-624 Available at http://www.ncbi.nlm.nih.gov/pubmed/19838124

13 Seal PS, Jackson DA, Chamot E, et al Temporal trends in presentation for outpatient HIV medical care 2000-2010:

implications for short-term mortality J Gen Intern Med Jul 2011;26(7):745-750 Available at http://www.ncbi.nlm.nih.gov/pubmed/21465301

14 Perbost I, Malafronte B, Pradier C, et al In the era of highly active antiretroviral therapy, why are HIV-infected patients

still admitted to hospital for an inaugural opportunistic infection? HIV Med Jul 2005;6(4):232-239 Available at http://www.ncbi.nlm.nih.gov/pubmed/16011527

15 Palacios R, Hidalgo A, Reina C, de la Torre M, Marquez M, Santos J Effect of antiretroviral therapy on admissions of

HIV-infected patients to an intensive care unit HIV Med Apr 2006;7(3):193-196 Available at http://www.ncbi.nlm.nih.gov/pubmed/16494634

16 Gardner EM, McLees MP, Steiner JF, Del Rio C, Burman WJ The spectrum of engagement in HIV care and its

relevance to test-and-treat strategies for prevention of HIV infection Clin Infect Dis Mar 15 2011;52(6):793-800

Available at http://www.ncbi.nlm.nih.gov/pubmed/21367734

17 Greenberg AE, Hader SL, Masur H, Young AT, Skillicorn J, Dieffenbach CW Fighting HIV/AIDS in Washington, D.C

Health affairs Nov-Dec 2009;28(6):1677-1687 Available at http://www.ncbi.nlm.nih.gov/pubmed/19887408

18 Gebo KA, Fleishman JA, Reilly ED, Moore RD, Network HIVR High rates of primary Mycobacterium avium complex

and Pneumocystis jiroveci prophylaxis in the United States Medical care Sep 2005;43(9 Suppl):III23-30 Available at

http://www.ncbi.nlm.nih.gov/pubmed/16116306

19 Bonnet F, Lewden C, May T, et al Opportunistic infections as causes of death in HIV-infected patients in the HAART

era in France Scandinavian journal of infectious diseases 2005;37(6-7):482-487 Available at http://www.ncbi.nlm.nih.gov/pubmed/16089023

20 Teshale EH, Hanson DL, Wolfe MI, et al Reasons for lack of appropriate receipt of primary Pneumocystis jiroveci

pneumonia prophylaxis among HIV-infected persons receiving treatment in the United States: 1994-2003 Clin Infect

Dis Mar 15 2007;44(6):879-883 Available at http://www.ncbi.nlm.nih.gov/pubmed/17304464

21 Gebo KA, Fleishman JA, Moore RD Hospitalizations for metabolic conditions, opportunistic infections, and injection

drug use among HIV patients: trends between 1996 and 2000 in 12 states J Acquir Immune Defic Syndr Dec 15

22 Betz ME, Gebo KA, Barber E, et al Patterns of diagnoses in hospital admissions in a multistate cohort of

HIV-positive adults in 2001 Medical care Sep 2005;43(9 Suppl):III3-14 Available at http://www.ncbi.nlm.nih.gov/

pubmed/16116304

23 Moorman AC, Buchacz K, Richardson JT, al e Temporal trends in hospitalizations and hospital-associated diagnoses

in the HIV Outpatient Study (HOPS) 1994-2002 In: XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada Abstract MOPE0071

24 Louie JK, Hsu LC, Osmond DH, Katz MH, Schwarcz SK Trends in causes of death among persons with acquired

immunodeficiency syndrome in the era of highly active antiretroviral therapy, San Francisco, 1994-1998 J Infect Dis

Oct 1 2002;186(7):1023-1027 Available at http://www.ncbi.nlm.nih.gov/pubmed/12232845

25 Palella FJ, Jr., Baker RK, Moorman AC, et al Mortality in the highly active antiretroviral therapy era: changing causes

of death and disease in the HIV outpatient study J Acquir Immune Defic Syndr Sep 2006;43(1):27-34 Available at

26 Smit C, Geskus R, Walker S, et al Effective therapy has altered the spectrum of cause-specific mortality following HIV

seroconversion AIDS Mar 21 2006;20(5):741-749 Available at http://www.ncbi.nlm.nih.gov/pubmed/16514305

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27 Buchacz K, Baker RK, Moorman AC, et al Rates of hospitalizations and associated diagnoses in a large multisite

cohort of HIV patients in the United States, 1994-2005 AIDS Jul 11 2008;22(11):1345-1354 Available at http://www.ncbi.nlm.nih.gov/pubmed/18580614

28 Buchacz K, Baker RK, Palella FJ, Jr., et al AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort

study AIDS Jun 19 2010;24(10):1549-1559 Available at http://www.ncbi.nlm.nih.gov/pubmed/20502317

29 Lawn SD, Butera ST, Folks TM Contribution of immune activation to the pathogenesis and transmission of human

immunodeficiency virus type 1 infection Clin Microbiol Rev Oct 2001;14(4):753-777, table of contents Available at

30 Toossi Z, Mayanja-Kizza H, Hirsch CS, et al Impact of tuberculosis (TB) on HIV-1 activity in dually infected

patients Clinical and experimental immunology Feb 2001;123(2):233-238 Available at http://www.ncbi.nlm.nih.gov/pubmed/11207653

31 Sadiq ST, McSorley J, Copas AJ, et al The effects of early syphilis on CD4 counts and HIV-1 RNA viral loads in

blood and semen Sexually transmitted infections Oct 2005;81(5):380-385 Available at http://www.ncbi.nlm.nih.gov/pubmed/16199736

32 Bentwich Z Concurrent infections that rise the HIV viral load Journal of HIV Therapy Aug 2003;8(3):72-75

33 Kublin JG, Patnaik P, Jere CS, et al Effect of Plasmodium falciparum malaria on concentration of HIV-1-RNA in the

blood of adults in rural Malawi: a prospective cohort study Lancet Jan 15-21 2005;365(9455):233-240 Available at

34 Abu-Raddad LJ, Patnaik P, Kublin JG Dual infection with HIV and malaria fuels the spread of both diseases in

sub-Saharan Africa Science Dec 8 2006;314(5805):1603-1606 Available at http://www.ncbi.nlm.nih.gov/pubmed/17158329

35 Quinn TC, Wawer MJ, Sewankambo N, et al Viral load and heterosexual transmission of human immunodeficiency

virus type 1 Rakai Project Study Group N Engl J Med Mar 30 2000;342(13):921-929 Available at http://www.ncbi.nlm.nih.gov/pubmed/10738050

36 DiRienzo AG, van Der Horst C, Finkelstein DM, Frame P, Bozzette SA, Tashima KT Efficacy of sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced

trimethoprim-HIV infection AIDS research and human retroviruses Jan 20 2002;18(2):89-94 Available at http://www.ncbi.nlm.nih.gov/pubmed/11839141

37 Wiktor SZ, Sassan-Morokro M, Grant AD, et al Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d’Ivoire: a randomised controlled

trial Lancet May 1 1999;353(9163):1469-1475 Available at http://www.ncbi.nlm.nih.gov/pubmed/10232312

38 Whalen CC, Johnson JL, Okwera A, et al A trial of three regimens to prevent tuberculosis in Ugandan adults infected

with the human immunodeficiency virus Uganda-Case Western Reserve University Research Collaboration N Engl J

Med Sep 18 1997;337(12):801-808 Available at http://www.ncbi.nlm.nih.gov/pubmed/9295239

39 Anglaret X, Chene G, Attia A, et al Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected

adults in Abidjan, Cote d’Ivoire: a randomised trial Cotrimo-CI Study Group Lancet May 1

40 Chintu C, Bhat GJ, Walker AS, et al Co-trimoxazole as prophylaxis against opportunistic infections in

HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial Lancet Nov 20-26

41 Centers for Disease C Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with

human immunodeficiency virus MMWR Morb Mortal Wkly Rep Jun 16 1989;38 Suppl 5(Suppl 5):1-9 Available at

42 Masur H Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease

in patients infected with the human immunodeficiency virus Public Health Service Task Force on Prophylaxis and

Therapy for Mycobacterium avium Complex N Engl J Med Sep 16 1993;329(12):898-904 Available at http://www.ncbi.nlm.nih.gov/pubmed/8395019

43 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human

immunodeficiency virus: a summary MMWR Recomm Rep Jul 14 1995;44(RR-8):1-34 Available at http://www.ncbi.nlm.nih.gov/pubmed/7565547

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44 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human

immunodeficiency virus USPHS/IDSA Prevention of Opportunistic Infections Working Group MMWR Recomm Rep

Jun 27 1997;46(RR-12):1-46 Available at http://www.ncbi.nlm.nih.gov/pubmed/9214702

immunodeficiency virus U.S Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA) MMWR

Recomm Rep Aug 20 1999;48(RR-10):1-59, 61-56 Available at http://www.ncbi.nlm.nih.gov/pubmed/10499670

46 Kaplan JE, Masur H, Holmes KK, Usphs, Infectious Disease Society of A Guidelines for preventing opportunistic infections among HIV-infected persons—2002 Recommendations of the U.S Public Health Service and the Infectious

Diseases Society of America MMWR Recomm Rep Jun 14 2002;51(RR-8):1-52 Available at http://www.ncbi.nlm.nih.gov/pubmed/12081007

47 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency

virus: disease-specific recommendations USPHS/IDSA Prevention of Opportunistic Infections Working Group Clin Infect

Dis Aug 1995;21 Suppl 1:S32-43 Available at http://www.ncbi.nlm.nih.gov/pubmed/8547510

immunodeficiency virus: disease-specific recommendations USPHS/IDSA Prevention of Opportunistic Infections

Working Group US Public Health Services/Infectious Diseases Society of America Clin Infect Dis Oct 1997;25 Suppl

3:S313-335 Available at http://www.ncbi.nlm.nih.gov/pubmed/9356832

immunodeficiency virus Clin Infect Dis Apr 2000;30 Suppl 1:S29-65 Available at http://www.ncbi.nlm.nih.gov/pubmed/10770913

50 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human

immunodeficiency virus: a summary Ann Intern Med Feb 1 1996;124(3):349-368 Available at http://www.ncbi.nlm.nih.gov/pubmed/8554235

immunodeficiency virus Ann Intern Med Nov 15 1997;127(10):922-946 Available at http://www.ncbi.nlm.nih.gov/pubmed/9382373

52 1997 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with HIV: Part I Prevention of exposure U.S Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention American family physician Sep 1 1997;56(3):823-834 Available at http://www.ncbi.nlm.nih.gov/pubmed/9301575

53 1999 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with HIV: part I

Prevention of exposure American family physician Jan 1 2000;61(1):163-174 Available at http://www.ncbi.nlm.nih.gov/pubmed/10643957

54 Antiretroviral therapy and medical management of pediatric HIV infection and 1997 USPHS/IDSA report on the

prevention of opportunistic infections in persons infected with human immunodeficiency virus Pediatrics Oct

1998;102(4 Pt 2):999-1085 Available at http://www.ncbi.nlm.nih.gov/pubmed/9826994

55 Kaplan JE, Masur H, Jaffe HW, Holmes KK Preventing opportunistic infections in persons infected with HIV: 1997

guidelines JAMA Jul 23-30 1997;278(4):337-338 Available at http://www.ncbi.nlm.nih.gov/pubmed/9228443

56 Brooks JT, Kaplan JE, Masur H What’s new in the 2009 US guidelines for prevention and treatment of opportunistic

infections among adults and adolescents with HIV? Top HIV Med Jul-Aug 2009;17(3):109-114 Available at http://www.ncbi.nlm.nih.gov/pubmed/19675369

57 Benson CA, Kaplan JE, Masur H, et al Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases

Society of America MMWR Recomm Rep Dec 17 2004;53(RR-15):1-112 Available at http://www.ncbi.nlm.nih.gov/pubmed/15841069

58 Mofenson LM, Oleske J, Serchuck L, et al Treating opportunistic infections among HIV-exposed and infected children:

recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America MMWR

Recomm Rep Dec 3 2004;53(RR-14):1-92 Available at http://www.ncbi.nlm.nih.gov/pubmed/15577752

59 Kaplan JE, Benson C, Holmes KH, et al Guidelines for prevention and treatment of opportunistic infections in infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine

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HIV-Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents A-10

Association of the Infectious Diseases Society of America MMWR Recomm Rep Apr 10 2009;58(RR-4):1-207; quiz

CE201-204 Available at http://www.ncbi.nlm.nih.gov/pubmed/19357635

60 Mofenson LM, Brady MT, Danner SP, et al Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and

the American Academy of Pediatrics MMWR Recomm Rep Sep 4 2009;58(RR-11):1-166 Available at http://www.ncbi.nlm.nih.gov/pubmed/19730409

61 Cruickshank DP, Wigton TR, Hays PM Maternal physiology in pregnancy In: Gabbe SG, Neibyl JR, Simpson JL, eds Obstetrics: Normal and Problem Pregnancies New York, NY: Churchchill Livingstone, 1996

62 ACOG Committee on Obstetric Practice ACOG Committee Opinion Number 299, September 2004 (replaces No 158,

September 1995) Guidelines for diagnostic imaging during pregnancy Obstet Gynecol Sep 2004;104(3):647-651

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Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents B-1

Pneumocystis Pneumonia (Last updated July 25, 2017; last reviewed July 25, 2017)

Epidemiology

Pneumocystis pneumonia (PCP) is caused by Pneumocystis jirovecii, a ubiquitous fungus The taxonomy

of the organism has been changed; Pneumocystis carinii now refers only to the Pneumocystis that infects rats, and P jirovecii refers to the distinct species that infects humans The abbreviation PCP is still used to designate Pneumocystis pneumonia Initial infection with P jirovecii usually occurs in early childhood; two- thirds of healthy children have antibodies to P jirovecii by ages 2 to 4 years.1

Rodent studies and case clusters in immunosuppressed patients suggest that Pneumocystis spreads by

the airborne route Disease probably occurs by new acquisition of infection and by reactivation of latent infection.2-11 Before the widespread use of PCP prophylaxis and antiretroviral therapy (ART), PCP occurred

in 70% to 80% of patients with AIDS;12 the course of treated PCP was associated with a 20% to 40%

mortality rate in individuals with profound immunosuppression Approximately 90% of PCP cases occurred

in patients with CD4 T-lymphocyte (CD4 cell) counts <200 cells/mm3 Other factors associated with a higher risk of PCP in the pre-ART era included CD4 cell percentage <14%, previous episodes of PCP, oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV RNA levels.13,14

The incidence of PCP has declined substantially with widespread use of PCP prophylaxis and ART; recent incidence among patients with AIDS in Western Europe and the United States is <1 case per 100 person- years.15-17 Most cases now occur in patients who are unaware of their HIV infection or are not receiving ongoing care for HIV,18 and in those with advanced immunosuppression (CD4 counts <100 cells/mm3).19

Clinical Manifestations

In HIV-infected patients, the most common manifestations of PCP are subacute onset of progressive dyspnea, fever, non-productive cough, and chest discomfort that worsens within days to weeks The fulminant

pneumonia observed in patients who are not infected with HIV is less common.20,21

In mild cases, pulmonary examination usually is normal at rest With exertion, tachypnea, tachycardia, and diffuse dry (cellophane) rales may be observed.21 Oral thrush is a common co-infection Fever is apparent in most cases and may be the predominant symptom in some patients Extrapulmonary disease is rare but can occur in any organ and has been associated with use of aerosolized pentamidine prophylaxis.22

Hypoxemia, the most characteristic laboratory abnormality, can range from mild (room air arterial oxygen [pO2] ≥70 mm Hg or alveolar-arterial O2 gradient, [A-a] DO2 <35 mm Hg) to moderate ([A-a] DO2 ≥35 and <45 mm Hg) to severe ([A-a] DO2 ≥45 mm Hg) Oxygen desaturation with exercise is often abnormal but is non-specific.23 Elevation of lactate dehydrogenase levels to >500 mg/dL is common but also non- specific.24 The chest radiograph typically demonstrates diffuse, bilateral, symmetrical “ground-glass”

interstitial infiltrates emanating from the hila in a butterfly pattern;21 however, a chest radiograph may be normal in patients with early disease.25 Atypical radiographic presentations also occur, such as nodules, blebs and cysts, asymmetric disease, upper lobe localization, intrathoracic adenopathy, and pneumothorax Spontaneous pneumothorax in a patient with HIV infection should raise the suspicion of PCP.26,27 Cavitation, and pleural effusion are uncommon in the absence of other pulmonary pathogens or malignancy, and their presence may indicate an alternative diagnosis or an additional pathology In fact, approximately 13% to 18% of patients with documented PCP have another concurrent cause of pulmonary dysfunction, such as tuberculosis (TB), Kaposi sarcoma (KS), or bacterial pneumonia.28,29

Thin-section computed tomography (CT) is a useful adjunctive study, since even in patients with

mild-to-moderate symptoms and a normal chest radiograph, a CT scan will be abnormal, demonstrating

“ground-glass” attenuation that may be patchy, while a normal CT has a high negative predictive value.30,31

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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents B-2

Diagnosis

Because clinical presentation, blood tests, and chest radiographs are not pathognomonic for PCP, and

because the organism cannot be cultivated routinely, histopathologic or cytopathologic demonstration of organisms in tissue, bronchoalveolar lavage (BAL) fluid, or induced sputum samples20,28,29,32 is required for

a definitive diagnosis Spontaneously expectorated sputum has low sensitivity and should not be submitted

to the laboratory to diagnose PCP Giemsa, Diff-Quik, and Wright stains detect both the cystic and trophic forms but do not stain the cyst wall; Grocott-Gomori methenamine silver, Gram-Weigert, cresyl violet, and toluidine blue stain the cyst wall Some laboratories prefer direct immunofluorescent staining The sensitivity and specificity of respiratory samples for PCP depend on the stain being used, the experience

of the microbiologist or pathologist, the pathogen load, and specimen quality Previous studies of stained respiratory tract samples obtained by various methods indicate the following relative diagnostic sensitivities: induced sputum <50% to >90%, bronchoscopy with BAL 90% to 99%, transbronchial biopsy 95% to 100%, and open lung biopsy 95% to 100%.

Polymerase chain reaction (PCR) is an alternative method for diagnosing PCP.31 PCR is highly sensitive and

specific for detecting Pneumocystis; however, PCR cannot reliably distinguish colonization from disease,

although higher organism loads as determined by Q-PCR assays are likely to represent clinically significant disease.33-35 1,3ß-D-glucan (a component of the cell wall of Pneumocystis cysts) is often elevated in patients

with PCP, but while the assay sensitivity appears to be high, and thus a diagnosis of PCP is less likely in patients with a low level (e.g <80 pg/ml using the Fungitell assay), the specificity for establishing a PCP diagnosis is low,17,36-38 since many other fungal diseases, as well as hemodialysis cellulose mebranes and some drugs can produce elevation

Because several disease processes produce similar clinical manifestations, a specific diagnosis of PCP should

be sought rather than relying on a presumptive diagnosis, especially in patients with moderate-to-severe disease Treatment can be initiated before making a definitive diagnosis because organisms persist in clinical specimens for days or weeks after effective therapy is initiated.32

Preventing Exposure

Pneumocystis can be quantified in the air near patients with PCP,39 and multiple outbreaks, each caused by a

distinct strain of Pneumocystis, have been documented among kidney transplant patients.5-11,40 Although these strongly suggest that high-risk patients without PCP may benefit from isolation from other patients with

known PCP infection, data are insufficient to support isolation as standard practice (CIII).

Preventing Disease

Indication for Primary Prophylaxis

HIV-infected adults and adolescents, including pregnant women and those on ART, should receive

chemoprophylaxis against PCP if they have CD4 counts <200 cells/mm3 (AI).12,13,41 Persons who have

a CD4 cell percentage of <14% should also be considered for prophylaxis (BII).12,13,41 Initiation of

chemoprophylaxis at CD4 counts between 200 and 250 cells/mm3 also should be considered when starting

ART must be delayed and frequent monitoring of CD4 counts, such as every 3 months, is impossible (BII).13Patients receiving pyrimethamine-sulfadiazine for treatment or suppression of toxoplasmosis do not require

additional prophylaxis for PCP (AII).42

Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended prophylactic agent (AI).41,43-45 One

double-strength tablet daily is the preferred regimen (AI), but one single-strength tablet daily45 also is

effective and may be better tolerated than the double-strength tablet (AI) One double-strength tablet three times weekly also is effective (BI).46 TMP-SMX at a dose of one double-strength tablet daily confers cross protection against toxoplasmosis47 and many respiratory bacterial infections.43,48 Lower doses of TMP-SMX may also confer such protection, though data addressing this are unavailable TMP-SMX chemoprophylaxis

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should be continued, if clinically feasible, in patients who have non-life-threatening adverse reactions In those who discontinue TMP-SMX because of a mild adverse reaction, re-institution should be considered

after the reaction has resolved (AII) Therapy should be permanently discontinued (with no rechallenge) in

patients with life-threatening adverse reactions including possible or definite Stevens-Johnson syndrome or

toxic epidermal necrolysis (TEN) (AIII) Patients who have experienced adverse events, including fever and

rash, may better tolerate re-introduction of the drug if the dose is gradually increased according to published

regimens (BI)49,50 or if TMP-SMX is given at a reduced dose or frequency (CIII) As many as 70% of patients

can tolerate such re-institution of therapy.48

For patients who cannot tolerate TMP-SMX, alternative prophylactic regimens include dapsone (BI),43 dapsone

plus pyrimethamine plus leucovorin (BI),51-53 aerosolized pentamidine administered with the Respirgard II

nebulizer (manufactured by Marquest; Englewood, Colorado) (BI),44 and atovaquone (BI).54,55 Atovaquone is

as effective as aerosolized pentamidine54 or dapsone55 but substantially more expensive than the other regimens For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMX, recommended alternatives for

prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine plus leucovorin (BI),51-53

or atovaquone, with or without pyrimethamine, plus leucovorin (CIII)

The following regimens cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient:

• Aerosolized pentamidine administered by nebulization devices other than the Respirgard II nebulizer

• Intermittently administered parenteral pentamidine

• Oral clindamycin plus primaquine

Clinicians can consider using these agents, however, in situations in which the recommended agents cannot be

administered or are not tolerated (CIII).

Discontinuing Primary Prophylaxis

Primary Pneumocystis prophylaxis should be discontinued for adult and adolescent patients who have

responded to ART with an increase in CD4 counts from <200 cells/mm3 to >200 cells/mm3 for >3 months

(AI) In observational and randomized studies supporting this recommendation, most patients had CD4

counts >200 cells/mm3 for more than 3 months before discontinuing PCP prophylaxis.56-65 The median CD4 count at the time prophylaxis was discontinued was >300 cells/mm3, most patients had a CD4 cell percentage

≥14%, and many had sustained suppression of HIV plasma RNA levels below detection limits for the assay employed Median follow-up was 6 to 19 months.

Discontinuing primary prophylaxis in these patients is recommended because its preventive benefits against PCP, toxoplasmosis, and bacterial infections are limited;58,64 stopping the drugs reduces pill burden, cost, and the potential for drug toxicity, drug interactions, and selection of drug-resistant pathogens Prophylaxis should

be reintroduced if the CD4 count decreases to <200 cells/mm3 (AIII).

A combined analysis of 12 European cohorts16 and a case series66 found a low incidence of PCP in patients with CD4 counts between 100 and 200 cells/mm3, who were receiving ART and had HIV plasma viral loads

<50 to 400 copies/mL, and who had stopped or never received PCP prophylaxis, suggesting that primary and secondary PCP prophylaxis can be safely discontinued in patients with CD4 counts between 100 to 200 cells/

mm3 and HIV plasma RNA levels below limits of detection with commercial assays Data on which to base specific recommendations are inadequate, but one approach would be to stop primary prophylaxis in patients with CD4 counts of 100 to 200 cells/mm3 if HIV plasma RNA levels remain below limits of detection for at

least 3 to 6 months (BII) Similar observations have been made with regard to stopping primary prophylaxis

for Toxoplasma encephalitis.67

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Treating Disease

TMP-SMX is the treatment of choice for PCP (AI).68,69 The dose must be adjusted for abnormal renal

function Multiple randomized clinical trials indicate that TMP-SMX is as effective as parenteral

pentamidine and more effective than other regimens Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because efficacy is questionable and some evidence exists for a higher

failure rate (AII).70 Oral outpatient therapy with TMP-SMX is highly effective in patients with

mild-to-moderate disease (AI).69

Mutations associated with resistance to sulfa drugs have been documented, but their effect on clinical

outcome is uncertain.71-74 Patients who have PCP despite TMP-SMX prophylaxis usually can be treated

effectively with standard doses of TMP-SMX (BIII).

Patients with documented or suspected PCP and moderate-to-severe disease, defined by room air pO2 <70

mm Hg or Alveolar-arterial O2 gradient ≥35 mm Hg, should receive adjunctive corticosteroids as early as

possible and certainly within 72 hours after starting specific PCP therapy (AI).75-80 The benefits of starting steroids later are unclear, but most clinicians would use them in such circumstances for patients with

moderate-to-severe disease (BIII) Intravenous methylprednisolone at 75% of the respective oral prednisone

dose can be used if parenteral administration is necessary.

Alternative therapeutic regimens for mild-to-moderate disease include: dapsone and TMP (BI),69,81 which may have efficacy similar to TMP-SMX and fewer side effects, but is less convenient because of the

number of pills; primaquine plus clindamycin (BI)82-84 (the clindamycin component can be administered intravenously [IV] for more severe cases, but primaquine is only available orally); and atovaquone

suspension (BI),55,56,68,85 which is less effective than TMP-SMX for mild-to-moderate disease but has fewer side effects Whenever possible, patients should be tested for glucose-6-phosphate dehydrogenase deficiency (G6PD) deficiency before primaquine or dapsone is administered.

Alternative therapeutic regimens for patients with moderate-to-severe disease include

clindamycin-primaquine or IV pentamidine (AI).84,86,87 Some clinicians prefer clindamycin-primaquine because of its higher degree of efficacy and lesser toxicity compared with pentamidine.84,88-90

Aerosolized pentamidine should not be used to treat PCP because its efficacy is limited and it is associated with more frequent relapse (AI).86,91,92

The recommended duration of therapy for PCP (irrespective of regimen) is 21 days (AII).20 The probability and rate of response to therapy depend on the agent used, number of previous PCP episodes, severity of pulmonary illness, degree of immunodeficiency, timing of initiation of therapy and comorbidities.

The overall prognosis remains poor for patients who have such severe hypoxemia that admission to an intensive care unit (ICU) is necessary However, in recent years, such patients have had much better survival than in the past, perhaps because of better management of comorbidities and better supportive care.93-96Because long-term survival is possible for patients in whom ART is effective, HIV-infected individuals with severe PCP should be offered ICU admission or mechanical ventilation if needed, just as with HIV-

uninfected patients (AII).

Special Consideration with Regards to Starting ART

ART should be initiated in patients not already on it, when possible, within 2 weeks of diagnosis of PCP

(AI) In a randomized controlled trial of 282 patients with opportunistic infections (OIs) other than TB, 63%

of whom had definite or presumptive PCP, a significantly lower incidence of AIDS progression or death (a secondary study endpoint) was seen in subjects randomized to early (median 12 days after initiation of therapy for OI) versus deferred initiation of ART (median 45 days).97 Of note, no patients with PCP and respiratory failure requiring intubation were enrolled in the study,97 and initiating ART in such patients is problematic due to the lack of parenteral preparations and unpredictble absorption of oral medications, as

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well as potential drug interactions with agents commonly used in the ICU.98

Paradoxical immune reconstitution inflammatory syndrome (IRIS) is rare but has been reported following PCP.99 Most cases have occurred within weeks of the episode of PCP; symptoms include fever and

recurrence or exacerbation of pulmonary symptoms including cough and shortness of breath, as well as worsening of a previously improving chest radiograph Although IRIS in the setting of PCP has only rarely been life-threatening,100 patients should be closely followed for recurrence of symptoms after initiation of ART Management of PCP-associated IRIS is not well defined; some experts would consider corticosteroids

in patients with respiratory deterioration if other causes are ruled out.

Monitoring of Response to Therapy and Adverse Events (Including IRIS)

Careful monitoring during therapy is important to evaluate response to treatment and to detect toxicity as soon as possible Follow-up after therapy includes assessment for early relapse, especially when therapy has been with an agent other than TMP-SMX or was shortened for toxicity

In HIV-infected patients, rates of adverse reaction to TMP-SMX are high (20%–85%).68,69,81,83,87,101-105

Common adverse effects are rash (30%–55%) (including Stevens-Johnson syndrome), fever (30%–40%), leukopenia (30%–40%), thrombocytopenia (15%), azotemia (1%–5%), hepatitis (20%), and hyperkalemia

Supportive care for common adverse effects should be attempted before TMP-SMX is discontinued (AIII)

Rashes often can be “treated through” with antihistamines, nausea can be controlled with antiemetics, and fever can be managed with antipyretics.

The most common adverse effects of alternative therapies include methemoglobinemia and hemolysis with dapsone or primaquine (especially in those with G6PD deficiency); rash and fever with

dapsone;69,81 azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, electrolyte abnormalities, and cardiac dysrhythmia with pentamidine;85-87,104 anemia, rash, fever, and diarrhea with primaquine and

clindamycin;69,82,83 and headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone.68,103

Managing Treatment Failure

Clinical failure is defined as lack of improvement or worsening of respiratory function documented by arterial blood gases (ABGs) after at least 4 to 8 days of anti-PCP treatment Failure attributed to lack of drug efficacy occurs in approximately 10% of those with mild-to-moderate disease No convincing clinical trials exist on which to base recommendations for the management of treatment failure attributed to lack of drug efficacy Clinicians should wait at least 4 to 8 days before switching therapy for lack of clinical improvement

(BIII) In the absence of corticosteroid therapy, early and reversible deterioration within the first 3 to 5 days

of therapy is typical, probably because of the inflammatory response caused by antibiotic-induced lysis

of organisms in the lung Other concomitant infections must be excluded as a cause of clinical failure;28,29bronchoscopy with BAL should be strongly considered to evaluate for this possibility, even if the procedure was conducted before initiating therapy.

Treatment failure attributed to treatment-limiting toxicities occurs in up to one-third of patients.69 Switching

to another regimen is the appropriate management for treatment-related toxicity (BII) When TMP-SMX is

not effective or cannot be used for moderate-to-severe disease because of toxicity, the common practice is

to use parenteral pentamidine or oral primaquine combined with intravenous clindamycin (BII).83,87,105 For

mild disease, atovaquone is a reasonable alternative (BII) Although a meta-analysis, systematic review, and

cohort study concluded that the combination of clindamycin and primaquine might be the most effective regimen for salvage therapy,84,89,90 no prospective clinical trials have evaluated the optimal approach to patients who experience a therapy failure with TMP-SMX.

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Preventing Recurrence

When to Start Secondary Prophylaxis

Secondary PCP prophylaxis with TMP-SMX should be initiated immediately upon successful completion

of therapy and maintained until immune reconstitution occurs as a result of ART (see below) (AI).106 For patients who are intolerant of TMP-SMX, the alternatives are dapsone, dapsone plus pyrimethamine plus leucovorin, atovaquone, and aerosolized pentamidine

When to Stop Secondary Prophylaxis

Secondary prophylaxis should be discontinued in adult and adolescent patients whose CD4 counts have increased from <200 to >200 cells mm3 for >3 months as a result of ART (AII) Reports from observational

studies57,63,107,108 and from two randomized trials64,109 and a combined analysis of eight European cohorts being followed prospectively110 support this recommendation In these studies, patients responded to ART with

an increase in CD4 counts to ≥200 cells/mm3 for >3 months At the time prophylaxis was discontinued, the median CD4 count was >300 cells/mm3 and most patients had a CD4 cell percentage >14% Most patients had sustained suppression of plasma HIV RNA levels below the limits of detection for the assay employed; the longest follow-up was 40 months Based on results from the COHERE study, secondary prophylaxis in patients with CD4 counts of 100 to 200 cells/mm3 can potentially be discontinued if HIV plasma RNA levels

remain below limits of detection for at least 3 to 6 months (BII).111

When to Restart Primary or Secondary Prophylaxis

Primary or secondary prophylaxis should be reintroduced if the CD4 count decreases to <100 cells/mm3

(AIII) regardless of the HIV plasma viral load Prophylaxis should also be reintroduced for patients with

CD4 counts of 100-200 cells/mm3 with HIV plasma viral load above detection limits of the utilized assay

(AIII) Based on results from the COHERE study, primary or secondary prophylaxis may not need to be

restarted in patients with CD4 counts of 100 to 200 cells/mm3 who have had HIV plasma RNA levels below

limits of detection for at least 3 to 6 months (BII).16,111

If an episode of PCP occurs at a CD4 count >200 cells/mm3 while on ART, it would be prudent to (then) continue PCP prophylaxis for life, regardless of how high the CD4 cell count rises as a consequence of ART

(BIII) For patients in whom PCP occurs at a CD4 count >200 cells/mm3 while not on ART, discontinuation

of prophylaxis can be considered once HIV plasma RNA levels are suppressed to below limits of detection

for at least 3 to 6 months, although there are no data to support recommendations in this setting (CIII)

Special Considerations During Pregnancy

PCP diagnostic considerations for pregnant women are the same as for women who are not pregnant

Indications for therapy are the same as for non-pregnant women Some data suggest an increased risk of PCP-associated mortality in pregnancy compared with non-pregnant adults, although there are no large, well- controlled studies evaluating the impact of pregnancy on PCP outcomes.112

The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies can be used if

patients are unable to tolerate or are unresponsive to TMP-SMX (AI).113 In case-control studies, trimethoprim has been associated with an increased risk of neural tube defects and cardiovascular, urinary tract, and

multiple anomalies after first-trimester exposure.114-116 One small study reported an increased risk of birth defects in infants born to women receiving antiretroviarals and folate antagonists, primarily trimethoprim, by contrast no increase was observed among those with exposure to either an antiretroviral or a folate antagonist alone.117 Although a small increased risk of birth defects may be associated with first-trimester exposure to trimethoprim, women in their first trimester with PCP still should be treated with TMP-SMX because of its

considerable benefit (AIII)

Although folic acid supplementation of 0.4 mg/day is routinely recommended for all pregnant women,118

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there are no trials evaluating whether supplementation at higher levels (such as the 4 mg/day recommended for pregnant women with a previous infant with a neural tube defect) would reduce the risk of birth defects associated with first-trimester TMP-SMX use in HIV-infected women Epidemiologic data suggest that folic acid supplementation may reduce the risk of congenital anomalies.115,116 In a large, population-based, case-control study, the increased odds of congenital cardiovascular anomalies associated with TMP-SMX use in pregnancy were not seen in women also receiving folic acid supplementation, most of who received

6 mg/day (odds ratio [OR] 1.24; 95% confidence interval [CI]: 0.94-1.62).119 Although the risk of multiple congenital abnomralies associated with TMP-SMX use persisted despite supplemental folic acid, the OR decreased from 6.4 (TMP-SMX, no folic acid) to 1.9 (TMP-SMX plus folic acid) As such, clinicians can consider giving supplemental folic acid (>0.4 mg/day routinely recommended) to women in their first

trimester who are on TMP-SMX (BIII) On the other hand, a randomized, controlled trial demonstrated that

adding folinic acid to TMP-SMX treatment for PCP was associated with an increased risk of therapeutic failure and death.70 In addition, there are case reports of failure of TMP-SMX prophylaxis in the setting of concurrent folinic acid use.120 Therefore, if supplemental folic acid (>0.4 mg/day routinely recommended)

is to be given, its use should be limited to the first trimester during the teratogenic window (AIII) Whether

or not a woman receives supplemental folic acid during the first trimester, a follow-up ultrasound is

recommended at 18 to 20 weeks to assess fetal anatomy (BIII).

A randomized, controlled trial published in 1956 found that premature infants receiving prophylactic

penicillin/sulfisoxazole were at significantly higher risk of mortality, specifically kernicterus, compared with infants who received oxytetracycline.121 Because of these findings, some clinicians are concerned about the risk of neonatal kernicterus in the setting of maternal sulfonamide or dapsone use near delivery, although no published studies to date link late third-trimester exposure to either drug with neonatal death or kernicterus Adjunctive corticosteroid therapy should be used to improve the mother’s treatment outcome as indicated

in non-pregnant adults (AIII).122-125 Patients with documented or suspected PCP and moderate-to-severe disease, as defined by room air pO2 <70 mm Hg or arterial-alveolar O2 gradient >35 mm Hg, should receive adjunctive corticosteroids as early as possible A systematic review of case-control studies evaluating women with first-trimester exposure to corticosteroids found a 3.4 increase in odds of delivering a baby with a cleft palate.126 On the other hand, other large population-based studies have not found an association between maternal use of corticosteroids and congenital anomalies.127,128 Corticosteroid use in pregnancy may be associated with an increased risk of maternal hypertension, glucose intolerance/gestational diabetes, and infection.129 Maternal glucose levels should be monitored closely when corticosteroids are used in the third

trimester because the risk of glucose intolerance is increased (AIII) Moreover, women receiving 20 mg/day

of prednisone (or its dosing equivalent for other exogenous corticosteroids) for more than 3 weeks may have

a suppressed hypothalamic-pituitary-adrenal (HPA) axis and consideration should be given to use of

stress-dose corticosteroids during delivery (BIII) HPA axis suppression is rarely seen among neonates born to

women who recieved chronic corticosteroids during pregnancy.

Alternative therapeutic regimens for mild-to-moderate disease include dapsone and TMP, primaquine plus clindamycin, atovaquone suspension, and IV pentamidine

Dapsone appears to cross the placenta.130,131 Over the past several decades it has been used safely to

treat leprosy, malaria, and various dermatologic conditions during pregnancy.131,132 Long-term therapy is associated with a risk of mild maternal hemolysis, and exposed fetuses with G6PD deficiency are at potential risk (albeit extremely low) of hemolytic anemia.133

Clindamycin, which appears to cross the placenta, is a Food and Drug Administration (FDA) Pregnancy Category B medication and is considered safe for use throughout pregnancy.

Primaquine generally is not used in pregnancy because of the risk of maternal hemolysis As with dapsone, there is potential risk of hemolytic anemia in an exposed fetus with G6PD deficiency The degree of

intravascular hemolysis appears to be associated with both dose of primaquine and severity of G6PD

deficiency.134

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Data on atovaquone in humans are limited but preclinical studies have not demonstrated toxicity.134

Pentamidine is embryotoxic but not teratogenic in rats and rabbits.135

All-cause pneumonia during pregnancy increases rates of preterm labor and delivery Pregnant women with

pneumonia after week 20 of gestation should be closely monitored for evidence of contractions (BIII),

Chemoprophylaxis for PCP should be administered to pregnant women, the same as for other adults and

adolescents (AIII) TMP-SMX is the recommended prophylactic agent Given theoretical concerns about

possible teratogenicity associated with first-trimester drug exposures, health care providers may consider using alternative prophylactic regimens such as aerosolized pentamidine or oral atovaquone during this

period (CIII) rather than withholding chemoprophylaxis.

Preconception Care

Clinicians who are providing pre-conception care for HIV-infected women receiving PCP prophylaxis can discuss with their patients the option of deferring pregnancy until PCP prophylaxis can be safely

discontinued; that is, until the CD4 cell count is >200 cells/mm3 for 3 months (BIII).

Recommendations for Prevention and Treatment of Pneumocystis Pneumonia (PCP)

Preventing 1st Episode of PCP (Primary Prophylaxis)

Indications for Initiating Primary Prophylaxis:

• CD4 count <200 cells/mm3 (AI) or

• CD4% <14% of total lymphocyte count (BII) or

• CD4 count >200 but <250 cells/mm3, if ART cannot be initiated, and if CD4 cell count monitoring (e.g., every 3 months) is not

possible (BII)

Note—Patients who are receiving pyrimethamine/sulfadiazine for treatment or suppression of toxoplasmosis do not require

additional prophylaxis for PCP (AII).

Preferred Therapy:

• TMP-SMX, 1 DS PO dailya (AI) or

• TMP-SMX, 1 SS PO dailya (AI).

Alternative Therapy:

• TMP-SMX 1 DS PO three times weekly (BI) or

• Dapsoneb,c 100 mg PO daily or 50 mg PO BID (BI) or

• Dapsoneb 50 mg PO daily + (pyrimethamine 50 mg + leucovorin 25 mg) PO weekly (BI) or

• (Dapsoneb 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) PO weekly (BI) or

• Aerosolized pentamidinec 300 mg via Respigard II™ nebulizer every month (BI) or

• Atovaquone 1500 mg PO daily with food (BI) or

• (Atovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg) PO daily with food (CIII).

Indication for Discontinuing Primary Prophylaxis:

• CD4 count increased from <200 cells/mm3 to ≥200 cells/mm3 for at least 3 months in response to ART (AI)

• Can consider if CD4 count 100-200 cells/mm3 and HIV RNA remain below limit of detection for at least 3-6 months (BII)

Indication for Restarting Primary Prophylaxis:

• CD4 count <100 cells/mm3 regardless of HIV RNA (AIII)

• CD4 count 100-200 cells/mm3 and with HIV RNA above detection limit of the assay (AIII).

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• Primaquineb 30 mg (base) PO once daily + (Clindamycin [IV 600 q6h or 900 mg q8h] or [PO 450 mg q6h or 600 mg q8h]) (AI).

**Adjunctive corticosteroids are indicated in moderate to severe cases (see indications and dosage recommendations below)

For Mild to Moderate PCP—Total Duration = 21 days (AII):

Preferred Therapy:

• TMP-SMX: (TMP 15–20 mg/kg/day and SMX 75–100 mg/kg/day), given PO in 3 divided doses (AI) or

• TMP-SMX DS - 2 tablets TID (AI)

Alternative Therapy:

• Dapsoneb 100 mg PO daily + TMP 15 mg/kg/day PO (3 divided doses) (BI) or

• Primaquineb 30 mg (base) PO daily + Clindamycin PO (450 mg q6h or 600 mg q8h) (BI) or

• Atovaquone 750 mg PO BID with food (BI)

Adjunctive Corticosteroids:

For Moderate to Severe PCP Based on the Following Criteria (AI):

• PaO2 <70 mmHg at room air or

• Alveolar-arterial O2 gradient ≥35 mm Hg

Dosing Schedule:

Prednisone doses (beginning as early as possible and within 72 hours of PCP therapy) (AI):

IV methylprednisolone can be given as 75% of prednisone dose

Days 1–5 40 mg PO BID

Days 6–10 40 mg PO daily

Days 11–21 20 mg PO daily

Preventing Subsequent Episode of PCP (Secondary Prophylaxis)

Indications for Initiating Secondary Prophylaxis:

• TMP-SMX 1 DS PO three times weekly (BI) or

• Dapsoneb,c 100 mg PO daily or 50 mg PO BID (BI) or

• Dapsoneb 50 mg PO daily + (pyrimethamine 50 mg + leucovorin 25 mg) PO weekly (BI) or

• (Dapsoneb 200 mg + pyrimethamine 75 mg + leucovorin 25 mg) PO weekly (BI) or

• Aerosolized pentamidinec 300 mg via Respigard II™ nebulizer every month (BI) or

• Atovaquone 1500 mg PO daily with food (BI) or

• (Atovaquone 1500 mg + pyrimethamine 25 mg + leucovorin 10 mg) PO daily with food (CIII)

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a TMP-SMX DS once daily also confers protection against toxoplasmosis and many respiratory bacterial infections; lower dose also likely confers protection

b Whenever possible, patients should be tested for G6PD deficiency before administration of dapsone or primaquine Alternative agent should be used if the patient is found to have G6PD deficiency

c Aerosolized pentamidine or dapsone (without pyrimethamine) should not be used for PCP prophylaxis in patients who are

seropositive for Toxoplasma gondii.

Acronyms: BID = twice daily; DS = double strength; IV = intravenously; PCP = Pneumocystis pneumonia; PO = orally; q “n” h = every

“n” hour; SS = single strength; TID = three times daily; TMP = trimethoprim; TMP-SMX = trimethoprim-sulfamethoxazole

Indications for Discontinuing Secondary Prophylaxis:

• CD4 count increased from <200 cells/mm3 to >200 cells/mm3 for >3 months as a result of ART (BII) or

• Can consider if CD4 count 100-200 cells/µL and HIV RNA remain below limits of detection for at least 3-6 months (BII)

• For patients in whom PCP occurs at a CD4 count >200 cells/mm3 while not on ART, discontinuation of prophylaxis can be

considered once HIV plasma RNA levels are suppressed to below limits of detection for at least 3 to 6 months, although there are

no data to support recommendations in this setting (CIII).

Note: If an episode of PCP occurs at a CD4 count >200 cells/mm3 while on ART, it would be prudent to then continue PCP

prophylaxis for life, regardless of how high the CD4 cell count rises as a consequence of ART (BIII)

Indications for Restarting Secondary Prophylaxis:

• CD4 count falls to <200 cells/mm3 (AIII) or

Other Considerations/Comments:

• For patients with non-life-threatening adverse reactions to TMP-SMX, the drug should be continued if clinically feasible

• If TMP-SMX is discontinued because of a mild adverse reaction, re-institution should be considered after the reaction has resolved

(AII) The dose can be increased gradually (desensitization) (BI) or given at a reduced dose or frequency (CIII).

• Therapy should be permanently discontinued, with no rechallenge, in patients with possible or definite Stevens-Johnson Syndrome

or toxic epidermal necrolysis (AIII).

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with advanced human immunodeficiency virus infection NIAID AIDS Clinical Trials Group N Engl J Med Mar 16

Trang 29

44 Schneider MM, Hoepelman AI, Eeftinck Schattenkerk JK, et al A controlled trial of aerosolized pentamidine or

trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection The Dutch AIDS Treatment Group N Engl J Med Dec 24 1992;327(26):1836-1841

45 Schneider MM, Nielsen TL, Nelsing S, et al Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole

as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus

Dutch AIDS Treatment Group J Infect Dis Jun 1995;171(6):1632-1636 Available at http://www.ncbi.nlm.nih.gov/pubmed/7769306

46 El-Sadr WM, Luskin-Hawk R, Yurik TM, et al A randomized trial of daily and thrice-weekly

trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) Clin Infect Dis Oct

47 Carr A, Tindall B, Brew BJ, et al Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis

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pubmed/1351371

48 Hardy WD, Feinberg J, Finkelstein DM, et al A controlled trial of trimethoprim-sulfamethoxazole or aerosolized

pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired

immunodeficiency syndrome AIDS Clinical Trials Group Protocol 021 N Engl J Med Dec 24 1992;327(26):1842-1848

49 Para MF, Finkelstein D, Becker S, Dohn M, Walawander A, Black JR Reduced toxicity with gradual initiation of

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pubmed/11015150

50 Leoung GS, Stanford JF, Giordano MF, et al Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct

rechallenge for Pneumocystis carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ J Infect Dis Oct 15 2001;184(8):992-997 Available at http://www.ncbi.nlm.nih.gov/pubmed/11574913

51 Podzamczer D, Salazar A, Jimenez J, et al Intermittent trimethoprim-sulfamethoxazole compared with

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52 Opravil M, Hirschel B, Lazzarin A, et al Once-weekly administration of dapsone/pyrimethamine vs aerosolized

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53 Girard PM, Landman R, Gaudebout C, et al Dapsone-pyrimethamine compared with aerosolized pentamidine as primary

prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection The PRIO Study Group N Engl

J Med 1993;328(21):1514-1520 Available at https://www.ncbi.nlm.nih.gov/pubmed/8479488

54 Chan C, Montaner J, Lefebvre EA, et al Atovaquone suspension compared with aerosolized pentamidine for prevention

of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides J Infect Dis Aug 1999;180(2):369-376 Available at http://www.ncbi.nlm.nih.gov/pubmed/10395851

55 El-Sadr WM, Murphy RL, Yurik TM, et al Atovaquone compared with dapsone for the prevention of Pneumocystis

carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both Community

Program for Clinical Research on AIDS and the AIDS Clinical Trials Group N Engl J Med Dec 24

56 Furrer H, Egger M, Opravil M, et al Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy Swiss HIV Cohort Study N Engl J Med Apr 29

57 Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW Risk for preventable opportunistic infections in persons with

AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds J Infect Dis Aug

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58 Mussini C, Pezzotti P, Govoni A, et al Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia

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59 Schneider MM, Borleffs JC, Stolk RP, Jaspers CA, Hoepelman AI Discontinuation of prophylaxis for Pneumocystis

cariniii pneumonia in HIV-1-infected patients treated with highly active antiretroviral therapy Lancet Jan 16

60 Weverling GJ, Mocroft A, Ledergerber B, et al Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start

of highly active antiretroviral therapy in HIV-1 infection EuroSIDA Study Group Lancet Apr 17

61 Yangco BG, Von Bargen JC, Moorman AC, Holmberg SD Discontinuation of chemoprophylaxis against Pneumocystis

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62 Furrer H, Opravil M, Rossi M, et al Discontinuation of primary prophylaxis in HIV-infected patients at high risk of

Pneumocystis carinii pneumonia: prospective multicentre study AIDS Mar 9 2001;15(4):501-507 Available at http://www.ncbi.nlm.nih.gov/pubmed/11242147

63 Kirk O, Lundgren JD, Pedersen C, Nielsen H, Gerstoft J Can chemoprophylaxis against opportunistic infections

be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy? AIDS Sep 10

64 Lopez Bernaldo de Quiros JC, Miro JM, Pena JM, et al A randomized trial of the discontinuation of primary and

secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection Grupo de Estudio del SIDA 04/98 N Engl J Med Jan 18 2001;344(3):159-167 Available at http://www.ncbi.nlm.nih.gov/pubmed/11172138

65 Green H, Hay P, Dunn DT, McCormack S, Investigators S A prospective multicentre study of discontinuing prophylaxis

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66 D’Egidio GE, Kravcik S, Cooper CL, Cameron DW, Fergusson DA, Angel JB Pneumocystis jiroveci pneumonia

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20 2007;21(13):1711-1715 Available at http://www.ncbi.nlm.nih.gov/pubmed/17690568

67 Miro J, Esteve A, Furrer H, Opportunistic Infection Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord Safety of Stopping Primary T gondii Prophylaxis With Suppressed Viremia and CD4>100 CROI; 2016; Boston, Massachusetts

68 Hughes W, Leoung G, Kramer F, et al Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS N Engl J Med May 27 1993;328(21):1521-1527 Available at

70 Safrin S, Lee BL, Sande MA Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii

pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death J Infect Dis Oct

71 Crothers K, Beard CB, Turner J, et al Severity and outcome of HIV-associated Pneumocystis pneumonia containing

Pneumocystis jirovecii dihydropteroate synthase gene mutations AIDS May 20 2005;19(8):801-805 Available at http://www.ncbi.nlm.nih.gov/pubmed/15867494

72 Huang L, Crothers K, Atzori C, et al Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance

Emerg Infect Dis Oct 2004;10(10):1721-1728 Available at http://www.ncbi.nlm.nih.gov/pubmed/15504256

73 Stein CR, Poole C, Kazanjian P, Meshnick SR Sulfa use, dihydropteroate synthase mutations, and Pneumocystis jiroveccii

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74 Alvarez-Martinez MJ, Miro JM, Valls ME, et al Prevalence of dihydropteroate synthase genotypes before and after the introduction of combined antiretroviral therapy and their influence on the outcome of Pneumocystis pneumonia in

HIV-1-infected patients Diagn Microbiol Infect Dis Sep 2010;68(1):60-65 Available at http://www.ncbi.nlm.nih.gov/pubmed/20727472

75 Nielsen TL, Eeftinck Schattenkerk JK, Jensen BN, et al Adjunctive corticosteroid therapy for Pneumocystis carinii

pneumonia in AIDS: a randomized European multicenter open label study J Acquir Immune Defic Syndr

76 Bozzette SA, Sattler FR, Chiu J, et al A controlled trial of early adjunctive treatment with corticosteroids for

Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome California Collaborative Treatment Group

N Engl J Med Nov 22 1990;323(21):1451-1457 Available at http://www.ncbi.nlm.nih.gov/pubmed/2233917

77 The National Institutes of Health-University of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis

pneumonia in the acquired immunodeficiency syndrome N Engl J Med Nov 22 1990;323(21):1500-1504 Available at

78 Montaner JS, Lawson LM, Levitt N, Belzberg A, Schechter MT, Ruedy J Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS)

Ann Intern Med Jul 1 1990;113(1):14-20 Available at http://www.ncbi.nlm.nih.gov/pubmed/2190515

79 Gallant JE, Chaisson RE, Moore RD The effect of adjunctive corticosteroids for the treatment of Pneumocystis carinii

pneumonia on mortality and subsequent complications Chest Nov 1998;114(5):1258-1263 Available at http://www.ncbi.nlm.nih.gov/pubmed/9823998

80 Briel M, Bucher HC, Boscacci R, Furrer H Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients

with HIV-infection Cochrane Database Syst Rev 2006;3:CD006150(3):CD006150 Available at http://www.ncbi.nlm.nih.gov/pubmed/16856118

81 Medina I, Mills J, Leoung G, et al Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency

syndrome A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone N Engl J Med Sep 20

82 Black JR, Feinberg J, Murphy RL, et al Clindamycin and primaquine therapy for mild-to-moderate episodes of

Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044 Clin Infect Dis Jun

84 Smego RA, Jr., Nagar S, Maloba B, Popara M A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia

Arch Intern Med Jun 25 2001;161(12):1529-1533 Available at http://www.ncbi.nlm.nih.gov/pubmed/11427101

85 Dohn MN, Weinberg WG, Torres RA, et al Oral atovaquone compared with intravenous pentamidine for Pneumocystis

carinii pneumonia in patients with AIDS Atovaquone Study Group Ann Intern Med Aug 1 1994;121(3):174-180

86 Conte JE, Jr., Chernoff D, Feigal DW, Jr., Joseph P, McDonald C, Golden JA Intravenous or inhaled pentamidine for

treating Pneumocystis carinii pneumonia in AIDS A randomized trial Ann Intern Med Aug 1 1990;113(3):203-209

87 Wharton JM, Coleman DL, Wofsy CB, et al Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis

carinii pneumonia in the acquired immunodeficiency syndrome A prospective randomized trial Ann Intern Med Jul

88 Kim T, Kim SH, Park KH, et al Clindamycin-primaquine versus pentamidine for the second-line treatment of

pneumocystis pneumonia J Infect Chemother Oct 2009;15(5):343-346 Available at http://www.ncbi.nlm.nih.gov/pubmed/19856077

89 Helweg-Larsen J, Benfield T, Atzori C, Miller RF Clinical efficacy of first- and second-line treatments for HIV-associated

Pneumocystis jirovecii pneumonia: a tri-centre cohort study J Antimicrob Chemother Dec 2009;64(6):1282-1290

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90 Benfield T, Atzori C, Miller RF, Helweg-Larsen J Second-line salvage treatment of AIDS-associated Pneumocystis

jirovecii pneumonia: a case series and systematic review J Acquir Immune Defic Syndr May 1 2008;48(1):63-67

91 Soo Hoo GW, Mohsenifar Z, Meyer RD Inhaled or intravenous pentamidine therapy for Pneumocystis carinii pneumonia

in AIDS A randomized trial Ann Intern Med Aug 1 1990;113(3):195-202 Available at http://www.ncbi.nlm.nih.gov/pubmed/2197910

92 Montgomery AB, Feigal DW, Jr., Sattler F, et al Pentamidine aerosol versus trimethoprim-sulfamethoxazole for

Pneumocystis carinii in acquired immune deficiency syndrome Am J Respir Crit Care Med Apr 1995;151(4):1068-1074

93 Dworkin MS, Hanson DL, Navin TR Survival of patients with AIDS, after diagnosis of Pneumocystis carinii

pneumonia, in the United States J Infect Dis May 1 2001;183(9):1409-1412 Available at http://www.ncbi.nlm.nih.gov/pubmed/11294675

94 Morris A, Wachter RM, Luce J, Turner J, Huang L Improved survival with highly active antiretroviral therapy in

HIV-infected patients with severe Pneumocystis carinii pneumonia AIDS Jan 3 2003;17(1):73-80 Available at http://www.ncbi.nlm.nih.gov/pubmed/12478071

95 Miller RF, Allen E, Copas A, Singer M, Edwards SG Improved survival for HIV infected patients with severe

Pneumocystis jirovecii pneumonia is independent of highly active antiretroviral therapy Thorax Aug

96 Powell K, Davis JL, Morris AM, Chi A, Bensley MR, Huang L Survival for patients With HIV admitted to the ICU

continues to improve in the current era of combination antiretroviral therapy Chest Jan 2009;135(1):11-17 Available at

97 Zolopa A, Andersen J, Powderly W, et al Early antiretroviral therapy reduces AIDS progression/death in individuals with

acute opportunistic infections: a multicenter randomized strategy trial PLoS One 2009;4(5):e5575 Available at http://www.ncbi.nlm.nih.gov/pubmed/19440326

98 Akgun KM, Miller RF Critical Care in Human Immunodeficiency Virus-Infected Patients Semin Respir Crit Care Med

Apr 2016;37(2):303-317 Available at http://www.ncbi.nlm.nih.gov/pubmed/26974306

99 Grant PM, Komarow L, Andersen J, et al Risk factor analyses for immune reconstitution inflammatory syndrome in a

randomized study of early vs deferred ART during an opportunistic infection PLoS One 2010;5(7):e11416 Available at

100 Jagannathan P, Davis E, Jacobson M, Huang L Life-threatening immune reconstitution inflammatory syndrome after

Pneumocystis pneumonia: a cautionary case series AIDS Aug 24 2009;23(13):1794-1796 Available at http://www.ncbi.nlm.nih.gov/pubmed/19684486

101 Eeftinck Schattenkerk JK, Lange JM, van Steenwijk RP, Danner SA Can the course of high dose cotrimoxazole for

Pneumocystis carinii pneumonia in AIDS be shorter? A possible solution to the problem of cotrimoxazole toxicity J

Intern Med May 1990;227(5):359-362 Available at http://www.ncbi.nlm.nih.gov/pubmed/2341830

102 Gordin FM, Simon GL, Wofsy CB, Mills J Adverse reactions to trimethoprim-sulfamethoxazole in patients with the

acquired immunodeficiency syndrome Ann Intern Med Apr 1984;100(4):495-499 Available at http://www.ncbi.nlm.nih.gov/pubmed/6230976

103 Hughes WT, LaFon SW, Scott JD, Masur H Adverse events associated with trimethoprim-sulfamethoxazole and

atovaquone during the treatment of AIDS-related Pneumocystis carinii pneumonia J Infect Dis May

104 Klein NC, Duncanson FP, Lenox TH, et al Trimethoprim-sulfamethoxazole versus pentamidine for Pneumocystis carinii

pneumonia in AIDS patients: results of a large prospective randomized treatment trial AIDS Mar 1992;6(3):301-305

105 Sattler FR, Frame P, Davis R, et al Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate

to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter

investigation of the AIDS Clinical Trials Group Protocol 029/031 J Infect Dis Jul 1994;170(1):165-172 Available at

106 Masur H, Kaplan JE, Holmes KK, Service USPH, Infectious Diseases Society of A Guidelines for preventing

opportunistic infections among HIV-infected persons 2002 Recommendations of the U.S Public Health Service and the

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Infectious Diseases Society of America Ann Intern Med Sep 3 2002;137(5 Pt 2):435-478 Available at http://www.ncbi.nlm.nih.gov/pubmed/12617574

107 Soriano V, Dona C, Rodriguez-Rosado R, Barreiro P, Gonzalez-Lahoz J Discontinuation of secondary prophylaxis

for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy AIDS Mar 10

108 Zellweger C, Opravil M, Bernasconi E, et al Long-term safety of discontinuation of secondary prophylaxis against Pneumocystis pneumonia: prospective multicentre study AIDS Oct 21 2004;18(15):2047-2053 Available at http://www.ncbi.nlm.nih.gov/pubmed/15577626

109 Mussini C, Pezzotti P, Antinori A, et al Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia

in human immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group Clin Infect Dis Mar 1

110 Ledergerber B, Mocroft A, Reiss P, et al Discontinuation of secondary prophylaxis against Pneumocystis carinii

pneumonia in patients with HIV infection who have a response to antiretroviral therapy Eight European Study Groups N Engl J Med Jan 18 2001;344(3):168-174 Available at http://www.ncbi.nlm.nih.gov/pubmed/11188837

111 Miro JM Stopping Secondary TE Prophylaxis in Suppressed Patients with CD4 100-200 Is Not Safe CROI; 2017; Seattle, Washington

112 Ahmad H, Mehta NJ, Manikal VM, et al Pneumocystis carinii pneumonia in pregnancy Chest Aug

113 Connelly RT, Lourwood DL Pneumocystis carinii pneumonia prophylaxis during pregnancy Pharmacotherapy Jul-Aug

114 Czeizel AE, Rockenbauer M, Sorensen HT OJ The teratogenic risk of trimethoprim-sulfonamides: a population based

case-control study Reprod Toxicol;15:637-46 2001 Available at https://www.ncbi.nlm.nih.gov/pubmed/11738517

115 Hernandez-Diaz S, Werler MM, Walker AM MA Folic acid antagonists during pregnancy and the risk of birth defects N Engl J Med;343:1608-14 2000 Available at https://www.ncbi.nlm.nih.gov/pubmed/11096168

116 Hernandez-Diaz S, Werler MM, Walker AM, AA M Neural tube defects in relation to use of folic acid antagonistis

during pregnancy Am J Epidemiol;153:961-8 2001 Available at https://www.ncbi.nlm.nih.gov/pubmed/11384952

117 Jungmann EM, Mercey D, DeRuiter A, et al Is first trimester exposure to the combination of antiretoviral therapy and

folate antagonists a risk factor for congenital abnormalities? Sex Transm Inf 2001;77:441-3 2001 Available at https://www.ncbi.nlm.nih.gov/pubmed/11714944

118 Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects

MMWR Recomm Rep Sep 11 1992;41(RR-14):1-7 Available at http://www.ncbi.nlm.nih.gov/pubmed/1522835

119 Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J The teratogenic risk of trimethoprim-sulfonamides: a population

based case-control study Reprod Toxicol Nov-Dec 2001;15(6):637-646 Available at http://www.ncbi.nlm.nih.gov/pubmed/11738517

120 Razavi B, Lund B, Allen BL, Schlesinger L Failure of trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis carinii pneumonia with concurrent leucovorin use Infection Jan 2002;30(1):41-42 Available at http://www.ncbi.nlm.nih.gov/pubmed/11876516

121 Andersen DH, Blanc WA, Crozier DN, Silverman WA A difference in mortality rate and incidence of kernicterus among

premature infants allotted to two prophylactic antibacterial regimens Pediatrics Oct 1956;18(4):614-625 Available at

122 Albino JA, Shapiro JM Respiratory failure in pregnancy due to Pneumocystis carinii: report a successful outcome Obstet

Gynecol 1994;83(5 Pt 2):823-824 Available at https://www.ncbi.nlm.nih.gov/pubmed/8159362

123 Madinger NE, Greenspoon JS, Ellrodt AG Pneumonia during pregnancy: has modern technology improved maternal and fetal outcome? Am J Obstet Gynecol Sep 1989;161(3):657-662 Available at http://www.ncbi.nlm.nih.gov/

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126 Park-Wyllie L, Mazzotta P, Pastuszak A, et al Birth defects after maternal exposure to corticosteroids: prospective cohort

study and meta-analysis of epidemiological studies Teratology Dec 2000;62(6):385-392 Available at http://www.ncbi.nlm.nih.gov/pubmed/11091360

127 Czeizel AE, Rockenbauer M Population-based case-control study of teratogenic potential of corticosteroids Teratology

Nov 1997;56(5):335-340 Available at http://www.ncbi.nlm.nih.gov/pubmed/9451758

128 Kallen B Maternal drug use and infant cleft lip/palate with special reference to corticoids Cleft Palate Craniofac J Nov

2003;40(6):624-628 Available at https://www.ncbi.nlm.nih.gov/pubmed/14577813

129 Ostensen M, Khamashta M, Lockshin M, et al Anti-inflammatory and immunosuppressive drugs and reproduction

Arthritis Res Ther 2006;8(3):209 Available at http://www.ncbi.nlm.nih.gov/pubmed/16712713

130 Zuidema J, Hilbers-Modderman ES, Merkus FW Clinical pharmacokinetics of dapsone Clin Pharmacokinet Jul-Aug

131 Brabin BJ, Eggelte TA, Parise M, Verhoeff F Dapsone therapy for malaria during pregnancy: maternal and fetal outcomes

Drug Saf 2004;27(9):633-648 Available at http://www.ncbi.nlm.nih.gov/pubmed/15230645

132 Newman RD, Parise ME, Slutsker L, Nahlen B, Steketee RW Safety, efficacy and determinants of effectiveness of antimalarial drugs during pregnancy: implications for prevention programmes in Plasmodium falciparum-endemic

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135 Harstad TW, Little BB, Bawdon RE, Knoll K, Roe D, Gilstrap LC, 3rd Embryofetal effects of pentamidine isethionate

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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents C-1

Toxoplasma gondii Encephalitis (Last updated July 25, 2017; last reviewed July 25, 2017)

Toxoplasmic encephalitis (TE) is caused by the protozoan Toxoplasma gondii Disease appears to occur

almost exclusively because of reactivation of latent tissue cysts.1-4 Primary infection occasionally is associated with acute cerebral or disseminated disease.

Epidemiology

Seroprevalence of anti-Toxoplasma antibody varies substantially among different geographic locales, with

a prevalence of approximately 11% in the United States, versus 50% to 80% in certain European, Latin

American, and African countries.4-6 In the era before antiretroviral therapy (ART), the 12-month incidence

of TE was approximately 33% in patients with advanced immunosuppression who were seropositive for T gondii and not receiving prophylaxis with drugs against the disease A low incidence of toxoplasmosis is seen in patients who are seronegative for T gondii If patients are truly seronegative, their toxoplasmosis

presumably represents one of three possible scenarios:

1) Primary infection,

2) Re-activation of latent disease in individuals who cannot produce detectable antibodies, or

3) Testing with insensitive assays.7,8

Clinical disease is rare among patients with CD4 T lymphocyte (CD4) cell counts >200 cells/µL Patients with CD4 counts <50 cells/µL are at greatest risk.1,3,8,9 Primary infection occurs after eating undercooked meat containing tissue cysts or ingesting oocysts that have been shed in cat feces and sporulated in the environment,

a process that takes at least 24 hours In the United States, eating raw shellfish including oysters, clams, and mussels recently was identified as a novel risk factor for acute infection.10 Up to 50% of individuals with documented primary infection do not have an identifiable risk factor.11 Patients may be infected with the parasite even in the absence of conventional risk factors for infection in their epidemiological history The organism is not transmitted through person-to-person contact.

Clinical Manifestations

Among patients with AIDS, the most common clinical presentation of T gondii infection is focal encephalitis

with headache, confusion, or motor weakness and fever.1,3,9 Patients may also present with non-focal

manifestations, including only non-specific headache and psychiatric symptoms Focal neurological

abnormalities may be present on physical examination, and in the absence of treatment, disease progression results in seizures, stupor, coma, and death Retinochoroiditis, pneumonia, and evidence of other multifocal organ system involvement can occur but are rare in patients with AIDS Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain will typically show multiple contrast-enhancing lesions in the grey matter of the cortex or basal ganglia, often with associated edema.1,9,12-14 Toxoplasmosis also can manifest

as a single brain lesion or diffuse encephalitis without evidence of focal brain lesions on imaging studies.15This latter presentation tends to be rapidly progressive and fatal

Diagnosis

HIV-infected patients with TE are almost uniformly seropositive for anti-toxoplasma immunoglobulin G (IgG) antibodies.1,3,9,16 The absence of IgG antibody makes a diagnosis of toxoplasmosis unlikely but not impossible Anti-toxoplasma immunoglobulin M (IgM) antibodies usually are absent Quantitative antibody titers are not useful for diagnosis.

Definitive diagnosis of TE requires a compatible clinical syndrome; identification of one or more mass lesions

by CT or MRI, and detection of the organism in a clinical sample On imaging studies, lesions are usually ring-enhancing and have a predilection for the basal ganglia MRI has sensitivity superior to that of CT studies

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for radiological diagnosis of TE MRI should be obtained in patients with equivocal or negative CT studies Positron emission tomography13 or single-photon emission computed tomography scanning14 may be helpful

in distinguishing between TE and primary central nervous system (CNS) lymphoma, but no imaging technique

is completely specific For TE, detection of the organism requires a brain biopsy, which is most commonly performed by a stereotactic CT-guided needle biopsy Hematoxylin and eosin stains can be used for detection

of T gondii, but sensitivity is significantly increased if immunoperoxidase staining is used and if experienced

laboratories process the specimens.17 If safe and feasible, a lumbar puncture should be performed for T

gondii polymerase chain reaction (PCR), as well as for cytology, culture, cryptococcal antigen and PCR for Mycobacterium tuberculosis, Epstein-Barr Virus (EBV) and JC Virus (JCV), either at initial presentation or subsequently, especially in patients in whom empiric therapy fails Detection of T gondii by PCR in CSF has

high specificity (96%–100%), but low sensitivity (50%), especially once specific anti-toxoplasma therapy has been started.18-20

The differential diagnosis of focal neurological disease in patients with AIDS most often includes primary CNS lymphoma and progressive multifocal leucoencephalopathy (PML) In the absence of immune

reconstitution inflammatory syndrome (IRIS), PML (but not lymphoma) can be distinguished on the basis

of imaging studies PML lesions typically involve white matter rather than gray matter, are non-contrast enhancing, and produce no mass effect Less common causes of focal neurologic disease in patients with AIDS include mycobacterial infection (especially tuberculosis [TB]); fungal infection, such as cryptococcosis; Chagas disease; and pyogenic brain abscess, particularly in IV drug abusers

Most clinicians initially rely on an empiric diagnosis, which can be established as an objective response,

documented by clinical and radiographic improvement, to specific anti-T gondii therapy in the absence of

a likely alternative diagnosis Brain biopsy is reserved for patients who fail to respond to specific therapy, although earlier biopsy should be strongly considered if results from imaging, serology, or CSF PCR studies are negative and/or suggest an etiology other than toxoplasmosis In patients with contrast-enhancing mass lesions, detection of EBV and JCV by PCR in CSF is highly suggestive of CNS lymphoma21,22 or PML,23 respectively

Preventing Exposure

HIV-infected individuals should be tested for IgG antibody to Toxoplasma soon after they are diagnosed

with HIV to detect latent infection with T gondii (BIII) They also should be counseled regarding sources of

Toxoplasma infection, especially if they lack IgG antibody to Toxoplasma

To minimize risk of acquiring toxoplasmosis, HIV-infected individuals should be advised not to eat raw or undercooked meat, including undercooked lamb, beef, pork, or venison, and not to eat raw shellfish including

oysters, clams, and mussels (BIII) Lamb, beef, venison, and pork should be cooked to an internal temperature

of 165°F to 170°F;24 meat cooked until it is no longer pink inside usually has an internal temperature of 165°F

to 170°F, and therefore, from a more practical perspective, satisfies this requirement To minimize the risk for acquiring toxoplasmosis, HIV-infected individuals should wash their hands after contact with raw meat and after gardening or other contact with soil; they should also wash fruits and vegetables well before eating

them raw (BIII) Patients who are seronegative and who own cats should be advised to have someone who

is HIV-negative and not pregnant change the litter box daily If they must change the litter box themselves,

they should wear gloves and wash their hands thoroughly afterwards (BIII) HIV-infected patients also should

be encouraged to keep their cats inside and not to adopt or handle stray cats (BIII) Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats (BIII) Patients do not need to be advised to part with their cats or to have their cats tested for toxoplasmosis (AII).

Preventing Disease

Indication for Primary Prophylaxis

Toxoplasma-seropositive patients who have CD4 counts <100 cells/µL should receive prophylaxis against

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TE (AII).25,26 All patients at risk for toxoplasmosis are also at risk for developing Pneumocystis jirovecii

pneumonia (PCP), and should be receiving PCP prophylaxis They should be managed as follows: patients receiving trimethoprim-sulfamethoxazole (TMP-SMX) or atovaquone for PCP prophylaxis require no

additional medications; patients receiving dapsone should have pyrimethamine plus leucovorin added to the regimen or be switched to TMP-SMX or atovaquone; patients receiving aerosol pentamidine should

be switched if possible to a regimen which also has anti-toxoplasma activity, i.e switching to either

trimethoprim-sulfamethoxazole or atovaquone if that is feasible For patients in whom other alternatives are

not possible, pyrimethamine alone (plus leucovorin) may have some efficacy as primary prophylaxis (CIII).8The double-strength-tablet daily dose of TMP-SMX, which is the preferred regimen for PCP prophylaxis,

is also effective against TE and is recommended (AII) TMP-SMX, one double-strength tablet three times weekly, is an alternative (BIII) If patients cannot tolerate TMP-SMX, the recommended alternative is dapsone-pyrimethamine plus leucovorin, which is also effective against PCP (BI).27-29 Atovaquone with or without pyrimethamine/leucovorin is active against PCP and also can be considered for toxoplasmosis as

well as PCP, (CIII) Aerosolized pentamidine does not protect against TE and is not recommended for antitoxoplasma prophylaxis (AI).25,30

Discontinuing Primary Prophylaxis

Prophylaxis against TE should be discontinued in adult and adolescent patients receiving ART whose CD4

counts increase to >200 cells/µL for more than 3 months (AI) Multiple observational studies31-33 and two randomized trials34,35 have reported that primary prophylaxis can be discontinued, with minimal risk for development of TE, in patients receiving ART whose CD4 counts increase from <200 cells/µL to >200 cells/

µL for more than 3 months In these studies, most patients were taking HIV protease inhibitor-containing regimens and the median CD4 count at the time prophylaxis was discontinued was >300 cells/µL At the time prophylaxis was discontinued, most patients had sustained suppression of plasma HIV RNA levels below the detection limits of available assays; the median follow-up was 7 to 22 months CD4 count increases to >200 cells/µL were studied because regimens used for prophylaxis of TE also provide PCP prophylaxis, and the risk of PCP in untreated patients increases once the CD4 count is <200 cells/µL Thus, the recommendation specifies discontinuing prophylaxis after an increase to >200 cells/µL When CD4 counts are >200 cells/

μL for at least 3 months, primary TE prophylaxis should be discontinued because it adds little value in preventing toxoplasmosis and increases pill burden, potential for drug toxicity and interaction, likelihood of development of drug-resistant pathogens, and cost

A combined analysis of 10 European cohorts found a low incidence of TE in patients with CD4 counts between 100 and 200 cells/mm3, who were receiving ART and had HIV RNA plasma viral loads <400

copies/mL, and who had stopped or never received TE prophylaxis, suggesting that primary TE prophylaxis can be safely discontinued in patients with CD4 counts 100 to 200 cells/mm3 and HIV plasma RNA levels below limits of detection with commercial assays.36 Similar observations have been made with regard to stopping primary or secondary prophylaxis for PCP.36-38 Data on which to base specific recommendations are inadequate, but one approach would be to stop primary prophylaxis in patients with CD4 counts of 100 to

200 cells/mm3 if HIV plasma RNA levels remain below limits of detection for at least 3 to 6 months (BII).36

Treating Disease

The initial therapy of choice for TE consists of the combination of pyrimethamine plus sulfadiazine plus

leucovorin (AI).2,39-41 Pyrimethamine penetrates the brain parenchyma efficiently even in the absence of inflammation.42 Leucovorin reduces the likelihood of development of hematologic toxicities associated with pyrimethamine therapy.43 Pyrimethamine plus clindamycin plus leucovorin (AI)39,40 is the preferred alternative regimen for patients with TE who cannot tolerate sulfadiazine or do not respond to first-line therapy This combination, however, does not prevent PCP, therefore additional PCP prophylaxis must be

administered when it is used (AII) (see discussion under Preventing Recurrence )

In a small (77 patients) randomized trial, TMP-SMX was reported to be effective and better tolerated than

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pyrimethamine-sulfadiazine.44 Others have reported similar efficacy in open-label observational studies.45

TMP-SMX has less in vitro activity and experience using this drug to treat toxoplasmosis in developed

countries is limited However, if pyrimethamine is unavailable or there is a delay in obtaining it, TMP-SMX

should be utilized in place of pyrimethamine-sulfadiazine or pyrimethamine-clindamycin (BI) For patients

with a history of sulfa allergy, sulfa desensitization should be attempted using one of several published

strategies (BI).46-51 During the desensitization period, atovaquone with or without pyrimethamine should be

administered until therapeutic doses of TMP-SMX are achieved (CIII).

No well-studied options exist for patients who cannot take an oral regimen No parenteral formulation of pyrimethamine exists and the only widely available parenteral sulfonamide is the sulfamethoxazole component

of TMP-SMX Some specialists will use parenteral TMP-SMX (BI) or oral pyrimethamine plus parenteral clindamycin (CIII) as initial treatment in severely ill patients who require parenteral therapy.

Atovaquone (with meals or oral nutritional supplements) plus pyrimethamine plus leucovorin, or atovaquone plus sulfadiazine, or, for patients intolerant of both pyrimethamine and sulfadiazine, atovaquone as a single agent, have also been shown to be effective in treating TE, although the relative efficacy compared with the

previous regimens is unknown (BII)52,53,54 If atovaquone is used alone, clinicians should be aware that the absorption of the drug from patient to patient is highly variable; plasma levels >18.5 µg/mL are associated with

an improved response rate but atovaquone therapeutic drug monitoring is not routinely available.53-55

The following regimens have been reported to have activity in treatment of TE in small cohorts of patients

or in case reports of one or several patients: azithromycin plus pyrimethamine plus leucovorin (CII);56,57

clarithromycin plus pyrimethamine plus leucovorin (CIII);58 5-fluorouracil plus clindamycin (CIII),59 dapsone plus pyrimethamine plus leucovorin;60 and minocycline or doxycycline combined with either pyrimethamine

plus leucovorin, sulfadiazine, or clarithromycin (CIII).61,62 Although the clarithromycin dose used in the only published study was 1g twice a day, doses >500 mg have been associated with increased mortality in HIV-

infected patients treated for disseminated Mycobacterium avium Complex Doses >500 mg twice a day should

not be used (BIII).

Clinical response to acute therapy occurs in 90% of patients with TE within 14 days of initiation of appropriate anti-toxoplasma treatment.2 The reasons why some patients fail therapy are not clearly proven; whether such failures are due to poor adherence or to other host factors or antimicrobial resistance has not been well delineated Acute therapy for TE should be continued for at least 6 weeks, if there is clinical and radiologic improvement

(BII).1-4 Longer courses may be necessary if clinical or radiologic disease is extensive or response is incomplete

at 6 weeks After completion of the acute therapy, all patients should be continued on chronic maintenance

therapy as outlined below (see Preventing Recurrence section below) The radiologic goals for treatment include resolution of the lesion(s) in terms of size, contrast enhancement, and associated edema, although residual

contrast-enhancing lesions may persist for prolonged periods Adjunctive corticosteroids such as dexamethasone should only be administered to patients with TE when they are clinically indicated to treat a mass effect

associated with focal lesions or associated edema (BIII) In those treated with corticosteroids, caution may be

needed in diagnosing CNS toxoplasmosis on the basis of treatment response, since primary CNS lymphoma may respond clinically and radiographically to corticosteroids alone; these patients should be monitored carefully

as corticosteroids are tapered In addition, corticosteroids should be discontinued as soon as clinically feasible because of their potential to cause immunosuppression Patients receiving corticosteroids should be monitored closely for development of other opportunistic infections (OIs), including cytomegalovirus retinitis and TB.

Anticonvulsants should be administered to patients with TE who have a history of seizures (AII), but should not be administered prophylactically to all patients (BII) Anticonvulsants, if indicated, should be continued at

least through the period of acute therapy.

Special Considerations with Regard to Starting ART

There are no data on which to base a recommendation regarding when to start ART in a patient with TE

However, many physicians would initiate ART within 2 to 3 weeks after the diagnosis of toxoplasmosis (CIII),

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based on the significantly lower incidence of AIDS progression or death (a secondary study endpoint)

seen in the ART arm of a controlled trial of 282 patients with OIs other than TB (only 5% of whom had toxoplasmosis) who were randomized to early (median 12 days after initiation of OI therapy) versus deferred (median 45 days) initiation of ART.63

Monitoring of Response to Therapy and Adverse Events (including IRIS)

Changes in antibody titers are not useful for monitoring responses to therapy Patients with TE should

be monitored routinely for adverse events and clinical and radiologic improvement (AIII) Common

pyrimethamine toxicities such as rash, nausea, and bone marrow suppression (neutropenia, anemia, and thrombocytopenia) often can be reversed by increasing the leucovorin dose to 10, 25, or 50 mg 4 times daily

(CIII).

Common sulfadiazine toxicities include rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea,

renal insufficiency, and crystalluria Common clindamycin toxicities include fever, rash, nausea, diarrhea

(including pseudomembranous colitis or diarrhea related to Clostridium difficile toxin), and hepatotoxicity

Common TMP-SMX toxicities include rash, fever, leukopenia, thrombocytopenia, and hepatotoxicity

Common atovaquone toxicities include nausea, vomiting, diarrhea, rash, headache, hepatotoxicity, and fever Drug interactions between anticonvulsants and antiretroviral agents should be evaluated carefully; if necessary, doses should be adjusted or alternative anticonvulsants should be used.

IRIS associated with TE has been reported but appears to be rare (~5% in one report).64-66 Most cases develop

as paradoxical worsening with increase in the size and number of lesions, peri-lesional edema, and greater enhancement in T1.65,67,68 Given the rarity of TE-associated IRIS, recommendations for management of such events are difficult to develop

Managing Treatment Failure

A brain biopsy should be strongly considered in patients who did not have an initial biopsy prior to therapy

and who fail to respond to initial therapy for TE (BII) as defined by clinical or radiologic deterioration

during the first week despite adequate therapy, or who do not show clinical improvement within 10 to

14 days A switch to an alternative regimen, as previously described, should be considered for those who undergo brain biopsy and have confirmed histopathologic evidence of TE, or who have a CSF PCR positive

for T gondii (BIII) In patients who adhere to their regimens, disease recurrence is unusual in the setting of

chronic maintenance therapy after an initial clinical and radiographic response

Preventing Recurrence

When to Start Chronic Maintenance Therapy

Patients who have completed initial therapy for TE should be given chronic maintenance therapy to

suppress infection (AI)39,40 until immune reconstitution occurs as a consequence of ART, in which case treatment discontinuation is indicated The combination of pyrimethamine plus sulfadiazine plus leucovorin

is highly effective as suppressive therapy for patients with TE (AI) and provides protection against PCP (AII) Although sulfadiazine is routinely dosed as a four-times-a-day regimen, a pharmacokinetic study

suggests bioequivalence for the same total daily dose when given either twice or four times a day,69 and limited clinical experience suggests that twice-daily dosing is effective.70 Pyrimethamine plus clindamycin

is commonly used as suppressive therapy for patients with TE who cannot tolerate sulfa drugs (BI)

Because of the high failure rate observed with lower doses,39 a dose of 600 mg clindamycin every 8

hours is recommended (CIII) Because this regimen does not provide protection against PCP (AII), an

additional agent, such as aerosol pentamidine, must be used Atovaquone with or without pyrimethamine or sulfadiazine is also active against both TE54,55 and PCP71 (BII) A small, uncontrolled study in patients who

had been receiving ART for a median of 13 months suggested that TMP-SMX could be used as a suppressive regimen to reduce pill burden.72 For patients being treated with TMP-SMX, this drug should be continued as

chronic maintenance, at a reduced dose of 1 double-strength tablet twice daily (BII) or once daily (BII) The

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lower dose may be associated with an increased risk of relapse, and if the once daily dosing is used, a gradual transition may be beneficial (e.g follow acute therapy with 4-6 weeks of 1 double-strength tablet twice daily

before lowering to 1 double-strength tablet once daily (CIII).44,45,72

Although there are no data on the long-term suppressive efficacy of the other alternative regimens noted above, clinicians might consider using these agents in unusual situations in which the recommended agents cannot be

administered (CIII)

When to Stop Chronic Maintenance Therappy

Adult and adolescent patients receiving chronic maintenance therapy for TE are at low risk for recurrence

of TE if they have successfully completed initial therapy for TE, remain asymptomatic with regard to signs and symptoms of TE, and have an increase in their CD4 counts to >200 cells/µL after ART that is sustained for more than 6 months.32,35,73,74 Discontinuing chronic maintenance therapy in such patients is a reasonable consideration, although occasional recurrences have been reported The recommendation is based on results in a limited number of patients from observational studies and one randomized clinical trial and inference from more extensive cumulative data indicating the safety of discontinuing secondary prophylaxis for other OIs during

advanced disease (BI) As part of the evaluation to determine whether discontinuation of therapy is appropriate,

some specialists recommend obtaining an MRI of the brain to assess for resolution of brain lesions

When to Restart Primary Prophylaxis or Maintenance Therapy

Primary prophylaxis should be reintroduced if the CD4 count decreases to <100 cells/mm3 (AIII) regardless

of the HIV plasma viral load Based on results from the COHERE study, primary prophylaxis may not need to

be restarted in patients with CD4 counts of 100 to 200 cells/mm3 who have had HIV plasma RNA levels below

limits of detection for at least 3 to 6 months (BII).36,37 For patients with CD4 counts of 100-200 cells/µL with HIV plasma viral load above detection limits of the utilized assay, PCP prophylaxis should be reintroduced, and this will provide prophylaxis for toxoplasmosis as well.

Because there are no published data examining the risk of recurrence in patients stopping chronic maintenance therapy for TE when the CD4 count is between 100 and 200 cells/µL, and recurrent TE can be debilitating and potentially life-threatening, maintenance therapy should be reintroduced if the CD4 count decreases to <200

cells/µL (AIII) regardless of the HIV plasma viral load.75

Special Considerations During Pregnancy

Documentation of baseline maternal T gondii serologic status (IgG) should be obtained in HIV-infected

women who become pregnant because of concerns regarding congenital toxoplasmosis Although perinatal

transmission of T gondii normally occurs only with acute infection in the immunocompetent host, case reports

have documented transmission with reactivation of chronic infection in HIV-infected women with severe

immunosuppression.76,77 Knowing maternal toxoplasmosis sero-status at the beginning of pregnancy may be helpful in delineating future risks and interpreting serologic testing performed later in pregnancy should there be heightened concerns for maternal infection and/or fetal transmission.

Primary T gondii infection can typically be distinguished from chronic infection with the use of multiple

serologic assays, including IgG, IgM, IgA, and IgE antibodies; IgG avidity; and the differential agglutination tests.78,79 Because serologic testing is often difficult to interpret, pregnant HIV-infected women with suspected

primary T gondii infection during pregnancy should be managed in consultation with a maternal-fetal medicine

specialist who can access specialized laboratory testing (BIII)79,80 (e.g., the Palo Alto Medical Foundation Toxoplasmosis Serology Laboratory; Palo Alto, CA; http://www.pamf.org/serology/ at 650-853-4828 and toxolab@pamf.org; and the National Collaborative Chicago-based Congenital Toxoplasmosis Study; Chicago, IL; http://www.uchospitals.edu/specialties/infectious-diseases/toxoplasmosis/ at 773-834-4131 and rmcleod@ midway.uchicago.edu)

Toxoplasmosis diagnostic considerations are the same in pregnant women as in non-pregnant women

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