2ars0r2018 Overview of prevention of opportunistic infections in HI-nfected patients - UpToDate U plot Date’ Mfficial reprint from UpToDate® www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved. o. Wolters Kluwer Overview of prevention of opportunistic infections in HIV- infected patients Authors: John G Bartlett, MD, Paul E Sax, MD Section Editor: Martin S Hirsch, MD Deputy Editor: Meg Sullivan, MD All topics are updated as new evidence becomes available and our peer review process is complete, Literature review current through: Sep 2019, | This topic last updated: May 08, 2018. INTRODUCTION Untreated HIV infection and HIV-related immunosuppression significantly increase the risk of acquiring opportunistic infections due to bacteria, viruses, fungi, and protozoa, These opportunistic infections (Ols) were a major source of morbidity and mortality in HIV-infected patients prior to the development of effective antiretroviral therapy (ART) and still occur today, mostly in patients who are not receiving ART, Strategies for the prevention of Ols involve the use of antimicrobials, immunizations, and public health measures. An overview of these different strategies will be reviewed here, More detailed discussions of the treatment and prevention of specific opportunistic infections are discussed elsewhere. + (See "Treatment and prevention of Pneumocystis infection in HIV-infected patients".) ‘See "Toxoplasmosis in HIV-infected patients” See "Diagnosis and treatment of histoplasmosis in HIV-infected patients" ) ‘See "Cryptococcus neoformans meningoencephalits in patients with HIV infection: Treatment ( ( + ( ( and prevention’) + (See "Treatment of AIDS-related cytomegalovirus retinitis",) * (See "Treatment and prevention of cryptosporidiosis".) hitpstiwwuuplodate com/contensloverview-otprevention-oF-opparlunstcinfections-in-hwinfected-patentsprint?search=hivBsource=search resull... 1/112ars0r2018 Overview of prevention of opportunistic infections in HInfected patients - UpToDate EPIDEMIOLOGY OF OPPORTUNISTIC INFECTIONS Opportunistic infections (Ols) are defined as infections that are more frequent or more severe because of immunosuppression [1]. Untreated HIV infection is associated with a progressive reduction in cell-mediated immunity as reflected by the CD4 count. Prior to the introduction of antiretroviral therapy (ART), Ols were the principal cause of morbidity and mortality in HIV-infected individuals. As examples, in the absence of antiretroviral therapy and antimicrobial therapy, the risk of developing certain Ols is as follows: + Pneumocystis pneumonia (PCP) - The risk of PCP without prophylaxis is 40 to 50 percent per year in those with a CD4 count <100 cells/microL. (See "Treatment and prevention of * Toxoplasmosis — For HIV-infected individuals who are seropositive for Toxoplasma gondii and have a CD4 count <100 cells/microL,, the probability of reactivated toxoplasmosis is. approximately 30 percent per year. (See “Toxoplasmosis in HIV-infected patients", section on ‘Prevalence of infection’.) * Disseminated Mycobacterium avium complex (MAC) - For patients with a CD4 count <50 cells/microL, the risk of developing disseminated MAC can be as high as 40 percent per year. The risk increases with decreasing CD4 cell count [2]. (See "Mycobacterium avium complex (MAC) infections in persons with HIV" Impact of antimicrobial prevention — Antimicrobial agents can be administered to decrease the risk of developing an Ol. Prior to the introduction of potent antiretroviral therapy regimens, the use of antimicrobial therapy for severely immunosuppressed individuals (eg, CD4 count <200 cells/microL) was associated with significant reductions in the rate of Ols. As examples: * The risk of PCP is ninefold lower with the use of antibiotic prophylaxis, and failure of primary prophylaxis is most commonly due to nonadherence and/or profound immunosuppression (CD4 count <50 cells/microL) [3-5]. (See "Treatment and prevention of Pneumocystis infection in HIV- infected patients", section o1 eventing initial infection’.) * The risk of toxoplasma reactivation is less than 3 percent for patients who receive suppression with trimethoprim-sulfamethoxazole [6]. (See "Toxoplasmosis in HIV-infected patients", section on ‘Primary prophylaxis’.) Impact of antiretroviral therapy — Antiretroviral therapy is the most important strategy for preventing Ols. The widespread use of effective ART starting in the mid-1990s has led to a dramatic reduction in the incidence of Ols as illustrated in the studies below: hitpsiwu uptodate. com/contensloverview-otprevantion-oF-opparlunstcifections-in-hwinfected-patentsprint?search=hivBsource=search resul... 2/11ronon019 COverviw of prevention of opportunist infections in Hivinected pains - UpToDate * Ina cohort study of 2410 patients in Switzerland from 1995 to 1997, the incidence of any Ol decreased from 15.1 per 100 person-years in the six months before initiating ART to 7.7 and 2.6 per 100 person-years in the first three and six months after starting ART, respectively [7]. The rate continued to decrease and was 2.2 per 100 person-years between 9 and 15 months after starting ART. * Ina multicenter study of more than 8500 HIV-infected patients in the United States, the rate of Ols declined from 140 per 1000 person-years in 1995 (prior to the introduction of potent ART) to less than 20 per 1000 person-years in 2007 [8] * An analysis of 1255 patients who had at least one CD4 count <100 cells/microL found that the incidence of a major Ol (Pneumocystis jirovecii pneumonia, MAC, and/or cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid- 1997 [9]. * Similar trends have been noted in resource-limited settings. (See "Global epidemiology of HIV infection’.) Because ART results in the restoration of cellular immunity, the vast majority of patients who discontinue antimicrobial therapy after adequate immune recovery are no longer at risk for developing section on ‘Preventing initial infe persons with HIV", section on ‘Prevention of MAC disease’.) APPROACH TO INFECTION PREVENTION Restoring cellular immunity with antiretroviral therapy (ART) is the best way to prevent opportunistic fected patient".) infections (Ols). (See "Selecting antiretroviral regimens for the treatment-naive Hl ‘A number of infections can also be prevented by immunization (eg, Streptococcus pneumoniae, hepatitis B virus). Vaccine efficacy may be compromised in advanced disease; thus, some providers may choose to wait on certain immunizations until ART has been started and some degree of immune recovery has occurred. A detailed discussion of immunizations in HIV-infected patients is found elsewhere. (See "Immunizations in HIV-infected patients" and "Pneumococcal immunization in Hi\-infected adults" and "Prevention of hepatitis B virus infection in the H|V-infected adult", section on ‘Vaccination’.) Additional preventive strategies are needed for HIV-infected individuals who have evidence of significant immunosuppression. Such patients are usually those who are not receiving ART (eg, those hitpstiwwucuplodate.com/contenisloverview-otprevantion-oF-opparlunstcinfections-in-hwinfected-patientsprint?search=hivBsource=search resull... 3/112ar012019 (Overview of prevention of opportunistic infections in HIVnfected patients - UpToDate who are unaware of their diagnosis, have recently started therapy, or are prescribed ART but are not adherent to their treatment) [1]. These additional strategies include: * Avoiding exposure ~ For certain pathogens, patients can prevent infection by avoiding exposure. As an example, patients without evidence of prior exposure to Toxoplasma gondii should avoid contact with cat feces (eg, changing cat litter) or eating undercooked meat. The risk of infection with other pathogens can also be reduced by appropriate precautions; such pathogens include Bartonella henselae, Bartonella quintana, Coccidioides spp, Cryptococcus spp, Cystoisospora, cytomegalovirus, varicella-zoster virus, and Histoplasma capsulatum. More detailed discussions on how to prevent exposure to specific organisms are found in the individual issues’ and "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on ‘Transmission’ and "Diagnosis and treatment of histoplasmosis in HIV-infected patients’, section on ‘Prevention’ and "Coccidioidomycosis in immunocompromised and pregnant persons”. section on ‘Prevention’ and “Toxoplasmosis in immunocompetent hosts", section on ‘Prevention’ and "Treatment and prevention of cryptosporidiosis" and "Treatment and prevention of cryptosporidiosis", section on ‘Prevention’ * Antimicrobial therapy - Antimicrobial agents can be administered to immunocompromised individuals with HIV infection, in conjunction with starting ART, to decrease the risk of developing certain Ols (eg, P.jirovecii pneumonia (PCP), toxoplasmosis, tuberculosis). For most infections, the decision to initiate antimicrobial therapy depends upon the CD4 count, (See ‘When to administer antimicrobial therapy’ below.) Antimicrobials are not generally recommended to prevent active infection with pathogens such as Bartonella spp, Candida spp, Cryptosporidium, or cytomegalovirus, for one or more of the following reasons: + Such pathogens are associated with a low incidence of disease. + There are concems that antimicrobial therapy can result in the development of drug resistance. + Antimicrobials can result in significant side effects and drug interactions. Instead, patients should be monitored for signs and symptoms of disease. (See ‘Early Detection’ below.) In selected rare patients (eg, those with highly chaotic psychosocial situations) who are at extremely high risk for poor adherence, we may elect to prescribe only ART at first, and not risk distracting the patient with agents for Ol prevention. Since ART is the most effective intervention hitpstiwwu uptodate. com/contensloverview-otprevantion-oF-opparlunstcinfections-in-hwinfected-patentsprint?search=hivBsource=search_resul... 4/11partor2o1e ‘Overview of prevention of opportunistic infections in HIV-infected patien's- UpToDate to prevent Ols, clinicians should prioritize HIV ART. If preventive therapy is still needed once they start ART, it can still be initiated at a later time. WHEN TO ADMINISTER ANTIMICROBIAL THERAPY We administer antimicrobial therapy to certain HIV-infected patients with the goal of preventing a clinically significant opportunistic infection (Ol). Such treatment is typically initiated as the individual’s cell-mediated immunity (ie, CD4 cell count) dectines. Antimicrobial therapy can be used in several settings: * To prevent infection in uninfected individuals (eg, primary prophylaxis for P.jirovecii). (See ‘Pneumocystis’ below.). * To prevent active infection by pathogens that are present in the body, but are dormant (eg, T. gondii, Mycobacterium tuberculosis). (See ‘Toxoplasma’ below and ‘Tuberculosis’ below.) * To treat asymptomat immunocompromised individuals who have a positive antigen or serologic test that indicates infection, despite the absence of symptoms (eg, C. immitis, C. neoformans) (see ‘Caccidioidomycosis’ below and ‘Cryptococcus’ below). This approach, referred to as preemptive therapy, allows for the use of simpler regimens, with fewer side effects, and avoids the complications associated with symptomatic disease. The use of antimicrobial therapy to prevent the development of common Ols is described below. The use of antimicrobial agents to prevent Ols in HIV-infected women who are pregnant, as well as Ols in individuals who travel to or reside in specific geographic areas with endemic infections (eg, talaromycosis, malaria, Chagas disease) are discussed elsewhere. (See "Prenatal evaluation of the HiV-infected woman in resource-rich settings" and "Diagnosis and treatment of Talaromyces (Penicillium) mameffei infection’, section on ‘Prevention’ and “Chagas disease in the immunosuppressed host".) All. CD4 counts Tuberculosis — All HIV-infected individuals, regardless of CD4 count, should be screened for latent tuberculosis using either an interferon gamma release assay or tuberculin skin testing, unless they have a prior documented history of TB or a positive screening test [10]. (See "Approach to diagnosis of latent tuberculosis infection (tuberculosis screening) in adults", section on ‘HIV infection’) Therapy for latent infection should be administered to those who test positive and are without evidence of active disease. Additional indications for treatment are discussed elsewhere. (See hitpstiwwu uptodate. com/contensloverview-otprevantion-oF-opparlunstcinfections-in-hwinfected-patentsprint?search=hivBsource=search resul... 5/112ars0r2018 Overview of prevention of opportunistic infections in HInfected patients - UpToDate ) "Treatment of latent tuberculosis infection in nonpregnant adults with HIV infectio CD4 counts $250 cells/microL Coccidioidomycosis — We perform annual IgG and IgM serologic screening for Coccidioides spp in asymptomatic patients with CD4 counts $250 cells/microL. who live in endemic regions (eg, Arizona or California). We administer preemptive therapy with fluconazole therapy to such patients if they have a newly positive serologic test. We discontinue therapy in patients receiving antiretroviral (ART) when their CD4 count is >250 cells/microL for at least six months. (See "Coccidioidomycosis in immunocompromised and pregnant persons", section on ‘Patients with HIV/AIDS'.) CD4 counts $200 cells/microL Pneumocystis — We recommend trimethoprim-sulfamethoxazole (TMP-SMX) to prevent PCP for patients with a CD4 count $200 cells/microL.. For patients who cannot take TMP-SMX, alternative agents include dapsone, atovaquone suspension, or aerosolized pentamidine (table 1) Antimicrobial may be discontinued when ART results in an increase in the CD4 count to >200 cells/microL for more than three months. It is also reasonable to discontinue primary prophylaxis in patients with a CD4 count between 100 and 200 cells/microl. if they are receiving ART and have had an undetectable viral load for approximately six months. (See “Treatment and prevention of CD4 counts $150 cells/microL Histoplasmosis — In general, we do not administer antifungal prophylaxis with itraconazole to prevent primary infection with histoplasmosis since there are limited data to suggest the efficacy of prophylaxis, and most patients will have immune recovery (je, increased CD4 count) on ART. However, in areas where histoplasmosis is hyperendemic (>10 cases/100 patient-years), such as certain parts of South America and French Guiana, some providers administer itraconazole (200 mg daily) to patients with CD4 counts <150 cells/microL. For such patients, prophylaxis can be discontinued when the CD4 cell count is >150 cells/microl. for more than six months after initiation of ART [1]. (See "Diagnosis and treatment of histoplasmosis in HIV-infected patients", section on ‘Prevention’.) CD4 counts <100 cells/microL. Toxoplasma — We administer suppressive therapy with TMP-SMX to prevent reactivation of T. gondii in patients with a CD4 count <100 cells/microL and a positive T. gondii IgG serology (See “Initial eve ition of the HIV-infecte It" hitpsthwwu uptodate. com/contensloverview-otprevantion-oF-opparlunstcinfections-in-hwinfected-patentsprint?search=hivBsource=search resul... 6/112ar012019 (Overview of prevention of opportunistic infections in HIVnfected patients - UpToDate For patients who have contraindications to TMP-SMX, we use dapsone plus pyrimethamine and leucovorin. If the patient is intolerant or allergic to the above two regimens, we administer atovaquone with or without pyrimethamine and leucovorin. Monotherapy with dapsone, pyrimethamine, azithromycin, or clarithromycin should not be used. Among patients receiving ART, we discontinue suppressive therapy when the CD4 count is >200 cells/microL for at least three months. (See "Toxoplasmosis in HIV-infected patients") Cryptococcus — Preventive therapy for cryptococcal disease is generally not recommended because of drug interactions, adverse effects, potential for antifungal drug resistance, cost, and the lack of overall survival benefit [1,11]. However, for certain patients with a CD4 count <100 cells/microL, especially those in resource-limited settings, screening for serum cryptococcal antigen and preemptive therapy for those who test positive may be useful to prevent symptomatic infection The use of preemptive therapy is discussed in detail elsewhere. (See "Cryptococcus neoformans and treatment of early infection’) CD4 counts $50 cells/microL Mycobacterium avium complex (MAC) — For patients who are initiating ART, we do not routinely administer antimicrobial prophylaxis to prevent infection with Mycobacterium avium complex (MAC). Although MAC prophylaxis with a macrolide had been common practice for all patients with a CD4 count <50 cells/microL prior to the introduction of effective ART, our approach has changed since the risk of MAC infection is low in the setting of ART, the outcome of MAC disease does not differ among those who did or did not receive prophylaxis [12,13], and there are no clinical trial data on MAC prophylaxis in the era of effective ART. Furthermore, some patients may have asymptomatic infection with MAC that becomes evident after starting ART due to an immune reconstitution inflammatory syndrome. In this setting, if single-drug therapy with azithromycin was used for prophylaxis, it might select for macrolide drug resistance. (See "Mycobacterium avium complex (MAC) infections in persons with HIV", section on ‘Treatment failure’) However, on rare occasion, there may be a temporary delay in initiating ART among those with a CD4 count <50 cells/microl. (eg, patient refusal). Unless there are concerns that the patient may have active MAC infection (eg, fevers, weight loss), MAC prophylaxis should be initiated and continued until ART is started. If there is concern for active infection, a mycobacterial blood culture should first be obtained, and prophylaxis should be delayed for 7 to 10 days, pending the results. A more detailed discussion of MAC prophylaxis is presented elsewhere. (See "Mycobacterium avium complex (MAC) infections in persons with HIV", section on ‘Prevention of MAC disease'.) hitpstiwwucuplodate.com/contensloverview-otprevantion-oF-opparlunstcifections-in-hwinfected-patentsprint?search=hivBsource=search resull... 7/112ars0r2018 Overview of prevention of opportunistic infections in HInfected patients - UpToDate EARLY DETECTION Patients should be educated about the signs and symptoms of opportunistic infections and/or screened for evidence of disease, especially if they are severely immunocompromised. As an example, we do not administer therapy to prevent cytomegalovirus (CMV) infection to those who are seropositive because of cost, risk of resistance, and lack of proven survival benefit, Such patients should be educated about the signs and symptoms of CMV disease, such as CMV retinitis (eg, increased floaters, decreased visual acuity). In addition, some experts recommend yearly ophthalmologic exams for all patients with a CD4 count <50 cells/microL to identify CMV and/or other infections that have ocular manifestations. However, this screening strategy for asymptomatic patients is typically not needed since most patients who start ART will have prompt recovery of their CD4 cell count to >50 cells/microL. (See "Primary care of the HIV-infected adult", section on ‘Patients with low CD4 cell counts'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in HIV- infected adults and adolescents”. ) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5" to 6'" grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10" to 12!" grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon Here are the patient education articles that are relevant to this topic. We encourage you to print or e- mail these topics to your patients, (You can also locate patient education articles on a variety of subjects by searching on “patient info" and the keyword(s) of interest.) * Basics topics (see "Patient education: Hepatitis B (The Basics)" and "Patient education: Vaccines for adults with HIV (The Basics)") hitpsthwwu uptodate com/contensloverview-otprevantion-oF-opparlunstcinfections-in-hwinfected-patientsprint?search=hivBsource=search resul... 6/112ars0r2018 Overview of prevention of opportunistic infections in HI-nfected patients - UpToDate * Beyond the Basics topic (see "Patient educatioi SUMMARY AND RECOMMENDATIONS * Prior to the introduction of antiretroviral therapy (ART), opportunistic infections (Ol) were the principal cause of morbidity and mortality in HIV-infected individuals. (See ‘Epidemiology of opportunistic infections' above.) * Restoring cellular immunity with ART is the best way to prevent Ols. However, additional strategies are needed for HIV-infected individuals who have evidence of significant immunocompromise. Such strategies include avoiding specific exposures and/or the use of antimicrobial agents or vaccines. (See ‘Approach to infection prevention’ above.) * Antimicrobial therapy is typically initiated according to CD4 cell count thresholds. For certain Patients, the decision to initiate antimicrobial therapy also depends upon prior exposure to the pathogen. (See ‘When to administer antimicrobial therapy’ above.) * Patients should be educated about the signs and symptoms of opportunistic infections and/or screened for evidence of disease, especially if they are severely immunocompromised. (See ‘Early Detection! above.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 3747 Version 32.0 hitpsiwwu uptodate com/contenisloverview-otprevantion-oF-opparlunstcinfections-in-hwinfected-patentsprint?search=hivBsource=search resul... 9/112ern0r2019 Overview of prevention of opportunistic infections in HI-nfected patients ~ UpToDate GRAPHICS Regimens for Pneumocystis pneumonia prophylaxis in adults and adolescents Drug Oral dose* Preferred regimen Selected adverse reactions ‘Trimethoprim-sulfamethoxazole | 1 DS tablet daily (cotrimoxazole) OR 1 SS tablet daily Fever, rash, neutropenia, gastrointestinal Upset, transaminase elevation Alternative regimens® “Timethoprim-sulfamethoxazole | 1 DS tablet three times per (cotrimoxazole) week® oR Dapsone '50 mg twice dally oR 100 mg daily oR [Atovaquone suspension 1500 mg orally once daily given with food” oR Combination of: Dapsone 50 mg dally plus Pyrimethamine 50 mg weekly plus Leveovorin 25 mg weekly oR Combination of: Dapsone 200 mg weekly plus Pyrimethamine 75 mg weekly plus Leveoverin 25 mg weekly oR Aerosolized pentemidine 300 mg monthly (via Respirgard UH nebulizer) Fever, rash, neutropenia, gastrointestinal Upset, transeminase elevation Fever, rash, gastrointestinal upset, methemoglobinemia, hemolytic anemia (check Tor G6PD deficiency) Gastrointestinal distress, rash Fever, rash, gastrointestinal upset, methemoglobinemia, hemolytic anemia (check for G6PD deficiency) Folate deficiency, gastrointestinal upset, rash Rash, thrombocytosis, wheezing, anaphylactoid reactions Fever, rash, gastrointestinal upset, methemoglobinemia, hemolytic anemia (check for G6PD deficiency) Folate deficiency, gastrointestinal upset, rash Rash, thrombocytosis, wheezing, anaphylactoid reactions Cough, wheezing, extrapulmonary pneumocystosis Arregimen that provides prophylaxis for PCP and toxoplasmosis should be administered to HIV-infected patients who are IgG seropositive for toxoplasmosis AND have a CD4 count <100 cells/microL. DS: couble-strength oral tablet, 160 mg trimethoprim with 800 mg sulfamethoxazole; SS: single-strength oral tablet, 80 mg trimethoprim with 400 mg sulfamethoxazole; G6PO: glucose-6-phosphate dehydrogenase; PCP: Pneumocystis pneumonia; HIV: human immunodeficiency virus; IgG: immunoglobulin G; TMP-SMX: trimethoprim-sulfamethoxazole The doses recommenced in the table are intended for patients with normal renal function; the doses of some of these agents must be adjusted in patients with renal insufficiency. {This regimen is also the preferred regimen for prevention of toxoplasmosis. [A This regimen is considered an alternative regimen for prevention of toxoplasmosis. hips: ww uptodate. com/contansloverviow-ot prevertion-f-opporlunstcifections-ir-hinfected-patientsprint?search=hiv&sou2ern0r2019 Overview of prevention of opportunistic infections in HInfected patients - UpToDate © Of the alternative regimens for prevention of PCP, TMP-SMX three times weekly Is generally preferred. If patients cannot tolerate TMP-SMX, we prefer to use dapsone (or dapsone with pyrimethamine and leucovorin for patients who require prophylaxis for toxoplasmosis) rather than atovaquone. Dapsone Is a sulfone that is usually tolerated by persons who have adverse reactions to TMP-SMX. However, in patients who have had serious reactions to TMP-SMX (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis, rash with fever and systemic symptoms, serum sickness, or hemolytic anemia), it may be prudent to avoid dapsone, Aerosolized pentamidine should be used for PCP prophylaxis only when no other alternatives are available, Adapted from: 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. https:/aidsinfo.nih, gov/contentfles/Ivauidelines/adult_0i,pdf (Accessed on June 23, 2017). Graphic 79988 Version 11.0, hips: ww uptodate. com/contansloverviow-ot prevertion-f-opporlunstcifections-ir-hinfected-patientsprint?search=hiv&sou nn